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ion and interpretation. Data was compared and contrasted using purposive sampling criteria, e.g. comparing data between patients with different GOLD stages by the first author and in regular discussions with the last author Trustworthiness To ensure confirmability and dependability, members of the research team met at least monthly to discuss the quality of the interviews as well as temporary results. Additionally, the first and the fourth authors coded two transcripts independently. With the exception of one code, all codes matched. The different coding was discussed and a consensus found. Results Sample characteristics Eleven patients participated (7 females, aged 51-81 years, FEV1 (17%-96%) (Table 4). Of the interviews, seven took place at patients' homes, three at a hospital and one in a rehabilitation clinic. The interviews lasted between 30 and 78 min.Table 4. Participant characteristics. Participant characteristics N = 11 Age in years (median, range) 67 (51-81) Gender female/male (number) 7/4 BMI kg/m2 (median, range) 21.5 (15.8-42) FEV1 (median, range) 50 (17-96) Use of oxygen (number) None 6 Up to 1.75 L/min 2 More than 1.75 L/min 3 Stage of COPD (number) COPD 1 A 2 COPD 1 B 1 COPD 2 A 1 COPD 2 D 1 COPD 3 D 3 COPD 4 B 1 COPD 4 D 2 MMRC score (median, range) 18 (2-27) CAT score (median, range) 2 (0-4) Exacerbations in the last year (median, range) 1 (0-6) Marital status (number) Married 5 Divorced 3 Widowed 3 Living situation (number) Living alone 5 Living with spouse 5 Living with a child 1 Nationality (number) Swiss 9 Other 2 Highest level of education (number) Compulsory education 3 Apprenticeship 4 Higher apprenticeship/college 4 Working situation (number) Retired 6 Unemployed 1 Employed full-time 1 Employed part-time 1 Invalidity insurance pension 2 Qualitative results Patients reported six main sources of COPD-related emotional distress, namely, physical symptoms, treatment, restricted physical mobility, restricted social participation, unpredictability of disease course and stigma. In addition, three influencing factors emerged: life events, living situation and multi-morbidity. The main and subcategories are displayed in Table 5.Table 5. Categories. Main category Subcategory Physical symptoms Breathlessness Cough/mucus Fatigue Pain Erectile dysfunction Incontinence Treatment Oxygen therapy Recommendation for smoking cessation Relationship with the treatment team Lack of benefit from medications Restricted physical mobility Enormous physical and mental effort Uncontrollable circumstances outside the home Revealing of illness Restricted social participation Loss of daily contacts Difficulties participating in social activities Difficulties participating in conversations Unpredictability of disease course Inability to plan the future life Uncertainty in relationships COPD as stigmatizing disease Failure in the past Label of "Brought about their own illness" Non-COPD-related distress Multimorbidity Live events Living situation Emotional distress arose due to an interaction of all of these sources. The basis of emotional distress is formed by physical symptoms and treatment. The two in combination, especially breathlessness and oxygen therapy, lead directly to restricted physical mobility and are contributing factors for restricted social participation. Distress due to the unpredictability of disease course and COPD as a stigmatizing disease result from the overall experience of COPD .Figure 1. Sources of emotional distress and their interaction. Physical symptoms Physical symptoms led to emotional distress when they are uncontrollable and not able to be explained. Breathlessness was the leading symptom, followed by coughing and mucus, fatigue, pain, erectile dysfunction and incontinence. For the majority, breathlessness was a permanent and very stressful physical symptom that dominates everyday life and thoughts. As a consequence, participants experienced despair, powerlessness and unwillingness to live."(...) The first thought is about breathing and the last thought is about breathing (...) that's already really stressful (...) I have to tell you honestly, sometimes I think: "I've had enough". No, no, I can't go on anymore (...) It's too much for me (...) Sometimes it makes me feel desperate. To the extent that I don't want to live anymore (...)" Emma, COPD GOLD 2 D Coughing was experienced as disruptive for all participants. Patients with COPD three and four experienced coughing combined with feelings of despair and helplessness, because episodes can last for hours. For patients with COPD GOLD Stage 1 and 2, coughing may have been the only sign of COPD. Coughing was described as distressing because it interfered with everyday activities such as having a conversation or sleeping. Breathlessness and coughing caused fatigue. Furthermore, fatigue was reported as a source of distress by one patient with COPD 2 because the source of the symptom was not clear to her: It was present in the morning despite of having had enough sleep. Pain was mentioned by nine participants, but only three participants spoke about pain related to COPD. For one patient with mild COPD, who underwent an operation due to pneumothorax, the pain was not so distressing. She was told that it might last for 6 months which helped her cope with it. In contrast, another patient who always felt chest pain when he experienced breathlessness described the pain as more distressing than the breathlessness itself. One patient with COPD GOLD 3 experienced erectile dysfunction as burdensome because he assumed that the reason lies in his masculinity. He experienced relief after his family doctor had explained the connection with COPD and suggested the treatment with medication. Three patients, one of them male, spoke of incontinence due to COPD and how highly distressing it was because of its unpredictability and negative impact on daily activities. They either did not reach the toilet in time or they lost urine during coughing. These situations were accompanied by feelings of shame and anger. Treatment Each of the participants described at least one therapeutic element as a source of emotional distress. Distressing elements were oxygen therapy (CIPAP, BIPAP included), the recommendation for smoking cessation, relationship with the treatment team and lack of benefit from medications. Participants with COPD 1 and 2 described increased emotional distress in relation to smoking cessation and treatment teams. Participants with COPD 3 and 4 named oxygen therapy as the strongest trigger for various negative emotions. Two male patients in need of oxygen therapy in the form of BIPAP or CIPAP emphasized that despite having to adjust to the noise and uncomfortable mask initially, they did not feel emotionally distressed because it had no impact on their daily activities. This contrasts strongly with patients who needed continuous oxygen therapy COT via nasal cannula. They felt restricted in mobility due to the weight of the device, the shortness of the tube and the device's lack of practicability. For all patients who had not yet quit smoking, the recommendation for smoking cessation triggered feelings of anger. On the one hand, they had not stopped yet because they did not see the point in it, had no motivation or had already made several frustrating attempts with distressing adverse effects such as stomach pain. On the other hand, smoking cessation was experienced as a continually recurring topic mentioned by doctors. The following were mentioned as a source of distress impeding the relationship with the treatment team and leading to considering a change of physician: a lack of time invested by the team and a lack of continuity, insufficient information about treatment options and COPD in general and not being taken seriously, particularly by pneumologists and general practitioners. Two of the eleven participants, both with moderate COPD, did not have to take medication for COPD. Patients with severe and very severe COPD who had to take pills and inhale regularly all described this as part of their daily routine and not as distressing. Medication triggered negative feelings only when it did not bring relief from symptoms. Restricted physical mobility Participants with COPD 3, 4 and one patient with COPD 2 emphasized that their radius of movement got smaller as their disease progressed. For patients with a high symptom burden and oxygen therapy, there were three hindrances contributing to restricted physical mobility: enormous physical and mental effort, uncontrollable circumstances outside the home and looking obviously ill in front of others. All three barriers again led to negative emotions as they contributed to the fact that patients eventually became housebound. In contrast, participants with COPD 1 and 2 who did not suffer from any symptoms and did not need oxygen therapy pointed out that COPD did not cause them distress because they experienced no limitations in their daily activities. Patients with COPD 3 and 4 stated that COPD affected all areas of life because everything entailed an enormous physical and mental effort. Even normal things such as taking a shower or going downstairs to the cellar took physical effort that they are sometimes incapable of making. Due to breathlessness and dependence on oxygen therapy in particular, the mobility of patients with severe and very severe COPD (and for one patient with moderate COPD), was restricted. As soon as the patients moved they were confronted with their physical limitations. This resulted in reduced scope of movement which eventually led to an inability to take care of themselves or to carry out daily activities like vacuum cleaning, lifting things, cleaning the house and carrying out daily morning routines like personal hygiene. These physical restrictions triggered intense negative emotions such as anger, sadness and frustration. This enormous physical effort also entailed a mental effort as patients were obliged to constantly assess whether the (physical) effort was in fact worth it. This continuously distressing evaluation process intensified as the disease progresses. The incessant uncertainty of what their health condition will be like from one moment to the next and the unpredictability of symptom severity may lead to continual anxiety during daily activities or when patients leave the house. In addition, uncontrollable circumstances when outside the home, including strong smells, crowded places, or narrow spaces are described as very distressing because they can cause breathlessness and general discomfort. Several patients stated that they never knew whether they might unexpectedly have to return back home because of sudden breathlessness. This anxiety persists in every kind of daily activity whether it happens in public or at home. One woman points out:"(...) somehow everything scares you a little. Sometimes, if you`re not feeling well enough to go outside and you still leave your apartment (...) you think: (...) Will I be able to return back home on my own?'" Maria, COPD GOLD 3 D When being physically active, patients had to stand still, use an oxygen device/nasal cannula, or to breathe heavily and visibly. Physical activity revealed the illness in front of others, which made it into another source of distress, triggering feelings of shame and anger. Participants explained that they did not want others to see them being ill or suffering. Restricted social participation As a result, their participation in social life with activities such as pursuing a hobby, meeting other people or going to work grew increasingly more difficult. At this point in the interview, some participants started to cry and expressed strong negative emotions ranging from anger, disappointment and frustration to depression. Eventually, the lives of some participants, especially the older ones, were completely restricted to their own homes. Three sources of emotional distress were found regarding restricted social participation: losing daily contacts, difficulty participating in social activities and difficulty participating in conversations. Due to the increasing inability to leave their apartment, it grew more difficult to maintain social contacts on a day-to-day basis, leading to feelings of being home bound and being forgotten by the outside world. Not being able to participate in social activities such as hiking, cycling, skiing, dancing, attending a play or concert or going to a restaurant with others triggered feelings of loneliness, worthlessness and frustration."(...) when you can't go out and do anything, you get depressed. If they call and ask you to come to the cinema or the theatre and you have to say: I can't, you're bound to get depressed (...) and no one visits you." Ruth, COPD GOLD 4 D Some patients realized at a certain point that they were no longer able to keep up with others and that meeting people spontaneously or keeping long-term appointments was challenging. Consequently, they only left the house with friends and family members who supported them and were willing to adapt activities to their state of health. Being dependent on other people's consideration resulted in feelings of being a burden or of experiencing themselves as "a disabled person" when, for example, they had to ask others to reduce their pace. Patients in a relationship pointed out that their partners were also subject to all of these restrictions. They emphasized that they did not want to be a burden and therefore let their partners pursue their hobbies on their own, even if they feared drifting apart. Another source of distress was the declining ability to have longer conversations, be it on the telephone or face-to-face. For some patients, as the disease progressed it became more and more difficult to speak while walking or having a meal with friends due to breathlessness. Unpredictability of disease course Unpredictability of disease course was for most patients a source of strong emotional distress, because knowing that the disease and the limitations will get worse made it difficult to plan the future. This triggered feelings of anxiety, sadness and uncertainty:"It turns your existence upside down (...) You had a plan for the time after your retirement. And that plan won't work anymore. You have to turn everything around and you have to change it (the life plan) completely (...)." Kevin, COPD GOLD 4 B Uncertainty over the course of the disease also entailed uncertainty regarding how existing partnerships would develop in future or whether life made any sense at all. Four female participants talked about how they sometimes thought they would be better off dead because they no longer wanted to live like this or endure the disease progression. Two participants revealed that they were planning to rely on euthanasia. COPD as a stigmatizing disease All of the patients who had previously been smokers reported the failure of not having quit earlier, connected with feelings of guilt and shame. Moreover, some participants, regardless of severity of COPD, reported feeling that they have been labelled as having "brought about their own illness", namely by health professionals, relatives, friends, but also by society in general. Most participants acknowledged smoking as a major cause of COPD. At the same time, they all asserted that reasons other than smoking have also contributed to their acquiring COPD, for example, exposure at workplaces and air pollution, but that nobody had taken that seriously. This was a potential source of anger. Both patients suffering from antitrypsine deficiency strongly emphasized that they had never smoked. In addition, they stressed that they did not want to "give a false impression" or of "having screwed up by themselves" Non-COPD-related distress Participants reported some sources of non-COPD-related distress that can interact negatively with COPD-related distress. Namely, multimorbidity, life events and living situation. For older patients with COPD 3 and 4 who suffered from multimorbidity such as heart failure or osteoporosis, COPD was accompanied by the most limiting symptoms. However, they related that the situation, which involved other health problems, was also linked to emotional distress. In contrast, two patients with COPD 1 lung cancer who had had myocardial infarctions regarded COPD as a "side issue" and therefore less of a burden than other health problems. Stressful life situations such as disputes at work, in the neighbourhood, within the family or even the death of a relative were described as challenging. Such events intensified breathlessness. Patients reported that, due to COPD, they were no longer as resilient as before when confronted with critical life events. The living situation and the general environmental situation of patients could be distressing. Living alone, on an upper floor without a lift, or problems accessing shopping facilities could also reinforce the COPD - related distress. Discussion This study aimed to identify sources of emotional distress arising from living with COPD from patients' personal perspectives. To our knowledge, this is the first study with the aim of finding sources of distress. Physical symptoms, treatment, restricted physical mobility, restricted social participation, COPD as a stigmatizing disease and unpredictability of the disease course were identified as major sources of COPD-related emotional distress. Additionally, three significant triggers of non-COPD-related emotional distress, namely multimorbidity, life events and living situation were found to have the potential to interact negatively with COPD-related emotional distress. In line with the existing body of research,5 shortness of breath, cough and phlegm, as well as pain were identified as common and distressing symptoms in patients with COPD. Although several quantitative studies indicate that sexual dysfunction and urinary incontinence are very common in both women and men with COPD,18,19 our study underlines their distressing aspect, particularly in younger patients. It highlights the need to systematically screen and discuss these intimate symptoms with patients. A restricted social life has been identified as distressing in other studies,20 with the reaction of our participants indicating that it may be the strongest contributing source of COPD-related emotional distress This highlights the need for strategies to be developed regarding COPD patients that might increase their feelings of security when leaving the house. This can include calling in a companion service, calling a taxi, creating an action plan and involving relatives.21 In addition, peer support and interaction with nurses was perceived as helpful to diminish the feeling of isolation.22 Patients who smoked reported experiencing stigmatization by health professionals, friends and family, as well as society in general. This is in line with other findings that report stigma as being an additional contributor to social isolation, feelings of loneliness and guilt and an influencing factor on medication-adherence and help-seeking.23,24 Notably, in the present study the relationship to health professionals was described as an important source of distress. Unmet needs and a lack of trust in the treatment team have been reported as significantly impeding disease management in patients with COPD.25 Our study highlights the necessity of a coordinated care model for patients with COPD, with a focus on continuity in care as a perquisite to building a trustful relationship, which in turn has the potential to impact outcomes.22,26 This would facilitate the approach when addressing sensitive topics such as smoking cessation, urinary incontinence, sexual dysfunction, stigmatization, and social isolation as well as the consideration of euthanasia. By contrasting our study to the conceptual model of emotional distress,15 our study confirmed the theoretical framework that COPD-related emotional distress arose from an interaction of all six sources. New was the identification of stigma as an additional source, which in turn influences social interaction and self-image. Interestingly, this is the main difference to the model, where stigmatizing disease was not identified as a source of distress. One explanation may be that the model development also included studies with Cystic Fibrosis (CF). As CF is an inherited disease, the aspect of a "self-inflicted disease" might be omitted and thus perceived stigmatization might not be an important and distressing issue. This study highlights the need for the current practice to be supplemented by the assessment and treatment of COPD-related emotional distress. Furthermore, all patients currently experiencing emotional distress as well as those without any signs should be regularly assessed to recognize the presence of sources of distress at an early stage of the disease. An assessment should be developed to assess sources of distress in these patients. The present study serves as the basis for the development of such a questionnaire and the results should be evaluated and confirmed by a quantitative study. In addition, the interaction of the different sources of COPD-related emotional distress and their impact on adherence and decision-making regarding self-management needs further investigation. This study was conducted pre-COVID, prompting the question of whether the pandemic would have influenced the results. COPD patients were more vulnerable to COVID-19 and at risk for complications and poorer outcomes.27 Patients who were aware of being at high-risk, redrew socially in order to avoid infection, especially in the early stages of the pandemic. This led to increased levels of anxiety and feelings of loneliness.28 This indicates that patients with COPD may have experienced higher levels of illness-related emotional distress during the pandemic, but that the sources were the same as found in this research, namely unpredictability and restricted social participation. This study has some strengths and limitations: Comparing and contrasting the patients' stories using Framework Analysis allowed the depiction of a common story. The purposive sampling resulted in a heterogeneous group that allowed a broad description of patients' experiences. However, there are also limitations that must be mentioned. First, participants were recruited from a single hospital and included only two patients with a migration background. Possibly patients from other geographical and cultural backgrounds may have described other sources of distress. No additional sources of distress were detected after the tenth interview. In addition to redundancy in the reported sources of distress, a conceptual depth of how the sources were reported by patients in different stages of the disease was observed. This is at a rather early stage, but not surprising because the research question had a clear focus, was discovery-oriented, and the research was embedded in a pre-existing theoretical framework.29 Conclusion Living with COPD is associated with emotional distress and the sources are manifold, ranging from burdensome symptoms or treatment to restrictions in daily life and social participation, as well as stigma and unpredictability of the disease. Further, emotional distress seems to affect self-management in COPD, highlighting the importance of the concept of illness-related emotional distress in COPD. The next steps would be the development of a patient-reported experience measure for assessing illness-related emotional distress to clarify its role in self-management and patient outcomes. Acknowledgements We thank Jane White for editing support. ORCID iDs Christian Clarenbach Gabriela Schmid-Mohler The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. |
IDCases IDCases IDCases 2214-2509 Elsevier S2214-2509(23)00050-1 10.1016/j.idcr.2023.e01726 e01726 Case Report A rare case of an immunocompetent patient with isolated pulmonary mucormycosis Rouientan Hamidreza [email protected] a Gilani Abolfazl [email protected] b Sarmadian Roham [email protected] c*1 Rezaei zadeh Rukerd Mohammad [email protected] d a Urology and Nephrology Research Center, Department of Urology, Shahid Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Islamic Republic of Iran b Department of Pediatric Surgery, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran c Infectious Diseases Reseach Center, Arak University of Medical Sciences, Arak, Islamic Republic of Iran d Gastroentrology and Hepatology Research Center, Institute of Basic and Clinical Physiology Sciences, Kerman University of Medical Sciences, Kerman, Islamic Republic of Iran * Corresponding author. [email protected] 1 ORCID: 0000-0003-0264-8903. 28 2 2023 2023 28 2 2023 31 e0172626 1 2023 16 2 2023 27 2 2023 (c) 2023 The Authors 2023 This is an open access article under the CC BY license ). As one of the most lethal infections caused by fungi, pulmonary mucormycosis usually affects patients who are immunocompromised. Isolated pulmonary mucormycosis in immunocompetent patients is very rare.This report describes a 65-year-old immunocompetent man, who was first treated with antibiotics after being diagnosed with a lung infection, then after the lack of response to treatment, he was diagnosed with mucormycosis in further investigations. Finally, the patient died due to a lack of response to treatment. Despite its rarity, it is important to consider other differential diagnoses such as pulmonary mucormycosis if the pneumonic process does not respond to medical treatment. Keywords Pulmonary mucormycosis Pneumonia Immunocompetent Case report pmcIntroduction The term mucormycosis refers to a group of potentially life-threatening fungi that affect several different parts of the body , . It usually occurs in immunocompromised patients suffering from hematological malignancy, or diabetes mellitus, or patients receiving long-term immunosuppressive therapy following a hematological stem cell transplant or solid organ transplant . In the absence of any of the risk factors listed above, the presence of pulmonary mucormycosis is extremely rare . Due to its nonspecific presentation, pulmonary mucormycosis is easily misdiagnosed, especially in immunocompetent patients, which could result in serious consequences. Since its incidence has increased significantly in recent decades, it poses a serious threat to the health of humans . The present study describes a case of isolated pulmonary mucormycosis in a previously healthy adult man. This study aims to help clinicians identify pulmonary mucormycosis as early as possible, especially in immunocompetent patients, to improve therapeutic efficacy and prognosis. Case presentation A 65-year-old man presented to an outpatient clinic with complaints of productive cough (without blood streaks in sputum) and chest pain lasting four weeks. He had a complaint of bilateral chest pain that was aggravated by deep breathing. His past medical history included hypertension, which was controlled by a daily dose of 50 mg of hydrochlorothiazide. His symptoms included fever, weight loss, and progressive myalgia. The patient was a lifelong nonsmoker without known sick contact and recent travel. Vital signs were stable. Apart from bilateral rales in his lower lungs, his physical examination was otherwise unremarkable. Relevant laboratory findings were as follows: white blood cell: 12.9 x 10^9/L (reference interval: 4-10 x10^9/L); neutrophil%: 86.9 % (reference interval: 40.0-75.0 %); lymphocyte%: 10.8 % (reference interval: 20.0-50.0 %); C-reactive protein = 17 mg/L, erythrocyte sedimentation rate = 56 mm/h. Chest radiograph showed bilateral nonhomogeneous opacity in the lower zone (Fig. 1). The result of the polymerase chain reaction (PCR) for SARS-CoV-2 was reported as negative. On the same day, the patient was discharged in good general condition with oral antibiotics (625 mg co-amoxiclav, three times a day for ten days).Fig. 1 Chest X-ray posterior-anterior view showing bilateral nonhomogeneous opacities in the lower zone. Fig. 1 He returned after 17 days with complaints of dyspnea and fever. There were no significant findings in the initial laboratory test and physical examination in this admission, except for an oral temperature of 38.3 degC and a white blood cell count of 13.5 x 10^9/L (reference interval: 4.0-10.0 x 10^9). SARS-CoV-2 PCR was performed again, and the result was negative. Video bronchoscopy showed a bilateral purulent secretion with bronchoalveolar lavage negative for mycobacterium. Electrocardiography and echocardiography were both normal during the cardiology consultation. After 2 days of intravenous antibiotics administration, the patient was discharged in good general condition. On the 44th day following the onset of his initial symptoms, he returned with dyspnea and right leg edema. During the physical examination, bilaterally decreased lung sounds and decreased oxygen saturation were observed. Abnormal paraclinical tests were as follows: white blood cells 15.8 x 10^9/L (reference interval: 4.0-10.0 x 109) and deep vein thrombosis (DVT) in the right leg on ultrasound. The electrocardiogram, urine test, liver function, electrolyte test, and renal function were all normal. Fig. 2 shows the lung Computed tomography (CT) scan taken on this admission. The chest CT scan revealed pulmonary infection without a pulmonary embolism. Accordingly, treatment for severe community-acquired pneumonia including ceftriaxone ampule 1 gr every 12 h, and levofloxacin ampule 500 mg daily, as well as DVT treatment including apixaban 10 mg twice daily (BID) for seven days and then 5 mg twice daily were continued.Fig. 2 Chest CT scan showing bilateral ground glass opacities and consolidations in lower lobes of the lungs. Fig. 2 On day 51, after no significant improvement in the patient's chief complaint, a lung Computed tomography, bronchoscopy, and transbronchial biopsy were performed. The bronchoscopy revealed purulent secretions, and the lung Computed tomography revealed necrotizing pneumonitis. Therefore, intravenous antibiotics consisting of vancomycin ampule 1 g immediately and 1 g every 12 h, meropenem ampule 2 g immediately and 1 g every 8 h, and levofloxacin ampule 500 mg daily were administered. On day 54, a transbronchial biopsy was performed, and while there was no growth in the culture, histology revealed mucormycosis (Fig. 3). Therefore, treatment with linezolid 500 mg two times a day, colomycin three times a day, and amphotericin B liposomal 300 mg daily was initiated.Fig. 3 Lung biopsy specimen showing colonies of broad, right-angled branching, non-septate hyphae (40 x magnification). Fig. 3 The patient's condition deteriorated during the hospitalization. The lung Computed tomography after 19 days of treatment for mucormycosis is shown in Fig. 4.Fig. 4 Chest CT scan showing progression of ground glass opacities into consolidation, and large cavitary lesions in bilateral lung fields. Fig. 4 Twenty-five days after the initiation of the specific treatment for mucormycosis, the patient did not respond to the therapy and succumbed to disseminated intravascular coagulation and respiratory failure which eventually led to death. Discussion Mucormycosis is an acute, progressive, and fatal disease that can affect people of almost all ages. Immunosuppression is considered to be the most important risk factor for mucormycosis . Fungal growth produces an abundance of airborne spores that are constantly inhaled by humans. Despite constant exposure, infections are rare because the immune system has the ability to effectively neutralize these spores. Clinically, there are only a few cases of pulmonary mucormycosis in immunocompetent individuals. According to a systematic review conducted by He et al. between 2010 and 2020, only 16 cases of isolated pulmonary mucormycosis in immunocompetent patients have been reported . In their research, nearly all patients were diagnosed either through bronchoalveolar lavage culture (50 %) or histopathologic assessment of biopsy (42 %); the remaining case was verified via autopsy.Overall, about 43 % of patients with confirmed fungal infection died despite receiving antifungal drugs. Our case was also an immunocompetent patient identified with pulmonary mucormycosis following a transbronchial lung biopsy, and antifungal treatment was initiated. In the end, though, he did not respond to the treatment and expired. The history of exposure to mucor spores from decaying food, soil, and animal excrement may serve as a diagnostic basis for pulmonary mucormycosis . In the case we described, the patient was a 65-year-old farmer and rancher. In terms of diagnosing the disease at an early stage, conventional diagnostic techniques, such as clinical diagnosis, serology, histopathology, and radiology, have limitations. Therefore, advanced diagnostic tools such as nucleic acid diagnostics, advanced serological tests, PCR (pan-Mucorale test), and multiplex PCR are necessary. The use of these techniques allows clinicians to detect this invasive fungus at an incipient stage, preventing adverse outcomes . In our case, mucormycosis was not initially considered a differential diagnosis, and pan-mucorale PCR was not requested, because the patient had no underlying disease. The transbronchial biopsy and subsequent histopathological assessment led to the diagnosis. Lobectomies have been shown to be successful in curing individuals with early-stage lung infection , . Unfortunately, many patients present with severe involvement that cannot be resected, and/or severe thrombocytopenia that makes surgery impossible. In these cases, antifungals should be given as soon as possible, and efforts should be made to improve immune function and treat any underlying medical issues that may be contributing to the fungal infection . Our patient was given a definitive diagnosis when he had severe lung involvement and surgery could have little effect on enhancing his prognosis. Thus, he did not undergo surgery and antifungal medication was administered; nevertheless, it had little effect on the disease's improvement, and the patient died. Conclusion In conclusion, pulmonary mucormycosis in immunocompetent patients is rare, which indicates the importance of being alert to potential mucormycosis infections in immunocompetent patients. Due to the high mortality rate of this disease, early diagnosis and treatment are vital to the prognosis of patients. CRediT authorship contribution statement Conceptualization: Roham Sarmadian. Methodology: -. Validation: Abolfazl Gilani. Formal analysis: -. Investigation: Abolfazl Gilani, Roham Sarmadian. Resources: Abolfazl Gilani. Data curation: -. Writing - original draft: Hamidreza Rouientan, Mohammad Rezai zadeh Rukerd. Writing - review & editing: Roham Sarmadian, Mohammad Rezai zadeh Rukerd. Visualization: Hamidreza Rouientan. Supervision: Roham Sarmadian. Project administration: Abolfazl Gilani. Funding acquisition: -. Ethical approval Ethical issues (including plagiarism, data fabrication, and double publication) have been completely observed by the authors. The patient's legal guardians (his wife and children) gave written informed consent to publish as a case report. Our institution does not require ethical approval for reporting individual cases or case series. Consent This case report was conducted in accordance with the World Medical Association Declaration of Helsinki. The patient's legal guardians (his wife and children) have given us informed consent for publication as a case report. Funding This research did not receive any funding. Competing Interest The authors disclose no competing interest. Acknowledgments None to declare. Authors' contribution HR and RS were the principal investigators of the study. HR, AG, and RS were included in preparing the concept and design. MR and RS revisited the manuscript and critically evaluated the intellectual contents. All authors participated in preparing the final draft of the manuscript, revised the manuscript, and critically evaluated the intellectual contents. All authors have read and approved the manuscript's content and confirmed the accuracy or integrity of any part of the work. References 1 Jeong W. Keighley C. Wolfe R. Lee W.L. Slavin M.A. Kong D.C.M. The epidemiology and clinical manifestations of mucormycosis: a systematic review and meta-analysis of case reports Clin Microbiol Infect 25 1 2019 26 34 10.1016/j.cmi.2018.07.011 30036666 2 Acosta-Espana J.D. Voigt K. 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Mucormycosis diagnosis revisited: current and emerging diagnostic methodologies for the invasive fungal infection (review) Exp Ther Med 25 1 2023 47 10.3892/etm.2022.11746 36569440 7 Tedder M. Spratt J.A. Anstadt M.P. Hegde S.S. Tedder S.D. Lowe J.E. Pulmonary mucormycosis: results of medical and surgical therapy Ann Thorac Surg 57 4 1994 1044 1050 8166512 8 Gonzalez C.E. Couriel D.R. Walsh T.J. Disseminated zygomycosis in a neutropenic patient: successful treatment with amphotericin B lipid complex and granulocyte colony-stimulating factor Clin Infect Dis 24 2 1997 192 196 9114146 9 Cox G.M. Post T.W. Mucormycosis (zygomycosis) 2021 Uptodate Waltham, MA |
Epilepsy Curr Epilepsy Curr EPI spepi Epilepsy Currents 1535-7597 1535-7511 SAGE Publications Sage CA: Los Angeles, CA 36923330 10.1177/15357597221135717 10.1177_15357597221135717 Current Literature In Basic Science Sex on the Brain: Reproductive Comorbidities in Temporal Lobe Epilepsy Carpenter Jenna C. PhD Lignani Gabriele PhD Department of Clinical and Experimental Epilepsy, Queen Square Institute of Neurology, University College London, London 29 11 2022 Jan-Feb 2023 23 1 5860 (c) The Author(s) 2022 2022 SAGE Publications This article is distributed under the terms of the Creative Commons Attribution 4.0 License ) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages ). Increased GABA Transmission to GnRH Neurons After Intrahippocampal Kainic Acid Injection in Mice Is Sex-Specific and Associated With Estrous Cycle Disruption Ingram RJ, Leverton LK, Daniels VC, Li J, Christian-Hinman CA. Neurobiol Dis. 2022;172:105822. doi:10.1016/j.nbd.2022.105822 Patients with epilepsy develop reproductive endocrine comorbidities at a rate higher than that of the general population. Clinical studies have identified disrupted luteinizing hormone (LH) release patterns in patients of both sexes, suggesting potential epilepsy-associated changes in hypothalamic gonadotropin-releasing hormone (GnRH) neuron function. In previous work, we found that GnRH neuron firing is increased in diestrous females and males in the intrahippocampal kainic acid (IHKA) mouse model of temporal lobe epilepsy. Notably, GABAA receptor activation is depolarizing in adult GnRH neurons. Therefore, here we tested the hypothesis that increased GnRH neuron firing in IHKA mice is associated with increased GABAergic drive to GnRH neurons. When ionotropic glutamate receptors (iGluRs) were blocked to isolate GABAergic postsynaptic currents (PSCs), no differences in PSC frequency were seen between GnRH neurons from control and IHKA diestrous females. In the absence of iGluR blockade, however, GABA PSC frequency was increased in GnRH neurons from IHKA females with disrupted estrous cycles, but not saline-injected controls nor IHKA females without estrous cycle disruption. GABA PSC amplitude was also increased in IHKA females with disrupted estrous cycles. These findings suggest the presence of an iGluR-dependent increase in feed-forward GABAergic transmission to GnRH neurons specific to IHKA females with comorbid cycle disruption. In males, GABA PSC frequency and amplitude were unchanged but PSC duration was reduced. Together, these findings suggest that increased GABA transmission helps drive elevated firing in IHKA females on diestrus and indicate the presence of a sex-specific hypothalamic mechanism underlying reproductive endocrine dysfunction in IHKA mice. Medical Research Council MR/S011005/1 typesetterts3 cover-dateJanuary-February 2023 pmcCommentary Epilepsy, particularly temporal lobe epilepsy (TLE), is associated with reproductive endocrine disorders in both men and women. 1 Approximately 60% of women with TLE, not using anti-seizure drugs (ASDs), suffer comorbidities such as menstrual disorders and polycystic ovary syndrome. 2 In men, semen abnormalities and low serum testosterone levels are common. 1 Susceptibility to comorbid disturbances is influenced by the location of the epileptic focus, seizure laterality, and the influence of ASDs. 3 Significantly, the relationship between epileptic activity and reproductive endocrine dysfunction is bidirectional; seizure activity can induce dysfunction of the hypothalamic-pituitary-gonadal (HPG) axis, altering serum levels of gonadal hormones, which can further exacerbate seizure activity. 1 It is unsurprising, therefore, that the development and impact of reproductive endocrine disorders in epilepsy is significantly impacted by biological sex. The menstrual cycle, or the equivalent rodent estrous cycle, is controlled by the hypothalamic regulation of gonadotropin secretion from the pituitary gland by gonadotropin-releasing hormone (GnRH) neurons. Gonadotropin-releasing hormone neurons are the central output pathway in the neural control of the HPG axis and are likely mediators of epilepsy-associated reproductive dysfunction. 4 Previous work in TLE mouse models found altered activity of GnRH neurons to be associated with reproductive disruption in the form of prolonged estrous cycles. 5 Importantly, estrous stage had a differential effect on GnRH activity in irregularly cycling mice; GnRH neurons were hyperexcitable in diestrus and hypoexcitable, or silent, on estrous. This led the authors to propose that GnRH neuron hyperexcitability in diestrus is a possible driver of comorbid reproductive dysfunction. 5 Here, Ingram and colleagues aimed to investigate the circuit mechanisms underlying GnRH neuron hyperexcitability. 6 Ingram and colleagues investigated GABAergic signaling in the hypothalamus as the driver of GnRH neuron hyperexcitability because GABA is the dominant fast synaptic input received by GnRH neurons and paradoxically has an excitatory depolarizing effect in adults similar to the GABA shift seen in immature neurons.2 They studied this in the well-established intrahippocampal kainic acid (IHKA) mouse model of TLE. Unilateral IHKA injection results in chronic epilepsy and hippocampal sclerosis following status epilepticus (SE) with histological features of neuronal loss and reactive gliosis. 7 Status epilepticus was confirmed by video monitoring of behavioral seizures (Racine >= 3) in the 5 hours immediately after injection. Chronic epilepsy was not directly established, instead the authors refer to their previous study where 100% of mice were found to develop spontaneous recurrent seizures 1 month after injection. 8 Cycle monitoring was performed before, and then 1 month after, injection. Importantly, as in humans, not all mice developed reproductive comorbidities, allowing for the neural differences associated with prolonged estrous cycle length to be dissociated from the effects of epilepsy. The female mice were thus stratified into 3 experimental groups: "KA-regular" (4/5 day cycle), "KA-long" (>=7 day cycle), and "saline" controls. Two months after injection, the authors performed electrophysiological recordings of genetically labeled GnRH neurons in acute hypothalamic slices of mice during diestrus. 6 The authors observed an increased frequency and amplitude of spontaneous GABAergic inputs onto GnRH neurons in the KA-long group compared to KA-regular and saline groups. The duration of events was also greater for KA-long neurons compared to controls, overall revealing that enhanced GABAergic drive differentiates KA-long and KA-regular mice. Importantly, these differences were not so evident in the presence of blockers of ionotropic glutamatergic transmission. This suggests that hyperexcitability is generated upstream of the GABAergic afferents projecting onto GnRH neurons and that the increased GABAergic drive is potentially due to an increased activity of upstream glutamatergic neurons. 6 Next, the authors wanted to see whether this effect was also seen in male KA mice. They found no differences in the amplitude or frequency of GABAergic inputs, only observing a slight decrease in event duration. 6 Reproductive endocrine abnormalities in males were not investigated, which may have drawn out some individual differences. However, testosterone levels were not previously found to be altered for males in this model. 5 Overall, the authors uncover a sex-specific mechanism for GnRH hyperexcitability in female mice, relating to increased GABAergic drive that is related to estrous cycle disruption. 6 Their working model is that upstream anteroventral periventricular kisspeptin neurons receive increased glutamatergic inputs which results in a feedforward enhancement of GABAergic transmission onto GnRH neurons. The authors acknowledge, however, that the HPG is regulated by multiple feedback loops and the model they propose may not be the cause of estrous cycle disruption. Future studies could directly test the causal role of increased GABAergic drive by selecting inhibiting the GABAergic neurons and assessing its effect on estrous cycle disruption. Another potential follow-up study could assess the impact of sex hormone feedback on the development of GnRH hyperexcitability. A previous study using the IHKA model found altered levels of E2 and P4 in mice with disrupted cycles, which could influence GABAergic transmission given that these neurons express estrogen receptors, and progesterone metabolites have a powerful antiepileptic effect on the brain. 5 The important question remains as to why some epileptic mice develop reproductive comorbidities while others do not. The development of reproductive comorbidity does not appear to correlate with seizure burden or the degree of hippocampal sclerosis, suggesting that changes secondary to the primary hippocampal lesion are at play. 9 In the IHKA model, neuronal loss and circuit reorganization may extend further than the hippocampus, such that it could be worthwhile to perform histological examinations of connected structures. The hippocampus and hypothalamus are synaptically connected, such that the hyperexcitability of the epileptic hippocampus may be driving increased GABAergic signaling in the hypothalamus. Understanding the mechanisms underlying increased GABAergic signaling in vulnerable mice will be important for the development of targeted interventions, especially because some ASDs can further exacerbate endocrine disruption. Whether novel anti-epileptic treatments, such as gene therapy, 10 targeting hippocampal hyperexcitability can positively impact upon reproductive endocrine comorbidities is an important question, which could shed light on the permanence of such alterations and whether adjunct therapies are needed. Overall, this study is an important demonstration of sex differences in the development of comorbidities in epilepsy. Stratifying males and females, as well as taking in consideration the estrous cycle stage, can reveal specific mechanisms that may otherwise be masked by variability. The management of reproductive comorbidities through a sex-specific lens is important for seizure control and quality of life, given the potent feedback that peripheral sex hormones can exert on the brain. Research that examines, rather than excludes female variability, promises to deliver more effective treatments. Jenna C. Carpenter, PhD and Gabriele Lignani, PhD Department of Clinical and Experimental Epilepsy, Queen Square Institute of Neurology, University College London, London The author(s) declared no potential conflicts of interest with respect tothe research, authorship, and/or publication of this article. ORCID iD: Gabriele Lignani References 1 Herzog AG . Disorders of reproduction in patients with epilepsy: primary neurological mechanisms. Seizure. 2008;17 (2 ):101-110.18165118 2 Herzog AG Seibel MM Schomer DL Vaitukaitis JL Geschwind N . Reproductive endocrine disorders in women with partial seizures of temporal lobe origin. Arch Neurol. 1986;43 (4 ):341-346.2937394 3 Herzog AG Coleman AE Jacobs AR , et al. Relationship of sexual dysfunction to epilepsy laterality and reproductive hormone levels in women. Epilepsy Behav. 2003;4 (4 ):407-413.12899861 4 Pennell PB . Hormonal aspects of epilepsy. Neuronal Clin. 2009;27 (4 ):941. 5 Li J Robare JA Gao L , et al. Dynamic and sex-specific changes in gonadotropin-releasing hormone neuron activity and excitability in a mouse model of temporal lobe epilepsy. eNeuro. 2018;5 (5 ):ENEURO.0273-18.2018. 6 Ingram RJ Leverton LK Daniels VC Li J Christian-Hinman CA . Increased GABA transmission to GnRH neurons after intrahippocampal kainic acid injection in mice is sex-specific and associated with estrous cycle disruption. Neurobiol Dis. 2022;172 :105822. doi:10.1016/j.nbd.2022.105822 35868435 7 Rusina E Bernard C Williamson A . The kainic acid models of temporal lobe epilepsy. eNeuro. 2021;8 (2 ):ENEURO.0337-20.2021. 8 Cutia CA Leverton LK Ge X Youssef R Raetzman LT Christian-Hinman CA . Phenotypic differences based on lateralization of intrahippocampal kainic acid injection in female mice. Exp Neurol. 2022;355 :114118.35597270 9 Li J Christian-Hinman CA . Epilepsy-associated increase in gonadotropin-releasing hormone neuron firing in diestrous female mice is independent of chronic seizure burden severity. Epilepsy Res. 2022;184 :106948.35690025 10 Colasante G Qiu Y Massimino L , et al. In vivo CRISPRa decreases seizures and rescues cognitive deficits in a rodent model of epilepsy. Brain. 2020;143 (3 ):891-905.32129831 |
Front Surg Front Surg Front. Surg. Frontiers in Surgery 2296-875X Frontiers Media S.A. 10.3389/fsurg.2023.1140016 Surgery Case Report Case report: Resection of a giant right ventricular myxoma Rao Jin + Yang Qian + Yin Liang Yu Yue Xi Wang Xu Jibin Zhang Yufeng * Wang Zhinong * Department of Cardiothoracic Surgery, Changzheng Hospital, Naval Medical University, Shanghai, China Edited by: Sandro Gelsomino, Maastricht University, Netherlands Reviewed by: Maruti Haranal, U N Mehta Institute of Cardiology and Research, India Giacomo Bianchi, Toscana Gabriele Monasterio Foundation, Italy * Correspondence: Yufeng Zhang [email protected] Zhinong Wang [email protected] + These authors have contributed equally to this work and share the first authorship Specialty Section: This article was submitted to Heart Surgery, a section of the journal Frontiers in Surgery 27 2 2023 2023 10 114001610 1 2023 03 2 2023 (c) 2023 Rao, Yang, Yin, Yu, Xi, Xu, Zhang and Wang. 2023 Rao, Yang, Yin, Yu, Xi, Xu, Zhang and Wang This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Myxoma constitutes the main subtype of all benign cardiac tumors, tending to be more common in women and occurring mostly in the left and right atria. Its classic clinical presentations are intracardiac obstruction, embolization, and systemic or constitutional symptoms, such as fever, in decreasing order. Several imaging techniques such as echocardiography, computed tomography, and angiocardiography contribute to the diagnosis of myxoma, ruling out significant coronary diseases, and assessment of myocardial invasion and tumor involvement of adjacent structures. Surgical resection is the only effective therapeutic option for patients with cardiac myxoma. Here, we report a unique case of a middle-aged man who presented with a giant myxoma and a 3-day history of chest tightness and shortness of breath after physical activity. Subsequently, transthoracic echocardiography revealed a mass of solid echodensity located within the right ventricle, complicated by abnormal hemodynamics. A cardiac computed tomographic angiography showed a large homogeneous density filling defect consuming most parts of the right ventricle and protruding from beat to beat. A surgical resection and histological study later successfully confirmed the diagnosis, and the patient's postoperative recovery course was found to be uneventful. ventricular myxoma resection right ventricle outflow tract echocardiography cardiac computed tomographic angiography pmcIntroduction Primary cardiac tumors are uncommonly encountered clinical problems, of which myxomas account for over 50% and 10% of cardiac tumors in adults and children, respectively (1, 2). The vast majority of myxoma cases are sporadic and occur more commonly in women (3). Only less than 5% of myxomas, which have varying sizes, occur in the ventricles (4). Our search for myxoma cases for the year 2021 in the PubMed database revealed that 120 of all 126 myxomas occurred in the atria, having a size of 1-10 cm. In this article, we describe a patient with a 2-month history of increasing chest tightness and shortness of breath and a significant distention of jugular veins. Both transthoracic echocardiography (TTE) and cardiac computed tomographic angiography (CCTA) revealed a space-occupying mass in the ventricle. Histopathology confirmed the diagnosis of myxoma. Case presentation A 53-year-old man presented to the cardiovascular surgery clinic on 14 September 2021, with the chief complaint of a 3-day history of chest tightness and shortness of breath. The above-mentioned symptoms began to appear 3 days before presentation, after physical activity, with each episode lasting 5 min and resolving after a rest. The patient immediately visited the local hospital, where relevant tests were performed, which suggested an intraventricular space-occupying lesion, mild tricuspid regurgitation, incomplete right bundle branch block, and ST/T changes. Since a radical cure was unavailable in the previous healthcare setting, he was transferred to our hospital for surgical treatment. The patient had a medical history of hypertension for more than 3 years, for which he was not taking any pressure-lowering medications, and had undergone one surgical procedure for a right-leg fracture over two decades ago. On hospital admission, his blood pressure level was 146/90 mm Hg, and body temperature, pulse, and respiratory rates were within normal limits. On physical examination, a significant distention of the jugular veins and a systolic blowing murmur were noted on the 4th and 5th intercostal spaces on the left margin of the sternum. Cardiac enlargement toward the lower left was recorded on percussion. No abnormalities were detected on respiratory auscultation. TTE revealed a mass located within the right ventricle , complicated by moderate tricuspid regurgitation and ascending aortic dilatation with mild aortic valve regurgitation. Chest CT and CCTA showed a large homogeneous density mass consuming most parts of the right ventricle (RV) with protrusion into the RV outflow tract and proximal main pulmonary artery during systole and relocation during diastole. According to the evaluation of TTE and CCTA, the possibility of multiple myxomas in other cardiac chambers was minimal. Figure 1 Imaging examination. Transthoracic echocardiography (A) and cardiac computed tomographic angiography (B-D) revealed a mass located within the right ventricle (black arrow). RV, right ventricle; LA, left atrium; LV, left ventricle; and AO, aorta. The patient underwent a resection of the mass (measuring 110 x 51 x 43 mm, R0 as assessed by histology) with concomitant tricuspid annuloplasty under cardiopulmonary bypass. The biopsy showed a hemorrhagic and colloidal appearance, and a diagnosis of RV myxoma was made. During the procedure, the heart was exposed through a median sternotomy for gaining a better surgical view of the resection area and cardiac mass removal. A right atriotomy was performed parallel to the atrioventricular groove to fully reveal the myxoma, which was completely resected along its pedicle without the occurrence of any massive intraoperative hemorrhage. An intraoperative investigation did not reveal any right atrium mass. Then, Kay tricuspid annuloplasty was performed to ensure normal hemodynamics of the right heart. The postoperative recovery course was uneventful, and the patient was discharged without any complications. A histological study later confirmed that the myxomatous cells were irregular in shape and sparsely dispersed in the interstitial space . The differential diagnosis of cardiac myxoma should include other benign cardiac tumors such as lipoma, papillary fibroelastoma, and rhabdomyoma, together constituting a similar proportion of benign cardiac tumors. At the 15-month postoperative follow-up, the patient resumed normal activities with a complete resolution of his symptoms, and TTE showed the competence of tricuspid and pulmonary valves with satisfactory hemodynamic control. The patient was instructed to receive periodic echocardiographic follow-up examinations. If this patient had been left to progress without any medical interventions, the myxoma would have continued to simulate the right ventricular outflow tract and even caused pulmonic valve obstruction. In addition, if myxoma detachment had occurred, the right-sided myxomatous emboli might have obstructed the pulmonary arteries and caused pulmonary hypertension and even death from acute obstruction. Figure 2 The patient underwent a resection of the mass (measuring 110 x 51 x 43 mm). Figure 3 Histology found that myxomatous cells were irregular in shape and sparsely dispersed in the interstitial spaces (red arrow). Discussion In this study, we reported the case of a 53-year-old male patient with a giant ventricular cardiac myxoma, who was admitted to our hospital with a 3-day history of chest tightness and shortness of breath after physical activity. The local hospital, which was the patient's initial point of contact, performed TTE and found a space-occupying lesion in the right ventricle and its outflow tract, which was further confirmed by TTE, CCTA, and histological examination after admission to our hospital. Cardiac myxomas usually arise solitarily in the left atrium (75%), right atrium (10%-20%), and heart ventricle (5%), and most have a size of a few centimeters (5, 6). The occurrence of myxoma is approximately 3 per 2 million population, and a right ventricular myxoma with concomitant tricuspid regurgitation is even rarer (7). To the best of our knowledge, only a few myxomas have a size of >110 mm in diameter, let alone locating at a particular anatomical site, the right ventricle, at the same time (8). Compared with other reported cases of cardiac myxoma, this case draws special attention because of the giant size and anatomical location of the myxoma. Although the myxoma protruded into the RV outflow tract and proximal main pulmonary artery during systole, the patient presented with reduced physical performance and signs of anomalous venous drainage other than shock or aborted sudden cardiac death, indicating that the clinical presentation was not severe. Considering the benign characteristics of myxoma, pericardial fluid analysis and positron emission tomography were not performed. Carney complex was ruled out because of the nature of the patient's presentation; Carney complex is a genetic disorder characterized by a combination of cardiac and cutaneous myxomas, endocrine hyperfunction, and distinctive pigmented lesions of the skin and mucosal surfaces (9). As for surgical management, resection is the only effective therapeutic option for ventricular myxoma and should not be delayed because death from obstruction may occur in patients awaiting an operation. Ventricular myxomas are usually approached through the atrioventricular valve for exposure and resection. The approach through a direct incision into the ventricle is not preferred. The operation should be performed without full-thickness excision of the ventricular wall, given that the recurrence rate of cardiac myxoma is approximately 5% and may be observed even months or years after surgery (10). In addition, long-term follow-up with TTE is needed in all patients in order to improve their quality of life and decrease morbidity and mortality rates (11). We are aware that our case report might have some limitations. First, the patient did not undergo cardiac magnetic resonance imaging, which involves a more thorough examination of the soft tissue and has a higher temporal resolution (12). In addition, it remains difficult to assess the long-term survival rates because of an inadequate follow-up time of 15 months. In our case, the characteristics of the patient were middle age, a giant right ventricular myxoma, and RV outflow tract obstruction, which may provide important insights for cardiologists and cardiac surgeons. In addition, surgical resection and tricuspid annuloplasty showed a good response in our patient. Further follow-up and more clinical experience are required for providing better treatment for those with unique myxomas. Acknowledgments The authors thank the patient for giving his consent to publish this report and also thank the treatment group for their joint effort. Data availability statement The original contributions presented in the study are included in the article/Supplementary Material; further inquiries can be directed to the corresponding author. Ethics statement The studies involving human participants were reviewed and approved by the Ethics Committee of Shanghai Changzheng Hospital. The patients/participants provided their written informed consent to participate in this study. Author contributions JR and QY cowrote the paper. LY, YY, and WX collected the clinical data. JX, YZ, and ZW were consulted for clinical issues. All authors contributed to and revised the final manuscript. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. Supplementary material The Supplementary Material for this article can be found online at: References 1. Reynen K . Frequency of primary tumors of the heart. Am J Cardiol. (1996) 77 :107. 10.1016/S0002-9149(97)89149-7 8540447 2. Poterucha TJ Kochav J O'Connor DS Rosner GF . Cardiac tumors: clinical presentation, diagnosis, and management. Curr Treat Options Oncol. (2019) 20 :66. 10.1007/s11864-019-0662-1 31250250 3. Pinede L Duhaut P Loire R . Clinical presentation of left atrial cardiac myxoma. A series of 112 consecutive cases. Medicine (Baltimore). (2001) 80 :159-72. 10.1097/00005792-200105000-00002 11388092 4. Samanidis G Khoury M Balanika M Perrea DN . Current challenges in the diagnosis and treatment of cardiac myxoma. Kardiologia polska. (2020) 78 (4 ):269-77. 10.33963/KP.15254 32207702 5. Jaravaza DR Lalla U Zaharie SD de Jager LJ . Unusual presentation of atrial myxoma: a case report and review of the literature. Am J Med Case Rep. (2021) 22 :e931437. 10.12659/AJCR.931437 6. Li Y Li X Wang X Chen L . Biatrial myxoma floating like a butterfly: a case report and review of the literature. Medicine (Baltimore). (2018) 97 :e9558. 10.1097/MD.0000000000009558 29504977 7. Kacar P Pavsic N Bervar M Strazar ZD Zadnik V Jelenc M Cardiac myxoma: single tertiary centre experience. Radiol Oncol. (2022) 56 :535-40. 10.2478/raon-2022-0041 36259335 8. Wang H Li Q Xue M Zhao P Cui J . Cardiac myxoma: a rare case series of 3 patients and a literature review. J Ultrasaound Med. (2017) 36 :2361-6. 10.1002/jum.14264 9. Correa R Salpea P Stratakis CA . Carney complex: an update. Eur J Endocrinol. (2015) 173 :M85-97. 10.1530/EJE-15-0209 26130139 10. Pitsava G Zhu C Sundaram R Mills JL Stratakis CA . Predicting the risk of cardiac myxoma in carney complex. Genetics in medicine: official journal of the American College of Medical Genetics. (2021) 23 (1 ):80-5. 10.1038/s41436-020-00956-3 32893266 11. Gaszewska-Zurek E Zurek P Wilczynski M Krzych L Bachowski R Jasinski M Cardiac myxoma - clinical presentation and long-term post-operative follow-up. Kardiol Pol. (2011) 69 :329-34. PMID: 21523664 12. Kassop D Donovan MS Cheezum MK Nguyen BT Gambill NB Blankstein R Cardiac masses on cardiac CT: a review. Curr Cardiovasc Imaging Rep. (2014) 7 :9281. 10.1007/s12410-014-9281-1 25018846 |
Int J Surg Case Rep Int J Surg Case Rep International Journal of Surgery Case Reports 2210-2612 Elsevier S2210-2612(23)00084-6 10.1016/j.ijscr.2023.107956 107956 Case Report Inferior mesenteric vein preserving lymphadenectomy in high left segmental colectomy for splenic flexure melanoma: A case report Crowe Amy [email protected] a* Nasser Ra a Seth Ishith abc Lee Angus ab a Department of General Surgery, Bendigo Health, Victoria 3550, Australia b Department of Surgery, The University of Melbourne Medical School, Victoria 3052, Australia c Central Clinical School, Monash University, Victoria 3004, Australia * Corresponding author. [email protected] 02 3 2023 3 2023 02 3 2023 104 1079565 12 2022 23 2 2023 27 2 2023 Crown Copyright (c) 2023 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd. 2023 This is an open access article under the CC BY license ). Introduction and importance Surgical resection is the mainstay for management of splenic flexure cancers, with the aim of achieving adequate lymphadenectomy. Left-sided bowel resections often require ligation of the inferior mesenteric vein (IMV) for mesocolic dissection or lymphadenectomy which can result in congestive colitis on the anal side of the anastomosis secondary to poor venous outflow. Preserving the IMV may mitigate this risk but is technically difficult and can compromise oncological resection. This case report is a rare example of high left segmental resection of the splenic flexure with preservation of the IMV in a patient with splenic flexure melanoma. Case presentation A non-obstructing lesion was discovered in a 73-year-old male who underwent colonoscopy following a positive faecal occult blood test. Biopsy of the lesion confirmed a melanoma. This patient had a history of cutaneous melanoma which was excised 20 years prior. A laparoscopic high left segmental colectomy was performed, and metastatic melanoma was identified in 3 of 12 regional lymph nodes. The patient recovered with no complications. Clinical discussion This patient underwent high left segmental colectomy to achieve oncological clearance while resecting minimal bowel and preserving bowel function. The IMV was spared in this surgery to prevent venous congestion. Reports of colitis following left sided colectomy have been described, whereby colitis is thought to result from a mismatch in arterial perfusion and venous drainage following IMV resection. Conclusion This case highlights the potential role of preservation of the inferior mesenteric vein in a rare case of splenic flexure melanoma. Highlights * Preservation of inferior mesenteric vein in left-sided colectomy is rare and adequate lymph node retrieval is important. * Preservation of inferior mesenteric vein in left-sided colectomy allows to prevent congestion and colitis. * Multi-disciplinary discussion for splenic flexure carcinomas are indicated. Keywords Splenic flexure Cancer Melanoma Colectomy Inferior mesenteric vein pmc1 Introduction Splenic flexure carcinomas (SFCs) represent 2-8 % of all colorectal tumors. Although there is literature available on the management of SFCs, there is no worldwide consensus on optimal surgical management . Currently, surgical treatment includes extended right hemicolectomy, left hemicolectomy, subtotal colectomy, or segmental colectomy , , and considers the anatomy, vascular supply and lymph node drainage of mid-gut and hind-gut structures. Retrospective studies suggest no differences in survival outcomes or post-operative complications between surgical approaches, therefore treatment is case-based , , , , . Left-sided colectomy typically resects the inferior mesenteric vein (IMV) which reduces portal venous drainage of the colon, potentially resulting in venous congestion. Multiple reports demonstrate delayed onset regional congestive colitis on the anal side of the anastomosis after left-sided colon cancer surgery, where IMV ligation is postulated to disrupt colonic microcirculation , , . Adequate lymphadenectomy during mesocolic resection with preservation of the IMV has been reported in two cases however the difficulty with this approach is to ensure adequate lymph node retrieval for oncological resection alongside a technically challenging dissection , . This case report provides an example of adequate lymph node dissection which preserved the IMV during a high left segmental colectomy in a patient who presented with isolated melanoma of the splenic flexure. Appropriate written and verbal consent was obtained from the patient and the case report followed the SCARE guidelines . 2 Presentation of case A 73 year old male underwent a colonoscopy for a positive faecal occult blood test. His past medical history includes melanoma (Clark level 4) of the back which was completely excised 20 years prior, and hypertension. A non-obstructing lesion was found at the splenic flexure (Fig. 1) and tattooed. Biopsy at colonoscopy showed melanoma and the patient completed staging with MRI brain, PET CT and CT chest, abdomen and pelvis which identified the isolated lesion in the splenic flexure with no evidence of other metastatic diseases (Fig. 2, Fig. 3). The patient proceeded to undergo a laparoscopic high left segmental colectomy with preservation of the IMV. Histopathology of the operative specimen, a segment of colon 200 mm in length, confirmed a 30 mm melanoma penetrating through the bowel wall with clear margins. Metastatic melanoma was identified in 3 of the 12 retrieved regional lymph nodes. B-RAF mutation was detected through immunohistochemistry.Fig. 1 Mucosal lesion identified with colonoscopy. Fig. 1 Fig. 2 Coronal CT image identifying lesion in the splenic flexure (white arrow). Fig. 2 Fig. 3 A) Axial PET scan identifying avid lesion in the splenic flexure, B) coronal section of PET scan identifying the lesion in the splenic flexure. Fig. 3 Following surgical resection, the patient recovered without complications was content with the management and was discharged home four days post operatively after regaining bowel function. Following a discussion at a multi-disciplinary meeting, the patient opted for surveillance as an alternative to adjuvant immunotherapy based on the potential risk profile of the treatment and unknown benefits. The initial plan for surveillance included a clinical review and 3 monthly PET and MRI scan, however the patient was unable to maintain ongoing imaging after 6 months due to the high burden of appointments and travel time required. Colonoscopy at 12 months post-operatively showed a single benign polyp. At 18 months post-operatively no signs of recurrence were observed, and clinical surveillance is ongoing. 2.1 Technical component The procedure took place in a modified Lloyd-Davis position with the right arm tucked in. Infraumbilical 10 mm Hasson port was placed and 14 mmHg pneumoperitoneum was established. Three 5 mm working ports were inserted in the RUQ, LUQ, and LLQ. Fig. 4 identifies key anatomical structures where the IMV drains towards the inferior border of the pancreas.Fig. 4 Intra-operative image demonstrating key anatomy, the inferior mesenteric vein highlighted to show its path superiorly towards pancreas. Fig. 4 Following the identification of the IMV we utilised a sub-IMV approach with medial to lateral dissection to enter the plane between the mesocolon and Gerotas fascia. This was performed using a combination of blunt dissection and Ligasure. The gonadal vessels lie deep to the plane of dissection. The ascending branch of the left colic artery was ligated as skeletonization of the IMV continued towards the inferior border of the pancreas.Fig. 5 Intra-operative image of skeletonised inferior mesenteric vein following mesocolic dissection. Fig. 5 Fig. 6 The operative specimen following segmental colectomy. Fig. 6 A window into the lesser sac was created with an infra-colic approach through the transverse mesocolon to the right of middle colic artery. The left branch of the middle colic artery was ligated with Ligasure while the remaining colon and sigmoid colon were further mobilised medially to allow for tension-free extra-corporeal anastomosis (side to side stapled). Fig. 5 shows a skeletonised IMV. The specimen (Fig. 6) was extracted through a small Alexis wound retractor. The operative procedure can be seen in the supplementary video file. 3 Discussion The splenic flexure is situated at a watershed area between the mid-gut and hindgut. The splenic flexure receives vascular tributaries from the superior mesenteric artery (SMA) and inferior mesenteric artery (IMA), although Griffiths et al. discovered the splenic flexure received most of its blood supply by tributaries of the IMA, with just 11 % supplied by the left branch of the middle colic artery, a branch of SMA , . Lymph node drainage from the splenic flexure is variable and its pattern is uncertain, although malignancy is thought to spread predominantly along the paracolic arcade, left branch of the middle colic artery, left colic artery, and towards the root of the IMV . Surgical resection must incorporate resection of the malignancy with a margin of healthy tissue, in addition to that necessitated by arterial ligation and adequate lymphadenectomy. A recent meta-analysis of non-randomised studies indicated no significant difference in short term surgical complications or oncological outcomes between common surgical resection options , leaving no clear pathway for surgical resection of splenic flexure cancers , , , . For this patient, a high left segmental colectomy was performed, requiring ligation of the left branch of the middle colic artery and the ascending branch of the left colic artery (Fig. 7).Fig. 7 Schematic of arterial supply to the colon and resection specimen. A. Superior mesenteric artery B. Middle colic artery C. Right branch of the middle colic artery D. Left branch of the middle colic artery E. Inferior mesenteric artery F. Left colic artery G. Ascending branch of the left colic artery. Fig. 7 Multiple reports of colitis following left sided colectomy have been published , , . These reports postulate that congestive colitis may occur when there is a mismatch in arterial perfusion and venous drainage, however the number of cases is low and therefore the full scope of the impacts of vessel ligation or preservation on patient outcomes is not well understood. Which vessels to ligate will depend on the area of resection and the ability to achieve adequate lymphadenectomy while avoiding surgical complications secondary to reduced perfusion such as ischemic colitis or anastomotic leakage. Fujii et al. describe four cases of delayed congestive colitis at the anal side of anastomosis out of 191 patients who underwent left hemicolectomy whereby the superior rectal artery was preserved and the IMV was dissected at the inferior margin of the pancreas . Inoue et al. also reported a case of chronic progressive colitis following sigmoidectomy with sparing of the superior rectal artery and ligation of the IMV . Therefore, preservation of the IMV in procedures that preserve the SMA and IMA may help prevent venous congestion, however dissection around the IMV during lymph node retrieval is technically difficult . This case report demonstrates the feasibility of IMV preservation without compromising oncological principles, however further prospective studies would aid in validating the feasibility and safety of this technique on a larger scale. The patient in this case has a history of cutaneous melanoma Clarke level IV. Histopathology of the operative specimen indicated a 30 mm ulcerated melanoma (SOX-10 positive, BRAF positive) penetrating through bowel wall and present in 3/12 lymph nodes. It is not known whether this lesion represents a primary mucosal melanoma or a recurrence of his previous cutaneous melanoma. Regardless, operative intervention is recommended for metastatic melanoma to the GI tract for both symptom management and to prolong survival , . Metastatic cutaneous melanoma in the colon is rare and is usually diagnosed on autopsy , . Primary mucosal melanomas are rare (1.4 % of all melanomas), and mucosal melanomas of the colon are rarer still - accounting for 0.9 % of all mucosal melanomas . Positive B-RAF mutation is present in 4 % of cases of mucosal melanoma in the lower GI region (lower GI tract, genital, anorectal) . This may support the diagnosis of metastatic cutaneous melanoma. Whilst metastasis to the bowel 5 years following initial treatment has been reported , , to the authors knowledge this would be the first report of metastasis to the colon found pre-mortem 20 years following initial management. 4 Conclusions This case report demonstrates a rare case of melanoma of indeterminate origin in the colon, and considers the technical difficulty and potential role of IMV preservation in colectomy. Furthermore, this case report highlights the paucity of literature on the surgical management of splenic flexure carcinomas and emphasizes that worldwide consensus is needed for optimal management. Abbreviations IMV inferior mesenteric vein IMA inferior mesenteric artery SMA superior mesenteric artery The following are the supplementary data related to this article.Supplementary Video 1 Colonic melanoma. Supplementary Video 1 Patient consent Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Sources of funding None. Ethical approval The ethics was exempt from ethical approved due to being a case report, aligned with institutional values ). Author contribution Amy Crowe: Study concept and design, literature review, manuscript writing, manuscript review and editing. Ra Nassar: Manuscript review and editing, pictorial editing. Ishith Seth: Manuscript review and editing. Angus Lee: Supervising surgeon, study concept and design, manuscript review and editing. Guarantor Dr. Ishith Seth, BBiomed(Hons), MD. Research registration N/A. Declaration of competing interest None declared. References 1 Chenevas-Paule Q. Trilling B. Sage P. Girard E. Faucheron J. Laparoscopic segmental left colectomy for splenic flexure carcinoma: a single institution experience Tech. Coloproctol. 24 1 2020 41 48 31834555 2 Wang X. Zheng Z. Chen M. Lu X. Huang S. Huang Y. Chi P. Subtotal colectomy, extended right hemicolectomy, left hemicolectomy, or splenic flexure colectomy for splenic flexure tumors: a network meta-analysis Int. J. Color. Dis. 36 2 2021 311 322 3 Nakagoe T. Sawai T. Tsuji T. Jibiki M. Ohbatake M. Nanashima A. Yamaguchi H. Yasutake T. Kurosaki N. Ayabe H. Surgical treatment and subsequent outcome of patients with carcinoma of the splenic flexure Surg. Today 31 3 2001 204 209 11318121 4 Rega D. Pace U. Scala D. Chiodini P. Granata V. Fares Bucci A. Pecori B. Delrio P. Treatment of splenic flexure colon cancer: a comparison of three different surgical procedures: experience of a high volume cancer center Sci. Rep. 9 1 2019 1 7 30626917 5 Martinez-Perez A. Brunetti F. Vitali G.C. Abdalla S. Ris F. de'Angelis N. Surgical treatment of colon cancer of the splenic flexure: a systematic review and meta-analysis Surg. Laparosc. Endosc. Percutan. Tech. 27 5 2017 318 327 28796653 6 Grieco M. Cassini D. Spoletini D. Soligo E. Grattarola E. Baldazzi G. Testa S. Carlini M. Laparoscopic resection of splenic flexure colon cancers: a retrospective multi-center study with 117 cases Updat. Surg. 71 2 2019 349 357 7 Fujii T. Toda S. Nishihara Y. Maeda Y. Hiramatsu K. Hanaoka Y. Sato R. Matoba S. Ueno M. Kuroyanagi H. Congestive ischemic colitis occurring after resection of left colon cancer: 4 case series Surg. Case Rep. 6 1 2020 175 32691181 8 Inoue Y. Hashimoto T. Kitajima M. Fujita F. Ito Y. Furui J. Eguchi S. A case of chronic progressive ischemic colitis occuring 10 months after sigmoidectomy Nihon Gekakei Rengo Gakkaishi 40 4 2015 786 790 9 Nozue M. Taniguchi H. Kawamoto T. Koike N. Shinozaki E. Adachi S. Todoroki T. Fukao K. Refractory proctosigmoiditis probably caused by inferior mesenteric vein ligation at sigmoidectomy Hepato-Gastroenterology 51 58 2004 980 982 15239228 10 Melani A.G.F. Pandini R.V. Lima M.B. Bertulucci P. Spinelli A. Laparoscopic left colectomy with intracorporeal anastomosis: a complete mesocolic excision with preservation of the inferior mesenteric vein-a video vignette Color. Dis. 22 12 2020 2337-2337 11 Xiaolong Ma X.G. Chen Hai Peng Zhao Zhi Xun Yang Ming Total laparoscopic left hemicolectomy with preservation of inferior mesenteric artery and vein combined with natural orifice specimen extraction Kerala Surg. J. 27 1 2021 67 70 12 Agha R.A. Franchi T. Sohrabi C. Mathew G. for the SCARE Group The SCARE 2020 guideline: updating consensus Surgical Case Report (SCARE) guidelines Int. J. Surg. 84 2020 226 230 33181358 13 Griffiths J. Surgical anatomy of the blood supply of the distal colon: arris and gale lecture delivered at the Royal College of Surgeons of England on 27th march 1956 Ann. R. Coll. Surg. Engl. 19 4 1956 241 13363265 14 Patel K. Ward S. Packer T. Brown S. Marsden J. Thomson M. Ismail T. Malignant melanoma of the gastro-intestinal tract: a case series Int. J. Surg. 12 5 2014 523 527 24576592 15 Agrawal S. Yao T.-J. Coit D.G. Surgery for melanoma metastatic to the gastrointestinal tract Ann. Surg. Oncol. 6 4 1999 336 344 10379853 16 Samo S. Sherid M. Husein H. Sulaiman S. Vainder J.A. Metastatic malignant melanoma to the colon: a case report and review of the literature J. Gastrointest. Cancer 45 2 2014 221 224 23553262 17 Laoveeravat P. Wongjarupong N. Smith L. Wachtel M.S. Islam S. Isolated asymptomatic metastatic melanoma to the colon: a case report Cureus 11 2 2019 18 Mihajlovic M. Vlajkovic S. Jovanovic P. Stefanovic V. Primary mucosal melanomas: a comprehensive review Int. J. Clin. Exp. Pathol. 5 8 2012 739 23071856 19 Nassar K.W. Tan A.C. The mutational landscape of mucosal melanoma Seminars in Cancer Biology 2020 2020 Elsevier 139 148 20 Eloubeidi M.A. Gaede J.T. Davis W.Z. Isolated metastatic melanoma to the colon mimicking colon cancer Gastrointest. Endosc. 52 6 2000 751 752 11115908 |
JTO Clin Res Rep JTO Clin Res Rep JTO Clinical and Research Reports 2666-3643 Elsevier S2666-3643(23)00007-3 10.1016/j.jtocrr.2023.100468 100468 Brief Report Brief Report: Severe Pneumonitis After Combined Thoracic Radiotherapy and Osimertinib Smith Clayton P. MD a Xiang Michael MD, PhD a Yoon Stephanie M. MD a Lee Alan MD a Ruan Dan PhD a Goldman Jonathan W. MD b Cummings Amy L. MD b Lisberg Aaron MD b Garon Edward B. MD, MS b Moghanaki Drew MD, MPH [email protected] a* a Department of Radiation Oncology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California b Division of Hematology and Oncology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California * Corresponding author. Address for correspondence: Drew Moghanaki, MD, MPH, Department of Radiation Oncology, David Geffen School of Medicine, University of California Los Angeles, 200 Medical Plaza Driveway, Suite #B265, Los Angeles, CA 90095-6951. [email protected] 02 2 2023 3 2023 02 2 2023 4 3 1004685 12 2022 18 1 2023 18 1 2023 This is an open access article under the CC BY license ). Introduction Osimertinib is an effective treatment for metastatic NSCLC. Occasionally, thoracic radiation therapy (TRT) is delivered to patients receiving osimertinib to treat residual or progressing pulmonary tumors. Anecdotal reports suggest that the delivery of TRT in combination with osimertinib may be associated with a high risk of severe pneumonitis. Methods A retrospective study was performed at a single academic medical center in the United States to investigate the incidence of severe pneumonitis among patients treated with combined TRT and osimertinib between June 2016 and December 2021. Baseline patient characteristics, tumor size and location, and dosimetric parameters were evaluated. The highest grade of radiation pneumonitis that developed within 6 months of treatment was scored in accordance with the Common Terminology Criteria for Adverse Events version 5.0. Results A total of 16 patients were identified who were treated with combined TRT and osimertinib. All had a diagnosis of metastatic NSCLC. Treatment-related grade greater than or equal to 2 pneumonitis developed in 56%, grade greater than or equal to 3 in 37.5%, and grade 4 in 6.3%; no patient developed grade 5 pneumonitis. Median time to any-grade pneumonitis was 29 days (1-84 d); all patients had symptom resolution with expectant management or oral steroid therapies. All patients discovered to have grade greater than or equal to 3 pneumonitis (n = 6) received TRT to tumors located within 2 cm of the proximal bronchial tree, including tumors abutting the proximal bronchial tree (n = 2) and within the mediastinum (n = 1). Conclusions The combination of TRT with osimertinib was associated with a high rate of severe pneumonitis that required oral steroid medications. Larger studies are needed to validate these findings and to understand the clinical and treatment factors that influence this risk and how they can be mitigated. Keywords Pneumonitis Radiation therapy Osimertinib EGFR-mutated NSCLC pmcIntroduction EGFR tyrosine kinase inhibitors (TKIs) have improved outcomes for patients with NSCLC.1, 2, 3 The third-generation EGFR TKI osimertinib was found to have survival benefits than first-generation agents gefitinib and erlotinib, and it is now a standard of care for metastatic NSCLC.4 Depending on clinical scenarios, thoracic radiation therapy (TRT) may be prescribed to oligoremnant or oligoprogressive tumors in the lungs to improve tumor control. Randomized trials are ongoing to evaluate the value of radiation therapy in patients with oligometastatic NSCLC after initial response to a TKI (NCT03256981). Although the role of TRT in patients with oligometastatic NSCLC seems promising, there is a paucity of data on its safety when combined with osimertinib. It is known that osimertinib causes interstitial lung disease in approximately 4% of patients.5 TRT can also cause severe pneumonitis in 3% to 5% of patients with oligometastatic NSCLC.6 The first reported case of severe pneumonitis associated with combined TRT and osimertinib was from Tenon Hospital in Paris by Sanchis-Borja et al.7 in 2019. A case series (n = 11) from Shandong Cancer Hospital by Jia et al.8 in 2020 reported a grade greater than or equal to 3 pneumonitis rate of 54.5% and one fatal complication. Given the limited data available, an independent review was performed to evaluate the rate of severe pneumonitis with combined TRT and osimertinib at our institution. Materials and Methods A retrospective study was performed to identify patients who were treated with combined TRT and osimertinib between June 2016 and December 2021 at a single academic medical center. Patients were excluded if they had a history of interstitial lung disease. This work was completed under a waiver of informed consent. Baseline patient characteristics, tumor size and location, and dosimetric parameters were recorded. Tumor location was coded as central (within 1-2 cm of the proximal bronchial tree), ultracentral (within 1 cm of the proximal bronchial tree), mediastinal (within the mediastinum), or peripheral (all other lung parenchymal locations). All patients underwent stereotactic body radiation therapy (SBRT) or intensity-modulated radiation therapy with photon therapy. TRT treatment plans were developed using four-dimensional computed tomography simulations and daily image guidance using cone beam computed tomography. Patients received osimertinib orally at 80 mg daily until disease progression was deemed uncontrollable by a medical oncologist or until the patient developed intolerable toxicities. The primary outcome of interest was severe grade greater than or equal to 3 pneumonitis within 6 months of TRT based on documentation in the electronic health record in accordance with the Common Terminology Criteria for Adverse Events version 5.0. Results A total of 16 patients were treated with combined TRT and osimertinib over the study time period; the median age was 70 years and all had a diagnosis of metastatic NSCLC (Table 1). The TRT treatment site was peripheral in four (25%), central in four (25%), ultracentral in seven (44%), and mediastinal in one (6%). TRT was delivered with a median prescription dose of 50 Gy (11-65 Gy) in a median of 7.5 fractions (1-15 fractions); the median duration of TRT was 10 days (1-22 d).Table 1 Patient and Treatment Characteristics Patient Age (y) Pulmonary Comorbidity Smoking Status at TRT Pack-Year Smoking History Duration of Osimertinib Before TRT (mo) Osimertinib Sequence With TRT Tumor Location Tumor Volume (mL) TRT Dose Prescription Volume of Ipsilateral Lung >= 20 Gy (mL) Pneumonitis Grade Time to Symptomatic Pneumonitis From TRT Start Date (d) 1 63 None Never smoker Unknown 7 Concurrent Peripheral 6.4 18 Gy x 3 45 0 - 2 69 None Prior smoker 30 21 Concurrent Peripheral 1.6 10 Gy x 5 21 0 - 3 85 None Never smoker Unknown 5 Concurrent Peripheral 0.5 18 Gy x 3 27 2 69 4 95 None Never smoker Unknown 28 Concurrent Peripheral 24.9 11 Gy x 1 0 2 4 5 72 None Never smoker Unknown 13 Concurrent Central 9.8 18 Gy x 3 162 0 - 6 82 None Prior smoker Unknown <1 Concurrent Central 14.0 6.5 Gy x 10 154 3 42 7 76 Asthma Never smoker Unknown 10 Concurrent Central 6.8 12.5 Gy x 4 153 3 61 8 70 Emphysema, asthma Current smoker Unknown 6 Concurrent Central 0.7 18 Gy x 3 63 4 8 9 54 None Never smoker Unknown 18 Concurrent Ultracentral 9.2 4 Gy x 15 136 0 - 10 51 None Prior smoker 5 2 Held 24 h before and after TRT Ultracentral 27.9 5 Gy x 10 356 0 - 11 77 None Never smoker Unknown <1 Held 48 h before and after TRT Ultracentral 50.8 4 Gy x 10 384 0 - 12 72 None Prior smoker Unknown 4 Concurrent Ultracentral 428 3 Gy x 10 154 0 - 13 60 None Prior smoker Unknown 5 Concurrent Ultracentral 43.9 8 Gy x 5 226 2 11 14 63 None Never smoker Unknown 16 Concurrent Ultracentral 3.6 6.5 Gy x 10 111 3 97 15 63 None Never smoker Unknown 12 Concurrent Ultracentral 23.8 4 Gy x 10 218 3 45 16a 42 None Prior smoker 1.5 <1 Concurrent Mediastinal - 2.5 Gy x 11 - 3 38 RT, radiation therapy; TRT, thoracic radiation therapy. a TRT was discontinued after 11 fractions due to development of intolerable esophagitis; comprehensive treatment records were unavailable to ascertain tumor volume and volume of ipsilateral lung receiving >=20 Gy. Red indicates patients who developed grade 3 or higher radiation pneumonitis. The median follow-up time was 13 months (1-61 mo). Nine patients developed grade greater than or equal to 2 pneumonitis (56%) with a median time to onset of 29 days (1-84 d); the severity of pneumonitis was grade greater than or equal to 3 in six patients (37.5%). A single patient with a history of chronic obstructive pulmonary disease requiring multiple previous hospitalizations developed grade 4 pneumonitis after TRT; no patients were identified with grade 5 pneumonitis. As displayed in Figure 1, TRT plans resulting in grade greater than or equal to 3 pneumonitis targeted tumors that were central in three (50%), ultracentral in two (33%), and mediastinal in one (17%). The TRT prescriptions were SBRT in three to four fractions for two patients (33%) and consisted of a protracted course of hypofractionated radiation therapy in 10 to 11 fractions for four patients (66.6%). Two of 16 patients withheld osimertinib 24 to 48 hours before and after TRT, both of whom had tumors in an ultracentral location, and neither was found to have developed pneumonitis. Severe pneumonitis was not associated with the use of SBRT versus hypofractionated TRT or mean lung dose. All patients developing grade 2 pneumonitis had resolution of symptoms with expectant management; patients developing grade 3 to 4 pneumonitis had symptom resolution with oral steroid therapies.Figure 1 Thoracic radiation therapy treatment plans for patients who developed grade 3 or higher pneumonitis. Discussion To best of our knowledge, this is the largest study to date investigating the risk of severe pneumonitis after combined TRT and osimertinib in patients with metastatic NSCLC. It is also the first report on the topic from a North American institution. The findings support previously reported safety concerns whenever TRT is delivered to patients receiving osimertinib. EGFR TKIs are generally safe with a severe pneumonitis risk of less than 5%.4,9,10 Reports published as early as 2014 have identified that the combination of curative-intent TRT with first-generation TKIs increases the risk up to 23% in patients with stage III NSCLC.9,11,12 More recent reports, including this one, reveal the risk of severe pneumonitis may be as high as 45% with the combination of SBRT and hypofractionated TRT with the third-generation osimertinib for patients with stage IV NSCLC. It deserves emphasis that severe pneumonitis events in this report were limited to patients who received TRT for tumors located within 2 cm of the proximal bronchial tree. Previous studies have revealed that SBRT targeting this area is independently associated with a high risk of severe pneumonitis.13 Nevertheless, the TRT doses delivered with osimertinib in this report were moderate in comparison to previous studies and thus were unlikely to have been the sole contributor to pulmonary injury. The small size of this case series limited the ability to analyze contributions of TRT prescriptions independent of its possible interactions with osimertinib. Limitations This is a small case series of patients at a single institution who were referred for TRT from a broader cohort of patients with EGFR-mutated NSCLC. Although these data are important to the growing body of literature in TKI-based therapy combined with TRT, this group of patients is very diverse and dissimilar, and thus it can be challenging to make meaningful conclusions. Therefore, the generalizability of the reported findings to broader populations cannot be known without a larger study. Conclusions The combination of TRT and osimertinib was associated with a high rate of severe pneumonitis limited to patients with pulmonary tumors located within 2 cm of the proximal bronchial tree. These data raise questions about safety issues that are not currently listed in treatment guidelines, although it should be noted that meaningful conclusions are difficult to make based on a small retrospective case series study. Further research is indicated to validate these findings in larger cohorts to determine whether patient selection and treatment factors can be modified to mitigate this risk. CRediT Authorship Contribution Statement Clayton P. Smith: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Roles/Writing Original draft, Writing Review and editing. Michael H. Xiang: Data curation, Formal analysis, Writing Review and editing. Stephanie M. Yoon: Methodology, Writing Review and editing. Alan Lee: Writing Review and editing. Dan Ruan: Data curation. Jonathan W. Goldman: Writing Review and editing. Amy L. Cummings: Writing Review and editing. Aaron Lisberg: Writing Review and editing. Edward B. Garon: Writing Review and editing. Drew Moghanaki: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Project administration, Roles/Writing Original draft, Writing Review and editing. Acknowledgments This work is supported by the Stanley Iezman and Nancy Stark Endowment for Thoracic Radiation Oncology Research. Aaron Lisberg is supported by NIH-NCI K08 CA245249-01 and a 10.13039/100002192 LUNGevity 2019 Career Development Award. Disclosure: Dr. Goldman reports research grants and honoraria from AstraZeneca. Dr. Lisberg reports having employment of immediate family member (wife) at Boston Scientific, who owns stock of <5% equity; receiving commercial research grants from Daiichi Sankyo, Calithera Biosciences, AstraZeneca, Dracen Pharmaceuticals, and WindMIL; and serving as consultant/advisory board for AstraZeneca, Bristol-Myers Squibb, Leica Biosystems, Jazz Pharmaceuticals, Novocure, Pfizer, MorphoSys, Eli Lilly, Oncocyte, Novartis, Regeneron, Janssen Oncology, and Sanofi group of companies. Dr. Garon reports serving as consultant and/or advisor for AbbVie, ABL-Bio, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Dracen Pharmaceuticals, EMD Serono, Eisai, Eli Lilly, Gilead, GlaxoSmithKline, Merck, Natera, Novartis, Personalis, Regeneron, Sanofi, Shionogi, and Xilio; receiving grant/research support from ABL-Bio, AstraZeneca, Bristol-Myers Squibb, Dynavax Technologies, Eli Lilly, EMD Serono, Genentech, Iovance Biotherapeutics, Merck, Mirati Therapeutics, Neon, and Novartis. Dr. Moghanaki serves as a consultant for AstraZeneca. The remaining authors declare no conflict of interest. Cite this article as: Smith CP, Xiang MH, Yoon SM, et al. Brief report: severe pneumonitis after combined thoracic radiotherapy and osimertinib. JTO Clin Res Rep. 2023;3:100468. References 1 Wu Y.L. Zhou C. Liam C.K. First-line erlotinib versus gemcitabine/cisplatin in patients with advanced EGFR mutation-positive non-small-cell lung cancer: analyses from the phase III, randomized, open-label, ENSURE study Ann Oncol 26 2015 1883 1889 26105600 2 Rosell R. Carcereny E. Gervais R. Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial Lancet Oncol 13 2012 239 246 22285168 3 Zhou C. Wu Y.L. Chen G. Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study Lancet Oncol 12 2011 735 742 21783417 4 Ramalingam S.S. Vansteenkiste J. Planchard D. Overall survival with osimertinib in untreated, EGFR-mutated advanced NSCLC N Engl J Med 382 2020 41 50 31751012 5 Soria J.C. Ohe Y. Vansteenkiste J. Osimertinib in untreated EGFR-mutated advanced non-small-cell lung cancer N Engl J Med 378 2018 113 125 29151359 6 Siva S. Kron T. Bressel M. A randomised phase II trial of stereotactic ablative fractionated radiotherapy versus radiosurgery for oligometastatic neoplasia to the lung (TROG 13.01 SAFRON II) BMC Cancer 16 2016 183 26944262 7 Sanchis-Borja M. Parrot A. Sroussi D. Rivin Del Campo E. Fallet V. Cadranel J. Dramatic radiation recall pneumonitis induced by osimertinib after palliative thoracic radiotherapy for lung cancer J Thorac Oncol 14 2019 e224 e226 31558233 8 Jia W. Guo H. Jing W. An especially high rate of radiation pneumonitis observed in patients treated with thoracic radiotherapy and simultaneous osimertinib Radiother Oncol J Eur Soc Ther Radiol Oncol 152 2020 96 100 9 Wang X.S. Bai Y.F. Verma V. Randomized trial of first-line tyrosine kinase inhibitor with or without radiotherapy for synchronous oligometastatic EGFR-mutated NSCLC [e-pub ahead of print] J Natl Cancer Inst 114 2022 djac015 10 Wu Y.L. Cheng Y. Zhou X. Dacomitinib versus gefitinib as first-line treatment for patients with EGFR-mutation-positive non-small-cell lung cancer (ARCHER 1050): a randomised, open-label, phase 3 trial Lancet Oncol 18 2017 1454 1466 28958502 11 Zhuang H. Yuan Z. Chang J.Y. Radiation pneumonitis in patients with non-small-cell lung cancer treated with erlotinib concurrent with thoracic radiotherapy J Thorac Oncol 9 2014 882 885 24828665 12 Xu K. Liang J. Zhang T. Clinical outcomes and radiation pneumonitis after concurrent EGFR -tyrosine kinase inhibitors and radiotherapy for unresectable stage III non-small cell lung cancer Thorac Cancer 12 2021 814 823 33501781 13 Swaminath A. Ritter T. Louie A.V. Performing SBRT in the fly-with-caution zone: are we heeding the advice of Daedalus? Int J Radiat Oncol Biol Phys 112 2022 586 589 35101193 |
Methotrexate administration for the treatment of tubal ectopic pregnancies has been shown to cause tubal mass enlargement. Our hypothesis was that, by administrating Methotrexate, a local necrotic reaction occurs, leading to hematoma formation and eventually fallopian tube rupture. Salpingectomy specimens were collected, analysed and divided into three equal groups: patients who received Methotrexate but who ultimately failed medical treatment, patients who had a viable ectopic pregnancy and patients with a self-resolving ectopic pregnancy that were operated due to other medical indications. The specimens were dyed using the Cleaved Caspase-3 (Asp175) Rabbit mA. Specimens were divided into three equal groups and analysed. The patients in self-resolving ectopic pregnancy group were older and had more pregnancies. Rates of apoptosis were found to be less than 1% per slide. Necrosis was not evident in any of the pathological specimens. It seems Methotrexate administration does not lead to a significant tubal necrotic reaction. Further studies are required. apoptosis ectopic Methotrexate necrosis pregnancy source-schema-version-number2.0 cover-dateApril 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:13.03.2023 Gil Y , Zubkov A , Balayla J , Cohen A , Levin I . Apoptosis versus necrosis in tubal ectopic pregnancies following Methotrexate. Int J Exp Path. 2023;104 :76-80. doi:10.1111/iep.12465 pmc1 INTRODUCTION Systemic, intramuscular (I.M) Methotrexate (MTX) therapy is the treatment of choice for non-ruptured, haemodynamically stable, ectopic pregnancies. Reported success rates for a single dose MTX therapy are high and are inversely proportional to b-hCG levels. 1 , 2 , 3 The mechanism of action of MTX is through inhibition of the metabolism of folic acid. By inhibiting the enzyme Dihydrofolate reductase, it prevents purine and thymidylic acid synthesis, which in turn interferes with DNA synthesis, repair and cellular replication. It is an antimetabolite which disrupts actively growing cells, and as such it is used for the treatment of cancer, autoimmune diseases, ectopic pregnancy, as well as other conditions in which rapid cellular proliferation underlies its pathophysiology. 3 Methotrexate has not only been shown to cause apoptosis in various tissues, such as platelets, but also has been shown to cause necrosis in other tissues, such as renal cells. 4 , 5 , 6 In haemodynamically stable patients with tubal ectopic pregnancies, expectant management and serial b-hCG follow-up leading to spontaneous resolution have been repeatedly shown to be a safe and effective treatment alternative, and in fact, in our institution, this so called "watchful waiting," is the preferred approach for most patients. 7 , 8 Previous studies have shown that after MTX administration, there is enlargement of the tubal mass with hematoma formation. This enlargement was shown to persist even up to 63 days and follow the biochemical (b-hCG) resolution. 9 , 10 This hematoma may eventually render the mass unstable and subsequently lead to rupture of the fallopian tube. Our hypothesis was that when an extra-uterine pregnancy spontaneously resolves, an apoptotic reaction takes place as part of a physiological process, which leads to a gradual disappearance of the gestational tissue. During this process, hematoma formation and tubal enlargement are limited or do not happen at all, subsequently leading to reduced risk for fallopian tube rupture. Studies on apoptosis in gestational tissue are sparse. Kokawa et al. 11 investigated possible effects of implantation on apoptosis. After examining the cleavage of DNA in human chorionic villi and decidua in both intrauterine and ectopic pregnancies, a ladder pattern, which is a histological hallmark of apoptosis, representing breakdown of DNA, was present in the villi of tubal pregnancies. Likewise, an in-situ analysis revealed that apoptotic cells were predominant in the syncytiotrophoblast in tubal pregnancy. This study demonstrated that apoptosis occurs in the villi, but not in the decidua of tubal pregnancies, unlike the pattern observed in a normal, intrauterine pregnancy. This finding encouraged us to further look for an apoptotic reaction in the fallopian tubes of ectopic pregnancies, and to determine whether differences in apoptotic rates existed on specimens exposed to MTX therapy. 2 MATERIALS AND METHODS All cases of tubal ectopic pregnancies treated in our university affiliated tertiary medical centre between January 2011 and June 2013 were reviewed. The institutional review board "Helsinki Committee" approved the study design, protocol and waiver of informed consent. A total of 30 pathological specimens of fallopian tubes were randomly selected by serial order and collected. All specimens were embedded in a formaldehyde solution. We divided the patients into three equal study groups: Group "A," n = 10, included haemodynamically stable patients who underwent salpingectomy after treatment failure with MTX. Group "B," n = 10, included haemodynamically stable patients who were operated because of a viable extra uterine pregnancy with a foetal heart rate. Finally, Group "C," n = 10, included patients who had a self-resolving ectopic pregnancy but were operated according to physician's decision based on relative indications for surgery (ex. patient with a known tubal factor) or due to patients' request. Treatment failure was defined as constant increase of b-hCG levels after second dose of I.M MTX. A single pathologist, aware only of the group's name, but blinded to the patient's other personal details, group's classification or the different treatment approaches, dyed and examined all of the specimens and documented the results according to consecutive serial numbers. The specimens were put on slides and dyed using the Cleaved Caspase-3 (Asp175) Rabbit monoclonal antibody (Cleaved Caspase-3 antibody, #9579; Cell Signaling Technology). Caspase-3 is a critical executioner of apoptosis, as it is either partially or totally responsible for the proteolytic cleavage of many key proteins, such as the nuclear enzyme polymerase. 12 Activation of caspase-3 requires proteolytic processing of its inactive zymogen into activated p17 and p12 fragments. 13 The Cleaved Caspase-3 Rabbit monoclonal antibody recognizes endogenous levels of caspase-3 protein when cleaved at Asp175. The antibody is produced by immunizing animals with a synthetic peptide corresponding to residues surrounding Asp175 of human Caspase-3 protein. 14 The slides were viewed under a light microscope, with an x100 magnification. The percentage of apoptosis was measured according to the manufacturer's instructions (Cell Signaling Technology). In addition, signs of a necrotic reaction such as generalized swelling of cell membranes, chromatin condensation, breakdown of plasma membranes, infiltration with inflammatory cells and nucleus shrinkage were assessed. The pathologist performed quantification and registration of the slides. The results were then transferred to the head researcher who uncovered the batch number and separated the results according to the different groups. Data analysis was carried out with analysis of variance for continuous variables and chi-square for proportions and categorical variables. By convention, statistical significance was defined with a p-value <.05. 3 RESULTS A total of 30 pathological specimens were analysed. After initial assessment, none of the patients was excluded from the study. The patients in group "C," with the self-resolving ectopic pregnancy, were older (33.4 vs. 30.8 and 32.3, p > .05), had more pregnancies (3.8 vs. 2.4 and 2.4, p > .05) and greater history of live born children (Table 1). In addition, they had the lowest b-hCG levels (Tables 2 and 3) and spent more days in the hospital. Patients in group "C" were also more likely to have conceived spontaneously. TABLE 1 Demographics. Group A B C p-Value Number of patients 10 10 10 >.05 Median age 30.8 32.3 33.4 >.05 Gravidity 2.4 2.4 3.8 >.05 Parity 1.0 0.33 2.1 >.05 Mean gestational week 5.93 6.5 6.61 >.05 Hospitalization days 3.3 2.66 4.6 >.05 Note: A Methotrexate Failure; B Ectopic Pregnancy with Pulse; C Self-resolving Ectopic Pregnancy. TABLE 2 Conception. Group A B C p-Value Spontaneous conception n = 4 n = 5 n = 7 >.05 Post IVF treatment n = 3 n = 3 n = 2 >.05 Post IUI/OI treatment n = 3 n = 2 n = 1 >.05 Note: A Methotrexate Failure; B Ectopic Pregnancy with Pulse; C Self-resolving Ectopic Pregnancy. Abbreviations: IUI, Intrauterine Insemination; IVF, In Vitro Fertilization; OI, Ovulation Induction. TABLE 3 b-HCG levels. Group/Patient number A B C I 10,660 1088 2537 II 3327 n/a 252 III 2624 18,439 n/a IV 9422 47,278 2049 V 2607 3905 2195 VI n/a n/a 4757 VII n/a 5400 1700 VIII 7784 1257 1176 IX 1446 n/a 1207 X 2179 n/a 1073 Note: A Methotrexate Failure; B Ectopic Pregnancy with Pulse; C Self-resolving Ectopic Pregnancy. After applying the antibody and employing the appropriate smears, all slides were viewed under light microscope. A total of 0-2 apoptotic cells per slide were viewed for all specimens from all study groups, regardless of treatment group. The subsequent apoptotic rate was lower than 1% . Histological signs of necrosis were not evident in either of the pathological specimens. Due to the low number of cells identified, these findings did not confer any statistical significance. It was observed that apoptosis can be found in trophoblastic cells of tubal ectopic pregnancies after salpingectomy which is not the regular component found in trophoblast turnover. 15 FIGURE 1 (A) Fallopian Tube, H&E Staining. BC, Blood Clot; MS, Muscular Wall; PL, Plica. Magnification 100x. (B) Villi in Fallopian Tube. The Villi is surrounded by RBC. The outer layer is composed of Syncytiotrophoblast. The inner layer is composed of Cytotrophoblast. The stroma of the Villi contains Hofbauer cells (Macrophages). Haematoxylin and Eosin Stain, Magnification 100x. (C) Villi Fallopian Tube, Same area as Figure 2, Cleaved Caspase - 3 Staining. Red Arrow - Apoptotic Epithelial Cell, Magnification 100x. 4 DISCUSSION To the best of our knowledge, this was the first attempt to examine the cellular reaction in the fallopian tubes after systemic MTX therapy for tubal ectopic pregnancies. Our objective was to demonstrate that MTX, which is a common, widely used treatment for patients with tubal ectopic pregnancies may actually lead to a pathological process in the fallopian tube, thus rendering it more friable, subsequently increasing the chances of fallopian tube rupture. That is in contrast to a more physiological process, possibly apoptosis, of a ectopic pregnancy. Elkholy et al. 16 have examined the effect of intraperitoneal MTX in rats on fallopian tubes and found that in high doses it can induce long-term irreversible damage. In contrast, Kooi et al. 17 showed that even injecting MTX directly into the fallopian tube does not cause damage or make it more susceptible to rupture, though this study included only five specimens and so it is unclear if the sample is sufficient to reach a valid conclusion. Unfortunately, the results of our study did not validate our hypothesis and we found low rates of both apoptosis and necrosis in the fallopian tubes after MTX therapy. After reviewing our methods, we found a few possible explanations for these results. First, there could have been inadequacy of the cleaved Caspase-3 for the fallopian tube tissue or for the formaldehyde fixation. Second, the Methotrexate therapy may not have provoked a cellular reaction on the gestational tissue. Third, some studies have shown a time and dose-dependent reaction to Methotrexate. As the MTX dose used is relatively low and exposure is short in ectopic pregnancies, it is possible that the reaction observed was therefore only partial. Fourth, both apoptosis and necrosis are gradual processes and so, if the procedures were preformed relatively soon after the MTX injection, it is possible that the full extent of the pathological reaction had yet to occur at the time of salpingectomy. Finally, the small sample size used in this study may have prevented us from reaching significant conclusions. Ectopic pregnancies present one of the most frequent challenges to the practicing gynaecologist. Although Methotrexate is usually considered to be a valid treatment option for haemodynamically stable patients, the full pathophysiological mechanism and consequences following its administration remain unclear. It is in our collective interest to know and fully understand the full extent and possible sequalae of the treatments were administrating. Although the results did not meet our exceptions, we believe our hypothesis may still have a foundation and that the importance of this subject is significant. This subject needs to be further evaluated. We will continue to pursue the matter and are searching for the right histopathological approach in order to prove our hypothesis. Our hypothesis that apoptosis rather than necrosis and hematoma formation is the dominant mechanism of self-resolving ectopic pregnancies could be the explanation of fewer rupture cases after treatment, and could further promote our "watchful waiting" protocol in the treatment of ectopic pregnancies. We invite our colleagues to further investigate the subject and are willing to share our knowledge and experience in the field. AUTHOR CONTRIBUTIONS YG, IL: Conception & design. YG, AZ, JB, AC: Acquisition & analysis of data. YG, AZ, IL: Manuscript/figures Drafting. JB: Others. FUNDING INFORMATION No funding was received for this study. CONFLICT OF INTEREST The authors have no conflicts of interest to report. ACKNOWLEDGEMENT None. |
Degradation of the articular cartilage is a hallmark of osteoarthritis, a progressive and chronic musculoskeletal condition, affecting millions of people worldwide. The activation of several signalling cascades is altered during disease development: among them, the Wnt signalling plays a pivotal role in the maintenance of tissue homeostasis. Increasing evidence is showing that its activation needs to be maintained within a certain range to avoid the triggering of degenerative mechanisms. In this review, we summarise our current knowledge about how a balanced activation of the Wnt signalling is maintained in the articular cartilage, with a particular focus on receptor-mediated mechanisms. articular cartilage osteoarthritis Wnt Medical Research Council 10.13039/501100000265 MR/S008608/1 source-schema-version-number2.0 cover-dateApril 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:13.03.2023 Gill AK , McCormick PJ , Sochart D , Nalesso G . Wnt signalling in the articular cartilage: A matter of balance. Int J Exp Path. 2023;104 :56-63. doi:10.1111/iep.12472 pmc1 OSTEOARTHRITIS Osteoarthritis (OA) is a chronic and degenerative musculoskeletal condition, affecting 16% of the worldwide population over the age of 15. 1 From a clinical point of view, OA is characterised by progressive and irreversible degeneration of the articular cartilage (AC), inflammation of the synovial lining and abnormal subchondral bone remodelling. 2 Osteoarthritis is a multifactorial disease: ageing, genetic predisposition, history of trauma and co-morbidities, such as diabetes or hypercholesterolemia, have been associated with the onset of OA or the exacerbation of its symptoms and clinical features. 3 , 4 , 5 No pharmacological treatment can revert the progression of the disease, and pain relief is the main therapeutic option for patients. When this does not suffice anymore and joint mobility is completely compromised, the patient is offered a joint replacement surgery. This option is not devoid of potential post-operative complications, especially in the most elderly patients. Furthermore, in 30% of patients, joint replacement with a prosthesis does not resolve chronic pain, thereby only partially improving patients' quality of life. 6 2 THE ARTICULAR CARTILAGE The AC is the connective tissue covering the edges of the bones in the diarthrodial joints. The tissue allows a smooth diarthrosis being elastic and conferring resistance to compression upon the joint. Its main constituents are a thick extracellular matrix (ECM), made of proteoglycans and collagens, and only one cell type, the chondrocyte. Proteoglycans are negatively charged molecules providing the AC with its high resistance to compressive loads by attracting water into the tissue. Collagens are organised in fibres conferring the AC tensile strength. 7 Chondrocytes are responsible for the turnover of ECM components by expressing and secreting both ECM components and the enzymes responsible for their degradation, such as metalloproteases (MMPs). As the AC is nonvascularised and noninnervated, the tissue relies on the subchondral bone and the synovial fluid to receive nutrients and to maintain the necessary tissue lubrication. 8 , 9 3 DEGRADATION OF THE ARTICULAR CARTILAGE IN OSTEOARTHRITIS During the development of OA, the metabolic balance in the AC skews towards catabolism. The expression and activity of MMPs, such as MMP3 and MMP13, and A Disintegrin And Metalloproteinase with Thrombospondin Motifs (ADAMTs) enzymes, such as ADAMTS4 and ADAMTS5 are strongly upregulated in the AC along disease progression. 10 Conversely, the expression of some tissue inhibitors of metalloproteases (TIMPs) is reduced. 11 Metalloproteases cut and degrade proteoglycans and collagens, leading to tissue erosion and to the onset of the disease. Increasing evidence suggests that OA is an abnormal recapitulation of osteogenesis. Bones are derived from the cartilage anlagen: chondrocytes in the anlage undergo a coordinated process of proliferation and maturation which culminates in hypertrophic maturation. Hypertrophic chondrocytes (HC) can then indirectly and directly contribute to bone formation. In the first case, HC undergo terminal differentiation, driving the secretion of mineralised cartilage and blood vessels invasion, after which they die through apoptosis. Vascular invasion allows the arrival of blood vessel-associated pericytes, osteoclasts and bone progenitor cells in the anlage, promoting bone formation. Hypertrophic chondrocytes can also transdifferentiate into osteoblasts, therefore directly generating bone tissue. 12 , 13 , 14 Differently, synovial joints originate from the condensation of mesenchymal cells in structures called interzones. Interzone cells directly differentiate into articular chondrocytes, which do not undergo hypertrophic differentiation. 15 During the development of OA, deregulation of several signalling cascades can lead articular chondrocytes to restart the differentiation process from where it had been interrupted during joint development and undergo hypertrophic maturation and calcification. 16 These phenomena contribute to the loss of elasticity and resistance to compression of the ECM, leading to tissue destruction and ultimately compromising joint mobility and inducing pain. 16 4 THE WNT SIGNALLING Deregulation of the Wnt signalling plays a major role in the development and progression of OA. Wnts are a family of 19 glycosylated and lipid-modified ligands activating a complex network of signalling pathways. To activate any of these pathways, Wnts engage with the Frizzled (FZD) family of receptors. The Wnt/FZD complexes associate with different co-receptors, leading to the initiation of specific intracellular signalling. The association of FZDs with the Low-density Lipoprotein-Related Protein 5 or 6 (LRP5/6) receptors leads to the destabilisation of a multiprotein 'destruction complex' which includes among its members Axin2, Adenomatous polyposis coli (APC), Glycogen Synthase Kinase 3 (GSK3), Casein Kinase 1 (CK1), protein phosphatase 1A (PP2A) and the E3-ubiquitinin ligase beta-transducin repeat-containing protein (b-TrCp). In the absence of an activating stimulus, the complex traps b-catenin within the cytoplasm and addresses it for ubiquitin-mediated degradation. 17 The disaggregation of the destruction complex promotes the accumulation of b-catenin which can then translocate to the nucleus where it binds to components of the T-cell factor/lymphoid enhancer factor (TCF/LEF) family of proteins, promoting the transcription of cell and context-specific genes. 18 Among these, Axin2 seems to be a well-preserved target across cell types and species. 19 Frizzled, however, have also been reported to associate with other co-receptors, such as the Receptor Tyrosine Kinase-like Orphan Receptor 2 (ROR2) and the Related to Receptor Tyrosine Kinase (RYK), 20 , 21 promoting the activation of less characterised signalling cascades. These have been grouped under the name of b-catenin-independent pathways. Their triggering does not promote the accumulation of b-catenin but leads instead to the activation of other downstream targets such as Calcium Calmodulin Kinase II (CaMKII), 22 , 23 Protein Kinase A (PKA) and Protein Kinase C (PKC). 24 , 25 5 THE WNT SIGNALLING IN OA The Wnt/b-catenin-dependent signalling is the most characterised of the Wnt pathways at molecular level. The activation of this pathway is required and sufficient for synovial joint formation; 26 however, it needs to be tightly regulated in a space-dependent manner to allow the integrity of the tissue to be maintained in the adult life. 27 , 28 Overactivation of the Wnt/b-catenin signalling has indeed been associated with degradation of the AC in OA. Polymorphisms in genes expressing components and/or modulators of this pathway have been linked to a higher risk of developing OA. The Arg200Trp and the Arg324Gly substitutions in the secreted Frizzled-Related Protein 3 (sFRP3), a soluble scavenger of Wnt ligands, lead to loss-of-function mutations which have been reported to be more frequent in patients with clinical signs of OA. 29 , 30 , 31 sFRP3-deficient mice developed more severe cartilage destruction both in a model of inflammatory arthritis and in a surgically induced OA model. 32 , 33 In addition, the expression of Dikkopf1 (Dkk1), an inhibitor of the Wnt/b-catenin pathway, is lower in the AC of OA patients in comparison to healthy donors. 34 Increased expression of b-catenin has been detected in the AC of OA patients and of mice in which OA was surgically induced. 35 , 36 , 37 However, overactivation of the Wnt/b-catenin pathway in the tissue both through genetic manipulation or pharmacological modulation did not conclusively determine a cause-effect link between the activation of this branch of the Wnt signalling and tissue degeneration. Genetic activation of the b-catenin gene in the AC promoted OA development in mice. This was associated with increased expression of MMP13 and ADAMTS5, upregulation of hypertrophic markers such as Collagen Type X (ColX) and increased cell death, both in the temporomandibular joint (TMJ) and in the knee joint. 38 , 39 An additional study from Cai et al. showed that mechanical stress can promote TMJ OA via overactivation of the Wnt/b-catenin signalling. 40 However, loss of b-catenin transcriptional activity was also shown to disrupt tissue homeostasis and promote the development of OA-like lesions in the AC. Overexpression of the inhibitor of b-catenin and TCF-4 (ICAT) led to reduced chondrocyte proliferation, increased apoptosis and reduced skeletal grown after birth in mice. 41 These mice also developed spontaneous OA with ageing. 42 Downregulation of b-catenin in the superficial cells of the AC also induced downregulated expression of lubricin (PRG4), an important joint lubricant, and OA-like cartilage degeneration. Indeed, modulation of PRG4 expression at mRNA level has been shown to be linked to the activation of the Wnt/b-catenin signalling in isolated chondrocytes. 43 These data suggest that a tight regulation of the Wnt/b-catenin signalling in space and time within the AC is required to maintain tissue homeostasis; however, the mechanisms regulating this balanced activation remain largely uncharacterised. 6 THE WNT/b-CATENIN-INDEPENDENT SIGNALLING NETWORK IN THE AC The role of the Wnt/b-catenin-independent pathways in the AC and OA is far less characterised. Our current knowledge is mainly derived from developmental studies. The Wnt5a/ROR2 pathway has an important homeostatic function in the musculoskeletal system. Patients affected by Robinow Syndrome, a condition characterised by several dysmorphic features associated with skeletal dysplasia, bear mutations in either Wnt5a or ROR2 genes. 44 , 45 , 46 Studies in vivo showed that Wnt5a drives limb elongation in a concentration-dependent manner during development by activating the Planar Cell Polarity (PCP) pathway in chondrocytes. 47 As for the Wnt/b-catenin pathway, the ROR2 pathway also seems to get re-activated in the AC in OA: the expression of Wnt5a and of the ROR2 targets Yes-associated protein (YAP) and connective growth factor (CTGF) are upregulated in the AC of OA patients. ROR2 blockade supported an anabolic response in the AC in an in vivo model of OA, although through Wnt-independent mechanisms. 48 The Wnt/CaMKII pathway has also been shown to have a pivotal role in bone and cartilage development. Studies in chicken and mice showed that activation of CaMKII promotes cartilage hypertrophic differentiation during limb formation. 49 , 50 Several studies showed that CaMKII is activated in OA, both in human and in animal models of the disease. 51 , 52 We have recently shown that pharmacological blockade of CaMKII can exacerbate cartilage damage in a murine model of OA. 51 This is in keeping with a recent in vitro study showing that inhibition of CaMKII can decrease the anabolic activity of bone morphogenetic proteins 2 and 4 on the synthesis of ECM components in isolated chondrocytes 53 but it is in contrast with previous work from the Saito's group showing that CaMKII can promote OA development in mice via activation of the Hes1 transcription factor. 52 7 b-CATENIN-DEPENDENT AND -INDEPENDENT PATHWAYS: A MATTER OF BALANCE What is then the role of the Wnt signalling in the AC and OA? Can it be considered as a therapeutic target for this disease? An answer to this question comes from the recent discovery of the first molecule classified as a disease-modifying drug for the treatment of OA, SM04690, now known under the commercial name of Lorecivivint. Lorecivivint, which is currently in Phase III clinical trial, is an inhibitor of Cdc2-like kinase (CLK1), an enzyme-regulating splicing events, and blocks the activation of the Wnt signalling at transcriptional level. Nonetheless, the drug also inhibits the Dual-specificity tyrosine phosphorylation-regulated kinase 1A, which modulates the inflammatory response. 54 The discovery of this drug highlights how our understanding of the molecular events, intrinsic and extrinsic to the pathway, is still relatively poor and that the lack of this information is potentially dampening the development of additional therapeutics. Integrative approaches, aimed at investigating the simultaneous modulation of multiple molecules, will therefore be required to understand how tissue homeostasis is maintained and could be re-established once disrupted. Our recent work contributed to unravel the complexity of the regulation of the Wnt signalling in the AC. We showed that a single ligand, Wnt3a, could promote both intracellular accumulation of b-catenin and intracellular activation of CaMKII in the AC, thus simultaneously activating b-catenin-dependent and -independent branches of the Wnt signalling. Critically, while the first increases proportionally to Wnt3a concentration and drives proliferation, the second response is higher when chondrocytes are stimulated with low concentrations of Wnt3a and drives phenotypic changes. 23 These two physiological outcomes are in a steady-state equilibrium under normal conditions and are reciprocally inhibitory, leading to the hypothesis that signalling pathway interactions must be considered to understand how homeostasis is maintained in the tissue. This concept has recently been extrapolated to describe the interaction among the separate branches of the signalling in mathematical terms. 55 Our more recent data further validated this hypothesis by showing that while the Wnt/CaMKII pathway is also upregulated in OA in vivo, its pharmacological inhibition exacerbated cartilage degradation in a murine model of the disease. 51 Wnt3a has been shown to mediate the simultaneous activation of b-catenin-dependent and Ca2+-dependent pathways in other biological systems 24 , 56 , 57 which have been shown to be reciprocally regulatory. 58 Separately, we showed that Wnt16 also shares the ability of mediating multiple and contrasting signals in the cartilage. 43 Despite promoting anabolic effects through the activation of the Wnt/b-catenin pathway, Wnt16 antagonises the activation of this signalling cascade when induced by Wnt3a, therefore avoiding the activation of the pathway over a certain threshold. 43 Taken together, these data strengthen the argument that a fine-tuned balance in the activation of the Wnt signalling is required to maintain cartilage homeostasis and that buffering mechanisms - for example competitive antagonism of ligands for the same receptors or epigenetic modifications - are in place to avoid prolonged perturbation of this equilibrium, as when this occurs, it can lead to tissue degeneration and OA development . FIGURE 1 Schematic representation illustrating the importance of three branches of the Wnt-signalling network in the maintenance of cartilage homeostasis. 8 MAINTAINING THE BALANCE: THE ROLE OF RECEPTORS AND CO-RECEPTORS Ligands and receptors are important gatekeepers of the activation of the different Wnt pathways. Beyond Wnt3a, Wnt5a and Wnt7a have been reported to activate b-catenin-dependent and -independent pathways 59 , 60 , 61 in a context-specific manner. Engagement of Wnt ligands with different isoforms of FZDs is linked to the activation of both b-catenin-dependent and -independent pathways. Interaction of FZDs with different co-receptors is also considered pivotal in determining which branch of the network is going to be activated. Nonetheless, a detailed characterisation of the specificity of binding of different ligands for different isoforms, as well as how the availability in the extracellular environment of other Wnts can influence their affinity and specificity of binding, remains unclear for most tissues and primary cells. The generation of fluorescence and luminescence-based biosensors has allowed some progresses in this direction. 62 Bourhis and colleagues demonstrated that in insect cells, individual Wnts can simultaneously bind to different domains of LRP6. They also showed that Wnt5a, Wnt5b and Wnt3a can all bind to FZD8. While simultaneous interactions for the same receptors are possible, the affinity of the different ligands for the different isoforms and binding sites can vary. Therefore, the binding scenario and the activation of different intracellular signalling can indeed be different depending on the availability of different ligands in the extracellular space. 63 Furthermore, also the availability of FZD on the cell surface can be influenced by external factors: R-spondins, Wnt agonists binding to leucine-rich repeat-containing G-protein-coupled receptors (LGRs), decrease the ubiquitination of FZD receptors, reducing their turnover and therefore potentiating the activation of the Wnt/b-catenin pathway. 64 Finally, the activity and availability of different co-receptors such as LRP-5 and 6 can also add up to the complexity of this signalling network. Studies in vivo showed that deficiency of LRP5 can exacerbate or decrease degeneration of the AC in murine models of osteoarthritis, in a model-dependent way. 65 , 66 This suggests that external factors, such as biomechanics and inflammation, can also alter the signalling response, through vastly uncharacterised mechanisms. Frizzled are a family of seven-span transmembrane G-coupled receptors. 67 G protein-coupled-receptor are not solely limited to activating and initiating their own downstream signalling pathways; they are also able to communicate with each other, influencing and mediating the activation and subsequent downstream signalling of one another. This can occur through synergistic crosstalk interactions between either different signalling transduction pathways, through either the same/different classes of GPCRs or through competitive antagonism, whereby they are able to communicate and prevent their own signal transduction pathway. 68 As a result, this can influence the potency and efficacy of the signalling, which, at times, can resemble behaviour that is typically observed with allosteric interactions. Crosstalk can occur between GPCRs coupled to different G proteins, enhancing the cellular response of one of the pathways. This could be interactions between Gq-coupled receptors or Gq-coupled receptors. In the case of smooth muscle contraction, crosstalk occurs between Gq-coupled receptors. 68 When there is no crosstalk among GPCRs and their downstream signalling, noradrenaline activates the Gq-coupled a-adrenergic receptors, resulting in smooth muscle contractions. However, in the presence of Neuropeptide Y (NPY), a co-transmitter that activates the Gi-coupled Neuropeptide Y receptors, crosstalk initiates with a-adrenergic receptors, enhancing the smooth muscle contractions. An advantage to this augmented response is that lower concentrations of noradrenaline are thus required to elicit smooth muscle contraction when co-administered with NPY. 68 Synergistic interactions can also occur between different classes of GPCRs. The Smoothened Receptor (SMO) is a Class F GPCR that, upon activation, mediates Sonic Hedgehog (SHH) signalling. Pusapati et al showed, using CRISPR experiments, that the sensitivity of NIH/3 T3 fibroblasts and spinal neural progenitors to SHH is increased when there is a loss of GPR161, an orphan Class A GPCR (Pusapati et al., 2018). It is important to note that the signalling still depends on the SMO receptor, however, through increasing sensitivity to the morphogen SHH. This shows the unique manner in which GPR161 is able to interact with the SMO receptor, influencing its subsequent signalling. 69 Finally, Civciristov and colleagues demonstrated that GPCRs can also respond differently to high and low concentrations of the same ligands. The response to low concentrations of the ligands was spatially and temporally distinct and resulted in different intracellular proteomic profiles. This was due to the preassembly of GPCR high-order complexes to the plasma membrane. 70 The characterisation of how the activation of the Wnt signalling is mediated at receptor level in the AC and in musculoskeletal tissues remains vastly unknown. While this presents multiple challenges, it has, however, the potential to allow the development of new therapeutic strategies to re-establish tissue homeostasis and halt OA progression. 9 CONCLUSIONS Several intracellular mechanisms have been shown to be key in maintaining the right threshold of activation of the different branches of the Wnt signalling network. 71 , 72 Some of these have been reviewed recently by us and others in other reviews 73 , 74 , 75 , 76 and will also be discussed in future publications. The overall message of this review is the consideration that a change of mindset in the way we consider signalling pathways as a pharmacological target for OA and other diseases is needed. As already highlighted by Amerongen and Nusse in 2009, 77 we should stop considering the Wnt signalling as a group of individual and linear signalling cascades but rather start considering them as a network, whose branches interact with each other and reciprocally influence their activation or repression state. It is also clear that we should not define ligand/receptor interaction as absolute concepts, but rather we should validate them within specific biological contexts taking in account and, when possible, mimicking, the extracellular environment characterising different tissues in physiology and disease. System biology approaches and mathematical models will become essential tools to be used to clarify these complicated interactions. Clarifying how the balance of this intricate network is maintained will be pivotal for the discovery of new therapeutic targets, where the treatment will probably not focus anymore on individual molecules but on the re-establishment of the overall signalling homeostasis. CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. ACKNOWLEDGEMENT This work was funded by the Medical Research Council (grant reference MR/S008608/1). |
Post Reprod Health Post Reprod Health spmin MIN Post Reproductive Health 2053-3691 2053-3705 SAGE Publications Sage UK: London, England 36357006 10.1177_20533691221139902 10.1177/20533691221139902 BMS Consensus statement Prevention and treatment of osteoporosis in women Stevenson John in collaboration with the medical advisory council of the British Menopause Society National Heart and Lung Institute, 90897 Imperial College London, Royal Brompton Hospital, London, UK John Stevenson, National Heart and Lung Institute, Imperial College London, Royal Brompton Hospital, Sydney Street, London SW3 6LR, UK. Email: [email protected] 10 11 2022 3 2023 29 1 1114 (c) The Author(s) 2022 2022 British Menopause Society This article is distributed under the terms of the Creative Commons Attribution 4.0 License ) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ). typesetterts10 pmcSummary This guidance regarding estrogen and non-estrogen-based treatments for osteoporosis responds to the controversies about the benefits and risks of individual agents. Treatment choice should be based on up to date evidence-based information and targeted to individual women's needs. Introduction Osteoporosis is very much a disease of older women affecting 1 in 3 women compared to 1 in 5 men. Osteoporosis is as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Fractures of the wrist, hip and vertebrae, which are the main clinical manifestations of osteoporosis, have enormous impact on quality of life, result in significant economic burden and are associated with considerable excess mortality. The annual number of hip fractures in the UK due to osteoporosis has risen by 44% from 70,000 in 2006 to >100,000 in 2020.1 Pharmacological and non-pharmacological therapies will be examined (Table 1).Table 1. Interventions for the prevention and treatment of osteoporosis. * Hormone replacement therapy Estrogen alone Estrogen plus progestogen Tibolone * Bisphosphonates Alendronate Risedronate Ibandronate Zoledronate * Denosumab * Raloxifene * Parathyroid hormone peptides * Romozosumab * Calcium and vitamin D * Exercise Pharmacological interventions All pharmacological interventions except for parathyroid hormone act mainly by inhibiting bone resorption. Very few data exist about long-term efficacy for reducing fractures (that is, more than 10 years of treatment) and about the safety of combinations of therapy. In many of the controlled studies, the placebo group received calcium and vitamin D supplements. Hormone replacement therapy There is evidence from randomized controlled trials including the Women's Health Initiative (WHI) that hormone replacement therapy (HRT) reduces the risk of both spine and hip as well as other osteoporotic fractures even in women at low risk2 as well as in those with established osteoporosis.3 The 'standard' bone conserving doses of estrogen were considered to be oral estradiol 2 mg, conjugated equine estrogens 0.625 mg and transdermal 50 mcg patch. However, it is now evident that lower doses also conserve bone mass.4 Epidemiological studies have suggested that for HRT to be an effective method of preventing fracture, continuous use is required. However, it has been shown that just a few years treatment with HRT around the time of menopause may have a long term effect on fracture reduction.5 European regulatory authorities (December 2003) advised that HRT should not be used as a first line treatment for osteoporosis prevention as the risks outweigh the benefits.6 This view was robustly challenged,7 but despite a subsequent wealth of further evidence, the regulatory authorities have not revised their position. Yet HRT is an effective, safe and inexpensive treatment. Whilst alternatives are available for the treatment of osteoporosis in elderly women, estrogen still remains the best and safest option for prevention, particularly in younger (aged less than 60 years) and/or symptomatic women.8 The initiation of HRT for fracture prevention in women over 60 needs the starting dose to be tailored to the age of the woman.9 Estrogen-based therapy remains the treatment of choice in women with premature ovarian insufficiency.10 No clinical trial evidence attests the efficacy or safety of the use of non-estrogen-based treatments, such as bisphosphonates, denosumab or raloxifene, in these women. Although some women will be happy to take HRT for life to manage osteoporosis, others may view treatment as a continuum of options for bone protection and may wish to change to other agents such as a bisphosphonate because of the possible small increase in risk of diagnosis of breast cancer associated with the long-term use of combined HRT. Bisphosphonates Bisphosphonates are chemical analogues of naturally occurring pyrophosphates thus allowing them to be integrated into bone where they have a direct effect on osteoclasts, thereby reducing bone resorption. This makes metabolism an extremely slow process, indeed the skeletal half-life of alendronate has been estimated as high as over 12 years. There are concerns about effects on the fetal skeleton and bisphosphonates are not advised in women with fertility aspirations. However, they are widely used for postmenopausal women and are effective in fracture prevention.11 Alendronate, risedronate, ibandronate and zoledronate are all used in the treatment of postmenopausal osteoporosis, and are also used in corticosteroid-induced osteoporosis. The question of how long to prescribe a bisphosphonate has not been fully clarified yet. There are concerns about fatigue damage due to oversuppression of bone remodelling with long-term use in some individuals leading to femoral fragility fractures and also development of osteonecrosis in the jaw. Although such adverse effects are very rare (around 1 in 5000 women per year), 5 years of treatment with a 1-to 2-year 'holiday' have been proposed to try to reduce these risks.12 This may not be applicable in glucocorticoid-induced osteoporosis because of the very long skeletal retention time of bisphosphonates, any very long term adverse effects still remain unknown. They should therefore be avoided where possible in younger (e.g. aged <65 years) patients. The vast majority of reports of osteonecrosis of the jaw refer mainly to intravenous bisphosphonates used in the oncological setting. Very few cases have been reported in women using oral bisphosphonates for osteoporosis. These cases usually, but not exclusively, follow dental extractions, and dental review could be considered in women with significant dental disease before initiation of bisphosphonates therapy. Fragility fractures of the femoral shaft have now been increasingly reported in patients on long term bisphosphates. These occur spontaneously but may be preceded by thigh pain and the presence of cortical 'beaking' on plain radiographs of the femur.13 Alendronate Alendronate reduces vertebral and non-vertebral fractures by 50% in randomized controlled trials in osteoporotic women.14 The dose for osteoporosis treatment is 70 mg once weekly. Risedronate Risedronate reduces vertebral and non-vertebral fractures in randomized controlled trials.15 The dose for treatment of established disease is 35 mg once weekly. Ibandronate Ibandronate has been shown to reduce the incidence of vertebral, but not non-vertebral fractures by 50% in randomized controlled trials undertaken in postmenopausal women.16 The dose is 150 mg orally once a month, or 3 mg by intravenous injection every 3 months. Zoledronate Zoledronate has been shown to reduce both spine and hip fracture osteoporotic incidence in the elderly.17 It is given in a dose of 5 mg as an annual intravenous infusion. It is the most potent of the currently used bisphosphonates and hence has the highest rate of adverse effects mainly after the first infusion, which can also include atrial fibrillation and inflammatory eye disease. Creatinine clearance should be confirmed to be >35 mL/min prior. Denosumab Denosumab is a monoclonal antibody to receptor activator of nuclear factor k-B ligand (RANK-L), a major signal promoting osteoclast activity. It is as effective as the bisphosphonates in terms of spine and hip fracture reduction in osteoporotic women,18 but also has similar adverse effects in terms of osteonecrosis of the jaw and femoral fragility fractures. However, it is not retained in the skeleton and may be a safer option for younger women. Because RANK-L also has a role in the immune system, denosumab is associated with an increased risk of infections and should be avoided in patients with increased susceptibility. There is evidence of an accelerated loss of bone on discontinuation of denosumab and hence a concern about an increased risk of fractures.19 It may be prudent to introduce another treatment when discontinuing denosumab. Selective estradiol receptor modulators These compounds possess estrogenic actions in certain tissues and anti-estrogenic actions in others. Raloxifene is licensed for the prevention of osteoporosis-related vertebral fracture. It reduces vertebral but not non-vertebral fracture by around 35%.20 The dose is 60 mg/day. It also reduces the risk of breast cancer to the same extent as tamoxifen.21 Side effects include hot flushes and calf cramps. It was thought that it could be cardioprotective from its effects on lipids, and the Raloxifene Use for the Heart (RUTH) study found that it did reduce the risk of coronary heart disease in those initiating treatment below age 60 years, but it increased the risk of fatal stroke and venous thromboembolism.20 Parathyroid hormone peptides Recombinant 1-34 parathyroid hormone (teriparatide), given as a subcutaneous daily injection of 20 mg, reduces vertebral and non-vertebral fractures in postmenopausal women with osteoporosis.22 It has been shown to reduce the risk of vertebral and non-vertebral, but not hip, fractures. Because it costs considerably more than other options, it is reserved for patients with severe osteoporosis who are unable to tolerate, or seem to be unresponsive to, other treatments. Romozosumab Romozosumab is a monoclonal antibody which binds sclerostin, a natural inhibitor of the Wnt/LRP pathway which is a major signal to osteoblasts to promote bone formation. Thus, blocking sclerostin action leads to an increase in bone formation.23 Romozosumab is given by subcutaneous injection every 2 weeks for a 12-month course. Non-pharmacological interventions Advice should be given to menopausal women regarding lifestyle modification and bone health. This should include information on a balanced diet, adequate calcium and vitamin D intake, exercise and smoking cessation as well as avoidance of excessive alcohol intake. Calcium and vitamin D Provision of adequate dietary or supplemental calcium and vitamin D can be a part of osteoporosis management. The effects of calcium and vitamin D supplements alone or in combination on fracture, however, are contradictory and may depend on the study population.24,25 Hip fracture reduction has been shown in elderly women in residential care, but such women may be more frail, have lower dietary intakes of calcium and vitamin D and are at higher risk of fracture than those living in the community in whom fracture reduction has not been shown. Furthermore, the Women's Health Initiative Study showed an increase in kidney stones in low-risk women taking calcium and vitamin D supplements,26 and there are controversial claims about increased cardiovascular risk being associated with such supplements. The British Menopause Society/Women's Health Concern recommends a daily intake of 1000 mg calcium and 1000iu vitamin D.27 Exercise Although certain exercise regimens may increase bone density, a role for exercise in preventing osteoporotic fractures has not been convincingly shown.28 Exercise regimens can be helpful in the management of established osteoporosis. The benefits are mainly related to increased wellbeing, muscle strength, postural stability and a reduction of chronic pain rather than an increase of skeletal mass. Exercise has to be structured carefully because of concerns about falls and fractures. Summary practice points 1. HRT reduces the risk of both spine and hip as well as other osteoporotic fractures. 2. Estrogen remains the treatment of choice for osteoporosis prevention in experiencing menopause. It is especially important in those with premature ovarian insufficiency. It should be considered for osteoporosis prevention in women over the age of 60 who continue to benefit from HRT in terms of menopause symptom relief. 3. Bisphosphonates are effective for treatment of established osteoporosis, reducing both spine and hip fractures. 4. Bisphosphonates have a very long skeletal retention time and hence should be used with caution in younger postmenopausal women (e.g. those aged below 65 years). 5. Denosumab is an effective treatment for reducing spine and hip fractures in osteoporotic women. 6. Denosumab should be avoided in women with increased susceptibility to infections. 7. There may be an increased risk of fractures after denosumab discontinuation. 8. Provision of adequate dietary or supplemental calcium and vitamin D is a part of osteoporosis management. 9. The effects of calcium and vitamin D supplements alone on fracture reduction, however, are contradictory and may depend on the study population. The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article. References 1 National Institute for Health and Care Excellence. Osteoporosis; assessing the risk of clinical fracture: Clinical Guideline (CG146), 2012. Last updated February 2017. 2 Manson JE Chlebowski RT Stefanick ML , et al. Menopausal hormone therapy and health outcomes during the interventions and postintervention and extended poststopping phases of the women's health initiative randomized trials. JAMA 2013; 310 : 1353-1368.24084921 3 Lufkin EG Wahner HW O'Fallon WM , et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Int Med 1992; 117 : 1-9.1534476 4 Lees B Stevenson JC . The prevention of osteoporosis using sequential low-dose hormone replacement therapy with estradiol-17 and dydrogesterone. Osteoporos Int 2001; 12 : 251-258.11420773 5 Bagger YZ Tanko LB Alexandersen P , et al. Two to three years of hormone replacement treatment in healthy women have long-term preventive effects on bone mass and osteoporotic fractures: the PERF study. Bone 2004; 34 : 728-735.15050905 6 Committee on Safety of Medicines. Further advice on safety of HRT: risk:benefit unfavourable for first-line use in prevention of osteoporosis. CEM/CMO/2003/19, www.mhra.gov.uk (accessed 07 November 2022). 7 Stevenson JC International Consensus Group on HRT and Regulatory Issues. HRT, osteoporosis and regulatory authorities Quis custodiet ipsos custodes? Hum Reprod 2006; 21 : 1668-1671 16556675 8 Rozenburg S Al-Dhagri N Aubertine-Leheudre M , et al. Is there a role for a menopausal hormone therapy in the management of postmenopausal osteoporosis? Osteoporos Int 2020; 31 : 2271-2286.32642851 9 Lobo RA Pickar JH Stevenson JC , et al. Back to the future: hormone replacement therapy as part of a prevention strategy for women at the onset of menopause. Atherosclerosis 2016; 254 : 282-290.27745704 10 Hamoda H Panay N Pedder H , et al. The British Menopause Society & Women's Health Concern 2020 recommendations on hormone replacement therapy in menopausal women. Post Reprod Health 2020; 26 (4 ): 181-209. DOI: 10.1177/2053369120957514 33045914 11 Jansen JP Bergman GJ Huels J , et al. The efficacy of bisphosphonates in the prevention of vertebral, hip, and nonvertebral-nonhip fractures in osteoporosis: a network meta-analysis. Semin Arthritis Rheum 2011; 40 : 275-284.20828791 12 Anagnostis PG Stevenson JC . Bisphosphonate drug holidays - when, why and for how long? Climacteric 2015; 18 (suppl 2 ): 32-38.26507608 13 Shane E Burr D Ebeling PR , et al. Atypical subtrochanteric and diaphyseal femoral fractures: a second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2014; 29 : 1-23.23712442 14 Black DM Schwartz AV Ensrud KE , et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006; 296 : 2927-2938.17190893 15 Silverman SL Watts NB Delmas PD , et al. Effectiveness of bisphosphonates on nonvertebral and hip fractures in the first year of therapy: the risedronate and alendronate (REAL) cohort study. Osteoporos Int 2007; 18 : 25-34.17106785 16 Di Munno O Seddie AD . Efficacy of ibandronate: a long term confirmation. Clin Cases Miner Bone Metab 2010; 7 : 23-26.22461287 17 Black DM Reid IR Cauley JA , et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 2015; 30 : 934-944.25545380 18 Cummings SR San Martin J McClung MR , et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009; 361 : 756-765.19671655 19 Tsourdi E Langdahl B Cohen-Solal M , et al. Discontinuation of denosumab therapy for osteoporosis: a systematic review and position statement by ECTS. Bone 2017; 105 : 11-17.28789921 20 Barrett-Connor E Mosca L Collins P , et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med 2006; 355 : 125-137.16837676 21 Vogel VG Costantino JP Wickerham DL , et al. Effects of tamoxifen vs raloxifene on the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 2006; 295 : 2727-2741.16754727 22 Neer RM Arnaud CD Zanchetta JR , et al. Effect of parathyroid hormone on vertebral bone mass and fracture incidence among postmenopausal women with osteoporosis. N Engl J Med 2001; 344 : 1434-1441.11346808 23 Cosman F Crittenden DE Adachi JD , et al. Romozosumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016; 375 : 1532-1543.27641143 24 Zhao J-G Zeng X-T Wang J , et al. Association between calcium or vitamin D supplementation and fracture incidence in community-dwelling older adults. A systematic review and meta-analysis. JAMA 2017; 318 : 2466-2482.29279934 25 Cano A Chedraui P Goulis DG , et al. Calcium in the prevention of postmenopausal osteoporosis: EMAS clinical guide. Maturitas 2018; 107 : 7-12.29169584 26 Jackson RD LaCroix AZ Gass M , et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354 : 669-683.16481635 27 Howe TE Shea B Dawson LJ , et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev 2011; 7 : CD000333. 28 Silva RB Eslick GD Duque D . Exercise for falls and fracture prevention in long term care facilities: a systematic review and meta-analysis. JAMDA 2013; 14 : 685-689.23860265 |
Psychol Med Psychol Med PSM Psychological Medicine 0033-2917 1469-8978 Cambridge University Press Cambridge, UK 10.1017/S0033291721005286 S0033291721005286 Correspondence Unsparing self-critique strengthens the field, but Bailey et al. overstate the 'problems with delay discounting' Stein Jeffrey S. 1 MacKillop James 2 McClure Samuel M. 3 Bickel Warren K. 1 1 Fralin Biomedical Research Institute at VTC, Virginia Tech, Roanoke, VA, USA 2 Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, ON, Canada 3 Department of Psychology, Arizona State University, Tempe, AZ, USA Author for correspondence: Jeffrey S. Stein, E-mail: [email protected] 3 2023 28 2 2022 53 4 16581659 24 11 2021 07 12 2021 (c) The Author(s) 2022 2022 The Author(s) This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence ), which permits unrestricted re-use, distribution and reproduction, provided the original article is properly cited. pmcWe agree with a fundamental premise of Bailey, Romeu, and Finn's (2021) recent paper; that is, understanding the limitations of the delay discounting (DD) paradigm will increase the value of research on intertemporal choice (ITC) in clinical disorders. To this agreement, however, we add two provisos. First, the significance of those limitations should be determined by systematic review and meta-analysis, not selective review or personal opinion. Bailey et al.'s narrative review reflects a bias for their position that DD measures have not been adequately validated and lack generalizability, without regard for evidence that may mitigate these concerns. Second, the strengths of the paradigm should be acknowledged in order to avoid, in the pursuit of progress, weakening the measures we seek to refine. In what follows, we highlight our agreements and disagreements with Bailey et al.'s three major concerns: convergent validity, divergent validity, and generalizability of DD measures. Convergent validity Bailey et al. acknowledge the well-known observation that DD is largely uncorrelated with measures of impulsivity. While accurate, this view fails to characterize the state of the field. Impulsivity itself is a multifactorial construct showing little correlation among its putative forms (e.g. acting without forethought, response disinhibition, and DD). Decades of research have failed to identify common neurobiological mechanisms among these various 'impulsivities', and the effects of behavioral and pharmacological interventions vary across forms. For these and other reasons, some have called for rejecting the superordinate construct of impulsivity in favor of continued, rigorous inquiry of its various component measures (Strickland & Johnson, 2021). We agree with this perspective. Bailey et al. outline additional concerns over convergent validity, arguing that DD has yet to show strong and replicable associations with other cognitive and personality measures. These authors also suggest that, in order to be considered an 'important' individual difference, DD should show incremental validity over these other measures when examining associations with substance use disorder (SUD) and other clinical disorders. We agree that DD has shown relatively modest associations with executive function and personality measures, but these findings are replicable at the behavioral and neurobiological levels. Such consistent, but limited, covariance with a variety of measures suggests not necessarily, as Bailey et al. argue, that DD is an unimportant individual difference, but rather that its determinants are multivariate. Moreover, Bailey et al. disregard emerging evidence of incremental validity. Specifically, using machine-learning approaches to predict SUD, measures of DD outperform the Stroop task, Iowa Gambling task, Continuous Performance task, and other measures of attention, planning, and inhibitory control (e.g. Bickel, Moody, Eddy, & Franck, 2017). Nonetheless, we agree that the literature would benefit from additional studies examining incremental validity, particularly in predicting health behaviors beyond substance use. Divergent validity Bailey et al. note concerns over divergent validity of the DD paradigm, citing evidence that elevated DD is robustly associated with not only SUD but various other psychiatric disorders, including depression, bipolar disorder, and schizophrenia (for a meta-analysis, see Amlung et al., 2019). Thus, as Bailey et al. argue, measures of DD may not differentially predict diagnostic status among patients with varied disorders. This remains an empirical question and more research should examine the specificity of such associations. However, some research provides emerging evidence of divergent validity. For example, SUD and comorbid mood and personality disorders are interactively associated with higher DD compared to SUD alone (e.g. Moody, Franck, & Bickel, 2016). Conversely, anorexia nervosa is associated with lower DD compared to healthy controls (for a meta-analysis, see Amlung et al., 2019). Thus, DD rates at opposing ends of a continuum are associated with divergent pathology. More generally, we note that the well-documented comorbidity between SUD and other psychiatric disorders suggests transdiagnostic risk factors and etiologies. That DD is associated with a variety of clinical endpoints is not necessarily a cause for concern, but may instead be a strength of the paradigm and provides the opportunity to investigate a single decision-making process relevant to a broad range of disorders. However, further research is needed to understand the circumstances under which genetic, neurobiological, or environmental predispositions manifest in divergent phenotypes. Indeed, this pursuit is a focus of the NIH's Research Domain Criteria (RDoC), an area in which DD holds some promise (e.g. Levitt et al., 2022). Generalizability Bailey et al. argue that little evidence suggests that DD is a generalizable measure of decision-making. In the process, these authors disregard evidence of reliable correlations in measures of discounting across different commodities (e.g. money, food, health, and drugs of abuse; for a systematic review, see Odum et al., 2020). Thus, contrary to the limited findings reviewed by Bailey et al., knowledge of how an individual discounts one delayed commodity provides information about how they are likely to discount other delayed commodities. Given this correspondence, the majority of studies on DD preferentially examine discounting of monetary outcomes because, unlike non-monetary outcomes, money is universally valued, easily quantifiable, highly fungible, and its utility curve is approximately linear across a broad range of values. We recognize, however, that discounting of non-monetary, pathology-relevant commodities in some circumstances may provide incremental validity over the study of monetary outcomes (e.g. discounting of food in the study of obesity; for a meta-analysis, see Amlung, Petker, Jackson, Balodis, & MacKillop, 2016). As such, future research should continue to examine the relationship between non-monetary discounting, SUD, and other disorders. Moreover, choice arrangements that may more closely model real-world ITC should also be explored (Green & Myerson, 2019). For example, 'cross-commodity' discounting tasks arrange choices between qualitatively different immediate and delayed outcomes, which may characterize intertemporal tradeoffs evident in health-related decision-making (e.g. immediate food v. delayed weight loss in the study of obesity). Conclusions In the era of the 'replication crisis', the links between DD and clinical disorders are notably robust. At the heart of Bailey et al.'s concerns is the gap between theoretical concepts (in this case, ITC) and their operational definitions (in this case, DD). Critically, ITC is multifaceted, including multiple dimensions of time orientation (past, present, and future), gains and losses, and cross-commodity choice. Bailey et al. take issue with the fact the literature operationalizes ITC in only one way (DD), contending this provides an incomplete perspective. We do not disagree and likewise recommend a more fulsome study of the published varieties of ITC. Indeed, we have conducted empirical research mapping these less studied varieties. Fundamentally, however, promoting this more expansive perspective should not justify overstating the limitations of the robust and trenchant literature on DD in SUD and other disorders. Financial support This research received no specific grant from any funding agency, commercial, or not-for-profit sectors. Conflict of interest Although the following activities/relationships do not create conflicts of interest pertaining to this manuscript, in the interest of full disclosure, the authors would like to report the following: JSS works on a project supported by Indivior, Inc. and has received subcontract funding through an NIH grant awarded to BEAM Diagnostics, Inc. JM is a principal in BEAM Diagnostics, Inc. and is a consultant for Clairvoyant Therapeutics, Inc. WKB is a principal in HealthSim, LLC; BEAM Diagnostics, Inc.; and Red 5 Group, LLC. WKB also serves on the scientific advisory board for Sober Grid, Inc. and Ria Health; and serves as a consultant for Boehringer Ingelheim International; and works on a project supported by Indivior, Inc. SMM has no disclosures to report. References Amlung, M., Marsden, E., Holshausen, K., Morris, V., Patel, H., Vedelago, L., ... McCabe, R. E. (2019). Delay discounting as a transdiagnostic process in psychiatric disorders: A meta-analysis. JAMA Psychiatry, 76 (11 ), 1176-1186. doi: 10.1001/jamapsychiatry.2019.2102.31461131 Amlung, M., Petker, T., Jackson, J., Balodis, I., & MacKillop, J. (2016). Steep discounting of delayed monetary and food rewards in obesity: A meta-analysis. Psychological Medicine, 46 (11 ), 2423-2434. doi: 10.1017/S0033291716000866.27299672 Bailey, A. J., Romeu, R. J., & Finn, P. R. (2021). The problems with delay discounting: A critical review of current practices and clinical applications. Psychological Medicine, 51 , 1799-1806. doi: 10.1017/S0033291721002282.34184631 Bickel, W. K., Moody, L. N., Eddy, C. R., & Franck, C. T. (2017). Neurocognitive dysfunction in addiction: Testing hypotheses of diffuse versus selective phenotypic dysfunction with a classification-based approach. Experimental and Clinical Psychopharmacology, 25 (4 ), 322-332. doi: 10.1037/pha0000115.28782983 Green, L., & Myerson, J. (2019). On the complexity of discounting, choice situations, and people. Perspectives on Behavior Science, 42 (3 ), 433-443. doi: 10.1007/s40614-019-00209-y.31976443 Levitt, E. E., Oshri, A., Amlung, M., Ray, L. A., Sanchez-Roige, S., Palmer, A. A., ... MacKillop, J. (2022). Evaluation of delay discounting as a transdiagnostic Research Domain Criteria indicator in 1388 general community adults. Psychological Medicine. Advance Online Publication. doi:10.1017/S0033291721005110. Moody, L., Franck, C., & Bickel, W. K. (2016). Comorbid depression, antisocial personality, and substance dependence: Relationship with delay discounting. Drug and Alcohol Dependence, 160 , 190-196. doi: 10.1016/j.drugalcdep.2016.01.009.26846198 Odum, A. L., Becker, R. J., Haynes, J. M., Galizio, A., Frye, C. C. J., Downey, H., ... Perez, D. M. (2020). Delay discounting of different outcomes: Review and theory. Journal of the Experimental Analysis of Behavior, 113 (3 ), 657-679. doi: 10.1002/jeab.589.32147840 Strickland, J. C., & Johnson, M. W. (2021). Rejecting impulsivity as a psychological construct: A theoretical, empirical, and sociocultural argument. Psychological Review, 128 (2 ), 336-361. doi: 10.1037/rev0000263.32969672 |
J Law Med Ethics J Law Med Ethics JME The Journal of Law, Medicine & Ethics 1073-1105 1748-720X Cambridge University Press New York, USA 36883407 10.1017/jme.2023.26 S1073110523000268 Columns: Public Health and the Law Federalism's Fallacy at the Forefront of Public Health Law Wiley Lindsay F. Yearby Ruqaiijah Clark Brietta R. Mohapatra Seema Hodge James G. Jr. 1 * Ghaith Summer 1 * Krumholz Lauren 1 * 1: ARIZONA STATE UNIVERSITY, PHOENIX, AZ, USA About This Column James G. Hodge, Jr., J.D., LL.M., serves as the section editor for Public Health and the Law. He is the Peter Kiewit Foundation Professor of Law and Director, Center for Public Health Law and Policy, Sandra Day O'Connor College of Law, Arizona State University (ASU). Winter 2022 50 4 Health Justice: Engaging Critical Perspectives in Health Law and Policy 848851 (c) The Author(s) 2023 2023 The Author(s) This is an Open Access article, distributed under the terms of the Creative Commons Commons Attribution licence ), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Amid undulating conceptions of the role and prowess of federalism emerges its central constitutional role: protecting American liberties against unwarranted governmental intrusions. To the extent that federalism is used as a guise for withdrawing fundamental rights to abortion by the U.S. Supreme Court in Dobbs v. Jackson Women's Health Organization, individual rights are sacrificed in contravention of constitutional structural norms. Keywords Supreme Court Constitution Federalism Rights Liberty Public Health pmcMany Americans understand federalism as the constitutional principle dividing powers between federal and state governments. The national government's enumerated powers are distinct from sovereign powers reserved to the states via the Tenth Amendment.1 That's federalism in a nutshell.2 Though easily conceptualized, constitutional jurisprudence over federalism is highly complex.3 Like a pendulum, federalism oscillates over time between federal and state powers, especially in the field of public health law where governments regularly clash over their authorities, as evinced vividly during the COVID-19 pandemic.4 Determining "who's in charge" in public health emergencies and routine interventions,5 however, is not the sole determinant of federalism. Its constitutional role involves assessments of individual rights with mixed and sometimes notorious results.6 In its 1905 decision in Jacobson v. Massachusetts,7 the U.S. Supreme Court examined its own limits under federalism to balance state-based vaccine mandates against alleged individual liberty infringements amid a smallpox outbreak. Fast forward 117 years later, the Court invoked federalism for a very different end with immense public health repercussions. In Dobbs v. Jackson Women's Health Organization (2022),8 it cast aside nearly 50 years of precedence to reverse a fundamental constitutional right to abortion in deference to states' sovereign authorities.9 Essentially, the Court stripped individuals of constitutional protections partly out of respect for federalism. Between these two seminal public health decisions lies a constitutional conundrum: how exactly should federalism influence the outcome of rights-based assessments? In each case, federalism is assessed to ultimately limit the scope or recognition of constitutional rights in different contexts. As examined below, this structurally-grounded view underscores a fallacy of federalism. The fabrication is not that constitutional rights may be limited by states' compelling interests. No right is absolute.10 Rather, the misconception lies in how federalism is wielded to constrain individual rights. As espoused by Constitutional framers, scholars, and Supreme Court justices alike, federalism is about protecting Americans' freedoms, not outright denying them. Federalism as a Stopgap to Judicial Interventions: Jacobson In Jacobson, arguably the most famous and well-cited public health law case in American history,11 the Supreme Court considered purported liberty infringements under substantive due process raised by Reverend Henning Jacobson. Jacobson resisted a local mandate to be vaccinated for smallpox in Cambridge. His claims were ultimately rejected by the Court which recognized harm avoidance principles squarely built into constitutional rights to liberty.12 "[T]he liberty secured by the Constitution," espoused Justice Harlan for the majority, "does not import an absolute right in each person to be, at all times and in all circumstances, wholly freed from restraint[s],"13 including vaccine mandates.In Dobbs, however, the Court literally creates a public health crisis by derailing a firmly-held constitutional interest in furtherance of states' sovereign powers. It simultaneously generates a legal crisis by provoking a wave of state anti-abortion laws, extensive litigation, and political wrangling. In the Court's view, individual liberty interests stop where direct harms to others may follow. Even as it affirmed its undeniable constitutional authority to adjudicate the meaning of "liberty," the Court's rights-based assessment was shaped by its recognition of prevailing principles of federalism prioritizing states' roles in protecting the public's health. Public health and safety "are matters that do not ordinarily concern the national government,"14 noted Justice Harlan. The Court "should not invade the domain of local authority except when it is plainly necessary to do so."15 Justice Harlan acknowledged the Court's limitations to counter legitimate exercises of public health powers by Massachusetts officials acting under their sovereign powers. In Jacobson, the crafted balance between individual liberty interests and state public health powers favors government not just because of principles of harm avoidance, but also out of respect for federalism. Federalism as a Factor for Limiting Constitutional Rights: Dobbs The Supreme Court's decision in Jacobson can be validated by the fact that liberty interests may be at their lowest ebb constitutionally in the face of deadly outbreaks, as seen as well during the COVID-19 pandemic. In Dobbs, however, the Court literally creates a public health crisis by derailing a firmly-held constitutional interest in furtherance of states' sovereign powers. It simultaneously generates a legal crisis by provoking a wave of state anti-abortion laws, extensive litigation, and political wrangling. In Dobbs, the Court resonates federalism concerns in its reliance on democratic processes and judicial neutrality to withdraw the long-standing constitutional right to abortion. Writing for the majority, Justice Alito pronounces from the onset how 26 states "have expressly asked this Court to ... allow [them] to regulate or prohibit pre-viability abortions,"16 concluding "[i]t is time to ... return the issue of abortion to the people's elected representatives."17 According to the Dobbs majority, when the federal constitutional right to abortion was originally bestowed in 1973 in Roe v. Wade, 18 30 states prohibited abortion even as other states had liberalized their related laws. "Roe abruptly ended that political process,"19 observes Justice Alito. Concurring Justice Kavanaugh echoes the same need to "return" decision-making on abortion to states' democratic processes, finding insufficient constitutional authority for the Court to create new rights.20 The majority argues further how abortion is neither deeply-rooted in the nation's history nor was it outside the realm of states' criminalization when the Fourteenth Amendment was ratified in 1868.21 As a result, the Dobbs Court characterizes precedence in Roe and Planned Parenthood v. Casey 22 as "substantial restrictions" on the inherent authority of states to regulate abortion.23 In essence, federalism won out in Dobbs over continued recognition of constitutionally-recognized rights. On the day Dobbs was released, June 24, 2022, Senator Rick Scott (R-FL) celebrated the decision for "defend[ing] ... the foundational principle of federalism."24 Senator Kevin Cramer (R-ND) declared Dobbs a win for "states' rights."25 One commentator analyzed how Dobbs weaponized states' rights,26 rekindling "harsh images of federalism"27 from prior decades buttressing state resistance to desegregation and other civil rights that are now firmly recognized at every level of government.28 Federalism as a Preserver of Rights and Freedoms Supreme Court deference to state sovereignty in reversing a firmly-held constitutional right to abortion in Dobbs misconstrues underlying foundations of federalism. Ultimately, federalism is not about denying inherent liberty interests under substantive due process; it is about promoting them. The Constitutional framers clearly intended federalism to protect the "liberty of individualized citizens,"29 by offering "double security" for "the rights of the people."30 In the Federalist papers, Alexander Hamilton explained how "federalism is a safeguard ... against the overextension of government's power."31 As one modern commentator espouses, federalism provides a "two-tiered protection of individual rights" through the Fourteenth Amendment affording a "guaranteed minimum of protection," with states able to proffer greater assurances.32 Multiple constitutional law commentators conclude how adjudicating federalism invariably entails promotion of individual rights. Professor Jonathan Adler equates federalism directly with the protection of individual rights.33 Dean Erwin Chemerinsky argues how it enhances liberties in furthering societal objectives.34 In the context of civil rights, Professor James Blumstein illustrates how federalism "decentralizes decision-making to promote autonomy, democracy, and freedom."35 Another commentator surmises, "federalism is not merely a means to diffuse power; it is a principle to ... [protect] the rights and privileges of all citizens."36 In 2002, Michigan Supreme Court Chief Justice Maura Corrigan described the "integral role" of the judiciary in protecting federalism to safeguard individual rights.37 Her view is backed by existing U.S. Supreme Court jurisprudence prior to Dobbs.38 In Boyd v. United States 39 (1886), the Court rejected criminal charges against an individual compelled to produce private documents contrary to Fourth Amendment privacy protections. Justice Bradley proclaimed the Court's duty is to be "watchful for the constitutional rights of the citizen ... against any stealthy encroachments."40 A century later in Garcia v. San Antonio Metropolitan Transit Authority 41 (1985), dissenting Justice Powell observed how "the constitutionally mandated balance of power [is] ... designed to protect our fundamental liberties."42 Numerous Justices have since explicitly observed how federalism functions to preserve individual rights in decisions (among others) related to (1) retirement requirements for state judges;43 (2) gun possession;44 (3) prescribing rights for physician-assisted suicide;45 (4) alleged possession or use of a chemical weapon;46 and (5) licensing of sports gambling.47 Collectively these decisions support how federalism "was adopted by the Framers to ensure the protection of 'our fundamental liberties,'"48 which are distinct from and "not simply derivative of the rights of the States."49 As Justice Kennedy concludes in Bond v. United States in 2011, "[f]ederalism secures the freedom of the individual."50 That federalism is about protecting, promoting, and even advancing liberty interests intimates how the Dobbs Court erred in concluding that states' interests warrant a return of regulatory authority over abortion. To the contrary, Americans' fundamental freedoms adjudicated by Justices nearly a half-century ago merit continued respect for bestowed rights against their summary withdrawal. Under Dobbs' majority reasoning, manifold other liberty interests previously framed by the Court (e.g., contraception, sexual intimacy, marital equality) may be at risk of reversal with epic potential impacts on population health and well-being.51 Doing so under the guise of federalism not only disrespects Americans' freedoms, but also resounds historically-rejected premises of states' rights as constitutionally-viable reasons to deny individual liberties. Positing constitutional structural principles like federalism in support of reversals of settled, rights-based reasoning is a dangerous path for the Court to follow. Ultimately, it may find the trail ends where federalism begins: at the doorstep of liberty. Acknowledgments The authors thank Jennifer L. Piatt, J.D., Research Scholar, ASU Sandra Day O'Connor College of Law, for her review, edits, and comments to this manuscript. James G. Hodge, Jr., J.D., LL.M. , is the Peter Kiewit Foundation Professor of Law and Director, Center for Public Health Law and Policy, Sandra Day O'Connor College of Law, Arizona State University (ASU). Summer Ghaith are legal researchers, Center for Public Health Law and Policy, Sandra Day O'Connor College of Law, ASU. Lauren Krumholz are legal researchers, Center for Public Health Law and Policy, Sandra Day O'Connor College of Law, ASU. Note The authors do not have any conflicts of interest to report. No specific entity provided funding for the production of the manuscript. References 1. State Pol'y Network: SPN Blog, What is Federalism? (June 11, 2021), available at < (last visited September 26, 2022). 2. J.G. Hodge, Jr., "The Role of New Federalism and Public Health Law," Journal of Law & Health 12 , no. 2 (1997-98): 309-357, available at < (last visited September 26, 2022).10539296 3. A. Tsesis , "Safeguarding Fundamental Rights: Judicial Incursion into Legislative Authority," Social Justice 41 (2014): 47, available at < (last visited September 26, 2022). 4. J.G. Hodge, Jr. et al. , "Legal Interventions to Counter COVID-19 Denialism," Journal of Law, Medicine & Ethics 49 , no. 4 (2021): 677-682, available at < (last visited September 26, 2022). 5. M.M. Mello and W.E. Parmet , "Public Health Law After Covid-19," New England Journal of Medicine 385 , no. 13 (2021): 1153-55, available at < (last visited September 26, 2022).34469644 6. C. Fried, Saying What the Law Is: The Constitution in the Supreme Court (2004): at 46-47. 7. Jacobson v. Massachusetts, 197 U.S. 11 (1905). 8. Dobbs v. Jackson Women's Health Organization, 142 S. Ct. 2228 (2022). 9. J.G. Hodge, Jr. et al. , "Curbing Reversals of Non-Textual Constitutional Rights," Maryland Law Journal of Race, Religion, Gender & Class 22 , no. 2 (2022), available at < (last visited Jan. 6, 2023). 10. J.G. Hodge, Jr., Public Health Law in a Nutshell (4th ed. 2021): at 69. 11. W. E. Parmet et al. , "Individual Rights vs. the Public's Health 100 Years After Jacobson v . Massachusetts," New England Journal of Medicine 352 , no. 7 (2005): 652, available at < (last visited September 26, 2022).15716558 12. L.O. Gostin , Public Health Law: Power, Duty, Restraint (2nd ed. 2008): 126-128. 13. Jacobson, 197 U.S. at 26. 14. Id. at 38. 15. Id. 16. Dobbs, 142 S. Ct. at 2242. 17. Id. at 2243. 18. Roe v. Wade, 410 U.S. 113 (1973). 19. Dobbs, 142 S. Ct. at 2241. 20. Id. at 2305. 21. Id. at 2252-54. 22. Planned Parenthood v. Casey, 505 U.S. 833 (1992). 23. Dobbs, 142 S. Ct. at 2255, n. 40. 24. "Sen. Rick Scott: SCOTUS is Right to Protect Life, Respect Federalism & Reverse Roe," Office of Senator Rick Scott, June 24, 2022, available at < (last visited September 26, 2022). 25. "Statement on Dobbs v. Jackson Women's Health Organization SCOTUS Decision," Office of Senator Kevin Cramer, June 24, 2022, available at < (last visited September 2, 2022). 26. W. Brown , "Alito's Dobbs Decision Will Further Degrade Democracy," The Washington Post, June 27, 2022, available at < (last visited September 26, 2022). 27. P.H. Schuck , "Introduction: Some Reflections on the Federalism Debate," Yale Law & Policy Review 14 , no. 2 (1996): 4, available at < (last visited September 26, 2022). 28. R. Schapiro, Polyphonic Federalism (2009): 46. 29. M.S. Greve , "Federalism's Renaissance?" in Real Federalism: Why It Matters, How It Could Happen (1999): 11. 30. J. Madison , The Federalist No. 51 (C. Rossiter ed. 1961): 323. 31. C.J. Peters , "Comment: Federalism and Two Conceptions of Rights," Wayne Law Review 47 (2002): 947, available at < (last visited September 26, 2022). 32. M.A. Feigenbaum , "The Preservation of Individual Liberty Through the Separation of Powers and Federalism: Reflections on the Shaping of Constitutional Immortality," Emory Law Journal 37 , no. 3 (1988): 623, available at < (last visited September 26, 2022). 33. J.H. Adler , "The Role of the Judiciary in Preserving Federalism," Georgetown Journal of Law & Public Policy 2002 (2002): 50, available at < (last visited September 26, 2022). 34. E. Chemerinsky , "The Assumptions of Federalism," Stanford Law Review 58 , no. 6 (2006): 1790, available at < (last visited September 26, 2022). 35. J.F. Blumstein , "Federalism and Civil Rights: Complementary and Competing Paradigms," Vanderbilt Law Review 47 , no. 5 (1994): 1252, available at < (last visited September 26, 2022). 36. W.W. Allen , "The Constitution Empowers Us: Federalism and Protecting Civil Rights Through Diffused Government," The Federal Lawyer 68 , no. 1 (2021): 3-4, available at < (last visited September 26, 2022). 37. Hon. M.D. Corrigan , "The Two Faces of Federalism," Georgetown Journal of Law & Public Policy (2002): 48 , available at < (last visited Jan. 6, 2023). 38. Feigenbaum, supra note 32, at 622. 39. Boyd v. United States, 116 U.S. 616 (1886). 40. Id. at 635. 41. Garcia v. San Antonio Metro. Transit Auth., 469 U.S. 528 (1985). 42. Id. at 572. 43. Gregory v. Ashcroft, 501 U.S. 452 (1991). 44. United States v. Lopez, 514 U.S. 549 (1995). 45. Gonzales v. Oregon, 546 U.S. 243 (2006). 46. Bond v. United States, 564 U.S. 211 (2011). 47. Murphy v. Nat'l. Collegiate Athletic Ass'n., 200 L. Ed. 2d 854 (2018). 48. Gregory, 501 U.S. at 458. 49. Bond, 564 U.S. at 222. 50. Id. 51. Hodge, Jr. et al., supra note 9.. |
J Law Med Ethics J Law Med Ethics JME The Journal of Law, Medicine & Ethics 1073-1105 1748-720X Cambridge University Press New York, USA 36883386 10.1017/jme.2023.2 S1073110523000025 Symposium Articles INTRODUCTION: What is Health Justice? Wiley Lindsay F. Yearby Ruqaiijah Clark Brietta R. Mohapatra Seema Wiley Lindsay F. 1 * Yearby Ruqaiijah 2 * Clark Brietta R. 3 * Mohapatra Seema 4 * 1. UCLA SCHOOL OF LAW, LOS ANGELES, CA, USA 2. THE OHIO STATE COLLEGE SCHOOL OF LAW, COLUMBUS, OH, USA 3. LOYOLA LAW SCHOOL, LOYOLA MARYMOUNT UNIVERSITY, LOS ANGELES, CA, USA 4. SOUTHERN METHODIST UNIVERSITY SCHOOL OF LAW, DALLAS, TX, USA. Winter 2022 50 4 Health Justice: Engaging Critical Perspectives in Health Law and Policy 636640 (c) The Author(s) 2023 2023 The Author(s) This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence ), which permits unrestricted re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Health justice is both a community-led movement for power building and transformational change and a community-oriented framework for health law scholarship. Health justice is distinguished by a distinctively social ethic of care that reframes the relationship between health care, public health, and the social determinants of health, and names subordination as the root cause of health inequities. Keywords Social Justice Community Social Determinants of Health Public Health Health Care Access pmcHealth justice is not only a framework for scholarly discourse and research, but also a movement for power building and transformational change to eliminate health inequities and secure distinctively collective interests in access to health care and healthy living conditions. As a framework for health law and policy scholarship, health justice focuses particularly on the role of laws, policies, and institutions in creating, perpetuating, and (potentially) dismantling subordination within health care, public health, and beyond which it names as the root cause of health inequities. As a movement, health justice seeks to recognize and build the power of individuals and communities affected by health inequities to create and sustain conditions that support health and justice. Health Justice as a Scholarly Framework As a framework for advocating for, guiding, and explaining progressive health reforms, health justice is distinguished by its embrace of a distinctively social, communitarian ethic of care and its reframing of the relationship between health care, public health, and the social determinants of health.1 "Rather than merely adopting social justice as the 'core value' of public health as ... others have done," health justice demands that social justice should be embraced as "a core value of health law and policy writ large."2 Health justice situates access to health care within a capacious model of the social determinants of health. Rather than describing the social determinants of health as unmet social needs of individuals that exist "upstream" and separate from health care encounters, health justice treats health care access as one among many socially constructed determinants of health outcomes that operate at structural, institutional, and individual levels. Health justice demands a self-critical orientation that is, health justice requires a probing and critical eye to root out the influence of classism, racism, and other forms of social and cultural bias on the design and implementation of measures purportedly aimed at reducing health disparities. Health justice also requires a commitment to reforms developed through collective action grounded in community engagement, empowerment, and participatory parity. With regard to the laws governing health care financing and delivery more specifically, a health justice model suggests additional principles.3 It recognizes the importance of distinctively collective, public interests in universal access to affordable, high quality health care alongside the individual interests of patients, providers, and payers. It prioritizes prevention and integration of public health goals within health care decisionmaking. Finally, health justice asserts the importance of collective oversight through inclusive, democratic governance secured through robust protections for the civil and political rights of individuals to guide stewardship of health care resources and ensure equitable distribution of the burdens and benefits of public investments in health.As a movement, health justice seeks to recognize and build the power of individuals and communities affected by health inequities to create and sustain conditions that support health and justice. Emily Benfer's work on the health justice framework (like that of some of the authors who are featured in this volume) has been particularly influential and is grounded in her work with medical legal partnerships.4 Benfer recently collaborated with James Bhandary-Alexander; Yael Cannon, Medha Makhlouf, and Tomar Pierson-Brown to develop an agenda for medical legal partnerships to advance health justice in the post-pandemic world. They organized their agenda around six key themes: (1) transdisciplinary collaboration, (2) upstream interventions, (3) adaptability, (4) racial justice, (5) systemic advocacy, and (6) community-based strategies.5 Benfer was initially slated to join us as a co-editor of this issue, but her important work with the Biden administration precluded her from doing so. Elizabeth Tobin Tyler and Joel B. Teitelbaum have published an essential primer of readings in health justice, which has been adopted by many medical legal partnership clinics and other interprofessional academic courses to guide students.6 Other scholars have applied, expanded, and refined the health justice framework. Medha Makhlouf has explored the meaning of community in the health justice framework by applying it to the experience of newcomers to the United States.7 Angela Harris and Aysha Pamukcu have applied a health justice framework to develop a new civil rights of health.8 Matt Lawrence has applied the health justice framework to critique the safety net metaphor for public benefits.9 Robyn Powell has applied the health justice framework to address health inequities experienced by people with disabilities.10 Thalia Gonzalez, Alexis Etow, and Cesar De La Vega have applied health justice to school discipline and policing.11 Rachel Rebouche has applied the health justice framework to abortion access.12 Health Justice as a Community-Led Movement Health justice is work that is community-led and seeks to eliminate the poverty, discrimination, and other forms of subordination that have prevented people living in low-income households and communities, Black individuals and members of other racial minority groups, women, disabled people, newcomers to this country, and LGTBQIA+ individuals from accessing resources such as health care, employment, and housing. This work was started by groups such as the Poor People's Campaign, the Black Panther Party (BPP), the Young Lords, and the AIDS Coalition to Unleash Power (ACT-UP). The BPP and the Young Lords created free health clinics in their neighborhoods that were the foundation for federal qualified health centers, while ACT-UP successfully campaigned for access to HIV and AIDS treatment. The Praxis Project and the Asian Pacific Environmental Network (APEN), who have joined in our discussions about health justice, continue the health justice movement. The Praxis Project, a national movement-support intermediary committed to capacity building for social change, is working on developing fields of work in ways that encourage multi-level, trans-disciplinary learning and collaboration across issues, across the country, and across the globe. APEN's work is grounded in the leadership of immigrant and refugee community members to develop an alternative agenda for environmental, social and economic justice. Health Justice in the Covid-19 Pandemic The Covid-19 pandemic has provided a particularly compelling and tragic lens through which to understand the value of a health justice approach. Disparities in Covid-19 infections, disease outcomes, and access to healthcare were stark and linked not only to health care system discrimination and inequity, but also to inequity throughout society: certain workers were at greatest risk; residential segregation and lack of employment protections made access to care more difficult for some; many communities lacked the resources needed to help children and families living on the margins to navigate disruptions in education and income. Numerous scholars and practitioners have argued for a more just and effective response to the Covid-19 pandemic (and to the new public health threats already emerging as the perceived threat from Covid-19 subsides). Health justice provides the model for such an approach because it demands legal and policy responses that are structural, supportive, and empowering.13 Realizing health justice requires addressing the structural determinants of health that are the root cause of health inequities, such as the social and economic policies that create unequal conditions in health care, employment, housing, and education. This requires attention to the relationship between health care and public health laws and broader patterns of subordination throughout society. Reformers must "address the role of health care laws and policies in reinforcing or, alternatively, dismantling racism, economic injustice, and other forms of social subordination."14 Health justice also demands that policymakers and health officials prioritize the provision of material resources and legal protections over interventions aimed at inducing or mandating individual behavior change. This requires an interrogation of inequities in the current distribution of health-related burdens and benefits, and efforts to ensure that on-going public investments in health care and public health are being equitably distributed in accordance with need. In short, health care reformers must prioritize distributive justice measured with attention to the health outcomes and wellbeing of subordinated communities, in addition to the intermediate indicators of health care access, quality, and cost. Communities that have been disenfranchised by racism, poverty, and other forms of subordination must be recognized, engaged, respected, and empowered as leaders in the development and implementation of interventions to eliminate health inequities and realize health justice. This means that the processes created to develop, evaluate, and reform laws and policies that shape health must incorporate mechanisms for combatting existing power imbalance and subordination, by centering community decision making and control.15 The Health Justice: Engaging Critical Perspectives in Health Initiative The mission of the Health Justice: Engaging Critical Perspectives in Health Law and Policy Initiative, which we co-chair, is to foster theory, practice, and action on health justice. Our focus is on applying critical perspectives including critical race theory, Lat Crit, ClassCrit, black feminist theory, feminist legal theory, queer theory, critical disability studies, critical trans legal studies, and more to the most pressing challenges in health law and policy. We have a big-tent vision of health law and policy, encompassing public health, the social (and structural, legal, economic, and political) determinants of health, health care, bioethics, and global health. We aim to encourage health law and policy scholars, advocates, workers, and justice movement activists to engage more deeply with critical perspectives. We also hope to encourage scholars, advocates, workers, and activists from various critical perspectives who have not previously engaged in the health law and policy sphere to do so as part of this project. When we came together in 2019 to form an organized initiative to engage critical perspectives in health law and policy to further develop the health justice framework and movement, we recognized that realizing health justice requires building community among academic experts and community organization leaders across disciplines and sectors. We partnered with co-sponsors, including the UCLA Health Law and Policy Program, the Institute for Healing Justice & Equity, ChangeLab Solutions, and the Satcher Health Leadership Institute at Morehouse School of Medicine, which each provided generous financial support for an in-person convening and this open-access journal issue. Our initial aim was to host a multi-day in-person conference in October 2020 featuring dozens of experts and thought leaders who responded to our call for proposals. When the pandemic hit, we were pulled in multiple directions, but we continued to carve out time for our community-building initiative by hosting a series of virtual workshops that brought together those who responded to our original call for proposals for interactive discussion. These workshops and the October 2020 virtual conference that they fed into (attracting several hundred attendees at a time when we were all still learning the ins and outs of virtual convening) were organized around three key themes: securing distributive justice, valuing human dignity, and empowering communities. We are grateful to the steering committee that shaped this initiative in its early months for their work on the conceptual framing of these themes: Emily Benfer, Brian Castrucci, Daniel Dawes, Sarah de Guia, Gregg Gonsalves, Nan Hunter, Dayna Bowen Matthew, Jamila Taylor, and with special gratitude for the many extra hours she devoted to this project Angela Harris. We also owe a debt to American University's Health Law and Policy Program, the first home of this initiative, and to the events and information technology offices of American University Washington College of Law (AUWCL), for making the virtual workshops and conference possible. Recordings from the virtual conference are hosted on AUWCL's Health Law and Policy Program website.The publication of this symposium marks an important milestone in our efforts to engage critical perspectives in health law and policy, with the goal of facilitating insights that would translate into practical tools for preparing and supporting the next generation of collaborative health leaders. We hope these papers will be useful to teachers in schools of law, public health, nursing, medicine, and public policy. We hope they will inspire new thinking, expansion, and meaning-making within and beyond classrooms and community-led reforms supported by agencies, legislatures, courts, and civic institutions. In the summer of 2021, we invited some of the participants from our 2020 workshops and conference, as well as new voices who had not previously been part of our initiative, to create a blog symposium hosted by the Petrie Flom Institute's Bill of Health Blog. Building on this foundation, in the winter of 2021-22, we recruited long-standing participants in this initiative and new ones to contribute the papers that appear in this volume and to convene for an in-person workshop hosted by the initiative's new home, UCLA's new Health Law and Policy Program, in October 2022. Our 2022 workshop featured many of the authors of this symposium issue as well as several commentators who enriched the papers that appear in this volume: Devon Carbado, Lauren Clark, Christine Cordero, Daniel Goldberg, Thalia Gonzalez, Kimberly Libman, Yvonne Mariajiminez, Ilan Meyer, Xavier Morales, and Lauren van Schilfgaarde. We are also grateful to the dozens of anonymous peer reviewers who lent their time and expertise to strengthen the papers we feature here. Workshop participants expressed many variations on the core themes of respect for community, partnership between scholars and community advocates, and calls to action to achieve health justice. They highlighted the need for social movement organizers and scholars to work together to build more just political, economic, legal, and social systems. They emphasized that doing this work requires coming to terms with the racialized nature of these systems and repairing and redressing the trauma these systems have caused. They focused on the need to ground health justice in the work of building what people need to thrive. Building on other social justice movements, participants emphasized that lawyers and others with specialized expertise should be on call and ready to help, but that community should lead these efforts. Scholars should accompany the community in this journey of equality and equity rather than attempting to take the lead. Some participants pointed out that this commitment to community-led efforts must involve granting communities the right to make mistakes as they try to address historical and community traumas. A central theme of the workshop was a call to break down silos and work collaboratively with community organizations and scholars in areas beyond those traditionally understood as being within the purview of health law and policy, such as education, the criminal legal system, the immigration system, labor and employment law, housing, transportation, food justice, and political economy. Throughout these efforts we have developed a growing bibliography of resources for advocates, authors, and commentators to use as they see fit, but we resisted defining health justice for the authors whose work is featured in this issue. We view health justice as an open-weave framework, which invites expansion, refinement, and meaning-making from multiple perspectives. Next Steps Our initiative is ongoing. The publication of this symposium marks an important milestone in our efforts to engage critical perspectives in health law and policy, with the goal of facilitating insights that would translate into practical tools for preparing and supporting the next generation of collaborative health leaders. We hope these papers will be useful to teachers in schools of law, public health, nursing, medicine, and public policy. We hope they will inspire new thinking, expansion, and meaning-making within and beyond classrooms and community-led reforms supported by agencies, legislatures, courts, and civic institutions. We are honored to provide this platform for the work of an immensely talented group of authors and grateful for the friendships, fellowship, community, and ongoing collaborations this project has fostered. Lindsay F. Wiley, J.D., M.P.H. , is a professor of law and Faculty Director of the Health Law and Policy Program at UCLA School of Law. Ruqaiijah Yearby, J.D., M.P.H., is the inaugural Kara J. Trott Professor in Health Law at the Moritz College of Law, The Ohio State University. Brietta R. Clark, J.D., is a professor of law and Rex J. Dibble Fellow at LMU Loyola Law School. Seema Mohapatra, J.D., M.P.H., is the MD Anderson Foundation Endowed Professor in Health Law and Professor of Law at SMU Dedman School of Law. Note The authors have no conflicts of interest to disclose. References 1. L.F. Wiley , "Health Law as Social Justice," Cornell Journal of Law & Public Policy 24 (2014): 47-105.26812890 2. Id., at 52. 3. L.F. Wiley , "From Patient Rights to Health Justice," Cardozo Law Review 37 (2016): 833-89; L.F. Wiley, E.Y. McCuskey, M.B. Lawrence, and E. Fuse Brown, "Health Reform Reconstruction," UC Davis Law Review 55 (2021): 657-742. 4. E.A. Benfer , "Health Justice: A Framework (and Call to Action) for the Elimination of Health Inequity and Social Injustice," American University Law Review 65 (2015): 275-351.28221739 5. E.A. Benfer , J. Bhandary-Alexander , Y. Cannon , M. Makhlouf and T. Pierson-Brown , "Setting the Health Justice Agenda: Addressing Health Inequity & Injustice in the Post-Pandemic Clinic," Clinical Law Review 28 (2021): 45-84. 6. E. Tobin-Tyler and J.B. Teitelbaum , Essentials of Health Justice: A Primer (Burlington, MA: Jones and Bartlett Learning, 2019). 7. M.D. Makhlouf , "Health Justice for Immigrants," University of Pennsylvania Journal of Law and Public Affairs 4 (2019): 235-311. 8. A.P. Harris and A. Pamukcu , "The Civil Rights of Health: A New Approach to Challenging Structural Inequality," UCLA Law Review 67 (2020): 758-832. 9. M.B. Lawrence , "Against the 'Safety Net,'" Florida Law Review 72 (2020): 49-71. 10. R.M. Powell , "Applying the Health Justice Framework to Address Health and Health Care Inequities Experienced by People with Disabilities During and After COVID-19," Washington Law Review 96 (2021): 93-138. 11. T. Gonzalez , A. Etow , and C. De La Vega , "A Health Justice Response to School Discipline and Policing," American University Law Review 71 (2022): 1927-1975. 12. R. Rebouche , "The Public Health Turn in Reproductive Rights," Washington & Lee Law Review 78 (2021): 1355-1432. 13. E. A. Benfer , S. Mohapatra , L. F. Wiley , and R. Yearby , "Health Justice Strategies to Combat the Pandemic: Eliminating Discrimination, Poverty, and Health Disparities During and After COVID-19," Yale Journal of Health Policy, Law, and Ethics 19 (2020): 122. 14. Id. at 663. 15. L. F. Wiley , E. Y. McCuskey , M. B. Lawrence , and E. Fuse Brown , "Health Reform Reconstruction," UC Davis Law Review (2021): 657-742, at 680. |
Aim Although tramadol has been suggested to have a higher risk of producing hallucinations than other opioids, reports of musical hallucinations are extremely rare. Case Presentation A 72-year-old woman came to our department complaining of auditory hallucinations. She had been diagnosed with lumbar spinal canal stenosis associated with herniated and slipped disks. Due to persistent back pain, tramadol was started, and the dose was increased to 300 mg/day. The next day, she began to hear nursery rhymes, songs of the Ministry of Education, and folk songs. The musical auditory hallucinations disappeared with the use of antipsychotics and the discontinuation of tramadol. No relapse of musical auditory hallucinations was observed after the discontinuation of antipsychotics. Conclusion Based on the clinical course, we concluded that the auditory hallucinations were musical hallucinations induced by tramadol. Due to persistent back pain, tramadol was started, and the dose was increased to 300 mg/day. The next day, she began to hear nursery rhymes, songs of the Ministry of Education, and folk songs. The musical auditory hallucinations disappeared with the use of antipsychotics and the discontinuation of tramadol. hallucinations music opioids tramadol source-schema-version-number2.0 cover-dateMarch 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:13.03.2023 Hase T , Yasui-Furukori N , Yamaguchi S , Shimoda K . A case of musical hallucinations induced by tramadol. Neuropsychopharmacol Rep. 2023;43 :160-162. 10.1002/npr2.12320 pmc1 INTRODUCTION Musical hallucination is a specific syndrome in which music is heard in the absence of external sound stimulation. Hearing loss, psychiatric disorders (schizophrenia, depression, and obsessive-compulsive disorder), organic brain lesions (brain atrophy, brain tumors, cerebrovascular disease, etc.), epilepsy, and drug addiction have been reported as causal factors for musical hallucinations. 1 , 2 , 3 However, drugs with a high frequency of overall hallucinations, including auditory hallucinations, include Parkinson's disease drugs, benzodiazepines and similar drugs, opioids, anticholinergic drugs such as antidepressants and antipsychotics, and non-central nervous system-acting drugs such as ertapenem and voriconazole. 4 In the present study, we encountered a patient with musical hallucinations caused by oral tramadol. Although tramadol has been suggested to have a higher risk of producing hallucinations than other opioids, 4 reports of musical hallucinations are extremely rare, and we present this case to demonstrate the need to be aware of the possibility of their occurrence. Written consent to report the case was obtained from the patient. 2 CASE PRESENTATION A 72-year-old woman came to our department complaining of auditory hallucinations. Six months earlier, she had developed severe low back pain and numbness in her left lower extremity, which made it difficult for her to walk. She had been diagnosed with lumbar spinal canal stenosis associated with herniated and slipped disks at another hospital. A few days after the onset of her condition, she was started on 75 mg of diclofenac sodium, 112.5 mg of tramadol, and 50 mg of pregabalin. Due to persistent back pain, she was referred to the pain clinic in our hospital 4 months later for block injections. The dose of tramadol was increased to 200 mg, and 1 month later (3 months ago), the dose was increased to 300 mg. The next day (87 days after starting tramadol), she began to hear nursery rhymes, songs of the Ministry of Education, and folk songs, among others, that she had sung in her childhood as part of a chorus. The songs consisted of male and female voices, divided into lower and higher parts, and the same song was repeated approximately 10 times before moving on to another song. Auditory hallucinations appeared mainly during periods of silence, such as before bedtime and while doing housework. Approximately 1 month after the auditory hallucinations began, the patient reported her symptoms to the prescribing physician, and the dose of tramadol was reduced to 200 mg and then to 100 mg 1 week later. After dose reduction, the auditory hallucinations decreased in volume, but the symptoms themselves remained. Magnetic resonance imaging (MRI) of the head and a hearing test were performed to rule out organic lesions, but neither examination showed any abnormalities by a physician General Medicine Department. No ear pain, redness, swelling, ear leaks, plugged ears, tinnitus, dizziness, or cerumen were observed. An electroencephalogram was not performed. There were no signs of psychiatric disease. Mini-mental examinations showed no cognitive dysfunction with a score of 28. Therefore, the patient was referred to our department and started on aripiprazole 3 mg, which further decreased the volume of auditory hallucinations. Two weeks later, tramadol was tapered off in 25 mg increments and discontinued after 6 days. After discontinuation, the patient's back pain continued without exacerbation with nonsteroidal anti-inflammatory drugs (NSAIDs) alone. After starting aripiprazole, the patient developed dysrhythmias and a skin rash that were suspected to be drug-related, so the drug was changed to risperidone 1 mg 42 days later. Ten days later (32 days after the discontinuation of tramadol), auditory hallucinations were almost nonexistent, but dizziness and rhythm disturbances were observed, so risperidone was discontinued 2 weeks after its initiation. After the discontinuation of risperidone, the auditory hallucinations did not recur, and the patient's mental status remained stable. A summary of the clinical course of this case is shown in Figure 1. FIGURE 1 Clinical course of the patient 3 DISCUSSION In this case, the patient was not suspected of having hearing loss, organic brain lesions, or psychiatric disease. The volume of the musical auditory hallucinations decreased with decreasing drug dose, and musical auditory hallucinations disappeared with the use of antipsychotics and the discontinuation of tramadol . No relapse of musical auditory hallucinations was observed after the discontinuation of antipsychotics, and based on the clinical course, we concluded that the auditory hallucinations were musical hallucinations induced by tramadol. Chronic pain improved with increasing tramadol dose. Furthermore, the musical auditory hallucinations are confined to nursery rhymes, and the auditory hallucinations cause neither pain nor comfort. Therefore, it is unlikely that psychological and social factors are the triggers for these auditory hallucinations. This is the second case of musical hallucinations induced by tramadol reported in the world. The first case was reported in a 74-year-old man with terminal lung cancer who was treated with 200 mg of tramadol. 5 The musical hallucinations appeared soon after the start of treatment, and the drug was discontinued on the basis of being a suspected side effect of tramadol. 5 Tramadol discontinuation led to the disappearance of the musical hallucinations 2 days later. 5 The patient had no organic brain lesions, psychiatric disorders, or history of auditory hallucinations that could have caused the musical hallucinations. 5 The patient's symptoms resolved immediately after the discontinuation of tramadol, whereas symptom resolution for the patient reported here required a longer period of time and antipsychotic medications. 5 Being female has been reported as a risk factor for musical hallucinations, 6 and sex differences may be related to the persistence of symptoms after the discontinuation of tramadol. A study using a database of all side effects of over-the-counter drugs in France reported 4784 adverse drug reactions with tramadol between 1985 and 2013, of which 240 were hallucinations. The odds ratio for a relationship between a drug and the occurrence of hallucinations was high for antiparkinsonian drugs (seven of the top 10 drugs: 17.2-23.1), as well as ertapenem (24.0), scopolamine (17.7), oxybutynin (16.6) and zolpidem (12.9). The odds ratio for tramadol was 6.3, which was second only to that of oxycodone (7.7) among opioids. 4 Drug-induced hallucinations may best reflect anticholinergic effects, and it has been suggested that the hallucinations produced by serotonin reuptake inhibitors, in addition to their anticholinergic effects, induce psychiatric symptoms through the serotonin receptor (5-HT-3) mediating dopamine release in the ventral striatum. 4 In addition, the three major opioid receptors, m, k, and d, are all present in the cochlea, inner and outer hair cells, bipolar cells of the spiral ganglion, and interdental cells of the spinal cord, and each has different functions. The functions of these opioid receptors include the regulation of neurotransmitters such as g-aminobutyric acid (GABA) and acetylcholine, the decrease in auditory afferent activity through k receptors, and the increase in auditory afferent activity through m receptors in the vestibule, suggesting that these opioid receptors play an important role in the adaptive response of the vestibular peripheral organs to metabolic load. 6 In addition to its opioid action (partial actuation of m receptors), tramadol has anticholinergic effects through muscarinic receptor antagonism and serotonin reuptake inhibition, which are assumed to induce hallucinations. 4 , 7 In addition, the antagonism of GABA receptors and noradrenaline reuptake inhibition of tramadol may also be involved in the appearance of hallucinations. 4 , 7 Risk factors for tramadol-induced hallucinations include advanced age, malignancy, chronic cerebral ischemia or atrophy, psychiatric disorders, and concomitant use of antidepressants and other drugs. 7 In particular, selective serotonin reuptake inhibitors increase the serotonergic effect of tramadol and inhibit CYP2D6, which is involved in tramadol metabolism. 7 The response to the onset of hallucinations is to discontinue tramadol or administer an antipsychotic (e.g., haloperidol or risperidone) for a short period of time. 7 4 CONCLUSION While tramadol has been reported to have a higher risk of producing hallucinations than other opioids, reports of musical hallucinations such as those, in this case, are very rare. Although infrequent, tramadol should be suspected as the causative agent when musical hallucinations occur, and appropriate action should be taken. AUTHOR CONTRIBUTIONS TH, NFY, SY, and KS were involved in the clinical investigations. TH and NYF wrote the manuscript. TH, NYF, and KS were involved in the literature review and revisions. All authors read and approved the final manuscript. CONFLICT OF INTEREST Kazutaka Shimoda has received research support from Novartis Pharma K.K., Dainippon Sumitomo Pharma Co., Astellas Pharma Inc., Meiji Seika Pharma Co., Ltd., Eisai Co., Ltd., Pfizer Inc., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., and Takeda Pharmaceutical Co., Ltd., and honoraria from Eisai Co., Ltd., Mitsubishi Tanabe Pharma Corporation, Takeda Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Janssen Pharmaceutical K.K., Shionogi & Co., Ltd., Dainippon Sumitomo Pharma Co., Daiichi Sankyo Co., and Pfizer Inc. The funders did not have any role in data collection or in the study design, analysis, decision to publish, or preparation of the manuscript. The remaining authors declare that they have no competing interests to report. ETHICS STATEMENT Approval of the Research Protocol by an Institutional Reviewer Board: The ethics committee of the School of Medicine at Dokkyo Medical University determined that there was no need to review this case. Informed Consent: Written informed consent was obtained from the parent for the publication of this case report. Registry and the Registration No. of the Study/Trial: Not available. Animal Studies: Not available. DATA AVAILABILITY STATEMENT Data sharing is not applicable to this article as details of the case cannot be disclosed in accordance with the Personal Information Protection Law. |
Aim Selective serotonin reuptake inhibitors (SSRIs) are used to treat major depressive disorder (MDD) and other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). In MDD treatment, SSRIs do not show remission in approximately 30% of patients, indicating a need for a better treatment option. Forced swimming test (FST) is a behavioral assay to evaluate depression-like behavior and antidepressant efficacy in rodents. In the present study, we evaluated the combination effect of brexpiprazole with SSRIs on FST in mice, in order to investigate their synergistic effect. Methods Brexpiprazole (0.003 mg/kg) was intraperitoneally injected to mice 15 min before testing. Escitalopram (10 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), or sertraline (15 mg/kg) were orally administered to mice 60 min before testing. Then, the mice were placed in water and immobility time was measured. Data from animals treated with escitalopram, fluoxetine, paroxetine, and sertraline were pooled as SSRI-treated group data. Results Combination treatment of brexpiprazole with SSRIs reduced immobility time in FST more than vehicle or each single treatment. A significant interaction effect was confirmed in the combination of brexpiprazole and SSRIs (p = 0.0411). Conclusion Efficacy of adjunctive brexpiprazole has already been demonstrated in clinical trials in MDD patients not adequately responding to antidepressants including escitalopram, fluoxetine, paroxetine, and sertraline. The synergistic antidepressant-like effect of brexpiprazole with SSRIs found in this study supports the already known clinical findings. Synergistic antidepressant-like effect of brexpiprazole with selective serotonin reuptake inhibitors was confirmed on the forced swimming test in mice. The combination treatment reduced immobility time in the forced swimming test more than vehicle or each single treatment. Brexpiprazole forced swimming test major depressive disorder psychiatric disorder selective serotonin reuptake inhibitor Otsuka Pharmaceutical 10.13039/501100007132 n/a source-schema-version-number2.0 cover-dateMarch 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:13.03.2023 Amada N , Hirose T , Suzuki M , Kakumoto Y , Futamura T , Maeda K , et al. Synergistic anti-depressive effect of combination treatment of Brexpiprazole and selective serotonin reuptake inhibitors on forced swimming test in mice. Neuropsychopharmacol Rep. 2023;43 :132-136. 10.1002/npr2.12316 pmc1 INTRODUCTION Major depressive disorder (MDD) is a world public health problem, which causes loss of productivity and increased mortality including suicide. 1 Selective serotonin reuptake inhibitors (SSRIs) are used to treat MDD and several other psychiatric disorders (e.g., obsessive compulsive disorder, social anxiety disorder, and panic disorder). 2 In the case of MDD treatment, it is considered that approximately 30% of patients do not respond to antidepressant treatment including SSRIs. 3 For patients with inadequate response to antidepressant treatment, evidence to show effectiveness of atypical antipsychotics as adjunctive treatment has been recognized. 4 , 5 However, atypical antipsychotics are associated with side effects such as weight gain, sedation, and akathisia. There is still a need for an effective, safe, and well-tolerated atypical antipsychotic for treatment of MDD patients. 5 Brexpiprazole is a serotonin-dopamine activity modulator developed as a novel treatment for psychiatric disorders. 6 , 7 Brexpiprazole is approved for the treatment of adults with schizophrenia in countries including the United States (US), Canada, Australia, Japan, and the European Union. 5 Brexpiprazole is also approved as an adjunctive therapy to antidepressants for adults with MDD in the United States and several other countries. 5 Brexpiprazole acts as a partial agonist at serotonin 5-HT1A and dopamine D2 receptors, and as an antagonist at 5-HT2A and noradrenaline a 1B/2C receptors. 6 Its risk for catalepsy (extrapyramidal symptoms) and hyperprolactinemia in animals is lower than the risk observed for risperidone. 6 , 7 Furthermore, we have shown in an animal study that brexpiprazole has a low risk of D2 receptor supersensitivity after a repeated administration, indicative of a low propensity to cause dopamine supersensitivity psychosis and tardive dyskinesia in the course of long-term treatment. 8 These tell us that brexpiprazole is likely a well-tolerated antipsychotic drug. Forced swimming test (FST) is used to evaluate depression-like behavior and antidepressant efficacy in rodents, in which immobility is thought to reflect behavioral despair in rodents. 9 , 10 In order to demonstrate synergistic antidepressant-like effect in animals, we evaluated combination effect of brexpiprazole with SSRIs, using each ineffective dose based on unpublished in-house data, on immobility time in FST in mice. For this combinatory study, we selected SSRIs (escitalopram, fluoxetine, paroxetine, and sertraline) already approved for treatment of MDD. 2 MATERIALS AND METHODS 2.1 Animals Male ddY mice (Japan SLC, Inc., 5 to 6 weeks old) were used. They were group-housed in individual cages with water and food (Oriental Yeast Co, Ltd., Tokyo, Japan) supplied ad libitum, and maintained under artificial lighting between 7:00 am to 7:00 pm. The room temperature and humidity were maintained at 23 +- 2degC and 60 +- 10%, respectively. 2.2 Treatment Brexpiprazole and SSRIs (escitalopram, fluoxetine, paroxetine, and sertraline) were synthesized at Otsuka Pharmaceutical Co., Ltd. For evaluation of the combination treatment, in order to avoid increase of per os (p.o.) administration volume and any influence on intestinal absorption, different administration routes were used for brexpiprazole (intraperitoneal: i.p.) and SSRIs (p.o.), which also enabled two ways (i.p. and p.o.) of vehicle treatment for the combination study. Brexpiprazole was dissolved in 1% lactic acid saline (vehicle-1) at the concentration of 0.0003 mg/ml. Vehicle-1 and brexpiprazole were injected to mice at a volume of 10 ml/kg (i.p.), 15 min before testing. Escitalopram, fluoxetine, paroxetine, and sertraline were suspended in 5% (w/v) gum arabic-distilled water solution (vehicle-2) at the concentration of 6 mg/ml, 7.5 mg/ml, 1 mg/ml, and 1.5 mg/ml, respectively. Vehicle-2 and these SSRIs were administered to mice at a volume of 10 ml/kg (p.o.), 60 min before testing. Ineffective doses of brexpiprazole and the SSRIs, based on unpublished in-house data, were used for the combination study. Our in-house data show that the plasma concentration of brexpiprazole is higher in i.p. than p.o. administration (data not shown). As a result, the i.p. dose of brexpiprazole used in this study was low. 2.3 Forced swimming test Animals were assigned to four groups (Table 1). FST was conducted according to previous reports with slight modification. 9 , 11 , 12 After the administration of brexpiprazole and either of SSRIs, each mouse was placed into an acrylic cylinder (25 cm high x 9 cm inner diameter) filled with water (23 +- 1degC) up to 10 cm from the bottom of cylinder for 6 min. Then, the mobility time of the mouse was measured using SCANET (Melquest Co., Ltd., Toyama, Japan), and the immobility time was determined during last 4 min. TABLE 1 Treatment Group Treatment-1 (i.p. injection) Treatment-2 (p.o. administration) N 1 Vehicle-1 Vehicle-2 37 2 Vehicle-1 SSRIs 37 3 Brexpiprazole Vehicle-2 37 4 Brexpiprazole SSRIs 37 Note: Vehicle-1: 1% lactic acid/saline. Vehicle-2: 5% (w/v) gum arabic-distilled water solution. Vehicle-1 and brexpiprazole (0.003 mg/kg) were i.p. injected to mice. SSRIs included escitalopram (60 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), and sertraline (15 mg/kg). Vehicle-2 and these SSRIs were p.o. administered to mice. 2.4 Statistical analysis Data from escitalopram, fluoxetine, paroxetine, and sertraline treatments were pooled as results from SSRI-treated animals. The synergistic effects of brexpiprazole and SSRIs were assessed by a factorial ANOVA with the test-day as a covariate. The presence or absence of synergistic effects of the combination was evaluated using interaction effects. The statistical analysis was conducted using SAS Software for Windows, Release 9.4 (SAS Institute Japan Ltd., Tokyo, Japan). The difference was considered statistically significant, when p value was <0.05. 3 RESULTS Group 4 (brexpiprazole + SSRIs) animals showed less immobility time compared to group 1 (vehicle-1 + vehicle-2), group 2 (vehicle-1 + SSRIs), and group 3 (brexpiprazole + vehicle-2) animals . There was a significant interaction effect in the combination of brexpiprazole and SSRIs (p = 0.0411). This indicates that brexpiprazole shows synergistic effect with SSRIs. FIGURE 1 Forced swimming test results. Mice were placed in water for 6 min and immobility time was determined during last 4 min. Data are expressed as mean +- SEM. Vehicle-1 (1% lactic acid/saline) and brexpiprazole (0.003 mg/kg) were i.p. injected to mice. Vehicle-2 (5% (w/v) gum arabic-distilled water solution) and SSRIs were p.o. administered to mice. SSRIs included escitalopram (60 mg/kg), fluoxetine (75 mg/kg), paroxetine (10 mg/kg), and sertraline (15 mg/kg). The interaction between brexpiprazole and SSRIs (p = 0.0411) was assessed by a factorial ANOVA with the test-day as a covariate (*p = 0.0411). TABLE 2 Forced swimming test results Group Immobility time (s) 1 Vehicle-1 + Vehicle-2 226.6 +- 3.7 2 Vehicle-1 + SSRIs 214.3 +- 3.7 3 Brexpiprazole + Vehicle-2 217.8 +- 3.7 4 Brexpiprazole + SSRIs 190.2 +- 3.7 a Note: Data are expressed as mean +- SEM. a A significant interaction between brexpiprazole and SSRIs was confirmed by a factorial ANOVA with the test-day as a covariate (p = 0.0411). 4 DISCUSSION Brexpiprazole is approved as an adjunctive therapy to antidepressants for the treatment of adults with MDD in the United States and other countries. 5 In its clinical trials, the efficacy of adjunctive brexpiprazole was demonstrated in MDD patients who did not respond adequately to antidepressant treatments including escitalopram, fluoxetine, paroxetine, and sertraline. 13 , 14 , 15 For determination of synergistic antidepressant-like effects of brexpiprazole with SSRIs in animals, in this study we selected and used SSRIs (escitalopram, fluoxetine, paroxetine, and sertraline) already approved for treatment of MDD. We demonstrated a significant synergistic effect of brexpiprazole and the SSRIs in mice, confirming clinical trial findings for the adjunctive effect of brexpiprazole to antidepressants. Brexpiprazole acts as a partial agonist at 5-HT1A and D2 receptors, and an antagonist at 5-HT2A and a 1B/2C receptors. 6 It has been hypothesized that the receptor binding and functional profile of brexpiprazole at these receptors may make brexpiprazole a better choice for adjunctive treatment of MDD than other products commonly used when there is insufficient response to antidepressants alone 15 because of the known antidepressant and anxiolytic effects of 5-HT1A receptor partial agonists and 5-HT2A receptor antagonists. 16 Antagonistic action on a 1 adrenergic receptors is considered to have potential therapeutic effect in MDD. 17 Overexpression of thea 2C adrenergic receptor increased immobility time in FST in mice, while knockout or antagonists of the receptor decreased. 18 , 19 Therefore, brexpiprazole has a favorable in vitro functional profile to show antidepressant effects. Although the contribution of D2 receptor partial agonist activity on MDD treatment is not well known, brexpiprazole's D2 receptor partial agonist activity may also be a potential contributor of its antidepressant effects. Moreover, brexpiprazole was well tolerated in its clinical trials in MDD patients. 13 , 14 , 15 It has been known that administration of not only typical antipsychotics but also atypical antipsychotics have a risk to cause tardive dyskinesia. 20 , 21 Long-term D2 receptor blockade can evoke dopamine D2 receptor supersensitivity both in animals and humans, which is considered to be a possible cause of tardive dyskinesia. 22 , 23 , 24 We previously reported that brexpiprazole had a low risk to induce D2 receptor supersensitivity in rats after repeated administration, 8 indicative of a low propensity to cause tardive dyskinesia. Indeed, no clinically relevant findings related to extrapyramidal symptoms were reported in a 52-week clinical study evaluating the safety and tolerability of brexpiprazole as adjunctive therapy in adult MDD patients. 5 In addition, according to Citrome's report, other antipsychotics approved as adjunctive agents for the treatment of MDD (aripiprazole and quetiapine extended release [ER]) and olanzapine-fluoxetine combination approved as a combination agent for the treatment of treatment-resistant MDD had a higher incidence of akathisia (aripiprazole) or sedation/somnolence (quetiapine ER and olanzapine-fluoxetine combination) than placebo treatment. 25 Data in the report indicate less incidence of akathisia with brexpiprazole than with aripiprazole, and for sedation/somnolence than quetiapine ER and olanzapine-fluoxetine combination. 25 Taken together with our present data and the known clinical data, brexpiprazole has a potential to be a better therapeutic choice for adjunctive treatment of MDD patients. AUTHOR CONTRIBUTIONS NA wrote the paper. TH conceived and designed the study, performed experiments. YK conducted and was responsible for statistics. KM, TF, and TK conceived the study, and reviewed the paper. MS reviewed the paper. All authors contributed to finalizing the paper and had final responsibility for the decision to submit for publication, took part in either drafting and/or revising the paper, and approved the final version of the paper. FUNDING INFORMATION Otsuka Pharmaceutical Co., Ltd. CONFLICT OF INTEREST TH retired from Otsuka Pharmaceutical Co., Ltd. All the other authors are employees and own stock of Otsuka Holdings Co., Ltd. ETHICAL APPROVAL Approval of the Research Protocol by an Institutional Reviewer Board The experimental procedure in this study was approved and conducted in accordance with Guidelines for Animal Care and Use in Otsuka Pharmaceutical Co, Ltd. Informed Consent: N/A. Registry and the Registration no. of the Study/trial: N/A. Animal Studies: The care and handling of the animals was in accordance with "Guidelines for Animal Care and Use in Otsuka Pharmaceutical Co, Ltd." Supporting information Data S1 Click here for additional data file. ACKNOWLEDGMENTS This research was supported by Otsuka Pharmaceutical Co., Ltd. We deeply appreciate Mr. Keiji Kakumoto and Ms. Reika Nishihara for advising on the statistical analysis. DATA AVAILABILITY STATEMENT All data are available in the Data S1. |
Introduction Kato et al. reported results of a 6-week, double-blind, randomized, placebo-controlled trial of lurasidone in adults with bipolar depression (BDep). Aim We performed a post hoc analysis using data from the lurasidone trial to predict later responses from early improvements. Methods An early improvement was defined as a >=20% reduction in Montgomery-Asberg Depression Rating Scale (MADRS) total score at Week 2; response was defined as a >=50% reduction in MADRS total score at Week 6; symptomatic remission were defined as a score of <=8 on MADRS total score at Week 6. Results Both sensitivity and negative predictive value (NPV) were higher for the remission outcome than for the response outcome. The interpretation of sensitivity and NPV in the lurasidone group when remission is an outcome is as follows. It means (1) that, from all remitters at Week 6, 80.6% was identified as such at Week 2 on the basis of their early improvement and (2) that a patient showing non-improvement at 2 weeks had 93.5% probability of being a non-remitters at Week 6. However, the values of specificity for both response and remission in the lurasidone group were not high. Conclusion Patients who did not show an early response at Week 2 cannot be predicted with a high probability to also show poor improvement at Week 6. In fact, some patients who did not show early response at 2 weeks might have marked improvement at 6 weeks. We performed a post-hoc analysis using data from the lurasidone trial to predict later responses from early improvements. Both sensitivity and negative predictive value values were higher for the remission outcome than for the response outcome. bipolar depression diagnostic test early improvement lurasidone source-schema-version-number2.0 cover-dateMarch 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:13.03.2023 Kishi T , Nakamura H , Kato T , Iwata N . A diagnostic test to examine early improvement as a predictor of later response to lurasidone in bipolar depression. Neuropsychopharmacol Rep. 2023;43 :137-140. 10.1002/npr2.12319 pmcIn 2020, Kato et al. 1 reported results of a 6-week, double-blind, randomized, placebo-controlled trial of lurasidone in adults with bipolar depression (BDep). The findings demonstrated that lurasidone 20-60 mg/day (LUR20-60) improved symptoms of depression and anxiety and was generally well-tolerated. Individuals with bipolar disorder (BD) have about a 12 times higher ratio of suicide deaths to suicide attempts than the general population. 2 , 3 This means that individuals with BD usually employ more lethal suicide methods compared with the general population. 2 Suicidal ideation is also about five times more frequent in individuals with BD than in the general population. 2 , 4 , 5 Thus, early intervention and treatment with medications, along with close observation and follow-up are needed to prevent suicide in individuals with BD. However, the length of time clinicians should wait before judging that a medication is not effective for BD is an unresolved clinical question. Here, we performed a post-hoc analysis using data from the LUR trial 1 to predict later responses from early improvements. The detailed characteristics of patients included in the LUR trial are presented in Table S1. All data were analyzed on an intention-to-treat basis using the last observation carried forward method. An early improvement was defined as a >=20% reduction in Montgomery-Asberg Depression Rating Scale (MADRS) 6 total score at week 2; response was defined as a >=50% reduction in MADRS total score at week 6; and symptomatic remission were defined as a score of <=8 on MADRS total score at week 6. We then assessed the association between early improvement at week 2 and treatment response or remission at week 6 using odds ratios (ORs) with 95% confidence intervals. Fisher's Exact Test was used to calculate the p values. Positive predictive value (PPV), negative predictive value (NPV), sensitivity, and specificity were also calculated for the response status at week 2 to predict a subsequent response at week 6. 7 , 8 We included 332 adults with BDep (male = 47.3%, mean age = 42.1 years, Table S1). The percentages of responders and remitters were shown Table 1. In the LUR20-60 treatment group, an early improvement was correlated with increased ORs for later favorable treatment response and remission (Table 1). From a clinical point of view, sensitivity and NPV are more important than specificity and PPV since the diagnostic test should mainly (1) ensure that LUR is not changed unnecessarily when the patient still has a good chance of responding (confirmed by high values of sensitivity), and (2) predict nonresponse satisfactorily (confirmed by high values of NPV). These values were higher for the remission outcome than for the response outcome. The interpretation of sensitivity and NPV in the LUR20-60 group when remission is an outcome is as follows. It means (1) that, from all remitters at week 6, 80.6%was identified as such at week 2 on the basis of their early improvement, and (2) that a patient showing non-improvement at 2 weeks had 93.5% probability of being a non-remitters at week 6. However, the values of specificity for both response and remission in the LUR20-60 treatment group were not high. As a result, patients who did not show an early response at week 2 cannot be predicted with a high probability to also show poor improvement at week 6. In fact, some patients who did not show early response at 2 weeks might have marked improvement at 6 weeks. In this case, for patients who are not responding early at week 2, clinicians may allow them to continue LUR20-60 treatment for a few more weeks. Thus, predicting treatment response at 2 weeks might be too early. Some patients also might show marked improvement after 6 weeks although we could not examine this hypothesis because we did not have the results after 6 weeks for all participants included in the trial. Another diagnostic test including other antipsychotic studies for patients with bipolar depression reported similar results to our study. 9 The placebo group also showed high OR for the prediction of response by early improvement. This could be interpreted that if clinicians tried "no treatment" in practice (e.g., to be certain about the diagnosis), clinicians could identify placebo responders early. The results could also be explained by the higher NPV. However, because PPV of placebo group was low, it does not necessarily mean that a patient who improves early on with placebo will eventually benefit from the placebo. Such placebo response has also been observed in schizophrenia studies. 7 , 8 , 10 The study had several limitations. First, a predict value decrease markedly as prevalence decreases. Because the definitions of response and remission were strict, the rates of those outcomes were low. Consequently, PPV values for remission were relatively low. Considering that the results of our study were based on a randomized trial, our results might not apply to clinical practice. Second, our study had a small sample size. Third, the lurasidone study 1 which was used for this study had the following exclusion criteria for the participants: (1) patients scored >=4 on MADRS 6 Item 10 (suicidal thoughts) at screening or baseline, and (2) patients responded Yes to the Columbia Suicide Severity Rating Scale 11 Item 4 (active suicidal ideation with some intent to act, without specific plan) or Item 5 (active suicidal ideation with specific plan and intent) at screening (within 6 months prior to screening) or at baseline, or were otherwise judged to be an imminent risk of suicide or injury to self, others, or property. Therefore, we could not investigate focusing on suicidal ideation. TABLE 1 Correlations between and predictive value of early improvement at week 2 and response and remission at week 6 Response Placebo LUR 20-60 mg Positive Negative Positive Negative Early improvement Positive 41 21 51 28 Negative 11 87 31 62 Sensitivity 78.8% 62.2% Specificity 80.6% 68.9% Positive predictive value 66.1% 64.6% Negative predictive value 88.8% 66.7% Odds ratio (95% CI) 15.44 (6.38-38.46) 3.64 (1.85-7.20) Fischer's Exact Test* <0.001 <0.001 Remission Placebo LUR 20-60 mg Positive Negative Positive Negative Early improvement Positive 13 49 25 54 Negative 2 96 6 87 Sensitivity 86.7% 80.6% Specificity 66.2% 61.7% Positive predictive value 21.0% 31.6% Negative predictive value 98.0% 93.5% Odds ratio (95% CI) 12.73 (2.68-118.85) 6.71 (2.45-21.10) Fischer's Exact Test* <0.001 <0.001 Abbreviations: 95% CI, 95% confidence interval; LUR, lurasidone. * A value of p-value <0.05 was considered statistically significant. Although we recognize that our results have multiple testing issues, we did not correct p-values as the sample size was small. All calculations were performed using the SAS software version 9.4. AUTHOR CONTRIBUTIONS Kishi was involved in the study conception and design and performed the statistical analysis. Kishi and Nakamura performed the acquisition and interpretation of the data. All the authors wrote the manuscript. Kato and Iwata supervised the review. FUNDING INFORMATION None. CONFLICT OF INTEREST HN is a full-time employee of Sumitomo Pharma Co., Ltd. Other authors declare that there are no conflicts of interest in relation to this study. We declare the following interests within the past 3 years: TKishi, TKato, and NI. TKishi has received speaker's honoraria from Sumitomo, Eisai, Janssen, Otsuka, Meiji, Tanabe-Mitsubishi, Viatris, and Takeda and research grants from Eisai, the Japanese Ministry of Health, Labour and Welfare, Grant-in-Aid for Scientific Research, and Japan Agency for Medical Research and Development. TKato reports grants and personal fees from Sumitomo Pharma Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Meiji Seika Pharma Co., Ltd., Shionogi & Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Eisai Co., Ltd., personal fees from Taisho Pharma Co., Ltd., Mochida Pharmaceutical Co., Janssen Pharmaceutical K.K., Janssen Asia Pacific, Yoshitomiyakuhin, MSD K.K., Kyowa Pharmaceutical Industry Co., Ltd., Taisho Pharmaceutical Co., Ltd., Teijin Pharma, Viatris, Mylan N.V., outside the submitted work. He is an Editor-in-Chief of Psychiatry and Clinical Neurosciences (Editor in Chief), and a chair of Bipolar Disorder Committee and a member of Treatment Guidelines Committee of the Japanese Society for Mood Disorders. NI has received speaker's honoraria from Sumitomo, Eisai, Eli Lilly, Janssen, Takeda, Meiji, Tanabe-Mitsubishi, Otsuka, and Viatris and research grants from Daiichi Sankyo, Eisai, Takeda, Sumitomo, Meiji, Tanabe-Mitsubishi, and Otsuka. ETHICS STATEMENT Approval of the Research Protocol by an Institutional Reviewer Board: N/A. Informed Consent: N/A. Registry and the Registration No. of the Study/Trial: N/A. Note that the data on which this post-hoc study is based was collected in a clinical trial with clinical trial registration number NCT01986101 in clinicaltrials.gov. Animal Studies: N/A. Supporting information Table S1. Click here for additional data file. ACKNOWLEDGMENTS We thank all participants of the current study. DATA AVAILABILITY STATEMENT Data sharing statement is as follows: Sumitomo Pharma Co., Ltd. makes individual patient, de-identified data sets, and associated clinical documents such as study protocol, statistical analysis plan, and clinical study report available upon request via the Clinical Study Data Request site ) within 12 months of posting the study results on clininicaltrials.gov. Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months. |
Heliyon Heliyon Heliyon 2405-8440 Elsevier S2405-8440(23)01245-8 10.1016/j.heliyon.2023.e14038 e14038 Case Report A case report of a self-inserted foreign body in the urethra/bladder causing urinary calculus formation, and a review of the literature Fotovat Amirreza a Yavari Samira b Ayati Mohsen a Nowroozi Mohammad Reza a Sharifi Laleh [email protected] [email protected] a* a Uro-Oncology Research Center, Tehran University of Medical Sciences, Tehran, Iran b Department of Anesthesiology, School of Medicine, Esfahan University of Medical Sciences, Esfahan, Iran * Corresponding author. Uro-Oncology Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran. [email protected][email protected] 26 2 2023 3 2023 26 2 2023 9 3 e1403813 12 2022 17 2 2023 20 2 2023 (c) 2023 The Authors 2023 This is an open access article under the CC BY license ). Several self-inserted foreign bodies have been reported in the lower genitourinary system. We report a 27-year-old man with suprapubic severe pain, purulent discharge from the urethra, and dribbling. He had a history of psychotic disorders and inserting an ink chamber of a pen into the urethra. Imaging showed hydronephrosis and a large urinary stone in the bladder with no sign of foreign body. During open cystotomy, we found that bladder stone was attached to a plastic tube that was extended into the patient's urethra. In such cases, timely surgery to prevent urinary retention and psychological support are required. Keywords Lower genitourinary system Foreign body Bladder Urethra Hydronephrosis Bladder stone pmc1 Introduction Several self-inserted foreign bodies have been reported in the lower genitourinary system, such as screws, pens, nuts, cables, etc. . Foreign objects in the lower urinary tract are often associated with long-term complications such as urinary tract infection (UTI), hematuria, increased urinary frequency, dysuria, urethral false passages, stricture, fistula, and pain . Self-insertion of objects into the urinary tract is quite rare in emergency visits. Imaging is necessary to detect the position, shape, and size of foreign bodies . Here, we report a male patient with transurethral self-insertion of the ink chamber of a pen into the urethra which caused a large calculus formation in the bladder. Case presentation: A 27-year-old man with the chief complaint of suprapubic severe pain, purulent discharge from the urethra, and dribbling was referred to a tertiary private clinic in Golpaygan, Iran. He declared a history of psychotic disorders and initiation of the signs after he attempted to insert a pen tube into the urethra. Laboratory examination confirmed a severe urinary tract infection (UTI) and creatinine equal to 2. X-ray and CT scan showed a large urinary stone in the bladder occupying almost all of the intravesical space with no sign of foreign object (Fig. 1, Fig. 2B), and mild to moderate bilateral hydronephrosis (Fig. 2A). The patient underwent open cystotomy with an initial diagnosis of bladder calculus and the possibility of a foreign body in the urethra and bladder.Fig. 1 Abdomen X-ray of the patient, showed a large urinary calculus in the bladder. Fig. 1 Fig. 2 CT scan without contrast showed: A-mild to moderate bilateral hydronephrosis, large urinary calculus in the bladder. Fig. 2 After opening the bladder during the surgical procedure, we discovered that the bladder stone was attached to a plastic tube that was extended into the patient's urethra (Fig. 3). According to the patient's history, we found out that the patient tried to insert a pen ink chamber inside the urethra, and probably it's plastic material and ink secretions led to bladder irritation and stone formation.Fig. 3 Removed bladder calculus attached to plastic ink chamber of pen. Fig. 3 Two days later, the patient was discharged in good general condition. The patient followed for checking the recovery status after surgery after 3 months. He had no pain or any sign of urethral obstruction and urinary retention. Blood examinations including UA, UC, and creatinine were normal. Control sonography showed no sign of hydronephrosis or complications such as a urethral stricture. The patient was referred to a psychology clinic to prevent other probable problems. Written informed consent was obtained from the patient for the publication of the collection of his clinical data. 2 Discussion Mostly, foreign bodies have been reported in the respiratory and gastrointestinal systems, but there is limited literature on the case of the lower urinary system. including case reports and small case series and there is a lack of data regarding management and epidemiology in this regard . Some of the unusual foreign bodies have been reported to be self-inserted into the urethral/vesicle such as olive seeds , Allen key , Tongue cleaner , Nail scissor , a telephone cable . Dayron Rodriguez et al., in 2020 showed that genitourinary foreign bodies have a crucial burden on healthcare systems. They found that they occurred frequently in younger female patients but penile and urethral/bladder foreign objects are more frequent in older men and were related to longer hospital admission days and costs . Some behaviors such as autoerotic stimulation, intoxication, senility, Psychosis With or Without Mood Disturbance, Cognitive Disorders, Malingering, and stash of drug through the urethra into the bladder to escape prosecution are reported as the cause of the self-insertion of foreign objects [ , , ]. Even, a suicidal attempt through the transurethral insertion of a cylindrical foreign body via the urethra causing bladder perforation has been reported. Autoerotic or accidental death was ruled out by psychological autopsy and this unique and painful method of suicide was confirmed . Almost one-third of male patients who suffered urethra/bladder foreign bodies had a history of major mental disorders . In addition to cistolithotomy and stone removal, patients should undergo a timely psychological evaluation. Determining predisposing factors of foreign body insertion can lead to management approaches that affect behavior motivation. Failure to recognize the underlying cause leaves the patient at risk of repeated injury. Medical personnel should be qualified to come across such patients. Sometimes, staff reactions such as confusion, laughter, derision, fear, embarrassment, and anger to such behaviors are severe and can disturb their compassionate role in treatment . Most foreign objects in the urinary system can be removed endoscopically but in the case of our patient, open surgical removal was necessary due to the large calculi formation in the bladder. Urethral stenosis is common after the removal of foreign objects because of tissue injury; therefore, antibiotics and tetanus prophylaxis are essential after surgical interventions . Foreign bodies in the bladder are the main risk factor for larger bladder stones. Any foreign body that makes its way into the bladder can act as scaffolding for calculus construction. The formation of stones is a step-by-step mechanism that has been well presented in the literature . Also, there are reports that urinary calculus in the bladder is associated with the risk of renal failure . Three reasons are described for the miss-diagnosis of self-inserted urethral foreign bodies. The first reason is the rare occurrence of this situation. Second is not having a correct history of the disease due to the unwillingness of patients to give information and third is the inefficiency of simple X-ray imaging to detect radiolucent objects . Although, our patient met all the possibilities of miss-diagnosis, fortunately, he underwent tempestive treatment due to the formation of a large stone in the bladder. Our case had developed bilateral hydronephrosis and mild renal failure because of his large bladder stone; but, timely surgery prevented bladder outlet obstruction and medical examination 3 months after the operation confirmed his complete recovery. 3 Conclusion The presented patient in this report was a case of self-inserted trans-urethral ink chamber of a pen leading to a large stone formation in his bladder. Timely removal of the stone prevented bladder outlet obstruction and reversed hydronephrosis. Psychological counseling and psychotherapy can be effective in preventing the recurrence of such cases. Author contribution statement All authors listed have significantly contributed to the investigation, development and writing of this article. </p> Funding statement This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Data availability statement No data was used for the research described in the article. Additional information No additional information is available for this paper. Declaration of competing interest The authors declare no competing interests. References 1 Tuncer H. Karacam H. Cam B. A self-inserted foreign body in the urinary bladder and urethra Cureus 13 7 2021 Jul 11 e16322 10.7759/cureus.16322.eCollection2021Jul 2 Winot S. Hill A.C. Simon E.L. A case report you can't make up: a bladder foreign body J. Emerg. Med. 61 1 2021 73 75 33972134 3 Rodriguez D. Epidemiology of genitourinary foreign bodies in the United States emergency room setting and its association with mental health disorders Int. J. Impot. Res. 32 4 2020 426 433 31506609 4 Bayraktar Z. Albayrak S. A self-inflicted male urethral/vesical foreign body (olive seed) causing complete urinary retention Urology Case Reports 16 2018 83 85 29204360 5 Mitterberger M. Allen key completely in male urethra: a case report Cases Journal 2 1 2009 7408 19829954 6 Dinesh A. Singh A. Neogi S. Tongue cleaner, an unusual foreign body in the urethra: a case report Australas. Med. J. 6 10 2013 Oct 31 508 510 10.4066/AMJ.2013.1851.eCollection2013 24223067 7 Cam B. Nail scissor as a rare foreign body in the urethra: case report Cureus 11 1 2019 Jan 8 e3851 10.7759/cureus.3851 8 Trehan R.K. Successful removal of a telephone cable, a foreign body through the urethra into the bladder: a case report J. Med. Case Rep. 1 153 2007 1752 1947 9 Mahadevappa N. Self-inflicted foreign bodies in lower genitourinary tract in males: our experience and review of literature Urol. Ann. 8 3 2016 338 342 27453657 10 Alemi M. Sardari Masihi M. Rare case of drug packing through urethra into the bladder with consequent bladder stone formation J-Res-Urol 4 1 2020 19 23 11 Unruh B.T. Insertion of foreign bodies (polyembolokoilamania): underpinnings and management strategies Prim Care Companion CNS Disord 14 1 2012 16 12 Diggs C.A. Suicidal transurethral perforation of bladder Am. J. Forensic Med. Pathol 7 2 1986 169 171 3740016 13 Komeya M. A huge bladder calculus causing acute renal failure Urolithiasis 41 1 2013 Feb 85 87 10.1007/s00240-012-0517-8 Epub 2012 Dec 21 23532429 14 Minter J. Chiovaro J. Renal failure with a large bladder calculus related to a foreign body: a case report Clin Case Rep 2 2 2014 48 50 25356243 |
Microbiology (Reading) Microbiology (Reading) micro micro Microbiology 1350-0872 1465-2080 Microbiology Society 36848206 001310 10.1099/mic.0.001310 Editorials Microbial Musings - Winter 2022 Thomas Gavin H. 1 * 1 Department of Biology, University of York, York, UK *Correspondence: Gavin H. Thomas, [email protected] 2022 31 12 2022 31 12 2022 168 12 micro00131014 2 2023 (c) 2023 The Authors 2023 This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author's institution. OpenAccessEmbargo0 pmcFull-Text As we close another year with microbiology still on our minds through continued circulation of SARS-COV-2 variants, a bacterial pathogen has now come into the public's attention in the UK with a number of deaths of children linked to Streptococcus pyogenes infections (Strep A). This bacterium is the cause of scarlet fever, a disease that has massively reduced in occurrence in the twentieth century, but is carried as a commensal by up to 15 % of children . As well as other diseases milder than scarlet fever, infection by the bacterium can also lead to rarer cases of invasive disease, which was the cause of the tragic child deaths in the UK. The bacterium generally responds well to antibiotic treatment in mild cases, which combined with a large decrease in the occurrence of scarlet fever has removed this pathogen from most people's attention, but clinicians and microbiologists recognize that it is still able to cause explosive outbreaks and remains circulating in the general population . A cousin of S. pyogenes is the feature of a new Microbe Profile and is another important human pathogen, that similarly was a major cause of mortality under the advent of antibiotics. This bacterium, Streptococcus pneumoniae , inhabits the upper respiratory tract of humans, often asymptomatically, but can then spread to other body sites and cause pneumonia, meningitis or otitis media (inner ear infection). The biology of this bacterium is described by Hasan Yesilkaya, Marco Oggiani (@mr_oggioni) and Peter Andrew from the University of Leicester, UK, who very clearly summarize its key features . It has a smallish genome of around 2 Mb, which encodes genes for a mainly sugar-based fermentative metabolism. The cells are usually seen as diplococci in spherical or lancet shapes (they look like two arrow heads pointing away from each other) and are non-motile. A key feature is their capsule layer, for which over 100 different biochemical forms are known. Capsular (smooth) and lab-isolated acapsular (rough) derivatives were indeed the basis of Griffith's landmark work on transformation in the 1920s after the bug had been first isolated by Pasteur back in 1881. Its genetic plasticity is another feature, which is mainly recombination based, allowing it to rapidly change capsule loci for example. The ability of streptococci to evolve rapidly also is aided by their high level of genetic competency and this links to another paper in this quarter on the mechanisms of this process in the related species Streptoccocus sinensis, another of the Mitis group of streptococci , but one which is able to infect heart valves in humans (endocarditis). The process of genetic competence is well understood in S. pneumoniae , where a competence-stimulating peptide (CSP) is the signal in a quorum-sensing-based mechanism . In this study from Alec Brennan, Anthony Harrington and colleagues in the group of Ytfah Tal-Gan at the University of Nevada, Reno (@unevadareno), USA, the authors wished to understand how similar this process is in S. sinensis . Typically in these systems a small propeptide, ComC, is secreted by the ComAB ABC transporter and accumulates in the immediate environs of the bacteria to be sensed by a receptor ComD and which subsequently activates a transcription factor ComE, that controls expression of other genes in a cascade, which leads to full competency within about 15 min. Here they first identify the processed ComC peptide, the CSP., by examining predictions from the genomes of S. sinensis and assessing peptides found in cell-free supernatant using mass spectrometry. They find a 16 amino peptide that shares similarity with other Mitis group streptococci, although there is significant sequence diversity amongst the different species. This CSP is released from early to mid-log phase as judged by the activation of expression of the comX gene that is switched on by the quorum-sensing pathway being activated. They show that synthetic CSP from their strain-induced competence, but this was not observed using a distinct CSP from a related strain, demonstrating high specificity of this sensing mechanism. To see which other genes are switched on they isolated RNA from matched cultures with added synthetic CSP or a DMSO control and used RNAseq to determine the differentially expressed genes. They find many of the genes they would have predicted to be involved in competence development, as expected, but also other genes involved in biofilm production and virulence. However, they directly assess biofilm formation in response to different concentrations of CSP and see no direct impact on this phenotype, suggesting there is additional regulatory control of biofilm formation, and they propose the differential regulation of some of the genes involved in this pathway by CSP might have become relevant during growth in the natural polymicrobial oral cavity. Sticking with the streptococci for a final paper on this genus of bacteria, we switch to the work of Microbiology Editor Andy Edwards (@bugsinblood) and his team at Imperial College, London . Authors Alicia Tickle and Elizabeth Ledger continue some research examining the effect of human serum on antibiotic resistance of important pathogens, following their earlier work on Staphylococcus aureus . They examine the response of streptococci to the membrane targeting antibiotic daptomycin and find the pre-exposure of the viridans group streptococci (VGS), namely, Streptococcus gordonnii and Streptococcus mutans , as well as related enterococci, to human serum, produces a high level of tolerance . They knew from their work in S. aureus that serum exposure leads to peptidoglycan accumulation and this was also observed in the bacteria studied in this paper. The lipid cardolipin was also implicated in the serum resistance mechanism, with a reduction in the effect when both cardiolipin synthases were removed, which likely has a pleitrophic effect on many membrane functions and this reduction was found to be independent from that of peptidoglycan overproduction. Together these data suggest mechanisms for the lack of efficacy of daptomycin in the body, mediated by serum-induced responses in multiple bacteria. However, their data also suggest routes to enhance daptomycin killing in vivo by, for example, the use of fosfomycin to inhibit the overproduction of peptidoglycan. One phenotype of bacterial cells that has come under much study and scrutiny is the phenomenon of persistence, namely the process where under some strong and sustained stress, such as antibiotic treatment, a subpopulation of cells survive and can grow again when the stress is removed. Xiaoyi Shi and Ashraf Zarken from the University of Cambridge, UK, present a detailed and critical analysis of the literature covering the different known triggers of persister formation, ranging from toxin-antitoxin modules, indole signalling and quorum sensing, which together suggest that multiple routes are likely to lead to persister formation . In this wide-ranging review they also consider the nature of persister formation as a stochastic or deterministic process and the potential involvement of epigenetic mechanisms. Finally, they assemble a table of pathogens and clinically relevant antibiotics and argue that these are the combinations that should be used to learn about persisters in more clinical settings. Reflecting on a key methodological step in the study of persisters, namely the isolation of surviving sub-populations, a related Methods papers was also published in this quarter outlining a flow-cytometry protocol to identify Pseudomonas aeruginosa persister cells . The protocol, from Shannon Grandy, Renee Raudonis and Zhenyu Cheng at Dalhousie University, Canada, presents their analysis of the best dyes to use with different strains of P. aeruginosa for the identification and isolation of antibiotic-induced persister cells. The staining and sorting can distinguish persisters from dead cells, however, they do note that even with improved recovery of persisters, they were unable to routinely regrow them on agar or in broth culture when isolated after long (24 h) treatment times with antibiotics, and while the media does make a difference in recovery rates, they propose that perhaps for cells in the persister states for this longer duration, addition cues beyond simple nutritional ones might be required. Next up is a nice review from Michelle Kammel , which follows on from two papers published in the journal of her work in Gary Sawer's group in Halle, Germany, on the mechanisms by which enterobacteria control the metabolic fate of formate . Briefly, this small organic acid is a major fermentation product of the enterobacterial mixed-acid fermentation and once made in the cytoplasm has two possible fates depending on other physiological factors in the cells. One of these uses formate in the cytoplasm and the other formate in the periplasm and so the FocA channel has a key role in controlling this partitioning of the substrate, and Kammel describes the latest research in understanding the function and regulation of this pentameric channel protein with some beautiful illustrations. Continuing the theme of the controlled movement of small molecules across membranes, transport, I want to unashamedly mention a paper from Adam Hughes and colleagues from the group of Anthony Wilkinson, from the York Structural Biology Laboratory (@YSBL_York), York, UK, as its back story is a nice example of a serendipitous observation leading into some nice insight into the evolution of ligand-binding specificity in proteins. I have been working with Tony for over a decade, always slightly awed by knowing that his group was the first to figure out how a general peptide transporter, in this case the Opp oligopeptide transporter from Salmonella enterica subsp. Typhimurium, was able to recognize almost any peptide between two to five amino acids by using only interactions between the main chain of the peptide ligand and the OppA protein and accommodating the variable amino acid side chains in water-filled pockets . Later we worked together to understand how a protein related to the OppA protein, known as a substrate-binding protein (SBP), was able to bind a specific peptide, in this case the murein tripeptide (Mtp) that is released in the periplasm of Escherichia coli during normal growth and then recycled . This protein, MppA, which originated through duplication of oppA and subsequent modification, now recognizes specifically the Mtp and murein tetrapeptide over any other peptide by using specific protein-ligand contacts that are selected against in the 'generalist' OppA protein. Jump forward a few years and Adam Hughes in Tony's lab included some peptide-binding SBPs to study in his PhD project on the structural biology of proteins involved in sporulation in Bacillus subtilis . DppE is a known peptide-binding SBP that was named after its apparent ability to bind and transport dipeptides, however, Adam discovered that when he crystalized it there was density in the binding site that was unambiguously Mtp! He showed the protein really did bind Mtp and we did some genome context analysis and realised the transporter genes sit with other genes we had previously implicated in Mtp recycling . Hence by comparing by MppA and DppE to the ancestral OppA we could see that both proteins had evolved to introduce the required specific contacts to become Mtp specific, but had changed different residues in the protein to create the same binding site through different evolutionary trajectories - a clear example of convergent evolution of a biochemical function. We close with a slightly more unusual, but likely highly referenced, publication from Abigail Bartlett and colleagues including Daniel Padfield (@padpadpadpad) in the group of Michiel Vos (@Michiel_Vos_010) at the University of Exeter, UK, who have completed a major task in assembling in a single publication a list of all bacteria that have been reported to infect humans . Although most of us can probably easily think of a few dozen pathogens, and medically minded microbiologists perhaps a few hundred, but they find over 1500 bacterial species implicated in human disease. About three quarters of these are 'established' pathogens, while the remainder they class as 'putative' as they have been found in fewer than three studies. What is fascinating is that these bacteria span 10 phyla and 24 classes of the bacterial world. They finish their mammoth task with a request - can somebody take on the task of converting this into a database and keeping this up to date for microbiologists? Sounds like a fantastic opportunity for some open science and collaborative and outreach opportunity that the Microbiology Society might support? We will be back in 2023 for more microbiology news and commentary when the journal moves to full open access (OA) meaning that everybody can read both the Musings and all the papers that are being described for free! Exciting times. Funding information This work received no specific grant from any funding agency. Conflicts of interest The author(s) declare that there are no conflicts of interest. Abbreviations: CSP, Competance stimulating peptide; Mtp, Murein tripeptide; OA, Open access; SBP, Substrate binding protein; VGS, Viridans group Streptococci. References 1 Wong SSY Yuen KY Streptococcus pyogenes and re-emergence of scarlet fever as a public health problem Emerg Microbes Infect 2012 1 e2 10.1038/emi.2012.9 26038416 2 Yesilkaya H Oggioni MR Andrew PW Streptococcus pneumoniae: "captain of the men of death" and financial burden Microbiology 2022 168 10.1099/mic.0.001275 3 Thomas GH Griffith, Frederick (1877-1941), microbiologist Oxford Dictionary of National Biography 2018 10.1093/odnb/9780198614128.013.51622 4 Brennan AA Harrington A Guo M Renshaw CP Tillett RL et al Investigating the Streptococcus sinensis competence regulon through a combination of transcriptome analysis and phenotypic evaluation Microbiology 2022 168 10.1099/mic.0.001256 5 Brennan AA Mehrani M Tal-Gan Y Modulating streptococcal phenotypes using signal peptide analogues Open Biol 2022 12 220143 10.1098/rsob.220143 35920042 6 de Groot RJ Structure, function and evolution of the hemagglutinin-esterase proteins of toroviruses Glycoconj J 2006 23 59 72 10.1007/s10719-006-5438-8 16575523 7 Ledger EVK Mesnage S Edwards AM Human serum triggers antibiotic tolerance in Staphylococcus aureus Nat Commun 2022 13 2041 10.1038/s41467-022-29717-3 35440121 8 Ledger EVK Sabnis A Edwards AM Polymyxin and lipopeptide antibiotics: membrane-targeting drugs of last resort Microbiology 2022 168 001136 10.1099/mic.0.001136 35118938 9 Tickle ARH Ledger EVK Edwards AM Human serum induces daptomycin tolerance in Enterococcus faecalis and viridans group streptococci Microbiology 2022 168 001282 10.1099/mic.0.001282 10 Shi X Zarkan A Bacterial survivors: evaluating the mechanisms of antibiotic persistence Microbiology 2022 168 10.1099/mic.0.001266 11 Grandy S Raudonis R Cheng Z The identification of Pseudomonas aeruginosa persisters using flow cytometry Microbiology 2022 168 10.1099/mic.0.001252 12 Kammel M Pinske C Sawers RG FocA and its central role in fine-tuning pH homeostasis of enterobacterial formate metabolism Microbiology 2022 168 10.1099/mic.0.001253 13 Kammel M Sawers RG The FocA channel functions to maintain intracellular formate homeostasis during Escherichia coli fermentation Microbiology 2022 168 1 6 10.1099/mic.0.001168 14 Kammel M Trebbin O Pinske C Sawers RG A single amino acid exchange converts FocA into a unidirectional efflux channel for formate Microbiology 2022 168 001132 10.1099/mic.0.001132 35084298 15 Tame JR Dodson EJ Murshudov G Higgins CF Wilkinson AJ The crystal structures of the oligopeptide-binding protein OppA complexed with tripeptide and tetrapeptide ligands Structure 1995 3 1395 1406 10.1016/s0969-2126(01)00276-3 8747465 16 Sleigh SH Tame JR Dodson EJ Wilkinson AJ Peptide binding in OppA, the crystal structures of the periplasmic oligopeptide binding protein in the unliganded form and in complex with lysyllysine Biochemistry 1997 36 9747 9758 10.1021/bi970457u 9245406 17 Maqbool A Levdikov VM Blagova EV Herve M Horler RSP et al Compensating stereochemical changes allow murein tripeptide to be accommodated in a conventional peptide-binding protein J Biol Chem 2011 286 31512 31521 10.1074/jbc.M111.267179 21705338 18 Maqbool A Herve M Mengin-Lecreulx D Wilkinson AJ Thomas GH MpaA is a murein-tripeptide-specific zinc carboxypeptidase that functions as part of a catabolic pathway for peptidoglycan-derived peptides in g-proteobacteria Biochem J 2012 448 329 341 10.1042/BJ20121164 22970852 19 Hughes AM Darby JF Dodson EJ Wilson SJ Turkenburg JP et al Peptide transport in Bacillus subtilis - structure and specificity in the extracellular solute binding proteins OppA and DppE Microbiology 2022 168 10.1099/mic.0.001274 20 Bartlett A Padfield D Lear L Bendall R Vos M A comprehensive list of bacterial pathogens infecting humans Microbiology 2022 168 2022 10.1099/mic.0.001269 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34851 Endocrinology/Diabetes/Metabolism Internal Medicine Neurology Amyotrophic Lateral Sclerosis-Related Respiratory Failure and Association With Inappropriate Secretion Syndrome of the Antidiuretic Hormone Muacevic Alexander Adler John R Ceriz Tiago Sr. 1 Diegues Andreia 1 Alves Sergio R 2 Simoes Pedro 1 Blanco Miriam P 2 1 Internal Medicine Department, Unidade Local de Saude do Nordeste, Braganca, PRT 2 Internal Medicine Department, Unidade Local de Saude de Braganca, Braganca, PRT Tiago Ceriz Sr. [email protected] 10 2 2023 2 2023 15 2 e348519 2 2023 Copyright (c) 2023, Ceriz et al. 2023 Ceriz et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from There is an unclear association between the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and amyotrophic lateral sclerosis (ALS), with few reports in the literature. We report the case of an 80-year-old man admitted to our emergency room with asthenia, dysphonia, dysphagia, weight loss, and euvolemic hyponatremia, indicating a SIADH. Posteriorly, the patient also developed respiratory failure, which, in association with the previous clinical presentation, led to the diagnosis of ALS. During her permanence at the hospital, the hyponatremia improved with noninvasive positive-pressure ventilation, and the association between these two identities was made. This case also shows that patients with ALS commonly suffer from chronic respiratory failure and still have a reserved prognosis. narcosis respiratory failure amyotrophic lateral sclerosis hyponatremia inappropriate secretion of antidiuretic hormone The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Hyponatremia is the most common hydroelectrolytic disorder in hospitalized patients. It is defined as excess water in relation to sodium in the extracellular fluid . There are different etiologies, with the syndrome of inappropriate antidiuretic hormone secretion (SIADH) being one of the more frequent causes . SIADH is a disorder of impaired water excretion caused by the inability to suppress the secretion of antidiuretic hormone (ADH) . This should be suspected in any patient with hyponatremia, hypoosmolality, and urine osmolality above 100 mosmol/kg . The etiology includes pathologies from different categories, such as drugs, neoplasia, disorders of the central nervous system (CNS), pulmonary diseases, surgery, hormone deficiency, HIV infection, and idiopathic causes. A large group of CNS disorders can be associated with SIADH, but the underlying mechanism that leads to hyponatremia in this particular group remains unclear . However, a few hypotheses are that in some cases, CNS disorders may stimulate the release of antidiuretic hormone from the neurohypophysis, and in other cases, severe restrictive respiratory failure requiring mechanical ventilation may cause hypersecretion of antidiuretic hormone, as in amyotrophic lateral sclerosis (ALS). Although rare, the association between SIADH and ALS has been described in a few cases. ALS is a debilitating, progressive disease with degeneration of motor neurons in the brain and spinal cord, causing weakness, muscle atrophy, fasciculations, and spasticity , as described in Canadian best practice recommendations for the management of amyotrophic lateral sclerosis . It is an etiologically diverse clinical entity that is the result of a combination of multiple preceding aberrations. The most common presentation, in about 70% of patients, is symptom onset in the limbs, with extremity weakness and impairment in mobility . Bulbar onset, with oropharyngeal muscle involvement affecting swallowing and speech, occurs in about 25% of cases . In addition to motor impairment, degeneration in the frontal and temporal lobes, resulting in cognitive or behavioral impairments, occurs in up to 50% of patients . The diagnosis of ALS is primarily clinical, but electrodiagnostic studies can further support the diagnosis, especially if the clinical picture is unclear. There are four categories that reflect the degree of clinical involvement described by the World Federation of Neurology (WFN) . Like the Canadian best practice recommendations for the management of amyotrophic lateral sclerosis, over time, strength progressively declines, and patients typically die from respiratory failure within five years of diagnosis. Despite increased research efforts in recent years, treatment options for ALS remain limited, and patient care is focused primarily on managing symptoms and optimizing function and quality of life , provided by a multidisciplinary team . The treatment of hyponatremia in SIADH includes the treatment of the underlying cause, initial therapy to raise the serum sodium, and sometimes prolonged therapy when persistent SIADH is identified . Here, we describe a case of a patient who initially presented with hyponatremia of multifactorial etiology and maintained the imbalance after the removal of all the predisposing factors and drugs. Additionally, besides hyponatremia, the patient also had unspecified dysphagia that evolved into narcosis, which led to the diagnosis of ALS . These two factors confirmed the diagnosis of ALS associated with SIADH. Case presentation An 80-year-old man was admitted to the emergency department due to asthenia, dysphonia, intermittent dysphagia for liquids and solids, and a weight loss of 14 kg in four months. This patient had prostatic benign hyperplasia, type 2 diabetes mellitus, atrial fibrillation, ischemic heart disease, and chronic heart failure as comorbidities and was being treated with furosemide, metolazone, eplerenone, carvedilol, amiodarone, apixaban, tamsulosin, omeprazole, ticagrelor, and acetylsalicylic acid. At admission, the examination revealed an arterial blood pressure of 108/59 mmHg, a heart rate of 60 bpm, and oxygen saturation levels of 95%. Of note is that the patient was euvolemic and had significant weight loss. A neurological examination revealed muscular atrophy without further alterations. The initial laboratory study showed hyponatremia (sodium levels of 122 mg/dL) and serum hypoosmolarity (253 mOsm/kg, with normal values between 280 and 300 mOsm/kg). Five days after thiazide suspension, sodium levels were 126 mg/dL and serum osmolarity was 264 mOsm/kg, with increased urinary sodium excretion, urinary osmolarity of 520 mOsm/kg, fractional sodium excretion of 1.5%, and without clinical signs of volume depletion or overload of extracellular fluid, suggesting SIADH (Tables 1-2). Table 1 Blood laboratory results - hospital admission ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; LDH: lactate dehydrogenase. Parameter Result Reference range Admission After stop thiazide Blood tests Hemoglobin 14.1 - 14-17.5 (g/dL) Leukocytosis 5.6 - 4.4-11.3 (x109/L) Platelet 223 - 150-450 (x109/L) Sodium 122 126 134-145 (mEq/L) Potassium 3.6 3.8 3.5-5.1 (mEq/L) Chloride 101 98 98-107 (mEq/L) Urea 20 19 17-43 (mg/dL) Creatinine 1.35 1.28 0.91-1.44 (mg/dL) Glucose 95 93 74-106 (mg/dL) AST 38 - <45 (IU/L) ALT 31 - <35 (IU/L) ALP 110 - 30-120 (IU/L) GGT 42 - <55 (IU/L) Total bilirubin 1.1 - 0.3-1.2 (mg/dL) Serum albumin 3.7 - 3.4-4.8 (g/dL) Total protein 7.3 - 6.6-8.3 (g/dL) Creatine kinase 178 157 <171 (IU/L) LDH 237 222 <248 (U/L) Reactive protein 0.05 - <0.1 (mg/dL) Table 2 Urinalysis results - hospital admission Parameter Result Reference range Urinalysis Urine osmolarity 520 300-900 (mOsm/kg) Urine sodium 88 40-220 (mEq/L) Urine potassium 31 20-60 (mEq/L) Urine creatinine 64 22-328 (mg/dL) The chest X-ray at admission showed no acute pleuroparenchymal abnormalities. Other causes of hyponatremia were excluded during the hospital stay, namely thyroid dysfunction, renal failure, and glucocorticoid deficit (Table 3). Table 3 Laboratory results - study during hospitalization ACTH: adrenocorticotropic hormone; BNP: B-type natriuretic peptide; C: complement; CMV: cytomegalovirus; HDL: high-density lipoprotein; Ig: immunoglobulin; LDL: low-density lipoprotein; TSH: thyroid stimulating hormone; T4: thyroxine; VDRL: venereal disease research laboratory. Parameter Result Reference range BNP 32 <100 (pg/mL) B12 vitamin 435 187-883 (pg/mL) Acid folic 12 3.1-20.5 (ng/mL) Ferrum 88 60-180 (ug/dL) Ferritin 200 4.63-204.00 (ng/mL) Transferrin saturation 26 20-50 (%) Uric acid 3 2.6-6.0 (mg/dL) Total cholesterol 180 <200 (mg/dL) LDL cholesterol 78 <155 (mg/dL) HDL cholesterol 47 30-60 (mg/dL) Triglycerides 143 <150 (mg/dL) TSH 0.77 0.35-4.94 (uUI/ml) Free T4 1.51 0.70-1.48 (ng/dL) Morning serum cortisol 15.1 6.2-19.4 (ug/dL) ACTH 29.2 7.2-63.3 (pg/mL) VDRL Negative HIV 1+2 Negative Antibodies anti-CMV IgG 1647.3 <6.0 - negative (UA/mL) Antibodies anti-CMV IgM 0,08 <0.85 >1.00 index - positive HBsAg 0.19 <1 - negative Anti-HBs >1000.00 <10.00 - no reactive Anti-HBc 0.88 <1.000 - no reactive Anti-HCV 0.11 <1 - negative IgG 13.15 7.0-16 (g/L) IgA 2.7 0.70-4.00 (g/L) IgM 1.01 0.4-2.3 (g/L) C3 1.00 0.9-1.8 (g/L) C4 0.33 0.1-0.4 (g/L) The etiological investigation and treatment of SIADH became a challenge, with slight correction of hyponatremia initially with the suspension of metolazone but without normalization. A thoracic and abdominopelvic computed tomography (CT) was performed, revealing calcified lymphadenopathy in the right hilum and subcarinal region, no pleural effusion, and no abdominal or pelvic alterations. Cerebral CT did not reveal alterations suggestive of space-occupying lesions, reporting signs of ischemic leukoencephalopathy and permeable cerebrospinal fluid pathways. Neck CT showed pneumatized sinus cavities without soft tissue thickening of the posterior cavum wall or appreciable deviation of the median raphe, describing infracentimetric lymph nodes in the jugular and posterior cervical chains and bilateral submandibular topography. The thyroid had regular contours, normal volume, and homogeneous enhancement. The upper gastrointestinal endoscopy also showed no alterations. Despite instituted measures, such as NaCl infusion at the beginning and then water restriction, a few days later patient s hyponatremias worsened and clinical dysphagia is more evident, with progressive respiratory insufficiency (RI) and carbon dioxide narcosis with the need for non-invasive positive-pressure ventilation (NPPV), that resulted in improvements, not only in ventilatory dynamics but also in hyponatremia. However, the patient's clinical condition and RI deteriorated again due to the development of nosocomial pneumonia, requiring invasive ventilation and admission to the intensive care unit (ICU). In the ICU, no microbiological isolations were made, and the patient completed a course of antibiotic therapy with ceftriaxone plus clarithromycin. Regardless of the infectious condition improvement, the respiratory failure was not showing the same clinical response. At this point, motor neuron disease is highly suspected, and the patient started riluzole with a slight improvement in his condition. Electromyography was then performed, revealing criteria for active denervation on the four limbs and trunk-findings that, together with the clinical evolution, are compatible with the diagnosis of ALS. Later, difficulty in ventilatory weaning led to a tracheostomy and a change to hybrid ventilation; however, the patient's clinical condition kept declining in spite of all the measures taken, and the patient died after 48 days of hospitalization . Figure 1 Clinical course, laboratory results and treatment evolution during hospitalization Serum sodium (mmol/L) and pCO2 (mmHg) arterial blood gas evolution during hospitalization and clinical course and treatment description as below. A - First five days: Patient stop diuretics and started NaCl infusion. B - At 5th day new sodium worsening despite treatment. Clinically euvolemia, SIADH suspicion. Patient started fluid restriction with slightly improvement. C - At 9th day observed hypercapnia coma, starting NPPV with improvement of both CO2 and Na+ levels. D - At 19th day patient developing respiratory failure with severe hypoxemia and slightly worsening hypercapnia, needing invasive ventilation. E - At 27th day extubation to NPPV. For motor neuron disease suspicion at 31th day riluzole was started. Although all effort patient day at 48th. Discussion Initially, the diagnosis of SIADH was not made because of the history of diuretic use, but with the elimination of this factor and the presence of clinical euvolemia, urinary osmolarity exceeding 100 mOsm/kg, and other urinary results, the diagnosis was confirmed . The diagnosis of ALS was made by clinic suspicion and confirmed with electromyography results. In SIADH, the only definitive treatment is the control of its underlying cause , so it is important to search for it. As described previously, the association between ALS and SIADH is rare, and the majority of cases described refer to the Asian population. The mechanism underlying this association is not fully understood, but intrathoracic circulatory dysfunction due to the atrophy of the respiratory muscles, leading to hypercapnia and hypoxia, may play a role in the development of SIADH, as possibly seen in this case and as described previously by Yoshida et al . First, hypoxia can cause constriction of the pulmonary vessels and decrease the venous return to the left atrium . Furthermore, it can directly or indirectly stimulate the hypothalamus via the carotid baroreceptors, and at the same time, hypercapnia can stimulate ADH hypersecretion via baroreceptors or by inducing acidosis . In this patient s case, the improvement in sodium level with the use of NPPV corroborates this theory, although there have not been enough studies. There are numerous complications associated with ALS, and in this case, respiratory decline with the necessity of ventilatory support, dysphagia, malnutrition, fatigue, and functional decline due to muscular weakness were observed. Unfortunately, the main treatment available for patients with this condition is symptomatic management and support. As for SIADH, the treatment consists of identification and resolution of the cause; however, in this case, complete management and resolution of the precipitating factors were not possible . Some studies describe Riluzole (50 mg twice per day) as the only drug that has been proven to favorably impact overall survival . Additional pharmacologic therapies are needed, and several clinical trials are currently in development in efforts to improve a prognosis that is still reserved. There are some factors that, if present at diagnosis, are associated with better survival rates; these include increased weight (mild obesity according to the body mass index), younger age, a higher ALS functional rating scale score, a higher forced vital capacity (FVC), and limb rather than bulbar symptoms. However, none of these factors were present in this patient s case . Conclusions We reported a rare finding of ALS-related respiratory failure that might be associated with SIADH. This case highlights the importance of SIADH investigation and the relevance of early recognition of ALS as a possible cause of SIADH. NPPV may ameliorate the control of SIADH in this clinical setting. So, this shows that supportive therapy for respiratory failure related to ALS improved the Na level in this patient. There are very few case reports supporting this theory in the literature. As was seen in this case, the complications associated with amyotrophic lateral sclerosis were diverse, particularly the respiratory decline and the necessity of further ventilatory support, which when associated with nosocomial infections increased the predisposition to poor prognosis and death. Tiago Ceriz and Andreia Diegues contributed equally to the work and should be considered co-first authors. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Clinical practice. The syndrome of inappropriate antidiuresis N Engl J Med Ellison DH Berl T 2064 2072 356 2007 17507705 2 Syndrome of inappropriate antidiuretic hormone secretion associated with amyotrophic lateral sclerosis in a patient developing carbon dioxide narcosis Intern Med Inoue Y Murakami T Nakamura T 797 803 56 2017 28381746 3 Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH) 2021 4 Amyotrophic lateral sclerosis associated with the syndrome of inappropriate secretion of antidiuretic hormone Intern Med Motoo Y Ohta H Okai T Sawabu N 1023 1025 31 1992 1477461 5 Canadian best practice recommendations for the management of amyotrophic lateral sclerosis CMAJ Shoesmith C Abrahao A Benstead T 0 68 192 2020 6 Overview of current and emerging therapies for amytrophic lateral sclerosis Am J Manag Care Chen JJ 0 7 26 2020 7 Urea treatment of syndrome of inappropriate antidiuretic hormone secretion secondary to amyotrophic lateral sclerosis Eur J Case Rep Intern Med Martin FJ Fernandez MG Gonzalez MC Escudero JC 1444 7 2020 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34852 Obstetrics/Gynecology Uterine Rupture With Placenta Percreta Following Multiple Adenomyomectomies Muacevic Alexander Adler John R Ogoyama Manabu 1 Yamamoto Kazuki 1 Suzuki Hirotada 1 Takahashi Hironori 1 Fujiwara Hiroyuki 1 1 Obstetrics and Gynecology, Jichi Medical University, Shimotsuke, JPN Manabu Ogoyama [email protected] 11 2 2023 2 2023 15 2 e3485211 2 2023 Copyright 2023, Ogoyama et al. 2023 Ogoyama et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Pregnancy following adenomyomectomy is challenging because uterine rupture or placenta accreta spectrum (PAS) is more likely to occur; however, optimal management has not yet been established. We herein present a case of uterine rupture with placenta percreta in a pregnant woman who underwent adenomyomectomy twice before pregnancy. Magnetic resonance imaging (MRI) was performed in the second trimester and imminent uterine rupture concomitant with PAS was suspected. The patient was immediately admitted to hospital for careful management. Although failed tocolysis forced delivery at 29 weeks of gestation, managed hospitalization allowed cesarean hysterectomy to be performed uneventfully. Extensive PAS was proven pathologically in the removed uterus. Pregnancies following multiple adenomyomectomies are considered to be high-risk. Therefore, a sufficient explanation of the risks associated with future pregnancies is needed, particularly following second adenomyomectomy. pregnancy cesarean hysterectomy placenta percreta uterine rupture adenomyomectomy The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Adenomyomectomy is one of the effective treatments for adenomyosis. Although dysmenorrhea and/or severe anemia may markedly improve after this procedure, the risk of uterine rupture in subsequent pregnancies is high [1-3]. Uterine rupture associated with a history of adenomyomectomy before pregnancy has two features as follows: it occurs at various stages of gestation [4-6] and is often complicated with placenta accreta spectrum (PAS), particularly placenta percreta. Uterine rupture with or without PAS occurring has been reported in pregnant women with a history of adenomyomectomy . Obstetricians need to consider maternal symptoms, including uterine contractions and abdominal pain, to detect uterine rupture and/or PAS. Most cases achieve a good outcome for both mother and child with the above-described cautious management [2-4,7,9]. However, since uterine rupture is rare, risk factors for uterine rupture in pregnant women with a history of adenomyomectomy before pregnancy currently remain unclear. Furthermore, the optimal management of pregnant women following adenomyomectomy has not yet been established. We herein present a case of uterine rupture with placenta percreta in a pregnant woman who underwent adenomyomectomy twice before pregnancy. Magnetic resonance imaging (MRI) was performed in the second trimester and threatened uterine rupture concomitant with PAS before delivery was strongly suspected. Case presentation A 40-year-old primiparous Japanese woman following in vitro fertilization was referred to our institution, which is a perinatal medical center, at 10 weeks of gestation because she had undergone adenomyomectomy twice before pregnancy. She was complicated by asymptomatic cholelithiasis. At 31 years of age, she underwent laparotomic adenomyomectomy for the first time and right ovarian endometrial cystectomy with severe dysmenorrheal symptoms (the weight of enucleated adenomyotic tissue was 104 g) at other institution. Since dysmenorrheal symptoms recurred, the patient underwent laparotomic adenomyomectomy again and bilateral endometrial cystectomy at the same institution at 38 years of age (the weight of enucleated adenomyotic tissue was 32 g). Adenomyotic tissue occupying the entire posterior wall of the uterus was removed each time, and the remaining anterior myometrium wall was used to form the uterus. The patient conceived 26 months after the second adenomyomectomy. She was admitted to our institute for the treatment of hyperemesis gravidarum from 102/7to 112/7 weeks of gestation. Transvaginal ultrasound revealed a subchorionic hematoma (SCH) of 2816 mm near the endocervical os. SCH extended up to 56 mm in length; however, abdominal pain was not observed at 13 weeks of gestation. Genital bleeding gradually stopped and SCH also shrank. Since the adenomyomectomy scar was present uterine posterior and the placenta was located there, the presence of PAS should be ruled out. However, ultrasound did not clearly show the presence or absence of PAS. MRI was performed at 22 weeks of gestation to evaluate the condition of the uterine wall and placenta because the patient was at high risk of uterine rupture. MRI revealed that the uterine wall was bulging outward from the bottom to the posterior wall of the uterus, suggesting the presence of PAS . Furthermore, the posterior wall of the uterus strongly adhered to the colon. Although she had no abdominal pain or bleeding, the patient was considered to be in a state of threatened uterine ruptureand, thus, was admitted to hospital for careful management from 230/7 weeks of gestation. We told her and her husband that we would perform hysterectomy at delivery due to placenta percreta, and we obtained their consent. Figure 1 MRI findings at 22 weeks of gestation. (a) T2-weighted MRI revealed that the uterine wall from the bottom to the posterior wall of the uterus was thinning and bulging outward (arrows). (b) A part of the maternal side of the placenta was exposed outside the posterior uterine wall, suggesting the presence of placenta percreta (arrowheads). She was managed with prophylactic tocolysis by ritodrine hydrochloride and bed rest; however, uterine contractions and shortening of the cervix (cervical length: 25 mm) were observed at 26 weeks of gestation. Tocolysis was enhanced by increasing ritodrine hydrochloride. Transabdominal ultrasound failed to identify the myometrium of the left side of the uterine fundus at which the placenta was located and showed multiple placental lacunae with hypervascularity. Although the patient was stable with tocolysis and bed rest, the preterm premature rupture of membranes (pPROM) occurred at 291/7 weeks of gestation. The fetus was in breech presentation and uterine contractions were increasing; therefore, an emergency cesarean section was performed under spinal anesthesia on the same day, yielding a female infant (1353 g, APGAR score: 7/8 {1/5 min}, umbilical artery pH: 7.408, base excess: -2.9 mmol/L). The posterior uterine wall was very thin and bulging outward with extensive adhesion of the mesentery of the sigmoid colon. In addition, a part of the maternal side of the placenta was exposed outside the posterior uterine wall. We considered it difficult to preserve the uterus. Since the placenta was partially detached and external bleeding had increased, a total hysterectomy was performed after the rapid dissection of adhesions between the uterus and sigmoid colon under general anesthesia. Intraoperative blood loss was 6060 mL and allogeneic blood transfusion (20 units{U} of red blood cells and 14 U of fresh frozen plasma {FFP}) was performed. The patient was admitted to the intensive care unit (ICU) for postoperative systemic management. She was transfused with an additional 4 U of FFP in the ICU and did not develop disseminated intravascular coagulation; therefore, she was returned to a maternity ward on the second postoperative day. The removed uterus showed that more than half of the placenta adhered to the left posterior side of the uterine fundus . Pathological findings revealed that most of the adhered part was placenta increta, while the remainder was placenta percreta. The maternal postoperative course was uneventful, and she was discharged on postoperative day 11. The neonate was admitted to the neonatal ICU. No obvious malformations were observed in the neonate. Although the neonate was incubated and managed for transient tachypnea of the newborn, the subsequent course was uneventful. Figure 2 The findings of the removed uterus and placenta. (a) A part of the maternal side of the placenta was exposed outside the posterior uterine wall (arrow). (b and c) The majority of the placenta was adherent to the left posterior side of the uterine fundus and the uterine wall at this location was thinning. Discussion This is the first detailed case report of pregnancy following multiple adenomyomectomies. MRI was performed at 22 weeks of gestation, which revealed the thinning and outward bulging of the uterine wall, leading to the diagnosis of imminent uterine rupture. The patient was immediately admitted to hospital for careful management to prolong the pregnancy period and prepare for delivery. Adenomyomectomy performed before pregnancy increases the risk of a number of adverse events in the subsequent pregnant women, including uterine rupture. In adenomyomectomy, when adenomyotic tissue with an extensive, diffuse, and complex distribution within the normal uterine myometrium is resected as much as possible, the uterus is reformed with the remaining normal myometrium . Therefore, the capacity of the uterus decreases and its tolerance for uterine contents with pregnancy is reduced. Furthermore, due to multiple suture points, the remaining uterus that is formed may be fragile. Numerous cases of uterine rupture after adenomyomectomy have been reported to date [1,2,4-6,11-13]. In contrast to myomectomy, uterine rupture after adenomyomectomy may occur at any time of pregnancy [4-6]. Furthermore, adenomyomectomy increases the risk of PAS in the subsequent pregnancy. When trying to resect as much adenomyotic tissue as possible, the endometrium often has to be opened. Hence, the risk of PAS will increase in the subsequent pregnancy. Therefore, the endometrium is missing, inducing excessive trophoblast invasion into the myometrium in subsequent pregnancies. If the fallopian tubes are removed with the resection of sufficient adenomyotic tissue, assisted reproductive technology is required for subsequent pregnancies. This may be another factor that increases the risk of PAS. Moreover, if total hysterectomy is required due to PAS with massive bleeding, adhesions between the uterus and surrounding tissues increase the difficulty of this procedure. When partial detachment of the placenta occurs concomitantly with PAS, the uterus needs to be removed as soon as possible due to continuous bleeding from the site of detachment. As in the present case, patients with adenomyosis are often complicated by uterine endometriosis, which can cause extrauterine adhesions. Due to these risks, possible uterine rupture needs to be considered in pregnancies following adenomyomectomy, which may occur at any time during pregnancy. In addition, the delivery needs to be managed by a multidisciplinary team including obstetricians, pediatricians, anesthesiologists, and surgeons. Therefore, it is fundamental not to recommend pregnancy to women who underwent adenomyomectomy. However, in fact, an increasing number of women are becoming pregnant after adenomyomectomy. The present case underwent adenomyomectomy twice before pregnancy. Furthermore, she had uterine endometriosis. The above-described risks (i.e., uterine rupture, PAS, and adhesion to the surrounding tissues) were very high. Although MRI at 22 weeks of gestation suggested imminent uterine rupture and the presence of PAS, we retrospectively considered the PAS lesion at the left posterior wall of the uterus to have formed much earlier. Persistent genital bleeding and SCH in early pregnancy also suggested this. MRI may have been performed earlier (e.g., in the early second trimester) and it is unclear whether this affected the management of this patient. Fortunately, neither intraperitoneal bleeding nor crucial rupture of the uterus occurred during pregnancy. Although pPROM and failed tocolysis forced delivery at 29 weeks of gestation, managed hospitalization allowed cesarean hysterectomy to be performed uneventfully with sufficient manpower. Pregnancies following multiple adenomyomectomies are rare. Only two pregnancies after multiple adenomyomectomies have been reported to date, and both cases were pregnant women who underwent adenomyomectomy twice and were published in Japanese . We summarized these case reports in Table 1. Both cases resulted in uterine rupture. One woman miscarried at 16 weeks of gestation and the other had a live baby at 31 weeks of gestation. Neither case was able to deliver after 34 weeks of gestation. The latter required hysterectomy due to placenta percreta, similar to the present case. On the other hand, good perinatal outcomes may be achieved following multiple adenomyomectomies that have not yet been reported when we consider a publication bias. There are currently no guidelines for the management of pregnancy following adenomyomectomy. In our institute, we admit pregnant women after adenomyomectomy to hospital for careful management after 22-25 weeks of gestation even if they are asymptomatic. If uterine contractions become frequent, tocolysis is initiated . However, it remains unclear whether hospitalization with bed rest and tocolysis prolongs pregnancy and decreases the risk of an adverse maternal event. Table 1 Pregnant women who underwent adenomyomectomy twice. GW: gestational weeks; IVF-ET: in vitro fertilization embryo (or blastocyst) transfer; NA: not available; PAS: placenta accreta spectrum; pPROM: preterm premature rupture of membranes Cases Author (year) Age (years) Gravida (G) and para (P) Mode of conception Age at 1st adenomyomectomy (years) Age at 2nd adenomyomectomy (years) Interval between 2nd adenomyomectomy and conception (months) Event (GW) Procedures Blood loss in the procedures (mL) Degree of PAS Fetal or neonatal outcome Birthweight (g) 1 Nishida (2016) 38 G3P0 IVF 32 38 9 Uterine rupture (31) Cesarean hysterectomy NA Increta Live birth NA 2 Nishida (2016) 34 G1P0 Natural 31 34 NA Uterine rupture (16) Repair of the uterus by laparotomy NA Percreta Abortion NA 3 This case (2022) 40 G1P0 IVF 31 38 26 pPROM (29) Cesarean hysterectomy 6060 Percreta Live birth 1353 Conclusions Pregnancies following multiple adenomyomectomies are at high risk of uterine rupture and PAS. Adenomyomectomy is a good treatment option for adenomyosis and may become more widespread in women who wish for future pregnancy. A sufficient explanation associated with the risks in future pregnancy is needed, particularly after second adenomyomectomy. Although it has not yet been clarified whether bed rest and tocolysis prolong pregnancy, hospitalization may be useful for securing the condition of the patient. We deeply thank Masato Nishida, who is the main surgeon performing adenomyomectomy at the Department of Obstetrics and Gynecology, National Hospital Organization, Kasumigaura Medical Center. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 National survey of uterine rupture in Japan: Annual Report of Perinatology Committee, Japan Society of Obstetrics and Gynecology, 2018 J Obstet Gynaecol Res Makino S Takeda S Kondoh E 763 765 45 2019 30854725 2 Association of uterine wall thickness with pregnancy outcome following uterine-sparing surgery for diffuse uterine adenomyosis Aust N Z J Obstet Gynaecol Otsubo Y Nishida M Arai Y Ichikawa R Taneichi A Sakanaka M 88 91 56 2016 26515936 3 Pregnancy and delivery outcomes in the women who have received adenomyomectomy: performed by a single surgeon by a uniform surgical technique Taiwan J Obstet Gynecol Kwack JY Lee SJ Kwon YS 99 102 60 2021 33495018 4 Monochorionic twin delivery after conservative surgical treatment of a patient with severe diffuse uterine adenomyosis without uterine rupture Obstet Gynecol Sci Kwack JY Jeon SB Kim K Lee SJ Kwon YS 311 315 59 2016 27462599 5 Spontaneous uterine rupture in the 35th week of gestation after laparoscopic adenomyomectomy Int Med Case Rep J Nagao Y Osato K Kubo M Kawamura T Ikeda T Yamawaki T 1 4 9 2016 26719729 6 Spontaneous uterine rupture in the 33rd week of IVF pregnancy after laparoscopically assisted enucleation of uterine adenomatoid tumor J Obstet Gynaecol Res Yazawa H Endo S Hayashi S Suzuki S Ito A Fujimori K 452 457 37 2011 21208342 7 Unexpected placenta accreta spectrum after the use of assisted reproductive technology in women with adenomyomectomy Fukushima J Med Sci Jin T Kyozuka H Fujimori M Nomura S Hakozaki Y Suzuki D Nomura Y 45 48 67 2021 33731511 8 Placenta accreta following laparoscopic adenomyomectomy: a case report Clin Exp Obstet Gynecol Matsuzaki S Yoshino K Tomimatsu T Takiuchi T Kumasawa K Kimura T 763 765 43 2016 30074335 9 Perinatal outcome of pregnancy after adenomyomectomy: summary of 10 cases with a brief literature review J Matern Fetal Neonatal Med Sugiyama M Takahashi H Baba Y 4145 4149 33 2020 30889999 10 Efficacy of laparoscopic adenomyomectomy using double-flap method for diffuse uterine adenomyosis BMC Womens Health Huang X Huang Q Chen S Zhang J Lin K Zhang X 15 2015 11 Adenomyosis and uterine rupture during labour in a primigravida: an unusual obstetric emergency in Nigeria Trop Doct Dim CC Agu PU Dim NR Ikeme AC 250 251 39 2009 19762587 12 Uterine rupture during pregnancy soon after a laparoscopic adenomyomectomy Reprod Med Biol Morimatsu Y Matsubara S Higashiyama N 175 177 6 2007 29699275 13 Spontaneous uterine rupture of a twin pregnancy after a laparoscopic adenomyomectomy: a case report J Minim Invasive Gynecol Wada S Kudo M Minakami H 166 168 13 2006 16527723 14 Prevention of uterine rupture during pregnancy after adenomyomectomy Gynecol Obstet Surg Nishida M Otsubo Y Ichikawa R Arai Y Sakanaka M 69 76 27 2016 |
Following a request from the European Commission, the Panel on Additives and Products or Substances used in Animal Feed (FEEDAP) was asked to deliver a scientific opinion on the safety and efficacy of Sorbiflore(r) ADVANCE, a feed additive consisting of Lacticaseibacillus rhamnosus CNCM I-3698 and Companilactobacillus sp.CNCM I-3699 intended to be used as a zootechnical additive (functional group: other zootechnical additives) in feed for chickens for fattening to improve their performance. In a previous opinion, the additive was described as containing viable but not cultivable cells of the two strains in a 1:1 ratio, with a minimum of total lactic acid bacteria counts of 5 x 108 viable forming units (VFU)/g additive. However, in that opinion, the Panel could not fully characterise the additive or conclude on its dermal/ocular irritancy or sensitisation potential. In the current assessment, the applicant provided supplementary information to address the missing information for the characterisation of the additive. The proposed methodology to discriminate and individually quantify the two strains composing the additive still presented limitations. Therefore, the Panel concluded that the data available do not allow to fully characterise the additive. The Panel was not in the position to conclude on the taxonomical identification of the strain CNCM I-3699, and consequently, on its eligibility for the application of the qualified presumption of safety (QPS) approach. Therefore, the previous conclusions on the safety of the additive based on the QPS approach could not be confirmed. The Panel was not in the position to conclude on the safety of the additive for the target species, consumer and the environment. Sorbiflore(r) ADVANCE is not irritant to skin. The Panel could not conclude on the eye irritancy or skin sensitisation potential of the additive. zootechnical additives other zootechnical additives Lacticaseibacillus rhamnosus CNCM I-3698 and Companilactobacillus sp.CNCM I-3699 chickens safety source-schema-version-number2.0 cover-dateMarch 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:13.03.2023 Suggested citation: EFSA FEEDAP Panel (EFSA Panel on Additives and Products or Substances used in Animal Feed) , Bampidis V , Azimonti G , Bastos ML , Christensen H , Dusemund B , Durjava M , Kouba M , Lopez-Alonso M , Lopez Puente S , Marcon F , Mayo B , Pechova A , Petkova M , Ramos F , Sanz Y , Villa RE , Woutersen R , Cocconcelli PS , Pettenati E , Anguita M and Brozzi R , 2023. Scientific Opinion on the safety and efficacy of a feed additive consisting of Lacticaseibacillus rhamnosus CNCM I-3698 and Companilactobacillus sp. CNCM I-3699 for chickens for fattening (STI Biotechnologie). EFSA Journal 2023;21 (3 ):7857, 8 pp. 10.2903/j.efsa.2023.7857 Requestor European Commission Question number EFSA-Q-2021-00536 Panel members Vasileios Bampidis, Giovanna Azimonti, Maria de Lourdes Bastos, Henrik Christensen, Birgit Dusemund, Mojca Durjava, Maryline Kouba, Marta Lopez-Alonso, Secundino Lopez Puente, Francesca Marcon, Baltasar Mayo, Alena Pechova, Mariana Petkova, Fernando Ramos, Yolanda Sanz, Roberto Edoardo Villa and Ruud Woutersen. Declarations of interest If you wish to access the declaration of interests of any expert contributing to an EFSA scientific assessment, please contact [email protected]. Acknowledgements The Panel wishes to thank the following for the support provided to this scientific output: Natalia Alija Novo and the Microbiology WG. EFSA may include images or other content for which it does not hold copyright. In such cases, EFSA indicates the copyright holder and users should seek permission to reproduce the content from the original source. Adopted: 31 January 2023 pmc1 Introduction 1.1 Background and terms of reference as provided by the requestor Regulation (EC) No 1831/2003 1 establishes the rules governing the Community authorisation of additives for use in animal nutrition. In particular, Article 9 defines the terms of authorisation by the Commission. The applicant, STI Biotechnologie, is seeking a Community authorisation Lactobacillus rhamnosus and Lactobacillus farciminis as an other zootechnical additive for chickens for fattening (Table 1). Table 1 Description of the substances Category of additive Zootechnical additives Functional group of additive Other zootechnical additives Description Lactobacillus rhamnosus & Lactobacillus farciminis Target animal category Chickens for fattening Applicant STI Biotechnologie Type of request New opinion On 19 March 2020, the Panel on Additives and Products or Substances used in Animal Feed of the European Food Safety Authority ('Authority'), in its opinion on the safety and efficacy of the product, could not conclude because the data provided do not allow a full characterisation of the additive, and therefore, uncertainty remains on the nature of the product in terms of viability, on the ratio between the active agents and on the stability of the additive. During the discussions with the Member States at a meeting of the Standing Committee on Plants, Animals, Food and Feed (Animal Nutrition section), it was suggested to check for the possibility to demonstrate the viability and stability of the additive. The Commission gave the possibility to the applicant to submit supplementary information and data in order to complete the assessment and to allow a revision of the EFSA's opinion. The new data have been received on 19 February 2021 and the applicant has been requested to transmit them to EFSA as well. In view of the above, the Commission asks the Authority to deliver a new opinion on Lactobacillus rhamnosus & Lactobacillus farciminis as a feed additive for chickens for fattening based on the additional data submitted by the applicant, in accordance with Article 29(1)(a) of Regulation (EC) No 178/2002. 1.2 Additional information EFSA issued two opinions on the safety and efficacy of the product consisting of Lacticaseibacillus (formerly Lactobacillus) rhamnosus, CNCM I-3698 and Companilactobacillus (formerly Lactobacillus) farciminis CNCM I-3699 (Sorbiflore(r) ADVANCE) when used as a zootechnical additive for weaned piglets (EFSA, 2008; EFSA FEEDAP Panel, 2020a), one opinion for chickens for fattening (EFSA FEEDAP Panel, 2020b), and one when used as a silage additive for all animal species (EFSA FEEDAP Panel, 2020c). Since the last opinions, the taxonomic designation of the species under assessment has been updated from Lactobacillus rhamnosus to Lacticaseibacillus rhamnosus and L. farciminis to Companilactobacillus farciminis (EFSA BIOHAZ Panel, 2020). The additive has not been authorised for chickens for fattening. 2 Data and methodologies 2.1 Data The present assessment is based on data submitted by the applicant in the form of supplementary information 2 to a previous application on the same product. 3 In accordance with Article 38 of the Regulation (EC) No 178/2002 and taking into account the protection of confidential information and of personal data in accordance with Articles 39 to 39e of the same Regulation, and of the Decision of EFSA's Executive Director laying down practical arrangements concerning transparency and confidentiality, 4 a non-confidential version of the supplementary information has been published on Open.EFSA. 5 The FEEDAP Panel used the data provided by the applicant together with data from other sources, such as previous risk assessments by EFSA or other expert bodies, peer-reviewed scientific papers, to deliver the present output. 2.2 Methodologies The approach followed by the FEEDAP Panel to assess the safety and the efficacy of Lactobacillus rhamnosus, CNCM I-3698 and Lactobacillus farciminis CNCM I-3699 (Sorbiflore(r) ADVANCE) is in line with the principles laid down in Regulation (EC) No 429/2008 6 and the relevant guidance documents: Guidance on studies concerning the safety of use of the additive for users/workers (EFSA FEEDAP Panel, 2012), Guidance on the identity, characterisation and conditions of use of feed additives (EFSA FEEEDAP Panel, 2017), Guidance on the characterisation of microorganisms used as feed additives or as production organisms (EFSA FEEDAP Panel, 2018). 3 Assessment The additive under assessment with the tradename Sorbiflore(r) ADVANCE is the result from the fermentation of a milk-based broth with two lactic acid bacteria (L. rhamnosus CNCM I-3698 and L. farciminis CNCM I-3699). Sorbiflore(r) ADVANCE is intended to be used as a zootechnical additive (functional group: other zootechnical additives) at the minimum level of 1.25 x 108 viable forming units (VFU)/kg and the maximum level of 5 x 108 VFU/kg complete feed for chickens for fattening, in order to improve their performance. In a previous opinion (EFSA FEEDAP Panel, 2020b), the applicant described the product as containing viable but not cultivable cells of the two strains in a 1:1 ratio, with a minimum total lactic acid bacteria (LAB) count of 5 x 108 VFU/g additive. However, in that opinion, the data available did not allow the Panel to fully characterise the additive or to conclude on its dermal/ocular irritancy potential and on its dermal sensitisation potential. The applicant has produced new data to address the limitations identified by the Panel which are described below. 3.1 Characterisation of the additive In the previous assessments (EFSA, 2008; EFSA FEEDAP Panel, 2020b), the strain CNCM I-3698 was taxonomically identified as Lactobacillus rhamnosus, and the strain CNCM I-3699 as Lactobacillus farciminis. The taxonomic designation of these species has been updated to Lacticaseibacillus rhamnosus and Companilactobacillus farciminis, respectively. The current names are used hereafter in the opinion. Additionally, in the new data set, the applicant indicated that the strain CNCM I-3699 has been reassigned to the species Companilactobacillus formosensis on the basis of the whole genome sequence (WGS) analysis. 7 However, no information was provided on the WGS-based analyses that assigned the strain CNCM I-3699 to the new species C. formosensis. In particular, no details were provided on the bioinformatics tools used, or whether representative type strains of species of the genus Companilactobacillus were included in the analysis. Consequently, the FEEDAP Panel is not in the position to conclude on the taxonomical identification of the strain CNCM I-3699. The additive is described as containing viable but not cultivable cells of the two bacterial strains in a 1:1 ratio, with a minimum total LAB number of 5 x 108 VFU/g additive. In the former opinion, the applicant proposed a method based on the use of propidium monoazide (PMA) coupled with real-time quantitative polymerase chain reaction (qPCR) to characterise the additive and confirm its inclusion level in the feed. The methodology foresees that the PMA is cell membrane-impermeable and selectively penetrates the dead cells with damaged membranes and, after photoactivation, cross-links with DNA. The resulting DNA monoadducts prevent the DNA amplification. Consequently, only the DNA from viable cells with intact membrane can be subject to qPCR following a proper lysis step. This method was evaluated in the previous opinion and the FEEDAP Panel concluded that it did not allow an unambiguous discrimination between the two lactobacilli strains. Consequently, a full characterisation of the additive in terms of nature, compliance with the specifications and stability could not be established. The applicant developed a new methodology using PMA coupled with qPCR to individually enumerate the two strains in feed, based on a set of primers and an internal probe designed to target strain-specific genes present in single copy in the genome of L. rhamnosus CNCM I-3698 or Companilactobacillus sp. CNCM I-3699. 7 However, details on the target genes were not provided. The specificity of the primers and probe used in the qPCR analysis aimed at identifying and quantifying L. rhamnosus CNCM I-3698 was tested on 30 DNA samples from eight species of Lactobacillaceae and 16 other bacterial species from different genera. No amplification signal was observed in any of the samples tested. Similarly, the same pool of strains was used to test the specificity of the primers and probe selected for Companilactobacillus sp. CNCM I-36998. No amplification signal was observed in any of the samples tested. However, the Panel notes that the set of primers/probe for L. rhamnosus CNCM I-3698 was not tested on Companilactobacillus sp. CNCM I-3699, and vice versa. Consequently, data showing that the proposed qPCR methods are strain-specific and adequate to discriminate and quantify L. rhamnosus CNCM I-3698 and Companilactobacillus sp. CNCM I-3699 in the additive is still lacking. As concerns the controls and sensitivity tests of the methodologies proposed, the applicant submitted studies conducted on the DNA extracted from the two strains of the additive with or without the PMA treatment, which are described below. The quantification efficiency of the qPCR methods was tested using the DNA extracted from dilutions of a broth culture from which the cell counts (CFU/mL) were determined by plate counting on MRS medium. Five logarithmic dilutions (from 7.8 x 105 to 78 genome-equivalent units (GU) per PCR tube of 2 mL) for L. rhamnosus CNCM I-3698 and four logarithmic dilutions (from 1 x 106 to 1 x 103 GU per PCR tube of 2 mL) in the case of Companilactobacillus sp. CNCM I-36998 were used. The experiments were made in triplicate. The Ct values of the calibration curve experiments were provided, while slope values were not. The limit of detection of the qPCR methods was determined by using 10 replicates per strain and per dilution at DNA concentrations of 78, 39, 19, 9 and 5 GU for L. rhamnosus CNCM I-3698 and 500, 250, 125, 62 and 31 GU for Companilactobacillus sp. CNCM I-3699 calculated per PCR tubes of 2 mL. In the absence of PMA, DNA of L. rhamnosus CNCM I-3698 was detected in all the 10 replicates only at the highest concentration, while only in seven to eight replicates out of 10 the amplification occurred in the experiments with Companilactobacillus sp. CNCM I-3699. The PMA treatment was efficient in eliminating the free Companilactobacillus sp. CNCM I-3699 DNA in samples with a concentration <= 125 GU per PCR tube. Differently, the PMA treatment was unable to eliminate the free DNA in all the samples of L. rhamnosus CNCM I-3698 tested at lower concentrations (<= 39 GU per PCR tube). No data were provided on the efficacy of the PMA treatment and the qPCR methods to differentiate between viable, dead or inactivated cells. Six samples (three batches of the additive, the additive in a premixture, a mash and a pelleted feed) were analysed with and without the PMA treatment for the quantification of both strains, using the qPCR method described above. No certificate of analysis was provided for any of the test items. The detected GU values were substantially identical between the PMA treated and untreated samples, suggesting that most of the cells present an intact cellular membrane. However, no data were provided to allow reaching conclusions on the individual enumeration of the two strains, and therefore, on compliance with the specifications of the additive. The proposed methodology to individually enumerate the two strains composing the additive still presents limitations. In particular: (i) the capacity of the specific qPCR detection and quantification methods to discriminate between the two strains has not been tested (i.e. the method developed for CNCM I-3698 was not applied on CNCM I-3699 and vice versa), (ii) no demonstration of the efficacy of the PMA treatment and the qPCR methods to differentiate between viable, dead or inactivated cells was provided. Therefore, based on the available data, the Panel is not in the position to conclude on the full characterisation of the additive under assessment. 3.2 Safety In the former opinion (EFSA FEEDAP Panel, 2020b), the Panel concluded that the active agents (Lactobacillus rhamnosus CNCM I-3698 and Lactobacillus farciminis CNCM I-3699) fulfilled the requirements of the QPS approach to the assessment of safety, no concerns were expected from other components of the additive, therefore, Sorbiflore(r) ADVANCE was presumed to be safe for the target animals, consumers and the environment. In view of the applicant's new statement that strain CNCM I-3699 has been reassigned to the species Companilactobacillus formosensis, but owing to the lack of data, the FEEDAP Panel is not in the position to conclude on the taxonomical identification of this strain, and consequently, on its eligibility for the application of the qualified presumption of safety (QPS) approach to safety assessment. Therefore, the former conclusions on the safety of the additive based on the QPS approach cannot be confirmed (EFSA FEEDAP Panel, 2020b). As regards the safety for the user, in the former opinion the Panel concluded that 'Despite the request, no information was provided on the inhalation toxicity of the additive or on its skin/eye irritation and skin sensitisation potential. The dustiness of the preparations tested indicated a potential for users to be exposed via inhalation to be likely. Given the proteinaceous nature of the active agents, the additive should be considered a respiratory sensitiser. In the absence of data, the FEEDAP Panel cannot conclude on the irritancy of the additive to skin and eyes and on its dermal sensitisation potential'. The applicant has now submitted a skin irritation study. 8 The skin irritation potential of the additive was tested in an in vitro study performed according to OECD TG 439. The results of the study indicated that the additive is non-irritant to skin and classified in accordance with UN GHS as 'no Category'. In the absence of data, the Panel cannot conclude on the eye irritancy potential of the additive. The FEEDAP Panel notes that the OECD test guidelines available at present are designed to assess the skin sensitisation potential of chemical substances only and that currently no validated assays for assessing the sensitisation potential of microorganisms are available. Therefore, no conclusions can be drawn on the skin sensitisation potential of the additive. 4 Conclusions The proposed methodology to discriminate and individually quantify the two strains composing the additive still presents limitations. Therefore, the Panel concludes that the data available do not allow to fully characterise the additive under assessment. The FEEDAP Panel is not in the position to conclude on the taxonomical identification of one of the two bacterial strains composing the additive (strain CNCM I-3699), and consequently, on its eligibility for the application of the qualified presumption of safety (QPS) approach to safety assessment. Therefore, the former conclusions on the safety of the additive based on the QPS approach cannot be confirmed in the present assessment. The Panel cannot conclude on the safety of Sorbiflore(r) ADVANCE for the target species, consumer and the environment. The Panel reiterates its previous conclusions that Sorbiflore(r) ADVANCE should be considered a respiratory sensitiser. Based on the new data provided, the additive is not irritant to skin. The Panel cannot conclude on the eye irritancy or skin sensitisation potential of the additive. Abbreviations FEEDAP EFSA Scientific Panel on Additives and Products or Substances used in Animal Feed LOD limit of detection qPCR quantitative polymerase chain reaction PMA propidium monoazide VFU Viable forming unit WGS Whole genome sequence Notes 1 Regulation (EC) No 1831/2003 of the European Parliament and of the council of 22 September 2003 on the additives for use in animal nutrition. OJ L 268, 18.10.2003, p. 29. 2 FEED dossier reference: EFSA-Q-2021-00536. 3 FEED dossier reference: FAD-2017-0066 4 Decision available at: 5 Available at: 6 Commission Regulation (EC) No 429/2008 of 25 April 2008 on detailed rules for the implementation of Regulation (EC) No 1831/2003 of the European Parliament and of the Council as regards the preparation and the presentation of applications and the assessment and the authorisation of feed additives. OJ L 133, 22.5.2008, p. 1. 7 4. ANALYTICAL METHOD.pdf, 2. Report L. rhamnosus FULL VERSION and 3. Report L. farciminis FULL VERSION. 8 3_OECD 439. |
Front Mol Neurosci Front Mol Neurosci Front. Mol. Neurosci. Frontiers in Molecular Neuroscience 1662-5099 Frontiers Media S.A. 10.3389/fnmol.2023.1155905 Molecular Neuroscience Editorial Editorial: The protein kinase GSK3 in neurobiological functions and neuronal disorders Plattner Florian 1 * Hisanaga Shin-ichi 2 Chang Raymond Chuen-Chung 3 Matynia Anna 4 1Neuro-Research Strategies, Houston, TX, United States 2Department of Biological Sciences, Tokyo Metropolitan University, Hachioji, Japan 3Laboratory of Neurodegenerative Diseases, LKS Faculty of Medicine, School of Biomedical Sciences, The University of Hong Kong, Pokfulam, Hong Kong SAR, China 4Jules Stein Eye Institute, University of California, Los Angeles, Los Angeles, CA, United States Edited and reviewed by: Jean-Marc Taymans, Institut National de la Sante et de la Recherche Medicale (INSERM), France *Correspondence: Florian Plattner [email protected] This article was submitted to Molecular Signalling and Pathways, a section of the journal Frontiers in Molecular Neuroscience 27 2 2023 2023 16 115590531 1 2023 02 2 2023 Copyright (c) 2023 Plattner, Hisanaga, Chang and Matynia. 2023 Plattner, Hisanaga, Chang and Matynia This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial on the Research Topic The protein kinase GSK3 in neurobiological functions and neuronal disordersglycogen synthase kinase 3 protein kinase pharmacological inhibitor lithium neurodegenerative diseases bipolar disorder pmcSince its initial discovery more than 40 years ago, a series of significant discoveries and innovative research established a central role for glycogen synthase kinase 3 (GSK3) in many critical cellular processes, including gene expression, metabolism, cellular transport, cell proliferation and apoptosis. GSK3 is a highly conserved serine/threonine protein kinase that is present in all eukaryotes. GSK3 has a broad substrate range and is ubiquitously expressed. Interestingly, GSK3 is present at high levels in brain and specifically phosphorylates numerous neuronal proteins implicating it in a variety of neurobiological functions such as axonal transport, neuronal development, neuronal polarization as well as in the regulation of synaptic plasticity and memory formation (e.g., Hernandez et al., 2002; Hooper et al., 2007). Consistently, dysregulation of GSK3 has been associated with neuronal disorders, including Alzheimer's disease, bipolar disorder, schizophrenia, Fragile X Syndrome and Parkinson's disease. This central role in neurobiological functions and neuronal disorders has made GSK3 an attractive therapeutic target and sparked major drug development efforts. This Frontiers Research Topic features original research articles and reviews that provide new insights on neurobiological functions of GSK3 and an update on the current state of the GSK3 research field with a special emphasis on GSK3 inhibitors in pre-clinical research and their potential therapeutic application. We assembled this Topic with the aim to provide a contemporary reference point for GSK3 research and to stimulate future progress in our understanding of this complex field. Over the years, an enduring and far-reaching effort to develop specific GSK3 inhibitors has been driven by a number of critical discoveries. In contrast to most protein kinases, GSK3 can be active in its basal state and is inhibited in response to various physiological stimuli. Consistently, dysregulation and hyperactivation of GSK3 have been associated with numerous, diverse pathophysiological changes, which continuously prompted the demand for diverse, selective, and potent GSK3 inhibitors. The first GSK3 inhibitor discovered, was the cation lithium (Klein and Melton, 1996; Stambolic et al., 1996). Lithium is a commonly prescribed mood stabilizer, for which the mechanism of action is still not known. In this Topic, Chatterjee and Beaulieu review the evidence that links GSK3 inhibition to the therapeutic effects of lithium on mood. This review provides an overview of GSK3 biological functions and substrates that have been implicated in the effects of lithium with a focus on the transcription factor cAMP response element-binding protein (CREB), the RNA-binding protein FXR1, kinesin subunits, and the cytoskeletal regulator CRMP2. Indeed, understanding the mechanistic link between GSK3 inhibition and the therapeutic effects of lithium may prove critical to identify novel, more specific drug targets and to provide a rationale for the inhibitory action of ketamine and other antipsychotics toward GSK3. Following up on the recent advances in the development of pharmacological GSK3 inhibitors and their application in pre-clinical and clinical studies of neuronal disorders, is the next review in this Topic. Arciniegas Ruiz and Eldar-Finkelman present the current spectrum of GSK3 inhibitors of diverse chemotypes and inhibition modes, and summarize the use of these GSK3 inhibitors in clinical trials and in vivo animal models of CNS disorders ranging from mood and behavior disorders, autism and cognitive disabilities, to neurodegeneration, brain injury and pain. Despite there being currently no specific GSK3 inhibitors on the market, recent advances are encouraging and hopefully will lead to the development of GSK3 inhibitors suitable for clinical use. The importance of the development of novel GSK3 inhibitors for the study of neurobiological functions and pathophysiological processes is further exemplified by the original articles from Westmark et al., Di Re et al., and Lee et al. in this Topic. Taking advantage of an animal model for Fragile X Syndrome, a genetic condition causing intellectual disability, Westmark et al. investigated the effects of two different pharmacological GSK3 inhibitors on disease-associated behavioral changes in vivo as well as on biochemical and cytological read-outs in neuronal cultures. These experiments revealed an intriguing interplay between GSK3 activity and the expression of amyloid-beta precursor protein (APP), a molecule that has been critically implicated in Alzheimer's disease amongst other CNS disorders. This study also uncovered differential effects of the two tested GSK3 inhibitors on some of the read-outs, highlighting common complications encountered with pharmacological inhibitors. Functional differences between inhibitors may be due to a variety of factors, such as different specificity, off-target effects and altered bioavailability. Many commonly used inhibitors are directed toward the ATP binding site of a specific kinase. However, as ATP binding domains exhibit a high degree of structural homology between kinases, confounding side effects due to cross-reactivity are a common problem of this type of inhibitors. Di Re et al. examined the effect of pharmacological inhibition of GSK3 and of its inhibitory upstream regulator, Akt, on the functionality of the axon initial segment (AIS) that is required for neuronal firing. GSK3 inhibition induced no major changes, whereas Akt inhibition resulted in increased excitability in primary hippocampal neurons and altered subcellular localization of bIV spectrin. Lee et al. investigated the effect of pharmacological GSK3 inhibition on synaptic plasticity and memory formation in vivo in this Topic. Systemic administration of a selective GSK-3 inhibitor, CT99021, reversibly blocked NMDAR-dependent long-term depression (LTD) in the CA1 region of the hippocampus and facilitated learning in the Morris water maze (MWM) and T-maze. These data suggest that GSK3 may be involved in the fine-tuning of spatial memory acquisition and recall. The GSK3 inhibitor, CT99021, while selective for GSK3, does not discriminate between the two GSK3 isozymes that are generated from distinct genes. The two GSK3 isoforms, termed a and b, share high levels of homology, feature near identical substrate specificity and hence may have largely a common substrate range. Nevertheless, it has also become evident that there are GSK3 isoform-specific substrates and functions. Indeed, GSK3 isoform-inhibitors have been developed. In addition, there might also be functional interplay between the two GSK3 isoforms, which adds an additional layer of complexity to the analysis of GSK3 functions in neurobiological and pathophysiological processes. In order to gain insight on GSK3 isoform-specific roles in synaptic plasticity, Amini et al. evaluated long-term potentiation (LTP) in CA3-CA1 of the hippocampus from conditional GSK3a and GSK3b knockout mice in this Topic. Deletion of GSK3a in CA1 pyramidal neurons resulted in facilitation of CA3-CA1 LTP, whereas GSK3b deletion had no effect on LTP. Basal synaptic properties were not affected by either GSK3 deletion. These results support the notion that GSK3a plays a specific role in regulating CA1 LTP and adds a further example of diverging functions between GSK3 isoforms. But as occurs so often in research and is highlighted by the articles in the Topic, finding a novel answer raises a myriad of new, unsolved questions. In fact, despite a considerable research effort the neurobiological and pathophysiological roles of GSK3 remain still poorly understood. The complex biology of GSK3, including two isoforms, diverse regulatory mechanisms, countless substrates and its involvement in many different cellular functions, makes this a challenging research field and progress is hard to come by. Over the last few years, progress has been further hampered due to a shift in research focus away from investigating the mechanistic basis of physiological and pathophysiological processes as well as to changing funding priorities by sponsoring bodies. As we reflect on the past 40 years, there have been tremendous advances that single out GSK3 as a relevant, druggable target. Future research will unequivocally progress our mechanistic understanding of GSK3 functions and promote the development of GSK3-based therapeutic applications. Author contributions All authors listed have made substantial, direct, and intellectual contribution to the work and approved it for publication. We thank to all contributors of this Research Topic and the Frontiers team for guidance and their full support of this endeavor during the height of the COVID pandemic. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References Hernandez F. Borrell J. Guaza C. Avila J. Lucas J. J. (2002). Spatial learning deficit in transgenic mice that conditionally over-express GSK-3beta in the brain but do not form tau filaments. J. Neurochem. 83 , 1529-1533. 10.1046/j.1471-4159.2002.01269.x 12472906 Hooper C. Markevich V. Plattner F. Killick R. Schofield E. Engel T. . (2007). Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur. J. Neurosci. 25 , 81-86. 10.1111/j.1460-9568.2006.05245.x 17241269 Klein P. S. Melton D. A. (1996). A molecular mechanism for the effect of lithium on development. PNAS. 93,8455-8459. 10.1073/pnas.93.16.8455 8710892 Stambolic V. Ruel L. Woodgett J. R. (1996). Lithium inhibits glycogen synthase kinase-3 activity and mimics wingless signalling in intact cells. Curr. Biol. 6 , 1664-1668. 10.1016/S0960-9822(02)70790-2 8994831 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34853 Ophthalmology Otolaryngology Radiology Orbital Apex Syndrome Secondary to Huge Primary Ethmoidal Sinus Mucocele: A Case Report Muacevic Alexander Adler John R Loh Sue Anne 1 Wan Hitam Wan-Hazabbah 1 Ramli Ramiza Ramza 2 Sayuti Khairil Amir 3 Sonny Teo Khairy Shamel 1 1 Department of Ophthalmology and Visual Science, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, MYS 2 Department of Otorhinolaryngology-Head and Neck Surgery, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, MYS 3 Department of Radiology, School of Medical Sciences, Health Campus, Universiti Sains Malaysia, Kelantan, MYS Wan-Hazabbah Wan Hitam [email protected] 11 2 2023 2 2023 15 2 e3485310 2 2023 Copyright (c) 2023, Loh et al. 2023 Loh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Ethmoidal sinus mucoceles are benign expansile lesions that may progressively invade the orbit causing optic nerve compression and its nearby structures. We report a rare case of primary ethmoidal sinus mucocele instigating orbital apex syndrome. A 40-year-old man presented with right eye (RE) progressive blurring of vision with diplopia for 2 weeks. It was preceded by right-sided facial pain for 3 months. Clinical examination revealed RE proptosis with multiple cranial nerves palsy involving right cranial nerves II, III, IV, V, and VI, suggestive of right orbital apex syndrome. Magnetic resonance imaging (MRI) demonstrated right eye proptosis and right ethmoidal mucocele with intracranial and right intraorbital extension compressing the right medial rectus and optic nerve. The patient underwent an uncomplicated endoscopic sinus surgery resulting in a return to normal appearance and function post-operation. Thus, ethmoidal mucoceles are benign and curable with early recognition and intervention. mucocele ethmoidal mucocele marsupialization endoscopic sinus surgery orbital apex syndrome The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Paranasal sinus mucocele is a benign cystic lesion caused by obstruction of sinus ostia . This locally expansile mass is highly likely to invade the intraorbital or intracranial structures due to its proximity to the orbit and skull base, with possible adverse complications and morbidities . The wide range of ophthalmic manifestations includes proptosis, limitation of ocular movement, diplopia, lid swelling, ptosis, reduced vision, visual field defect, epiphora, and periorbital pain . It is rare for an ethmoidal sinus mucocele to cause orbital apex syndrome without obvious predisposing factors. Hence, we report a rare case of orbital apex syndrome secondary to the primary ethmoidal mucocele that was successfully treated. Case presentation A 40-year-old man, without any comorbidity, presented with progressive painless proptosis of the right eye (RE) for the past two years. Subsequently, he had right-sided facial pain for the past three months and started to have blurred vision and diplopia for the past two weeks. Further, no history of eye redness, swelling, or discharge was recorded. The patient also did not experience any nasal obstruction, epistaxis, fever, headache, dizziness, nausea, or vomiting. He had no history of trauma, head and neck disease, or surgery. His premorbid vision was good and he was not prescribed any glasses. On examination, there was non-axial proptosis of the RE measuring 22 mm and of the left eye (LE) measuring 15 mm, measured with a Hertel exophthalmometer. His best corrected visual acuity (BCVA) was 6/15 in the RE and 6/6 in his LE. His RE extraocular motility is slightly limited in adduction, abduction, and elevation with diplopia on horizontal gazes. There was a positive right relative afferent pupillary defect with reduced light brightness, red saturation, and color vision on Ishihara charting. Both anterior segments were unremarkable. Fundoscopy showed a normal optic disc and macula in both eyes. Humphrey's visual field showed superonasal defect over LE and severely depressed fields over RE (Mean deviation -29.65dB) . MRI revealed a right ethmoidal mucocele with intracranial and right intraorbital extension compressing the right medial rectus and optic nerve as well as RE proptosis . Figure 1 Humphrey visual field showed LE showed superonasal defect (a) and RE severely depressed fields (b). LE: left eye; RE: right eye Figure 2 Preoperative axial (a) and coronal (b) T2-weighted MRI image of the brain showing hyperintense lesion in the ethmoidal sinuses with intracranial and right intraorbital extension, right eye proptosis as well as mass effect affecting the right orbital apex. The patient was diagnosed with orbital apex syndrome secondary to ethmoidal mucocele and referred to the otorhinolaryngology team for surgical management to prevent further optic nerve damage and visual acuity deterioration. As part of treatment, an endoscopic marsupialization of the right ethmoidal mucocele with partial medial maxillectomy and right inferior and middle turbinectomies was performed. Intraoperatively, an incision was made at the inferior part of the mucocele and peanut butter-like mucus content was drained. Histopathology examination of the aspirate samples and tissues revealed mucocele content comprising fibro-collagenous tissues lined by respiratory epithelium with chronic inflammatory cells and granulation tissue. Postoperatively, he underwent a successful recovery with complete resolution of the proptosis and is still under our follow-up. Eight months of recovery period post-operation showed normal extraocular movement and no diplopia. Optic nerve function tests were also improved. His both eyes BCVA were 6/6 with normal fundoscopy findings. The bilateral eye (BE)visual field improved as evidenced by Humphrey's visual field of a normal LE visual field and RE central vision . Postoperative MRI brain showed no residual lesion . Figure 3 Humphrey visual field showed BE improved visual field. BE: bilateral eye Figure 4 Postoperative axial (a) and coronal (b) T2-weighted MRI image of the brain showing no residual lesion with the resolution of right eye proptosis with symmetrical optic nerves and preservation of extraocular muscles. Discussion Mucoceles can either be primary lesions presenting as mucus retention cysts or secondary lesions caused by various conditions including chronic obstruction of sinus Ostia, previous surgical procedures, mucosal inflammation, benign and malignant lesions, chronic infection, or allergic disease . The most common sites for paranasal sinus mucocele are the maxillary sinuses (50%) followed by frontoethmoidal (31%), ethmoidal (16%), and sphenoidal (3%) sinuses . Primary mucoceles are seldom reported but are typically found in ethmoidal sinuses like in our patient . The unusual thing about our case is that the patient reported no previous sinus issues or previous surgery. The ophthalmological manifestations may be variable depending on the location and size of the mucocele, involvement of adjacent tissues, and direction of expansion . In general, frontal and anterior ethmoid sinus mucocele tend to cause proptosis, eyeball displacement, and diplopia consistent with the presentation of our patient . However, our patient also had orbital apex syndrome suggested by reduced visual acuity, ophthalmoplegia, diplopia, and facial pain which are usually caused by sphenoid rather than ethmoidal mucoceles. MRI is crucial for mucocele diagnosis, determination of lesion location, and assessment of possible intraorbital and intracranial extension. MRI signal intensity is highly variable and depends on the proportion of water, mucus viscosity, and protein content of the tissues . The scan is also important to help differentiate mucoceles from other lesions. Mucoceles characteristically reveal a thin peripheral linear enhancement with central low-signal intensity on T1-weighted images. Differential diagnoses include paranasal sinus tumors (mostly show diffuse contrast enhancement), mucus retention cyst (does not fill the sinus and no bony expansion), antrochoanal polyp (focally protrudes through the ostiomeatal complex), acute sinusitis (no bony expansion) and Aspergillus sp. Infection (displays a low signal on both T2-weighted sequences, mimicking a normal aerated sinus). Previous studies revealed that the presence of air within an affected sinus rules out the possibility of a mucocele . Surgical intervention remains the gold standard of mucocele treatment. Ethmoidal mucoceles were conventionally treated with an external open obliterative procedure . Otherwise, endoscopic surgery can also be performed. The endoscopic marsupialization approach is preferred over the external approach as it has been reported to have lower complications, short recovery time, low recurrence rate, and morbidity . However, in cases with extensive intraorbital extensions, as in our patient, open or combined approaches are recommended . The external approach may directly expose the entire sinus, enable complete sinus removal, and prevent blind curettage of any exposed dura mater. Our patient had an extensive mass (3.9 x 4.9 x 3.8 cm) that affected the mid and posterior orbit and intracranial extension, but he was successfully treated via the endoscopic approach. Postoperatively, he has no residual mass on MRI and demonstrated resolution of symptoms. Thus, endoscopy could be a favorable approach for an extensive mass. The histopathological appearance of mucoceles has features of respiratory mucosa, lined by flattened, ciliated mucus-secreting columnar epithelium. In some cases, there may be areas of reactive bone formation adjacent to the epithelium. Chronic inflammation is often present with mucinous material. Rupture may cause granulation tissue, fibrosis, cholesterol granuloma, or cleft formation . The natural development of ethmoidal mucoceles is a gradual expansion, which may become erosive and destroy the surrounding bony wall. This may cause a variety of complications such as meningitis, meningoencephalitis, brain abscess, seizures, and cerebrospinal fluid fistulas. However, the prognosis remains good and it has a low recurrence rate if it is managed early and supported with long-term follow-up . Conclusions Although benign and rare, ethmoidal sinus mucoceles may lead to irreversible blindness due to the compression of the optic nerve and its adjacent structures. An early surgical intervention mainly via endoscopic sinus surgery may prevent permanent visual loss. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 The natural history and clinical characteristics of paranasal sinus mucoceles: a clinical review Int Forum Allergy Rhinol Scangas GA Gudis DA Kennedy DW 712 717 3 2013 23696282 2 Unilateral proptosis is a rare presentation of a posterior ethmoidal sinus mucocele J Med Sci Clin Res Nikam V Pawar V Pravina C Mustaque M 23122 23125 5 2017 3 Paranasal sinus mucoceles with ophthalmologic manifestations: a 17-year review of 96 cases Am J Rhinol Allergy Kim YS Kim K Lee JG Yoon JH Kim CH 272 275 25 2011 21819766 4 Complications of inflammatory diseases of the sinuses Otolaryngol Clin North Am Stankiewicz JA Newell DJ Park AH 639 655 26 1993 7692375 5 Sphenoidal mucocele presenting as acute cranial nerve palsies Saudi J Ophthalmol Cheng CS Sanjay S Yip CC Yuen HW 459 461 26 2012 23961035 6 Paranasal sinus mucocele Ear Nose Throat J Thompson LD 276 278 91 2012 22829031 7 Visual prognosis in compressive optic neuropathy secondary to sphenoid sinus mucocele: a systematic review Orbit Li E Howard MA Vining EM Becker RD Silbert J Lesser RL 280 286 37 2018 29303386 8 Mucoceles of the paranasal sinuses: MR imaging with CT correlation AJR Am J Roentgenol Van Tassel P Lee YY Jing BS De Pena CA 407 412 153 1989 2750628 9 Failed endoscopic sinus surgery: spectrum of CT findings in the frontal recess Radiographics Huang BY Lloyd KM DelGaudio JM Jablonowski E Hudgins PA 177 195 29 2009 19168844 10 Endoscopic management of 108 sinus mucoceles Laryngoscope Har-El G 2131 2134 111 2001 11802010 11 Single stage management of complex fronto-orbital mucoceles J Craniofac Surg Weitzel EK Hollier LH Calzada G Manolidis S 739 745 13 2002 12457085 |
J. Gynakol. Endokrinol. CH Journal fur Gynakologische Endokrinologie/Schweiz 1995-6924 2520-8500 Springer Vienna Vienna 288 10.1007/s41975-023-00288-w Schon Gewusst...? Schon gewusst ...? Saviez-vous que ...?Stute Petra [email protected] grid.411656.1 0000 0004 0479 0855 Abteilung fur Gynakologische Endokrinologie und Reproduktionsmedizin, Universitatsklinik fur Frauenheilkunde, Inselspital Bern, Friedbuhlstrasse 19, 3010 Bern, Schweiz 13 3 2023 13 3 2023 2023 26 1 3740 20 2 2023 (c) The Author(s) 2023 Open Access Dieser Artikel wird unter der Creative Commons Namensnennung 4.0 International Lizenz veroffentlicht, welche die Nutzung, Vervielfaltigung, Bearbeitung, Verbreitung und Wiedergabe in jeglichem Medium und Format erlaubt, sofern Sie den/die ursprunglichen Autor(en) und die Quelle ordnungsgemass nennen, einen Link zur Creative Commons Lizenz beifugen und angeben, ob Anderungen vorgenommen wurden. Die in diesem Artikel enthaltenen Bilder und sonstiges Drittmaterial unterliegen ebenfalls der genannten Creative Commons Lizenz, sofern sich aus der Abbildungslegende nichts anderes ergibt. Sofern das betreffende Material nicht unter der genannten Creative Commons Lizenz steht und die betreffende Handlung nicht nach gesetzlichen Vorschriften erlaubt ist, ist fur die oben aufgefuhrten Weiterverwendungen des Materials die Einwilligung des jeweiligen Rechteinhabers einzuholen. Weitere Details zur Lizenz entnehmen Sie bitte der Lizenzinformation auf University of BernOpen access funding provided by University of Bern issue-copyright-statement(c) Springer-Verlag GmbH Austria, ein Teil von Springer Nature 2023 pmcEinfluss einer HRT auf das Risiko fur eine Depression Originalpublikation Wium-Andersen MK et al (2022) Association of hormone therapy with depression during menopause in a cohort of Danish women. JAMA Netw Open 5(11):e2239491. Hintergrund. Erst im August 2022 wies das Positionspapier der Nordamerikanischen Menopause Gesellschaft (NAMS) daraufhin, dass (1) die antidepressive Wirkung von Ostrogenen ahnlich stark ist wie die von Antidepressiva, wenn sie depressiven Frauen in der Perimenopause mit oder ohne Hitzewallungen verabreicht werden (Level II) und (2) transdermales Ostradiol mit sequentiellem, mikronisiertem Progesteron depressive Symptome bei euthymischen Frauen in der Perimenopause vorbeugen kann (Level II). Diese Statements werden nun von einer prospektiven Kohortenstudie (Level IV) in Frage gestellt. Zusammenfassung. In einer danischen, registerbasierten, prospektiven Kohortenstudie wurden alle Frauen, die im Zeitraum 1995-2017 45 Jahre alt wurden, eingeschlossen (n = 825.238). Das Follow-up endete 2018 und war somit fur die eingeschlossenen Frauen unterschiedlich lang (ca. 1-23 Jahre). Wahrend des Follow-up wurden 13.069 Frauen (1,6 %) aufgrund einer Depression hospitalisiert (Inzidenz 17,3 Falle pro 10.000 Personenjahre). Wahrend des Follow-up initiierten 189.821 Frauen (23 %) eine systemische (Ostrogen mono (ET), Ostrogen-Gestagen-Kombination (EPT) oder lokale Hormonersatztherapie (HRT)). Das mediane Alter bei HRT-Start war 55 Jahre. Im Median wurden 33 HRT-Verschreibungen eingelost, wobei ca. 2/3 der Frauen mindestens funf Verschreibungen einlosten, am haufigsten fur eine lokale HRT (lokal 65,8 % vs. ET 7,8 % vs. EPT 26,4 %). Die Pravalenz einer fruheren Depression war insgesamt gering (2,4 %), wobei HRT-Anwenderinnen jedoch seltener davon betroffen waren als Nicht-Anwenderinnen (1,2 % vs. 2,8 %). Die Pravalenz einer fruheren Anwendung von Antidepressiva (19 %) und Schlafmedikamenten (14,4 %) war jedoch deutlich hoher! Das Ziel der Studie war es, die Assoziation zwischen einer HRT und einer spateren Depressionsdiagnose zu untersuchen. Die Assoziationen wurden unter Verwendung von Cox-Proportional- Fixed-Effects-Poisson-Regressionsmodellen untersucht. Alle Hazard Ratios (HR) wurden fur Bildungsniveau, Ehestatus, Geburten, fruhere Anwendung von hormonalen Kontrazeptiva und Schlafmedikamenten (aber nicht Antidepressiva!) und Komorbiditaten (Diabetes, Bluthochdruck, Apoplex, Herzerkrankung, fruhere Depression) adjustiert. Nur eine systemische, nicht aber eine lokale HRT war mit einem erhohten Risiko fur eine hospitalisierungspflichtige Depression verbunden; und dies v. a. bei 50-jahrigen HRT-Starterinnen (HR 1,50, 95 % KI 1,24-1,81) sowie v. a. im 1. Jahr nach Beginn einer Behandlung mit ET (HR 2,03, 95 % KI 1,21-3,41) bzw. EPT (HR 2,01, 95 % KI 1,26-3,21). Die Fallzahlen waren allerdings recht klein: Von den 649.279 45-jahrigen Frauen ohne Depression in der Vorgeschichte wurden innerhalb des 1. Beobachtungsjahr 74 Frauen aufgrund einer Depression hospitalisiert (vs. 534 der Nicht-Anwenderinnen). Eine lokale HRT nach 54 Jahren war dagegen mit einem signifikant geringeren Depressionsrisiko verbunden. Die Autoren kommen zu dem Schluss, dass eine systemische HRT mit einem hoheren Depressionsrisiko verbunden ist, insbesondere in den Jahren unmittelbar nach Behandlungsbeginn, wahrend eine lokal verabreichte Hormonbehandlung mit einem geringeren Depressionsrisiko fur Frauen ab 54 Jahren verbunden ist. Kommentar Die Skandinavischen Registerstudien bestechen regelmassig durch ihre hohen Fallzahlen. Dennoch lohnt sich ein kritischer Blick. Das Durchschnittsalter bei HRT-Start lag in der Postmenopause, was sich auch in der bevorzugt lokalen HRT-Verschreibung widerspiegelt. Die Indikation fur die Verschreibung einer systemischen HRT ist unklar, was bei Registerstudien auch nicht anders zu erwarten ist. Allerdings heisst es im Ergebnisteil, dass dies die erste Beobachtungsstudie sei, die Frauen prospektiv beobachte, die eine HRT aufgrund einer klinisch diagnostizierten Depression begannen. Wenn das so stimmte, dann wurde die Studie eher den Einfluss einer HRT auf das Hospitalisierungsrisiko (also den Schweregrad) einer Depression untersuchen. Wichtig an der Stelle ist, dass der Studienendpunkt die hospitalisierungspflichtige Depression war. Andere, auch schwachere, vielleicht auch positive Affektveranderungen wurden nicht erfasst. Die Pravalenz einer fruheren Anwendung von Psychopharmaka ist deutlich hoher als die der im Register dokumentierten fruheren Depressionen; diese Diskrepanz wird nicht geklart. Auch wird fur die fruhere Anwendung von Antidepressiva nicht adjustiert!? Auch zur systemischen HRT bleiben viele Fragen offen: unklar ist, welche Praparate eingesetzt wurden, welche Gestagene, welcher Applikationsmodus (oral, transdermal), welche Applikationsschemata (sequentiell, kontinuierlich-kombiniert), welche Dosis. Ausserdem wird die HRT-Therapiedauer nicht angegeben, da nur in ,,eingelosten Rezepten" gerechnet wird. Wie aber ist in Danemark die Verschreibungseinheit definiert? Wie z. B. in Deutschland mit maximal drei HRT-Packungen pro Rezept? Oder eher wie in der Schweiz, wo vorwiegend Jahresrezepte ausgestellt werden? Oder ganz variabel? Als Fazit bleibt, dass nach wie vor viele Fragen zum Einfluss einer HRT auf die Stimmung offenbleiben. Eine einzelne Studie sollte uns aber nicht davon abhalten, Frauen mit klimakterischem Syndrom die 1st-line Therapie HRT zu verschreiben. Brain Fog in den Wechseljahren Originalpublikation Maki PM, Jaff NG (2022) Brain fog in menopause: a health-care professional's guide for decision-making and counseling on cognition. Climacteric 301-9. 10.1080/13697137.2022.2122792. Hintergrund. Kognitive Beschwerden sind in den Wechseljahren haufig und mit einer reduzierten Lebensqualitat verbunden . Spatestens seit der Pandemie aufgrund von SARS-CoV-2 Infektionen ist den meisten der Begriff ,,brain fog" gelaufig, der nun auch zunehmend im Kontext der Wechseljahre gebraucht wird. Wie sollten Frauen mit ,,brain fog" in den Wechseljahren beraten werden? Zusammenfassung. Unter ,,Brain Fog" in den Wechseljahren versteht man verschiedene kognitive Symptome, die sich haufig als Schwierigkeiten im Gedachtnis und in derAufmerksamkeit manifestieren. Diese kognitiven Veranderungen in den Wechseljahren sollten nicht mit einer Demenz verwechselt werden. Eine Demenz vor 64 Jahren ist selten. Zu den haufigsten kognitiven Beschwerden zahlen Schwierigkeiten beim Lernen und im verbalen Gedachtnis. Die Symptome beginnen meist wahrend der menopausalen Transition. Die Beschwerden konnen storend und subjektiv besorgniserregend sein, der normale kognitive Funktionsumfang wird jedoch in der Regel beibehalten; nur etwa 11-13 % der Frauen weisen eine klinisch signifikante Beeintrachtigung auf. Die kognitiven Symptome sind mit Veranderungen der Ostrogenserumkonzentration, vasomotorischen Beschwerden, Schlaf und Stimmung assoziiert. Die Behandlung dieser Symptome kann sich positiv auf die Kognition auswirken. Es stellt sich die grundsatzliche Frage nach der Rolle der HRT im Hinblick auf die Kognition und Demenz. Eine HRT wird derzeit international weder zur Behandlung kognitiver Beschwerden in den Wechseljahren noch zur Pravention eines kognitiven Abbaus bzw. Demenzentwicklung empfohlen. Fragen zum Einfluss einer HRT auf die kognitiven Fahigkeiten bei Frauen mit storenden Hitzewallungen oder bei Frauen in der Perimenopause konnen mangels entsprechender Studien noch nicht beantwortet werden. Bei Frauen mit fruher Menopause (< 45 Jahren) unterstutzen Ostrogene den Erhalt der kognitiven Funktion und reduzieren das Demenzrisiko. Wenn eine HRT in der fruhen Postmenopause begonnen wird, ist kein negativer Einfluss auf die Kognition zu erwarten. Gleiches gilt fur den Einsatz von reinen Ostrogenen in der spaten Postmenopause. Bisher konnte nur fur die kombinierte HRT mit konjugierten equinen Ostrogenen (CEE) und Medroxyprogesteronacetat (MPA) ein negativer Einfluss auf die kognitive Funktion beobachtet werden, wenn diese nach 65 Jahren gestartet (!) wird. Die Kombination von oralem Estradiol und vaginalem Progesteron scheint dagegen auch bei Start in der spaten Postmenopause sicher zu sein. Verschiedene modifizierbare Risikofaktoren sind mit der kognitiven Gesundheit assoziiert. Hierzu zahlen Adipositas, Bluthochdruck, Diabetes, mangelnde korperliche Aktivitat, Rauchen, mangelnde kognitive Aktivitat, wenig soziale Interaktion, Schwerhorigkeit und Depression. Diese Risikofaktoren sollten moglichst gut gemanagt/reduziert werden. Es liegen bisher keine ausreichenden Daten vor, um zwischen kognitiven Beschwerden aufgrund der Wechseljahre und aufgrund von Long COVID unterscheiden zu konnen. Allerdings scheinen exekutive Funktionseinbussen bei SARS-CoV-2 ein herausragendes Merkmal zu sein, welche in der Regel in den Wechseljahren nicht beobachtet werden. Kommentar Das Review bietet praktische Empfehlungen zum Management von Frauen mit kognitiven Beschwerden in den Wechseljahren. Am wichtigsten ist, dass diese kognitiven Beschwerden nicht ein Vorbote der Demenz darstellen, wie haufig befurchtet. Auch das Demenzrisiko unter HRT wird aufgegriffen und verdeutlicht, dass ein erhohtes Risiko bisher nur fur asymptomatische (!) > 65-jahrige (!) Frauen beobachtet wurde, die erst zu diesem Zeitpunkt (!) mit einer oralen kombinierten HRT bestehend aus CEE und MPA (!) beginnen . Funding Open access funding provided by University of Bern Einhaltung ethischer Richtlinien Interessenkonflikt P. Stute gibt an, dass kein Interessenkonflikt besteht. Fur diesen Beitrag wurden von den Autor/-innen keine Studien an Menschen oder Tieren durchgefuhrt. Fur die aufgefuhrten Studien gelten die jeweils dort angegebenen ethischen Richtlinien. Nachdruck mit freundlicher Genehmigung aus dem Newsletter der Deutschen Menopause Gesellschaft e. V. und der Schweizerischen Gesellschaft fur Gynakologische Endokrinologie und Menopause Hinweis des Verlags Der Verlag bleibt in Hinblick auf geografische Zuordnungen und Gebietsbezeichnungen in veroffentlichten Karten und Institutsadressen neutral. Literatur 1. The 2022 Hormone Therapy Position Statement of The North American Menopause Society Advisory Panel The 2022 hormone therapy position statement of The North American Menopause Society Menopause 2022 29 7 767 794 10.1097/GME.0000000000002028 35797481 2. Greendale GA Karlamangla AS Maki PM The menopause transition and cognition JAMA 2020 323 15 1495 1496 10.1001/jama.2020.1757 32163094 3. Stute P Wienges J Koller AS Giese C Wesemuller W Janka H Baumgartner S Cognitive health after menopause: Does menopausal hormone therapy affect it? Best Pract Res Clin Endocrinol Metab 2021 35 6 101565 10.1016/j.beem.2021.101565 34538724 |
J Med Case Rep J Med Case Rep Journal of Medical Case Reports 1752-1947 BioMed Central London 36907903 3797 10.1186/s13256-023-03797-1 Case Report Isolated medial antebrachial cutaneous nerve injury after blunt trauma: a case report Babaeian Zahra 1 Ashraf Alireza [email protected] 2 Erfani Fariba 1 1 grid.412571.4 0000 0000 8819 4698 Student Research Committee, Department of Physical Medicine and Rehabilitation, Shiraz University of Medical Sciences, Shiraz, Iran 2 grid.412571.4 0000 0000 8819 4698 Department of Physical Medicine and Rehabilitation, Shiraz Geriatric Research Center, Shahid Faghihi Hospital, Shiraz University of Medical Sciences, Karimkhan Zand Street, Shiraz, 71348-44119 Iran 13 3 2023 13 3 2023 2023 17 9125 10 2022 30 1 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background The medial antebrachial cutaneous nerve is a branch of the brachial plexus that contains C8-T1 segments. Injury of this nerve by various mechanisms has been reported in the literature; however, currently, there is no reported case of medial antebrachial cutaneous nerve injury in the setting of acute blunt trauma. Case presentation This case report presents the case of a 34-year-old Persian female with dysesthesia and pain in the medial side of the forearm immediately following a blunt trauma by mechanism of elbow external rotation. On electrodiagnostic evaluation, the medial antebrachial cutaneous nerve sensory nerve action potential of the symptomatic side had a significant amplitude drop (more than 50%), compared with the other side. On follow-up electrodiagnosis, after several sessions of physical therapy, the medial antebrachial cutaneous nerve sensory nerve action potential still had a significant amplitude difference. Conclusion Blunt trauma can be one of the causes of medial antebrachial cutaneous nerve involvement. An electrodiagnostic study can be helpful in the diagnosis of this nerve injury after blunt trauma. Keywords Blunt trauma Electrodiagnosis Medial antebrachial cutaneous nerve injury MAC nerve injury issue-copyright-statement(c) The Author(s) 2023 pmcBackground The medial antebrachial cutaneous (MAC) nerve is a branch of the brachial plexus that carries fibers of C8-T1 segments . It is responsible for the medial side of the forearm and olecranon skin sensation . In the literature, MAC nerve involvement has been reported to have various mechanisms. We present a case of acute blunt trauma-induced injury to the MAC nerve that was diagnosed by a nerve conduction study. To the best of our knowledge, this is the first time that this nerve injury has been reported after acute blunt trauma. Case presentation A 34-year-old right-handed Persian female engineer was referred to the electrodiagnostic clinic due to dysesthesia and pain in the medial side of her right hand and forearm. She had a history of blunt trauma to her right forearm about 40 days before the first evaluation. The mechanism of trauma was an external rotation of the elbow. Abruptly, she developed lancinating pain and dysesthesia in the medial side of the forearm. After 2 days, the nature of the pain became dull. Also, paresthesia, tingling, and numbness started from the medial side of the elbow, to the hand and the fifth finger. She complained of difficulty in writing due to this annoying dysesthesia. There was no complaint of weakness in the affected limb. She was nulliparous. In her past medical history, she did not have any significant social, environmental, or drug history prior to diagnosis. She denied alcohol consumption or smoking. She did not have polyneuropathy, chronic systemic disease, phlebotomy, injection, or surgical intervention at the elbow. Also, there was no significant psychological disorder or related family history. On physical examination, she seemed well nourished with a blood pressure of 115/80 mmHg, pulse rate of 75 beats per minute, and axillary temperature of 36.2 degC at the first outpatient visit. The light touch and pinprick sensation were impaired on the medial side of the right forearm. Range of motion, manual muscle testing, and deep tendon reflexes were normal. Hoffmann's and Babinski signs were negative. Mild tenderness in the anteromedial part of the elbow was detected. There was no Tinel's sign around the elbow region. On nerve conduction study (NCS), sensory nerve action potential (SNAP) of the median (third finger), ulnar (fifth finger), radial (snuff box), and dorsal ulnar cutaneous nerves had normal peak latency and amplitude, without a significant difference to the asymptomatic side. On further evaluation, the medial antebrachial cutaneous nerve SNAP of the symptomatic side had a considerable amplitude drop (more than 50%) compared with the other side (as shown in Fig. 1 and Table 1). Also, compound nerve action potential (CNAP) of the ulnar nerve across the elbow by stimulating the wrist and recording above the elbow showed mild conduction block on the right side compared with the left.Fig. 1 Nerve conduction responses of both sides of the medial antebrachial cutaneous nerve. Lower trace: normal response obtained from the left side medial antebrachial cutaneous, peak latency 1.55 milliseconds, amplitude 26.9 mV. Upper trace: abnormal response obtained from the right side medial antebrachial cutaneous, peak latency 1.77 milliseconds, amplitude 7.6 mV (more than 50% amplitude drop compared with the other side) Table 1 The data of the first nerve conduction study of the case Nerve/site Onset latency (milliseconds) Peak latency (milliseconds) Amplitude (mV) Right ulnar CNAP 3.02 3.85 40.9 Left ulnar CNAP 3.02 3.65 70.5 Right MAC 1.46 1.77 7.6 Left MAC 1.09 1.51 26.9 mV microvolt, CNAP compound nerve action potential, MAC medial antebrachial cutaneous Motor NCS of the median and ulnar nerves was normal. F-wave of the abductor digiti minimi was normal. On needle electromyography of the right flexor carpi ulnaris and first dorsal interosseous, there was normal motor unit action potential (MUAP) and recruitment without spontaneous activity. In summary, this study showed isolated mild right medial antebrachial cutaneous nerve injury. The right elbow X-ray was normal. Magnetic resonance imaging of the right elbow revealed faintly visualized signal changes in the proximal and posterior aspect of the medial collateral ligament (MCL) with no definite evidence of defect or tear. A thin wall cyst with the same signal to synovial fluid just lateral to the olecranon was seen connecting to the joint space measuring 9 x 5 x 2 mm incidentally. On follow-up electrodiagnosis after 1 month, the conduction block in the right ulnar CNAP resolved, but the MAC nerve SNAP still had a significant amplitude difference (Table 2). She did not have any hospital admission or drug prescription. However, she had undergone several sessions of physical therapy during this period. This course of physical therapy included mobility of the elbow and wrist, stretching of forearm muscles, nerve gliding exercises for the ulnar nerve, and transcutaneous electrical nerve stimulation. Numbness and sensory complaints of the medial side of the right hand and fifth finger showed improvement, but the sensory disturbance remained at the medial side of the forearm until 6 months follow-up.Table 2 The data of the second nerve conduction study of the case (1 month later) Nerve/site Onset latency (milliseconds) Peak latency (milliseconds) Amplitude (mV) Right ulnar CNAP 3.33 4.06 58.6 Left ulnar CNAP 3.18 3.85 61.4 Right MAC 1.72 2.08 11.9 Left MAC 1.51 1.93 18.9 mV microvolt, CNAP compound nerve action potential, MAC medial antebrachial cutaneous Discussion In this case report study, we presented the case of a 34-year-old female with isolated MAC nerve injury after blunt trauma. The medial antebrachial cutaneous nerve originates from the medial cord of the brachial plexus in continuation of the lower trunk. The MAC nerve contains the fibers of C8 and T1 nerve roots . It descends through the brachial fascia along with the basilic vein, brachial artery, and median and ulnar nerves . At about 10 cm proximal to the medial epicondyle, it is divided into two branches (anterior and posterior) and continues to the wrist. It is a pure sensory nerve that innervates the anteromedial part of the distal arm, antecubital fossa, posterior olecranon region, and medial volar aspect of the forearm. Different variations were reported in the anatomical course of this nerve . In the literature, some reported causes of MAC nerve involvement include brachial plexopathy and thoracic outlet syndrome . This nerve involvement was also reported with tuberculoid leprosy neuritis and subcutaneous lipoma . There are some iatrogenic causes, including steroid injection due to medial epicondylitis, routine venipuncture, cubital tunnel surgery, loose body removal, elbow arthroscopy, open fractures fixation, tumor excision, panniculitis excision, brachial plexus block, and arthrolysis [12-20]. In one case report, it occurred after repetitive minor trauma . Injury of the MAC nerve occasionally occurred due to iatrogenic reasons during the interventions. To the best of our knowledge, this is the first injury of MAC nerve with blunt trauma with elbow external rotational mechanism. Because damage to this nerve rarely occurs, its evaluation may be missed in routine electrodiagnostic studies. Although spontaneous recovery of this nerve may be possible, the delay in timely diagnosis can cause imposing unnecessary diagnostic work-ups to evaluate other differential diagnoses of forearm dysesthesia. It may seem that MAC nerve injury has no important role in daily activity, but in this case, it interfered with her work-related activities, such as writing for extended periods. It affected her quality of life. Although spontaneous recovery of this nerve is possible, appropriate treatment could be administered promptly to assist the patient in early recovery. As a result, the patient would have the opportunity to conveniently return to work and routine daily life. Aiming to control the symptoms, we started conservative management for her. Physical therapy, including nerve gliding exercises, was done that was relatively effective, especially on the ulnar nerve block at the elbow. Conclusion Blunt trauma can be one of the causes of MAC nerve involvement. Because this nerve is not evaluated in routine electrodiagnostic study, damage to this nerve may be missed. It is recommended that this nerve be evaluated in any patient who presents with any sensory complaint in the medial side of the forearm and wrist. Abbreviations MAC Medial antebrachial cutaneous NCS Nerve conduction study SNAP Sensory nerve action potential CNAP Compound nerve action potential MUAP Motor unit action potential MCL Medial collateral ligament mV Microvolt Acknowledgements The authors would like to thank Shiraz University of Medical Sciences, Center for Development of Clinical Research of Nemazee Hospital. Also, the authors are grateful for editorial assistance from Dr. Nasrin Shokrpour and Dr. Fatemeh Babaeian. Author contributions AA visited the patient and did the electrodiagnostic study and analysis. ZB processed the data and significantly contributed to writing and editing the manuscript. FE contributed to the editing of the manuscript. All authors read and approved the final manuscript. Funding Not applicable. Availability of data and materials Not applicable. Declarations Ethics approval and consent to participate The patient had consented to participate in the study and for publishing the results. The ethics committee approved this study with the reference number IR.SUMS.MED.REC.1401.112. Consent for publication Written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal. Competing interests The authors declare that they have no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Stylianos K Konstantinos G Pavlos P Aliki F Brachial branches of the medial antebrachial cutaneous nerve: a case report with its clinical significance and a short review of the literature J Neurosci Rural Pract 2016 7 03 443 446 10.4103/0976-3147.182772 27365965 2. Benedikt S Parvizi D Feigl G Koch H Anatomy of the medial antebrachial cutaneous nerve and its significance in ulnar nerve surgery: an anatomical study J Plast Reconstr Aesthet Surg 2017 70 11 1582 1588 10.1016/j.bjps.2017.06.025 28756975 3. Polcaro L, Charlick M, Daly DT. Anatomy, head and neck, brachial plexus. StatPearls. 2021. 4. Thomas K, Sajjad H, Bordoni B. Anatomy, shoulder and upper limb, medial brachial cutaneous nerve. StatPearls. 2021. 5. Yildiz N Ardic F A rare cause of forearm pain: anterior branch of the medial antebrachial cutaneous nerve injury: a case report J Brachial Plex Peripher Nerve Inj 2008 3 1 1 4 18211681 6. Race CM Saldana MJ Anatomic course of the medial cutaneous nerves of the arm J Hand Surg 1991 16 1 48 52 10.1016/S0363-5023(10)80012-7 7. Ballard T, Smith T. Anatomy, medial antebrachial cutaneous nerve. StatPearls. 2020. 8. Seror P Medial antebrachial cutaneous nerve conduction study, a new tool to demonstrate mild lower brachial plexus lesions. 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Horowitz SH Peripheral nerve injury and causalgia secondary to routine venipuncture Neurology 1994 44 5 962 962 10.1212/WNL.44.5.962 8190306 15. Asheghan M Khatibi A Holisaz MT Paresthesia and forearm pain after phlebotomy due to medial antebrachial cutaneous nerve injury J Brachial Plex Peripher Nerve Inj 2011 6 01 e38 e39 16. Lowe JB III Maggi SP Mackinnon SE The position of crossing branches of the medial antebrachial cutaneous nerve during cubital tunnel surgery in humans Plast Reconstr Surg 2004 114 3 692 696 10.1097/01.PRS.0000130966.16460.3C 15318047 17. Sarris I Gobel F Gainer M Vardakas DG Vogt MT Sotereanos DG Medial brachial and antebrachial cutaneous nerve injuries: effect on outcome in revision cubital tunnel surgery J Reconstr Microsurg 2002 18 08 665 670 10.1055/s-2002-36497 12524584 18. Kelly EW Morrey BF O'Driscoll SW Complications of elbow arthroscopy JBJS 2001 83 1 25 10.2106/00004623-200101000-00004 19. 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Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34854 Ophthalmology A New Technique Using a 4-0 Nylon Thread as a Guide for Easy and Precise Tube Insertion of Ahmed Glaucoma Valve Implant Into Ciliary Sulcus Muacevic Alexander Adler John R Nitta Keisuke 1 Akiyama Hideo 1 1 Department of Ophthalmology, Gunma University Graduate School of Medicine, Maebashi, JPN Keisuke Nitta [email protected] 11 2 2023 2 2023 15 2 e348548 2 2023 Copyright (c) 2023, Nitta et al. 2023 Nitta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from We present a new technique for inserting the tube of the Ahmed glaucoma valve (AGV) (model FP7; Rancho Cucamonga, CA: New World Medical) implant into the ciliary sulcus, easily and precisely, using a 4-0 nylon thread as a guide. An 88-year-old woman received AGV implantation for secondary angle recession glaucoma with underlying pseudoexfoliation syndrome in her left eye. She had a history of trauma with mild intraocular lens (IOL) oscillation and poor mydriasis, with maximum pupil diameter of 3.5 mm. Ciliary sulcus tube insertion in such patients sometimes becomes difficult, however, using a 4-0 nylon thread as a guide, precise insertion was achieved easily in the following way. A 4-0 nylon thread was placed into the anterior chamber through a 1 mm incision opposite the site of the AGV implant. Subsequently, a 23G needle was inserted into the sclera 2 mm from the corneal limbus in the same quadrant as AGV implants. The tip of the 23G needle proceeded horizontally to the iris, through the sclera and ciliary body, and into the ciliary sulcus. At the center of the pupil, the 4-0 nylon thread was introduced into the lumen of the 23G needle. Subsequently, the 23G needle, together with the 4-0 nylon thread in the lumen was withdrawn out of the eye. The 4-0 nylon was then inserted into the tube lumen of the AGV implant. Finally, by using 4-0 nylon as a guide, the Ahmed tube was inserted into the ciliary sulcus precisely without much difficulty. intraocular lens oscillation trauma glaucoma case report poor mydriasis tube implant nylon ahmed glaucoma valve ciliary sulcus The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Ciliary sulcus tube insertion of Ahmed glaucoma valve (AGV) implant is a useful method nowadays as it is less likely to cause corneal endothelial cell loss than anterior chamber tube insertion . However, the low rigidity of AGV tube causes difficulties in insertion to ciliary sulcus, such as straying into the vitreous cavity or into an unidentifiable position, when using simple insertion methods . Several techniques have been reported to overcome these problems, although problems remain, such as the complexity and unreliability of the procedure, and costs of the materials used [4-8]. In this study, we report a simple and precise technique of AGV tube insertion into the ciliary sulcus using inexpensive 4-0 nylon thread as a guide. Case presentation An 88-year-old woman, with underlying both eyes pseudophakic and pseudoexfoliation syndrome, presented to us with uncontrolled intraocular pressure in the left eye for further management. She had undergone cataract surgery in both eyes 22 years ago, and since then had visited her local ophthalmologist for pseudoexfoliation (PEX) in her left eye, with intraocular pressure in the normal range. One year and six months ago, she sustained a fall and had a left eye traumatic infraorbital wall fracture with periorbital bruises. One year ago, the intraocular pressure (IOP) in her left eye increased to 43 mmHg, and she had been followed up with increased eye drops. The IOP gradually became uncontrolled, and she was referred to our department for surgery. At initial visit, corrected visual acuity was 20/25 in the right eye and 20/50 in the left eye, and IOP was 22 mmHg in the right eye and 40 mmHg in the left eye. Corneal endothelial cell density was 2577 cells/mm2 in the right eye and 2213 cells/mm2 in the left eye. A prostaglandin analog and a carbonic anhydrase inhibitor/a2-adrenergic receptor agonist eye drops were used in her left eye. Gonioscopic examination revealed angle recession from 2 to 7 o'clock in her left eye. In addition, her left eye showed poor mydriasis due to PEX, with a maximum pupil diameter of about 3.5 mm and mild intraocular lens oscillation. She has proceeded with AGV implant surgery in her left eye as the following procedure. Conjunctival incision in the superior temporal quadrant followed by sub-Tenon's capsule anesthesia was performed. Insertion sites of the superior rectus and external rectus muscles were identified, and the plate of the AGV implant was inserted into the space and fixed with 7-0 nylon threads at a position 9 mm from the corneal limbus. The tube was trimmed to length with the tip visible from the pupil. A 1 mm incision was made in the inferior nasal cornea and a viscoelastic material was injected into the anterior chamber to dilate the ciliary sulcus. Then, a 4-0 nylon thread was placed into the anterior chamber through a 1 mm incision . Subsequently, a 23G needle was inserted into the sclera 2 mm from the corneal limbus and the tip of the needle was advanced through the sclera and ciliary body, and into the ciliary sulcus, parallel to the iris plane . At the center of the pupil, the 4-0 nylon thread was introduced into the lumen of the 23G needle . The 23G needle was then withdrawn out of the eye so that the 4-0 nylon in the lumen was also withdrawn out of the eye . The 4-0 nylon was then inserted into the tube lumen of the AGV implant . Pushing the tube and the 4-0 nylon into the eye , with the 4-0 nylon as a guide, the tube tip was precisely implanted through the sclera and ciliary body and into the ciliary sulcus . Finally, the 4-0 nylon was withdrawn out of the eye from the 1 mm incision . The tube was covered with preserved sclera, and the conjunctiva was closed. At one month postoperatively, the tube was positioned appropriately in the ciliary sulcus without any interference to the iris. The IOP was 10 mmHg without glaucoma eyedrops, and the corneal endothelial cell density was 2545 cells/mm2 with no decrease compared to the preoperative density. Figure 1 Intraoperative images of 4-0 nylon guided tube insertion into ciliary sulcus from the surgeon's view. (a) A 4-0 nylon thread was inserted into anterior chamber from 1 mm incision. Poor mydriasis was seen. Before the process, the anterior chamber had been replaced with viscoelastic material, and the ciliary sulcus was also dilated. (b) A 23G needle was inserted into the sclera 2 mm from the corneal limbus, and the tip of the needle was advanced through the sclera and ciliary body, and into the ciliary sulcus, parallel to the iris plane. The tip of the needle was seen at the center of the pupil. (c) At the center of the pupil, the 4-0 nylon thread was introduced into the lumen of the 23G needle using forceps outside the eye. (d) The 23G needle was withdrawn out of the eye so that the 4-0 nylon in the lumen was also withdrawn out of the eye. (e) The 4-0 nylon was inserted into the tube lumen of the AGV implant using forceps. (f) The tube and the 4-0 nylon were inserted into the eye by forceps. (g) With the 4-0 nylon as a guide, the tube tip was precisely inserted through the sclera and ciliary body and into the ciliary sulcus. The tip of the tube was visible through the pupillary margin. (h) The 4-0 nylon was withdrawn out of the tube lumen, and the tube was left precisely into the ciliary sulcus. Figure 2 Schematic illustration of 4-0 nylon guided tube insertion into ciliary sulcus from the surgeon's view. The direction and focus of each step are illustrated by the red arrows. Blue line indicates a 4-0 nylon thread. Black trapezoid indicates a 23G needle. Green trapezoid indicates the tube of AGV implant. Blue square indicates a corneal 1 mm incision. Red curve indicates a scleral insertion 2 mm from corneal limbus. (a) A 4-0 nylon thread is inserted into anterior chamber from 1 mm incision. (b) A 23G needle is inserted into the sclera 2 mm from the corneal limbus, and the tip of the needle proceeded horizontally to the iris until the tip can be seen through the pupil. (c) At the center of the pupil, the 4-0 nylon thread is introduced into the lumen of the 23G needle. (d) The 23G needle is withdrawn out of the eye so that the 4-0 nylon in the lumen is also withdrawn out of the eye. (e) The 4-0 nylon is inserted into the tube lumen of the AGV implant. (f) The tube and the 4-0 nylon are pushed into the eye. (g) With the 4-0 nylon as a guide, the tube tip is precisely implanted through the sclera and ciliary body and into the ciliary sulcus. (h) The 4-0 nylon is withdrawn out of the eye from the 1 mm incision. The image is created by the authors of this study. Discussion Ciliary sulcus insertion is superior to anterior chamber insertion when compared with the corneal endothelial cell density loss rate . However, ciliary sulcus insertion is more difficult than anterior chamber insertion because the tube passes through invisible parts, such as the ciliary body and the back surface of the iris. Further, weak zonules, the formation of Elschnig pearls, or poor dilation of the pupil make ciliary sulcus insertion difficult . Asaoka et al. reported that 42/91 eyes (46%) were not successfully placed to ciliary sulcus with a single attempt, and 4/91 eyes (4.4%) were unable to achieve ciliary sulcus insertion . A technique for ciliary sulcus insertion has been reported using 10-0 nylon thread with straight needle to create a sliding knot, but the technique is complicated . Kasuga et al. have reported a tube insertion method using 4-0 nylon threads such as ours . In their method, a shortcut 4-0 nylon thread is placed in the tube lumen as a stent outside the eye to increase rigidity and facilitate insertion to the ciliary sulcus. However, this method has a potential risk of straying into the wrong place, such as the vitreous cavity, as it passes blindly through the sclera and ciliary body without a precise guide. In fact, the method of Kasuga et al. is reported to be a proline-assisted ciliary sulcus tube insertion method. On the other hand, our technique uses a 4-0 nylon thread as a guide, which completely passes through the same way as the 23G needle, so that no risk of straying is present. Furthermore, the method of Kasuga et al. required supplies such as disposable forceps to remove the proline from the anterior chamber, whereas in our method, the 4-0 proline thread can be removed from the anterior chamber by simply pulling it out of the eye and no forceps are required . In recent years, methods using a 21G needle or a 23G needle as a guide have also been reported . In these methods, the 21G or 23G needle penetrates in a straight direction with an incline from the corneal wound 180deg opposite to the AGV implant to the sclera at the tube insertion site. Therefore, the tube inserted using that needle as a guide is also inclined and at risk of tilting towards the iris and interfering with the iris back surface. On the other hand, our technique has lower risk of interfering with the iris because the 23G needle is inserted into the eye horizontally to the iris. In addition, compared to our technique, the method using a 23G needle requires a 9-0 or 10-0 nylon thread with needle , thus using more supplies, while the method using a 21G needle has the disadvantage that the wound is larger . A 4-0 nylon thread occupies 62% of the AGV tube lumen and is placed into the tube lumen after AGV surgery for hypotony . Although a 5-0 nylon thread or a 3-0 nylon thread can also enter the tube lumen, a 4-0 nylon thread seemed to be the appropriate size, thus used in this case. Since this is a case report, further studies are required in a large number of cases and the thread size needs to be considered. Conclusions Although tube insertion into the ciliary sulcus of AGV implants is a useful method, simple insertion methods sometimes have difficulty inserting the tube into the ciliary sulcus, resulting in straying into the vitreous cavity or insertion into unidentifiable positions. Our technique achieved simple and precise insertion of an AGV tube into the ciliary sulcus using inexpensive 4-0 nylon thread as a guide in a patient with IOL oscillation and poor mydriasis, who would otherwise have had difficulty with tube implantation into the ciliary sulcus. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 The effect of tube location on corneal endothelial cells in patients with Ahmed glaucoma valve Ophthalmology Zhang Q Liu Y Thanapaisal S 218 226 128 2021 32603727 2 Corneal endothelial cell changes and surgical results after Ahmed glaucoma valve implantation: ciliary sulcus versus anterior chamber tube placement Sci Rep Kim JY Lee JS Lee T Seo D Choi W Bae HW Kim CY 11 2021 3 Operative complications of glaucoma drainage implant tube insertion through the sulcus for pseudophakic eye J Glaucoma Asaoka S Kasuga T Matsunaga T 169 174 30 2021 4 Polypropylene suture-guided valve tube for posterior chamber implantation in patients with pseudophakic glaucoma J Cataract Refract Surg Moreno-Montanes J Fantes F Garcia-Gomez P 1828 1831 34 2008 19006725 5 Proline-assisted tube insertion through sulcus in Ahmed valve J Glaucoma Kasuga T Asaoka S Asada Y 106 107 29 2020 6 Ab interno implantation of glaucoma drainage devices tubes in the posterior chamber BMC Ophthalmol Moreno-Montanes J Guirao-Navarro C Argueso F 20 2020 7 Needle guided ab interno technique for tube insertion through the ciliary sulcus in uncontrolled glaucoma Eur J Ophthalmol Loayza-Gamboa W Martel-Ramirez V Inga-Condezo V Valderrama-Albino V Alvarado-Villacorta R Valera-Cornejo D 704 708 32 2022 33779334 8 Early outcomes of 21-gauge needle-guided ab interno tube sulcus placement of a non-valved implant in pseudophakic eyes Indian J Ophthalmol Maheshwari D Rao S Pawar N Kadar MA Ramakrishnan R 1051 1053 70 2022 35225573 9 Ab interno tube occlusion for postoperative hypotony in a patient with an Ahmed glaucoma drainage device J Glaucoma Feinstein M Moussa K Han Y 61 63 27 2018 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34856 Anesthesiology Pain Management General Surgery Emergency Awake Abdominal Surgery Under Thoracic Epidural Anaesthesia in a High-Risk Patient Within a Resource-Limited Setting Muacevic Alexander Adler John R Le Roux Johannes J 1 Wakabayashi Koji 1 Jooma Zainub 23 1 Anaesthesiology, Chris Hani Baragwanath Academic Hospital, Johannesburg, ZAF 2 Anaesthesia and Critical Care, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, ZAF 3 Anaesthesiology, University of the Witwatersrand, Johannesburg, Johannesburg, ZAF Johannes J. Le Roux [email protected] 11 2 2023 2 2023 15 2 e3485611 2 2023 Copyright (c) 2023, Le Roux et al. 2023 Le Roux et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Awake abdominal surgery is performed daily around the world for caesarean section surgery under lumbar subarachnoid anaesthesia and/or graded lumbar epidural anaesthesia. Reports of awake abdominal surgery under thoracic epidural anaesthesia (TEA) for patients with bowel obstruction are scarce, as this patient population is at high risk for pulmonary aspiration. In this report, we describe a case in which a graded TEA was successfully used as the sole anaesthetic technique in a patient with severe pulmonary disease undergoing an awake emergency laparotomy for bowel ischaemia for whom no postoperative intensive care monitoring was available. No anaesthetic or surgical complications occurred, and the patient was discharged home seven days after the surgical procedure. A 30-day follow-up revealed no residual anaesthetic or surgical complications, with a return to baseline function. emergency abdominal surgery loco-regional anaesthesia surgical stress response thoracic epidural analgesia awake laparotomy The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Emergency laparotomy is a common surgical procedure that carries a high risk of morbidity and mortality. In high-risk patients, mortality for emergency abdominal surgery ranges from 14.9% to 25% . It is frequently performed for patients with pre-existing diseases over and above their acute insult presenting a challenge for treating clinicians. Reports in the United Kingdom have found that patients presenting for emergency laparotomy constitute a "forgotten group" comprising a large proportion of surgical admissions, with death rates higher than in other high-income countries . Acknowledgement of these risks has led to collaborations and protocols such as the National Emergency Laparotomy Audit (NELA), Emergency Laparotomy Network, and the Emergency Laparotomy Collaborative in an endeavour to identify high-risk patients and tailor perioperative care to achieve better outcomes . A key component of improving outcomes has been the recognition of perioperative risk using formal risk assessments by various validated tools thereby allowing appropriate triage and expeditious care. The NELA risk assessment is one such tool validated for emergency laparotomy patients . The crucial role of postoperative intensive care after emergency laparotomy has also received important appreciation and forms part of the nine key standards advocated by NELA . Anaesthesia for emergency abdominal surgery is focused on minimizing the risk of pulmonary aspiration, maintaining haemodynamic stability, providing adequate analgesia, and reducing postoperative complications . General anaesthesia (GA) with tracheal intubation and multimodal analgesia is considered the norm to achieve these goals. However, this technique increases the risk of postoperative pulmonary complications in patients with pre-existing respiratory disease. We describe a case in which a graded thoracic epidural anaesthesia (TEA) was successfully used as the sole anaesthetic technique in a patient with severe pulmonary disease undergoing emergency laparotomy for bowel ischaemia for whom no postoperative intensive care unit (ICU) monitoring was available. Case presentation A 57-year-old male patient presented with an acute bowel obstruction to the emergency department and was diagnosed with small bowel ischaemia on an abdominal computed tomography scan. He was known to have chronic obstructive pulmonary disease (COPD) secondary to a 50-pack-year smoking history and had been dependent on home oxygen for four years. On examination, he was hypoxic on room air, and an arterial blood gas demonstrated type II respiratory failure: pH of 7.33, partial pressure of oxygen (PaO2) of 51 mmHg, partial pressure of carbon dioxide (PaCO2) of 66 mmHg, standard bicarbonate (HCO3) of 36 mmol/L, lactate of 4.0 mmol/L, and a potassium of 5.8 mmol/L. He was haemodynamically stable with a mean arterial pressure (MAP) of 70 mmHg and a pulse rate of 78 beats/minute. He was not dyspnoeic when lying flat, and had a respiratory rate of 14 breaths per minute, but had bilateral wheezes on auscultation. His chest X-ray showed hyperinflated lung fields but no signs of consolidation. He was scheduled for an emergency laparotomy, but postoperative intensive care unit (ICU) care was unavailable due to limited resources. An awake laparotomy under TEA was performed by inserting an epidural catheter at vertebral level T9/T10. In the left lateral position, the epidural space was located by a paramedian approach using a loss-of-resistance to saline technique, and the epidural catheter was secured 5 cm into the epidural space. A test dose of 3 mL 1.5% lignocaine with 1:200,000 adrenaline was administered. A T4-L2 anaesthetic level was obtained with 15 mL 0.5% bupivacaine with 1:200,000 adrenaline, given in 5 mL increments five minutes apart. The thoracic epidural was again bolused after 60 minutes with 8 mL of 0.5% bupivacaine with 1:200,000 adrenaline. No systemic analgesia was administered and epidural opioids were avoided to prevent potential respiratory embarrassment. A midline surgical incision was made extending from the T6 to L2 dermatome. The patient did not report any pain or discomfort intraoperatively. The nasogastric tube was suctioned multiple times perioperatively (total volume of 600 mL). Goal-directed fluid therapy was used to guide fluid management by monitoring static markers of cardiac output (heart rate, blood pressure, urine output, and capillary refill time). A total fluid volume of 1400 mL lactated Ringer's solution was administered. The total blood loss was estimated to be less than 100 mL (pre and postoperative haemoglobins were 10.4 g/dL and 10.1 g/dL, respectively) and urine output averaged 1.2 mL/kg/hr. A pre-operative MAP of 70 mmHg was defended intraoperatively with a low-dose phenylephrine infusion (0.2-0.4 mcg/kg/min). For the duration of the surgery (2 hours and 13 minutes), the patient's heart rate ranged between 64 and 81 beats/minute, MAP ranged between 70 and 81 mmHg, his serum glucose values ranged between 5.3 and 5.9 mmol/L, and his lactate levels showed a decreasing trend (2.4 mmol/L at end of surgery and 0.5 mmol/L three days post-operation). The patient's respiratory rate ranged between 12 and 16 breaths per minute during the perioperative period, and he did not show signs of respiratory embarrassment secondary to the TEA. Intraoperatively, his PaCO2 decreased to 62 mmHg and his PaO2 increased to 68 mmHg. A necrotic small bowel segment of 100 cm was resected followed by a primary anastomosis and abdominal closure . After surgery, the epidural catheter was removed, as the patient was transferred to a ward where TEA utilization and monitoring were not possible. He remained haemodynamically stable (MAP of 73 mmHg, heart rate of 74 beats/minute, and respiratory rate of 16 breaths/minute), and had a PaCO2 of 58 mmHg and PaO2 of 62 mmHg on room air in the immediate postoperative period. No complications were noted at follow-up, and the patient was discharged home seven days after his surgery. Figure 1 Necrotic small bowel segment Discussion It is well established that epidural anaesthesia and analgesia (EA) reduces postoperative complications and respiratory events and may improve long-term outcomes by attenuating the neuroendocrine stress response and by promoting earlier recovery of organ and gastrointestinal function . Furthermore, EA provides superior analgesia and is associated with reduced risks of venous thromboembolism, myocardial infarction, blood loss, and renal failure . For these reasons, EA is recognized as the gold standard for open colorectal surgery advised by the Enhanced Recovery After Surgery (ERAS) guidelines. Reviews on EA use for major abdominal surgery consistently showed clinically significant reductions in postoperative mortality, with up to 40% decreased odds of death reported . In a large cohort study using the US National Surgical Quality Improvement Program (NSQIP) database where surgical procedures and type of anaesthesia were matched (264,421 patients received GA and 64,119 patients received neuraxial or regional anaesthesia), there were significantly lower odds of several postoperative complications, especially respiratory complications, and decreased hospital length of stay, but not mortality, when regional anaesthesia was compared with GA (regional analgesia supplementing GA was not accounted for). Several systematic reviews have sought to clarify the role of epidural analgesia in abdominal surgery with the consistent finding that epidural analgesia results in a reduction in rest pain after major abdominal surgery . Similar ERAS care pathways for patients undergoing emergency laparotomy do not exist because of the paucity of evidence in the emergency setting due to the context-sensitive nature of the procedure. However, the foundation for improved outcomes is the same as for elective surgery, with the key elements being the attenuation of the stress response and subsequent organ dysfunction . Opioid analgesics are avoided when possible as it is associated with perioperative cognitive dysfunction and adverse respiratory and gastrointestinal effects . Neuraxial anaesthesia mitigates these risks and has been shown to reduce perioperative complications and fatal outcomes in patients undergoing emergency laparotomies . EA use in emergency laparotomy also reduces abdominal inflammation and facilitates respiratory recovery . Caution is advised when using central neuraxial techniques in patients at risk of haemodynamic collapse or with significant organ dysfunction. Our patient presented with stable haemodynamic and metabolic profiles, prompting the use of TEA for emergency surgery. While EA use may be regarded as controversial in COPD patients, a study by van Lier et al. showed that the theoretical effect of EA on respiratory muscle function by blunting intercostal nerve conduction was not clinically relevant . EA as compared to spinal anaesthesia causes much fewer changes in inspiratory capacity and expiratory reserve volume . EA also does not affect airway resistance and respiratory gas tensions and it has been shown to improve left ventricular function in high-risk patients by preserving ventricular pulmonary coupling resulting in an improved myocardial oxygen balance [7-9]. GA with tracheal intubation and altered respiratory mechanics may lead to a vulnerable state for right ventricular dynamics. This may be further compounded by the direct cardiodepressant effects of anaesthetic agents on myocardial function . Furthermore, GA affects functional residual capacity, worsens ventilation-perfusion (V:Q) mismatch, and impairs diaphragmatic function . Hence, in high-risk patients such as those with COPD who are at heightened risk of right ventricular dysfunction and adverse ventilatory effects under GA, it is reasonable to advocate for locoregional techniques to be implemented. The beneficial effects described above provide a hypothesis for expecting improved outcomes with EA use in emergency abdominal surgery. A Danish cohort study concluded that EA uses for emergency laparotomy resulted in decreased morbidity and mortality . Basar et al. performed a continuous spinal anaesthetic (CSA) as the sole technique in 21 elderly high-risk patients (mean Portsmouth Physiological and Operative Severity Score for the Enumeration of Mortality and Morbidity (P-POSSUM) score of 20.5%) undergoing abdominal surgery (ileostomy, colectomy, small bowel resection) and concluded that none of the patients who successfully underwent CSA required level 3 (ICU) care postoperatively. The average length of stay in critical care for this cohort receiving GA for emergency laparotomy in the UK is three days. Similarly, a study conducted in Italy at the start of the coronavirus disease 2019 (COVID-19) era revealed the feasibility of performing awake major abdominal surgery under EA . Thirteen patients assessed as frail with multiple comorbidities presented for undeferrable surgery at a time when ICU-bed availability was scarce. It was presumed that GA would have exacerbated their clinical condition and would mandate postoperative ICU admission. All patients in this cohort successfully underwent open laparotomy with EA and light sedation as the sole anaesthetic technique, thereby mitigating the need for postoperative ICU care. No complications of EA were encountered, and no adverse events occurred during the perioperative period as a whole. This ICU-preserving approach proved to be feasible and safe for emergency laparotomy at a time of severe ICU bed shortages. There are case reports of the successful use of non-invasive ventilation (NIV) intraoperatively in patients with respiratory disease, many of whom were dependent on oxygen therapy or had used NIV devices at home for respiratory support. Two such case reports describe the use of NIV in a patient with COPD and chronic type II respiratory failure and the use of continuous positive airway pressure (CPAP) ventilation in a patient with type I respiratory failure both undergoing lower limb surgery. In these cases, the use of NIV mitigated the need for mechanical ventilation in high-risk patients. A recent systematic review highlights the potential role of intraoperative NIV in patients with respiratory compromise undergoing surgery using neuraxial anaesthesia . These benefits include the reversal of alveolar hypoventilation, prevention or treatment of respiratory failure in "at risk" patients, and improvement of V:Q mismatch . However, caution is warranted when using NIV in certain instances: patients with altered levels of consciousness, severe respiratory compromise warranting immediate intubation, gastric distention, non-cooperative patients, and inability to clear respiratory secretions . In some of these instances, the use of a high-flow nasal cannula device may provide some level of support while obviating some potential problems. At present, in the absence of well-designed randomized controlled trials, judicious use of NIV in combination with neuraxial anaesthesia is recommended . Additionally, the effect of NIV on gastric distention in a patient undergoing laparotomy would preclude its use. As our patient was undergoing an explorative laparotomy for bowel obstruction supplemental, NIV was not considered. Considering our patient's comorbidities and current functional status, his risk for significant morbidity and mortality was high. His estimated mortality using the NELA risk adjustment model was 22.1%; a mortality of more than 10% mandates ICU admission . Using the P-POSSUM risk prediction model, he had an estimated 96.8% morbidity risk (haemorrhage, infection, wound dehiscence, anastomotic leak, thrombosis, cardiac failure, impaired renal function, and hypotension). His Assess Respiratory Risk in Surgical Patients in Catalonia (ARISCAT) score for postoperative pulmonary complications was 42% (respiratory failure, infection, pleural effusion, atelectasis, pneumothorax, bronchospasm, and aspiration pneumonitis). Conclusions In a resource-constrained environment, ICU bed shortages are common. However, emergency surgery must proceed, and the anaesthesia technique must be tailored to enable safe surgery while mitigating perioperative risk. EA proved to be a feasible and safe option for emergency abdominal surgery. This technique can be considered in select patients with relation to ICU-bed scarcity and complex comorbidities, with specific reference to chronic respiratory conditions. The supplemental use of NIV with EA should be considered judiciously based on the surgery performed and the patient's clinical condition. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Management of the patient presenting for emergency laparotomy BJA Educ Ilyas C Jones J Fortey S 113 118 19 2019 33456879 2 Awake major abdominal surgeries in the COVID-19 era Pain Res Manag Romanzi A Boleso N Di Palma G 8763429 2021 2021 33688385 3 The association between epidural analgesia and mortality in emergency abdominal surgery: a population-based cohort study Acta Anaesthesiol Scand Vester-Andersen M Lundstrom LH Moller MH 104 111 64 2020 31437307 4 Current approaches to acute postoperative pain management after major abdominal surgery: a narrative review and future directions Br J Anaesth Pirie K Traer E Finniss D Myles PS Riedel B 378 393 129 2022 35803751 5 Challenges in optimising recovery after emergency laparotomy Anaesthesia Foss NB Kehlet H 0 9 75 2020 6 Epidural analgesia is associated with improved health outcomes of surgical patients with chronic obstructive pulmonary disease Anesthesiology van Lier F van der Geest PJ Hoeks SE 315 321 115 2011 21796055 7 Non-invasive ventilation during surgery under neuraxial anaesthesia: a pathophysiological perspective on application and benefits and a systematic literature review Anaesthesiol Intensive Ther Corcione N Karim H Mina B 289 298 51 2019 31617693 8 Epidural anaesthesia and analgesia and outcome of major surgery: a randomised trial Lancet Rigg JR Jamrozik K Myles PS 1276 1282 359 2002 11965272 9 Effects of thoracic epidural anesthesia on neuronal cardiac regulation and cardiac function Anesthesiology Wink J Veering BT Aarts LPHJ Wouters PF 472 491 130 2019 30676423 10 Continuous spinal anaesthesia (CSA) for emergency laparotomy in high-risk elderly patients: technique and outcomes of a prospective service evaluation J Anesth Surg Niraj G Basar HMA Warusawitharana C Sebastian S Camacho E 130 133 4 2017 11 Intraoperative use of noninvasive ventilation during spinal anaesthesia in patients with severe chronic obstructive pulmonary disease undergoing orthopaedic surgery: a case report J Int Med Res Lee M So J Woo Y Jung J Chung YH Koo BS 50 2022 12 Perioperative non-invasive ventilation to avert intubation in sepsis-induced multi-organ failure patient undergoing emergency lower-limb surgery: a case report Romanian J Emer Surg Bharadwaj A Karim H Iqbal J Kesavankutty M 77 80 3 2021 |
BMC Ophthalmol BMC Ophthalmol BMC Ophthalmology 1471-2415 BioMed Central London 2842 10.1186/s12886-023-02842-3 Case Report Orbitofrontal cholesterol granuloma masquerading as frontal sinus mucoceles: report of two cases Li Ruimiao [email protected] 1 Ren Mingyu [email protected] 1 Wang Wenjing [email protected] 2 Li Ruixin [email protected] 1 Zhang Lili [email protected] 1 Liu Limin [email protected] 1 1 grid.440302.1 0000 0004 1757 7121 Department of Orbital Disease and Ocular Tumor, Hebei Eye Hospital, Xingtai, 054001 Hebei China 2 People's Hospital of Pingxiang County, Xingtai, 054001 Hebei China 13 3 2023 13 3 2023 2023 23 9814 9 2022 3 3 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The Creative Commons Public Domain Dedication waiver ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Background Two cases of orbitofrontal cholesterol granuloma masquerading as frontal sinus mucoceles were reported to understand image findings, clinical and histopathologic features of orbitofrontal cholesterol granuloma to improve its diagnosis and treatment. Case presentation Two East Asian patients aged 41 and 27 without personal or familial medical or trauma history presented with the common complaint of proptosis and inferomedial displacement of the eyeballs. The computed tomography (CT) of both cases showed an irregularly shaped, well-defined lesion in the left frontal bone associated with bony erosion. The lesions resulted in the bone absorption of frontal bone and orbital roof, which extended into the superior orbital space. Anterior orbitotomy through subbrow incision by drainage and curettage resulted in a curative outcome. The histopathological examination revealed inflammatory granulation tissues, fibrous capsule wall, cholesterol clefts with altered blood pigments, and calcifications, consistent with the diagnosis of cholesterol granuloma. No recurrence was observed for one year after surgery in one case and three years in the other. Conclusions When the following features are observed: orbital CT exhibits cystic lesion with irregular bone destruction in the superolateral orbit, magnetic resonance imaging (MRI) depicts lesions are hyperintense signals on T1 weighted images (T1WI), and T2 weighted images (T2WI), and the contrast-enhanced imaging reveals that the most of tumor is showed a non-significant enhancement, orbitofrontal cholesterol granuloma should be considered. Keywords Orbitofrontal cholesterol granuloma Frontal sinus mucoceles Diagnostic imaging Surgical therapy Case report Science and Technology Planning Project of Xingtai2022ZC228 Ren Mingyu issue-copyright-statement(c) The Author(s) 2023 pmcBackground Cholesterol granuloma is an osteolytic lesion with a granulomatous reaction surrounding cholesterol crystals, old hemorrhage, and a fibrous capsule . It has been reported in several locations, such as the peritoneum, lungs, breast, lymph nodes, kidney, and testis . Within the head and face location, it is mostly associated with bony structures, such as the mastoid antrum and air cells of temporal bone, jaw, nasal sinuses, skull base, and orbital bone . Orbital cholesterol granuloma generally occurs in the frontal bone in the superolateral aspect of orbit . However, the location of frontal sinus mucoceles is also similar, along with the bone invasion, which leads to misdiagnosis. The records of two patients with histologically confirmed cholesterol granuloma were reviewed. We summarized the typical clinical presentations, computed tomography (CT), and magnetic resonance imaging (MRI) results of the two patients to improve the diagnostic ability for this disease. Case presentation Case 1 A 41-year-old East Asian female patient with a one-year history of gradual painless proptosis in the left eye was admitted. There was no significant personal or familial medical and trauma history. Blood and urine tests were normal. She had no any disturbance in the lipid profile. The best-corrected visual acuity was 20/25 in the right eye and 20/33 in the left eye. The patient presented with painless proptosis, inwards and downward eyeball displacement, and upward restricted extraocular muscle movements. Hertel exophthalmometry readings were 16 mm in the right eye and 13 mm in the left. An irregularly shaped, well-defined soft mass was palpable in the superior aspect of left orbit. The rest of ocular examination was normal. CT scan displayed a 2.8 x 3.2 x 1.5 cm soft tissue mass in the left frontal sinus, eroding the floor of sinus, orbital roof, and extending into the superior orbital space (Fig. 1). Magnetic resonance imaging (MRI) exhibited an irregular mass, the lesions were hyperintense signals on T1 weighted images (T1WI) (Fig. 2). The lesions were isointense and hyperintense mixed signals on T2 weighted images (T2WI). Contrast-enhanced imaging demonstrated that most tumor parts reveal a non-significant enhancement. Resection was performed via an anterior orbitotomy. After incising the superolateral orbital periosteum, a cavity containing dark red liquid was accessed just inside the orbital rim. During the operation, the cystic fluid was aspirated, the cystic wall was removed (Fig. 3), and the abnormal bone was thoroughly curetted. The histopathological examination of cyst contents and wall revealed inflammatory granulation tissues, fibrous capsule wall, cholesterol clefts with altered blood pigments, and calcifications, consistent with the diagnosis of cholesterol granuloma (Fig. 4). There was no recurrence upon follow-up.Fig. 1 CT scan displayed a soft tissue mass in the left frontal sinus, eroding the floor of sinus, orbital roof, and extending into the superior orbital space Fig. 2 Enhanced magnetic resonance imaging showed a non-enhancing mass that presented hyperintense Fig. 3 Surgical sample showed a well-circumscribed cyst Fig. 4 The histopathological examination of cyst contents and wall revealed inflammatory granulation tissues, fibrous capsule wall, cholesterol clefts with altered blood pigments, and calcifications, consistent with the diagnosis of cholesterol granuloma Case 2 A 27-year-old East Asian male patient presented with proptosis and eyelid swelling in the left eye for ten days. There was no associated pain and history of trauma. The levels of serum low density lipoprotein cholesterol and triglyceride were higher, and apolipoprotein A1 was lower than normal. Other blood and urine tests were normal. On ocular examination, the best-corrected visual acuity was 20/20 in the right eye and 20/33 in the left eye. The patient presented with proptosis, inwards and downward eyeball displacement, and upward restricted extraocular muscle movements. Hertel exophthalmometry readings were 15 mm in the right eye and 17 mm in the left eye. An irregularly shaped soft lesion was palpable in the superior space of left orbit. The rest of ocular examination was normal. CT scan exhibited an irregularly shaped promiscuous dense occupying lesion in the left frontal bone, associated with bony erosion (Fig. 5). This lesion resulted in the bone absorption in the frontal bone and orbital roof, which penetrated down into the orbit. The boundary was relatively clear, and speckled high-density shadows could be seen inside. MRI displayed an irregular mass, the lesions were hyperintense signals on T1WI, and the lesions were isointense and hyperintense mixed signals with a thick hypointense ring around the lesions on T2WI. Contrast-enhanced imaging revealed that most parts of the tumor display a non-significant enhancement (Fig. 6). Resection was performed via an anterior orbitotomy. A dark brown mass was seen intraoperatively (Fig. 7). Management was by total excision of the lesion with curettage of the eroded bone to prevent a recurrence. The histopathological examination of the cyst contents and wall revealed cholesterol clefts, multinucleated giant cells, histiocytes, foamy macrophages, fiber textures, altered blood pigments, and calcifications, which was consistent with the diagnosis of cholesterol granuloma (Fig. 8). There was no recurrence upon three-year follow-up.Fig. 5 CT scan exhibited an irregularly shaped promiscuous dense occupying lesion in the left frontal bone, resulting in the bone absorption in the frontal bone and orbital roof, and penetrating down into the orbit Fig. 6 Contrast-enhanced imaging revealed that most parts of the tumor display a non-significant enhancement Fig. 7 The sample after complete resection Fig. 8 The histopathological examination of the cyst contents and wall revealed cholesterol clefts, multinucleated giant cells, histiocytes, foamy macrophages, fiber textures, altered blood pigments, and calcifications, which was consistent with the diagnosis of cholesterol granuloma Discussion and conclusions Orbital cholesterol granuloma is a relatively rare condition caused by a foreign body reaction against cholesterol crystals. It predominantly occurs in young or middle-aged men . The orbitofrontal cholesterol granuloma was initially described in 1902 by Denig . Other terms such as lipid granuloma, cholesteatoma, chronic haematic cyst, xanthomatosis, and histiocytic granuloma are also used for orbital cholesterol granuloma. However, these terms are inaccurate, and cholesterol granuloma is the most appropriate . However, histopathology confirmed that the mass contained cholesterol crystals, fibrous envelope, hemosiderin, granuloma, and other components, but the pathogenesis of cholesterol granuloma is still unclear. In the petrous, the pathogenesis is believed to be caused by ventilatory obstruction of the pneumatized temporal bone resulting in local tissue breakdown and deposition of cholesterol which then crystallizes and stimulates a granulomatous reaction . However, this mechanism does not apply to orbital cholesterol granuloma. In orbit, orbital hemorrhage of any cause, such as minor trauma, or spontaneous bleeding in an anticoagulant-treated patient, is the initiating event for cholesterol granuloma formation . Blood-derived products degrade cholesterol and deposit crystals that stimulate the growth of surrounding tissue to form granulomas . Nevertheless, only a minority of cases have a history of trauma . Moreover, neither of the two patients reported in this study had a history of trauma. It was speculated that a very mild trauma may have occurred inadvertently. Spontaneous bleeding caused by abnormal coagulation or blood vessel development could be one of the possibilities . Cholesterol granuloma may arise within the diploe of frontal bone , enlarge and erode through the outer table of the bone to extraperiosteal space above the lacrimal fossa. The lesion causes ophthalmological symptoms of upper eyelid swelling, ptosis, ocular distention, proptosis, hypoglobus, extraocular movement restriction, and diplopia. The typical features observed on CT are a well-defined lesion in the superolateral orbit, isodense with the brain, and extensive erosion adjacent to the frontal bone and lacrimal fossa. The typical findings on contrast-enhanced imaging are a non-enhancing mass that presented predominantly hyperintense and heterogeneous on both T1WI and T2WI, whereas the hyperintense signal is characteristic of chronic bleeding. The paramagnetic effect of haem iron (Fe3+) in methemoglobin results in the characteristic high signal on all images reflecting a shortening of the T1WI involved tissue and a lengthening of the T2WI . Orbitofrontal cholesterol granuloma is rare, has a prediliction to the frontal sinuses. The location of disease is similar to the frontal sinus mucoceles. Therefore, the two patients were misdiagnosed before surgery and should be differentiated from them. Mucoceles are expansive cysts of mucus secreted by goblet cells interspersed in the ciliated mucosa . Although all paranasal sinuses are susceptible, the frontal and ethmoidal sinuses have the highest incidence . They can occur at any age, but most patients with mucoceles are between [12-14]. Compromised sinus ventilation is the basic etiology of mucocele formation . The reasons may include (1) lesions of the nasal cavity and sinuses (or abnormal development), such as nasal polyps, sinus osteoma, and nasal septum deviation, and (2) inflammation or trauma leading to nasal adhesion and sinus obstruction . Mucoceles can compress and erode the surrounding bone wall, leading to absorption of the orbital wall as they grow gradually . Frontal sinus mucoceles frequently lead to the absorption of superior orbital wall, extending into the orbit, resulting in ocular symptoms and signs. The ocular manifestations are similar to orbital cholesterol granuloma. CT scan shows expansive growth of the mucoceles in the sinuses with absorption and destruction of adjacent bone and intrusion into surrounding structures. The clear boundary; the internal density is more uniform, mostly low density; a few can be equal or even high density. The density is dependent on the protein concentration of sac fluid. When protein concentration is high, density is high, whereas when protein concentration is low, density is low. Mucocele MRI signal intensity is quite distinct, and signal level may correlate with disease duration. Subsequently, patients with a short disease course have more moisture and hypointense presentation on T1WI. Patient with a long period of the disease has more protein, presenting hyperintense on T1WI . The mainstay of treatment for cholesterol granuloma is surgical resection with curettage of the abnormal bone to reduce the recurrence of disease. Cholesterol granuloma has typical histopathological features with cholesterol clefts, multinucleated giant cells, histiocytes, foamy macrophages, fiber textures, altered blood pigments, and calcifications. In conclusion, orbital cholesterol granuloma is relatively rare, has a prediliction to the frontal sinuses. Suppose the orbital CT shows a similar cystic lesion with irregular bone destruction in the superolateral orbit. In that case, MRI displays that the lesions are hyperintense signals on T1WI and T2WI, and the contrast-enhanced imaging reveals that most of the tumors are not significantly enhanced. The diagnosis of orbitofrontal cholesterol granuloma should be considered. Abbreviations CT Computed tomography MRI Magnetic resonance imaging T1WI T1 weighted images T2WI T2 weighted images Acknowledgements Not applicable. Authors' contributions During the study, all authors have contributed significantly. RL wrote the manuscript and collected the data. MR designed this study and collected the data. RL illustrated figures. LL revised the manuscript. WW and LZ together proposed the idea and supervised the project. All authors have read and approved the manuscript. Funding This work was supported by the Science and Technology Planning Project of Xingtai, No.2022ZC228. Availability of data and materials The data and materials used and/or analyzed during the present study are available from the corresponding author on reasonable request. Declarations Ethics approval and consent to participate Compliance with Ethics Guidelines. The patients provided informed consent for their clinical details to be known. This study was conducted in compliance with the guidelines of the Declaration of Helsinki. Consent for publication Written informed consent for publication was obtained from both of the involved patients. Competing interests The authors declare that they have no conflicts of interest. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Chow LP McNab AA Orbitofrontal cholesterol granuloma J Clin Neurosci 2005 12 2 206 209 10.1016/j.jocn.2003.09.006 15749436 2. Hughes JD Jacob JT Garrity JA Salomao DR Link MJ Orbitofrontal Cholesterol Granuloma: Four Case Reports and a Systematic Review of the English Literature World Neurosurg 2016 87 355 361 10.1016/j.wneu.2015.11.095 26724630 3. Gonzalez-Garcia R Roman-Romero L Cholesterol granuloma of the orbit Otolaryngol Head Neck Surg 2010 142 2 292 293 10.1016/j.otohns.2009.08.001 20115994 4. Yan J Cai Y Liu R Lin J Li J Cholesterol granuloma of the orbit J Craniofac Surg 2015 26 2 e124 e126 10.1097/SCS.0000000000001347 25710742 5. Selva D Phipps SE O'Connell JX White VA Rootman J Pathogenesis of orbital cholesterol granuloma Clin Exp Ophthalmol 2003 31 1 78 82 10.1046/j.1442-9071.2003.00605.x 12580900 6. 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Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34857 Medical Education Ophthalmology Right Superior Ophthalmic Vein Thrombosis Induced by Pansinusitis Muacevic Alexander Adler John R Elsaadawy Ahmed 1 Panchasara Binita 2 Yadav Abhijeet 2 1 Department of Psychiatry, Fairfield General Hospital, Bury, GBR 2 Department of Ophthalmology, West Suffolk Hospital, Bury St Edmunds, GBR Ahmed Elsaadawy [email protected] 11 2 2023 2 2023 15 2 e348577 2 2023 Copyright (c) 2023, Elsaadawy et al. 2023 Elsaadawy et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Superior ophthalmic vein thrombosis (SOVT) is a rare, sight-threatening condition. It can be clinically challenging to distinguish from pre-septal cellulitis or cavernous sinus thrombosis. Imaging is often a key to identifying SOVT, and multi-disciplinary input is paramount to ensuring the optimum outcome. This often involves the paediatricians, ophthalmologists and paediatric neurologists if necessary. We report a case of a young boy with right SOVT that had initially been diagnosed as pre-septal cellulitis. A contrast-enhanced computed tomography scan was performed, as the patient developed limited eye movement on elevation, which showed dilatation of the right ophthalmic vein with pansinusitis. He was successfully treated with anticoagulation and antibiotics. cavernous sinus thrombosis pre-septal cellulitis orbital cellulitis pansinusitis superior ophthalmic vein thrombosis The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction In the acute setting, orbital signs are often attributed to common pathologies such as peri-orbital cellulitis or sinus infections. This can result in an oversight of rarer conditions such as superior ophthalmic vein thrombosis (SOVT), which can have significant implications for patients. SOVT is caused by orbital congestion, which can occur as a result of infectious or non-infectious causes. The former includes orbital cellulitis, which may present with proptosis, diplopia and visual impairment, and can precipitate a SOVT or cavernous sinus thrombosis [1-3]. A key factor behind the successful management of such cases is early intervention and collaboration between the paediatric neurologists, paediatricians and ophthalmologists. This report aims to highlight presenting features of this condition in a younger age group and emphasise the importance of a multi-disciplinary approach to its management. Case presentation A healthy boy in his first decade of life with a background of previously treated exotropia, amblyopia and attention-deficit/hyperactivity disorder (ADHD) was brought to the emergency department by his mother. He had developed a low-grade fever and upper respiratory tract symptoms over the past week and had suffered a minor injury in which he hit his face onto a door at home. It was thought that the latter was the cause of his eyelid swelling; therefore, he was initially discharged with safety netting advice. The child returned the next day with worsening swelling, right-sided peri-orbital pain and tenderness along the medial canthus. At the time, there was no visual impairment or any neurological impairment detected on examination. His body temperature was 37.6*C, blood pressure was 104/59 mmHg, heart rate was 75 bpm and capillary refill time was under 2 seconds. Basic eye assessment in the emergency department revealed a Snellen visual acuity of 6/7.5 on the right eye (amblyopic eye) and 6/5 on the left eye with white conjunctivae, reactive pupils and normal eye movements. He was later seen by an ophthalmologist who agreed that this be treated as a pre-septal cellulitis, as his eye movements were full with no clinical signs to suggest deeper involvement. Despite admission and treatment with intravenous antibiotics, the lid swelling continued to worsen without conjunctival injection, and he gradually developed limitation and pain on attempted elevation of the right eye. Investigations In this case, before the decision was taken to perform imaging, the patient was being treated for pre-septal cellulitis with intravenous antibiotics; however, his symptoms continued to deteriorate. A contrast-enhanced computed tomography scan of the orbits, sinuses and brain was performed, which revealed pansinusitis with a collection adjacent to the right frontal sinus in addition to enlargement of the right superior ophthalmic vein with SOVT . He underwent repeat CT imaging few days later after commencing heparin to monitor his progress and determine ultimate resolution of the superior ophthalmic vein flow obstruction. Figure 1 Post-contrast CT (coronal view) showing right superior ophthalmic vein thrombosis with vein enlargement in comparison to the left side with sinusitis. Figure 2 Post-contrast CT (axial view) showing right superior ophthalmic vein thrombosis with vein enlargement in comparison to the left side. Differential diagnosis This child was initially presumed to have pre-septal cellulitis and was managed (albeit overcautiously) with intravenous antibiotics. One of the reasons for aggressive treatment initially was that the child's mother reported a significant reduction in his psychomotor activity that was not obvious to the examining clinicians who had not seen him when he was well. The difference was only apparent once the child was better given his background of ADHD. When the lid swelling worsened despite ongoing antibiotics, and the child developed a painful limitation of up-gaze, imaging was correctly obtained (with contrast) to rule out orbital involvement. It should be noted that at this point there was a very low suspicion of venous sinus thrombosis. In hindsight, one of the peculiarities of the eyelid swelling was that it was soft and "boggy" rather than tense or firm, as might be expected with cellulitis. This may have been an early clue to the aetiology of sluggish venous drainage. A point of interest here was the absence of conjunctival injection or chemosis. This serves as an important reminder that eye movement limitation is a more important marker of progression to orbital cellulitis or venous thrombosis. Treatment The initial phase of presumed pre-septal cellulitis was treated with intravenous co-amoxiclav, which was changed to intravenous ceftriaxone and oral metronidazole. Following the CT finding of SOVT, unfractionated heparin was added on advice of the paediatric neurologists, which was to be omitted just prior to the repeat CT scan (in case the CT revealed an abscess that required drainage). On advice of the paediatric haematologists, this was changed to low molecular weight heparin (LMWH) for long-term management once the CT ruled out a developing abscess. Outcome and follow-up The eyelid swelling had remarkably started to improve 24 hours after commencement of anticoagulation, despite no significant improvement on imaging at 48 hours of anti-coagulation. By the third or fourth day of anticoagulation, the swelling had virtually resolved and ocular elevation was nearly full with minimal pain. Over the next few days and weeks, the paediatric haematologists helped titrate dosage of the LMWH using anti-Xa factor levels. Given that this was a provoked cause of thrombosis, it was recommended that anti-coagulation be given for a period of three months, at which point a magnetic resonance imaging (MRI) or magnetic resonance venography (MRV) would be used to confirm complete resolution of the thrombosis. Ophthalmology follow-up a month after initial presentation showed complete resolution of eye symptoms, and the child was discharged from the eye clinic. He was followed up as an outpatient by the paediatricians until discontinuation of the anticoagulation. Apart from some persisting headaches, he was back to his usual energetic self. He joined football training and both he and his mother were pleased with the overall recovery. He was reviewed once more by the ophthalmologists due to persisting headaches; however, no clear cause for these was found. Discussion SOVT is a rare but serious condition that should be considered in certain orbital presentations. It carries a higher morbidity and mortality compared to other more prevalent diagnoses such as pre-septal cellulitis. The aetiology can be non-infectious secondary to inflammation, trauma or thrombophilia for example or infectious due to sinusitis or orbital cellulitis. Infection-related SOVT results in localised irritation and alteration of blood flow within vessels, which can lead to thrombosis in the cavernous sinus or along its tributaries including the superior ophthalmic vein . In our young patient, sinusitis was thought to have precipitated the SOVT. Diagnosis The impairment of venous drainage that occurs in SOVT results in congestion of the orbital veins, which can present in a number of ways . These include acute painful proptosis, pain on eye movement, swelling of the eyelids and, most importantly, a reduction in the visual acuity . Neuroimaging with contrast-enhanced CT or MRA (magnetic resonance angiography) is crucial to establishing a diagnosis of SOVT. This can also help to highlight any co-existent pathology that will require intervention such as an infective abscess or cavernous sinus thrombosis . The findings on a CT scan may include engorgement of the superior ophthalmic vein with a possible filling defect and surrounding oedema . As per the literature and our experience, once a diagnosis of SOVT is established, it is often successfully managed without serious complications . Management The mainstay of management is medical with anticoagulation, antibiotics and/or corticosteroids . Surgical intervention is usually reserved for when there is an orbital abscess or mass or if the patient has severe Graves' orbitopathy. Medical management A multi-disciplinary approach is needed to successfully manage SOVT. Where septic causes are considered, patients should have a full septic screen and be commenced on broad-spectrum antibiotics in line with local microbiology guidelines. In addition to this, anticoagulation is necessary to prevent further thrombosis . Surgical management A surgical approach is considered when medical management alone is insufficient to treat the underlying cause. Examples include drainage of an abscess and optic nerve decompression . Conclusions One should be vigilant lest missing this devastating, lethal pathology. SOVT mostly resolves without any sequelae with early detection and management. A focused history and physical examination to rule out orbital involvement and optic neuropathy are critical. Proper management is recommended with broad-spectrum intravenous antibiotics, anticoagulants and surgery, if needed, depending on the aetiology. A key factor behind the successful management of such cases is early intervention and collaboration between the paediatric neurologists, paediatricians and ophthalmologists. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Superior ophthalmic vein thrombosis: what radiologist and clinician must know? Eur J Radiol Open Sotoudeh H Shafaat O Aboueldahab N Vaphiades M Sotoudeh E Bernstock J 258 264 6 2019 31641683 2 Superior ophthalmic vein thrombosis: a rare complication of Graves' orbitopathy Orbit Sorrentino D Taubenslag KJ Bodily LM Duncan K Stefko T Yu JY 175 178 37 2018 29053044 3 Cavernous sinus thrombosis: current therapy J Oral Maxillofac Surg Desa V Green R 2085 2091 70 2012 22326173 4 Impact of superior ophthalmic vein thrombosis: a case series and literature review Orbit van der Poel NA de Witt KD van den Berg R de Win MM Mourits MP 226 232 38 2019 30040506 5 Spontaneous superior ophthalmic vein thrombosis: a rare entity with potentially devastating consequences Eye (Lond) Lim LH Scawn RL Whipple KM Oh SR Lucarelli MJ Korn BS Kikkawa DO 348 351 28 2014 24357838 6 Superior ophthalmic vein thrombosis 1 2023 2023 7 Septic superior ophthalmic vein thrombosis Clin Exp Ophthalmol Walker JC Sandhu A Pietris G 144 146 30 2002 11886421 |
Front Oncol Front Oncol Front. Oncol. Frontiers in Oncology 2234-943X Frontiers Media S.A. 10.3389/fonc.2023.1105080 Oncology Case Report Case report: A case of delayed cutaneous metastases from signet-ring cell mixed-type gastric cancer Yao Shaohua 1 + Zhou Peng 2 + Li Yiqing 2 * Li Qin 2 * 1 Department of Gastrointestinal Surgery, Huazhong University of Science and Technology Union Shenzhen Hospital, Shenzhen, China 2 Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China Edited by: Jorg Kleeff, University Hospital in Halle, Germany Reviewed by: Suraj Venna, Inova Health System, United States; Ludovico Carbone, University of Siena, Italy *Correspondence: Yiqing Li, [email protected]; Qin Li, [email protected] +These authors have contributed equally to this work This article was submitted to Gastrointestinal Cancers: Gastric and Esophageal Cancers, a section of the journal Frontiers in Oncology 27 2 2023 2023 13 110508022 11 2022 07 2 2023 Copyright (c) 2023 Yao, Zhou, Li and Li 2023 Yao, Zhou, Li and Li This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Background Signet-ring cell gastric carcinoma is a highly malignant tumor, with the characteristics of strong invasiveness, rapid progression, a high degree of malignancy, and generally poor prognosis. The most common site of metastases is the abdominal organs, especially the liver, while delayed cutaneous metastases are rare. Case presentation We report a case of cutaneous metastases on the head, groin, and thigh, which recurred 7 years after signet-ring cell gastric carcinoma surgery. The patient was diagnosed with a 2.0x1.5x1.0cm tumor at the angle of stomach, and treated with Billroth II distal gastrectomy accompanied with D2 lymph node dissection. According the pathology, the stage was pT1N3M0. Then the patient received two cycles of oxaliplatin and tegafur chemotherapy, which was discontinued due to the inability to tolerate the side effects of chemotherapy. Seven years after the surgery, the patient initially presented with a fleshy mass on the head and beaded nodules in the groin; then, the mass gradually became larger, along with the thighs turning red, swollen, and crusty. Firstly, the patient was diagnosed with "lower extremity lymphangitis" and treated mostly with anti-inflammatory, promote lymphatic return, detumescence and elastic force cannula in vascular surgery department. However, the symptoms relieved insufficient. Finally, the skin biopsy indicates a signet-ring cell gastric carcinoma cutaneous metastasis. The whole-body PET-CT examination showed multiple nodules with increased metabolism. Then the patient was transferred to The Department of Oncology for further chemotherapy. Conclusion Our case highlights that gastric tumor recurrence and metastasis should be highly suspected when skin lesions appear in patients with signet-ring cell gastric carcinoma. At the same time, multidisciplinary consultation and close cooperation between surgeons, oncologists, and dermatologists are of great significance to the diagnosis and treatment of this disease. signet-ring cell gastric carcinoma cutaneous metastases late recurrence case report post operative metastasis pmcIntroduction Cutaneous metastases of gastric carcinoma are extremely rare. Multiple studies have reported the prevalence of cutaneous metastases ranging from 0.2% to 2.2% (1), predominantly in males. The outcomes of postoperative gastric carcinoma are usually assessed by the 5-year survival rate. Cutaneous metastases generally occur within 1-3 years postoperatively, whereas reports of cutaneous metastases over 5 years are even rarer. Among histopathological subtypes of gastric carcinoma, signet-ring cell (SRC) carcinoma has a greater propensity for distant and cutaneous metastases. Furthermore, SRC gastric carcinoma is more prone to lymphatic metastasis compared with other histopathological subtypes of gastric carcinoma (2). Case report A 61-year-old man was admitted to our hospital in May 2022 for three progressively enlarging masses in the left groin area and head, along with redness and swelling of the left thigh for more than half a year. He had a history of a major gastrectomy in 2015 after being diagnosed with gastric carcinoma. The patient was diagnosed with a 2.0x1.5x1.0cm tumor at the angle of stomach, and treated with Billroth II distal gastrectomy accompanied with D2 lymph node dissection. The postoperative histopathology of the primary lesion was mixed invasive adenocarcinoma, of which signet-ring cell carcinoma accounted for 80%, and tubular adenocarcinoma accounted for 20% . The pathological stage was pT1N3M0. So, the patient received two cycles of oxaliplatin and tegafur chemotherapy, which was discontinued due to the inability to tolerate the side effects of chemotherapy. No tumor recurrence was found in the annual gastroscopy and CT-scan for 4 years after the operation; then, no follow-up was performed due to the COVID-19 epidemic. Figure 1 Postoperative pathology of gastric carcinoma in 2015. However, after 6 years, the patient developed a beaded nodular tumor in the left groin area and two fleshy nodules on the scalp, accompanied by redness and swelling from the upper left thigh to the groin area; there was no obvious fever or pain. This patient was diagnosed with "lymphangitis of lower limbs" in several major hospitals and was prescribed anti-inflammatory and detumescence treatment. After repeated treatment, the tumor in the left groin area and scalp gradually increased, and the skin of the left lower extremity was red, swollen, and scleroderma-like. Finally, he came to our hospital for treatment. A physical examination revealed moderate pitting edema of the left lower extremity, redness and swelling of the thigh with scleroderma-like changes, bead-like nodules of about 5*20cm in the groin area , and two fleshy masses of about 3*3cm in size on the scalp . The laboratory examinations showed that the blood routine, procalcitonin, liver, and kidney function were not abnormal, and the tumor markers carbohydrate antigen 72-4 and CA125 were elevated. A skin biopsy was performed on the groin mass, and the pathology showed metastatic poorly differentiated carcinoma, some of which were signet-ring cell carcinoma; immunohistochemical staining showed: PCK(+), CK7(+), CK20(-), CDX2(+), SATB2(-), and HER2(0) . A whole-body PET-CT examination showed multiple humus-like hypodense nodules on the skin surface from the left groin to the thigh, secondary lymphedema, and slightly increased metabolic diffusion . There was also localized thickening of the skin on the top of the left head and back of the neck, and slightly increased metabolism. The above suggested the possibility of malignant tumor metastatic lesions . After the diagnosis was confirmed, the patient was transferred to the oncology department for chemotherapy of Nivolumab combined with SOX. Four times of chemotherapy had been performed, and the efficacy was evaluated as reduced SD. Due to the COVID-2019 epidemic, the patient did not come to our hospital for subsequent chemotherapy treatment as planned. Figure 2 Cutaneous metastatic carcinomas. (A) Beaded mass in left groin area and erythematous scleroderma of the left thigh; (B, C) Two fleshy masses on the scalp. Figure 3 Skin biopsy of the groin mass; the pathology showed metastatic poorly differentiated carcinoma, some of which were signet-ring cell carcinoma. Figure 4 PET-CT examination. (A) Multiple humus-like hypodense nodules on the skin surface from the left groin to the thigh, secondary lymphedema, and slightly increased metabolic diffusion; (B) Localized thickening of the skin on the top of the left head and back of the neck and slightly increased metabolism. Discussion Cutaneous metastases usually develop from breast cancer, lung cancer, colorectal cancer, ovarian cancer, and other tumors (3), while metastases from stomach cancer to skin are extremely rare. Cutaneous metastases of gastric carcinoma are classified into the following three categories: (a) nodular, (b) inflammatory, and (c) sclerodermoid; the most common type is nodular type, followed by inflammatory (4). However, these three types occurred simultaneously in this case. The most common sites of metastases include the neck, back, abdomen, and inguinal regions. Meanwhile, the lesions can evolve into single or multiple nodules with an erysipelas-like morphology (also confirmed in this patient). Erysipelas carcinoma resembles an acute skin infection; different from skin infections, erysipelas carcinoma does not cause fever or leukocytosis, and antibiotics are ineffective (5). This case presented with a nodular appearance at first, followed by erysipelas-like changes and skin scleroderma-like changes in the lower extremities. After being treated as lymphangitis and lymphedema of the lower limbs in many large hospitals in China, his symptoms were not alleviated. The diagnosis was not confirmed until a skin biopsy was performed half a year later; so, the best treatment opportunity was missed. The pathogenesis of cutaneous metastases is still unclear. According to previous observations, poorly differentiated adenocarcinomas with signet-ring cell characteristics are closely related to the occurrence of cutaneous metastases. The proportion of SRC is inversely related to aggressive behavior, higher risk of metastases and poor prognosis in mixed-type gastric cancer (6). Some of the potential mechanisms are hematogenous or lymphatic metastasis. Holmgren L proposed the concept of "tumor dormancy" (7), as the reason for delayed skin metastases in gastric cancer, which refers to the state of small residual lesions or isolated micrometastases without causing symptoms for a long period of time (8). However, the triggers that activate dormant cells to lead to relapse have not been identified. In this case, the patient showed advanced recurrence of stage IIB gastric cancer, histopathology of the primary tumor was pT1 and N3, and the patient received only two adjuvant chemotherapy sessions after surgery. If an adequate course of adjuvant chemotherapy is given, it may reduce the risk of cancer recurrence. Cutaneous metastasis of gastric cancer is one of the markers of an advanced tumor stage, suggesting a poor prognosis for patients, but about 61% of patients still receive active treatment with surgery, chemotherapy, or radiation therapy (9). Although the application of active treatment can significantly improve prognosis, there are many patients did not tolerate chemotherapy which likely increased their recurrence risk of disease. A new study analyzed the molecular profiling of signet-ring cell carcinoma (SRCC) from the stomach and colon by using NGS, immunohistochemistry and in situ hybridization, suggest that SRCCS harbor a similar molecular profile, regardless of the tumor location, means tailored therapy may become available for these patients in the future (10). Liu Shuzhen et al. reported 51 cases of skin metastases of malignant tumors; of these, 8 patients did not receive active antitumor treatment and died within 4 months (11). Among the 43 patients who received treatment, the median survival time was significantly longer than untreated patients, indicating that active treatment can prolong the survival of patients with skin metastases of malignant tumors, especially those without vital organ metastases. Consequently, Signet-ring cell gastric cancer has a higher incidence of long-term cutaneous metastasis than other types of gastric cancer, and the possibility of tumor recurrence and metastasis should be highly suspected when skin lesions appear in patients with a clinical history of gastric cancer. Therefore, early diagnosis and treatment is extremely important. At the same time, multidisciplinary consultation and close cooperation between surgeons, oncologists, and dermatologists are of great significance to the diagnosis and treatment of this disease. Data availability statement The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. Ethics statement The studies involving human participants were reviewed and approved by Ethics Committee of Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the patient for the publication of the case report and the accompanying images. Author contributions QL and YL made substantial contributions to design the research work. SY and PZ made substantial contributions to collecting the clinical data. SY and PZ wrote the initial draft of the manuscript. QL and YL revised the paper for important intellectual content. All authors contributed to the article and approved the submitted version. Acknowledgments We would like to thank the help of Prof. Yang Liu who is a dermatologist in our hospital, Zheng Xiong for making a substantial contribution to the collection of clinical data, and Shuting Gao and Jinqian Mao for performing the histological examination of the tumor tissues. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References 1 Kim YS Lee JH Park YM Lee JY . Cutaneous metastasis of gastric cancer mimicking primary inflammatory breast cancer. Ann Dermatol (2015) 27 (6 ):767-8. doi: 10.5021/ad.2015.27.6.767 2 Choi WJ Jue MS Ko JY Ro YS . An unusual case of carcinoma erysipelatoides originating from gastric adenocarcinoma. Ann Dermatol (2011) 23 (3 ):375-8. doi: 10.5021/ad.2011.23.3.375 3 Strickley JD Jenson AB Jung JY . Cutaneous metastasis. Hematol/Oncol Clinics North Am (2019) 33 (1 ):173-97. doi: 10.1016/j.hoc.2018.08.008 4 Brownstein MH Helwig EB . Spread of tumors to the skin. Arch Dermatol (1973) 107 (1 ):80-6. doi: 10.1001/archderm.1973.01620160052015 5 Lookingbill DP Spangler N Helm KF . Cutaneous metastases in patients with metastatic carcinoma: A retrospective study of 4020 patients. J Am Acad Dermatol (1993) 29 (2 Pt 1 ):228-36. doi: 10.1016/0190-9622(93)70173-Q 6 Marano L Ambrosio MR Resca L Carbone L Carpineto Samorani O Petrioli R . The Percentage of Signet Ring Cells Is Inversely Related to Aggressive Behavior and Poor Prognosis in Mixed-Type Gastric Cancer. Front Oncol (2020) 12 :897218. doi: 10.3389/fonc.2022.897218 7 Holmgren L O'reilly MS Folkman J . Dormancy of micrometastases: Balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nat Med (1995) 1 (2 ):149-53. doi: 10.1038/nm0295-149 8 Kang Y Pantel K . Tumor cell dissemination: emerging biological insights from animal models and cancer patients. Cancer Cell (2013) 23 (5 ):573-81. doi: 10.1016/j.ccr.2013.04.017 9 Cesaretti M Malerba M Basso V Boccardo C Santoni R D'Alessandro G . Cutaneous metastasis from primary gastric cancer: A case report and review of the literature. Cutis (2014) 93 (4 ):E9-13. 10 Puccini A Poorman K Catalano F Seeber A Goldberg RM Salem ME . Molecular profiling of signet-ring-cell carcinoma (SRCC) from the stomach and colon reveals potential new therapeutic targets. Oncogene (2022) 41 (26 ):3455-60. doi: 10.1038/s41388-022-02350-6 11 Shuzhen L Yulan S Fang J Haiyang L Zhihai W Guowei D . Clinical analysis of cutaneous metastatic carcinoma. Chin J Leprosy Dermatol (2004) 20 (1 ):3. doi: 10.3969/j.issn.1009-1157.2004.01.004 |
Discov glob soc Discover Global Society 2731-9687 Springer International Publishing Cham 1 10.1007/s44282-023-00001-z Editorial Inaugural editorial post COVID-19 global society: issues, challenges and edging forward Baikady Rajendra [email protected] 123 1 grid.440670.1 0000 0004 1764 8188 Central University of Kerala, Kasaragod, India 2 grid.412988.e 0000 0001 0109 131X University of Johannesburg, Johannesburg, South Africa 3 grid.21100.32 0000 0004 1936 9430 York University, Toronto, Canada 13 3 2023 13 3 2023 2023 1 1 1(c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit The COVID-19 pandemic outbreak in the later part of 2020 resulted in enormous social and economic disruption leading to a quick transformation of global society. A health crisis that interrupted the lives of every individual across the globe, soon changed in to a human, economic and social crisis. All segments of the society irrespective of their status and privilege experienced the challenges posed by COVID-19 pandemic, however the marginalized and vulnerable populations including people living in poverty situations, older persons, persons with disabilities, youth, and indigenous peoples in developing, less developed and middle-income countries had the greater impact on their lives and livelihood. Furthermore, homeless population, people effected by war and conflict, people without access to running water, refugees, migrants, or displaced population continues to face the aftermaths of the pandemic. issue-copyright-statement(c) The Author(s) 2023 pmcHow COVID-19 impacted global society The pandemic resulted in tremendous human suffering with serious and long-term implications for people's health, well-being and quality of life. It did not only bring in public health issues to the global population but also brought in issues related to social interconnectedness, subjective well-being and stress, mental health, personal security, financial vulnerability, lack of trust in social institutions, relationships and administrations and modern medical systems. Inequality and social disparity were at high in developing and less developed countries even before the outbreak of the pandemic. However, the factors such as job loss, salary cut, lack of employment opportunities, lockdown and social restrictions during the pandemic further deteriorated the economic condition of overall population. The gap between the rich and poor elaborated, while poor experiencing several adverse effects of the pandemic that might not be experienced by economically advanced population. In terms of death and loss of lives, even well-developed countries with advanced medical systems were not able to save lives. Death rates increased in an alarming way and the globe watched it in horror and shock. These death rates in the developed countries in the west revealed the untold stories of health disparity and economic vulnerability. The pandemic exposed a large number of populations across the nation states to unexpected trauma, shock and fear of loss, anxiety and grief. The unknown fear of loss and anxiety resulted in social isolation, increased visit to hospitals, increase in violence, crime and other social problems. While one section of the population who were privileged to avail hospital facilities in both developed and developing countries rushed to hospitals with hope to save theirs and their loved one's lives. On the other hand, poor and underprivileged population who could not offered hospital care and medication depended on home remedies and community care. These trends further give an idea about the deprivation and inequality persisting in our global society. COVID-19 and our lives Covid 19 pandemic has profoundly changed our lives. On the one hand Millions of people lost their lives, and another large section of population lost their livelihood and employment. Societies across the globe started witnessing widened inequalities, undermined progress on global poverty and lack of clean energy, food and health care. Social impact of the pandemic resulted in weakening social connections and relationships, trust issues in relationships among the peoples which resulted in the social and communal harmony. COVID-19 pandemic also revealed the amount of digital inequality or digital divides existed between the population. With the lockdowns/ restrictions imposed on public movement and social life, people relayed on internet for buying food and work from home, where as educational activities across the world moved online from traditional teaching and learning. However, the effectiveness of these activities depends on the availability of infrastructure, internet connectivity and the speed, computer competency or the skills required for using computer and internet devises effectively and efficiently. However available literature documents great difficulties experienced by rural populations in accessing online facilities during COVID-19 pandemic . Further student community experienced the most deprivation in terms of digital divide as studies pointed out there were communication and participation issues in online learning under COVID-19 . In terms of Youth population, they witnessed the school closure, lack of infrastructure facilities to continue online or distance learning and most importantly missing social life among the peer groups. Further a large number of youth and children, especially girls were under the threat of discontinuing the schooling in the post covid era. Health care facility and availability of health care, especially for the poor section of the society was another concern during the COVID-19 pandemic. On the one hand health care facility to prevent and promote health was available through various measures such as wearing a mask, using hand sanitizer, washing hand and maintain social distance in crowded areas. However, health inequality or the disparity in terms of health acre accessibility resulted in deteriorated health of poor and underprivileged section across the globe. In countries where health care is largely privatized had the issues of overcharging and irrational cost. Where as developed countries with advanced health care facilities had fewer resources such as hospital beads and human resource to support and provide health care. Hence saving lives was a major challenge across the globe. Available literature also reviles that the deprived and underprivileged communities witnessed more deaths than the any other section of the population [4-7] In terms of employment millions lost their working opportunity while worst hit are workers in the informal economy, young people and women. The pandemic has had a disproportionate impact on the people living with low income in middle-income countries. Building back a better, sustainable and equal society United nations in the year 2015 formulated and adopted 17 Sustainable Development Goals, also called as global goals to accelerate the development of global economy, reduce inequality, poverty, bring in gender equality, strengthen social institutions and overall wellbeing. However, outbreak of COVID-19 resulted as an obstacle for achieving the sustainability goals by 2030. COVID-19 pandemic disrupted several areas where considerable progress was achieved by several countries irrespective of their financial status and availability of resources. One such destruction is widening gender inequality. SDGs aimed for considerable reduction in gender inequality by 2030. However, the pandemic resulted in widening gender gap in terms of increased drop in employment opportunities for women, increased working hours, invisible and unpaid work and lack of protection and safety . Hence the post COVID pandemic society need to intensify initiatives to empower women through social security, women friendly employment policies and inclusive social policy initiatives. Another major area where COVID-19 had its impact is poverty reduction. Impact of COVID-19 on Social, economic and political aspects in global society resulted in increased poverty and disparity in global society. Loss of employment, increased medical expenditure, loss of family income due to death of earning members in the family and closure of business and small-scale industries led to increased debt and financial disparity. Thus, making the goal of achieving poverty free society by 2030 a non-achievable dream for many countries in the globe. In order to tackle this issue development programmes, economic investment and the social security policy in the post pandemic era should make minimizing poverty arising from COVID-19 as an important policy priority. Further priority should also be given to engaging unemployed youth and populations in economic development, while ensuring safety, social security and decent working condition of existing workforce. Building strong institutions, facilitating peace and inclusive growth, developing and maintain strong international collaboration and coordination are also the priorities of post COVID-19 development to build a strong global society. In a world with widening inequality and disproportion of resources it is reasonable to build international cooperation where poor countries in the global south can avail the support and guidance from the developed economies. In order to reduce the power imbalance and exploitation by the western economies the government and administration in the global south need to find ways and means in developing and implementing mutually beneficial international collaboration. Further development in the post COVID society should also focus on enhancing all the four domains of health, including physical, psychological, social, and spiritual domains, thus contributing to the Sustainability Goal of health for all by 2030. About discover global society Societies across the globe are undergoing rapid growth and transformation. The processes of globalization, neoliberal market, and technological advancement has resulted in unprecedented social change and development. Changing social norms, values, and ethical issues in a contemporary global society demands further investigations of several social parameters to better understand the societal challenges while working towards a more sustainable future. Discover Global Society is an international, inclusive journal that provides opportunities to educators, researchers, and scientists across various social science disciplines for rapid dissemination of their research findings related to key societal issues and challenges. Showcasing authorship from diverse backgrounds and covering perspectives from both the global south and north, Discover Global Society includes articles that will influence social policy at different levels. Discover Global Society is an international and interdisciplinary journal that aims to publish the finest research findings on the complexities of modern global society and its development and challenges. While open to a variety of perspectives, we particularly encourage scholarship that examines the effects of globalization, neoliberalism, and growing internationalism on different aspects of societies and their challenges in different regions and regimes. Further research that examines the intersection of social, political, and economic aspects of the growing societal concerns within intercultural communities and societies are particularly encouraged. The journal is open to different methodological and theoretical approaches and seeks to publish articles that appeal to a wide readership, including policymakers and practitioners. Topics Discover Global Society covers a broad range of topics related to different societal issues, development challenges, and current transformations. Research on societies at the local, national, and international levels around the world are encouraged. Research findings contributing to the advancement of the UN Sustainable Development Goals (SDGs) are particularly encouraged. Specific topics covered by Discover Global Society includes (but not limited to).Social problems Social change and social issues Complexities of modern and globalized societies Movement of people Global infrastructure Sustainability Urbanization Global governance and issues related to governance Public policy Social policy and welfare Social security Globalization Culture Inequality Poverty Development and discrimination Gender Nationalism Religion Ethnicity Migration Terrorism and criminal activities Genocides Health and environmental degradation Youth and adolescent issues Disability Community development Social development Social policy and social work Edging forward COVID-19 pandemics has given us an opportunity to accelerate the research, teaching and practice in the areas of social problems, social change and inequality. Learning from various interventions, experiments, loss and gains during the past three years need for comprehensive, systematic, evidence based and participatory social policy in a post COVID-19 society is advocated by both researchers, practitioners and academics across the disciplines and geographical boundaries. If not addressed through evidence-based policies, the inequality, exclusion, discrimination and global unemployment produced by the pandemic may impact global society both in the medium and long term. Furthermore, administrations in each country should make sure that vulnerable and marginalized sections of the society are well covered by comprehensive and universal social protection measures to fight against and overcome shocks posed by pandemic. Well-coordinated governance, protecting left behind people and places, and supporting small businesses and vulnerable workers should be the policy priorities in the post pandemic era. Both state and non-state initiatives in bringing back social and economic normality in post covid society can not be overlooked. Learning from the lessons of pandemic administration should work towards building more resilient and long-term support system to achieve overall wellbeing while focusing on the upliftment of marginalized and vulnerable population. Greater thrust is required in ensuring job security, improving poor quality housing, environmental quality, intervening with mental and other health challenges and social isolation. In order to achieve the sustainable development goals and overall wellbeing of global population, Discover Global Society seek out to promote high quality, evidence-based research findings on all aspects of global society. Author contribution The author drafted, read and approved the final manuscript. Data availability Not applicable. Declarations Competing interests Not applicable. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Ramsetty A Adams C Impact of the digital divide in the age of COVID-19 J Am Med Inform Assoc 2020 27 7 1147 1148 10.1093/jamia/ocaa078 32343813 2. Watts G COVID-19 and the digital divide in the UK Lancet Digit Health 2020 2 8 e395 e396 10.1016/S2589-7500(20)30169-2 32835198 3. Stelitano, L, Doan, S, Woo, A, Diliberti, M, Kaufman, J, and Henry, D. The digital divide and COVID-19: teachers' perceptions of inequities in students' internet access and participation in remote learning. 2020. 4. Burstrom B Tao W Social determinants of health and inequalities in COVID-19 Eur J Pub Health 2020 30 4 617 618 10.1093/eurpub/ckaa095 32638998 5. Galvani AP Parpia AS Pandey A Sah P Colon K Friedman G Fitzpatrick MC Universal healthcare as pandemic preparedness: the lives and costs that could have been saved during the COVID-19 pandemic Proc Nation Acad Sci 2022 119 25 2200536119 10.1073/pnas.2200536119 6. Grome HN Raman R Katz BD Fill MM Jones TF Schaffner W Dunn J Research full report: disparities in COVID-19 mortality rates: implications for rural health policy and preparedness J Publ Health Manag Pract 2022 28 5 478 10.1097/PHH.0000000000001507 7. Raine S Liu A Mintz J Wahood W Huntley K Haffizulla F Racial and ethnic disparities in COVID-19 outcomes: social determination of health Int J Environ Res Publ Health 2020 17 21 8115 10.3390/ijerph17218115 8. Reichelt, M., Makovi, K, and Sargsyan, A. The impact of COVID-19 on gender inequality in the labor market and gender-role attitudes. European Soci. 2020 10.1080/14616696.2020.1823010. |
Front Plant Sci Front Plant Sci Front. Plant Sci. Frontiers in Plant Science 1664-462X Frontiers Media S.A. 10.3389/fpls.2023.1163839 Plant Science Editorial Editorial: Precision control technology and application in agricultural pest and disease control Tang Yunchao 1 Chen Chao 2 Leite Antonio Candea 3 Xiong Ya 3 * 1 College of Urban and Rural Construction, Zhongkai University of Agriculture and Engineering, Guangzhou, China 2 Department of Mechanical and Aerospace Engineering, Monash University, Melbourne, VIC, Australia 3 Faculty of Science and Technology, Norwegian University of Life Science, As, Norway Edited and Reviewed by: Lei Shu, Nanjing Agricultural University, China *Correspondence: Ya Xiong, [email protected] This article was submitted to Sustainable and Intelligent Phytoprotection, a section of the journal Frontiers in Plant Science 27 2 2023 2023 14 116383911 2 2023 20 2 2023 Copyright (c) 2023 Tang, Chen, Leite and Xiong 2023 Tang, Chen, Leite and Xiong This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial on the Research Topic Precision control technology and application in agricultural pest and disease control computer vision digital precision monitoring seedling protection green pesticides eco-friendly pest control technology spraying system pmc1 Introduction The Food and Agriculture Organization of the United Nations (FAO) reports that up to 40% of global crop production is lost annually due to weeds, pests, and diseases, and these losses could worsen without proper pest and disease management (OECD/FAO, 2012). Conventional approaches to pest monitoring and management are insufficient in meeting present demands in terms of efficiency, coverage, and cost-effectiveness. (Wolff et al., 2016). To address this issue, the development of smart pest control technology (Kanwal et al., 2022), the improvement of agricultural pest control systems, and stronger regulation of foreign species are demanded to collect pest outbreak data in a timely, accurate, and comprehensive manner. In the future, the focus of agricultural pest control will be on developing the fundamental theories, key technologies, and major products and equipment of "preventable," "controllable," "treatable," and "green" pest control throughout the process. 2 Articles in this research topic Given the need for precision pest and disease control, this special topic was organized which collected several research papers, covering pest and disease monitoring, detection and classification methods, as well as the development of control systems, with a strong focus on disease detection. 2.1 Detection and monitoring of plant pest and disease Maize disease detection and classification has attracted great attention. Fu et al. proposed a maize spectral recovery disease detection framework based on HSCNN+ and maize disease detection CNN to complete low-cost and high-precision maize disease detection. They found an ideal spectral recovered model to reconstruct HSI data from the raw maize RGB data. Haque et al. presented a lightweight CNN model to classify different severity stages of Maydis leaf blight disease. Their results showed that the proposed model outperformed most of the commonly used pretrained models in terms of classification accuracy. Similarly, Albahli and Masood presented an end-to-end learning CNN architecture, namely EANet, to identify multi-class maize diseases. An attention mechanism was used to improve the performance of recognizing multiple diseases. Results showed that the proposed method was able to classify maize leaf diseases in complex background settings. Researchers also demonstrated pest and disease monitoring and recognition methods for rice crops and jujube trees. Li et al. developed an intelligent monitoring system to detect the disease and pest lesions on the rice canopy. They proposed an improved YOLO-DPD model to capture the features of rice disease and pest lesions. Wu et al. used hyperspectral remote sensing images from UAVs to recognize and monitor spider mite infestations in jujube trees. The recognition model combined spectral features and spatial information, and has performed well in the experiments. 2.2 Pest and disease control system and mechanisms In addition to detection and monitoring, researchers also showed recent developments for pest and disease control system. Li et al. developed a real-time target spraying system based on an improved CNN model. Field tests demonstrated that their spraying system could accurately hit target weeds. Jiang et al. studied the wetting and deposition mechanism of spraying droplet. They found the best nozzle type, spray pressure and wind speed settings for spray coverage and droplet density. 3 Perspectives The editorials suggest that further research and technology application should be conducted in the following areas: 3.1 Construction and application of a digital and precise monitoring and early warning technology system for agricultural, forestry, and grassland pest control The editorial team suggests that we should focus on the lack of accurate monitoring and early warning technologies for major pests and diseases in agriculture, and develop core key technologies such as intelligent pest and disease identification and automatic counting technology, and machine learning-based image recognition technology. We should research and develop key technologies, core equipment, and imaging acquisition standards for ground-based camera capture, low-altitude unmanned aerial vehicle remote sensing, and high-altitude radar monitoring of pests and diseases, and establish a massive high-quality image database. We should also develop big data collection, multi-source information processing and transmission, and rapid monitoring and evaluation technologies based on the Internet of Things and cloud computing, and establish a nationwide database of agricultural and forestry pest and disease occurrence and their suitable environments. We should break through the large-scale intelligent identification and quantification extraction method based on machine vision, establish a multi-temporal comprehensive forecasting and warning model based on multi-source information on the occurrence and breeding dynamics of major pests and diseases, host growth conditions, and meteorological adaptation. Finally, we should develop an integrated and map-based analysis platform for real-time accurate monitoring, early warning and efficient information dissemination of emerging pest and disease outbreaks, and construct a spatiotemporal dynamic visualization and intelligent monitoring and warning system for pest and disease populations. 3.2 Mechanisms of signal communication between pest diseases and crops and new controlling-attracting techniques The editorial team recommends research in four areas to develop new strategies and techniques for pest and disease control: Firstly, researchers should investigate the mechanisms of signal communication during major pest and disease outbreaks in crops and analyze the information exchange between individual pests and diseases that lead to such outbreaks. Secondly, researchers should elucidate the mechanisms of identification, decoding, and transmission of inter-species information flow between pests, diseases, and crops. Thirdly, researchers should explore the defense responses and regulatory mechanisms of crops against pest and disease infestations. Finally, to develop new strategies and techniques for pest and disease control, researchers should also actively develop high-throughput screening methods to identify chemical communication substances and their analogues, design target-releasing and enhancing agents, and research and develop pest and disease control products for field use based on the interactions between biological information flows. 3.3 Research and development of mechanisms and control technologies for important pests and diseases resistance in agriculture The editorial team believes that in order to combat important pests and pathogens that pose a serious threat to major crops such as rice, corn, cotton, and vegetables worldwide, we need to conduct risk assessments and interactive resistance studies on these pests and their resistance to new drug agents. We need to analyze the molecular mechanisms of resistance formation from aspects such as target mutation and detoxification metabolism enhancement. Research is needed on the genetic diversity and adaptive evolution mechanisms of resistance genes. The causes and evolutionary laws of multidrug resistance should also be studied. Furthermore, we should develop resistance diagnosis, monitoring, warning, and control technologies based on key resistance genes. 3.4 Succession laws of pests diseases and the whole-process green control technology system The editorial team proposes urgent research to address the major challenges presented by the catastrophic mechanisms and control techniques associated with serious pest and disease outbreaks, including the Yangtze River Delta beetle, canker disease, and other serious pests and diseases that pose a major threat to the safety of key protected forests worldwide. The effects of industrial structure adjustment and climate change on the succession patterns of major pests and diseases, such as diamondback moth, tobacco whitefly, root-knot nematode, and viral diseases, are examined to clarify their harmful rules and mechanisms. This includes investigating the adaptation, harmful variation, regional disasters, and periodic outbreak mechanisms of pests and diseases under changing climatic conditions; conducting health evaluations, precise monitoring, and big data forecasting of protective forests, and researching the autonomous pest resistance of main afforestation species and its induced enhancement techniques; integrating and optimizing the diverse and coordinated application technologies of different pest control technologies and products such as lures, natural enemies, microorganisms, and natural active substances; developing natural pest and disease control techniques that focus on forest optimization, nurturing, and renewal measures; and constructing integrated green pest and disease control technology schemes for multiple pest and disease types throughout the entire growth cycle. 3.5 Exploration of biocontrol microbial resources and their interaction mechanisms with plants The editorial team points out the current shortage of important biological control products for pest and disease management. To address this issue, we need to focus on major crops such as grains, oilseeds, economic crops, and forest and grassland plants, and screen for highly efficient biocontrol microbial strains. We advocate for scholars to study the persistence and control mechanisms of biocontrol microbes, identify new functional genes of biocontrol strains, use modern biological breeding technology to modify production strains, enhance product biocontrol activity, broaden the spectrum of insecticidal and fungicidal activities, and improve stress resistance. We aim to overcome the three waste problems of biocontrol microbial fermentation, develop efficient green production processes and supporting equipment, create new formulations and products for important pests and diseases and corresponding application technologies that are suitable for the planting technology system. We aim to reveal the pathogenic mechanisms of microbial pathogens and plant immune defense mechanisms, develop new strategies and technologies for plant disease control, analyze the interactions among plants, pests, and natural enemies, and the impact mechanisms of multiple ecological factors such as microbes and the environment, and develop new green pest control technologies for agriculture and forestry. Author contributions All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. Acknowledgments We express our sincerest gratitude to all contributors for their unwavering dedication to this Research Topic. Our heartfelt thanks go out to the reviewers and the members of the Frontiers Editorial Team for their invaluable support. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References Kanwal S. Khan M. A. Saleem S. Tahir M. N. Muntaha S. T. Samreen T. . (2022). Integration of precision agriculture techniques for pest management. Environ. Sci. Proc. 19 . doi: 10.3390/environsciproc2022023019 OECD/FAO (2012). OECD-FAO agricultural outlook 2012 (Paris: OECD Publishing). doi: 10.1787/agr_outlook-2012-en Wolff J. N. Tompkins D. M. Gemmell N. J. Dowling D. K. (2016). Mitonuclear interactions, mtDNA-mediated thermal plasticity and implications for the Trojan female technique for pest control. Sci. Rep., 6 (1 ):1-7. doi: 10.1038/srep30016 28442746 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34864 Infectious Disease Kala-Azar: A Case Report Muacevic Alexander Adler John R Jancar Nina 1 Sousa Goncalves Filipa 1 Duro Jose 1 Pinto Ines 1 Oliveira Tiago 2 Aguiar Patricio 13 1 Internal Medicine, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte, Lisbon, PRT 2 Pathology, Hospital de Santa Maria, Centro Hospitalar Universitario Lisboa Norte, Lisbon, PRT 3 Medicine Department, Faculty of Medicine, Lisbon University, Lisbon, PRT Nina Jancar [email protected] 11 2 2023 2 2023 15 2 e3486411 2 2023 Copyright (c) 2023, Jancar et al. 2023 Jancar et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Leishmaniasis is a zoonosis caused by unicellular protozoans Leishmania. The transmission can be zoonotic or anthroponotic, depending on the species, and the main vector is the phlebotomine sandfly. The disease is endemic in the tropics of Asia and Africa but is considered rare in Portugal, especially in immunocompetent hosts. Its main clinical syndromes constitute cutaneous leishmaniasis, mucocutaneous disease, and visceral leishmaniasis. The latter is also known as kala-azar and is caused by the infection of the phagocytes of the reticuloendothelial system, causing the typical symptoms: fever, hepatosplenomegaly, and pancytopenia. The clinical manifestations are non-specific, frequently causing a delay in the diagnosis, especially in nonendemic areas and immunocompetent hosts. Early diagnosis and treatment are essential, given the high mortality rate in untreated patients. The diagnosis is based on the direct visualization of the protozoan and molecular methods, such as polymerase chain reaction tests. Amphotericin B is considered the first-line treatment. We present a case of visceral leishmaniasis in an immunocompetent patient with fever, hepatosplenomegaly, and pancytopenia. unintentional weight loss immunocompetent adult high fever "pancytopenia" visceral leishmaniasis (vl) The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Visceral leishmaniasis, also known as kala-azar, is a systemic disease caused by unicellular protozoans of the genus Leishmania (principally Leishmania donovani (L. donovani) and Leishmania infantum (L. infantum), depending on the geographical area), transmitted by phlebotomine sandflies [1-3]. The disease is endemic in the rural areas of the tropics of Asia, East Africa, and Brazil but is hypoendemic in Portugal . The principal clinical syndromes associated with the Leishmania infection are cutaneous leishmaniasis, mucocutaneous leishmaniasis, and visceral leishmaniosis, caused by systemic dissemination of the parasites through the reticuloendothelial system [1-3]. Clinical manifestations of visceral leishmaniasis are non-specific , and a high index of suspicion is necessary to diagnose the disease in non-endemic areas. When untreated, the disease is associated with a high mortality rate . Case presentation We present a case of a 38-year-old woman with a history of primary hyperparathyroidism, having undergone parathyroidectomy and depression, for which she was medicated with escitalopram and bromazepam. The patient presented with vespertine fever, night sweats, weight loss (6.1% of the total body weight), anorexia, and non-productive cough, which started about a month before the hospitalization. The patient was of African descent and had moved to Portugal from the Democratic Republic of Sao Tome and Principe (not an endemic area for leishmaniasis) three years before the hospitalization and had traveled there six months before the onset of symptoms. There was no other relevant epidemiologic history, such as insect bites, contact with dogs, or other domesticated or wild animals. At admission, pallor of the mucosa and splenomegaly were identified. Laboratory investigations revealed new-onset pancytopenia (normocytic anemia 10.3g/dL, leukopenia 2700/mL, and thrombocytopenia 90000/mL) and C-reactive protein elevation (14mg/dL) (Table 1). Table 1 Laboratory tests performed at admission, showed pancytopenia CRP: C-reactive protein; IGRA: Interferon-gamma release assay Laboratory test Value at admission Normal range Hemoglobin 10.3g/dL 12-15.3g/dL Leukocytes 2700x109 4000-11000x109 Platelets 90000 x109 150-450 x109 CRP 14mg/dL <0.5 mg/dL IGRA Negative - The peripheral blood smear was unremarkable, and blood infectious serologies, including human immunodeficiency virus (HIV), hepatitis B and C, cytomegalovirus (CMV), parvovirus B19, Epstein-Barr virus (EBV), as well as Brucella, Coxiella burnetii, Rickettsia conorii and the enzyme-linked immunoassay test for Leishmania, were all negative (Table 2). Malaria parasites were not found on the peripheral blood smear. The Interferon-g release assays (IGRA) test was negative as well. Table 2 Infectious serologies solicited Infectious serologies Result Human immunodeficiency virus (HIV) Negative Hepatitis B Negative Hepatitis C Negative Parvovirus B-19 Negative Cytomegalovirus (CMV) Negative Epstein-Barr virus (EBV) Negative Brucella spp. Negative Rickettsia conorii Negative Coxiella burnetii Negative Leishmania spp. Negative The whole-body computerized tomography (CT) showed discrete hepatosplenomegaly and para-aortic lymphadenopathy . Given the persistent fever and pancytopenia during the hospitalization, a positron emission tomography (PET) was solicited, and intense metabolic activity of the spleen and bone marrow was detected. Figure 1 Abdominal CT scan showing hepatosplenomegaly CT: computerized tomography A myelogram and bone marrow biopsy were performed, evidencing multiple Leishmania, thus confirming the diagnosis of visceral leishmaniasis or kala-azar . Figure 2 Microscopical analysis of the bone marrow that shows normal cellularity (A). At 40x magnification, numerous macrophages with round and basophilic intracytoplasmic organisms that corresponded to Leishmania amastigotes are seen (B). These organisms are also readily visualized in a Giemsa staining (C) Treatment with intravenous liposomal amphotericin B (3mg/kg/day, for five days) was started, with the resolution of the fever, thrombocytopenia, and leucopenia, maintaining only anemia (10g/dL) on hospital discharge. Discussion Visceral leishmaniasis (VL) is a systemic disease caused by unicellular protozoans from the Leishmania genus, typically transmitted by female phlebotomine sandflies . Although nearly 90% of all worldwide cases occur in Bangladesh, India, Nepal, Sudan, and Brazil, Leishmania is endemic in some Mediterranean and Middle East countries . VL is typically caused by L. donovani, found almost exclusively in the Old World, and L. infantum, endemic in Latin America and the Mediterranean . The transmission is either anthroponotic, in the case of L. donovani, or zoonotic, as in L. infantum, with dogs, rodents, foxes, and other animals serving as the main reservoir . Despite the geographic localization, visceral leishmaniosis is hypoendemic in Portugal, with an incidence rate of 0.1 cases per 100,000 inhabitants , and is more frequently diagnosed in the pediatric population and immunocompromised patients . The incubation period can vary between 2 weeks and 18 months, but the disease can take years to become symptomatic . After the inoculation of the promastigote form into the skin, the parasites are internalized by phagocytes (dendritic cells and macrophages) in the skin, where they transform into amastigotes, replicate, and later disseminate through lymphatic and blood vessels and infect the phagocytes of the reticuloendothelial system [2-3], resulting in infiltration of the bone marrow and hepatosplenomegaly . The most common clinical manifestations are fever, weight loss, fatigue, and hepatosplenomegaly , but the symptoms may be atypical in immunocompromised (especially AIDS-acquired immunodeficiency syndrome) patients . As the disease progresses, fatigue aggravation due to anemia and abdominal pain due to hepatosplenomegaly may occur [2-3,8]; gastrointestinal involvement, causing diarrhea, pleural effusion, and pulmonary nodules, are also described . Typical laboratory findings include anemia, leukopenia, pancytopenia, increased transaminases, and hypergammaglobulinemia . A high index of suspicion is necessary to diagnose VL since its clinical presentation is non-specific and can be associated with other infectious diseases, such as tuberculosis, malaria, and brucellosis, as well as hematologic malignancies and macrophage activation syndrome . Traditionally, the gold standard for the diagnosis has been direct visualization of the parasite on microscopy or culture of invasive samples . Still, molecular methods have the highest sensitivity and specificity . Therefore, a step-wise approach is recommended in the diagnosis of VL ; non-invasive tests, such as serology and polymerase chain reaction (PCR) tests, should be the first to be performed . In contrast to immunocompromised patients, serology has good sensitivity and specificity (80%-100%) in immunocompetent patients . When the diagnosis can't be ruled out or reliably confirmed, bone marrow, lymph nodes, or spleen samples should be obtained . Spleen biopsy has the best sensitivity (93%-99%) , but because of the risk of spleen hemorrhage, bone marrow aspirate is preferred, despite the lower sensitivity (53%-86%) . RK39 and rK28-based rapid diagnostic tests have been implemented, but their sensitivity and specificity vary according to the geographical location, being highest in the Indian continent [9-10] and, thus, not very useful to diagnose VL in Portugal. Our patient was of African descent and had moved to Portugal from the Democratic Republic of Sao Tome and Principe three years before the hospitalization; she had visited the country about six months before the hospitalization. According to the World Health Organization (WHO), no autochthonous cases have been reported in the country up until now . No insect bites or contact with dogs or other domesticated or wild animals were reported. She presented with typical symptoms of intermittent fever, weight loss (6.1%), night sweats and fatigue, and splenomegaly was observed at admission. The laboratory results confirmed pancytopenia. Although she presented a typical clinical picture, it is not specific to leishmaniasis, and the patient did not refer high-risk epidemiologic history for leishmaniasis. Other parasitic and bacterial infections were excluded, including malaria, an endemic disease in Sao Tome, tuberculosis, brucellosis, and rickettsiosis. Viral infections, causing fever and pancytopenia, were also ruled out. The serology for Leishmania in the peripheral blood was negative. Further investigation was performed to confirm leishmaniosis and exclude eventual hematologic disease. Hepatosplenomegaly was documented on the CT scan; intense metabolic activity of the spleen and bone marrow was detected on the PET scan. Given the high risk of post-procedure hemorrhage, a bone marrow biopsy and myelogram were performed instead of a spleen biopsy. Multiple Leishmania parasites were observed on microscopy, confirming the diagnosis of VL. When not treated, VL is associated with a high mortality rate . Therefore, all symptomatic patients should be treated according to the current guidelines, and the treatment should be adapted to the patient's immune status and the geographic location where the infection was acquired . Currently, amphotericin B and miltefosine (for L. donovani) are considered the first-line treatment, with pentavalent antimony being an alternative treatment in patients that do not tolerate the treatments mentioned above . Clinical parameters correlate with the response to the treatment, and invasive methods are not recommended to monitor the response . Our patient was started on liposomal amphotericin B (3mg/kg/day intravenously for five days, and on days 14 and 21) after an infectious disease consult, with the resolution of fever and normalization of thrombocytopenia and leukopenia, maintaining discrete anemia. Conclusions Visceral leishmaniasis is a systemic, potentially fatal disease caused by protozoa of the Leishmania genus. It is transmitted by sandflies, and its natural reservoir is dogs, foxes, and rodents. Due to its non-specific clinical presentation, a high index of suspicion is necessary to diagnose the disease, especially in non-endemic areas and immunocompetent patients. A prompt diagnosis and exclusion of other infectious and hematologic diseases are crucial. The timely institution of treatment has a direct impact on the prognosis. Direct visualization and molecular tests are the most sensitive and specific tools for diagnosis. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Diagnosis and treatment of leishmaniasis: Clinical practice guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH) Clin Infect Dis Aronson N Herwaldt BL Libman M 1539 1557 63 2016 27941143 2 Leishmaniasis: clinical syndromes and treatment Q J Med B.S. MCGWIRE and A.R. SATOSKAR 7 14 107 2014 3 Visceral leishmaniasis: what are the needs for diagnosis, treatment and control? Nat Rev Microbiol Chappuis F Sundar S Hailu A 873 882 5 2007 17938629 4 Seroprevalence and risk factors associated with leishmania infection in dogs from Portugal Microorganisms Almeida M Maia C Cristovao JM 10 2022 5 Holiday souvenirs from the Mediterranean: three instructive cases of visceral leishmaniasis Scand J Infect Dis Buonomano R Brinkmann F Leupin N Boscacci R Zimmermann A Muller N Fux CA 777 781 41 2009 19593691 6 Epidemiology of visceral leishmaniasis Clin Epidemiol Ready PD 147 154 6 2014 24833919 7 Leishmaniose em Portugal no inicio do seculo XXI Anais IHMT Maia C Campino L 25 28 13 2014 8 Visceral leishmaniasis: Kala-azar Diagn Cytopathol Safavi M Eshaghi H Hajihassani Z 446 448 49 2021 33225605 9 Visceral leishmaniasis: Recent advances in diagnostics and treatment regimens Infect Dis Clin North Am van Griensven J Diro E 79 99 33 2019 30712769 10 Diagnostic accuracy of direct agglutination test, rK39 ELISA and six rapid diagnostic tests among visceral leishmaniasis patients with and without HIV coinfection in Ethiopia PLoS Negl Trop Dis Kassa M Abdellati S Cnops L 0 14 2020 11 World Health Organization: Leishmaniasis 1 2023 2021 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34861 General Surgery Other Nutrition Spontaneous Enteral Migration of a Feeding Jejunostomy Tube: An Unusual Complication Muacevic Alexander Adler John R Kundal Ashikesh 1 Singh Sudhir 1 Sharma Jyoti 1 S Dhivakar 1 Karn Summi 1 1 Department of General Surgery, All India Institute of Medical Sciences, Rishikesh, Rishikesh, IND Sudhir Singh [email protected] 11 2 2023 2 2023 15 2 e348617 2 2023 Copyright (c) 2023, Kundal et al. 2023 Kundal et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Established consensus suggests that enteral nutrition is more beneficial in patients with a functioning gut than parenteral nutrition. It helps in early physical rehabilitation from a disease or surgical stress and is associated with fewer complications compared to parenteral nutrition. Jejunal feeding is one of the routine modes of enteral nutrition in patients with gastric dysfunction, either due to surgery or critical illness. Various complications have been reported when using feeding tubes, grouped as mechanical, infectious, gastrointestinal, and metabolic. Here, we report an unusual case of a 47-year male with a history of prepyloric perforation repair leak who presented to us on postoperative day 14 with an enterocutaneous fistula and a feeding jejunostomy tube in situ. He was evaluated and managed conservatively and discharged on enteral feeds, both orally and via a jejunostomy tube. One month after discharge, he presented with features of intestinal obstruction with a missing jejunostomy tube. Radiological investigations suggested enteral migration of the jejunostomy tube, which was managed non-operatively, and the patient was discharged on day three post-admission after per rectal expulsion of the tube. nutrition postoperative complications feeding tube migration feeding jejunostomy acute intestinal obstruction The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Early resumption of feeding is essential in managing surgical patients to counteract the surgical stress causing a catabolic state and enhance postoperative recovery, resulting in a shorter hospital stay. Enteral feeding is preferred over parenteral nutrition in patients with a functional gastrointestinal tract . While the oral route is considered the best route for enteral nutrition, feeding through a jejunostomy tube is preferred in patients unable to feed adequately through the oral route due to pathology in the upper gastrointestinal tract, i.e., esophageal, gastric, or prepyloric pathology . Jejunal tube feeding is performed as an ancillary procedure in various major upper gastrointestinal tract surgeries where gastric dysfunction is expected . It is a simple, cheap, and easy way of enteral nutrition through small bowel access. However, various complications related to feeding jejunostomy (FJ) have been reported and classified as mechanical, metabolic, nutritional, and septic complications. Although tube obstruction, displacement, kinking, coiling, and bowel perforations have been commonly reported, enteric migration of FJ is a rare and dreaded occurrence . This case report describes an unusual complication of enteric migration of the FJ tube in a patient with postoperative enterocutaneous fistula along with its management. Case presentation A 47-year-old male underwent exploratory laparotomy with modified Graham's patch repair at a private hospital for non-steroidal anti-inflammatory drug-induced prepyloric perforation. On postoperative day two, he was re-explored with suspicion of a patch repair leak. Primary repair of the perforation site with FJ was done using a 16 Fr Foley catheter. The patient developed bilious discharge from the midline wound postoperatively and was referred to our institute for further management. On presentation, the patient had a high-output enterocutaneous fistula through the midline wound with an FJ tube in situ, which was fixed to the anterior abdominal wall with a silk suture. He had no signs of peritonitis. The patient was resuscitated and managed conservatively on the lines of an enterocutaneous fistula. He was started on antibiotics, parenteral nutrition, and enteral feeds via a jejunostomy tube with adequate skin care. A three-in-one total parenteral nutrition consisting of dextrose, amino acids, and lipid emulsion was supplemented along with curd-based jejunostomy feeds. About 50% of the total caloric requirement was supplemented by total parenteral nutrition (TPN) while the rest was supplemented by jejunostomy feeds. The fistula output gradually decreased over the course of the hospital stay. TPN was gradually tapered and jejunostomy feeds were increased. A low-residue oral diet consisting of bread, eggs, bananas, and roasted gram flour (sattu) was introduced, and the patient was discharged after 10 days of admission on oral and jejunal feeds. The patient was advised to visit the outpatient department after 10 days but he did not follow up. He then presented to the emergency one month later with features of intestinal obstruction and the absence of the jejunostomy tube. He denied any history of accidental pulling out of the tube. On abdominal examination, the enterocutaneous fistula was replaced by a healed scar, and an opening measuring approximately 1 x 1 cm was seen at the previous FJ site. The abdomen was distended with exaggerated bowel sounds. With suspicion of antegrade migration of the FJ tube, contrast-enhanced CT (CECT) of the abdomen was done, which showed an inflated balloon of Foley's catheter with a 33.1 mm diameter situated at a displacement of 78.3 mm in the sagittal section and 133.1 mm in the coronal section from the location of the tube jejunostomy site on the anterior abdominal wall . Figure 1 Contrast-enhanced CT showing Foley catheter bulb in the terminal ileum. Figure 2 Contrast-enhanced CT (coronal section) showing a displacement of 133.1 mm of Foley catheter from the jejunotomy site. Figure 3 Contrast-enhanced CT (sagittal section ) showing a 78.3 mm displacement of Foley from the jejunostomy site. Interventional radiologists performed a fluoroscopic-guided rupture of Foley's catheter balloon, which was expelled intact, per rectum, after the third day of the procedure, and the patient was discharged . Figure 4 Foley catheter expelled per rectally. On follow-up after 10 days, the patient had recovered well, and the FJ site was completely healed. Discussion Enteral tube feeding is the preferred mode of nutrition in patients who cannot tolerate it orally but have a functional gastrointestinal tract. The enteral tube is placed distal to the pathologic part of the upper gastrointestinal tract [1-3]. The tube opted for FJ can be a simple Ryle's tube, Foley's catheter, mushroom-tip catheter, or special feeding catheter, depending on the availability and the surgeon's preference . Enteral tube placement has complications, as with other procedures. The incidence of complication rates mentioned in the literature is approximately 12% in patients with enteral tubes, which have been grouped under gastrointestinal, mechanical, or metabolic complications . Common complications include bowel obstruction, bowel perforation, intussusception, or, as in our case, enteral migration. Although a rare complication, enteral migration of the jejunostomy tube can lead to grave consequences, including bowel obstruction, pressure necrosis, and subsequent bowel perforation. Various factors must be anticipated and taken care of beforehand to prevent the migration of tubes during the follow-up visit. Adequate tube fixation is essential, and care must be taken to ensure its integrity during follow-up. This fixation may cut through and lead to migration or expulsion of the tube, as was suspected in this case. The use of retention disks and retention rings for holding the feeding tube at the fixation site is considered better for preventing migration. Patient education is another factor that can improve the outcome of enteral tube feeding therapy. The patient and caretaker must be educated on how to use and flush the tube and fixation site care and should be vigilant for signs of infection or impending migration. This will help in the early recognition and reporting of feeding tube-related complications. The available literature has mentioned both conservative management with spontaneous per rectal expulsion of the tube and surgical removal of the migrated jejunostomy tube for the management of such cases . Conservative management was opted in this case, and radiological intervention played an important role in visualizing the overinflated balloon and its fluoroscopic-guided rupture, which facilitated the movement of Foley's through the gut and reduced the subsequent risk of pressure necrosis and perforation. Here, gut peristalsis proved as an excellent therapeutic modality in itself. However, close monitoring after admission is essential in the case of conservative management. Frequent clinical examination is necessary to recognize possible serious consequences such as acute intestinal obstruction or perforation. Failure of conservative management demands surgical or endoscopic removal. Conclusions Apart from a meticulous creation of FJ, efforts should be made to avoid enteral migration of the jejunostomy tube. These include proper fixation of the tube with the parietal wall and skin, use of an external retention device, use of tubes with a dilated external end, marking of the outer part of the tube, frequent checking of the position and outer length of the tube before each feeding, and educating patients and their caretakers to examine the fixation site for signs of suture disruption. Conservative treatment is viable for managing patients with a migrated tube but requires close clinical monitoring. Moreover, it also depends on the patient's clinical condition and the surgeon's discretion in choosing a suitable treatment option. If conservative management fails, surgical or endoscopic procedures must be kept as a last resort. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Benefits and limitations of enteral nutrition in the early postoperative period Langenbecks Arch Surg Dervenis C Avgerinos C Lytras D Delis S 441 449 387 2003 12607126 2 Advantages of enteral nutrition over parenteral nutrition Therap Adv Gastroenterol Seres DS Valcarcel M Guillaume A 157 167 6 2013 3 Enteral feeding. Nasogastric, nasojejunal, percutaneous endoscopic gastrostomy, or jejunostomy: its indications and limitations Postgrad Med J Pearce CB Duncan HD 198 204 78 2002 11930022 4 Study of feeding jejunostomy as an add on procedure in upper gastrointestinal surgeries Indian J Surg Shenoy J Adapala RK 275 282 77 2015 26730009 5 Complications associated with enteral nutrition using tube jejunostomy after esophageal reconstruction J Gastrointest Dig Syst Boukerrouche A 252 5 2015 6 Jejunostomy: techniques, indications, and complications World J Surg Tapia J Murguia R Garcia G de los Monteros PE Onate E 596 602 23 1999 10227930 7 Enteral access devices: types, function, care, and challenges Nutr Clin Pract Lord LM 16 38 33 2018 29365361 8 Uncommon complication of feeding jejunostomy: a case report JGH Open Basil T Sundaramurthi S Huthalm S Goyal A Dasarathan S Dharanipragada K 444 445 3 2019 31633054 9 Successful conservative management of spontaneous antegrade migration of feeding jejunostomy Euroasian J Hepatogastroenterol Krishnamurthy G Pandit N Singh H Singh R 84 86 7 2017 29201780 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34865 Endocrinology/Diabetes/Metabolism Ophthalmology Hematology Central Retinal Artery Occlusion in a Young Patient With a Hidden Unusual Sickle Cell Trait Muacevic Alexander Adler John R Semidey Valmore A 1 Magliyah Moustafa S 2 Alali Naif 3 Hashem Faris 3 ALBalawi Hani B 3 1 Vitreoretinal Division, King Khaled Eye Specialist Hospital, Riyadh, SAU 2 Department of Ophthalmology, Prince Mohammed Medical City, Aljouf, SAU 3 Ophthalmology Division, Department of Surgery, Faculty of Medicine, University of Tabuk, Tabuk, SAU Faris Hashem [email protected] 11 2 2023 2 2023 15 2 e3486511 2 2023 Copyright (c) 2023, Semidey et al. 2023 Semidey et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Sickle cell trait is considered a benign condition. Ophthalmic manifestations are infrequent but can result in significant visual deterioration. We present a case of a 33-year-old male, not known to have any medical illnesses, who presented to the ophthalmological emergency room complaining of a sudden onset of painless and profound left eye vision loss for 12 hours. The patient denied any medication use, past eye trauma, or surgery. On detailed ophthalmologic examination, the best-corrected visual acuity (BCVA) was 20/20 in the right eye and hand movement in the left eye. Dilated fundus examination of the left eye showed a central retinal artery occlusion (CRAO) with pale, white retinal swelling and a macular cherry-red spot. Fundus fluorescein angiography showed delayed arterial filling with persistently reduced macular perfusion. CRAO was diagnosed in an otherwise healthy young male. Systemic workup was negative except for protein electrophoresis, which showed sickle cell trait, and HbA1C was 7.8%. Later, atrophic macular changes with a pale optic disc were observed, and BCVA was reduced to light perception. CRAO in young patients amounts to diverse causes, which require extensive systemic workup. In addition, the concurrence of the sickle cell trait with diabetes mellitus might have a role in CRAO development. vision loss hemoglobin electrophoresis sickle cell trait crao central retinal artery occlusion The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction In 1859, von Graefe first described central retinal artery occlusion (CRAO) . It is considered an ocular emergency and an ocular analog of acute ischemic cerebral stroke. Management includes controlling the acute event, localizing the site of vascular occlusion, and trying to prevent other occurrences in the eye or other locations . CRAO is characterized by a compromised blood flow to the inner layers of the retina, which are supplied by the central retinal artery. It presents slightly more in men than women . The incidence is around one in 100,000 in the general population . Based on pathogenesis, CRAO broadly can be classified as arteritic and non-arteritic. Non-arteritic presentation is responsible for more than 90% of the CRAO cases, and 70% of non-arteritic cases are associated with carotid artery disease; it is worth mentioning that in the EAGLE study, more than 70% of patients had carotid artery stenosis . Other non-arteritic causes include hematological conditions and hypercoagulable states (such as antiphospholipid syndrome, deficiency of factor V Leiden, deficiency of antithrombin, protein C or protein S deficiency, elevated levels of fibrinogen or dysfunctional fibrinogen, elevated levels of coagulation factors VIII, IX, or XI, aplastic anemia, erythrocytosis, hemochromatosis, immune thrombocytopenic purpura, leukemia, and sickle cell disease), emboli of cardiac origin, and others. Giant cell arteritis is the most common etiology of the arteritic type of CRAO . Patients with CRAO usually complain of unilateral, sudden, painless, and profound loss of vision, and around one-third of patients have visual acuity of counting fingers or worse . In young patients, CRAO may be correlated to a known preexisting systemic disease, the initial presentation of an undiagnosed disease, or hereditary diseases such as Fabry disease. Those patients usually have more obscure and diverse etiological causes that require extensive workup, as in our case . We report a rare case of CRAO in a young male who presented to the ophthalmology emergency room complaining of sudden painless loss of vision, claiming that he is medically free. Case presentation A 33-year-old male with no previous medical history presented to the ophthalmological emergency room complaining of a sudden onset of painless and profound loss of vision in his left eye for around 12 hours. On taking a history, the patient denied taking any medication use, past eye trauma, or surgery. On detailed ophthalmologic examination, the best-corrected visual acuity (BCVA) was 20/20 in the right eye and hand movement in the left eye. There was an afferent pupillary defect on the left pupil. The slit lamp examination showed that the right eyelids, conjunctiva, and cornea were within normal limits. The anterior chamber was deep and quiet. The lens was clear. Dilated fundus examination of the right eye showed a flat retina, normal macular reflex, healthy optic nerve head, and normal retinal vasculature. The left eye examination showed lids, conjunctiva, and cornea within normal limits. The anterior chamber was deep and quiet. The lens was clear. Dilated fundus examination of the left eye showed a picture of CRAO with pale whitening and swelling of the retina with a cherry-red spot in the macula. Optical coherence tomography (OCT) of the left eye showed marked edematous and thickened inner retina with poorly differentiated retinal layers . Figure 1 Multimodal imaging of the left eye of a 33-year-old male with sickle cell trait. (A) A colored fundus photo of the left eye showing a cherry-red spot at the macula. (B) A spectral-domain optical coherence tomography showing inner retinal thickening with poor differentiation of retinal layers. Fundus fluorescein angiography showed an early delay of the arterial filling with persistently reduced macular perfusion . Figure 2 FFA of the left eye upon presentation. (A) An early phase FFA shows a delay in the filling of retinal arteries. (B) A late-phase FFA shows reduced macular perfusion. FFA, fundus fluorescein angiography A complete workup was performed, and all the results came back negative except hemoglobin electrophoresis, which showed sickle cell trait (SCT); hemoglobin A1C was 7.8%. The patient also had elevated triglycerides. The basic workup lab results are shown in Table 1. Table 1 The patient's workup lab results Test item Value Reference range White blood cell count 8.3 x 109/L 4.5-11.0 x 109/L Neutrophil % 52.0% 54%-62% Lymphocyte % 39.8% 25%-33% Monocyte % 5.6% 3%-7% Eosinophil % 1.1% 1%-3% Basophil % 1.4% 0%-0.75% Red blood cell count 6.57 x 1012/L Male: 4.3-5.9 x 1012/L Hemoglobin 113 g/L Male: 135-175 g/L Hematocrit 0.404 L/L Male: 0.41-0.53 L/L Mean corpuscular volume 61.5 fL 80-100 fL Mean corpuscular hemoglobin 17.2 pg/cell 25-35 pg/cell Mean corpuscular hemoglobin concentration 279 g/L 320-360 g/L Red cell distribution width 17.3% 12%-15% Platelet count 328 x 109/L 150-400 x 109/L Mean platelet volume 8.3 fL 7.5-11.5 fL Sickle cell screen Positive - Hemoglobin A 68.60 - Hemoglobin F 1.6 - Hemoglobin S 28.6 - Hemoglobin A2 1.2 - Diagnosis Sickle cell trait (heterozygous A/S) expected range: hemoglobin A levels are higher than hemoglobin S - C-reactive protein 2.16 mg/L <3.0 mg/L Glucose - random 11.2 mmol/L <7.77 mmol/L Prothrombin time 11.0 seconds 11-15 seconds International normalized ratio 1.1 1.1 or below Activated partial thromboplastin time 22 seconds 25-40 seconds Is the patient receiving anticoagulants? No - Glycosylated hemoglobin (HbA1C) 7.8% <5.7% Cholesterol - total 4.9 mmol/L <5.2 mmol/L Cholesterol (low-density lipoprotein) 1.00 mmol/L 1.0-1.6 mmol/L Cholesterol (high-density lipoprotein) 3.0 mmol/L <4.2 mmol/L Triglycerides 4.39 mmol/L <1.70 mmol/L A more intensive workup was performed, including the levels of lupus anticoagulant, anticardiolipin, factor V Leiden, antithrombin, protein C, and protein S, which were all unremarkable. Electrocardiogram, transthoracic echocardiography, and carotid Doppler were all within normal limits. Then, the patient was referred to internal medicine and hematology consultants for further management. Two months later, visual acuity was reduced to light perception, and atrophic macular changes with the pale optic disc were noted, as well as full-thickness atrophy of the retina and reverse shadowing on OCT . Figure 3 Multimodal imaging of the left eye two months later. (A) A colored fundus photo shows an atrophic macular area with a pale optic disc. (B) An optical coherence tomography shows full-thickness retinal thinning and atrophy. Discussion Sickle cell disease is a group of inherited red blood cell diseases in which an amino acid substitution in hemoglobin protein leads to abnormal hemoglobin structure and function. In SCT, patients usually have one normal gene for normal hemoglobin, whereas the other gene codes for abnormal sickling hemoglobin; it is estimated that the prevalence rate of SCT in the United States is around 9% among African Americans . In the past, SCT was considered a benign condition because the patients did not get a vaso-occlusive crisis. Compared with the general population, SCT patients usually have the same mortality rate and the same quality of life . Many ophthalmologists also consider the trait status of the patients as a benign entity . However, recent studies have shown that SCT is probably linked to complicated hyphema, acute chest syndrome, and venous thromboembolic events . In addition, CRAO has been reported in many subtypes of sickle cell hemoglobinopathies such as SS and S-thal, but it is rare in SCT . This case reports spontaneous CRAO in an otherwise healthy young male and suggests that CRAO in these cases usually has more obscure and diverse etiological causes that require extensive workup. Concurrence of undiagnosed diabetes mellitus (DM) and SCT makes these presentations overlap, resulting in difficulty in establishing which causes the CRAO and which is a trigger factor. However, most likely undiagnosed type 2 DM may be the trigger but not the cause of CRAO, as uncontrolled DM can lead to oxidative stress and dehydration, leading to the environmental favor of sickling. Even more, there are reports in the literature of spontaneous sickling leading to CRAO in patients with SCT [14-16]. These patients need close follow-up and observation for any CRAO complication such as the risk of development of ocular neovascularization, as well as a proper referral to a medical doctor to manage all risk factors such as control of type 2 DM. This case gives us an example of an undiagnosed systemic disease that may be picked up and diagnosed by an ophthalmologist. Conclusions In young individuals, CRAO is frequently due to more complex etiological factors requiring extensive systemic workup. In addition, the association of the SCT with early DM may have contributed to the development of CRAO. Patients with spontaneous CRAO need to be closely monitored and watched for any CRAO complications. Referral to a medical doctor should also be made to handle all risk factors, especially DM. This case illustrates how an ophthalmologist might identify and diagnose a systemic condition that has gone undetected. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Ueber embolie der arteria centralis retinae als ursache plotzlicher erblindung Archiv fur Opthalmologie von Graefe A 136 157 5 1859 2 An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Sacco RL Kasner SE Broderick JP 2064 2089 44 2013 23652265 3 Nationwide incidence of clinically diagnosed central retinal artery occlusion in Korea, 2008 to 2011 Ophthalmology Park SJ Choi NK Seo KH Park KH Woo SJ 1933 1938 121 2014 24913283 4 Central retinal artery occlusion StatPearls [Internet] Farris W Waymack JR Treasure Island, FL StatPearls Publishing 2022 5 Cardiovascular risk factors in central retinal artery occlusion: results of a prospective and standardized medical examination Ophthalmology Callizo J Feltgen N Pantenburg S 1881 1888 122 2015 26231133 6 Management of central retinal artery occlusion: a scientific statement from the American Heart Association Stroke Mac Grory B Schrag M Biousse V 0 94 52 2021 7 Central retinal artery occlusion: visual outcome Am J Ophthalmol Hayreh SS Zimmerman MB 376 391 140 2005 16138997 8 Retinal arterial obstruction in children and young adults Ophthalmology Brown GC Magargal LE Shields JA Goldberg RE Walsh PN 18 25 88 1981 7243224 9 How benign is sickle cell trait? EBioMedicine Gibson JS Rees DC 21 22 11 2016 27580691 10 Sickle cell trait StatPearls [Internet] Ashorobi D Ramsey A Yarrarapu SNS Bhatt R Treasure Island, FL StatPearls Publishing 2022 11 Sickle retinopathy in patients with sickle trait Eye (Lond) Jackson H Bentley CR Hingorani M Atkinson P Aclimandos WA Thompson GM 589 593 9 (Pt 5) 1995 8543078 12 Complications associated with sickle cell trait: a brief narrative review Am J Med Tsaras G Owusu-Ansah A Boateng FO Amoateng-Adjepong Y 507 512 122 2009 19393983 13 Correction-spontaneous central retinal artery occlusion in hemoglobin SC disease Am J Ophthalmol Fine LC Petrovic V V Irvine AR Bhisitkul RB 906 907 130 2000 11124334 14 Spontaneous central retinal artery occlusion in a teenager with sickle cell trait Middle East Afr J Ophthalmol Pai SA Hebri SP Dekhain MA 119 121 22 2015 25624687 15 The effect of oxidative stress on human red cells glutathione peroxidase, glutathione reductase level, and prevalence of anemia among diabetics N Am J Med Sci Waggiallah H Alzohairy M 344 347 3 2011 22540111 16 Oxidative stress in sickle cell disease; pathophysiology and potential implications for disease management Am J Hematol Nur E Biemond BJ Otten HM Brandjes DP Schnog JJ 484 489 86 2011 21544855 |
] OR burden*[Title/Abstract] OR "time allocation*"[Title/Abstract] OR "training need*"[Title/Abstract] OR "training requirement*"[Title/Abstract]) AND ("community health workers"[MeSH Terms] OR CHW[tiab] OR CHWs[tiab] OR "Community health worker*"[Title/Abstract] OR "community health volunteer*"[Title/Abstract] OR "health volunteer*"[Title/Abstract] OR "health promoter*"[Title/Abstract] OR "village health worker*"[Title/Abstract] OR "primary health worker*"[Title/Abstract] OR "rural health worker*"[Title/Abstract] OR "community health officer*"[Title/Abstract] OR "women development army"[Title/Abstract] OR "development army"[Title/Abstract] OR "women development armies"[Title/Abstract] OR "development armies"[Title/Abstract] OR "health extension worker*"[Title/Abstract] OR "voluntary health worker*"[Title/Abstract] OR "volunteer health worker*"[Title/Abstract] OR "lay health worker*" [Title/Abstract] OR "community health assistant*"[Title/Abstract] OR "community health aide"[Title/Abstract] OR "community health aides"[Title/Abstract] OR "community volunteer*"[Title/Abstract] OR "village health volunteer*" [Title/Abstract]) OR accredited social health activist*[tiab] OR ASHA worker*[tiab] OR auxiliary health worker*[tiab] OR health auxiliar*[tiab] OR barefoot doctor*[tiab] OR community health practitioner*[tiab] OR medical auxiliar*[tiab]. Embase: 'workload'/exp OR 'workload':ti,ab,kw OR 'work load':ti,ab,kw OR burden*:ti,ab,kw OR 'time allocation*':ti,ab,kw OR 'training need*':ti,ab,kw OR 'training requirement*':ti,ab,kw AND 'health auxiliary'/exp OR 'community health volunteer*':ti,ab,kw OR 'health volunteer*':ti,ab,kw OR 'health promoter*':ti,ab,kw OR 'village health worker*':ti,ab,kw OR 'primary health worker*':ti,ab,kw OR 'rural health worker*':ti,ab,kw OR 'community health officer*':ti,ab,kw OR 'women development army':ti,ab,kw OR 'development army':ti,ab,kw OR 'women development armies':ti,ab,kw OR 'development armies':ti,ab,kw OR 'health extension worker*':ti,ab,kw OR 'voluntary health worker*':ti,ab,kw OR 'volunteer health worker*':ti,ab,kw OR 'lay health worker*':ti,ab,kw OR 'community health assistant*':ti,ab,kw OR 'community health aide':ti,ab,kw OR 'community health aides':ti,ab,kw OR 'community volunteer*':ti,ab,kw OR 'village health volunteer*':ti,ab,kw OR 'accredited social health activist*':ti,ab,kw OR 'ASHA worker*':ti,ab,kw OR 'auxiliary health worker*':ti,ab,kw OR 'health auxiliar*':ti,ab,kw OR 'barefoot doctor*':ti,ab,kw OR 'community health practitioner*':ti,ab,kw OR 'medical auxiliar*':ti,ab,kw. Scopus: (workload* OR "work load*" OR burden* OR "time allocation*" OR "training need*" OR "training requirement*") AND ("Community health worker*" OR "community health volunteer*" OR CHW OR CHWs OR "health volunteer*" OR "health promoter*" OR "village health worker*" OR "primary health worker*" OR "rural health worker*" OR "community health officer*" OR "women development army" OR "development army" OR "women development armies" OR "development armies" OR "health extension worker*" OR "voluntary health worker*" OR "volunteer health worker*" OR "lay health worker*" OR "community health assistant*" OR "community health aide" OR "community health aides" OR "community volunteer*" OR "village health volunteer*" OR "accredited social health activist*" OR "ASHA worker*" OR "auxiliary health worker*" OR "health auxiliar*" OR "barefoot doctor*" OR "community health practitioner*" OR "medical auxiliar*"). We conducted initial search on Dec 21/2021 that resulted in 619 articles on PubMed. The search was updated on March 17, 2022 to include additional search terms on PubMed and including two additional databases (Scopus and Embase). Study selection and critical appraisal First, all study articles found using the search terms from the 3 electronic databases were imported to Endnote version 9 and duplicate articles were removed. Next, articles not in English language, study protocols, review articles, and overviews were removed. The titles and abstracts were then screened by two authors (TA and TA) independently based on the predefined eligibility criteria (Quantitative, Qualitative, and mixed-method study articles conducted in LMICs that explicitly reported on workload of CHWs). Finally, two authors (TA and TA) performed critical appraisal for the selected full articles using The Mixed Methods Appraisal Tool (MMAT) version 2018 . Overall score from the ratings of each criterion was not calculated as it is not recommended when applying the MMAT tool . Rather, the reviewers discussed on the assessments of each study based on each criterion. Consensus was reached on the disagreements of the ratings through discussion. Forty-three articles passed the quality assessment stage and were included into the final data extraction and analysis. The Study selection process is presented below using PRISMA flow diagram (Fig 1). 10.1371/journal.pone.0282717.g001 Fig 1 Flow diagram for database searches and study selection. Data extraction Excel data extraction form was developed that captured the following contents: first author, publication year, country where the study was conducted, main objective, study design/type, type of community health worker (paid or volunteer), sample size, general perceived workload and subcomponents of workload. Data was extracted by one reviewer. Any measure of workload was eligible for inclusion. Results on workload may be reported either as a general perceived workload or in terms of different subcomponents of workload. The reported workload was extracted as it is reported in each study and categories were made by the reviewers. Data synthesis and integration A convergent integrated approach was applied to synthesize quantitative and qualitative data concurrently . To allow integration of quantitative data with qualitative data, quantitative data was transformed into qualitative data("qualitized") by extracting quantitative data and converting it into textual descriptions. Qualitative data were coded and categorized into themes. The qualitative and "qualitized" data were then compared to create integrated themes. Results We identified 632 unique records; 44 met our inclusion criteria. Forty-three articles were of good methodological quality and included in to the final data extraction and analysis. One article did not pass the methodological quality assessment because it used similar data source with one of the included studies. Detailed characteristics of the reviewed studies is provided as a S1 File. In summary, 20 studies were qualitative, 13 mixed-methods, and 10 quantitative studies. Almost half of the studies (n = 22) addressed volunteer CHWs, and the remaining articles (n = 21) addressed paid CHWs. The integrated findings and sample qualitative and "qualitized" data are summarized in S1 Table. In almost all of the included studies (except one study), CHWs reported that they have a considerable amount of workload. The finding in this one article differs from the other included articles in that additional tasks (on nutritional interventions) was considered as positive rather than its effect on increasing burden on them. The perceived workload reported from the other 42 articles was comparable among paid and volunteer CHWs, and in all quantitative, qualitative, and mixed-methods studies. Further looking at the workload experiences reported in each study, four subcomponents (integrated findings) were identified: tasks; lack of transport; catchment area; and competing socio-cultural and economic demands. The integrated findings are explored below. Tasks The number of tasks assigned to CHWs was the most frequently mentioned aspect that contributed for CHW's perceived workload. In 77.6%(n = 33) of the included articles, CHWs reported that they feel overburdened by the number of tasks assigned to them. The workload related to tasks was assessed in the 33 articles differently. In the 29 articles [22-50], CHWs directly responded their views in terms of multiple tasks contributing for their workload where as in the 4 articles [51-54], CHWs reflected on their workload in terms of working for long hours (which could indirectly be linked to having multiple tasks). These findings were reported in a similar pattern in all quantitative, qualitative, and mixed-methods studies included in this review. Besides, there was no contracting finding among volunteers and paid CHWs in terms of this theme. Lack of transport In 11 (25.6%) of the reviewed articles, lack of transport was reported as one of the aspects that contributed for their high perceived workload [10, 24, 25, 29, 33, 49, 50, 54-57]. This theme emerged mostly from mixed-methods(n = 5) and qualitative studies (n = 5), and only one quantitative study contributed to this theme. Lack of transport was a common finding in both volunteer and paid CHWs. Both types of CHWs reported that they walk for long distances because of the remoteness of the households and that lack of transport increased their workload. Catchment area/number of households In 6(14%) of the reviewed articles, CHWs reported that they serve a high number of households under their catchment area which contributed to their increased workload [10, 56, 58-61]. High number of households was assessed differently by which serving more than 30 households and 240 households were considered equally as high. Competing economic and socio-cultural demands In 6 articles (14%), CHWs reported that the work compromised their socio-cultural and economic demands in their daily life . This was particularly reported by volunteer CHWs instead of paid CHWs. The volunteer CHWs in these 4 articles indicated that the more they spend time on the community work, the more they face challenges in their households in terms of missing family caring responsibility and losing money-generating activities to support their family. This theme arose from CHWs in both quantitative and qualitative studies. In one qualitative study, CHWs indicated that they are doing time-consuming voluntary work that deserved monthly salary, and they were initially poor and now getting poorer after they joined due to out - expenditure for work related activities . This finding was complemented by quantitative data whereby 37% of volunteer workers have high number of households under their catchment area and this resulted in time-aways from their important economic endeavors . Discussion In this mixed-methods systematic review, we observed that CHWs experienced a considerable amount of perceived workload. The perceived workload was comparable among paid and volunteer CHWs. Further looking at the subcomponents of workload, the major elements of workload were reflected in terms of multiple tasks, lack of transport, large catchment area, and competing socio-cultural and economic demands (mainly reported by volunteer CHWs). A common finding in our review was around multiple tasks being the major aspect of workload. Community health workers in 77.6% of the reviewed articles reported that they are required to perform a very broad-range of tasks ranging from multiple health programs to agricultural and political sectors. While there is no known fair/ideal number of tasks that would be manageable by CHWs, too many roles could have a negative impact on level of productivity . It was further noted in the reviewed articles that CHWs perform tasks that are not described in their job descriptions and sometimes perform tasks that they are not trained for or do not have the required knowledge and skill. Reports show that when CHWs are overwhelmed by a broad-range of tasks, they tend to select few that they prefer to do and ignore the others , which could in turn, affect the overall success of the CHW program. A recent review by WHO working group also emphasizes the importance of clearly defined tasks that align with the appropriate renumeration and support . On the other hand, how well the tasks are organized or integrated is crucial. Even though the number of tasks is high, integrating the timing and approach of implementation may decrease workload and increase productivity . Lack of transport was the other common subcomponent of workload which was reported by 25.6% of the reviewed articles. Most of the CHWs in these articles reported a feeling of exhaustion to perform their duties after walking for long hours to cover their target households. The design of community health programs in several countries has been mainly focused on the amount of time that would be required to finish a given task, and less attention has been given to the effect of time spent to access the target households on productivity. Although we found limited data on the link between transport availability and productivity, it appears that lack of attention to travel time and lack of transport to access the households is a key factor for the productivity of CHWs. Furthermore, a combined effect of lack of transport and number of households might have implications on productivity. We found that perceived workload among paid and volunteer CHWs was comparable; both groups of CHWs reported that they have high workload. However, looking at the subcomponents of workload, competing socio-cultural and economic demands was an important element to volunteer CHWs than paid CHWs. Unlike the paid CHWs, unpaid volunteer CHWs cited that they are also expected to do income generating activities to support their families. As such, expecting volunteer CHWs to work for many hours per week creates extra burden, which would eventually lead them to leave their responsibility . In some situations, volunteer CHWs have out of pocket expenditures for a work-related activity that led them to get poorer after joining the volunteer work . We included articles from three widely used electronic databases, and considered both paid and volunteer CHWs. However, the findings from this review should be interpreted with the following limitations. First, we did not include articles that were not published in English, articles that were not published in peer-reviewed journals, and articles that we do not have full access. Second, perceived workload was assessed in the reviewed articles differently. Some of the articles were focused on the task, while the others focus on the hours worked per week, or whether lack of transport was a challenge in their day-to-day activities. As such, one subcomponent of workload was not mentioned in the article does not necessarily mean it was not a problem in those interviewed participants. Number of households under CHWs catchment area was also categorized differently in that the number of households in one setting may be categorized as high whereas it is categorized as low in another setting. A comprehensive investigation of workload using high-quality measurement instruments would be required to solve this gap. In conclusion, this review highlighted that for many CHWs, their workload is overwhelming. In addition to the increasing number of tasks that the CHWs are expected to perform, lack of transport further intensified their workload. While acknowledging the benefit of decentralization and task shifting strategy to increase access to health services to remote areas, program managers need to make a careful consideration as to how the additional tasks can be well integrated into the existing responsibilities of CHWs. It is also critical that when workload of CHWs is investigated all the integral components of workload (number of tasks, catchment area/number of households, and availability of transport) need to be considered and not solely on the number of tasks per CHW. Supporting information S1 Table Summary of integrated findings related to workload. (DOCX) Click here for additional data file. S1 File Detailed characteristics of the reviewed articles. (DOCX) Click here for additional data file. S2 File Completed PRISMA 2020 checklist. (DOCX) Click here for additional data file. We would like to thank Claire Twose, Lead Informationist at Welch Medical Library, Johns Hopkins University for conducting additional literature searches in the electronic databases. |
is somewhat long, so I suggest compressing the introduction of the research background. Job/workflow/task scheduling for cloud computing has attracted so much attention. The shortcomings of the existing works, such as should be further analyzed. As stated in the Abstract and Introduction, this manuscript does introduce a hybrid approach. But what are its new features? I suggest highlighting this aspect. What is the allowable optimization delay when scheduling jobs in the public cloud? In some real-time application scenarios, the permissible delay is as low as milliseconds. But, the time overheads of cuckoo search and grey wolf techniques are considerable. It is necessary to investigate this respect. Reviewer #2: In this paper, an efficient job scheduling algorithm, the Efficient Hybrid Job Scheduling Optimization, is proposed for better resource allocation and job scheduling. Then, Make span, computation time, adaptation, iteration-based performance and success rate are used to compare previous studies. The experimental results show that the method is superior. This work, appears to be applicable, but the paper seems to have some problems. 1.Please simplify the abstract section by suggesting that the author focus more on the innovative points of the paper and their contributions. 2.Please update the serial number of the citation, e.g. in the first paragraph of the introduction, that is, "According to , cloud data centres will handle 94% of computing workload by 2021. ". 3.In the literature survey section, it is suggested that the author describe the relevant research results in recent years. I suggest the author to introduce some recent proposed meta-heuristics such as slime mould algorithm (SMA), Hunger Games Search (HGS), RUN Kutta optimizer (RUN), Colony Predation Algorithm (CPA) and Harris Hawk Optimization (HHO) to make the paper get more readers. 4.In the introduction section, the novelty of the work is missing. There is no sufficient justification as to why such a proposal is needed. It is recommended that the author elaborate on the shortcomings of the basic GWO and then elaborate on the main points about how your proposal will alleviate the existing problems of the GWO. 5.Please ask the author to standardize the abbreviations of the chart names. For example, it is suggested to change "Figure 1" to "Fig. 1". 6.Please ask the author to standardize the description of formula symbols in the manuscript. For example, formula letters should be uniformly italicized, etc. 7.The related work in section 2 is not clearly categorized. The related work section is too simplistic for this topic. To better highlight the related work, it is recommended that the author add a brief table of the main elements. 8.For the parameters a and b in Eq. (4), it is suggested that the author gives them in the text. Similarly, the parameters W1 and W2 in Eq. (20) are the same. 9.For Eq. (6), it is suggested that the author draws the levy distribution. 10.Please ask the author to recheck the sentence, that is, "The contender has the best chance of succeeding the wolf as the new leader. acts as an advisor or consultant for". 11.In between the concluding chapters, it is advisable to have a separate discussion section to analyze the experiments conducted in this paper in depth, what are the advantages and disadvantages compared to the existing methods? What are the specific shortcomings? To facilitate a better tour for the reader. 12.Limitations of this work should be added in the conclusion section. 13.References should include DOI numbers, please reorganize and adjust them by the author. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: No Reviewer #2: No ********** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". 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Attachment Submitted filename: Response to Reviewers.docx Click here for additional data file. 10.1371/journal.pone.0282600.r003 Decision Letter 1 Lin Shih-Wei Academic Editor (c) 2023 Shih-Wei Lin 2023 Shih-Wei Lin This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version1 21 Feb 2023 An Efficient Hybrid Job Scheduling Optimization (EHJSO) Approach to Enhance Resource Search using Cuckoo and Grey Wolf job optimization for cloud environment. PONE-D-22-30865R1 Dear Dr. Eppipanious, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you'll receive an e-mail detailing the required amendments. 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Reviewer #1: No Reviewer #2: No ********** 10.1371/journal.pone.0282600.r004 Acceptance letter Lin Shih-Wei Academic Editor (c) 2023 Shih-Wei Lin 2023 Shih-Wei Lin This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 3 Mar 2023 PONE-D-22-30865R1 An Efficient Hybrid Job Scheduling Optimization (EHJSO) Approach to Enhance Resource Search using Cuckoo and Grey Wolf job optimization for cloud environment. Dear Dr. Baburaj: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. 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: Some parts of the abstract are hard to follow and AVF both with and without thrombosis should be clearly defined when presenting results. Introduction: There should be a strong body of literature on AVF thrombosis and patency, relevant and as scientific base for the introduction. At present introduction lacks the scientific touch. Methods: Sample characteristics with the statement of ethical approval details etc. would define the work better? The methods could be better formulated to be easier to read and interpret. Also, some of the nice flow charts could be in supplement? Essentially at present methods is hard to follow and still does not include required details. Results: Over 500 VA and only little over 227 enrolled rationales? Figure 3 shows the explanation, but authors should either refer to figure 3 after stating 227 enrolled or explain briefly why half of the VA were excluded. It would be nice to have more detailed demographic data presented. Tables should have subheading containing the appendixes written out and be more comprehensive. Figures should have detailed legend? Now these legends seem to be missing. The discussion should be more fluent. ********** 6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files. If you choose "no", your identity will remain anonymous but your review may still be made public. Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy. Reviewer #1: Yes: Aram Baram Reviewer #2: No Reviewer #3: No ********** [NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". 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Attachment Submitted filename: 27.1.2023.docx Click here for additional data file. 10.1371/journal.pone.0282891.r002 Author response to Decision Letter 0 Submission Version1 5 Feb 2023 Author's response to reviews Title: Characterization of hemodialysis fistulas experienced abrupt thrombosis and determination of a proper follow-up protocol: A retrospective cohort study and an interventionist's perspective Authors: Matt Chiung-Yu Chen ([email protected]) Mei-Jui Weng ([email protected]) Lee-Hua Chao ([email protected]) Version: 1, Date 5th Feb 2023 Author's response to reviews Manuscript number: PONE-S-23-01053. R1 Journal Requirements: 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming A: The manuscript has been thoroughly reviewed to ensure it meets PLOS ONE's style requirements. 2. In your revised cover letter, please address the following prompts: A: A paragraph addressing the data availability of this study has been added to the revised cover letter as follows: "The authors confirm that all data underlying the findings are fully available without restriction. All data have been deposited to Figshare (doi: 10.6084/m9.figshare.21996920)." 3. Please include your full ethics statement in the 'Methods' section of your manuscript file. In your statement, please include the full name of the IRB or ethics committee who approved or waived your study, as well as whether or not you obtained informed written or verbal consent. If consent was waived for your study, please include this information in your statement as well. A: A sub-section entitled "Patient population and study design" has been added to the Methods section as follows: "Between November 2020 and February 2021, patients referred to our institution for treatment of vascular access (VA) sites were enrolled in this study. All VA sites were treated and followed according to our routine protocols. After obtaining approval from our hospital's institutional review board committee (IRB number: 20220011B), the patients' electronic imaging and medical records were reviewed. Data for this study was collected prospectively and routinely recorded after each treatment was completed. To conduct this study, the collected data was retrieved and analyzed retrospectively." Reviewer #2: 1. The title is retrospective, but the method is prospective? A: The authors are sorry for the ambiguity. The data in this study was collected prospectively, which was routinely recorded after each treatment was completed. To conduct this study, the collected data was retrieved analyzed retrospectively. 2. AVF and AVG are different, from the pathology viewpoint, the acute thrombosis has some difference, this data should be separated. What is the diameter of the prosthetic graft? and what is the materials? + A: We are sorry for the ambiguity. The study, as stated in the Methods section and shown in Fig 3, only autogenous AVFs were included. All AVGs were excluded per the exclusion criteria of this study. 3. In the paper, the assisted primary patency rate for n-abtAVF(periodic) is 100% at the first year, and 98% at the 4th and 8th year, this is extremely higher than the commonly reported patent rate; and 8 years is a long time for CKD patient. A: Thanks for your pertinent comments. A paragraph addressing this issue had been added into the Discussion section as follows:" In this study, AVFs without a history of abrupt thrombosis and under periodic follow-up (n-abtAVF(periodic)) had a high thrombosis-free or assisted primary patency of 100% at 1 year and 98% at 4 and 8 years. Aragoncillo et al. also reported a high assisted primary patency of 91% at 1 year (estimated from the survival plot) for AVFs under flow surveillance. Tessitore et al reported a lower assisted primary patency of 85% at 1 year and 75% at 4 years (estimated from the survival plot) when subclinical stenoses in AVFs were detected using flow surveillance and treated preemptively. However, 30% of the AVFs in their treatment group were failing AVFs (Qa<=350 or recirculation>5%), which might explain their relatively low assisted primary patency." 4. Are these patients received anticoagulation therapy? Should be present the data and discuss. A: Thanks for your comments. The duration and types of anticoagulants vary for the patients in this study. The question is very difficult to answer. For example, if a patient takes anticoagulants only for a few days or weeks during a three-year follow-up period, yes, he received anticoagulation therapy but it is nearly impossible to assess the effect of such an anti-coagulation regimen on his AVF patency. Moreover, our aim is to discuss about AVF, and discussing the effect of anticoagulants on AVF patency would make the Discussion section out of focus. 5. How could the authors discriminate the technique failures induced thrombosis? A: Thanks for your comments. We didn't mention technique failures induced thrombosis in this manuscript but technical failure for salvage of a thrombotic AVF, especially the salvage -challenging AVFs. 6. What are the diameters of the artery and vein? A: Thanks for your comments. For a given AVF, the diameter varies from the anastomosis to the outflow veins. Could you specify your question? Reviewer #3: 1. The order of presented issues could be more logical, results and observations should be more accurately presented. A: Thanks for your comments. The Methods section has been extensively rewritten and the order of its sub-sections have been re-arranged. 2. Tables should have all appendixes explained and legends be more detailed and even figure legends were not on a file for the review. Tables should have subheading containing the appendixes written out and be more comprehensive. Figures should have detailed legend? Now these legends seem to be missing. A: Thanks for your pertinent comments. The appendixes of Table 2 have been written out. Detailed figure legends were added to Figs 4~7. 3. Also it would be interesting to have a demographic data correlated with the AVF requiring additional procedures and the ones that function just fine. A: The authors agree with you that it would be interesting to correlate demographic data with AVFs that require additional procedures and those that functioning well without intervention. However, we do not have approval from the Institutional Review Board (IRB) to review those well-functioning AVFs that do not require any intervention. 4. Abstract: Some parts of the abstract are hard to follow and AVF both with and without thrombosis should be clearly defined when presenting results. A: Due to the word count limit of 300-500 words for the Abstract section, we cannot provide too much detail. Definitions have been included in the Definitions subsection of the Methods section. 5. Introduction: There should be a strong body of literature on AVF thrombosis and patency, relevant and as scientific base for the introduction. At present introduction lacks the scientific touch. A: Thank you for your insightful comments. The Introduction section has been thoroughly rewritten and the necessary scientific background has been provided. Three new paragraphs have been added: the first one addressed the "dysfunctional hypothesis", the second discussed the presence of subclinical stenosis, and the third focused on the thrombosis-high-risk stenosis and its implications for AVF abrupt thrombosis. 6. Methods: Sample characteristics with the statement of ethical approval details etc. would define the work better? The methods could be better formulated to be easier to read and interpret. A: Thanks for your comments. We have revised the Methods section to make it easier to read and interpret. 7. Also, some of the nice flow charts could be in supplement? Essentially at present methods is hard to follow and still does not include required details. A: Thanks for your suggestion. The authors prefer to keep Figures 1-3 in their current locations rather than moving them to the Supporting Information section. This would be convenient for readers, as they may want to view the detailed sub-protocol flow charts after reading the sub-protocol definitions, and they can access these flow charts easily. 8. Results: Over 500 VA and only little over 227 enrolled rationales? Figure 3 shows the explanation, but authors should either refer to figure 3 after stating 227 enrolled or explain briefly why half of the VA were excluded. A: Thanks for your comments. The paragraph has been rewritten as follows: "A total of 505 VA sites in 505 patients were treated during the study period. Of them, 227 AVFs were enrolled. The study flow diagram is shown in Figure 3. Most of the excluded VA sites were AVGs, n=149 (29.5%)." 9. The discussion should be more fluent. A: Thanks for your comments. We have added a paragraph to the Discussion section addressing the high thrombosis-free primary patency of the n-abtAVF(periodic) group, which should make the section easier to follow. Additionally, a professional editor has edited the manuscript. Attachment Submitted filename: Point by point letter_PLOS ONE_r1.docx Click here for additional data file. 10.1371/journal.pone.0282891.r003 Decision Letter 1 Ranjan Redoy Academic Editor (c) 2023 Redoy Ranjan 2023 Redoy Ranjan This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Submission Version1 27 Feb 2023 Characterization of Hemodialysis Fistulas Experienced Abrupt Thrombosis and Determination of a Proper Follow-up Protocol: A Retrospective Cohort Study and an Interventionist's Perspective PONE-D-23-00790R1 Dear Dr. Chen, We're pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements. Within one week, you'll receive an e-mail detailing the required amendments. When these have been addressed, you'll receive a formal acceptance letter and your manuscript will be scheduled for publication. An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at [email protected]. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they'll be preparing press materials, please inform our press team as soon as possible no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact [email protected]. Kind regards, Redoy Ranjan, MBBS, MRCSEd, Ch.M., MS (CV&TS), FACS Academic Editor PLOS ONE Additional Editor Comments (optional): Review Comments to the Author Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: (No Response) Reviewer #2: The authors have addressed all of the reviewer's concerns. the quality of the paper is now improved, Reviewer #3: All given comments have been addressed. The present manuscript has been improved significantly after revision 10.1371/journal.pone.0282891.r004 Acceptance letter Ranjan Redoy Academic Editor (c) 2023 Redoy Ranjan 2023 Redoy Ranjan This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. 2 Mar 2023 PONE-D-23-00790R1 Characterization of hemodialysis fistulas experienced abrupt thrombosis and determination of a proper follow-up protocol: A retrospective cohort study and an interventionist's perspective Dear Dr. Chen: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact [email protected]. If we can help with anything else, please email us at [email protected]. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Redoy Ranjan Academic Editor PLOS ONE |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34870 Internal Medicine Neurology Infectious Disease Severe Neurocysticercosis in an Immunocompetent Male Without Travel to an Endemic Region: A Case Report Muacevic Alexander Adler John R Sakhuja Anuradha 1 KC Sharada 1 Wortsman Joshua 1 Shrestha Dhan B 1 Aryal Barun B 1 Kwatra Vishal 1 Verda Larissa 1 1 Department of Internal Medicine, Mount Sinai Hospital, Chicago, USA Barun B. Aryal [email protected] 11 2 2023 2 2023 15 2 e348705 9 2022 26 1 2023 Copyright 2023, Sakhuja et al. 2023 Sakhuja et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Neurocysticercosis is a neglected parasitic cause of seizures in the United States. It can have a wide array of presentations depending on the location and number of cysticercoids. The severity of symptoms varies with the location of the lesion in the brain and to the extent of the number of neurocysticercoids and host immune response. In the severe form of neurocysticercosis, it can present as an acute encephalitic picture. We present a case of severe neurocysticercosis in a patient without any significant travel history. Neurocysticercosis in nonendemic areas can be diagnostically challenging, given the lack of travel history as in our patient. Neurocysticercosis should be kept as a differential in all cases of seizures without prior history of seizure episodes. cerebral cysticercosis encephalitic neurocysticercosis teniasis seizure neurocysticercosis The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Seizures have a variety of causes, including metabolic, neurologic, infectious, and drug-induced, and hence provide a diagnostic dilemma in evaluation during the first episode . The infectious agents can be bacterial, viral, or parasitic, leading to seizures. Among the infectious causes of seizure, neurocysticercosis is one of the most common parasitic infections of the central nervous system in the endemic region. In areas where pig farming is practiced, especially in low-income nations,neurocysticercosis is endemic . Although not endemic in the United States, neurocysticercosis accounts for 2.1% of all emergency department visits for seizures . In the United States, it is particularly seen in immigrants and those with a travel history . Neurocysticercosis has been identified as a neglected parasitic infection in the United States . Here, we present a case report of encephalitic neurocysticercosis in a person native to Chicago without any travel history to the neurocysticercosis endemic region. Case presentation A 40-year-old Hispanic male with no reported past medical history was brought in by ambulance after two episodes of witnessed seizures, each lasting for approximately 10 seconds. On presentation to the emergency department, the patient was found to be hypoxic, with oxygen saturation of 60% on room air, which increased to 96% on 15 L of O2 via a nonrebreather mask. He was unresponsive to painful stimuli with agonal respirations and tachycardia. Cough and gag reflexes were absent. He had bleeding from the oral cavity with injury to his tongue.He did not have any prior episodes of seizures and was not under any medications. The patient had lived all his life in Chicago and had no history of travel to regions endemic to neurocysticercosis. The patient was intubated for airway protection and started on midazolam seizure dosing and fentanyl for sedation.His COVID-19 rapid test was positive. His labs showed leukocytosis and an acidotic state consistent with seizures. His urine drug screen was positive for cocaine metabolites. On admission, a computed tomography (CT) of the head demonstrated multiple areas of vasogenic edema throughout the supratentorial brain bilaterally, greater in the left anterior frontal lobe with multiple lesions.He was given a loading dose of levetiracetam and started on a maintenance dose thereafter. Given the CT head findings, a pan CT scan was obtained that did not show any significant abnormal findings. MRI brain showed innumerable ring-enhancing lesions throughout the supratentorial and infratentorial brain and in the midbrain and pons with the mass effect, particularly in the posterior fossa near the fourth ventricle and quadrigeminal plate cistern .Multidisciplinary teams, including Infectious disease, neurology, neurosurgery, and oncology services, were consulted. The patient was started on high-intensity steroids and levetiracetam. Serological labs, including Treponema pallidum, Blastomyces, Cryptococcus, cytomegalovirus (CMV), hepatitis panel, Toxoplasma, and tuberculosis, were sent, all of which came back negative. Then a lumbar puncture was performed, which did not show any notable findings. An echocardiogram was negative for any cardiac/valvular pathology. Figure 1 MRI brain on presentation with axial sections (flair) (both A and B) showing multiple ring-enhancing lesions (white arrows). MRI, magnetic resonance imaging Given thenegative workup and high clinical imaging suspicion of neurocysticercosis, the decision was made to start empiric treatment with albendazole and praziquantel along with high-intensity steroids. When all serology came back negative for any significant findings, a decision was made to perform a brain biopsy. MRI brain was repeated before the brain biopsy, which showed innumerable small ring-enhancing lesions seen throughout the cerebral and cerebellar hemispheres, as well as the brainstem and cervical-medullary junction . Lesions increased in number from the previous imaging. He underwent a brain biopsy where larvaewere seen and a cyst with larvae was removed intraoperatively. Ophthalmology evaluation was negative for intraophthlamic infection. Figure 2 MRI brain before biopsy (T1-weighted) showing multiple ring-enhancing lesions (white arrows) on the (A) sagittal section and (B) coronal section. MRI, magnetic resonance imaging The patient underwent a tracheostomy during the hospital course due to ventilator-dependent respiratory failure. The hospital course was complicated by persistent thrombocytopenia not responding to a large amount of platelet transfusion. Eventually, he had improvement in mentation and was weaned off the ventilator. He continued to improve clinically, and after a month of hospital stay, he was discharged to a subacute rehab center. Levetiracetam was continued at discharge. He was subsequently discharged from the acute rehabilitation facility to the care of his family with the continuation of physical therapy. Subsequent brain imaging shows gradual resolution of lesions. During a follow-up visit one year after the initialpresentation, he showed neurological improvementbut reported persistent numbness of bilateral upper and lower extremities and right-hand tremors. Discussion Cysticercosis is caused due to tissue infection from Taenia solium. Neurocysticercosis is an infection of the central nervous system by the larval stage of the parasite . The manifestations of neurocysticercosis depend on the location of implantation of cysticercoids, which can be intraparenchymal or extra parenchymal . Intraparenchymal neurocysticercosis typically presents with seizure, whereas extra-parenchymal neurocysticercosis presents with hydrocephalus and raised intracranial pressure . Our patient had multiple intraparenchymal cysticercoids, leading to diffused cerebral edema, and presented with multiple seizures and a severe presentation. Neurocysticercosis can present with a wide variety of neurological presentations mimicking a wide range of diseases, especially in endemic regions . In a retrospective study of an academic hospital in the United States, headachesand seizures were found to be the most common presenting complaint of neurocysticercosis . The diagnosis of neurocysticercosis depends on the travel history or origin of the patient, endemicity of neurocysticercosis in the region, imaging findings, and serological tests . Imaging studies can detect the viable phase, degenerative phase, and dead or calcified phase of parenchymal neurocysticercosis as well as the cysts of extra-parenchymal neurocysticercosis . CT can better delineate the dead or calcified forms of intraparenchymal neurocysticercosis than MRI. However, for all other extra-parenchymal forms, MRI is superior to CT for the diagnosis of neurocysticercosis . In our patient, CT could not identify the lesions, whereas MRI did show ring-enhancing lesions in multiple locations, which were not diagnosed with neurocysticercosis by the imaging. Furthermore, there was severe cerebral edema mimicking the acute encephalitic picture. The encephalitic form of neurocysticercosis occurs when the body reacts to a high load of T. solium . Cysticercotic encephalitis is more common in children and females . However, our patient is an adult male with the clinical picture. Serological tests available for diagnosis of neurocysticercosis include enzyme-linked immunoelectrotransfer blot (EITB) and enzyme-linked immunosorbent assay (ELISA). EITB has better sensitivity than ELISA and is preferred for diagnosis . However, EITB is not available readily. Because of a lack of travel history and being unable to diagnose from the imaging findings, our patient went for a brain biopsy where larvae were noted intraoperatively. Albendazole along with praziquantel is recommended for the management of more than two viable cysts. Furthermore, corticosteroids should be given for the resolution of associated inflammation and cerebral edema . Our patient improved both clinically and radiologically under the treatment and was successfully weaned off the ventilator. He underwent physical therapy with some improvement in neurological function. Subsequent imaging showed gradual resolution of the lesions.However, he continued to have significant neurological deficits. One year after the initialpresentation, he was undergoing outpatient physical and occupational therapy. Conclusions We presented a case of neurocysticercosis in a patient in the United States without any travel history. Neurocysticercosis should be kept as a differential diagnosis of all seizure cases even in the nonendemic regions without relevant travel history. Multiple neurocysticercosis infestations can present with an acute encephalitic picture, complicating the diagnosis. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Initial management of seizure in adults New Engl J Med Smith PEM 251 263 385 2021 34260837 2 From seizures to epilepsy and its substrates: neurocysticercosis Epilepsia Singh G Burneo JG Sander JW 783 792 54 2013 23621876 3 Neglected Parasitic Infections: What Family Physicians 3 2022 2021 4 Neurocysticercosis at a large academic center in the USA Open Forum Infect Dis Ramanathan M Cordova L Bertran-Lopez J Lichtenberger P Lichtenberger P 455 456 8 2021 5 Clinical symptoms, diagnosis, and treatment of neurocysticercosis Lancet Neurol Garcia HH Nash TE Del Brutto OH 1202 1215 13 2014 25453460 6 A prognostic classification of cerebral cysticercosis: therapeutic implications J Neurol Neurosurg Psychiatry Estaol B Corona T Abad P 1131 1134 49 1986 3783174 7 Neurocysticercosis: updated concepts about an old disease Lancet Neurol Garcia HH del Brutto OH 653 661 4 2005 16168934 8 New diagnostic criteria for neurocysticercosis: Reliability and validity Ann Neurol Carpio A Fleury A Romo ML 434 442 80 2016 27438337 9 Diagnosis and Treatment of Neurocysticercosis: 2017 Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH) Am J Trop Med Hyg White AC Jr Coyle CM Rajshekhar V 945 966 98 2018 29644966 10 Neurocysticercosis: an update Lancet Infect Dis Carpio A 751 762 2 2002 12467692 11 Imaging spectrum of neurocysticercosis Radiology of Infectious Diseases Zhao J-L Lerner A Shu Z Gao X-J Zee C-S 94 102 1 2015 12 Massive neurocysticercosis: encephalitic versus non-encephalitic Am J Trop Med Hyg Del Brutto OH Campos X 381 87 2012 22956716 13 Cysticercotic encephalitis: a severe form in young females Am J Trop Med Hyg Rangel R Torres B Del Bruto O Sotelo J 387 392 36 1987 3826497 14 Evaluation of the performance of 5 commercialized enzyme immunoassays for the detection of Taenia solium antibodies and for the diagnosis of neurocysticercosis Diagn Microbiol Infect Dis Carod JF Randrianarison M Razafimahefa J 85 89 72 2012 22085773 |
J Exp Bot J Exp Bot exbotj Journal of Experimental Botany 0022-0957 1460-2431 Oxford University Press UK 36913621 10.1093/jxb/erac513 erac513 eXtra Botany Insight AcademicSubjects/SCI01210 Phosphoglucomutase comes into the spotlight Doello Sofia Interfaculty Institute of Microbiology and Infection Medicine, University of Tubingen, Germany Forchhammer Karl Interfaculty Institute of Microbiology and Infection Medicine, University of Tubingen, Germany Corresponding author: [email protected] 13 3 2023 13 3 2023 13 3 2023 74 5 12931296 22 12 2022 23 12 2022 13 3 2023 (c) The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Experimental Biology. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. This article comments on: Ortega-Martinez P, Roldan M, Diaz-Troya S, Florencio FJ. 2023. Stress response requires an efficient glycogen and central carbon metabolism connection by phosphoglucomutases in cyanobacteria. Journal of Experimental Botany 74, 1532-1550 Cyanobacteria glycogen phosphoglucomutase starch Synechocystis pmc Phosphoglucomutase (PGM) has recently gained attention as a key regulatory point in the metabolism of carbon storage compounds. In this issue, Ortega-Martinez et al. (2023) advance our understanding of the contribution of the different PGM isoforms to the carbon flux between glycogen and the central carbon metabolism in the cyanobacterium Synechocystis. Glycogen is a rapidly metabolizable storage form of glucose that acts as an essential metabolic buffer in many organisms. It consists of b-1,4-linked d-glycosyl units that are interconnected through b-1,6 branching points, forming a large, hydrosoluble polymer. With its large accessible surface-to-volume ratio, it allows for rapid storage and mobilization of glucose units (Colpaert et al., 2020). Glycogen is widely distributed in prokaryotes and appears to be present in all cyanobacteria, which use it as energy storage for night-time survival (Grundel et al., 2012). Several cyanobacterial strains additionally contain forms of a semi-crystalline polyglucan, related to starch, the crystalline glucose storage polymer of plants (Ball et al., 2011). Phylogenetic reconstruction suggests that during plant evolution, primordial glycogen metabolism in the common ancestor of Archaeplastida was modified into starch metabolism through modifications of branching/debranching reactions (Ball et al., 2011; Chabi et al., 2021). Besides its role in survival during dark periods, glycogen metabolism has been proved to be essential in the model cyanobacterial strain Synechocystis sp. PCC 6803 for acclimation to macronutrient deficiency, in particular nitrogen (Grundel et al., 2012; Hickman et al., 2013), and long-term survival in a chlorotic state (Klotz et al., 2016). In addition to serving as a form of carbon storage, glycogen metabolism plays an important role in balancing energy homeostasis, allowing the control of the intracellular energy charge to prevent the over-reduction of electron carriers and collapse of the electron transport chain (Cano et al., 2018). Glycogen and starch metabolism require the initial synthesis of glucose-1-phosphate (G1P) from glucose-6-phosphate (G6P), a reaction catalysed by the bi-directional enzyme phosphoglucomutase (PGM). This reaction represents a pivotal point connecting central carbon metabolism with glycogen synthesis/degradation (Stiers et al., 2017). Despite this central position in the metabolic network, cyanobacterial PGMs had received little attention until recently, perhaps because the synthesis of ADP-glucose from G1P by ADP-glucose pyrophosphorylase (AGP) was considered the rate-limiting step in glycogen formation (Ballicora et al., 2003) (see Box 1). Box 1. Schematic representation of the glycogen biosynthetic and catabolic pathway Phosphoglucomutases catalyse the interconversion of glucose-1-phosphate (G1P) and glucose-6-phosphate (G6P), a reaction that connects synthesis and degradation of glycogen to the central carbon metabolism. During glycogen synthesis, G1P is obtained from G6P via the phosphoglucomutase reaction and converted to ADP-glucose (ADP-Glc) by the ADP-glucose pyrophosphorylase (AGP) for subsequent polymerization by the glycogen synthase (GlgA) and branching enzymes (GlgB). Glycogen degradation is mediated by the glycogen phosphorylase (GlgP) and debranching enzymes (GlgX) to yield G1P, which is then converted to G6P by the phosphoglucomutases. In Synechocystis, two enzymes are capable of carrying out the phosphoglucomutase reaction: Sll0726 (PGM), which is responsible for 99% of the phosphoglucomutase activity, and Slr1334 (PGM/PMM). Although Slr1334 only has a minor contribution in the interconversion of G1P and G6P, it is able to catalyse an additional reaction of great importance: the synthesis of glucose-1,6-bisphosphate (G1,6BP) from G1P or G6P and fructose-1,6-bisphosphate (F1,6BP) (represented in blue). G1,6BP functions as an activator compound for Sll0726, thus regulating a fundamental reaction for carbon metabolism. For most of the enzymes involved in glycogen synthesis and degradation, Synechocystis harbours two genes encoding two different isoforms that are required under different physiological conditions (Yoo et al., 2014; Doello et al., 2018; Koch et al., 2019; Neumann et al., 2022b, Preprint). PGM is no exception to this: the genes corresponding to the Cyanobase ORFs sll0726 and slr1334 encode potential phosphoglucomutases. The sll0726 product (PGM) is highly homologous to other bacterial phosphoglucomutases and was suggested to represent a target of thioredoxin regulation (Lindahl and Florencio, 2003), while the enzyme encoded by slr1334 was predicted to encode a phosphogluco/phosphomannomutase bifunctional enzyme (PGM/PMM) (Liu et al., 2013). Until recently, only a single published study addressed the question of the differential function of the two potential phosphoglucomutases by a genetic approach (Liu et al., 2013). Whereas PGM (Sll0726), which was shown to provide most of the phosphoglucomutase activity, could be inactivated, segregation of PGM/PMM (Slr1334) knockout failed. This suggested an essential function of this gene, although PGM/PMM contributed only a very minor part of the total phosphoglucomutase activity in cell extracts. Further awareness of the importance of glycogen metabolism was raised by studies of the acclimation to nitrogen starvation in Synechocystis (Doello et al., 2018; Neumann et al., 2021), regulation of diurnal metabolism (Selim et al., 2021), or its connection to polyhydroxybutyrate (PHB) formation (Koch et al., 2019). Recent biochemical analyses gave further insights into the function and regulation of PGM (Doello et al., 2022; Neumann et al., 2022a, see below). The present work by Ortega-Martinez et al. (2023), in this issue of JXB, represents an important step towards a deeper understanding of cyanobacterial glycogen metabolism by revisiting the functional significance of phosphoglucomutase for the overall physiology of Synechocystis. The authors revealed that PGM is 10 times more abundant than PGM/PMM, and confirmed by mutant analysis that PGM contributes 99% of the total PGM activity. To find out how limitation of carbon flux to and from glycogen affects Synechocystis physiology under various environmental perturbations, the phenotype of PGM, PGM/PMM, and AGP mutants was systematically analysed. Although the PGM mutant could still produce a residual amount of glycogen, it showed similar growth defects to an AGP-deficient strain, which is completely devoid of glycogen. The study confirmed the requirement of glycogen metabolism for efficient acclimation to periods of nitrogen starvation, and for night-time survival with long night phases (16 h). In contrast, no defect was observed when cells were grown with short night periods (8 h). Glycogen synthesis and PGM activity were also found to be required for acclimation to high light conditions as the AGP-deficient mutants lost viability upon prolonged exposure to a photosynthetic photon flux density of 200 mmol photons s-1 m-2. However, PGM and AGP mutants showed different responses towards high salt acclimation. Whereas the PGM-deficient strain could tolerate 0.5 M NaCl treatment, the AGP-deficient mutant was unable to do so, probably because of its inability to synthesize the compatible solute glucosylglycerol (GG), which needs ADP-glucose. Strikingly, almost wild-type levels of GG were detected in the PGM-deficient strain, despite the very low residual PGM activity ascribable to the presence of PGM/PMM. Overexpression of PGM/PMM in a PGM-deficient background using a strong promoter increased the total phosphoglucomutase activity to ~20% of wild-type levels. This was sufficient to phenotypically compensate for the lack of PGM, as all growth and acclimation defects of the PGM-deficient mutant could be complemented. This confirmed that PGM/PMM can in fact carry out phosphoglucomutase activity. Measuring the cellular levels of G1P and G6P yielded a remarkable result: although glycogen synthesis requires conversion of G6P to G1P and blocking this pathway should result in increased levels of G6P, the PGM mutant showed higher G1P levels under all tested conditions as compared with the wild type, whereas G6P only accumulated during nitrogen deprivation. Overexpression of PGM/PMM reverted the metabolite concentrations to the wild-type levels, confirming that the increased levels of G1P and G6P in the PGM mutant were caused by the low phosphoglucomutase activity of PGM/PMM. To clarify whether PGM/PMM is an essential protein in Synechocystis, Ortega-Martinez et al. expressed an additional copy of the slr1334 gene under a tuneable ParsB promoter, which allowed deletion of the respective wild-type locus. As long as the ParsB promoter was turned on by the addition of arsenite, cells could grow. However, in the absence of the inducer, the cells stopped growing, clearly demonstrating that slr1334 is an essential gene in Synechocystis. Altogether, this study opens up intriguing new questions regarding the role of glycogen metabolism in stress acclimation. This work coincides with and perfectly complements two recent studies on the function of PGM in Synechocystis. Doello et al. (2022) revealed a novel regulatory mechanism to control PGM activity. During nitrogen starvation, the enzyme is phosphorylated on a conserved regulatory seryl residue near the catalytic site, which inhibits its activity. This preserves the glycogen stores by preventing carbon flux from glycogen into central metabolism during prolonged periods of nitrogen starvation. Upon resuscitation, when combined nitrogen is available again, the enzyme is dephosphorylated, restoring its activity and allowing efficient glycogen mobilization upon demand. Intriguingly, a conserved phosphorylation event has been reported for the mammalian PGM homologue, suggesting that these regulatory mechanisms may be widely distributed. A second study revealed the molecular function of the product of slr1334, which was annotated as PGM/PMM. Neumann et al. (2022a) revealed that Slr1334 catalyses the synthesis of the activator molecule for phosphoglucomutase, glucose-1,6-bisphosphate (G1,6BP), using G1P or G6P and fructose-1,6-bisphosphate (F1,6BP) as substrates (see Box 1). How this activator compound is synthesized in bacteria was so far unknown. Slr1334 belongs to a distinct family of phosphohexomutases, which is present in many cyanobacteria, deep branching bacteria, and archaea, and it appears that members of this family represent prokaryotic G1,6BP synthases. This function may provide a straight-forward explanation for the puzzling physiological role of Slr1334. Mutants that are deficient in glycogen metabolism are perfectly viable under non-stressing growth conditions, whereas depletion of Slr1334 abrogates cell growth, as shown by Ortega-Martinez et al. (2023). This strongly indicates a role for Slr1334 beyond glycogen metabolism. The activator molecule G1,6BP might be necessary for the activation of vital functions, as it has been reported that G1,6BP can activate other enzymes, such as the essential phosphoglucosamine mutase in Escherichia coli (Jolly et al., 1999). These recent studies place the phosphoglucomutase reaction into the spotlight for a better understanding of cyanobacterial glycogen metabolism. To emerge is the picture of a highly sophisticated network of metabolic regulation in which a key role is played by the phosphorylated and bisphopshorylated sugar molecules. Our knowledge on how glycogen turnover provides robustness to the maintenance of cellular homeostasis is fundamental to metabolic engineering of cyanobacteria with the aim of using them as green cell factories. References Ball S , ColleoniC, CenciU, RajJN, TirtiauxC. 2011. The evolution of glycogen and starch metabolism in eukaryotes gives molecular clues to understand the establishment of plastid endosymbiosis. Journal of Experimental Botany 62 , 1775-1801.21220783 Ballicora MA , IglesiasAA, PreissJ. 2003. ADP-glucose pyrophosphorylase, a regulatory enzyme for bacterial glycogen synthesis. Microbiology and Molecular Biology Reviews 67 , 213-225.12794190 Cano M , HollandSC, Artie, J, BurnapRL, GhirardiM, MorganJA, YuJ. 2018. Glycogen synthesis and metabolite overflow contribute to energy balancing in cyanobacteria. Cell Reports 23 , 667-672.29669272 Chabi M , LeleuM, FermontL, ColpaertM, ColleoniC, BallSG, CenciU. 2021. Retracing storage polysaccharide evolution in Stramenopila. Frontiers in Plant Science 12 , 629045.33747010 Colpaert M , ChabiM, CenciU, ColleoniC. 2020. Storage polysaccharides in prokaryotes: glycogen, granulose, and starch-like granules. In: JendrossekD, ed. Bacterial organelles and organelle-linked inclusions. Cham: Springer, 177-204. Doello S , KlotzA, MakowkaA, GutekunsK, ForchhammerK. 2018. A specific glycogen mobilization strategy enables rapid awakening of dormant cyanobacteria from chlorosis. Plant Physiology 177 , 594-603.29703865 Doello S , NeumannN, ForchhammerK. 2022. Regulatory phosphorylation event of phosphoglucomutase 1 tunes its activity to regulate glycogen metabolism. FEBS Journal 289 , 6005-6020.35509259 Grundel M , ScheunemannR, LockauW, ZilligesY. 2012. Impaired glycogen synthesis causes metabolic overflow reactions and affects stress responses in the cyanobacterium Synechocystis sp. PCC 6803. Microbiology 158 , 3032-3043.23038809 Hickman JW , KotovicKM, MillerC, WarrenerP, KaiserB, JuristaT, BuddeM, CrossF, RobertsJM, CarletonM. 2013. Glycogen synthesis is a required component of the nitrogen stress response in Synechococcus elongatus PCC 7942. Algal Research 2 , 98-106. Jolly L , FerrariP, BlanotD, van HeijenoortJ, FassyF, Mengin-LecreulxD. 1999. Reaction mechanism of phosphoglucosamine mutase from Escherichia coli. Journal of Bacteriology 262 , 202-210. Klotz A , GeorgJ, BucinskaL, WatanabeS, ReimannV, JanuszewskiW, SobotkaR, JendrossekD, HessWR, ForchhammerK. 2016. Awakening of a dormant cyanobacterium from nitrogen chlorosis reveals a genetically determined program. Current Biology 26 , 2862-2872.27720620 Koch M , DoelloS, GutekunstK, ForchhammerK. 2019. PHB is produced from glycogen turn-over during nitrogen starvation in Synechocystis sp. PCC 6803. International Journal of Molecular Sciences 20 , 1942.31010017 Lindahl M , FlorencioFJ. 2003. Thioredoxin-linked processes in cyanobacteria are as numerous as in chloroplasts, but targets are different. Proceedings of the National Academy of Sciences USA 100 , 16107-16112. Liu L , HuHH, GaoH, XuXD. 2013. Role of two phosphohexomutase genes in glycogen synthesis in Synechocystis sp. PCC6803. Chinese Science Bulletin 58 , 4616-4621. Neumann N , DoelloS, ForchhammerK. 2021. Recovery of unicellular cyanobacteria from nitrogen chlorosis: a model for resuscitation of dormant bacteria. Microbial Physiology 31 , 78-87.33878759 Neumann N , FrizS, ForchhammerK. 2022a. Glucose-1,6-bisphosphate, a key metabolic regulator, is synthesized by a distinct family of a-phosphohexomutases widely distributed in prokaryotes. mBio 13 , e0146922.35856562 Neumann N , LeeK, ForchhammerK. 2022b. On the role and regulation of glycogen catabolic isoenzymes in Synechocystis sp. PCC6803. BioRxiv. doi:10.1101/2022.11.21.517384 [Preprint]. Ortega-Martinez P , RoldanM, Diaz-TroyaS, FlorencioFJ. 2023. Stress response requires an efficient glycogen and central carbon metabolism connection by phosphoglucomutases in cyanobacteria. Journal of Experimental Botany 74 , 1532-1550.36454663 Selim KA , HaffnerM, BurkhardtM, et al . 2021. Diurnal metabolic control in cyanobacteria requires perception of second messenger signaling molecule c-di-AMP by the carbon control protein SbtB. Science Advances 7 , eabk0568.34878830 Stiers KM , MuenksAG, BeamerLJ. 2017. Biology, mechanism, and structure of enzymes in the a-d-phosphohexomutase superfamily. Advances in Protein Chemistry and Structural Biology 109 , 265-304.28683921 Yoo SH , LeeBH, MoonY, SpaldingMH, JaneJL. 2014. Glycogen synthase isoforms in Synechocystis sp. 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Summary We present promor, a comprehensive, user-friendly R package that streamlines label-free quantification proteomics data analysis and building machine learning-based predictive models with top protein candidates. Availability and implementation promor is freely available as an open source R package on the Comprehensive R Archive Network (CRAN) ) and distributed under the Lesser General Public License (version 2.1 or later). Development version of promor is maintained on GitHub ) and additional documentation and tutorials are provided on the package website ). Supplementary information Supplementary data are available at Bioinformatics Advances online. Hampton Roads Biomedical Research Consortium pmc1 Introduction Label-free quantification (LFQ) approaches are commonly used in mass spectrometry-based proteomics. One of the most widely used software tools for protein identification and quantification is MaxQuant (Tyanova et al., 2016a). The downstream analysis of MaxQuant output files can be complex and often challenging to those inexperienced in proteomics data analysis. Some tools available for this purpose are implemented as graphical user interface (GUI) applications [e.g. LFQ-Analyst (Shah et al., 2019), ProVision (Gallant et al., 2020), ProteoSign (Efstathiou et al., 2017)], among which, one of the most popular is the MaxQuant-associated tool, Perseus (Tyanova et al., 2016b). Perseus is an extensive software suite that offers a range of features to analyze several different types of proteomics data. While Perseus is fairly easy to use, the user interface with its wide range of options can be overwhelming at times to new users. Furthermore, the inability to save previously used analytical settings in GUI applications such as Perseus may present challenges to researchers looking to standardize data analysis. Other tools, such as MSstats (Choi et al., 2014), protti (Quast et al., 2022), pmartR (Stratton et al., 2019) and DEP (Zhang et al., 2018) are primarily implemented as R packages and provide greater analytical flexibility and reproducibility to proteomics data analysis workflows. While these available software all offer analytical capability to perform the steps in typical proteomics data analysis workflows, users may need additional software to perform tasks specific to their research domain (e.g. clinical applications, biomarker discovery). In recent years, machine learning (ML) has made its presence felt in the field of proteomics. Particularly in biomarker research, ML is becoming a popular tool to derive candidate biomarker panels from proteomics data (Bader et al., 2020; Virreira Winter et al., 2021). ML algorithms are now being widely employed to build proteomics-based predictive models of disease prognosis and diagnosis (Desaire et al., 2022; Mann et al., 2021). When building a proteomics-based predictive model, choosing a robust panel of protein candidates can greatly improve the accuracy of the model. In this regard, ML-based predictive models could benefit from narrowing down protein features to those that show significant differences in abundance between groups of interest. In the current landscape of proteomics data analytical tools, the capability to seamlessly transition from differential expression analysis to predictive modeling is limited. Realizing this need, we developed promor, a comprehensive, user-friendly, R package that streamlines differential expression analysis and predictive modeling of label-free proteomics data. promor provides an all-in-one reproducible workflow that integrates tools to perform quality control, visualization and differential expression analysis of label-free proteomics data. Furthermore, promor integrates tools to build ML-based predictive models using top protein candidates identified through differential expression analysis, assess model performance, determine feature importance and estimate the predictive power of the models. 2 Overview 2.1 Implementation promor is implemented in R (>=3.5.0) and relies on packages such as imputeLCMD (Lazar et al., 2016), limma (Ritchie et al., 2015) and caret (Kuhn, 2008) for back-end pre-processing, differential expression analysis and ML-based modeling, respectively. As input, promor requires a user-generated tab-delimited text file containing the experimental design and a MaxQuant-produced 'proteinGroups.txt' file or a standard quantitative table of protein intensities, which could be produced by any proteomic data analysis software. For visualization, promor employs the popular ggplot2 (Wickham et al., 2016) architecture and produces ggplot objects, which allows for further customization (Fig. 1). Fig. 1. An overview of suggested promor workflows. (A) Proteomics data analysis workflow includes analytical functions for pre-processing, quality control, missing data imputation, data normalization and differential expression analysis. (B) Modeling workflow includes analytical functions for pre-processing the output of differential expression analysis, model building and model evaluation. (C) Several plotting functions are provided to visualize data and produce publication-ready figures using color blind-friendly palettes 2.2 Proteomics data analysis promor can be used to analyze any bottom-up label-free proteomics data (e.g. raw, LFQ or iBAQ). Multiple functions are provided for quality control, visualization, missing data imputation, normalization and differential expression analysis (Table 1 and Fig. 1A). Table 1. Analytical and visualization functions in promora Function name Input Tasks Output create_df A proteinGroups.txt file from MaxQuant/a standard input file containing a quantitative matrix of protein intensity data. A tab-delimited text file containing the experimental design. Creates a data frame of LFQ protein intensities. Removes contaminant proteins, proteins identified only by site, reverse sequence proteins and proteins identified by two or fewer unique peptides. Converts zeros to missing values. Log2 transforms the values. raw_df aver_techreps raw_df If technical replicates are present in the data, computes average intensity across technical replicates for each sample. raw_df filterbygroup_na raw_df Filters out proteins with >34% missing values (<66% valid values) in at least one of the groups. raw_df impute_na raw_df/norm_df Imputes missing values using the 'minProb' method. imp_df normalize_data raw_df/imp_df Normalizes the data using the 'quantile' method. norm_df find_dep norm_df/imp_df Identifies differentially expressed proteins with an absolute log2 fold change >1 at an adjusted P-value <0.05. fit_df pre_process norm_df/imp_df fit_df Extracts protein intensity data for the top 20 differentially expressed proteins, removes proteins that show high pairwise correlation (>0.90) and converts the data into a format suitable for modeling. model_df split_data model_df Splits data into training (70%) and test (30%) data sets while preserving the overall class distribution of the data. split_df train_models split_df Trains ML models on the training data set using the default list of ML algorithms ('svmRadial', 'glm', 'rf', 'xgbLinear', 'naive_bayes'), performs 10-fold cross validation three times, calculates re-sampling-based performance measures for the models and outputs the best model for each algorithm. model_list test_models split_df model_list Uses the models built using the training data to predict the test data. probability_list corr_plot raw_df Generates scatter plots showing the correlation between pairs of technical replicates. ggplot heatmap_na raw_df Generates a heatmap to show the missing data distribution in the matrix. ggplot impute_plot raw_df/norm_df imp_df Generates a global density plot showing the data distribution before and after missing data imputation. ggplot norm_plot raw_df/imp_df norm_df Generates box plots showing the sample data distributions before and after data normalization. ggplot heatmap_de imp_df/norm_df fit_df Generates a heatmap of protein intensities for the top 20 differentially expressed proteins. ggplot volcano_plot fit_df Generates a volcano plot highlighting significantly differentially expressed proteins (absolute log2 fold change >1 at an adjusted P-value <0.05). ggplot feature_plot model_df Generates box plots showing protein intensity differences among groups (classes). ggplot varimp_plot model_list Generates lollipop plots showing the importance of different proteins (features) in the models built. ggplot performance_plot model_list Generates boxplots showing the performance (accuracy and kappa) of models built using different ML algorithms. ggplot roc_plot split_df probability_list Generates receiver operating characteristic (ROC) curves showing the predictive power of the models built using different ML algorithms. ggplot a This table describes the tasks and the output produced by the functions under default settings. To demonstrate the utility of promor for analyzing label-free proteomics data that do not contain technical replicates, we analyzed a previously published proteome benchmark data set by Cox et al. (2014) (PRIDE ID: PXD000279). The data set consists of LFQ protein intensity data for 6694 proteins quantified from HeLa (H) and Escherichia coli (L) lysates that were mixed at defined ratios. There were six samples in total. Three biological replicates represented each of the two groups. The results from the analysis were visualized at multiple stages (Supplementary Figs S1-S5). First, we pre-processed the data using the create_df function with default settings. create_df function removed contaminant proteins, proteins identified 'only-by-site', reverse sequence proteins and proteins identified by two or fewer unique peptides. To remove proteins with a high proportion of missing values, we used the filterbygroup_na function, setting the highest allowed missing data percentage in either group at 40%. Next, we imputed the missing data in the data frame using the impute_na function with the default 'minProb' method assuming that the missing values are left-censored. Since the data have already been normalized with the MaxLFQ algorithm (Cox et al., 2014) in MaxQuant, we did not further normalize the data in promor. The output of imputation (imp_df object) was used in the differential expression analysis, performed using the default settings in the find_dep function. We identified 1294 significantly differentially expressed proteins between the 'H' and 'L' groups in the data (Supplementary Table S1 and Supplementary Figs S4 and S5). Furthermore, to test the utility of promor for analyzing label-free proteomics data that contain technical replicates, we analyzed previously published data by Ramond et al. (2015) (PRIDE ID: PXD001584). This data set consists of LFQ protein intensity data obtained from two strains (WT wild type and D8 DargP mutant) of Francisella tularensis, a pathogenic bacterium responsible for the zoonotic disease tularemia. The proteinGroups.txt file contained LFQ data for 1265 proteins across 18 samples representing the two conditions (WT and D8) with three biological replicates in each condition and three technical replicates for each biological replicate. A step-by-step tutorial providing a detailed description of the workflow and the implementation choices are provided here: 2.3 Building predictive models In promor, multiple functions are provided to build predictive models with differentially expressed proteins and assess model performance (Table 1 and Fig. 1B). Over 200 ML algorithms are made accessible through the caret package (Kuhn, 2008) for building predictive models. For users inexperienced in complex ML algorithms, promor provides a default list of five widely used classification-based algorithms, chosen to represent a variety of ML model types (e.g. random forest, support vector machines, generalized linear models, naive bayes and gradient boosting). However, while many different algorithms can be applied to proteomics data, it is important to note that not all of them are well-suited to address the problem at hand. The choice of machine algorithms should be carefully decided according to the prediction task, data type, sample size and the number of features (proteins) in the data set. We tested the use of promor for building predictive models by analyzing a previously published data set by Suvarna et al. (2021) (PRIDE ID: PXD022296). In the original study, the authors built proteomics-based classification models to predict COVID severity in patients. To avoid class imbalance in the data, only a subset of the samples were used from the original proteinGroups.txt file. The steps leading up to differential expression analysis are described in detail here: The results from differential expression analysis (fit_df object) and the normalized data frame (norm_df object) were used in the modeling workflow. The fit_df and norm_df objects were pre-processed with the pre_process function to convert the data into a model_df object. Next, we split the data into training and test data sets using the split_data function. The training data set contained 70% of the data (29 samples), while the test data set contained the remaining 30% (6 samples). The train_models function was run on the training data set in the split_df object with four selected ML algorithms: random forest (rf), support vector machine with linear kernel (svmLinear), naive bayes (naive_bayes) and K-nearest neighbor (knn). The four algorithms were chosen based on their suitability for building models using few features (8 proteins) and samples (35 samples). Furthermore, a k-fold cross-validation (k = 10, repeats = 3) was employed to evaluate model performance. The output was used to test the models on the test data set included in the split_df object. The results from the analysis were visualized at multiple levels during the modeling workflow (Supplementary Figs. S6-S9). The model built with the 'naive_bayes' algorithm performed best in terms of accuracy (85.5) and Area Under the Curve (AUC = 88.9%) (Supplementary Fig. S9). 2.4 Benchmarking We compared the performance of promor against Perseus using the previously mentioned Cox et al. (2014) (PRIDE ID: PXD000279) data set. An identical workflow and parameters to those mentioned in Section 2.2 were used in Perseus. In Perseus, we used the imputeLCMD plugin to implement the 'minProb' imputation method, and the limma plugin to implement the moderated t-test. We observed a significant overlap in the differentially expressed proteins identified by both programs (98.85%) (Supplementary Tables S1 and S2 and Fig. 2A). The number of proteins that were only identified by a single program could be attributed to the random sampling during missing value imputation. Furthermore, the calculated log-fold changes and P-values were strongly correlated between the two programs (Fig. 2B and C). R code for benchmarking analysis is provided on github at Fig. 2. A comparison between promor and Perseus using the proteome benchmark data set, Cox et al. (2014). (A) A Venn diagram showing the overlap of the significantly differentially expressed proteins identified by promor and Perseus. Scatterplots of the resulting protein log2 fold changes (B) and log10P-values (C) of differentially expressed proteins as calculated by promor and Perseus 3 Conclusions We present promor, a user-friendly, comprehensive R package that facilitates seamless transition from differential expression analysis of label-free proteomics data to building predictive models with top protein candidates; a feature that could be particularly useful in clinical and biomarker research. Supplementary Material vbad025_Supplementary_Data Click here for additional data file. Acknowledgments We wish to thank Asitha I. Senanayake for his helpful comments and discussions on software development. Author contributions Chathurani Ranathunge (Conceptualization, Data curation, Formal analysis, Methodology, Software, Validation, Visualization, Writing original draft, Writing review & editing [lead]), Sagar S. Patel (Formal analysis, Investigation, Validation, Writing review & editing [supporting]), Lubna Pinky (Formal analysis, Investigation, Validation, Writing review & editing [supporting]), Vanessa L. Correll (Formal analysis, Investigation, Validation, Writing review & editing [supporting]), Shimin Chen (Formal analysis, Investigation, Validation, Writing review & editing [supporting]), John Semmes (Funding acquisition, Supervision [supporting]), Robert K. Armstrong (Funding acquisition [supporting], Project administration [supporting], Resources [lead], Writing review & editing [supporting]), C. Donald Combs (Funding acquisition [lead], Project administration [lead], Resources [lead], Writing review & editing [supporting]), and Julius O. Nyalwidhe (Methodology [supporting], Supervision [lead], Writing review & editing [supporting]) Funding This work was supported by The Hampton Roads Biomedical Research Consortium (Digital Patient Project). Conflict of Interest: none declared. |
Oncotarget Oncotarget Impact Journals LLC Oncotarget 1949-2553 Impact Journals LLC 28371 10.18632/oncotarget.28371 Editorial Proof-of-principle: targeted childhood leukemia prevention Cobaleda Cesar Ramirez-Orellana Manuel Vicente-Duenas Carolina Weiss Andreas Nichols Kim E. Sanchez-Garcia Isidro Correspondence to: Cesar Cobaleda, Immune System Development and Function Unit, Centro de Biologia Molecular Severo Ochoa (Consejo Superior de Investigaciones Cientificas - Universidad Autonoma de Madrid), Madrid, Spain email [email protected] 2023 11 3 2023 14 190192 17 1 2023 Copyright: (c) 2023 Cobaleda et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. leukemia infection murine models genetic susceptibility prevention pmcCancer is the most common cause of disease-related childhood mortality in developed countries, with B-cell acute lymphoblastic leukemia (B-ALL) representing the most frequent. A salient characteristic underlying some cases of childhood B-ALL is the presence of congenital mutations (either inherited or de novo) that are compatible with normal lymphocyte development, but lead to the appearance of a silent population of preleukemic cells that acquire additional genetic mutations and ultimately progress to full-blown B-ALL. The precise mechanisms underlying malignant transformation have been difficult to ascertain due to their development in otherwise healthy-appearing children. Notably, several decades ago, delayed exposure to common infections was postulated as a triggering factor leading to the appearance of the secondary genetic lesions required for B-ALL to develop . Using mouse models genetically engineered to carry leukemia-predisposing germline mutations found in human B-ALL patients, several recent studies have demonstrated the existence of this infection-triggered process in the progression towards B-ALL, providing evidence that different types of immune stress can activate the clonal evolution of preleukemic precursors [2-4]. One key aspect identified through these studies is that the transforming effect of infection does not result from the outgrowth of preleukemic clones already carrying one or more second hits; instead, the effect of infection-induced immune stress is to trigger the actual appearance of these second mutations, thereby directly causing progression to B-ALL . Under these premises, it becomes conceivable that one could prevent the development of B-ALL by eliminating the preleukemic clone [1-5]. However, one would have to find a way to specifically target these preleukemic cells. Recently, a mouse model recapitulating the phenotype of a leukemia-predisposition syndrome has allowed us to carry out a proof-of-principle experiment to achieve this very goal. Children carrying heterozygous mutations affecting the B-cell master regulator gene PAX5 are predisposed to develop B-ALL; similarly, 25% of heterozygous Pax5+/- mice develop leukemia, but only after experiencing an immune stress, such as exposure to infection [2-4]. Furthermore, the B-leukemias that appear in Pax5+/- animals acquire similar mutations as observed in the leukemic blasts from humans harboring pathogenic PAX5 variants, including activating mutations affecting the Janus Kinases (JAKs) . We previously demonstrated that, in Pax5+/- mice, early B cell precursors (pro-B cells) are very dependent upon interleukin-7 (IL-7) for their survival. Further, blockade of IL-7 signaling by treatment with the JAK1/2 inhibitor ruxolitinib led to apoptosis of Pax5+/- pre-leukemic B cells in vitro . Taking advantage of this knowledge, we have recently used Pax5+/- mice to evaluate whether in vivo treatment with ruxolitinib early in life will kill preleukemic cells and, therefore, prevent the development of acute leukemia . Pharmacokinetic studies were performed to determine appropriate doses and then wild-type (WT) and Pax5+/- mice were fed with ruxolitinib in their chow. Mirroring the in vitro results indicating high dependence on IL-7 signaling, treatment with ruxolitinib mainly led to the disappearance of B-cell progenitors in Pax5+/-, but not in WT, animals . Therefore, in the next experiment, both experimental Pax5+/- and control WT animals were fed with ruxolitinib containing chow for 14 or 28 days, starting from the moment they were transferred from a specific-pathogen-free animal house (SPF, where they had been born and weaned) to a conventional facility, where they were exposed to common mouse pathogens . The animals treated with ruxolitinib for the longer period (28 days) exhibited a significant 90% reduction in the incidence of B-ALL when compared to untreated mice, or to animals treated only for 14 days . Figure 1 Targeted prevention of progression to B-ALL. In most Pax5+/- mice, preleukemic progenitor B cells (shown as blue cells) are compatible with a normal hematopoietic development. However, immune stressors, such as exposure to common mouse pathogens after transfer to a non-SPF animal facility, trigger progression to B-ALL (red cells) through the appearance of secondary mutations affecting the Jak/Stat pathway. Transient treatment of Pax5+/- mice with the Jak1/2 inhibitor ruxolitinib destroys these progression-prone preleukemic cells and significantly reduces the risk of leukemia development. These results demonstrate that there is a window of opportunity in early postnatal life during which preventing the progression to B-ALL in predisposed children might be possible. Mo: months-old. Ultra-deep sequencing studies of Pax5+/- mice had previously shown that the activating mutations affecting Jak are only detected once the animals already present with the full-blown B-ALL, and never during the preleukemic period . Furthermore, when a constitutively activated Jak3V670A transgene is added to the Pax5+/- genotype, the animals develop B-ALL immediately and without the need of exposure to any immune stress. Therefore, it is unlikely that the reduction of the incidence of acute leukemia after treatment with a Jak inhibitor for 28 days is due to the selective death of Pax5+/- progenitors already harboring leukemogenic mutations in this pathway. On the contrary, one can conclude that ruxolitinib is acting by eliminating predisposed preleukemic B cells before the second hit leading to B-ALL arises in them . These data show that ruxolitinib-mediated inhibition of the JAK-STAT pathway in predisposed Pax5+/- animals prevents the development of leukemia, and suggest that an analogous approach could be used to prevent progression to B-ALL in children at increased genetic risk, either because they are carriers of PAX5 or due to other predisposing germline mutations. Importantly, since the beneficial action of ruxolitinib in predisposed animals could be achieved following transient treatment with the drug, one can extrapolate that any future treatment of predisposed children need not be sustained for a long period, but just administered during a specific time window during their childhood. It is becoming increasingly clear that the existence of latent pretumoral cells is common to many types of both hematologic and solid cancers ; therefore, the concept described here could be considered a proof-of-principle strategy for the development of similar prophylactic approaches to prevent the progression of other malignancies. Still, some aspects remain unclear. For example, why do the majority of genetically predisposed animals (and most genetically predisposed children) not develop leukemia and stay healthy? In addition, what are the mechanisms by which environmental factors such as infection promote the acquisition of secondary mutations leading to malignant progression of preleukemic cells? These and other important questions still need to be answered if we are to fully understand and avert the appearance of B-ALL. ACKNOWLEDGMENTS We are indebted to all members of our groups for useful discussions and for their critical reading of the manuscript. Research at C. Cobaleda's laboratory was partially supported by Ministerio de Ciencia e Innovacion/AEI/FEDER (PID2021-122787OB-I00), and a Research Contract with the "Fundacion Sindrome de Wolf-Hirschhorn o 4p-". Institutional grants from the "Fundacion Ramon Areces" and "Banco de Santander" to the CBMSO are also acknowledged. Research in C. Vicente-Duenas group has been funded by Instituto de Salud Carlos III through the project "PI22/00379 and by a "Miguel Servet Grant" [CPII19/00024 - AES 2017-2020; co-funded by European Regional Development Fund (ERDF)/European Social Fund (ESF) "A way to make Europe"/"Investing in your future"]. Kim Nichols receives funding from the American Lebanese Syrian Associated Charities (ALSAC) and R01CA241452 from the National Cancer Institute Research in ISG group is partially supported by FEDER and by RTI2018-093314-B-I00 MCIU/AEI/FEDER, UE; by PID2021-122185OB-I00 MCIU/AEI/FEDER, UE, and by Junta de Castilla y Leon (UIC-017, and CSI144P20). M. Ramirez-Orellana and I. Sanchez-Garcia have been supported by the Fundacion Unoentrecienmil (CUNINA project). C. Cobaleda, M. Ramirez-Orellana, and I. Sanchez-Garcia have been supported by the Fundacion Cientifica de la Asociacion Espanola contra el Cancer (PRYCO211305SANC). Author contributions The authors contributed equally to all aspects of the article. CONFLICTS OF INTEREST Dr. Nichols reports research support from Incyte. A.W. is a full-time employee of Novartis Pharma AG. The remaining authors declare no competing financial interests. REFERENCES 1. Cobaleda C , et al . Nat Rev Immunol. 2021; 21 :570-81. 10.1038/s41577-021-00505-2. 33558682 2. Martin-Lorenzo A , et al . Cancer Discov. 2015; 5 :1328-43. 10.1158/2159-8290.CD-15-0892. 26408659 3. Rodriguez-Hernandez G , et al . Cancer Res. 2017; 77 :4365-77. 10.1158/0008-5472.CAN-17-0701. 28630052 4. Vicente-Duenas C , et al . Blood. 2020; 136 :2003-17. 10.1182/blood.2019004381. 32911536 5. Cobaleda C , et al . Trends Immunol. 2021; 42 :371-74. 10.1016/j.it.2021.03.004. 33773925 6. Casado-Garcia A , et al . Cancer Res. 2022; 82 :1098-109. 10.1158/0008-5472.CAN-21-3386. 35131871 7. Pareja F , et al . Cancer Discov. 2022; 12 :949-57. 10.1158/2159-8290.CD-21-1110. 34949653 |
Educ Technol Res Dev Educ Technol Res Dev Educational Technology Research and Development 1042-1629 1556-6501 Springer US New York 10211 10.1007/s11423-023-10211-6 Cultural and Regional Perspectives Higher education teachers' digital competencies for a blended future Howard Sarah K. [email protected] 12Sarah K. Howard is an Associate Professor of Digital Technologies in Education, at the University of Wollongong and a visiting Professor at the Vrije Universiteit Brussel. She is the Education Lead in the SMART Infrastructure Facility and a full-member of the Early Start Research Institute. Her research looks at technology-related change in education, specifically teacher practice and integration in learning. Tondeur Jo 12Jo Tondeur is an Associate Professor at the Vrije Universiteit Brussel and a visiting Professor at the University of Wollongong. Prior to academia he was a teacher across various levels of schooling. His research interests are in the field of educational innovation, technology use, online and blended learning, and professional development. 1 grid.1007.6 0000 0004 0486 528X University of Wollongong, Northfields Ave., Wollongong, 2522 Australia 2 grid.8767.e 0000 0001 2290 8069 Vrije Universiteit Brussel, Brussels, Belgium 13 3 2023 13 3 2023 2023 71 1 16 19 2 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Welcome to this special issue, focussing on teachers' digital competencies in Higher Education. The articles in this special issue explore the question of how digital competencies in higher education are conceptualized after the Great Online Transition, during and after the pandemic. A few of the topics addressed in the special issue are: new competency frameworks, the issue of disciplines and artificial intelligence and looks into the future of higher education learning and teaching. In this preface to the special issue, we first present a brief introduction to the context and the problem statement. We then provide a summary of each of the ten papers included in this special issue, we present how they are related and how each article makes a unique contribution to the main goal of the special issue. Finally, the implications are discussed together with suggestions for future research. Keywords Digital competence Teacher Higher education The University of WollongongOpen Access funding enabled and organized by CAUL and its Member Institutions issue-copyright-statement(c) Association for Educational Communications and Technology 2023 pmcIntroduction to the special issue The global COVID-19 pandemic catalyzed a significant 'shift to digital' in teaching and learning in higher education. Namely, this has been a result of the Great Online Transition (GOT) and global shift to online remote teaching (Howard et al., 2022). While this event has brought online teaching and digital technologies to the forefront of educational practice, the hope is that it has also opened the door to future innovation and change, new thinking and considerations about how we teach and learn. Therefore, it is now the time to consider how higher education teaching and learning has and potentially will continue to change as a result of this 1-2 year remote 'experiment'. Yet, online teaching and learning is not new to higher education (Kebritchi et al., 2017; Scherer et al., 2021). Prior to this, and for almost two decades, institutions for higher education across the world have been gradually adopting online and blended learning practices (Singh & Thurman, 2019), but the nature and quality of online teaching and learning has been inconsistent (Bernard et al., 2014; Howard et al., 2020). As a result, what is expected for on-going digitally-supported learning in higher education has been unclear. This clouds how to best prepare higher education teachers with the necessary digital competencies needed to design and support future online and blended-learning experiences (Bolliger et al., 2019). This new focus presents a challenging but interesting opportunity for higher education institutions. They are in a position to consider how they might sustain and leverage online practices adopted during emergency remote teaching into blended learning to a possible blended future for higher education. An area of great interest will be how higher education teachers integrate and develop online practices adopted during the GOT as they return to their usual teaching, or in some cases where teaching is permanently changed. It is essential to understand which digital competencies will be important and what kind of support is needed to support on-gonig change in their teaching practice (Bruggeman et al., 2021). Typically, in terms of building teachers' digital competencies, research has shown that higher education institutions commonly give consideration to technical issues, while pedagogical support is not often taken into consideration (Scherer et al., 2021). This is problematic, as technical competence is only part of the story. Considerations for pedagogical, social or well-being competencies are often missing from training. While there are a range of digital competency frameworks available to guide higher education practice, these should be reconsidered as expectations and approaches to teaching and learning are different after the GOT (McQuirter, 2020; Tondeur et al., 2017). Therefore, it remains largely undetermined: what do higher education teachers need to know about digital practice, teaching and learning? The answers to these questions will be critical in extending and sustaining rich online practices and developing blended learning after the GOT. In response to issues arising from the GOT, in 2021 ETRD published the special issue "Shifting to Digital: Informing the Rapid Development, Deployment, and Future of Teaching and Learning" (Lin & Johnson, 2021). One of the key messages for future research arising from this work was a lack of clarity in what should be included to support and train teachers for the digital shift (Yuno, 2020). In the current special issue we addressed this gap in knowledge on higher education teachers' digital competencies and teaching practice to support changes after the GOT. An example of this is An's (2021) response to Phillipsen et al.'s (2019) paper. Phillipsen et al. (2019) present a framework comprising what should be addressed for successful teacher professional development for online and blended learning. However, An (2021) notes that more research is needed to build a common understanding of the essential knowledge, skills, and competences for online teaching (cf. Bernard et al., 2014). It is in this space, and those spaces among other publications in the Shift to Digital, that was explored in the current special issue. To explore teachers' digital competencies as part of a post-GOT digital shift in higher education, the special issue unpacks competencies in relation to teachers' pedagogical beliefs, policy planning, professional development, leadership, preparing students for future work, etc. The variety of studies also consider current issues related to the digital competencies of teachers in higher education, e.g. which digital competencies teachers in higher education exactly need to work in the post-GOT age, how to developed these competencies for specific teachers' profiles, or how to develop teachers' digital competencies that are of particular interest in view of the outcomes and challenges of the COVID-19 pandemic (e.g., flexibility, autonomy of students or inequities of learning online). These can also be extended to considering future learning designs, expectations of digital technology use, and equitable access to quality learning experiences. Positioning the articles The first article, by Cook, Apps, Beckman and Bennett, first reviews empirical studies of emergency remote teaching to derive a conceptual frame for digital competence, which was then applied as a lens to analyze teaching in Australian universities. The findings provide a starting point for understanding digital competencies in Higher education in order to better understand the present and also to anticipate the future. More specifically, the authors suggest that institutions for higher education can better support the development of teachers' digital competence through practical operationalisations that connect technical and pedagogical knowledge, make digital possibilities across modes of delivery more explicit, and should also protect the well-being of educators. The second article brings the findings mentioned above together in a more generic framework of digital competencies for teachers in higher education, while extending the domains of pedagogical and technical knowledge to include empowering students. Tondeur, Howard, Van Zanten, Van der Neut, Gorissen, Kral and Uerz conducted a review to determine the state of digital competence research in general, similarities and differences between existing digital competence frameworks. Based on the outcomes of their review and the framework comparison, a framework was developed through expert meetings with policy makers and experts, and finally validated with practitioners. The resulting HeDiCom (Higher Education Digital Competence) framework provides guidance and clearer expectations of higher education teachers' digital competency which can guide innovation in practice beyond the GOT. When considering how teachers have engaged in change, and how this relates to developing competencies, it is necessary to look at their experiences. How teachers themself experience their teaching and digital competencies has been explored in the third article. This qualitative study by Gonzalez, Ponce and Fernandez examined teachers' experiences of teaching online during COVID-19 in Chile. The findings of their hybrid thematic analysis show that, despite problems faced by both pandemic and political disruption, there were several learned lessons: teachers employed an array of digital tools for maintaining content delivery and promoting interaction, deepened their understanding of course design and assessment, and developed an emphatic disposition to understand students' situations in the context of Chilean Higher Education. Students' experiences and their perceptions of teachers' digital competencies are also important, as they are a key factor in teachers' beliefs about teaching practice. Zhu investigated university teachers' digital competencies through the eyes of their students. This fourth article focused on a blended course on "Educational Technology" with theoretical and practical components in a Chinese university. The participants' responses to the open-ended questions provided in-depth views of the factors contributing to university teachers' digital competencies of blended teaching and how they can influence students' learning. Also the participants' expectations of future blended courses provided implications for teachers' digital competencies in blended teaching in post-COVID-19 era from learners' perspectives. The fifth paper begins to take a more granular look at factors at play in the development of competencies. Trevisan, De Rossi, Christensen, Knezek and Smits explored factors shaping digital competencies. The authors present findings on higher education faculty's reported dispositions and needs as they engaged with online teaching. They report on the findings of two surveys administered to higher education faculty worldwide during two time periods within the COVID-19 pandemic. The surveys inquired about internal (e.g., enthusiasm and resolutions) and external (i.e., support) facets of faculty's perception of online teaching at two time periods. The findings reveal different patterns of dispositions and different uses of technological affordances to foster online learning. These patterns were also found to change over time, highlighting different conditions possibly enabling or hindering the development of competencies for online teaching and learning. The research by Sang, Wang, Li, Xi and Yang deepens our understanding of developing competencies. They investigated the relationship between three specific factors in a Chinese normal university: digital competence, effort expectancy and teachers' work engagement. The results of their structural equation modeling indicated that Higher Education teachers' digital competence positively and significantly correlated with their work engagement and their effort expectancy. Overall, the findings imply that higher education teachers' digital competence is an important motivator for their work engagement. However, teachers' work is also strongly dictated by their specific disciplinary area. In the next paper, Starkey, Yates, Lundqvist, Ormond and Syvester explored the relationship between disciplines and higher education teachers' digital competencies for future-focussed digitally infused undergraduate programmes. Their case studies identified how disciplinary culture, context, and technology influence pedagogical practice and digital competencies needed to teach in undergraduate programmes in New Zealand (e.g., Applied Statistics, Critical Indigenous Studies, Geography). They conclude that higher education teachers require digital competencies that align with disciplinary culture and the specific technologies available. The special issue then begins to look forward to competencies and near-future changes in higher education teaching and learning. Tsz Kit Ng, Ka Lok Leung, Jiahong Su, Chi Wui Ng, and Kai Wah Chu consider the nature of Artificial Intelligence digital competencies. In their concept paper, they first explored the opportunities and challenges of employing AI systems and how they can enhance teaching, learning and assessment. To align with generic digital competence frameworks, they complemented the DigCompEdu framework and revised the P21's framework to accommodate AI technologies in order to provide an overview of the necessary AI digital competencies. To present which teachers' digital competencies are needed is an important first step in the context of Higher Education. The Dexter article takes a next step and can serve as guidance to organize faculty decision making. Her post-hoc analysis provided principles to capture how participants in each study linked any ICT competencies to overall coherent ICT integration competence. This reasoning shifts more responsibility for setting directions and crafting aligned professional learning to the organization in a way that exceeds the "help desk" model, to also leverage and work with any university units concerned with quality in teaching and learning. Finally, the conceptual paper by Markauskaite, Carvalho and Faws explored the role of higher education teachers' digital competencies to postdigital capabilities. In their future-oriented paper, they consider what it will take to be a teacher in a sustainable university and emerging trends at three levels of the educational ecosystem global developments, teachers' local practices, and daily activities. The authors argue that there is a need to move beyond person-centric theorisations of teacher digital competencies towards more holistic, ecological conceptualisations. It requires higher education teachers' agency and critical engagement with a future-oriented, sustainable university mission, which is at its core postdigital. Lesson learned and directions for future research It is critical that change momentum from remote teaching during the pandemic and the GOT is not lost in higher education. Never before has there been such a large-scale change initiative across education, which has resulted in this kind of dramatic reconsideration of teaching and learning in higher education. Universities have improved infrastructure, teachers and students have both upskilled, and everyone has been exposed to new practices. The articles presented in this special issue are all looking at how we can better understand teachers' digital competencies, which can support university policy, training and support structures to build on this strange and powerful event. Specifically, there is a significant need in the field for an understanding of where Higher Education teachers are currently with their digital competencies: what are teachers' doing well and where do they feel confident, and where is more work needed? Moving from this point, research is needed to further understand how competency frameworks are implemented, if they are fit for purpose, and their validity and relevance in different contexts. As we look into the future, digital competencies will only become more complex, particularly with growing pressures to integrate artificial intelligence and ways of working rapidly changing. Higher Education has not generally operated within a coherent body of accepted practices for teaching and learning, and this is not necessarily needed. However, digital technologies are changing and will continue to change how individuals and organizations interact, work, teach, learn and create knowledge. Better understanding of competencies needed for fruitful engagement, for individuals to exert agency and thrive, is sorely needed at this time. This special issue presents a first step to opening up this problem space in the field. Funding Open Access funding enabled and organized by CAUL and its Member Institutions. This study was not conducted with any funding sources. Declarations Conflict of interest The authors declare that they have no conflict of interest. Research involving human participants and/or animals The research did not involve human and/or animal participants. Therefore, there are no issues of informed consent in the research. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. 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ed Williams-Mohammed Framework Studies that use the voice of communities to explore poverty often converge on a handful of domains to characterize the multi-dimensionality of poverty . These domains form an ecosystem of factors that occur in various permutations for different communities to shape their experience of poverty and access to opportunity . These domains were reviewed by previous studies and are summarized by us in the Ecosystems of Opportunity meta-model presented in Fig. 2. The Ecosystems of Opportunities meta-model, which categorizes community resources into five domains, served as an open-ended exploration of assets and their relationships that exist within the community. Combining the Williams-Mohammed Framework with the Ecosystem of Opportunities meta-model allowed for a representation of both community assets and deficits (See Narrative / Vignette Analysis Script).Fig. 2 Ecosystems of Opportunities meta-model Vignette analysis and constructing architecture of systems map Vignette analysis spanned a series of 3 sessions. During these sessions analysis of vignettes were conducted according to Glaser and Strauss's grounded theory approach. Following the guidelines set out by Strauss, open, axial and selective coding of the vignettes were done in collaboration with the participating community's Knowledge-Interpreter. Extensive memoing was done to elaborate code categories and to conceptually relate codes with each other. Important concepts were discovered using concept respecification, leading to the development of a concept-indicator model [109-111] which, in its visual representation, evolved to become the architecture of systems map. Analysis was done in collaboration with the Knowledge-Interpreter and note-taking and map construction was done by the session facilitator (See Architecture of Systems Conceptual Model Building Script). Augmenting architecture of systems map After completing vignette enrichment, analysis, and construction of an architecture of systems map, each linked pair of concepts in the map formed search terms that were used to conduct a literature search using Google Scholar. When a relationship was identified in literature, the citation was added to the map, and where necessary the map was augmented with any additional factors and relationships (See Architecture of Systems Conceptual Model Augmenting Script). A web-browser based application was developed to simplify the process of implementing the methodology above including data collection for vignette development, diagramming and augmenting the architecture of systems map, conversion of diagram into a computable JSON object, and subsequent annotation for agent-based modeling. Session evaluation After each session, the Knowledge-Interpreter was asked if the sessions were useful, if they uncovered details that were insightful, and whether the sessions should be improved in any way. Because an exploration of architectural factors shaping community realities discusses historic and ongoing traumas on the community, the discussions themselves can serve to re-traumatize. There was space given after each session to discuss the format, spreading out discussions in order to give time to heal; prioritizing consent to engage and disengage to the extent they are comfortable, ensuring safety of the discussion space; ensuring transparency; and ensuring an ongoing relationship as collaborators leading an exploration of their own realities rather than objects of study. Results Each of the activities vignette development, vignette analysis and construction of architecture of systems map, and augmenting architecture of systems map resulted in artifacts that were valuable for both the communities and the research effort. Vignette development and enrichment Vignette construction resulted in a number of narratives that represented a spectrum of experiences, trajectories, and outcomes within a community. They yielded a narrative representation of lived experiences that summarized factors and their inter-relationships surrounding a community's reality. These narratives additionally gave space for communities to represent an asset-based perspective by pointing to a community's aspirations, strengths, actualization of their worldview, and the creation of a unique space emergent from a network of relationships between a community of people in commune with the universe. These narratives allowed for an expression of a sense of self and a focus that extended beyond barriers or deficit-focused strengths such as 'resilience'. Vignette analysis and constructing architecture of systems map The collaborative analysis of vignettes yielded an initial architecture of systemic factors map, which was insightful for the objective of this study to better understand the factors that inter-relate to form a system in which lived experience of poverty occurs. At the same time it was enlightening to the community in visualizing how factors beyond their individual efforts and choices shape their lives and their outcomes. This artifact showed: how the past shapes the present (e.g. the connection between red-lining policies from the past and current neighborhood features such as employment and schools); the relationship between how factors that serve to advantage one community can be the very same factors that disadvantage another (e.g. how infrastructure is developed in a city that decreases the property value of some communities while increasing it for others); that policies that are seemingly advantageous to all can encode advantaged identities and be marginalizing to populations that don't share those identities, that a confluence of factors shape advantage and disadvantage for a community (e.g. how wealth accumulating behavior of White communities is encoded into the tax code, disadvantaging Black identities); that communities contain within themselves factors and assets that allows them to survive and thrive in systems that may be otherwise disadvantaging for them (e.g. a sense of community in a neighborhood such that children have multiple households that are nurturing spaces and many adults that are a source of mentorship for children); and that across different communities there are pathways that are conserved and also that differ while leading to the same outcome (e.g. a conserved pathway of a feeling powerlessness when experiencing discrimination and being left out of societal advantages). Augmenting architecture of systems map A literature search examining each of the relationships surfaced in the architecture of systems map provided an opportunity for the community to contextualize existing research about them and hang published research about them on the frame of lived experience. It served to provide further insights into the system surrounding community realities. Some of the relationships were also recorded within literature, while other relationships that emerged from narratives were magnified further in literature through intermediary steps. The laborious process of conducting a literature search to examine relationships that emerged from community narratives was an exceedingly powerful process: it revealed the fracturing and fragmentation of community realities spread out across academic peer-reviewed siloes. This step led to the final Architecture of Systems Map (Fig. 3) and revealed the importance of community experience as the organizing force to inter-relate, synthesize, and reconstruct a coherent picture of the community that is otherwise spread disjointedly across a vast landscape of academic literature.Fig. 3 Architecture of systems map Session evaluations Results from post-session discussions revealed the value of the process to communities. Specifically, participants found that: (1) narrative exploration through open ended questions helped clarify how a confluence of historic, social, and policy factors restrict and shape choices and consequences within communities; (2) narrative exploration also helped to bring to light how strengths and assets in the community that allow it to survive and thrive against challenges that emerge from systems surrounding the community; (3) others in the community might benefit from seeing the ASF map so that they see how adverse outcomes in the community is not a consequence of an intrinsic defect within the community; (4) it was valuable to have engaged in an effort to develop a way to encode community voice and narratives into quantitative efforts like simulation modeling; and (5) it was valuable to have listened to narratives from a different community and seen the similarities and differences in how a common lived experience is shaped. In summary, this process was a significant benefit in showing that even if there is a vast body of research about a community, there is an alternative to modelers and researchers engaging with that corpus by themselves. This methodology showed that indigenous researchers are effective interpreters of their community's knowledge base, can develop coherent narratives of lived experiences within which research and knowledge is contextualized, and can collaboratively construct conceptual mappings necessary for simulation modeling. Discussion We implemented an innovative strategy to engage with a community's research base through collaborating with indigenous researchers. It showed a way to capture community representations, revealing the architecture of factors that form the system in which community lives are shaped, identifying policy determinants of community realities, and co-developing the structure and building blocks of an agent-based model. We found that community developed vignettes formed a fertile foundation for an in-depth exploration of underlying factors and their inter-relationships. The vignettes were composites representing a segment of community population, with multiple vignettes serving to capture a diversity of stories within a single community. The multiple vignettes revealing a spectrum of trajectories and outcomes served as a counter to the tendency to fix and essentialize community identities [112-114]. The modification of the script with a known cause-effect structure such as the Williams-Mohammed Framework allowed an unstructured but guided exploration to identify factors and their relationships shaping a community's lives. Additionally, it revealed a community's perspective on mechanisms through which barriers to opportunity are created. Utilizing the Ecosystems of Opportunity meta-model was helpful in identifying assets that define a community and their relationship with the universe around them. The systems of architecture map created from community narratives and its augmentation with literature search creates a powerful dialectic between community and academia. The map provides a relational deconstructed visualization of factors that shape a community's lived experiences, while a community's lived experiences shapes and unifies fragmented studies into a coherent whole. This suggested to us the potential role of community experience as a methodology to drive literature reviews to re-construct a coherent picture from many different research efforts. The architecture of systems output by this methodology is supported by literature that examines structural inequities [62, 115-123]. The architecture offers a useful way to bring together a wide spectrum of studies into a cohesive narrative whose construction emerges from community Knowledge-Bearers. The F.A.I.R. methodology is timely in light of the Executive Order On Advancing Racial Equity and Support for Underserved Communities Through the Federal Government, which stated "because advancing equity requires a systematic approach to embedding fairness in decision-making processes, executive departments and agencies (agencies) must recognize and work to redress inequities in their policies and programs that serve as barriers to equal opportunity" . The EO tasked each agency to conduct a review of select policies and programs, to which they responded with recommendations specific to their agency. However, the results of capturing community voice through the FAIR Framework revealed communities don't experience policies as discrete individual impacts. Rather, in the lived experience of communities interacting sets of policies from a spectrum of agencies form a "policy ecosystem". The "policy ecosystem" interacts with community realities, in the process shaping individual choices and lives, and creating barriers and exacerbating disparities . The methodology highlighted in this paper offers policy makers a systematic process to collaborate with communities, to give voice to their realities, and help map out systems of barriers. Mapping the architecture of systems impacting the community can lead to a simulation to anticipate how policies can interact with each other in a policy ecosystem and how, when applied to a community's realities, may impact outcomes and disparities. Furthermore, this effort revealed an alternative to modelers and researchers interpreting research about a community. This effort showed a systematic methodology to collaborate with indigenous researchers as access points for a community's body of research and as Knowledge-Interpreters to inform model construction, to reveal the multi-dimensionality of a community's reality, and to link those realities to policies. These types of insights can inform the modifiable inputs and visualizable outputs of an interactive simulation model. Furthermore, this effort underlines a significant space for Knowledge Interpreters - multi-epistemic researchers - as community researchers and advocates who straddle multiple epistemes. In the language of multiple vantage points contributing to knowledge production, . Interpreters can be more accurately described as multi-epistemic researchers, who are urgently needed in efforts to recenter and diversify systems of knowledge. Constructing an underlying conceptual model based on a community's knowledge base offers an opportunity to represent the perception of agents about their environment, and their interactions within it. By formally characterizing a community's perception of elements and relationships that make up the system within which they live their lives, a model can be enriched by agents' belief structures and perceptions that underly interactions and behaviors . Self-characterization as done in this framework revealed a number of policies that shape community realities and can therefore be useful for policy simulation efforts . A limitation of this process was the emotional impact it has on community partners. The process of exploring systemic barriers had the potential to re-traumatize community participants. This was mitigated through ensuring that partners had the power and choice to stop or take breaks or reconvene at a later time. Additionally, detailed discussions at the end of each session offered an opportunity to discuss the emotional impact of the process and allowed voice to be given to feelings that were elicited. This methodology is also limited in that it in its representation of community experiences through narratives and conceptual models, it excludes epistemologies that have alternate ways of phenomenological expression such as through experience, performance, dance, production of tapestries, etc. To work with alternate epistemologies, an additional step at the beginning of the FAIR Framework would surface and conform subsequent steps to the community's modes of knowledge generation, expression, representation, transmission, and recording. A key lesson we learned in implementing the FAIR Framework is that relationship building is the most important and foundational step of the entire process. Establishing a relationship of trust meant that community researchers were driving priorities, direction, and exploration and felt comfortable enough to allow FAIR facilitators into the sacred space of their memories and experiences. There are a number of ways to monitor and shape the relationship building process for trust . The formation of relationships around research efforts has the potential to elicit memories of past betrayals and traumas a community may have experienced [10-13, 16-18]. Relationship building requires investment to ensure there is space for healing, that benefit accrues to the community and isn't extractive, and ensures community has control during the effort and ongoing control over any outputs even after the initial participatory effort is complete. This effort is situated within academic knowledge-production whose output includes an audience of researchers and policymakers. A limitation of this situatedness is the knowing of the community's Knowledge-Bearer that the results of this collaboration in the margins would be presented to an audience in the center through an academic journal. The fear is that by representing challenges the community faces it may serve to ingrain stereotypes even when surrounded by a visual model revealing an architecture of systems creating those challenges. Dotson refers to this fear as "testimonial smothering" and defines it as "truncating of one's own testimony in order to insure that the testimony contains only content for which one's audience demonstrates testimonial competence" . Testimonial smothering is a mechanism of epistemic violence and is the consequence of the speaker's and their community's past experiences with the centered episteme and dominant systems of knowledge production, and their consequent anticipation that the testimonial may serve to further entrench misperceptions from the center about the margins . To mitigate this concern, we intend to submit these findings to academic forums possessing an audience of communities on the margins: the Global South, post-colonial societies, and indigenous communities. As next steps, we intend to convert the mappings into computational representations, which can be used in dashboards to help visualize the reason behind distributions of quantitative measures seen in data visualizations. We intend to discuss these mappings with community to identify and prioritize policy interventions. By translating these maps and policy strategies into agent-based models and policy levers, we hope to strengthen advocacy efforts and inform better policy making. Additionally, in this study we examined collaboration with a community's Knowledge-Bearer / Knowledge-Interpreter to represent primary knowledge of lived experiences and also to reclaim and interpret academic literature about that community into a coherent self-narrative. In future research we hope to use the framework reported in this study to collaborate with community Knowledge-Bearers and Knowledge-Interpreters (i.e. multi-epistemic researchers rooted in the margins) on primary data collection efforts. In conclusion, through this work we have added to the body of knowledge of participatory modeling of policies. We have contributed a methodology to: systematically collaborate with community Knowledge-Bearers / Knowledge-Interpreters to access and interpret a large body of community knowledge and voices; to reveal the impact of policy ecosystems on communities; and to surface equity considerations relevant to policymaking. Our work is promising for efforts that want to collaborate with communities for in-depth mapping of lived experiences to reveal policies shaping community realities. Supplementary Information Additional file 1. Participatory modeling scripts. Additional file 2. Output of participatory modeling scripts. Acknowledgements We thank Dr. Andreas Tolk for his valuable suggestions and contributions towards the systems science and simulation modeling portion of the manuscript. We are indebted to Dr. Uba Backonja and Joshua Stadlan for their close review of the manuscript and their recommendations on structure and organization. We are grateful to Dr. Erica Taylor and Dr. Jon Cline for their review, discussions, and recommendations related to the manuscript's overall contents and concepts. Authors' contributions YS contributed to the conception, design, analysis, and revision of the draft. MJ contributed to the conception, design, analysis, and revision of the draft. DL contributed to the conception, design, analysis, and revision of the draft. CG contributed to the conception, design, analysis, and revision of the draft. DW contributed to the design and revision of the draft. SW was a major contributor to the conception of this research. JP was a major contributor to the conception of this research. SR was a major contributor to the conception of this research. YS, MJ, DL, CG, DW, SW, JP, and SR have all approved the submitted version. Funding This research was funded by MITRE Corporation. MITRE was not involved in the design of the study; or the collection, analysis, and interpretation of data; or in the writing of the manuscript. Availability of data and materials All data (i.e. the narratives / vignettes) generated or analyzed during this study are included in this published article within the supplementary files. Declarations Ethics approval and consent to participate This manuscript does not report a study involving human participants, human data or human tissue. Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
Rheumatol Adv Pract Rheumatol Adv Pract rheumap Rheumatology Advances in Practice 2514-1775 Oxford University Press 10.1093/rap/rkad023 rkad023 Editorial AcademicSubjects/MED00010 Are genes the missing link to detect and prognosticate RA-ILD? Vermant Marie Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium Pulmonology, University Hospitals Leuven, Leuven, Belgium Goos Tinne Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium Pulmonology, University Hospitals Leuven, Leuven, Belgium Gogaert Stefan Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium Pulmonology, University Hospitals Leuven, Leuven, Belgium De Cock Diederik Biostatistics and Medical Informatics Research Group, Department of Public Health, Vrije Universiteit Brussel, Brussels, Belgium Verschueren Patrick Skeletal Biology and Engineering Research Center, Department of Development and Regeneration, KU Leuven, Leuven, Belgium Rheumatology, University Hospitals Leuven, Leuven, Belgium Wuyts Wim A Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium Pulmonology, University Hospitals Leuven, Leuven, Belgium Correspondence to: Wim A. Wuyts, Laboratory of Respiratory Diseases and Thoracic Surgery (BREATHE), Department of Chronic Diseases and Metabolism, KU Leuven, Herestraat 49, 3000 Leuven, Belgium. E-mail: [email protected] 2023 06 3 2023 06 3 2023 7 1 rkad02331 1 2023 13 3 2023 (c) The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution License ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. Research Foundation-Flanders 1SE4322N 1S73921N pmc This editorial refers to 'A genome-wide association study identifying single nucleotide polymorphisms in the PPFIBP2 gene was predictive for interstitial lung disease in rheumatoid arthritis patients' by Hayashi et al. . Approximately 10% of RA patients develop an interstitial lung disease (RA-ILD) during their disease course, although only a few studies have investigated the epidemiology in detail . Patients with RA-ILD clinically present with dyspnoea and dry cough. They predominantly have a usual interstitial pneumonia pattern on CT . The prognosis of RA-ILD with this CT pattern is comparable to idiopathic pulmonary fibrosis, resulting in a survival after ILD diagnosis of 3.2-10.2 years . Current screening modalities and treatments for the respiratory complications of RA are insufficient even with the arrival of antifibrotic drugs for CTD-ILD . Therefore, rapidly detecting RA-ILD is an unmet need. Multiple clinical RA-ILD risk factors have been identified, including male sex, ever smokers, RF positivity and the presence of anti-citrullinated antibodies (Table 1) . Furthermore, the following molecular biomarkers have already been linked with RA-ILD: epithelial cell-derived Krebs von den Lungen (KL-6) antigen, matrix metalloproteinase 7 (MMP-7), pulmonary and activation-regulated chemokine (PARC), surfactant protein D (SP-D), interferon-g-inducible protein 10 (IP-10/CXCL10) and malondialdehyde-acetaldehyde adducts antibodies (anti-MAA) . In addition, new prognostic genetic markers and risk stratification tools are being explored. Hayashi et al. performed a genome-wide association study in search of new genetic biomarkers. They showed an association between the presence of the rs6578890 single nucleotide polymorphism (SNP) in the PPFIA binding protein 2 (PPFIBP2) gene and RA-ILD presence. rs6578890 had not previously been described. The authors propose two causal mechanisms. First, a role for the PPFIBP2 gene, encoding liprin b-2, which plays a role in axon guidance and synapse development, is hypothesized. Second, a role for the distally located CYB5R2 gene is suggested. The expression of this cytochrome member gene is influenced by the rs6578890 SNP. These pathways and their possible causal roles in RA-ILD pathophysiology must be further investigated. Table 1 Overview of described RA-ILD risk factors in the literature Clinical risk factors Male Older age Ever smoker Serological biomarkers RF Anti-CCP antibodies (anti-CCP) Anti-malondialdehyde-acetaldehyde antibodies (anti-MAA) Krebs von den Lungen-6 (KL6) C-X-C motif chemokine ligand 10 (IP-10/CXCL10) IL-18 IL-13 Surfactant protein D (SP-D) Lysyl oxidase-like 2 (LOXL2) Matrix metalloproteinase 7 (MMP-7) Pulmonary and activation-regulated chemokine (PARC) Genetic biomarkers Described region Genetic polymorphisms MUC5B rs35705950 France, Greece, The Netherlands, USA, Japan, China Finland RPA3/UMAS rs12702634 Japan PPFIBP2 rs6578890 Japan Haplotypes DRB1*16, DRB1*15, DQB1*06 Japan Genetic mutations TERT, RTEL1, PARN, SFTPC France Telomere length <10th percentile France For all genetic risk factors, the region in which the risk factor was described was also included. In addition to this possible new genetic marker, a shared genetic predisposition in RA-ILD and familial pulmonary fibrosis has previously been described . In patients with RA-ILD, several mutations have been found in telomere-related and surfactant-related genes, similar to findings in patients with familial pulmonary fibrosis. Furthermore, short leucocyte telomere length (<10th percentile) has been associated with RA-ILD, progressive disease and early mortality . Recently the rs12702634 variant in the RPA3 (replication protein A3) and UMAD1 (UBAP1-MVB12-associated domain containing 1) genes was reported to be associated with RA-ILD in a Japanese cohort . These genes play an important role in the modulation of telomere elongation. Also, the functional MUC5B rs35705950 promoter variant has been identified as a risk factor for RA-ILD, whereas it was not associated with RA without ILD . A large observational study showed a more than 10-fold elevated risk of ILD when having both the MUC5B promotor variant and RA when compared with the general population. Based on these results, it was suggested to use the MUC5B rs35705950 promotor variant for genomic risk stratification in patients with RA . Surprisingly, in the recently published study by Hayashi et al. , no association was found with the MUC5B promotor variant rs35705950 and the presence of RA-ILD, but this could be due to the low penetrance of this variant in the Japanese population. As genetics and geography are closely linked, it is necessary to look at different predominant genomic biomarkers based on differences in geography . All these biomarkers, both molecular and genetic, lack validation and have not yet been implemented in daily practice. An explanation for this can be found on multiple levels. Large, prospective patient cohorts are currently missing. Also, there is a scarcity of knowledge concerning RA-ILD pathogenesis and natural history, complicating the establishment of causal relationships and the differentiation of biomarkers for prognosis and development. Furthermore, these biomarkers need to be specific and cost-effective before implementation in practice. With the arrival of new antifibrotic therapeutic interventions, detecting RA-ILD early might become even more important, assuming these agents effectively decrease fibrotic disease progression. Currently there is no standardized screening method. Detection by high-resolution CT (HRCT) is performed on a case-by-case basis, where initial symptoms, such as a dry cough or dyspnoea upon exertion, can be masked by limited physical activity. Although the radiation dose in HRCT has been reduced over the years, there is still a small associated risk. Robust studies investigating other screening modalities are thus required, aiming to develop and subsequently implement a pragmatic, standardized screening protocol. The study results by Hayashi et al. must be interpreted with caution due to the relatively small sample size and geographical bias, yet also with enthusiasm, as this study sets the scene for further research. First, the association between RA-ILD and the PPFIBP2 rs6578890 gene variant needs to be confirmed in larger study cohorts and different geographical regions. Second, the causal role of the PPFIBP2 and CYB5R2 genes in the development of ILDs needs to be explored. Third, a role for genomic biomarkers both as a monogenetic test or as a polygenetic testing array for detection of patients at risk for the development of RA-ILD and for further prognostic stratification based on the underlying pathogenic mechanism needs to be examined. To conclude, a multimodal screening tool is needed, incorporating clinical, radiological, physiological, molecular and as supported by this work genetic factors. The tool should focus on the detection and, ideally, the prognosis of RA-ILD. The genetic panel will probably have to be adapted to geographical regions. Moreover, the risk stratification tool should be tested and validated in a large patient cohort and multiple geographical zones. Although lots of gaps in our knowledge regarding RA-ILD still need to be bridged, genes might constitute the possible missing link to reliably detect and prognosticate RA-ILD and could even provide a basis for personalized medicine. Data availability No new data were presented in this article. Authors' contributions M.V., T.G., S.G., D.D., P.V., W.A.W. contributed to the conception and design of the work. M.V., T.G., S.G., D.D., P.V., W.A.W. drafted and revised the text critically. Funding This work was supported by the Research Foundation-Flanders, as both M.V. (1SE4322N) and T.G. (1S73921N) have a PhD Fellowship from this institution. Disclosure statement: The authors have declared no conflicts of interest. References 1 Hayashi S , MatsubaraT, FukudaK et al A genome-wide association study identifying single nucleotide polymorphisms in the PPFIBP2 gene was predictive for interstitial lung disease in rheumatoid arthritis patients. Rheumatol Adv Pract 2022;6 :rkac088.36382269 2 Jacob J , HiraniN, van MoorselCHM et al Predicting outcomes in rheumatoid arthritis related interstitial lung disease. Eur Respir J 2019;53 :1800869.30487199 3 Cano-Jimenez E , Vazquez RodriguezT, Martin-RoblesI et al Diagnostic delay of associated interstitial lung disease increases mortality in rheumatoid arthritis. Sci Rep 2021;11 :9184.33911185 4 Florescu A , GherghinaFL, MusetescuAE et al Novel biomarkers, diagnostic and therapeutic approach in rheumatoid arthritis interstitial lung disease-a narrative review. Biomedicines 2022;10 :1367.35740390 5 Juge PA , BorieR, KannengiesserC et al Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis. Eur Respir J 2017;49 :1602314.28495692 6 Juge P-A , LeeJS, EbsteinE et al MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease. N Engl J Med 2018;379 :2209-19.30345907 7 Shirai Y , HondaS, IkariK et al Association of the RPA3-UMAD1 locus with interstitial lung diseases complicated with rheumatoid arthritis in Japanese. Ann Rheum Dis 2020;79 :1305-9.32737115 8 Palomaki A , PalotieA, KoskelaJ et al Lifetime risk of rheumatoid arthritis-associated interstitial lung disease in MUC5B mutation carriers. Ann Rheum Dis 2021;80 :1530-6.34344703 9 Battey CJ , RalphPL, KernAD. Predicting geographic location from genetic variation with deep neural networks. Elife 2020;9 :e54507.32511092 10 Furukawa H , OkaS, ShimadaK et al Association of human leukocyte antigen with interstitial lung disease in rheumatoid arthritis: a protective role for shared epitope. PLoS One 2012;7 :e33133.22586441 |
101708638 46693 J Open Source Softw J Open Source Softw Journal of open source software 2475-9066 36919162 10.21105/joss.02017 nihpa1834877 Article ggalluvial: Layered Grammar for Alluvial Plots Brunson Jason Cory 1 1 Center for Quantitative Medicine, UConn Health 9 9 2022 2020 21 5 2020 13 3 2023 5 49 2017 License Authors of papers retain copyright and release the work under a Creative Commons Attribution 4.0 International License (CC-BY). Summary Alluvial diagrams use stacked bar plots and variable-width ribbons to represent multi-dimensional or repeated-measures data comprising categorical or ordinal variables (Bojanowski & Edwards, 2016; Rosvall & Bergstrom, 2010). The ggalluvial package extends the layered grammar of graphics of ggplot2 (Wickham, 2016) to generate alluvial diagrams from tidy data (Wickham, 2014). The package makes two key contributions to the R ecosystem. First, ggalluvial anchors the imprecise notion of an alluvial diagram to the rigid grammar of graphics (Wilkinson, 2006), which lends the plots more precise meaning and opens up many combinatorial possibilities. Second, ggalluvial adopts a distinctive geological nomenclature to distinguish "alluvial plots" and their graphical elements from Sankey diagrams and parallel sets plots, which I hope prove useful as these visualization tools converge toward common standards. pmcFunctionality The primary vignette thoroughly describes and illustrates the functionality of ggalluvial, and the reader is encouraged to browse the package documentation for comprehensive examples. In brief, the package contains stat and geom functions to add the following layers to a ggplot2 object: strata, or stacked bar plots, located in parallel along a (plotting) axis of (variable) axes or dimensions alluvia, ribbons through strata that connect the categories of individual cases or cohorts at different axes lodes, subdivisions of strata by their intersections with alluvia flows, segments of alluvia between strata Figure 1 illustrates these and other plot elements by visualizing changes in several students' curricula (based on their declared majors) across several academic terms. Each axis corresponds to an odd-valued term (1 through 15), at which the students are grouped into strata according to their curricula Art History, Ceramic, etc. The individual students can be tracked from term to term along their alluvia: for instance, one student started out in Digital Art, encoded by the blue ribbon, but had switched to Painting by the 11th term, where the ribbon turns pink. The partially transparent flows are colored according to their originating (not their terminating) terms, and the lodes where they intersect the strata are obscured by the solid-colored strata themselves. When a student's curriculum is unknown, they are grouped into the "missing" (NA) stratum, which is weighted negatively in this example. Plot layers are formed by pairing stats (statistical transformations) with geoms (mappings to graphical elements and properties); while every stat and geom has a conventional default, alternative grammatical pairings provide combinatorial richness to plotting possibilities. In the above example, the alluvium geom was paired with the flow stat, so that the flows of each alluvium could change color across the axes. Other meaningful stat-geom combinations can be found in the documentation, including pairings of the three alluvial stats (stratum, alluvium, and flow) with the text, errorbar, and pointrange geoms. Alluvial layers can interpret tidy data in either of two formats: long (one row per lode) and wide (one row per alluvium). These are related by the pivot operations of tidyr (Wickham et al., 2019) and can be toggled between using the custom functions to_lodes_form() and to_alluvia_form(). The alluvial stats require custom aesthetics either stratum and/or alluvium in combination with x, if the data are in long format, or some number of axis specifications (axis1, axis2, etc.), if the data are in wide format.1 Because the alluvial geoms are specialized to these stats, no pairings with outside stats are currently supported. Most of the stat parameters control how the strata at each axis, and the lodes within each stratum, are ordered vertically. By default, these orderings are independent of differentiation aesthetics, so that layers are consistent within and across plots unless otherwise specified. An auxiliary vignette details the effects of these parameters. They can also be set as global options. Concepts Visualizations of flow processes have long encoded magnitudes as ribbon widths, constituting a type called Sankey diagrams (Schmidt, 2008). A widely-used subtype for longitudinal categorical data represent categories as nodes threaded by edges that represent the trajectories and magnitudes of cases (Riehmann, Hanfler, & Froehlich, 2005). Their design anticipated parallel sets plots, which were adapted from parallel coordinates plots (Inselberg & Dimsdale, 1987; Wegman, 1990) to visualize multivariate categorical data, and which represent cohorts of equivalent cases as ribbons connecting categories represented as boxes (Kosara, Bendix, & Hauser, 2006). These in turn anticipated "alluvial diagrams", proposed to visualize changes in case memberships across successive cross-sections (Rosvall & Bergstrom, 2010). Several R packages have been developed to generate diagrams of these types, including riverplot (Weiner, 2017), networkD3 (Allaire, Gandrud, Russell, & Yetman, 2017), sankey (Csardi & Weiner, 2017), alluvial (Bojanowski & Edwards, 2016), ggparallel (Hofmann & Vendettuoli, 2013), ggforce (Pedersen, 2019), ggalluvial (Brunson, 2019), and ggpcp (Ge & Hofmann, 2019). Sankey, parallel sets, and alluvial diagrams are often conflated, and there is currently no consensus on what features are distinctive to each type. Moreover, their graphical elements go by a variety of names, often interchangeably. In order to more clearly describe the features of ggalluvial in relation to similar packages, I have found it useful to adopt a careful demarcation among these diagram types. Statistical graphics (here also simply called "plots") are diagrams that communicate statistical information using graphical methods (Friendly, 2005) and, more narrowly, are uniquely determined from data by a fixed set of plotting rules (Wilkinson, 2006). By design, graphics produced by ggplot2 extensions are plots: The stat, geom, and other layers of a ggplot object exactly reproduce a graphic from data (under the same parameter settings).2 Sankey diagrams are much more flexible. The earliest engine efficiency diagrams in this tradition could take a variety of forms to depict the same energy flow and were differently annotated for different audiences (Schmidt, 2008). Software implementations may use heuristic algorithms to position their graphical elements (Allaire et al., 2017; Csardi & Weiner, 2017) or enable users to manually, even interactively, adjust them (Allaire et al., 2017; Riehmann et al., 2005; Weiner, 2017). Paradoxically, Sankey diagrams are overwhelmingly used to represent flow, whereas the aforecited ggplot2 extensions are used to visualize a wide variety of data types. Arguably, these extensions are better understood as producing a different type of diagram. Parallel sets plots might be viewed as a subtype of Sankey diagram with the following features: Ribbons proceed monotonically along one dimension, and every ribbon encounters a box at every axis. These graphical constraints correspond to combinatorial constraints on the data, which amount to an id-key-value structure in which every id-key pair takes exactly one value (possibly zero or missing, and optionally weighted). In this sense, the plots produced by the ggplot2 extensions (and by the alluvial package) are parallel sets plots: Cohorts are partitioned into categories at each axis and connected by ribbons whose widths encode their magnitudes.3 The plots produced still vary in the shapes of ribbons, the arrangements of boxes, and the presence of gaps between boxes at the same axis. The exceptional geoms of ggparallel each offer common-angle as well as linear ribbons. Those of alluvial, ggforce, ggalluvial, and ggpcp offer one-parameter families that interpolate between straight and x-spline ribbons.4 The stats vertically arrange the elements (boxes and ribbons) at each axis. These distinct elements are rendered by separate layers in ggforce, ggalluvial, and ggpcp, following the additive (+) syntax of ggplot2. ggalluvial provides more levers of control over the statistical transformations, thereby over the messages conveyed by the plot, than the other packages.5 The ggalluvial package adopts the term alluvial plot for the subtype of parallel sets plots it produces, with the geological terminology introduced above.6 These alluvial plots are distinguished by two features: a prescribed order on the stacked elements at each axis, including both the values of the discrete variables and the ribbons connecting cases or cohorts between them; and a real-valued plotting dimension perpendicular to that of flow, along which these elements are stacked, so that gaps between them are precluded. In combination, these features confer greater meaning on the second plotting dimension. The first feature is shared by the other packages but is not essential to parallel sets plots; such plots could, for example, arrange boxes corresponding to repeated categorical decompositions differently at different axes. While most of the packages separate boxes at each axis with gaps, these can be reduced to zero, so that each package can create alluvial plots. (ggparallel and ggalluvial alone only produce alluvial plots.) These features are particularly important to some applications and, in my view, can fundamentally change the way a plot is interpreted. It is for this reason that I believe the new typology and terminology are warranted. Applications While most uses might be served equally well by other parallel sets plots or Sankey diagrams, alluvial plots seem exceptionally well-suited to three settings: repeated ordinal measures data, incomplete longitudinal data, and signed categorical data.7 Repeated ordinal measures data. Most Sankey, parallel sets, and alluvial implementations stack each bar plot in order of name or of size (though some follow user-provided hierarchies), and most insert gaps between categories for easy visual discrimination. Ordinal variables are most appropriately stacked in their own intrinsic and consistent order and, when the number of categories (hence of gaps) changes from axis to axis, vertical separations can obscure whether magnitude totals changed as well. A use case by Schlotter et al. (2019), to represent patients' physical limitations following an investigational right heart valve repair technique, illustrates the use of an ordinal stratum variable (a heart failure functional classification). Another, by North, Kothe, Klas, & Ling (2019), to represent ranked preferences among several definitions of veganism by survey respondents, illustrates the importance of consistency in their order. In both cases, the fixed heights of the bar plots conveyed that no individuals were lost to follow-up. Incomplete longitudinal data. Alluvial plots clearly indicate times at which longitudinal data are censored or otherwise missing: Certain strata, or the alluvia or flows connecting them, are present at one time point but absent at a previous or future one. Seekatz et al. (2018) use this feature to include in one alluvial plot a sample of Clostridium difficile-infected patients who had their infections ribotyped at multiple times. Patients were classified by dominant ribotype, and the alluvial plot showcased variability in this classification. While all 32 patients had at least two samples taken, only 3 had four, communicated by the shortening of the bar plots along the main dimension. Sjoding, Gong, Haas, & Iwashyna (2019) use a similar plot to trace patient groups receiving mechanical ventilation based on discretized tidal volumes, including a grey stratum for patients discontinued from intubation. Signed categorical data. Edwards & Pinkerton (2019) produced a novel alluvial plot to represent changes in ownership category of owners in a halibut fishery. The total number of owners changed from year to year as exiters were not exactly matched by new entrants. In order to depict an accurate total but include both new entrants and exiters at each year, the authors affixed a negative stratum for the exiter category to each bar plot.8 Such a feature has no analogue in Sankey diagrams or parallel sets plots but potentially wide-ranging applications: Bar plots may use "positive" and "negative" bars to represent signed categories, such as contributors to revenue versus deficit, or to contrast the bars divided along a binary variable such as gender across age groups in a population ("pyramid plots"). Alluvial plots provide a way to track cases and cohorts across such graphics, even when cases change sign. Future applications may demonstrate additional uses for this functionality. Acknowledgments I am grateful to many users for their feedback on every version of this package. Development benefitted from the use of resources and support of colleagues at UConn Health, and I have been supported in part by T90 training grant 5T90DE021989-07 from the National Institute of Dental and Craniofacial Research. Figure 1: Alluvial plot of changes in curricula by a cohort of art students 1 Because these aesthetics are not recognized by ggplot2, they produce warnings under some conditions. 2 There are exceptions. For example, the jitter geom in ggplot2 introduces randomness to symbol positions, and the repel geoms of ggrepel (Slowikowski, 2019) use heuristic algorithms to position text. 3 The possible exceptions are the hammock plots and common angle plots of ggparallel, which are contrasted with a stricter definition of parallel sets plots than I use here, in which ribbons are straight, their widths aggregate to box widths, and they meet without overlap at the sides of boxes, partitioning them (Hofmann & Vendettuoli, 2013). 4 Several alternative curves, based on Shaffer (2019), are in development. 5 Indeed, the dependency package easyalluvial (Koneswarakantha, 2019) was built on top of ggalluvial to exchange much of this flexibility for more expedient data exploration. 6 This has the unfortunate side effect of conflating search results from the geology literature. 7 To be sure, this is a subjective assessment that may be refuted by visualization effectiveness research. 8 The authors should be credited with this innovation, which I only implemented in ggalluvial after learning about their workaround to create it using a previous version. References Allaire JJ , Gandrud C , Russell K , & Yetman CJ (2017). networkD3: D3 JavaScript Network Graphs from R. Retrieved from Bojanowski M , & Edwards R (2016). alluvial: R Package for Creating Alluvial Diagrams. Retrieved from Brunson JC (2019). ggalluvial: Alluvial Plots in 'ggplot2'. Retrieved from Csardi G , & Weiner J (2017). sankey: Illustrate the Flow of Information or Material. Retrieved from Edwards DN , & Pinkerton E (2019). Rise of the investor class in the British Columbia Pacific halibut fishery. Marine Policy, 109 . doi:10.1016/j.marpol.2019.103676 Friendly M (2005). Milestones in the History of Data Visualization: A Case Study in Statistical Historiography. In Classification the ubiquitous challenge. Studies in classification, data analysis, and knowledge organization (pp. 34-52). Berlin/Heidelberg: Springer-Verlag. doi:10.1007/3-540-28084-7_4 Ge Y , & Hofmann H (2019). ggpcp: Parallel Coordinate Plots in the ggplot2 Framework. Retrieved from Hofmann H , & Vendettuoli M (2013). Common angle plots as perception-true visualizations of categorical associations. IEEE Transactions on Visualization and Computer Graphics, 19 (12 ), 2297-2305. doi:10.1109/TVCG.2013.140 24051796 Inselberg A , & Dimsdale B (1987). Parallel Coordinates for Visualizing Multi-Dimensional Geometry. In Computer graphics 1987 (pp. 25-44). Tokyo: Springer Japan. doi:10.1007/978-4-431-68057-4_3 Koneswarakantha B (2019). easyalluvial: Generate Alluvial Plots with a Single Line of Code. Retrieved from Kosara R , Bendix F , & Hauser H (2006). Parallel sets: Interactive exploration and visual analysis of categorical data. In IEEE transactions on visualization and computer graphics (Vol. 12 , pp. 558-568). doi:10.1109/TVCG.2006.76 16805264 North M , Kothe E , Klas A , & Ling M (2019). "It's not just a diet, it's a lifestyle": An Exploratory Study into Community Preferences of Vegan Definitions. PsyArXiv. doi:10.31234/OSF.IO/MKQN4 Pedersen TL (2019). ggforce: Accelerating 'ggplot2'. Retrieved from Riehmann P , Hanfler M , & Froehlich B (2005). Interactive Sankey diagrams. In IEEE symposium on information visualization, 2005. INFOVIS 2005. (pp. 233-240). IEEE. doi:10.1109/INFVIS.2005.1532152 Rosvall M , & Bergstrom CT (2010). Mapping Change in Large Networks. (Rapallo F ,Ed.)PLoS ONE, 5 (1 ), e8694. doi:10.1371/journal.pone.0008694 20111700 Schlotter F , Orban M , Rommel K , Besler C , Roeder M , Braun D , Unterhuber M , (2019). Aetiology-based clinical scenarios predict outcomes of transcatheter edge-to-edge tricuspid valve repair of functional tricuspid regurgitation. European Journal of Heart Failure, 21 (9 ), 1117-1125. doi:10.1002/ejhf.1547 31359620 Schmidt M (2008). The Sankey Diagram in Energy and Material Flow Management. Journal of Industrial Ecology, 12 (1 ), 82-94. doi:10.1111/j.1530-9290.2008.00004.x Seekatz AM , Wolfrum E , DeWald CM , Putler RKB , Vendrov KC , Rao K , & Young VB (2018). Presence of multiple Clostridium difficile strains at primary infection is associated with development of recurrent disease. Anaerobe, 53 , 74-81. doi:10.1016/j.anaerobe.2018.05.017 29859301 Shaffer J (2019, May 13). Sankey diagrams: Why i used the sigmoid function and why you probably shouldn't. Sjoding MW , Gong MN , Haas CF , & Iwashyna TJ (2019). Evaluating Delivery of Low Tidal Volume Ventilation in Six ICUs Using Electronic Health Record Data. Critical Care Medicine, 47 (1 ), 56-61. doi:10.1097/CCM.0000000000003469 30308549 Slowikowski K (2019). ggrepel: Automatically Position Non-Overlapping Text Labels with 'ggplot2'. Wegman EJ (1990). Hyperdimensional Data Analysis Using Parallel Coordinates. Journal of the American Statistical Association, 85 (411 ), 664-675. doi:10.1080/01621459.1990.10474926 Weiner J (2017). riverplot: Sankey or Ribbon Plots. Retrieved from Wickham H (2014). Tidy Data. Journal of Statistical Software, 59 (10 ), 1-23. doi:10.18637/jss.v059.i10 26917999 Wickham H (2016). ggplot2: Elegant Graphics for Data Analysis. New York: Springer-Verlag. doi:10.1007/978-0-387-98141-3 Wickham H , Averick M , Bryan J , Chang W , D'Agostino LM , Francois R , Grolemund G , (2019). Welcome to the Tidyverse. Journal of Open Source Software, 4 (43 ), 1686. doi:10.21105/joss.01686 Wilkinson L (2006). The Grammar of Graphics (2nd ed.). Springer Science & Business Media. doi:10.1007/0-387-28695-0 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34868 Neurology Pediatrics Radiology Dyke-Davidoff-Masson Syndrome: A Case Report Muacevic Alexander Adler John R Chunchu Venkata Anirudh 1 Kommalapati Nishitha 2 Pemma Sai Sarath Kumar 1 Mane Manohar Manish Prajwal 3 Nalamalapu Rahul Reddy 4 1 Medicine, Avalon University School of Medicine, Willemstad, CUW 2 Medicine, John F. Kennedy University, Willemstad, CUW 3 Surgery, Avalon University School of Medicine, Willemstad, CUW 4 Radiology, Alluri Sitarama Raju Academy of Medical Sciences, Eluru, IND Venkata Anirudh Chunchu [email protected] 11 2 2023 2 2023 15 2 e3486811 2 2023 Copyright (c) 2023, Chunchu et al. 2023 Chunchu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Dyke-Davidoff-Masson syndrome (DDMS) is a rare neurological entity that is predominantly seen in childhood. Here, we present the case of a 13-year-old girl who was brought to the pediatric ward for general examination with a previous history of seizures, speech difficulty, facial deviation, and progressive left-sided hemiparesis that started at the age of two, followed by delayed developmental milestones. Computed tomography (CT) and magnetic resonance imaging (MRI) of the brain showed right cerebral hemiatrophy, ventriculomegaly, hyperpneumatization of the sinus, the decreased caliber of cortical veins, and skull thickening on the right were all characteristic findings of DDMS. Based on the history, clinical presentation, and imaging findings from CT and MRI, DDMS was confirmed. Identifying DDMS in a clinical setting can be challenging because of low awareness of the condition and varied clinical presentations. Although CT and MRI imaging are the gold standards in diagnosing DDMS, the early manifestations of the disease cannot be well-appreciated on a CT and would likely require an MRI. Since there is no standardized protocol for managing DDMS, the treatment is primarily symptomatic. Early identification and diagnosis of the syndrome are essential to aid the child's mental and physical development through a multidisciplinary approach. There is also a need to improve awareness of DDMS so that the condition can be considered a potential differential diagnosis amongst other similar conditions and does not get misdiagnosed. The lack of a proper protocol for the management of DDMS prompts more research for a better understanding and early identification of the condition. dyke-davidoff-masson syndrome (ddms) magnetic resonance imaging (mri) computed tomography (ct) hyperpneumatization hemiplegia cerebral hemiatrophy The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Dyke-Davidoff-Masson Syndrome (DDMS) was first described by Dyke, Davidoff, and Masson in 1933 . It is characterized by hemiparesis, facial asymmetry, seizures, learning disabilities, and mental retardation. The etiology can be congenital or acquired. It is usually seen in childhood as a result of an intrauterine or early childhood alteration to the developing brain . Typical radiographic findings include cerebral hemiatrophy with ipsilateral ventriculomegaly, compensatory enlargement of the skull, and significant sulcal spaces . DDMS is relevant to the field of neurology and developmental pediatrics as it is a rare condition that has few documented cases in medical literature and can be easily misdiagnosed. DDMS can have a significant impact on a patient's development and quality of life. Here, we present the case of a 13-year-old female who has a history of seizures, speech difficulty, facial deviation, and progressive left-sided hemiparesis who was diagnosed with DDMS from MRI and CT. The report provides detailed information on the patient's medical history, physical examination, laboratory workups, and imaging findings. The report also highlights the characteristic clinical and radiographic findings of DDMS, as well as the possible causes and potential outcomes of the condition. This case report provides valuable information that can help other healthcare professionals in understanding and managing patients with DDMS. Case presentation A 13-year-old female with a past history of seizures, speech difficulty, facial deviation, and progressive left-sided hemiparesis was brought to the pediatric ward for a general examination. The patient was born at full term to non-consanguineous parents with no significant history of antenatal or perinatal complications. The patient has reached all developmental milestones and appeared normal until 22 months. At age two, she had a fever for three days, followed by multiple episodes of generalized tonic-clonic seizures, each lasting up to 2-3 minutes, during which she experienced stiffening of the left upper extremity and deviation of the gaze upwards. She was admitted and treated at the local hospital and started on antiepileptic medication. She has had two seizure episodes since then, one at the age of three and the other at the age of four. Gradually, she developed weakness in her left upper and lower extremities along with facial deviation, followed by delayed developmental milestones, including fine motor and language delays. She could not copy a circle or a triangle and did not know her name or gender until she was eight years old. The following year, she lost her ability to speak and developed poor dexterity in her left hand, which is steadily deteriorating. Her parents reported that she did not have hearing or visual problems. On physical examination, the patient is alert, oriented, and responsive to commands. Her intelligence quotient (IQ) was found to be 55, which corresponds to mild mental retardation. Vital signs: blood pressure was 110/72 mmHg, heart rate 82 beats per minute, respiratory rate 20 per minute, temperature 96degF, oxygen saturation 98%, and peripheral pulse 2+ bilaterally. She had a height and weight of 1.54 m and 63 kg, respectively, with a body mass index (BMI) of 26.6 kg/m2, which is over the expected weight for her height and age. Vision and hearing are normal. Cranial nerve and sensory examinations were unremarkable. No neurocutaneous markers were found. The gait is abnormal. A neurological exam revealed 3/5 power in the left upper and lower extremities, brisk reflexes, and a flexor plantar response. Power at the left wrist joint was 2/5. The right upper and lower extremities had a score of 5/5. Hypotonia on the left upper and lower limbs was present. Upper and lower limb sensation and proprioception were normal. There was no neck rigidity, signs of cerebellar dysfunction, or bladder-bowel involvement. Other systemic examinations were unremarkable. Laboratory workups include baseline investigations. Complete blood count and comprehensive metabolic panel investigations, such as renal, liver function, CRP, and electrolytes, were within normal limits. MRI of the brain revealed hemiatrophy changes in the right cerebral hemisphere with adjacent dilation of the ipsilateral ventricle and hyperpneumatization of the frontal sinus . In addition, a decreased caliber of cortical veins in the right cerebral hemisphere was noted. MRI of the brain revealed dilated lateral right ventricular horn . A plain and contrast CT of the brain was subsequently done, which revealed atrophy of the right cerebral hemisphere with dilatation of the ipsilateral ventricle and calvarial thickening noted in the right hemicranium . There is also a widening of sulci and atrophy of gyri on the right cerebral hemisphere . A final diagnosis of DDMS was made after comparing the imaging findings and clinical presentation. Figure 1 Axial T2-weighted MRI of the brain demonstrates hemiatrophy changes in the right cerebral hemisphere (white arrow) and hyperpneumatization of the frontal sinus (red arrow). MRI: magnetic resonance imaging Figure 2 Coronal T2 FLAIR MRI of the brain demonstrates dilated lateral horn of right ventricle. MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery Figure 3 Plain CT images of the brain show atrophy of the right cerebral hemisphere (green arrow) with ipsilateral ventriculomegaly (blue arrow) and ipsilateral calvarial thickening (yellow arrow). CT: computed tomography Figure 4 Plan CT images of the brain show widening of the sulci and atrophy of the gyri in the right cerebral hemisphere. CT: computed tomography Our patient was diagnosed with DDMS after carefully ruling out other neurological pathologies that can affect a similar pediatric age group and can present with similar symptoms. Imaging played a vital role in ruling out other disease conditions, especially pathologies like Rasmussen's encephalitis and Sturge-Weber syndrome (SWS). The patient's parents were educated about the syndrome and the disease's possible progression. The patient was advised to have frequent neurological follow-ups to take care of any symptomatic changes or to consider other needs like physiotherapy in the future with disease progression. Discussion DDMS was first defined in 1933 by Dyke, Davidoff, and Masson . It is a rare neurological condition characterized by cerebral hemiatrophy or hypoplasia. The etiology can be congenital or acquired, which is caused by an injury to the developing brain during the prenatal period or in early childhood, usually traumatic . Clinical features are variable and can be present with different manifestations according to the extent of brain injury. Patients typically present with clinical characteristics including facial asymmetry, recurrent seizures, contralateral hemiplegia, learning disability, mental retardation, and delayed developmental milestones. Occasionally, psychiatric disorders such as schizophrenia and schizoaffective disorder have also been reported. Cerebral hemiatrophy with ipsilateral ventriculomegaly, compensatory enlargement of the skull, and significant sulcal spaces are typical radiographic findings . Other observed radiologic findings include hyperpneumatization of the frontal sinuses, ethmoid air cells, mastoid air cells, and air cells of the petrous temporal bone on the affected side [5-7]. They hypothesized that these were compensatory alterations caused by congenital or acquired brain injuries that reduced cerebral cortical volume. The congenital form states that the cerebral insult likely occurred in-utero due to vascular malformation, cerebral infarction, coarctation of the mid-aortic arch, gestational vascular occlusion, and infections. In the acquired form, the cerebral insult likely occurred during the perinatal or postnatal period, caused by hypoxia, birth trauma, tumors, infections, prolonged febrile seizures, and intracranial hemorrhage . In both sexes, either of the hemispheres can be affected by DDMS. However, the involvement of the male sex and the left hemisphere has been demonstrated to be more prevalent . Identifying DDMS in a clinical setting can be challenging because of low awareness of the condition, and especially more so because of varied clinical presentations. Like in this patient where she initially presented only with seizures but then eventually, after a few years, displayed facial deviation, left-sided hemiparesis, speech difficulty, and mental deterioration. Any unsuspecting clinician would treat this patient only for the seizures and would fail to identify the larger cause, especially in underprivileged areas where it is difficult to obtain expensive imaging like MRI. Although CT and MRI imaging are the gold standards in diagnosing DDMS, the early manifestations of the disease cannot be well-appreciated on a CT and would likely require an MRI as it would provide more detail on cross-sectional images . A thorough history, extensive neurological and cognitive assessment along with characteristic radiologic findings are needed to provide a correct diagnosis of DDMS. Other differential diagnoses that should be differentiated from DDMS are Rasmussen encephalitis, SWS, Fishman syndrome, basal ganglia germinoma, linear nevus syndrome, and Silver-Russell syndrome, as these conditions share similar imaging findings and presentations as DDMS. Rasmussen encephalitis is a severe immune-mediated brain dysfunction in children with cognitive defects and seizures, with similar imaging findings as hemispheric atrophy, but calvarial changes are not observed . SWS is distinguished by the classic triad of glaucoma, port-wine nevus, and leptomeningeal angiomas, which are the sources of stroke-like symptoms, seizures, hemiparesis, mental retardation, along with developmental delays . Fishman syndrome is a rare congenital neurocutaneous disease characterized by intellectual disability, cerebral calcification, seizures, ipsilateral cerebral malformation, unilateral temporofrontal lipomatosis, and leptomeningeal lipomatosis . Basal ganglia germinoma may present with cerebral hemiatrophy and progressive hemiparesis . The characteristic features of linear nevus syndrome are facial nevus, cyclic refractory seizures, growth restriction, mental retardation, and unilateral ventriculomegaly . Silver-Russell syndrome is an imprinting gene disorder characterized by severe intrauterine and postnatal growth restriction. Along with a severe delay in developmental phenotype that affects the height and bone length, it has a characteristic facial phenotype (triangular face, micrognathia with pointed chin, thin wide mouth, and broad forehead). It is also accompanied by additional dysmorphic features like fifth finger clinodactyly and hemihypertrophy without affecting mental capacity . Since there is no standard protocol for managing DDMS, the treatment is primarily symptomatic, which includes anticonvulsants for seizures. In cases of intractable disabling seizures, hemispherectomy is an available neurosurgical option and has reported an 85% success rate. Long-term management includes physiotherapy for hemiparesis, occupational therapy, speech therapy for speech defects, psychiatric counseling, and medications if required . Conclusions DDMS is a rare syndrome with few cases described in medical literature, and it can be easily misdiagnosed by inexperienced clinicians if not diligently looked after. Early identification and diagnosis of the syndrome are essential to aid the child's mental and physical development through a multidisciplinary approach. Imaging studies play a crucial role in identifying such pathologies. Hence, although expensive, it is important to consider advanced imaging studies like MRI to facilitate the diagnosis and not stop after a CT to avoid any missed diagnosis of the disease. There is also a need to improve awareness of DDMS so that the condition can be considered a potential differential diagnosis amongst other similar conditions and does not get misdiagnosed. The lack of a proper protocol for the management of DDMS prompts more research and a better understanding of the condition. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Dyke-Davidoff-Masson syndrome: a case report with a literature review Radiol Case Rep Hamid M Cherradi S Satte A Bourazza A 2616 2618 17 2022 35663814 2 Dyke-Davidoff-Masson syndrome: a case report and review of literature Cureus Younas A Saim M Maqsood H Younus S Raza MH 0 12 2020 3 Dyke-Davidoff-Masson syndrome J Neurosci Rural Pract Behera MR Patnaik S Mohanty AK 411 413 3 2012 23189018 4 Treatment-refractory schizoaffective disorder in a patient with Dyke-Davidoff-Masson syndrome CNS Spectr Amann B Garcia de la Iglesia C McKenna P Pomarol-Clotet E Sanchez-Guerra M Orth M 36 40 14 2009 19169186 5 Cerebral hemiatrophy with homolateral hypertrophy of the skull and sinuses Surg Gynecol Obstet Dyke CG Davidoff LM Masson CB 588 600 57 1933 6 MR of craniocerebral hemiatrophy Clin Imaging Sener RN Jinkins JR 93 97 16 1992 1547482 7 Dyke-Davidoff-Masson syndrome (DDMS) Indian J Pediatr Pendse NA Bapna P Menghani V Diwan A 943 71 2004 15531842 8 Classical oral manifestations of Dyke-Davidoff-Masson syndrome: a case report with review of the literature J Korean Assoc Oral Maxillofac Surg Kalaskar R Kalaskar AR 198 203 44 2018 30181987 9 Left hemisphere and male sex dominance of cerebral hemiatrophy (Dyke-Davidoff-Masson Syndrome) Clin Imaging Unal O Tombul T Cirak B Anlar O Incesu L Kayan M 163 165 28 2004 15158218 10 Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement Brain Bien CG Granata T Antozzi C 454 471 128 2005 15689357 11 Computed tomography in cerebral hemiatrophy AJR Am J Roentgenol Jacoby CG Go RT Hahn FJ 5 9 129 1977 409143 12 Haberland syndrome: a very rare case report Indian J Health Sci Biomed Res Shah DJ Gupta R Solanki BB 328 330 9 2016 13 Linear nevus sebaceous syndrome in a child with infantile spasms and focal cortical dysplasia Cureus Salman S Fathalla W Akbari H 0 13 2021 14 Silver-Russell syndrome: genetic basis and molecular genetic testing Orphanet J Rare Dis Eggermann T Begemann M Binder G Spengler S 19 5 2010 20573229 15 Phenotype of genetically confirmed Silver-Russell syndrome beyond childhood J Med Genet Lokulo-Sodipe O Ballard L Child J 683 691 57 2020 32054688 16 Dyke-Davidoff-Masson syndrome: a delayed diagnosis of an acquired variant J Med Res Innov Kumar TS Vipul A Yadav R 121 2 2018 |
This study aims at presenting a case of symmetrical and bilateral thinning observed in a skull belonging to the skeleton of a mature woman from the medieval cemetery of Caravate (north Italy). Macroscopical, radiological, and histological analyses were performed to investigate the condition. The analyses allowed us to detect a progressive loss of both the outer table and the diploe, and the sparing of the inner table. As a controversial condition in the clinical and paleopathological literature, this case poses some difficulties in discussing the differential diagnosis. However, the sex determination, estimation of the age-at-death and different characteristics observed at the level of the postcranial bones, in particular the fractures recorded on different vertebral bodies, allowed us to correlate the biparietal thinning found in this subject to ageing and osteoporosis. Keywords Biparietal thinning Medieval Age north Italy osteoporosis paleopathology OPEN-ACCESSTRUE pmcSymmetrical and bilateral thinning (SBT) of the parietal bones is a controversial condition discussed both in palaeopathological and clinical literature. Indeed, in the past, SBT was described as a nonmetric trait, an anatomical variation, and a developmental anomaly. Although its etiology is still unknown, some authors have considered biparietal thinning as a pathological lesion.1,2 In modern clinic, it is particularly recorded in individuals aged over 60 years and registers an estimated incidence between 0.4% and 2.37%.3 Its incidence is probably underestimated, since the detection of this condition, mostly asymptomatic, usually occurs randomly during diagnostic analyses. However, this condition shows no connection with phenotype or predisposition for a specific geographic area.4 From a macroscopic and a radiological point of view, it is recognized as a flat oval or quadrilateral alteration.5 Microscopically, SBT is characterized by the erosion, loss of substance, and remodeling of the external table and diploe, and an intact inner table.1,2,4,6,7 Today, it is still not possible to clarify the origin of this type of lesion. Even if authors have elaborated several hypotheses linked to its etiology as senescence, trauma, muscular traction, inflammatory reaction, none of these can explain its symmetry, its localization, or its age/sex predilection.1-8 Palaeopathological literature shows several findings of SBT. The most ancient case has been documented in India, in a skull from the Bronze Age.9 The recorded cases come from different areas of the world. However, researches are especially concentrated on the Egyptian sample. In particular, one of the most extensive analysis on SBT find a prevalence of the condition in 4.9% of cases in a sample of about 1000 subjects10,11; in Breitinger study,12 4 skull out of 27 specimens (14.4% of prevalence) showed SBT; in Tomb 32 of the necropolis of Thebes, the occurrence of SBT was up to 30% (in a sample of 312 adults).13,14 The development of bioarchaeological sciences, through the excavations of other necropolis and the study of new osteoarchaeological samples, will certainly bring to light other evidence of this condition also in different places of the world. Moreover, the advanced observational methods applied on ancient human remains will allow discovering pathological signs from the past until now unknown and enriching the diagnostic analysis in the clinical experience. In this paper, we present a case of SBT recorded on the skeleton of a woman discovered in a medieval Italian cemetery 15,16 and discuss this condition from the morphological, radiological, and histological point of view. MATERIALS AND METHODS From 2001 to 2019, archaeological investigations conducted in the medieval site of the church of Saint Agostino in Caravate (Varese, north Italy) allowed us to discover a funeral area dated back to High Middle Ages, exploited approximately from the 11th century.17 Several archaeological phases have been recovered and, until now, 20 structured tombs, 2 of them reused as common ossuary, have been brought to light (Fig. 1).18,19 FIGURE 1 Planimetry of Caravate necropolis. The bioarchaeological study conducted by the researchers of the Centre of Research of Osteoarchaeology of the cemetery of Saint Agostine allowed us to discover different anthropological aspects of a medieval population of North-Western Lombardy.20,21 The skeleton under investigation laid inside an anthropomorphic tomb-oriented East-West (tomb 8). The upper portion from the skull to the pelvis lay on a raised level. The upper limbs were crossed on the abdomen whereas the lower ones were stretched parallel to each other. The column maintained its anatomical connection and the pubic symphysis was not disjoint. The kneecaps were fallen medially. The taphonomic characteristics of the inhumation, in association with the position of the tile covering the cranium, suggest a deposition in full space (Fig. 2). FIGURE 2 Tomb 8 of the cemetery area of Sant'Agostino in Caravate. In order to reconstruct the biological profile of the skeleton (Fig. 3A-B) we proceeded with the anthropological analysis. Sex determination was carried out by using macroscopic methods, through the observations of morphological features of the skull22 and the morphology23,24 and measures of the pelvis.25 Age at death was estimated through the analysis of cranial sutures,26 degenerative changes of the pubic symphysis and senescence of the auricular surface.27,28 Bone measurements and anthropometric index were calculated following Martin and Saller.29 We applied Trotter and Gleser formulae to obtain the determination of stature.30 To reveal pathological conditions, a depth observation of all bone segments was conducted. FIGURE 3 (A) state of preservation of the skeleton and (B) diagrammatic illustration of its state of its representation. Radiographic analyses were carried out at the Gaetano and Piera Borghi Foundation (Brebbia, VA). For the realization of the radiographic images, a DR Fujifilm machine was used with an exposure (100 ms) at 55 kV to 100 mA. Computer tomography analyses were performed with a Hitachi Eclos 16 machine with 90 to 120 kV, 100 to 400 mA exposure. Histological investigations were also carried out. The bone tissue sample was incorporated in Technovit 7200 resin. The thin section of 300 to 400 mm was observed under an Aristoplan Leitz optical microscope under normal light. RESULTS The skeleton of tomb 8 belonged to a woman with an estimated age at death of 45 to 55 years and 152 to 155 cm tall. The anthropometric measurements of the skull highlighted a brachycranic shape, and the postcranial indexes showed a general weakness of the biomechanical structures of the limbs. The parietal bones display 2 elliptical and symmetrical depressions: the right one measured 68.8 x 53.5 mm and the left one measured 73.0 x 57.1 mm. Both lesions show an antero-posterior direction and are located between the temporal line and the sagittal suture (Fig. 4). FIGURE 4 Elliptical and symmetrical depressions located between the temporal line and the sagittal suture of the skull of the individual from Tomb 8: (A) frontal view; (B) left lateral view; (C) superior view. The right parietal presents a minimum thickness of the cranial theca of 0.75 mm, whereas the left parietal of 0.79 mm. In section, the progressive disappearance of the diploe and the exposure of the internal surface was clearly visible (Fig. 5A). The endocranial surface also presents nonspecific multifocal lesions with a serpentine appearance, located on the frontal and on the parietals, from the frontal crest continuing along the superior sagittal sinus (Fig. 5B-C). The same aspect was also observed at the level of the areas of thinning (Fig. 5D-E). FIGURE 5 (A) Section of the left parietal with clearly disappearance of diploic tissue and exposure of the inner table; (B) serpentine lesions along the frontal crest and sagittal sinus on the endocranial surface of the frontal bone; (C-D) serpentine lesions and exposure of cribrotic tissue on the endocranial surface of parietal bones; (E) serpentine lesions at 16x magnification. On the skull, other pathological evidences were recorded. At the maxillary level, the subject is completely edentulous and in the mandible most teeth were lost in life (I2-M3 on the right and M1-M3 on the left side). Indeed, in the alveoli, a clear retraction of the vestibular bone tissue was observed. The mandibular sites of left C and I2 are affected by a cystic granuloma that caused part of the destruction of the cortical bone in the buccal position. The mandible and palatine bones are also affected by an extremely retracted and thin cortical tissue. On the post cranial skeleton arthrosis of the spine was highlighted. This condition is particularly expressed on the cervical and lumbar tracts where there was evident osteophytosis of the edges of the vertebral bodies. Besides, an advanced rarefaction of the cancellous bone was visible on the lumbar spine, whereas different lumbar vertebrae present compression fractures. The computer tomography analyses on the skull allowed us to better understand the lesions and to detect the progressive loss of the diploe and the external bone table, whereas the inner surface appears to be preserved (Fig. 6A-D). Radiological investigations made it possible to detect alterations of the typical curvature of the parietals and strongly expanded venous channels along the sagittal sinus visible in the coronal section. FIGURE 6 CT coronal vision, symmetrical depression of the parietals, (A) resorption of the external table and of the diploe, (B) 3d reconstruction of the skull, (C) left lateral view, (D) right lateral view. CT, computer tomography. The histology of an affected portion of parietal bone showed the presence of parallel bone lamellae extended along the entire length of the lower margin of the section. The median portion of the slice displays the presence of osteonic systems with visible Haversian canals surround by lamellar bone. In the upper margin of the section, we noted the absence of parallel lamellar bone covering the osteonic lamellae. Several slight irregularities along the margin were instead observed (Fig. 7A-B). FIGURE 7 Histological section of an affected portion of parietal bone, observed in normal light (10x magnification). The inner cranial table is on the lower side of the section. The presence of parallel bone lamellae in the lower margin is displayed. In the area above, in the median portion of the section, several osteonic structures immersed in lamellar bone are visible. (A) In the upper margin, no laminated outer layer is observed and several irregularities are noted along the border. In the lower margin of the section, a slight area of remodeling (B) and a thin canal opened in the lamellar bone are displayed (C). An osteonic structure, interested by the erosion and progressive thinning, is observable near the upper margin at the extreme right of the section (D). In the lower margin of the section, a slight area of bone loss and remodeling was observed (Fig. 7C-D). Moreover, a thin canal, opened in the lower marginal lamellar bone, was noted (Fig. 7C). DISCUSSION The skeleton shows symmetrical cranial depressions involving both parietal bones in the same location. This case proves to be very interesting, as the cranium appears to be affected by an intense remodeling and loss of substance. As the appearance of this condition respects a symmetrical and bilateral disposition on the parietal bones, our reading of the case refers to a severe condition of biparietal thinning. Albeit rarely documented, biparietal thinning appears to have been present elsewhere in the past and in today's clinic. Most of the authors agree in affirming that we can observe this condition at all latitudes and with greater frequency in female individuals with a ratio of 1:1.9, although the causes are still debated.3-6 Biparietal thinning is a condition that usually affects symmetrically the parietal bones; the lesions generally are oval-shaped and localized between the temporal line and the sagittal suture; the internal surface is usually spared whereas the outer table and diploe are thinned until their disappearance.1 Bruyn and Bots described 2 types of biparietal thinning related to each other: flat or grooved.1 In 1982, Cederlund classified the degree of the parietal thinning from a radiological point of view. Three stages were observed as follows: 1. thinning is barely recorded and in tomographic images a radiolucent area is highlighted; 2. a considerable thinning is documented, in particular the loss of more than half of the bone substance, even if the diploe is preserved, is noticeable; 3. external table is affected and the total loss of the diploe and of the outer table is recorded.3 As some academics highlight, magnetic resonance and computer tomography imaging show the thinning or the absence of the external table, the gradual loss of the diploe and an intact internal surface in the area of the lesion.6,7,31-33 For more than 2 centuries researchers have tried to investigate the etiological nature of this condition. The first detailed description of the condition was elaborated by Sandifort in 1783 in Exercitationes Academicae.34 Different causes have been associated to the condition by several authors. Among others, developmental dysplasia, constant pressure on bones, growth defects, diabetes mellitus, congenital dysplasia of the diploe, primary metastatic tumors, hormonal changes, inflammatory arthropathy associated with trauma, gonadal insufficiency, Gorham disease, senile changes of the temporal artery and simple anatomical variation, osteomyelitis, granulomatous diseases, aseptic necrosis, systemic mastocytosis prolonged steroid therapy, bone aneurysm, and cystic angiomatosis of bone.11 Indeed, many researchers linked the biparietal thinning condition to genetic factors11, others to vascular causes.35-37 Other authors consider the condition age-related,38,39 or a consequence of postmenopausal40,41 or senile osteoporosis,9,42 and atrophy.3,43 Moreover, many hypotheses about endocrine44 or muscular45 origins have been advanced. Indeed, the incidence of this condition in Egyptian and Moroccan contexts suggests a genetic predisposition,11,12,46,47 even if some authors hypothesize the development of the anomaly because of the custom of wearing heavy headgear.10 Even the habit of wearing constricting headgear from childhood could cause craniofacial changes. In fact, it is possible that cranial deformations in childhood lead to incisive bone reactions.48 However, only in the most severe cases, they affect the cortex of the skull, usually appearing as porous bone appositions above the ectocranial surface.48,49 Furthermore, the loss of cortical tissue during the voluntary modification practice could led to the death of the subject.48 Therefore, it is possible to suggest that the evidence recorded by us cannot be link to deformation practices undergone in childhood, especially taking into consideration the skeletal remodeling process that led to the turnover of the skeleton every 10 years.50 Moreover, paleopathological literature clearly shows how skull modification patterns differ from those of biparietal dystrophy condition. In fact, the modification of the neurocranium usually took place thanks to constrictions that weighed on the occipital bone, above all, and on the frontal bone, in order to obtain an elongation of the skull in its upper portion.51 The use of a mechanical constriction in the parieto superior norm are rare. Finally, the historical and cultural context also allows us to exclude that injuries observed in our sample are the result of voluntary deformation practices. In fact, although artificial or intentional cranial modification has been a common practice worldwide, 47,48,49,51,52 no case regarding the Italian Late Middle Ages has been found. As we have seen so far, it is evident that the etiology remains to be clarified, but at this point it is important to remember that, among the most acclaimed hypotheses, the senescence seems to be the most convincing. By the recorded clinical cases, the literature informs us that most cases have a minimum average age of 50, for men, and over 60 for women. It can be suggested that this condition may be related to the reduction or cessation of sex hormone activity.1 The hormonal disorder causes osteoporosis, a condition also linked to the lack of osteoclasts, especially in women of advanced age. It is evident that also for our case, conducting a differential diagnosis is difficult. Although, we can record the presence of bilateral parietal thinning of the third degree, stating to the classification of Cederlund,3 and, referring to the classification of Bruyn and Bots,1 of the groove type. Moreover, radiological, and histological analysis allowed observing the loss of the outer table and the remodeling and thinning of the diploic layer. Radiological images highlighted the thinning of the diploe until reaching the inner table and the total absence of the outer table. In particular, histological section showed the absence of external lamellar bone, indicating the loss of the outer table in the affected area. Furthermore, osteonic structure seems to be remodeled and interrupted by several irregularities. The widening of the venous furrows in the points of the lesion, clearly visible even on macroscopic analysis, were found without any pathological relevance but rather as the result of the normal senescence process.42 It is important to highlight that biparietal thinning is not often considered from a clinical point of view as in mild form usually it has not a pathological significance, except for the potential increased risk of fractures. In fact, cases of epidural hematomas and death caused by trauma, even of lesser entity, are reported in the literature in patients with parietal osteodystrophy.44-52 Indeed, our case presents also intracranial lesions, but these may be not related to biparietal thinning, and may rather be attributed to secondary factors. The abnormal vascular impressions on the intracranial surface noted in our case have already been recognized in the past as traces of inflammatory processes or hemorrhages of the meninges.53,54 These changes can be caused by a variety of infectious, including tuberculosis, or noninfectious conditions, such as trauma, scurvy, and epidural hematomas.55-59 On the other hand, there is often evidence of a correlation between biparietal thinning and senile or postmenopausal osteoporosis.6,40,41 A combination of factors in our case seems to partly respond to some hypotheses regarding the etiology of biparietal thinning. The skull, belonging to a mature female, could support the link to biparietal thinning, postmenopausal osteoporosis, and senile osteodystrophy. However, osteoporosis and senile osteodystrophy as primary causes of this anomaly are less plausible, as these conditions rarely affect cranial bones, rather involving vertebral and femoral bones.58 The reduction of the diploe could suggest continuous micro-traumatic stresses of a slight entity but repeated and protracted over time. These micro traumatisms may have caused a chronic inflammatory state with resorption of the epicranial aponeurosis and reduction of trabecular bone. The micro traumas may have been associated with normal bone degenerative phenomena due to age, probable pregnancies and lactation that may have triggered further inflammatory processes of the meninges or hematoma, which explain the deep grooves of the inner table. They may be caused by the typically female use of carrying loads on the head through circles that weigh mainly on the parietal bones.60 In our case, sex and age-at-death of the individual, together with several features observed at the level of post-cranial bones, in particular the pathological fractures of different lumbar vertebrae seem to support the hypothesis that relates biparietal thinning with the ageing process and osteoporosis.61 At the same time, the coexistence of lesions on the internal surface of cranial bones, attributable to possible inflammatory processes, leaves open the hypothesis of a micro-traumatic cause at the basis of the parietal thinning. Acknowledgments We would like to thank the Archaeological Superintendence of Lombardy for having directed the archaeological excavation and the Community Foundation of Varesotto and the Cariplo Foundation for having financed most of the bioarchaeological investigations of the site. The authors report no conflicts of interest. |
Braz J Cardiovasc Surg Braz J Cardiovasc Surg rbccv Brazilian Journal of Cardiovascular Surgery 0102-7638 1678-9741 Sociedade Brasileira de Cirurgia Cardiovascular 36897822 10.21470/1678-9741-2021-0197 Case Report Off-Pump Resection of Giant Intramural Left Ventricular Hydatid Cyst by Pleuropericardial Approach: a Case Report Shah Dhiren Mch, CTVS Substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work final approval of the version to be published 1 Gupta Kishore DNB, CTVS Substantial contributions to the conception or design of the work or the acquisition, analysis, or interpretation of data for the work drafting the work or revising it critically for important intellectual content final approval of the version to be published 1 Naik Dhaval DNB, CTVS Drafting the work or revising it critically for important intellectual content final approval of the version to be published 1 Dholakia Hiren MD Drafting the work or revising it critically for important intellectual content agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved final approval of the version to be published 1 Madan Surabhi MD Agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved final approval of the version to be published 1 1 Department of Cardiac Surgery, Care Institute of Medical Sciences (CIMS Hospital), Ahmedabad, Gujarat, India. Correspondence Address: Kishore Gupta, Care Institute of Medical Sciences, Science City Road, Ahmedabad, India - Zip Code: 380060, E-mail: [email protected]; [email protected] Jan-Feb 2023 Jan-Feb 2023 38 1 204208 24 1 2021 19 4 2021 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Primary cardiac hydatid cyst is a rare and fatal pathology, especially when involving the left ventricular free wall. A 44-year-old male was diagnosed with large intramural left ventricular hydatid cyst with wall thickness of 6 mm at the thinnest point. Cyst was accessed through pleuropericardial approach (left pleura opened, followed by entry into cyst directly through adjacent pericardium without removing the pericardial adhesions) which resulted in easy entry into the cyst, mitigating the risk of mechanical injury. This case report highlights that with detailed evaluation, cardiac hydatidosis can be addressed with off-pump technique, reducing the anaphylaxis risks and cardiopulmonary bypass-related effects. Pleura Cardiopulmonary Bypass Anaphylaxis Echinococcosis Echinococcus Pericardium Heart Ventricles Cysts pmcINTRODUCTION Hydatid cyst disease or echinococcosis is a zoonotic disease caused by infection with the metacestode stage of the tapeworm Echinococcus. Clinical manifestation of echinococcosis depends on the involved organ along with number and size of the cysts . Cardiac component as a part of multivisceral involvement is observed in < 2% of cases, with primary infection of the heart being an exceedingly rare condition (< 0.2%). Isolated primary cardiac hydatidosis being rare can be mistaken for ventricular aneurysm, atrial myxoma, or simple epicardial cyst. Cardiac hydatid cysts can be pericardial, endocardial, or, very rarely, intramural. Left sided cysts usually tend to grow subepicardially whereas right sided cysts have tendency to grow subendocardially and intracavitarily . The symptoms range from being asymptomatic to having a life-threatening course. As in our case, cardiac hydatid disease presented with chest pain and shortness of breath. Additionally, palpitations and recurrent syncope may also occur and are related to underlying cardiac arrhythmias or mechanical effect. Intracardiac rupture of cyst can result in pulmonary embolism or stroke . Release of cyst contents can induce a life-threatening allergic reaction, which might also be encountered during surgical excision of hydatid cysts . Surgical excision, usually with cardiopulmonary bypass (CPB) support, remains the mainstay of treatment even in asymptomatic patients due to risk of rupture, but excision needs to be therapeutically supplemented by anthelminthic medications in the preoperative and postoperative periods to prevent recurrences . The aim of our case report is to present a successful resection of giant left ventricular intramural hydatid cyst on beating heart and to outline important considerations during off-pump surgical excision. CASE REPORT A 44-year-old non-diabetic, normotensive male presented with history of left sided chest pain and cough with progressive dyspnea for the previous two months. The patient was examined and initially sent for high-resolution computed tomography (HRCT) scan and echocardiography. HRCT revealed large well encapsulated multiloculated mass measuring around 13.9 x 10 x 12.9 cm in size within the myocardium of the left ventricular free wall along with mild calcification of medial wall. HRCT also showed the mechanical effect causing reduction in left ventricular intraluminal volume and diaphragmatic depression. Cardiac magnetic resonance imaging (MRI) was done in order to delineate the extent and tissue penetration. MRI showed "beak sign" on the medial side of cyst indicating its myocardial origin and attenuated left ventricular wall thickness of 6-7 mm at the thinnest portion and 11-12 mm at the thickest portion. Reduction in left ventricular volumes was also noted . Coronary angiography was done to look for distortion of coronary anatomy and feeder vessel (if any) to the cyst, but it revealed normal epicardial coronaries. Immunoglobulin G echinococcal antibodies were found to be 16.8 units. Fig. 1 Transverse section on cardiac magnetic resonance imaging showing beak sign appearance indicating myocardial origin. After two weeks of prior albendazole therapy, the patient was prepped for surgery. Sternotomy was done, and, as anticipated, the pericardium was found adherent to whole epicardial surface . Adhesions were dissected superiorly and inferiorly. Due to dense adhesions over the lateral epicardial and cystic surface, left pleura was opened, and the cyst was approached from the lateral side . Whole left lung and epicardial surfaces were covered with 10% betadine-soaked sponges. Purse string sutures were placed over the aorta. The cyst was punctured with 18 gauze needle syringe, and around 100 ml of clear fluid was aspirated to partially decompress the cyst initially. After confirmation, the cyst was incised over the same portion, and fluid was sucked out directly without spillage into the nearby surgical field. Stay sutures were placed over the cyst wall followed by removal of daughter cysts, cystic fluid, and inner layer of cyst . Cavity was kept filled with betadine solution for two minutes. After removal of betadine, the lateral cystic wall was excised. Sponges were removed, and the whole pleural and pericardial cavity was washed with 1% betadine solution. Cyst wall and contents were sent for histopathology which showed eosinophilic lamellated cyst wall with presence of scolices and hooklets . The cyst wall showed marked fibrosis and dense chronic inflammation and congestion. Fig. 2 a) Intraoperative image showing adhesions over the epicardial surface; b) hydatid cyst seen bulging anteriorly and adhered to pericardium laterally; c) pleuropericardial approach showing entry into the cyst (stay sutures seen over cystic wall); d) large cystic cavity seen after emptying of contents. Fig. 3 Daughter cysts, cystic contents, and resected cystic wall. After resection, echocardiography showed moderate mitral regurgitation possibly due to decompression of the ventricular cavity, but the patient remained hemodynamically stable . Postoperatively, the patient had mild mitral regurgitation. He was placed on albendazole for two months after discharge. After three months of follow-up, the patient is clinically stable and has mild mitral regurgitation on echocardiography . Fig. 4 a) Transesophageal echocardiography image showing large left ventricular hydatid cyst; b) transesophageal echocardiography image after the resection of cyst showing mitral regurgitation (white arrow). Fig. 5 Historical and current information from the case report as episode of care organized in form of timeline. HRCT=high-resolution computed tomography; MRI=magnetic resonance imaging DISCUSSION The heart is a rare but potentially fatal site for hydatid cyst, especially in the left ventricular free wall. A commonly involved site is the left ventricle, followed by right ventricle, interventricular septum, atria, and pulmonary artery. In advanced cases, rupture is a lethal complication of cardiac hydatid cyst, especially if not treated timely following the initial diagnosis or if the patient is presented belatedly. We report our experience with a giant intramural left ventricular hydatid cyst which was successfully resected on beating heart. Cardiac intramural hydatid cyst is a rare entity, and its management should be based on multidisciplinary approach involving collaboration between surgeons, radiologists, and infectious disease specialists. To our knowledge, this is the largest and first intramural ventricular hydatid cyst removal done without CPB. Cardiac hydatid cyst resection is usually performed under CPB support, but detailed preoperative evaluation and careful intraoperative assessment can result in extirpation without CPB support. This can aid in avoiding the CPB-related effects and possible risk of anaphylactic shock had there been aspiration of fluid contents into the circulation. Certain factors seemed pivotal for off-pump cyst resection with successful outcome: Left ventricular wall thickness >= 6 mm adjacent to cyst with no apparent breach in myocardial wall on preoperative diagnostic modalities and intraoperative transesophageal echocardiography assessment. Clear fluid on aspiration along with partial decompression of the cyst prior to incision helps in avoiding any inadmissible complication or spillage. Once the cyst has been cleared off its contents, use of protoscolicidal agent followed by excision of germinative layer and resection of free cyst wall. Steady progression of the pathology and inflammation is the most likely reason for adhesions between cyst and pericardium. Pleuropericardial approach (entering into the cyst across the pericardium) mitigates the risk of mechanical injury and sudden rupture in an attempt to clear adhesions from pericardium. Covering the pleural and pericardial surface with betadine-soaked sponges before entering the cyst cavity helps in avoiding contamination. CONCLUSION In conclusion, primary hydatid cyst of the heart, specifically the intramural type, is rare. Detailed and meticulous assessment should be considered in large ventricular hydatid cyst in order to delineate the extent and to choose the surgical strategy with lesser risks and invasiveness. We are reporting this case to underline that cardiac hydatidosis can be addressed with off-pump technique approach as compared to empty beating on-pump technique and thereby reducing the risk of anaphylaxis and CPB-related effects. No financial support. This study was carried out at the Department of Cardiac Surgery, Care Institute of Medical Sciences (CIMS Hospital), Ahmedabad, Gujarat, India. No conflict of interest. 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Braz J Cardiovasc Surg Braz J Cardiovasc Surg rbccv Brazilian Journal of Cardiovascular Surgery 0102-7638 1678-9741 Sociedade Brasileira de Cirurgia Cardiovascular 35072401 10.21470/1678-9741-2020-0692 Case Report Total Thoracoscopic Surgery for Late Mitral Paravalvular Leakage Repair in A Beating Heart Liu Huanan MD 1 Liao Shengjie MD 1 Lin Zhaoming MD 1 Zhang Xiaoshen MD, PhD 1 1 Department of Cardiovascular Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, China. Correspondence Address: Xiaoshen Zhang, Department of Cardiovascular Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, China - Zip code: 510630, E-mail: [email protected] Jan-Feb 2023 Jan-Feb 2023 38 1 175178 14 12 2020 01 3 2021 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Paravalvular leakage (PVL) after mitral valve replacement is a troublesome complication that may lead to severe symptoms and reoperation. Previous case reports on total thoracoscopic cardiac surgery without aortic cross-clamping for repairing late PVL are rare. We describe a 64-year-old man who had undergone aortic and mitral valve replacement via median sternotomy eight years earlier, and who recently developed cardiac failure due to severe tricuspid regurgitation (TR) and PVL in the posterior mitral annulus. During total thoracoscopic surgery with using the beating heart technique, direct closure of the PVL was achieved via pledgeted mattress sutures, and tricuspid valvuloplasty was routinely performed to treat TR. This case indicated that total thoracoscopic surgery on a beating heart may be an excellent option for treating PVL concomitant with TR. Thoracoscopy Tricuspid Valve Insufficiency Sternotomy Constriction Cardiac Surgical Procedures Suture Techniques pmcINTRODUCTION Paravalvular leakage (PVL) is a well-known complication following valve replacement with an incidence between 5% and 32% . For patients who develop PVL after mitral valve replacement, aggressive surgical interventions are recommended because the long-term clinical outcomes of other treatments may be less favorable, such as lower event-free survival rates . Nevertheless, the failure rate of valve re-replacement is higher than that of direct suture repair of the leakage site . Median resternotomy for redo valve surgery often entails a high risk of hemorrhage and structural damage. The beating-heart technique without aortic cross-clamping and cardiac arrest may reduce the possibility of myocardial ischemia-reperfusion injury . Previous case reports on totally thoracoscopic surgery without aortic cross-clamping for repair of late PVL are rare. In this paper, we aimed to show the technical approach for total thoracoscopic surgical repair of the mitral valve with the beating-heart technique. CASE PRESENTATION An ethical approval was obtained from the institutional board and authorities. A 64-year-old man had a history of biological valve replacement for aortic and mitral regurgitation via a median sternotomy eight years earlier at another hospital. His postoperative course was uneventful until 2017, when he developed exertional dyspnea. With his condition deteriorating, he was transferred to our hospital. The patient developed severe heart failure (NYHA class IV). On physical examination, a diastolic rumbling murmur (Levine II/III) was heard over the left sternal border. Chest radiography revealed cardiomegaly with a cardiothoracic ratio of 54%. Preoperative transthoracic echocardiography (TTE) showed that the left ventricular ejection fraction (LVEF) was 31%, and severe tricuspid regurgitation (TR) was detected. The left atrium (49 mm) was enlarged. The left ventricular end-diastolic and end-systolic diameters were 48 and 34 mm, respectively, with mild PVL at the mitral position. The estimated pulmonary artery pressure, measured by TTE, was normal. Transesophageal echocardiography (TEE) confirmed PVL in the posterior mitral annulus . Coronary angiography and chest computed tomography were unremarkable. We performed total thoracoscopic surgery to treat PVL and TR with the beating-heart technique . Fig. 1 Preoperative transesophageal echocardiography of this patient showing paravalvular leakage in the mitral biological valve. Fig. 2 Views during thoracoscopy-assisted and beating-heart surgery. (A) Positions of skin incisions. (B) Minimally invasive tricuspid valvuloplasty. (C) Leakage site in the mitral annulus (asterisk); (D) Direct closure of mitral paravalvular leakage using pledgeted mattress sutures. Video Surgical procedure for tricuspid regurgitation and paravalvular leakage at the posterior mitral annulus. TECHNICAL DESCRIPTION The patient was intubated via a double-lumen endotracheal tube and placed under combined intravenous-inhalation anesthesia. He was then placed in the supine position with the right chest slightly elevated. Cardiopulmonary bypass (CPB) was established via right femoral arterial and venous cannulation. Three incisions were made for the insertion of working ports . A camera port, which functioned as the entrance for the thoracoscope (Olympus, Japan), was inserted along the right midaxillary line at the 5th intercostal space. An assist port was inserted on the right midaxillary line at the 3rd intercostal space. This port was used for placement of the superior vena cava drainage tube and left atrial suction tube during the operation. The 3rd port was inserted on the right anterior axillary line at the 4th intercostal space for placement of surgical instruments, such as scissors and needle holders. After a careful dissection of a stubborn pericardial adhesion, a Contour 3D annuloplasty ring (Medtronic, CA, USA) was accordingly implanted in the tricuspid annulus via a right atriotomy . Then, a drainage tube was inserted into the superior vena cava, and an incision was made in the atrial septum. The patient was placed in the head-down position, and carbon dioxide was continuously insufflated into the chest throughout the redo surgery to displace intracardiac air. After a left venting tube (WEGO, Shandong, China) was inserted into the pulmonary vein, the anterior wall of the left atrium was lifted by a blade retractor, which penetrated parasternally through the 4th intercostal space. The prosthetic mitral valve was well exposed and located without any disturbance of movement. However, a crack was found in the posterior mitral annulus (6-7 o'clock according to the surgeon's view), which had led to the PVL . Two pairs of stitches were placed through a fold of the polyester cardiovascular patch (Chest, Shanghai, China) and were then brought directly into the sewing ring. When the tying was completed, direct closure of the PVL was achieved by using pledgeted mattress sutures . The incisions in the atrial septum and the right atrium were then sutured with 4-0 Prolene (Ethicon). At the same time, the air was drawn out and exhausted to avoid air embolisms. After the patient was weaned from CPB, intraoperative TEE demonstrated the restoration of mitral and tricuspid valve competences . A chest drainage tube was placed through the camera port. Follow-up TTE revealed an LVEF of 54%. The postoperative recovery was uneventful and the patient was discharged 12 days after surgery. Fig. 3 Intraoperative transesophageal echocardiography showing no leakage. COMMENT PVL will complicate the postoperative course and can manifest as hemolytic anemia and/or heart failure. Mitral valves are more susceptible to symptomatic paravalvular leaks than other valves, and prosthetic leaks occur mostly in the early postoperative period . Although paravalvular leaks are more commonly seen in patients with mechanical valves than in those with bioprostheses, PVL in the biological valve was found in the patient in our study eight years after mitral valve replacement. Various causes can contribute to the development of PVL, such as infection, annular calcification and technical aspects of the replacement surgery. In our case, the patient showed no signs of infection or other systemic disorders that could have resulted in tissue fragility after we examined the laboratory data preoperatively and scrutinized the mitral annulus intraoperatively. Despite the lack of a pathological examination of the native tissue, the stitches and annulus showed no disruption, and the tissue was minimally calcified. The cause of late PVL in this case was speculated to be the liability of the sewing cuff to become detached from the native tissue at the weakest tying site of the initial surgery due to the accumulated stress in the mitral annulus. Medical treatment for clinically significant PVLs is mainly palliative. However, the gold standard treatment for severely symptomatic PVLs is surgical closure, including re-replacement and local repair. Because suture repair might prevent the development of new leaks better than a repetition of the valve replacement surgery and the previous sutures remained attached to the sewing cuff, we considered local repair of the PVL through the atrial septum to be the best option. Previously, full-thickness atrial septal tissue adjacent to the sewing cuff had been used for repairing anterior mitral PVLs, and satisfactory durability was achieved . However, this technique was adopted only in the anterior side of the mitral valve. Pledgeted mattress sutures in the preserved cuff were reported to be effective for repairing PVLs under median resternotomy and cardiac arrest . In this case, we managed to repair the mitral PVL by placing two pairs of mattress sutures in a beating heart under total thoracoscopic surgery. No residual leakage was observed. It is worth noting that this repair technique could be more suitable in non-infective mild and moderate PVLs . Fresh autologous pericardium is highly recommended as a patch material, but stubborn pericardial adhesion makes it inapplicable during redo cardiac surgery. Percutaneous repair of PVL has been reported as an alternative approach to surgery for patients who are not suitable for reoperation . However, this procedure requires a transcatheter device specifically designed to achieve promising results. In addition, the patient in our study showed severe tricuspid regurgitation, which also demanded valvuloplasty. Thus, reoperation was quite necessary. The reoperation was primarily performed via median sternotomy. Postoperative adhesions between the sternum and cardiac structures increased the risk of hemorrhage during resternotomy and subsequent dissection. Video-assisted thoracoscopic cardiac surgery is believed to have advantages over conventional open-heart surgery, including minimal access, less postoperative pain, a decreased risk of infection and quicker recovery, which contribute to lower operative mortality and greater patient satisfaction . Here, we applied total thoracoscopic surgery techniques for treating PVL and TR. This approach yielded excellent exposure of the mitral prosthesis and the tricuspid valve. Moreover, we used the beating-heart technique instead of cardioplegic arrest to perform valve surgery. The avoidance of aortic cross-clamping and the maintenance of continuous coronary perfusion lowered the risks of myocardial ischemia and reperfusion injury. Because we used the beating-heart technique, we observed the absence of periprosthetic leakage once the pledgeted mattress sutures were placed. Regarding air embolisms, we adopted deairing techniques with the patient in the head-down position, injection of carbon dioxide and left atrial venting. No neurological complications caused by air embolisms were observed using the aforementioned methods, confirming the results from other studies . CONCLUSION The outcome of this patient, who underwent totally thoracoscopic repair of a late PVL on a perfused beating heart, was favorable. This procedure is an excellent option for treating PVL concomitant with TR and we believe that some patients can benefit from this technique. No financial support. This study was carried out at the Department of Cardiovascular Surgery, The First Affiliated Hospital, Jinan University, Guangzhou, China. No conflict of interest. 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Braz J Cardiovasc Surg Braz J Cardiovasc Surg rbccv Brazilian Journal of Cardiovascular Surgery 0102-7638 1678-9741 Sociedade Brasileira de Cirurgia Cardiovascular 35072405 10.21470/1678-9741-2020-0735 Case Report Quadricuspid Aortic Valve with Ruptured Sinus of Valsalva Aneurysm: a Case Report Huang Shuran MD 1 Liu Xiaolong MD 2 Sun Zhanguo MD 2 1 Department of Intensive Care Unit, Affiliated Hospital of Jining Medical University, Shandong, People's Republic of China. 2 Department of Medical Imaging, Affiliated Hospital of Jining Medical University, Shandong, People's Republic of China. Correspondence Address: Zhanguo Sun, Department of Medical Imaging, Affiliated Hospital of Jining Medical University, No. 89, Guhuai Road, Jining City, Shandong, People's Republic of China, Zip Code: 272029, E-mail: [email protected] Jan-Feb 2023 Jan-Feb 2023 38 1 170174 31 12 2020 23 4 2021 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Quadricuspid aortic valve (QAV) and sinus of Valsalva aneurysm (SVA) are rare congenital anomalies. We report an elderly patient with QAV associated with a ruptured SVA to the right atrium. Transthoracic echocardiographic and computed tomographic images are presented. We emphasize the important role of computed tomography angiography in establishing and confirming the diagnosis and facilitating treatment planning. The patient was successfully operated by a minimally invasive approach. Quadricuspid Aortic Valve Sinus of Valsalva Aortic Aneurysm Computed Tomography Angiography Echocardiography Heart Atria Scientific Research Support Fund for Teachers of Jining Medical UniversityJYFC2019FKJ088 Financial support: This study was funded by the Scientific Research Support Fund for Teachers of Jining Medical University (No. JYFC2019FKJ088). pmcINTRODUCTION The most common type of aortic valve deformation is the bicuspid valve, followed by the unicuspid valve. Quadricuspid aortic valve (QAV) is a rare entity . Sinus of Valsalva aneurysm (SVA) is also an uncommon disorder which is usually caused by congenital weakness of the sinus wall. SVA is typically associated with a bicuspid aortic valve. Only few cases of the unusual association between QAV and SVA have been reported till date. We present an elderly patient who had QAV associated with a ruptured SVA to the right atrium. The diagnosis was established by transthoracic echocardiography (TTE) and computed tomography angiography (CTA). We highlight the important role of CTA in the preoperative workup of these patients. The patient was successfully operated via a minimally invasive approach. CASE REPORT A 63-year-old Chinese man presented with a history of shortness of breath and chest distress for seven months. His symptoms had aggravated in the last 10 days. His past medical history was unremarkable. Physical examination revealed a 3/6 diastolic murmur at 2-4 intercostal spaces along the left sternal border. Chest X-ray showed severe pulmonary emphysema. Electrocardiography (ECG) findings were normal. Because of pulmonary emphysema, TTE provided only limited findings; we obtained the images from the subcostal window instead of parasternal windows. The size of the left and right ventricles was normal, left ventricular ejection fraction was 61%, and diastolic function of the left ventricle was impaired in stage I. Subcostal short axis view showed thickening of aortic valve leaflets with mild aortic regurgitation; however, the number of aortic cusps could not be determined. Color Doppler revealed windsock deformity with a shunt from the accessory aortic cusp to the right atrium during systole and diastole. The velocity of the shunt was 5.7 m/s . Transesophageal echocardiography (TEE) was refused by the patient. Fig. 1 A) Subcostal short axis view of transthoracic echocardiogram showing thickened sinus of the accessory aortic cusp (arrow) with a windsock (four-point star) deformity and a shunt from right-aortic cusp to right atrium during systole and diastole by color Doppler. B) Continuous wave Doppler showing the shunt from left to right, most evident during diastole and attenuated during systole; the velocity of the shunt was 5.7 m/s. AO=aortic root; LA=left atrium; RA=right atrium; RV=right ventricle As part of chest distress evaluation and to rule out any associated coronary artery disease, an ECG-gated CTA scan was performed using dual-source computed tomography (SOMATOM definition, Siemens, Forchheim, Germany) with ECG-gated tube current modulation (tube voltage: 100 kV; full tube current was applied from 30% to 75% of the R-R interval). It revealed a QAV with three equal-sized cusps and a smaller accessory cusp . All the aortic valve leaflets were thickened, especially the accessory one, which was located between the right coronary sinus and the non-coronary sinus with mild calcification at its irregular margin. Different types of reconstruction, including multiplanar reconstruction, volume rendering, and virtual endoscopy, indicated a windsock fistulous connection between the accessory cusp and the right atrium, which projected along and just above the septal leaflet of the tricuspid valve. The windsock was 14 mm in length and 7 mm in width, with a 5-mm crevasse underneath. There was a diastolic shunting through the windsock into the right atrium, which appeared as a jet of blood with greater contrast material extending from the aorta into the right atrium . Nevertheless, the images reconstructed in systole demonstrated that the left-to-right shunt was less than in diastole, possibly due to the obstruction of the corresponding opened aortic valve leaflet. Multiphase reconstructed imaging indicated that the flow through the communication was predominately diastolic; however, some flow persisted during systole. Coronary arteries were normal with no plaque or deformity . Fig. 2 A) The right atrium has lesser amount of contrast material than the aorta, allowing visualization of a jet from the aorta to the right atrium though the windsock (four-point star). B) Multiplanar reconstruction in diastole by computed tomography angiography showing thickened aortic leaflets, especially the accessory one. A windsock (four-point star) developed from the accessory sinus. C) Virtual intra-aortic endoscopy image showing a quadricuspid aortic valve with three equal-sized cusps (1-3) and a smaller accessory cusp (4); the sinus of Valsalva aneurysm originated from the accessory sinus (arrow). D) Volume rendering image showing normal coronary arteries and the windsock (four-point star) with a shunt (arrow). 1=right coronary sinus; 2=left coronary sinus; 3=non-coronary sinus; 4=accessory sinus; LAD=left anterior descending artery; LCX=left circumflex coronary artery; RCA=right coronary artery The patient had no surgical indication for valve-replacement. Therefore, surgical correction of the ruptured SVA was performed. A small, right vertical infra-axillary thoracotomy was used. After entering the right chest at the fourth intercostal space, the right atrium was opened, and a windsock deformity was observed. The windsock in the right atrium was excised, and the remaining defect was closed by a "figure of eight" suture with 4-0 Prolene(r) string and reinforced by a Dacron(r) patch. Postoperative echocardiography showed no signs of residual shunt. The postoperative period was uneventful, and the patient was discharged eight days after operation. At 36-month follow-up, the patient has remained asymptomatic, and echocardiography revealed no progression of aortic regurgitation . Fig. 3 Timeline of the diagnosis and treatment process in the present case. CTA=computed tomography angiography; ECG=electrocardiography; QAV=quadricuspid aortic valve; SVA=sinus of Valsalva aneurysm; TTE=transthoracic echocardiography DISCUSSION QAV and SVA are rare congenital anomalies. To the best of our knowledge, only four case reports describing the unusual association between QAV and ruptured SVA have been published[2-5]. Our patient is the first such documented Chinese patient who was diagnosed by TTE and CTA; the operation was successfully performed by a minimally invasive approach. A summary of the previously reported cases (including the present case) is presented in Table 1. Age of onset in previous cases indicates that patients with these congenital anomalies typically become symptomatic in the prime of their life. However, some cases may not develop severe clinical manifestations, as seen in our case. The symptoms of all five patients are described in Table 1; four of these patients had a definite time of onset of symptoms, lasting from days to months. The very recent onset of symptoms suggested that the lesions were functionally well tolerated until the SVA ruptured caused it . Table 1 Summary of previously reported cases of QAV associated with ruptured SVA (including the present case). Author Age (years) Sex Symptoms Type of QAV AR Origin of SVA Ruptured into Diagnostic method Operation Unger P 41 Male Exertional dyspnea and peripheral edema for 8 days Not described Mild Right sinus RVOT TTE Not described Aggarwal SK 32 Male Sudden onset of chest pain 5 months earlier followed by exertional dyspnea Type A Mild to moderate Right anterior non-coronary sinus RA 2D and 3D TTE, CC Correction of SVA Yang EH 22 Female Gradually worsening dyspnea on exertion, orthopnea, and cough for 2 weeks Type B Severe Right sinus RA TTE Resection of the SVA; aortic valve replacement Akerem Khan SK 24 Female Intermittent chest pain, palpitations, and progressive dyspnea on exertion for several weeks Not described Not described Right anterior non-coronary sinus RA TTE, TEE, Correction of SVA (via median sternotomy) CTA Present case 61 Male Chest distress and shortness of breath for 7 months; symptom aggravation for 10 days Type B Mild Right anterior non-coronary sinus RA TTE, CTA Repaired SVA (via RVAT) 2D=two dimensional; 3D=three dimensional; AR=aortic regurgitation; CC=cardiac catheterization; CTA=computed tomography angiography; QAV=quadricuspid aortic valve; RA=right atrium; RVAT=right vertical infra-axillary thoracotomy; RVOT=right ventricular outflow tract; SVA=sinus of Valsalva aneurysm; TEE=transesophageal echocardiography; TTE=transthoracic echocardiography According to the size of each individual aortic valve cusp, QAV has been classified into seven different subtypes . The two most frequent types are type A (four equal cusps) and type B (three equal cusps with one smaller cusp). Type B QAVs reportedly have a higher proportion of normally functional valves than type A . In two of the four previously reported cases, the type of QAV was not clearly described; of the remaining two cases, one patient had type A, while the other patient had type B QAV; our case also had type B QAV. In all five patients described in Table 1, SVA of patients with QAV usually developed from the right anterior non-coronary sinus (3/5) and projected into the right atrium (4/5). Infrequently, SVA may originate in the right coronary sinus (2/5) and project in the outflow tract of the right ventricle (1/5). Accurate anatomical and functional assessment is an essential prerequisite for minimally invasive treatment of cardiac anomalies. TTE is a universally used technique; however, its use is limited in patients with severe pulmonary emphysema due to the limited echo window. In this case, preoperative TTE images did not allow for adequate anatomical delineation, even though it provided valuable hemodynamic information. TEE is considered as a better imaging modality as it provides a clear anatomical image of aortic valves and coronary ostia and can confirm the diagnosis of QAV as well as SAV . Multidetector CTA with its excellent temporal and spatial resolution and advanced post-processing reconstructions can allow detailed anatomical assessment of the aortic root structure. In our patient, it provided clear images of QAV, ruptured SAV, and the normal coronary arteries. This approach is helpful when the TTE window limits visualization and is an alternative to TEE for preoperative planning. Among the five cases described in Table 1, the surgical treatment can be classified into two categories. Aortic valve replacement and resection of SVA were done in one patient with severe aortic regurgitation, while simple correction of SVA was performed in four patients with mild to moderate aortic regurgitation. The surgical indication for QAV depends on the severity of aortic regurgitation; however, surgical management of SVA is essential once it is diagnosed. In our case, right vertical infra-axillary thoracotomy was used for resecting the SVA to avoid the standard median sternotomy and the associated discomfort. This port-access approach is widely used for mitral valvuloplasty, mitral valve replacement, atrial septal defect closure, and repair of other simple congenital heart defects; in addition, it provides excellent cosmetic and clinical outcomes . After resection of SVA, close follow-up assessment is required to monitor for progression of aortic regurgitation. CONCLUSION We reported a case of a patient who had QAV in association with ruptured SVA to the right atrium and reviewed the pertinent literature. Patients with this rare congenital anomaly typically show symptoms in early adulthood and present with a very recent onset of symptoms caused by SVA rupture. In the previously reported cases, most SVAs associated with QAV originated in the right or non-coronary sinus. TTE is the most widely used noninvasive diagnostic modality in these patients; however, TEE and CTA afford better anatomical and functional characterization of lesions, facilitating preoperative planning. This case report also highlights the use of a minimally invasive approach via a small, vertical right infra-axillary incision to correct the SVA. Financial support: This study was funded by the Scientific Research Support Fund for Teachers of Jining Medical University (No. JYFC2019FKJ088). This study was carried out at the Affiliated Hospital of Jining Medical University, Shandong, People's Republic of China. No conflict of interest. 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Braz J Cardiovasc Surg Braz J Cardiovasc Surg rbccv Brazilian Journal of Cardiovascular Surgery 0102-7638 1678-9741 Sociedade Brasileira de Cirurgia Cardiovascular 35072400 10.21470/1678-9741-2020-0679 Case Report A Rare Catastrophe: Three Cases of Aortic Root Dehiscence after Surgery Iyigun Taner MD 1 Timur Baris MD 1 Aksu Timucin MD 1 1 Department of Cardiovascular Surgery, Istanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Research and Training Hospital, Istanbul, Turkey. Correspondence Address: Baris Timur, Mehmet Akif Ersoy Gogus Kalp Damar Cerrahisi Egitim Arastirma Hastanesi, Kalp Damar Cerrahisi Bolumu, Bezirganbahce mevki, Kucukcekmece, Istanbul, Turkey, Zip Code: 34303, E-mail: [email protected] Jan-Feb 2023 Jan-Feb 2023 38 1 179182 08 4 2020 24 8 2021 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Ascending aortic pathologies may be life-threatening. Postoperative aortic root dehiscence is a very rare but extremely dangerous complication with a high mortality rate, and redo surgery is mandatory due to high risk of spontaneous rupture. We present three cases that had undergone Bentall procedure and had postoperative aortic root dehiscence. One of the patients presented with hemiplegia caused by septic embolus while the others had mild symptoms. Dr. Yakut's modified Bentall procedure, the flanged technique, was performed for each patient in redo surgery. Two patients were successfully discharged from the hospital, but one died due to intracranial hemorrhage and multiple organ failure. Aortic Diseases Ascending Aorta Dehiscence Cardiac Surgery Rupture Spontaneous pmcINTRODUCTION Ascending aortic pathologies may be life-threatening due to rupture or dissection. Acute untreated aortic dissection has a mortality rate up to 50% within 48 hours. Emergency surgery statistically significantly decreases the mortality rate. Elective cases have lower (3-5%) mortality rates compared with emergency cases (15-26%) . Bentall and De Bono first described the procedure for ascending aortic pathologies that include aortic valve and sinuses of Valsalva pathologies in 1968 . Bentall-De Bono procedure is an effective way to treat dilated ascending aorta with concomitant aortic root and aortic valve pathologies. Aortic root dehiscence and pseudoaneurysm formation following a surgery is a rare but extremely dangerous complication. The most common cause for graft dehiscence in these patients is infection, while surgical technical errors and recurrent aneurysmal dilatation are the other causes . Most common sites of dehiscence were the distal suture line, proximal valvular sutures, and coronary button anastomosis sites . Mortality rate for the patients complicated by aortic root dehiscence remains noticeably high even if they had the chance of emergency redo surgery . Here we present three cases of postoperative aortic root dehiscence. Case 1 A 51-year-old male patient with diagnosis of type 1 aortic dissection had rheumatoid arthritis. Echocardiography revealed dissection flap with moderate aortic valve insufficiency. Contrasted computed tomography (CT) proved the diagnosis of acute type 1 aortic dissection. He was successfully discharged at postoperative 12th day of Bentall procedure. Six months later, the patient was admitted to the emergency department suffering from dyspnea. Contrasted CT revealed type B dissection with periaortic hematoma. He was followed with medical therapy as he refused the surgery, but, unfortunately, he was transferred to the intensive care unit (ICU) in the fourth day of hospitalisation and undergone surgery. Modified Bentall procedure, the flanged technique, with mechanical aortic conduit was used for the patient whose aortic root was dehiscent by the proximal valvular sutures . Aortic root was also strengthened using bovine pericardium. Postoperative period was complicated by subdural hematoma, and the patient died four months after the surgery with multiorgan failure. Fig. 1 Preparation of Dr. Yakut's flanged Bentall graft. Case 2 A 45-year-old male patient with Marfanoid stature was admitted to our clinic with occasional chest and back pain. Contrasted CT and transthoracic echocardiography were performed. The ascending aorta and sinuses of Valsalva were 51 mm and 59 mm in diameter, respectively, with moderate aortic stenosis. After emergency preoperative follow-up, the patient underwent Bentall procedure. On the 7th day, he was discharged from the hospital without any complications. Two weeks after the surgery, the patient was admitted to the hospital with fever, dyspnea, and fatigue. Blood count and biochemical markers were within normal ranges, there was nothing remarkable in urine and blood cultures, and echocardiography was normal. At the 10th day of admission, with prophylactic antibiotic therapy, his general medical condition deteriorated, which was accompanied by tachycardia and hypotension. Leak from aortic root was diagnosed by transesophageal echocardiography, and hematoma around ascending aorta was shown by contrasted thorax CT . Emergency redo Bentall procedure, flanged technique, with mechanical aortic conduit was performed . Aortic root was strengthened using bovine pericardium. The patient was discharged at the postoperative 19th day without any other complications. Fig. 2 A, B) Preoperative images of the patients' dehiscenced aortic root. Case 3 A 69-year-old male patient with previous diagnosis of diabetes mellitus and hypertension suffering from angina provoked by physical exertion was hospitalised with the diagnosis of ascending aortic aneurysm and severe aortic regurgitation revealed by contrasted CT and transthoracic echocardiography. Atherosclerotic coronary artery disease was also diagnosed during preoperative follow-up. Coronary artery bypass grafting (CABG) (left anterior descending artery, obtuse marginal first and second branches of circumflex artery, and right coronary artery) and Bentall procedure with mechanical aortic conduit were performed. He was extubated seven hours after the surgery, discharged from ICU on the postoperative 1st day, and discharged from the hospital on the postoperative 7th day. Four months after surgery, in another hospital, infective endocarditis of mechanical valve was diagnosed after his admission with left sided hemiplegia caused by septic emboli. The patient was transferred to our hospital and after four days due to increasing thrombocyte count (from 47000 to 90000), and redo CABG and flanged Bentall technique with bioprosthetic aortic conduit were performed . Aortic root was strengthened using bovine pericardium. Vegetations were seen on the leaflet . He was discharged from the hospital on the postoperative 45th day after termination of antibiotic therapy and referred to physical therapy and rehabilitation for hemiplegia. DISCUSSION Aortic root dehiscence is a rare phenomenon. There are some limited series and case reports in the literature regarding pseudoaneurysm of thoracic aorta[3,4,7-11]. Due to its insidious onset, diagnosis of the pathology can be challenging. Clinical presentation of aortic root dehiscence may present with various symptoms. Different series and cases on the matter showed numerous symptoms such as heart failure, chest pain, syncope, headache (due to intracranial infarction), fever, dyspnea, and even seizures[3,7,9-11]. Symptoms such as heart failure and chest pain may lead the physician to further investigate the aorta and heart. However, nonspecific symptoms such as fever or symptoms of the central nervous system may mislead the physician. It should be kept in mind that patients that had undergone ascending aortic and aortic root surgery should be investigated thoroughly, no matter the symptoms he/she has. The underlying pathology that causes aortic pseudoaneurysm may vary as well. The most encountered reason was infection of various anatomic structures such as valve, aortic graft, or mediastinum[3,4,7-10]. Different types of microorganisms were reported to be isolated from the cultures, such as Staphylococcus aureus, Enterococcus, and Candida[3,8-10]. On the other hand, Gebhard et al. presented a case with high-dose corticosteroid use after the surgery. As a concomitant risk factor, using a prosthetic valved conduit increases the tendency for dehiscence of the aortic root. Moreover, predisposing factors like rheumatoid arthritis, history of prolonged corticosteroid use, and connective tissue disorder may complicate the postoperative period of successfully managed aortic root surgeries. The time interval and the reason of dehiscence after surgery may differ. There are cases reported up to 17 years after the first operation . Infectious and non-infectious causes were present for dehiscence to occur . Brewer et al. , Thubrikar et al. , and Lansac et al. proved the importance of the dynamic properties of aortic root. Therefore, using a mechanical conduit may disrupt this dynamic feature of the aortic root and ascending aorta and lead to dehiscence. Yakut's modified surgical technique leading to post-surgical aortic root most similar to physiological root may be the reason of surgical success . CONCLUSION Aortic root dehiscence after aortic root surgeries is an extremely rare but mortal complication. Redo surgery is mandatory due to high risk of spontaneous rupture. We prefer and advise the use of flanged Bentall technique for reoperations after root dehiscence, as it provides physiologic motion of the root more than other modified Bentall procedures. The flanged technique may be an effective alternative method for aortic root dehiscence after surgery. No financial support. This study was carried out at the Department of Cardiovascular Surgery, Istanbul Mehmet Akif Ersoy Thoracic and Cardiovascular Surgery Research and Training Hospital, Istanbul, Turkey. No conflict of interest. REFERENCES 1 Prakash P Patni R Asghar NM Chan KMJ Antanas M Ascending aorta aneurysms: pathophysiology and indications of surgery EJ Cardiol Pract 2011 10 7 screen 4 pages 2 Bentall H De Bono A A technique for complete replacement of the ascending aorta Thorax 1968 23 4 338 9 10.1136/thx.23.4.338 5664694 3 Atik FA Navia JL Svensson LG Vega PR Feng J Brizzio ME Surgical treatment of pseudoaneurysm of the thoracic aorta J Thorac Cardiovasc Surg 2006 132 2 379 85 10.1016/j.jtcvs.2006.03.052 16872966 4 Niederhauser U Kunzli A Genoni M Vogt P Lachat M Turina M Composite graft replacement of the aortic root: long-term results, incidence of reoperations Thorac Cardiovasc Surg 1999 47 5 317 21 10.1055/s-2007-1013165 10599960 5 Mulder EJ van Bockel JH Maas J van den Akker PJ Hermans J Morbidity and mortality of reconstructive surgery of noninfected false aneurysms detected long after aortic prosthetic reconstruction Arch Surg 1998 133 1 45 9 10.1001/archsurg.133.1.45 9438758 6 Yakut C A new modified Bentall procedure: the flanged technique Ann Thorac Surg 2001 71 6 2050 2 10.1016/s0003-4975(01)02439-0 11426805 7 Oh KT Derose J Taub C Fortune or misfortune: asymptomatic, delayed presentation of complete dehiscence of mechanical aortic valve conduit and pseudoaneurysm BMJ Case Rep 2016 2016 bcr2016216320 10.1136/bcr-2016-216320 8 Kannan A Smith C Subramanian S Janardhanan R A rare case of prosthetic endocarditis and dehiscence in a mechanical valved conduit BMJ Case Rep 2014 2014 bcr2013200720 10.1136/bcr-2013-200720 9 Stiver K Bayram M Orsinelli D Aortic root bentall graft disarticulation following repair of type a aortic dissection Echocardiography 2010 27 2 E27 9 10.1111/j.1540-8175.2009.01069.x 20380674 10 Tabakci MM Yazicioglu MV Toprak C Demirel M Avci A Collapse of aortic graft through its disarticulation secondary to periaortic root abscess: an unusual cause of syncope Echocardiography 2016 33 8 1267 8 10.1111/echo.13265 27342688 11 Gebhard C Biaggi P Stahli BE Schwarz U Felix C Falk V Complete graft dehiscence 8 months after repair of acute type A aortic dissection Eur Heart J Acute Cardiovasc Care 2013 2 1 72 6 10.1177/2048872612471214 24062936 12 Mohammadi S Bonnet N Leprince P Kolsi M Rama A Pavie A Reoperation for false aneurysm of the ascending aorta after its prosthetic replacement: surgical strategy Ann Thorac Surg 2005 79 1 147 52 discussion 152 10.1016/j.athoracsur.2004.06.032 15620933 13 Brewer RJ Deck JD Capati B Nolan SP The dynamic aortic root Its role in aortic valve function. J Thorac Cardiovasc Surg 1976 72 3 413 7 957758 14 Thubrikar M Bosher LP Nolan SP The mechanism of opening of the aortic valve J Thorac Cardiovasc Surg 1979 77 6 863 70 439922 15 Lansac E Lim HS Shomura Y Lim KH Rice NT Goetz W A four-dimensional study of the aortic root dynamics Eur J Cardiothorac Surg 2002 22 4 497 503 10.1016/s1010-7940(02)00405-0 12297162 |
Braz J Cardiovasc Surg Braz J Cardiovasc Surg rbccv Brazilian Journal of Cardiovascular Surgery 0102-7638 1678-9741 Sociedade Brasileira de Cirurgia Cardiovascular 35675494 10.21470/1678-9741-2021-0151 Case Report Venoarterial Extracorporeal Membrane Oxygenation as A Bridge to Surgery in Post-Myocardial Infarction Ventricular Septal Defect with Cardiogenic Shock: Case Report Besa Santiago MD 1 Walbaum Jonathan 2 Gonzalez Rodrigo MD, MSc 1 Baraona Fernando MD 3 Garrido-Olivares Luis MD, MSc 1 1 Cardiovascular Surgery, Division of Surgery, Pontificia Universidad Catolica, Santiago, Chile. 2 Medical Student, Pontificia Universidad Catolica, Santiago, Chile. 3 Division of Cardiovascular Disease, Pontificia Universidad Catolica, Santiago, Chile. Correspondence Address: Santiago Besa Bandeira Department of Cardiovascular Surgery, Diagonal Paraguay 362, Santiago, Chile, Zip Code: 8330077, E-mail: [email protected] Jan-Feb 2023 Jan-Feb 2023 38 1 191195 08 3 2021 13 6 2021 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We describe a 60-year-old woman with post-myocardial infarction (MI) ventricular septal defect (VSD) and cardiogenic shock who was successfully stabilized with veno-arterial extracorporeal membrane oxygenation (VA-ECMO) as a bridge therapy for the surgical closure of her VSD. This case highlights the role of VA-ECMO in the management of post-MI VSD to improve the results of surgical repair and patient survival. Extracorporeal Membrane Oxygenation Ventricular Heart Septal Defects Shock Cardiogenic Myocardial Infarctation Hospital Mortality pmcINTRODUCTION Post-myocardial infarction (MI) ventricular septal defect (VSD) is a rare mechanical complication that occurs in <1% of MI cases with mortality >90% if treated medically and 15-60% with surgical intervention . The most important risk factors include age, anterior wall MI and female sex, while current smoking and prior MI are protective factors . It is a medical emergency associated with cardiogenic shock, multiple organ failure and death . Immediate surgical closure is recommended as it drastically reduces mortality, but better surgical outcomes are obtained if delayed, as it allows hemodynamic stability, healing and organization of friable myocardial tissue . A proposed technique to delay surgical intervention is the use of preoperative venoarterial extracorporeal membrane oxygenation (VA-ECMO), which, according to the Extracorporeal Life Support Organisation (ELSO), is indicated in acute heart failure potentially reversible and unresponsive to conventional management, among other situations . In this context, acute heart failure due to post-MI VSD is an indication for ECMO support. We present a case in which VA-ECMO was successfully used as bridge therapy to surgery in a patient with cardiogenic shock associated with post-MI VSD. Case Report A 60-year-old woman with a history of hypertension and type 2 diabetes with no treatment for the past year was admitted to a regional hospital after more than 12 hours of oppressive chest pain and dyspnea. Blood pressure was 100/58 mmHg, oxygen saturation 90% and heart rate 98 beats/min. Holosystolic murmur at the apex and bilateral crackles were present. The electrocardiogram (ECG) showed an extensive anterior wall ST segment elevation compatible with MI. After failed thrombolysis with tenecteplase (no changes in ECG), the patient was transferred to another institution for a more complex care. Twenty-four hours after emergency room (ER) consultation, coronary angiography showed severe two-vessel disease with complete obstruction of proximal anterior descending artery (ADA) and 80% obstruction of proximal right coronary artery (RCA). Percutaneous angioplasty of ADA was unsuccessful. An apical VSD was discovered during the procedure. Echocardiography confirmed the VSD, with left ventricular ejection fraction (LVEF) of 40% . Therefore, the patient was transferred to our center for coronary artery bypass grafting surgery and VSD repair. Fig. 1 Diagnostic imaging. (A) Coronary angiography showing 80% obstruction of RCA (arrow) and (B) complete obstruction of the ADA (arrow). (C) 2D color echocardiographic image of apical VSD (arrow). Video 1 LV ventriculogram. After contrast injection, a septal-apical VSD is revealed. Estimated LVEF of 40%. Video 2 2D color echocardiogram. The apical 4-chamber view shows a non-restrictive VSD with left-to-right flow. The patient was admitted to our service 36 hours after consultation in cardiogenic shock (cardiac index = 1.2 l/min/m2) with evidence of renal and hepatic dysfunction and high-dose vasoactive support. The VA-ECMO was established through femoral access. Hemodynamic stability was achieved with suspension of vasoactive drugs within 48 hours and normalization of both renal and hepatic function within 4 days . Echocardiography during ECMO did not show left ventricle (LV) or right ventricle (RV) dilatation and chest radiography did not show pulmonary edema, thus no additional LV unloading device or venous drainage cannula were necessary. On day 5 of VA-ECMO, VSD was repaired by infarct exclusion using the David technique , along with a saphenous vein bypass graft to the RCA without incident. Both femoral arterial and venous ECMO cannulas were used for cardiopulmonary bypass (CPB) by adding only a superior vena cava cannula. ECMO circuit was kept circulating through a shunt during CPB and was reused after weaning from CPB. The patient was kept on VA-ECMO and gradually weaned, until successful disconnection on day 9. Weaning from invasive mechanical ventilation was achieved 48 hours after VA-ECMO disconnection. Fig. 2 Laboratory parameters during hospitalization. Evolution of serum creatinine, lactate and aspartate transaminase levels is shown before, during, and after ECMO support. ECMO connection led to an improvement in all parameters. On day 15, echocardiography showed a closed VSD and akinesia of the apex, mid-anteroseptal segment and all apical segments of the LV and LVEF of 40%. The patient was successfully discharged home 28 days after surgery. A timeline of patient evolution is detailed . Fig. 3 Summary timeline from the onset of patient's chest pain until discharge. The time of main events and interventions is shown. DISCUSSION Post-MI VSD is a rare complication of MI (<1% of cases) with mortality >90% if treated medically and 15-60% with surgical intervention . Incidence has decreased over the years as stated in the GUSTO-I trial, which could be attributed to more accessible early reperfusion therapy. Important risk factors for post-MI VSD include advanced age, anterior location of the infarction and female sex. Patients who develop post-MI VSD are more likely to have complete occlusion of the affected artery, which suggests that the pathophysiology of acute VSD involves sudden, severe ischemia and subsequent extensive necrosis, with increased risk in patients in whom early reperfusion is not successful . It is a medical emergency associated with cardiogenic shock, multiple organ failure and death . Immediate surgical closure is recommended as it significantly reduces mortality, but better surgical outcomes are obtained if it is delayed, as this allows for hemodynamic stability, healing and organization of friable myocardial tissue . A technique proposed to delay surgical intervention is the use of preoperative VA-ECMO, which, according to ELSO, is indicated in acute heart failure, potentially reversible and unresponsive to conventional management, among other situations . We believe that ECMO support is the best tool available to rescue a patient from cardiogenic shock, allowing for stabilization and improvement of all organ functions and for non-emergent, but planned, surgical repair. Mortality associated with surgical repair of post-MI VSD varies depending on the time of surgery, . A retrospective review using data from The Society of Thoracic Surgeons reported a mortality rate of 54.1% with early intervention (<7 days) and 18.4% with late intervention (>7 days) . Omar et al. describe that surgical repair and transcatheter closure (TCC) have a significantly lower mortality than medical management alone, 92% versus 61% respectively, and there is no difference in mortality between early TCC and early surgical repair. Shock at time of operation and time from infarction to surgery were the only significant independent predictors of mortality in a study conducted by Deja et al. . With respect to the surgical technique, infarct exclusion as described by David et al. is associated with lower mortality and a non-significant difference in mortality between anterior and posterior VSD . Surgical treatment with infarct exclusion and patch repair has been described as the treatment of choice in these patients . Guidelines published in 2013 stated that emergency surgical repair is recommended in all VSD patients, regardless of their preoperative hemodynamic status, but an update of these guidelines in 2017 recommended that delayed surgery could be considered in patients who respond well to aggressive heart failure therapy . Ventricular assist devices (VADs) have been used to decrease preload and afterload and allow myocardial rest and healing. This can be used both postoperatively, ensuring organ perfusion in the presence of a damaged heart, allowing relative recovery of organ function and clinical stability . It has the potential to allow patients in refractory cardiogenic shock to stabilize and undergo surgical VSD repair in more favorable conditions, with better surgical outcomes when surgery is delayed and decreasing the rate of recurrence and dehiscence . ECMO has many advantages over other VADs, such as its relatively easy implantation, complete cardiopulmonary support and relatively low anticoagulation requirements . On the other hand, despite providing RV unloading, it produces an increase in afterload that can impair LV unload for rest. LV distension is somewhat attenuated by the same VSD that works as a natural LV unloading port, but at the expense of increased left-to-right shunt and RV overload with subsequent worsening of pulmonary edema . Nevertheless, there are strategies to improve the hemodynamic effect of ECMO support and address the undesired effects. Adding an unloading device such as an intra-aortic balloon pump or ImpellaTM would reduce LV afterload and decrease shunt. Adding a venous drainage cannula would resolve the RV volume overload. A pulmonary artery cannula would achieve both mechanisms at the same time, indirectly venting the LV and managing the RV overload . None of these strategies were necessary for this patient, possibly because the systemic venous drainage was enough to manage the right overload, as would be expected in many of these patients. Furthermore, ECMO has been shown to be effective in maintaining optimal end-organ perfusion and gas exchange, thus facing the effects of severe pulmonary congestion secondary to shunt . As stated before, timing of definitive treatment must be carefully decided case-by-case, considering risk against benefit, as prolonged ECMO increases the risk of complications including coagulopathy, bleeding and infections, possibly compromising the benefit of delaying surgery . In a recent series of 8 patient cases, patients connected to ECMO before surgical intervention significantly improved end-organ perfusion biomarkers, demonstrating better organ function at the time of surgery. This may have contributed to better short-term surgical outcomes . In this study, surgical intervention was performed as soon as hemodynamic and organ function stabilized to prevent complications associated with ECMO described above, but it was concluded that there is no consensus regarding the time of intervention and further studies should be carried out . CONCLUSION Post-MI VSD is a life-threatening complication of myocardial infarction and requires surgical or percutaneous repair. Surgical results and survival can be drastically improved by previous stabilization of the patient with the use of VA-ECMO. No financial support. This study was carried out at the Cardiovascular Surgery, Division of Surgery, Pontificia Universidad Catolica, Santiago, Chile. No conflict of interest. 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GUSTO-I (global utilization of streptokinase and TPA for occluded coronary arteries) trial investigators Circulation 2000 101 1 27 32 10.1161/01.cir.101.1.27 10618300 3 Omar S Morgan GL Panchal HB Thourani V Rihal CS Patel R Management of post-myocardial infarction ventricular septal defects: a critical assessment J Interv Cardiol 2018 31 6 939 48 10.1111/joic.12556 30318677 4 Deja MA Szostek J Widenka K Szafron B Spyt TJ Hickey MS Post infarction ventricular septal defect - can we do better? Eur J Cardiothorac Surg 2000 18 2 194 201 10.1016/s1010-7940(00)00482-6 10925229 5 Morimura H Tabata M Delayed surgery after mechanical circulatory support for ventricular septal rupture with cardiogenic shock Interact Cardiovasc Thorac Surg 2020 31 6 868 73 10.1093/icvts/ivaa185 33118011 6 McLaughlin A McGiffin D Winearls J Tesar P Cole C Vallely M Veno-arterial ECMO in the setting of post-infarct ventricular septal defect: a bridge to surgical repair Heart Lung Circ 2016 25 11 1063 6 10.1016/j.hlc.2016.02.024 27374861 7 David TE Dale L Sun Z Postinfarction ventricular septal rupture: repair by endocardial patch with infarct exclusion J Thorac Cardiovasc Surg 1995 110 5 1315 22 10.1016/S0022-5223(95)70054-4 7475183 8 Jacob S Patel MJ Lima B Felius J Malyala RS Chamogeorgakis T Using extracorporeal membrane oxygenation support preoperatively and postoperatively as a successful bridge to recovery in a patient with a large infarct-induced ventricular septal defect Proc (Bayl Univ Med Cent) 2016 29 3 301 4 10.1080/08998280.2016.11929443 27365878 9 Rob D Spunda R Lindner J Rohn V Kunstyr J Balik M A rationale for early extracorporeal membrane oxygenation in patients with postinfarction ventricular septal rupture complicated by cardiogenic shock Eur J Heart Fail 2017 19 Suppl 2 97 103 10.1002/ejhf.852 28470920 10 Rohn V Spacek M Belohlavek J Tosovsky J Cardiogenic shock in patient with posterior postinfarction septal rupture successful treatment with extracorporeal membrane oxygenation (ECMO) as a ventricular assist device J Card Surg 2009 24 4 435 6 10.1111/j.1540-8191.2008.00710.x 18778295 11 Ronco D Matteucci M Ravaux JM Marra S Torchio F Corazzari C Mechanical circulatory support as a bridge to definitive treatment in post-infarction ventricular septal rupture JACC Cardiovasc Interv 2021 14 10 1053 66 10.1016/j.jcin.2021.02.046 34016403 12 Lorusso R Raffa GM Heuts S Lo Coco V Meani P Natour E Pulmonary artery cannulation to enhance extracorporeal membrane oxygenation management in acute cardiac failure Interact Cardiovasc Thorac Surg 2020 30 2 215 22 10.1093/icvts/ivz245 31665308 13 Pahuja M Schrage B Westermann D Basir MB Garan AR Burkhoff D Hemodynamic effects of mechanical circulatory support devices in ventricular septal defect Circ Heart Fail 2019 12 7 e005981 10.1161/CIRCHEARTFAILURE.119.005981 31296094 |
Braz J Cardiovasc Surg Braz J Cardiovasc Surg rbccv Brazilian Journal of Cardiovascular Surgery 0102-7638 1678-9741 Sociedade Brasileira de Cirurgia Cardiovascular 36259993 10.21470/1678-9741-2021-0354 Educational Forum Surgical Management of Massive Pulmonary Embolism Presenting with Cardiopulmonary Arrest: How Far Is Too Far? Rathore Kaushalendra FRACS 1 Newman Mark FRACS 1 1 Department of Cardiothoracic Surgery, Sir Charles Gairdner Hospital, Nedlands, Australia. Correspondence Address: Kaushalendra Rathore Sir Charles Gairdner Hospital Level 6, G block, Perth WA, Nedlands, Australia Zip Code: 6009 E-mail: [email protected] Jan-Feb 2023 Jan-Feb 2023 38 1 162165 16 6 2021 21 2 2022 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The incidence of diagnosed massive pulmonary embolism presenting to the Emergency Department is between 3% and 4.5% and it is associated with high mortality if not intervened timely. Cardiopulmonary arrest in this subset of patients carries a very poor prognosis, and various treating pathways have been applied with modest rate of success. Systemic thrombolysis is an established first line of treatment, but surgeons are often involved in the decision-making because of the improving surgical pulmonary embolectomy outcomes. Thrombosis Pulmonary Embolism Shock Heart Arrest Embolectomy pmcINTRODUCTION Approximately 20% of the patients presenting with pulmonary artery embolus can have massive pulmonary embolism (MPE), and it has a very high mortality rate in the first hour of presentation if it is not intervened promptly . Treating teams can be perplexed about the best possible management strategy in crunch time situations of haemodynamic instability progressing to cardiac arrest. Improving surgical outcomes of the index surgery as well as need for mechanical support devices in these unstable patients bring cardiac surgeons in the middle of decision making . There are numerous unanswered questions in this field when patient is referred with ongoing cardiopulmonary resuscitation (CPR), and there is still no consensus about the standard pathway to route these patients . Here we present the surgeon's perspective on this subject with the background of our own prior and continuing experience in this field . QUESTIONS A. Do surgeons have any role in the management of MPE? B. If at all, then when to intervene and how to manage these sick cases? C. Role of venoarterial extracorporeal membrane oxygenation (VA-ECMO). D. Surgical pulmonary embolectomy (SPE) vs. catheter-based thrombolysis. E. How far is too far? Where to stop? Discussion of Questions A. Clots in the pulmonary arteries do not allow proper forward flow in the distal pulmonary circulation and eventually reduce left ventricular preload, which may lead to the loss of cardiac output . If the surgical team is involved at this point for the SPE or for institution of VA-ECMO, then haemodynamic instability could be avoided. Poor haemodynamics are independent predictors of the high 30-day mortality, and early SPE approach can improve operative survival up to 93% . The right ventricle (RV) is thinner compared to the left ventricle, and that is the reason why RV is more sensitive to the acute afterload changes, and SPE is the swiftest modality to start "reverse remodeling of the RV dysfunction" by removing distal obstruction . Cardiopulmonary bypass (CPB) supports empty RVs by reducing preload and improves haemodynamic condition, giving opportunity to retrieve clots. A surge of attention in this field led to meaningful publications and unveiled continuous improvement in the SPE outcomes . A large meta-analysis has reported overall in-hospital mortality between 16% and 24%, but single-centre retrospective studies are reporting single-digit mortality, and these diferences in the overall outcomes are because of individual hospital protocols and timing of the surgery . Most of the publications reported that surgery was ofered in 35% of the cases after CPR, which is a known independent risk factor for poor outcomes. Results are better in the units where SPE is performed regularly and elected as a semi-urgent procedure before haemodynamic instability sets in. Our unit have published results of 82 cases with preoperative cardiac arrest in 14.64%, which was lower compared to many other reports (33.9%), and the reason behind these better outcomes can be contributed to our early operating policy . Kalra et al. have reported an overall hospital mortality rate of 26.3%, while in our study, it was 8.54%. But even in our study, once the patient required preoperative CPR, then mortality rate escalated to 58.34%, and again it reinforces the fact about early intervention . Five survivors in our study had cardiopulmonary arrest in the operating room, and CPR was performed prior to the sternotomy. Other seven patients went in cardiopulmonary arrest outside of operating room and could not be saved. Another unique complication seen among patients who required preoperative CPR was massive pulmonary haemorrhage through endotracheal tube (3/12 patients). Potential aetiology might be the pulmonary infarction caused by dislodgement of the clots from main pulmonary arteries into the distal circulation during cardiac massage . Other groups have also reported significant pulmonary haemorrhage caused by the pulmonary artery injury during clot removal from the branch arteries . Fig. 1 Computed tomography of pulmonary artery (axial view). Arrows show saddle pulmonary embolus obliterating bilateral pulmonary inflow. Fig. 2 Computed tomography of pulmonary artery (sagittal view). Arrows show right ventricular dilatation with reverse flow in inferior vena cava and clot in the pulmonary artery. Fig. 3 Computed tomography of pulmonary artery (coronal view). Arrow shows extensive clot burden in the pulmonary arteries with potential for distal thromboembolism. B. Management of out-of-hospital cardiac arrest (OOHCA) patients with MPE is another debatable field, where there are no perfect answers. Multiple factors play important role in the decision making and outcome, like duration of cardiopulmonary arrest, effectiveness of CPR, return of spontaneous cardiac activity, associated primary pathology, and the time before reaching to the Emergency Department . Early risk stratification is the key for good outcomes and, therefore, it is important to have quick tests, like serum lactate level, to triage high-risk cases and intervene early . Our protocol is to insert arterial pressure line during CPR to assess cardiac output and effectiveness of the cardiac compressions. Patients presented with prolonged, unwitnessed, and ineffective resuscitation are ruled out for any surgical intervention and managed with systemic thrombolysis only. On contrary to previous reports, recent literature is suggesting improvement in the survival with the use of systemic thrombolysis during the resuscitation, and these findings further escalate the complexity in the decision making . C. Although the results of VA-ECMO in MPE with cardiogenic shock are encouraging, overall outcomes of VA-ECMO during CPR are still poor, with reported in-hospital mortality of around 75% . Around 4-5% of the patients with MPE also have clots in the right atrium, RV (clots in transit), and acutely create instability by obliterating inflow and outflow valve. During ongoing CPR, establishing prompt CPB or VA-ECMO flows are paramount, but these intracardiac clots might get sucked in the venous cannula and cause distension of the heart by poor venous drainage. Various groups are recognising the importance of early haemodynamic stabilization by instituting VA-ECMO and managing patients either with thrombolysis or emergency SPE . VA-ECMO insertion gives time for the patient transfer to the operating rooms with sustaining sufficient cardiac output. But "only VA-ECMO" support group has 2-3-fold higher mortality rate compared to the patients in whom VA-ECMO was followed by SPE . D. Systemic thrombolysis and catheter-based therapies (CBT) continue to be the class I indication in the management of MPE, while SPE is ofered in selected unstable cases, but thorough review of the contemporary literature gives interesting insight on this subject . A recently published systemic review of 1,650 patients, who either underwent CBT (1,650 patients) or SPE (1,101 patients), presented similar in-hospital mortality if CBT or SPE was performed before cardiopulmonary arrest, but the advantages of SPE was complete clearance of the clots and more defnitive treatment in the long-term follow-up . Comparing outcomes among these treatment modalities are not straightforward as SPE cases are sicker (21.4% had prior CPR) and have higher clot burden compared to CBT patients. Keeling et al. have reported a multicentre series and again reinforced that if SPE is performed timely, then good early outcomes can be achieved with low in-hospital mortality, but if the patient is having ongoing CPR, then mortality rate is 32.1%. Lee et al. have reported that overall use of thrombolysis and SPE in the management of pulmonary embolism (PE) is around 1% and 0.4%, respectively, and both modalities give similar early outcomes . They have reported that patients in the SPE group had lower associated risks of early stroke, reintervention, and late recurrent PE compared with those in the thrombolysis group, and they have advocated SPE as it reduces future recurrence of PE. E. It is mandatory to make notes of the duration of the haemodynamic instability with serum markers' levels (D-dimers, troponins, and lactate), failure of the systemic thrombolysis, and duration of CPR before deciding the treatment modality. These are extremely relevant variables to decide whether to use "minimalistic approach" (VA-ECMO) or to perform index SPE surgery, with or without VA-ECMO support. Duration of the CPR makes big impact on the outcomes and that is the reason why in patients with OOHCA or in-hospital cardiac arrest where downtime is prolonged (30 minutes), surgeons have to critically analyse the situation and take consensual decision involving different treating teams . George et al. have reported in their retrospective analysis that three groups where ECMO consistently gives poor outcomes are patients with malignancy, cardiac arrest prior to initiation of ECMO, and patients with serum lactate > 6 mmol/l. Although there are no randomized trials to support, ECMO-facilitated resuscitation has been increasingly used to assist early return of perfusion and support further resuscitation in order to mitigate the multi-organ dysfunction. But ECMO-assisted CPR should be used judiciously and most often attempted in cases with potentially reversible clinical conditions with least comorbidities. LEARNING POINTS All available evidence supports prompt "risk stratification" and triage for the defnite treatment in patients with MPE. But, with the paucity of large randomized clinical trials, management of MPE with cardiopulmonary arrest is still an open debate with various choices. SPE can be a good option in these unstable patients, with centrally located massive clot with right ventricular strain and dilatation on echocardiography. Surgical outcomes are very poor in patients with OOHCA and in-hospital cardiac arrest (outside of operating room) and should be deferred in the favour of systemic thrombolysis with or without VA-ECMO support. This study was carried out at the Department of Cardiothoracic Surgery, Sir Charles Gairdner Hospital, Nedlands, Australia. No financial support. No conflict of interest. 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J Thorac Cardiovasc Surg 2018 155 3 1093 1094 10.1016/j.jtcvs.2017.10.045 29129419 8 Choi JH O'Malley TJ Maynes EJ Weber MP D'Antonio ND Mellado M Surgical pulmonary embolectomy outcomes for acute pulmonary embolism Ann Thorac Surg 2020 110 3 1072 1080 10.1016/j.athoracsur.2020.01.075 32151576 9 QiMin W LiangWan C DaoZhong C HanFan Q ZhongYao H XiaoFu D Clinical outcomes of acute pulmonary embolectomy as the first-line treatment for massive and submassive pulmonary embolism: a single-centre study in China J Cardiothorac Surg 2020 15 1 321 321 10.1186/s13019-020-01364-z 33087152 10 Kalra R Bajaj NS Arora P Arora G Crosland WA McGifn DC Surgical embolectomy for acute pulmonary embolism: systematic review and comprehensive meta-analyses Ann Thorac Surg 2017 103 3 982 990 10.1016/j.athoracsur.2016.11.016 28159170 11 George B Parazino M Omar HR Davis G Guglin M Gurley J A retrospective comparison of survivors and non-survivors of massive pulmonary embolism receiving veno-arterial extracorporeal membrane oxygenation support Resuscitation 2018 122 1 5 10.1016/j.resuscitation.2017.11.034 29128608 12 Bougouin W Marijon E Planquette B Karam N Dumas F Celermajer DS Pulmonary embolism related sudden cardiac arrest admitted alive at hospital: management and outcomes Resuscitation 2017 115 135 140 10.1016/j.resuscitation.2017.04.019 28432023 13 Meneveau N Guillon B Planquette B Piton G Kimmoun A Gaide-Chevronnay L Outcomes after extracorporeal membrane oxygenation for the treatment of high-risk pulmonary embolism: a multicentre series of 52 cases Eur Heart J 2018 39 47 4196 4204 10.1093/eurheartj/ehy464 30137303 14 Sharma V Goldberg HD Zubkus D Shears LL Kaczorowski DJ Successful management of cardiac arrest due to pulmonary embolus using extracorporeal membrane oxygenation and ultrasound-accelerated catheter-directed thrombolysis Ann Thorac Surg 2016 101 4 10.1016/j.athoracsur.2015.10.023 e107-9 27000611 15 Goldberg JB Spevack DM Ahsan S Rochlani Y Ohira S Spencer P Comparison of surgical embolectomy and veno-arterial extracorporeal membrane oxygenation for massive pulmonary embolism Semin Thorac Cardiovasc Surg 2021 S1043-0679 21 00292 00296 10.1053/j.semtcvs.2021.06.011 16 Konstantinides SV Meyer G Becattini C Bueno H Geersing GJ Harjola VP 2019 ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European respiratory society (ERS) Eur Heart J 2020 41 4 543 603 10.1093/eurheartj/ehz405 31504429 17 Loyalka P Ansari MZ Cheema FH Miller CC 3rd Rajagopal S Rajagopal K Surgical pulmonary embolectomy and catheter-based therapies for acute pulmonary embolism: a contemporary systematic review J Thorac Cardiovasc Surg 2018 156 6 2155 2167 10.1016/j.jtcvs.2018.05.085 30005883 18 Keeling WB Sundt T Leacche M Okita Y Binongo J Lasajanak Y Outcomes after surgical pulmonary embolectomy for acute pulmonary embolus: a multi-institutional study Ann Thorac Surg 2016 102 5 1498 1502 10.1016/j.athoracsur.2016.05.004 27373187 19 Lee T Itagaki S Chiang YP Egorova NN Adams DH Chikwe J Survival and recurrence after acute pulmonary embolism treated with pulmonary embolectomy or thrombolysis in New York State, 1999 to 2013 J Thorac Cardiovasc Surg 2018 155 3 1084 1090 10.1016/j.jtcvs.2017.07.074 e12 28942971 20 Laher AE Richards G Cardiac arrest due to pulmonary embolism Indian Heart J 2018 70 5 731 735 10.1016/j.ihj.2018.01.014 30392514 |
Braz J Cardiovasc Surg Braz J Cardiovasc Surg rbccv Brazilian Journal of Cardiovascular Surgery 0102-7638 1678-9741 Sociedade Brasileira de Cirurgia Cardiovascular 35436069 10.21470/1678-9741-2021-0096 Case Report Direct Anastomosis of Persistent Left Superior Vena Cava to Right Superior Vena Cava in a Pediatric Patient with Tetralogy of Fallot: an Alternative Technique Yilmaz Mustafa MD 1 Atalay Atakan MD 1 1 Department of Congenital Heart Surgery, Ankara State Hospital, Ankara, Turkey. Correspondence Address: Mustafa Yilmaz Department of Congenital Heart Surgery, Ankara State Hospital, Universiteler Mahallesi Cadde No: 9, Ankara, Turkey, Zip Code: 1604, E-mail: [email protected] Jan-Feb 2023 Jan-Feb 2023 38 1 166169 14 2 2021 21 8 2021 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The presence of persistent left superior vena cava to the left atrium connection without an innominate vein may give rise to technical challenges during intracardiac repair. In this report, the end-to-side anastomosis technique of the persistent left superior vena cava to the right superior vena cava is discussed in a patient with tetralogy of Fallot associated with persistent left superior vena cava draining directly into the left atrium. A successful end-to-side anastomosis between the persistent left superior vena cava and the right superior vena cava was performed and short-term anastomosis patency was documented via angiography. Congenital Heart Defects Hemodynamics Superior Vena Cava Left Atrium Surgical Anastomosis Cardiac Surgical Procedures pmcINTRODUCTION Persistent left superior vena cava (PLSVC) is the most common congenital thoracic venous system abnormality (0.3-0.5%). In congenital heart patients, the incidence increases approximately ten times and reaches 4.5%. PLSVC is observed in 20% of the patients with tetralogy of Fallot. This association can often be determined by preoperative examinations. However, occasionally, preoperative tests may be insufficient in the diagnosis of this association. The presence of PLSVC to the left atrium connection without an innominate vein may give rise to technical challenges during intracardiac repair when not determined prior to surgical intervention. In such situations, the surgeon should be aware of intra or extracardiac re-routing procedures to facilitate the intracardiac repair and eliminate the right-to-left shunt. In this case report, we will discuss the pros and cons of the end-to-side anastomosis technique of PLSVC to the right superior vena cava (SVC), which is an alternative extracardiac re-routing procedure, in a pediatric patient with tetralogy of Fallot who was admitted to the emergency department with a cyanotic spell attack. Case Presentation A 9-year-old girl was admitted to the emergency department with a deteriorated medical condition, agitation, and deep cyanosis. The patient's oxygen saturation was 40%, and the diagnosis was confirmed as tetralogy of Fallot with severe infundibular and valvular stenosis via transthoracic echocardiography. Due to the patient's advanced age, emergency cardiac catheterization was performed to evaluate additional abnormalities. No additional abnormalities were detected via cardiac catheterization. The patient was urgently operated on to complete repair of the tetralogy of Fallot after obtaining written informed consent. During the operation, PLSVC was detected, and there was no left innominate vein between the right and left SVC. The diameter of the PLSVC was equal to that of the right SVC, and it was coursing posterior to the left atrial appendage and in front of the left pulmonary artery. Considering the most common anatomy, we anticipated that the PLSVC would drain into the coronary sinus and planned to aspirate it through the coronary sinus during the operation. Right atriotomy was performed after cardiopulmonary bypass and cardiac arrest. The coronary sinus was visualized in its normal localization and was of normal diameter. The right atrial septum was then incised, and the left atrium was inspected. The PLSVC was temporarily occluded. Inspection of the left atrium revealed that the roof of the coronary sinus was intact, and that the PLSVC was connected to the left atrium directly. Since the diameter of the PLSVC was about the same size as the right SVC, and the measured proximal pressure was 40 mmHg during temporary occlusion, a re-routing procedure for PLSVC became mandatory. Due to the concern that the ischemic time would increase, we decided to divert the PLSVC drainage to the systemic venous system via an extracardiac route. Complete repair of the tetralogy of Fallot was performed with a transannular patch. Following cross-clamp removal, the PLSVC was transected from the left atrium, and all its proximal branches were ligated and divided under cardiopulmonary bypass support. Then the proximal part of the right SVC was dissected entirely free. The PLSVC was redirected to the right side over the anterosuperior aspect of the ascending aorta, and end-to-side anastomosis to the right SVC was performed. . No kinking or tension was observed on the suture line of the anastomosis. Fig. 1 Persistent left superior vena cava was carried over the ascending aorta and anastomosis was performed to the medial aspect of right superior vena cava. Black arrow=persistent left superior vena cava; yellow arrow=right superior vena cava; L=left; R=right Computed tomography angiography and cardiac catheterization prior to discharge showed that the PLSVC and the anastomosis were patent, and there was no sign of stenosis or thrombosis . Postoperative recovery of the patient was uneventful, and the patient was discharged with warfarin anticoagulation on the postoperative 5th day without any complications. Fig. 2 Computed tomography angiographic image of the persistent left superior vena cava. Black arrow=patent persistent left superior vena cava and anastomosis; star=proximal part of clavicula (patient has pectus carinatum deformity); LP=left posterior; RA=right anterior Fig. 3 Postoperative cardiac catheterization. Yellow arrow=persistent left superior vena cava; red arrow=patent persistent left superior vena cava - right superior vena cava anastomosis; star=ligated stump of hemiazygos vein After one month of discharge, the patient showed no symptoms of venous stasis. Currently, the patient is asymptomatic on the 6th postoperative month. Timeline of the case report has been presented in the Table 1. Table 1 Timeline of the case report. Day 1 Admission to the emergency department Symptom Deep cyanosis Deteriorated medical condition Diagnosis Echocardiography * Tetralogy of Fallot with severe pulmonary stenosis Cardiac catheterization * No additional abnormality Day 2 Cardiac operation Complete repair of Tetralogy of Fallot End-to-side anastomosis of the persistent left SVC to right SVC Day 6 Postoperative CT angiography and cardiac catheterization Anastomosis was patent No sign of stenosis or thrombosis Day 7 Discharge Discharged with warfarin anticoagulation 1st and 6th months after surgery The patient is asymptomatic and shows no signs of venous stasis CT=computed tomography; SVC=superior vena cava DISCUSSION Systemic venous system abnormalities are generally benign anatomical structures that do not cause hemodynamic disturbances. However, sometimes these abnormalities can cause serious hemodynamic consequences on their own or in conjunction with additional congenital pathologies and may need to be corrected. Detection of these abnormalities prior to congenital heart surgery may provide the application of various surgical modifications during the operation. PLSVC drains into the coronary sinus in 90% of all cases, and in only 8% of cases, the PLSVC is directly connected to the left atrium. The association of this situation with tetralogy of Fallot is much rarer. There are limited number of case reports describing this association in the literature . In cases where PLSVC drains directly into the left atrium, multiple surgical options are available. Ligation of PLSVC , intra-atrial baffle formation , transection of PLSVC with left atrial tissue and implantation to the right atrium , end-to-side anastomosis of PLSVC to the left pulmonary artery , a graft interposition between PLSVC and the right atrium , forming an intra-atrial conduit with an inverted left atrial appendage flap , and performing end-to-side anastomosis to the right SVC under or over the aortic arch are the surgical techniques reported in the literature[2-7]. Complex congenital pathologies are additionally detected in almost all cases where PLSVC is attached to the left atrium . Therefore, it is necessary to evaluate each anatomical structure individually and to decide the most appropriate surgical technique to perform according to this anatomical structure. In our patient, we preferred to perform an end-to-side direct anastomosis of the PLSVC to the right SVC for the following reasons: the accurate diagnosis of the patient was confirmed during the cross-clamping period , and the possibility of performing the anastomosis after complete repair and during the rewarming period on the beating heart . We had some concerns regarding the possible complications of intra-atrial baffle formation and extracardiac graft interposition techniques. In previous studies, it has been reported that the long-term patency of intra-atrial baffle formation is questionable due to the use of non-growing material and that it may become stenotic. Beside this, due to the lack of growth potential, extracardiac graft interposition is also not applicable for young children . In addition, these grafts may be compressed between the sternum and the aorta. In their cohort studies, van Son et al. , Ugaki et al. , and Cesnjevar et al. showed that anatomic end-to-side anastomosis of PLSVC to the right SVC, anterior to the aortic arch, is a safe, feasible, and reproducible technique. Kawada et al. and Reddy et al. performed the anastomosis by redirecting the PLSVC under the aortic arc. Since PLSVC runs through the mediastinum more posteriorly than the right SVC, they suggested a more natural connection between the two SVCs could be achieved. The authors state that while performing this procedure, one must be sure that there is sufficient space between the main pulmonary artery and the aorta. Otherwise, the PLSVC may be compressed between these two structures. Since the ascending aorta of the patient was dilated due to aortopathy (ascending aorta: 2.8 cm; Z-score: +3.79), we anticipated that the redirection of the PLSVC between the patient's aorta and the main pulmonary artery, which was augmented transannularly, would also cause compression. As defined in the literature, the vena cava was extensively dissected free, and proximal branches were ligated and separated , thus, approximately 3.5-4 cm of the PLSVC length was obtained. The PLSVC was transected from the left atrium roof and redirected over the anterosuperior part of the ascending aorta. Anastomosis was comfortably performed to the medial wall of the right SVC. No kinking or tension was observed in the anastomosis. The most significant disadvantage of this technique is the lack of knowledge concerning long-term vascular patency. In the literature, the longest follow-up period was 2.4 years . Studies with a longer follow-up period and larger patient cohorts are required to prove the durability of PLSVC and patency of anastomosis. CONCLUSION In conclusion, there are multiple surgical options for patients with PLSVC draining directly into the left atrium. All these surgical techniques have their own shortcomings. Considering the sample cases in the literature, we believe that end-to-side direct anastomosis of the PLSVC to the right SVC might be a safe and applicable technique for pediatric patients with PLSVC draining into the left atrium. No financial support. This study was carried out at the Department of Congenital Heart Surgery, Ankara State Hospital, Ankara, Turkey. No conflict of interest. REFERENCES 1 Ramman TR Dutta N Chowdhuri KR Agrawal S Girotra S Azad S Left superior vena cava draining into left atrium in tetralogy of fallot-four cases of a rare association World J Pediatr Congenit Heart Surg 2020 11 4 NP120 NP124 10.1177/2150135117742625 29506453 2 Fuchigami T Nishioka M Akashige T Nagata N A surgical integration technique for right-sided and left-sided superior venae cavae Ann Thorac Surg 2015 100 3 e63 e65 10.1016/j.athoracsur.2015.05.042 26354670 3 Kawada N Yamagishi M Morita K Kanazawa T Nakamura Y Extracardiac rerouting of the persistent left superior vena cava in the left isomerism heart Jpn J Thorac Cardiovasc Surg 2004 52 2 88 90 10.1007/s11748-004-0092-1 14997980 4 Komai H Naito Y Fujiwara K Operative technique for persistent left superior vena cava draining into the left atrium Ann Thorac Surg 1996 62 4 1188 1190 10.1016/0003-4975(96)00362-1 8823113 5 Reddy VM McElhinney DB Hanley FL Correction of left superior vena cava draining to the left atrium using extracardiac techniques Ann Thorac Surg 1997 63 6 1800 1802 10.1016/s0003-4975(97)83867-2 9205198 6 van Son JA Hambsch J Mohr FW Repair of complex unroofed coronary sinus by anastomosis of left to right superior vena cava Ann Thorac Surg 1998 65 1 280 281 10.1016/s0003-4975(97)01267-8 9456144 7 Vargas FJ Reconstructive methods for anomalous systemic venous return: surgical management of persistent left superior vena cava Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu 2008 31 38 10.1053/j.pcsu.2008.01.007 18396222 8 Ugaki S Kasahara S Fujii Y Sano S Anatomical repair of a persistent left superior vena cava into the left atrium Interact Cardiovasc Thorac Surg 2010 11 2 199 201 10.1510/icvts.2009.230581 20439305 9 Cesnjevar RA Harig F Dietz M Alkassar M Waellisch W Rueffer A Growth of hypoplastic mitral valves in hypoplastic left heart complex and similar constellations after anatomical left superior vena cava correction Eur J Cardiothorac Surg 2021 59 1 236 243 10.1093/ejcts/ezaa286 33068405 10 Chihara S Yasunaga H Todo K Anastomosis of left to right superior vena cava for repair of unroofed coronary sinus Gen Thorac Cardiovasc Surg 2012 60 4 244 246 10.1007/s11748-011-0815-z 22451150 |
Braz J Cardiovasc Surg Braz J Cardiovasc Surg rbccv Brazilian Journal of Cardiovascular Surgery 0102-7638 1678-9741 Sociedade Brasileira de Cirurgia Cardiovascular 36259998 10.21470/1678-9741-2021-0557 Case Report Tricuspid Valve-in-Valve Procedure with An Edwards S3 Valve in a 15-kg Child in Latin America Becerra Albert Franz Guerrero MD 1 Arevalo Jaime Ramon Cabrales MD 2 Senosiain Julian MD 1 Torres Alberto Enrique Garcia MD 2 Camacho Jaime MD 3 Reyes Nestor Fernando Sandoval MD 1 1 Department of Cardiac Surgery, Fundacion Cardioinfantil - Instituto de Cardiologia, Bogota, Cundinamarca, Colombia. 2 Department of Interventional Cardiologist, Fundacion Cardioinfantil - Instituto de Cardiologia, Bogota, Cundinamarca, Colombia. 3 Fundacion Cardioinfantil - Instituto de Cardiologia, Bogota, Cundinamarca, Colombia. Correspondence Address: Albert Franz Guerrero Becerra Department of Cardiac Surgery, Fundacion Cardioinfantil - Instituto de Cardiologia, Calle 138 n19-49, 0101, Bogota, Cundinamarca, Colombia Zip code: 110131 PlE-mail: [email protected] Jan-Feb 2023 Jan-Feb 2023 38 1 201203 02 11 2021 28 4 2022 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A 5-year-old child, weighing 15 kg, with three previous sternotomies, presented with right heart failure due to severe stenosis and regurgitation of the bioprosthetic tricuspid valve. A percutaneous tricuspid valve-in-valve procedure with an Edwards S3 valve was ofered for compassionate use, performed with no complications and with a significant clinical condition improvement. Tricuspid Valve Disease Congenital Heart Disease Transcatheter Valve Implantation Sternotomy Child pmcCASE PRESENTATION In 2018, a two-year-old male patient was brought in from a rural area in Colombia due to cyanotic congenital heart disease. He had multiple episodes of respiratory infections in addition to cyanosis on crying or physical exertion. On admission to Fundacion Cardioinfantil, an echocardiogram was performed revealing a double outlet right ventricle (DORV), side-by-side vessels, a subaortic ventricular septal defect (VSD), narrowed subaortic cone without gradient, and a large persistent ductus arteriosus with severe pulmonary hypertension. In May 2018, the patient was referred for surgical correction of DORV along with unrelated VSD closure with tunneled Dacron patch, disinsertion of the tricuspid papillary septal muscle and reimplantation in the Dacron patch, patent ductus arteriosus closure and tricuspid valve repair. In July 2018, the patient was readmitted due to stage C, Stevenson B decompensated heart failure. A new echocardiogram showed a grade III tricuspid regurgitation. He was again referred for surgery and a tricuspid valvuloplasty was performed using an autologous pericardial patch. One week following surgical correction, severe tricuspid regurgitation was observed. As a result, the tricuspid valve was replaced using a 25-mm Perimount biological prosthesis. Outpatient follow-up was done throughout the 2018-2019 period. The patient had a successful recovery, and no cardiovascular symptoms were observed. He was readmitted in October 2020 due to a fall from own height along with granuloma formation at the surgical site, mild dyspnea, tachypnea and occasional cough. Echocardiogram revealed severe stenosis of the biological tricuspid prosthesis with a mean gradient of 12-16 mmHg. The patient was referred for balloon valvuloplasty. At the end of the procedure, a grade 2-3 biological valve insufficiency was observed. TECHNICAL DESCRIPTION In this situation, a new surgery was ruled out at the heart team meeting, and a percutaneous tricuspid valve-in-valve procedure was ofered for compassionate use. Informed consent was obtained from the parents. The procedure followed the guidelines of the local ethics committee. In October 2020, the procedure was performed in the hybrid operating room under general anesthesia and using echocardiography to assess valve function as well as guiding implantation. The right jugular vein was punctured after echographic evaluation, with an 8-French sheath. The right femoral artery was punctured with a 5-French sheath for invasive blood pressure monitoring. Intravenous antibiotics and heparin were administered. Through the 8-French introducer, a 6-French JR 3.5 catheter was advanced, once positioned, the 14-French eSheath was placed, then the CONFIA guidewire was introduced and left in position in the right ventricle. We chose the 26-mm Edwards S3 valve (Edwards Lifesciences, Inc, Irvine, CA, USA) mounted on the balloon. Finally, the new valve was successfully positioned and implanted . No paravalvular leak or valve regurgitation was observed on transesophageal echocardiography. We decided to place a 26-mm Edwards S3 valve since the previous one was a 25-mm Perimount and the effective orifice for this valve was adequate. Fig. 1 Pre-OP: tricuspid valve gradient before implantation. Post-OP: tricuspid valve gradient 1 year after surgery. Fig. 2 Valve implantation exposed in a sequence. The patient remained in the intensive care unit for the first 24 hours, being discharged 4 days after admission, with improvement in the right heart failure symptoms, and on warfarin therapy for three months and antiplatelet therapy after completing the three months of anticoagulation. Two years later, the valve continues to perform well, without stenosis (mean gradient 2 mmHg) or regurgitation, and the patient is asymptomatic (NYHA I). COMMENT Tricuspid valve dysfunction is a relatively uncommon occurrence, with higher prevalence in individuals with congenital heart abnormalities, often involving complex patients . Severe tricuspid valve dysfunction and especially severe regurgitation are associated with increased mortality regardless of other factors. Surgical tricuspid valve replacement is the main indication for the treatment of severe tricuspid valve dysfunction (regurgitation, stenosis or mixed disease) . In the tricuspid position, bioprosthetic valves are generally preferred over mechanical valves, given the failure rates and anticoagulation-associated complications. However, these bioprosthetic valves undergo a gradual degeneration requiring successive replacements. Management of these patients is complicated by the presence of previous sternotomies and high surgical morbidity and mortality, which makes a percutaneous approach an appealing option . The implantation of percutaneous valves in the tricuspid position is still an of-label indication, but it can be an option to avoid reinterventions in tricuspid bioprosthesis. Here, we describe a case of successful percutaneous tricuspid valve-in-valve procedure, with a 26-mm Edwards Sapien S3(c) valve in a 15 kg boy. To the best of our knowledge, this is the smallest patient in which a tricuspid valve-in-valve procedure with an Edwards Sapien valve has been performed in Latin America. Sapien and Melody(c) valves (Medtronic Inc, Minneapolis, MN, USA) have been used in tricuspid valve-in-valve procedures , but Melody valve is significantly longer than Sapien, even though the valve can be cut to reducing its length it was an important issue in a 15 kg patient. Given the small size of our patient, with a small part of the sheath inside him, short distance and sharp curve between the sheath and the target, and an adequate diameter of the jugular vein, anticipating the possibility of difficulties in this step, we preferred to use a 14F eSheath, allowing to mount the Sapien valve on the balloon outside the patient, and reducing manipulation inside him. McElhinney et al. reported a multicenter registry with 152 cases of tricuspid valve-in-valve procedures with Melody and Sapien valves, with a medium-term follow-up. Successful implantation was performed in 150 patients, with a 30-day mortality of 3.3% (all NYHA III-IV at baseline). Estimated reintervention-free survival was 85+-3% at 1 year, with NYHA IV, baseline renal failure, and in-hospital acutely ill as statistically significant risk factors. All centers in the registry performed 1 to 3 procedures, showing that tricuspid valve-in-valve procedure appears to be technically straightforward and reproducible across a large number of centers despite the small volume, and confrming that the risk-benefit profile of tricuspid valve-in-valve procedures appear to be technically straightforward and reproducible across a large number of centers despite the small volume, and confrming that the risk-benefit profile of tricuspid valve-in-valve procedures is generally favorable. Percutaneous tricuspid valve-in-valve is a valuable option for treating complex patients with severe symptomatic tricuspid valve dysfunction, even in very small patients, and ofers the possibility of delaying and shortening surgical procedures throughout the lives of these patients. Unfortunately, there are no multicentric studies, nor medium-and long-term studies evaluating the durability and degree of degeneration of these prostheses at this age. This study was carried out at the Department of Cardiac Surgery, Fundacion Cardioinfantil - Instituto de Cardiologia, Bogota, Cundinamarca, Colombia. No financial support. No conflict of interest. REFERENCES 1 Fernandez-Doblas J Perez-Andreu J Betrian P Abella RF Pediatric tricuspid valve replacement with transcatheter bioprosthetic valve: an alternative option in high-risk patients Semin Thorac Cardiovasc Surg 2020 32 4 1021 1023 10.1053/j.semtcvs.2019.06.006 31233784 2 Challa A Markham R Walters D Percutaneous valve in valve in the tricuspid position in a patient with tetralogy of fallot BMJ Case Rep 2017 2017 10.1136/bcr-2017-221104 bcr2017221104 3 McElhinney DB Cabalka AK Aboulhosn JA Eicken A Boudjemline Y Schubert S Transcatheter tricuspid valve-in-valve implantation for the treatment of dysfunctional surgical bioprosthetic valves: an international, multicenter registry study Circulation 2016 133 16 1582 1593 10.1161/CIRCULATIONAHA.115.019353 26994123 4 Scarsini R Lunardi M Pesarini G Castriota F Feola M Ferrero V Long-term follow-up after trans-catheter tricuspid valve-in-valve replacement with balloon-expandable aortic valves Int J Cardiol 2017 235 141 146 10.1016/j.ijcard.2017.02.076 28279501 5 du Plessis FA Helbing WA Bogers AJ Excision of the tricuspid valve in a baby with candida endocarditis Cardiol Young 2007 17 5 545 547 10.1017/S104795110700056X 17540053 |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34869 Internal Medicine Neurology Pontine Infarct Resulting in Millard-Gubler Syndrome: A Case Report Muacevic Alexander Adler John R Patel Shivangi 1 Bhakta Ashika 1 Wortsman Joshua 2 Aryal Barun B 2 Shrestha Dhan B 3 Joshi Tilak 2 1 Internal Medicine, Ross University School of Medicine Barbados Campus, Barbados, BRB 2 Department of Internal Medicine, Mount Sinai Hospital, Chicago, USA 3 Department of Medicine, Mount Sinai Hospital, Chicago, USA Barun B. Aryal [email protected] 11 2 2023 2 2023 15 2 e348696 12 2022 29 1 2023 Copyright (c) 2023, Patel et al. 2023 Patel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Millard-Gubler syndrome is a crossed brainstem syndrome involving the facial nerve, abducens nerve, and the pyramidal tracts, typically resulting in ipsilateral facial weakness and contralateral hemiparesis. Here we report the case of a 76-year-old female with no pertinent past medical history who presented to the emergency department with acute left-sided facial droop and right upper extremity sensory loss. A pontine infarction was identified on imaging and she was managed medically with complete recovery. Pontine infarction can result in Millard-Gubler syndrome and present with facial weakness and subtle contralateral limb symptoms. pontine infarct case report facial nerve palsy hemiparesis millard-gubler syndrome The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Millard-Gubler syndrome is a rare ventral pontine syndrome that manifests with ipsilateral weakness of the eye upon abduction (abducens nerve), ipsilateral facial muscle weakness (facial nerve), and contralateral hemiparesis or hemiplegia of the upper and lower extremities (pyramidal tract fibers) [1-3]. This is usually due to unilateral lesion at the basal portion of the caudal pons as a result of a mass, hemorrhage, or rarely, infarction [4-7]. Hemorrhage and infarction are more common in older patients, while tumors and infections are more common in younger individuals. Bell's palsy is a result of an acute idiopathic peripheral facial nerve palsy due to a unilateral lower motor neuron lesion between the facial nerve nuclei and muscles. In this case report, we present a patient with acute onset facial droop with no apparent cause. Extensive workup was done to determine the presence of stroke and potential arterial stenosis. The patient was found to have an acute infarction at the left dorsal brainstem at the pontomedullary junction which, along with her clinical presentation, pointed to the diagnosis of Millard-Gubler syndrome. Case presentation A 76-year-old female with no significant past medical history presented to the emergency department with a left-sided facial droop that began one day prior and had been worsening. She also complained of numbness in her right fingers, which had resolved by the time of the presentation. She denied weakness in upper and lower extremities, slurred speech, and changes in gait. She also denied fever, chills, headache, changes in vision, chest pain, palpitations, shortness of breath, abdominal pain, nausea, vomiting, or dysuria. She denied any history of recent trauma, travel, or recent upper respiratory tract infection. She had never experienced similar symptoms before. Her family history was non-contributory. Upon arrival, she was afebrile, had a heart rate of 123, respiratory rate of 22, blood pressure of 191/103, and oxygen saturation of 96% on room air. On examination, her pupils were equal, round, and reactive to light and accommodation. Extraocular movements were intact bilaterally. Facial sensation was intact, but there was a left upper and lower facial palsy with decreased prominence of the left nasolabial fold. Motor and sensory examination of bilateral upper and lower extremities were normal and reflexes were intact. She was oriented to person, place, time, and situation and her speech was normal. The rest of the physical examination was unremarkable. Laboratory investigations showed no significant electrolyte abnormalities. Due to concern for acute or subacute stroke, a non-contrast computed tomography angiography of the head and neck was done. This revealed a sub-centimeter hypodensity in the left lentiform nucleus, reflecting an age-indeterminate lacunar infarct. There was also mild stenosis of the proximal basilar artery and moderate stenosis of the origin of the right posterior cerebral artery. There were no signs of hemorrhage. She was given aspirin and atorvastatin in the emergency room. Permissive hypertension was maintained for 24 hours and blood pressure was then managed with oral antihypertensive agents. Thrombolysis was not indicated since she presented more than 4.5 hours after the onset of symptoms. For better visualization of the lesion, a magnetic resonance imaging of the brain was ordered, which revealed a small infarct in the left dorsal brainstem at the pontomedullary junction consistent with an acute infarction, as seen in Figure 1. Figure 1 MRI brain showing small left dorsal brainstem infarct at the pontomedullary junction (white arrow) The patient was subsequently admitted for management of an ischemic stroke. Differential diagnoses included Bell's palsy and Millard-Gubler syndrome. Serological tests for Hepatitis B, Hepatitis C and HIV were negative. In order to rule out Lyme disease as the cause of facial nerve palsy, Lyme disease IgG/IgM antibodies were ordered, which came back negative. The diagnosis of Millard-Gubler syndrome was made based on imaging findings of acute pontine infarction and neurological findings of ipsilateral facial palsy. She was treated with dual antiplatelet therapy with aspirin and clopidogrel. Physical rehabilitation was initiated. By the eighth day of admission, her symptoms had completely resolved. She was then discharged, and after 21 days of dual anti-platelet therapy, she was switched to aspirin alone with the addition of a statin. On follow-up after eight weeks, she had no residual symptoms or new neurological symptoms. Discussion We presented the case of a 76-year-old female who presented with new-onset facial droop and decreased sensation in the upper right extremity which had resolved by itself. On imaging, a small acute infarction was identified in the left pontomedullary junction. A diagnosis of Millard-Gubler syndrome was made, and she recovered fully with physical rehabilitation. Millard-Gubler syndrome, also known as ventral pontine syndrome or facial abducens hemiplegia syndrome, was first described in 1858, and was classically associated with a pontine mass . Subsequent reports, however, have involved cases caused by bleeding and infarcts, and rarely neurocysticercosis [2-7,9,10]. The lesion lies above the level of the decussation of the pyramidal and spinothalamic tracts. As a result, the cranial nerve signs are ipsilateral whereas the limb symptoms are contralateral, resulting in the classical crossed brain stem syndrome . The involvement of the pyramidal tracts usually manifests in hemiplegia or hemiparesis of upper or lower extremities in addition to facial palsy [2-5,10]. In our case, there was no motor deficit in the extremities. The patient complained of right-sided upper extremity numbness which had resolved by the time of examination, and no sensory deficit in the extremities was present on initial or subsequent examinations. Unilateral facial weakness was prominent in this case, and the presentation was typical of peripheral facial palsy, with involvement of upper and lower face. One of the alternative diagnoses considered was Bell's palsy, which is a diagnosis of exclusion. However, presence of contralateral sensory symptoms, albeit transient, would not be expected in Bell's palsy. Other intracranial pathology such as tumors, vascular malformations, and neurocysticercosis were excluded via imaging. Herpes zoster reactivation is another potential cause of facial nerve palsy but would present with pain and vesicles on examination in affected dermatomes, which were not present in this case. Moreover, evidence of acute pontine infarction on imaging confirmed the diagnosis of Millard-Gubler syndrome. Our patient had a full recovery within one week of presentation. This is consistent with the clinical course described in case reports, especially those involving small acute infarcts . Brainstem infarcts are usually seen in the background of various risk factors such as hypertension, diabetes, and hyperlipidemia. Our patient had previously undiagnosed hypertension but no other significant medical history. Our case demonstrates the utility of imaging in diagnosing Millard-Gubler syndrome and distinguishing it from other differential diagnoses, especially in cases with an unconventional patient profile and presentation. Conclusions Millard-Gubler syndrome is a rare neurological syndrome resulting from pontine infarction. It can present with facial weakness and contralateral limb symptoms, which can sometimes be subtle or self-resolving. MR imaging can be very helpful in confirming the diagnosis and differentiating it from other differential diagnoses such as tumors, vascular malformations or other intracranial masses. Complete recovery is possible with supportive management. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Disorders of motility: paralysis and weakness Principles of Neurology Ropper AH Samuels MA Klein JP Prasad S 71 New York McGraw-Hill 2019 2 Millard-Gubler syndrome AJNR Am J Neuroradiol Matlis A Kleinman Y Korn-Lubetzki I 179 181 15 1994 8141053 3 Millard-Gubler syndrome: MR findings Neuroradiology Onbas O Kantarci M Alper F Karaca L Okur A 35 37 47 2005 15647948 4 Pontine cavernoma hemorrhage leading to Millard-Gubler syndrome Am J Phys Med Rehabil Kesikburun S Safaz I Alaca R 263 90 2011 20531153 5 Wall-eyed monocular internuclear ophthalmoplegia (WEMINO) and Millard-Gubler syndromes in a patient with isolated pontine infarction: topographic, oculomotor, and radiological analysis of two very uncommon conditions Case Rep Neurol Ceballos-Lizarraga R Palomino-Diaz C Romero-Figueroa JA 230 237 11 2019 31543808 6 Vertebrobasilar artery dissection manifesting as Millard-Gubler syndrome in a young ischemic stroke patient: a case report World J Clin Cases Li XT Yuan JL Hu WL 73 78 7 2019 30637255 7 Neurocysticercosis presenting as Millard Gubler syndrome J Neurosci Rural Pract Prasad R Kapoor K Srivastava A Mishra O 375 377 3 2012 23189006 8 The classical brain stem syndromes (translations of the original papers with notes on the evolution of clinical neuroanatomy) Med Hist Lewis PD 106 17 1973 9 Vertical muscle transposition with silicone band belting in VI nerve palsy BMJ Case Rep Dourado Leite R Freitas C Guimaraes S 2016 2016 10 Millard-Gubler syndrome associated with cerebellar ataxia in a patient with isolated paramedian pontine infarction - a rarely observed combination with a benign prognosis: a case report Case Rep Neurol Ayele BA Tadesse Y Guta B Zenebe G 239 245 13 2021 33976662 |
MMWR Morb Mortal Wkly Rep MMWR Morb Mortal Wkly Rep WR Morbidity and Mortality Weekly Report 0149-2195 1545-861X Centers for Disease Control and Prevention 36893049 mm7210a4 10.15585/mmwr.mm7210a4 Notes from the Field Notes from the Field: Increase in Pediatric Invasive Group A Streptococcus Infections Colorado and Minnesota, October-December 2022 Barnes Meghan MSPH 1 Youngkin Erin MPH 1 Zipprich Jennifer PhD 2 Bilski Kayla MPH 2 Gregory Christopher J. MD 3 Dominguez Samuel R. MD PhD 4 Mumm Erica MPH 2 McMahon Melissa MPH 2 Como-Sabetti Kathryn MPH 2 Lynfield Ruth MD 2 Chochua Sopio MD PhD 3 Onukwube Jennifer MPH 3 Arvay Melissa PhD 3 Herlihy Rachel MD 1 1Colorado Department of Public Health and Environment; 2Minnesota Department of Health; 3National Center for Immunization and Respiratory Diseases, CDC; 4University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado. Corresponding author: Meghan Barnes, [email protected]. 10 3 2023 10 3 2023 72 10 265267 All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. pmcDuring fall 2022, a resurgence of invasive group A Streptococcus (iGAS) infection in children and adolescents was observed in two of CDC's Emerging Infections Program (EIP)* surveillance sites: Colorado (Denver metropolitan area) and Minnesota (entire state). This increase followed historic declines in invasive bacterial diseases during 2020, concurrent with mitigation strategies implemented during the COVID-19 pandemic+ (1). Whereas reports of iGAS increased among all age groups, including adults, the increase among children and adolescents was notable, occurred earlier than seasonal increases during previous years, and accompanied a resurgence in hospitalizations for respiratory viral illnesses such as respiratory syncytial virus (RSV) and influenza. Viral infections, such as influenza and varicella, have been identified as risk factors for iGAS infection in children, adolescents, and adults (2) and can be reduced by vaccination. Surveillance for iGAS is conducted by 10 U.S. sites as part of EIP's Active Bacterial Core surveillance (ABCs).SS An analysis of cases among Colorado and Minnesota EIP site residents aged <18 years who met criteria for iGASP was conducted using ABCs data from the Colorado and Minnesota surveillance sites. Case counts, age distribution, and clinical characteristics of patients with iGAS infection were compared over three periods: baseline (January 1, 2016-December 31, 2019), pandemic (January 1, 2020-December 31, 2021), and recent increase (October 1-December 31, 2022). This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.** During October 1-December 31, 2022, a combined total of 34 cases was reported in the Colorado and Minnesota ABCs sites. In comparison, a 3-month average of 11 cases and four cases were observed during the same period in 2016-2019 and 2020-2021, respectively. Colorado patients identified during the recent increase were younger (median age = 3.1 years) than were those during the baseline period (5.6 years) and the pandemic period (6.2 years); this was not observed in Minnesota (median age = 4.0, 6.0, and 6.5 years in the baseline, pandemic, and recent increase periods, respectively). Two deaths (one each in Colorado and Minnesota) were noted during the recent increase period; overall, during 2016-2021, five deaths occurred (one in Colorado and four in Minnesota). Frequency of intensive care unit admission and length of hospital stay were similar during the recent increase (35.3% [12 of 34 patients]; 4.5 days) and baseline periods (34.4% [62 of 180], 5.0 days).++ Most cases (73.5% [25 of 34]) that occurred during the recent increase were in children and adolescents without underlying medical conditions. Among the 34 cases that occurred during the recent increase, 21 (61.8%) patients had an upper respiratory tract infection noted within the 2 weeks preceding their iGAS infection, six (17.6%) reported sore throat, and seven (20.6%) reported no preceding illness. Fifteen (44.1%) patients received positive test results for one or more respiratory viral pathogen during the 2 weeks before, or concurrent with, their iGAS infection. Viral respiratory pathogens identified included RSV (six, 17.6%), influenza A or B (six, 17.6%), and SARS-CoV-2 (three, 8.8%).SSSS Comparison of pediatric iGAS case counts, and influenza and RSV hospitalization rates during 2016-2022 showed an increase in iGAS infections coinciding with seasonal peaks in RSV and influenza hospitalization rates during most years except in 2021, when influenza and RSV hospitalizations were lower than those in previous or subsequent years . FIGURE Cases of invasive group A Streptococcus infections* and hospitalization rates+ for influenzaSS and respiratory syncytial virusP among children and adolescents aged <18 years Colorado and Minnesota, January 2016-December 2022** Abbreviations: iGAS = invasive group A Streptococcus infection; RSV = respiratory syncytial virus. * iGAS infections were identified through each state's Emerging Infections Program Active Bacterial Core surveillance systems. Cases in Colorado are from the Denver metropolitan area; cases in Minnesota throughout the state are reportable to the Minnesota Department of Health. + Hospitalizations per 100,000 population. SS Colorado influenza hospitalizations are reported from the Denver metropolitan area, and rates in children and adolescents aged <18 years were calculated using age-specific and geographically defined population data obtained from the Colorado Department of Local Affairs, Demography Office. Influenza hospitalizations in Minnesota throughout the state are reportable to the Minnesota Department of Health; Minnesota influenza hospitalization rates in children and adolescents aged <18 years were calculated using age-specific and statewide population data obtained from CDC WONDER. P RSV hospitalizations in Colorado were from the Denver metropolitan area; RSV hospitalization rates in children and adolescents aged <18 years were calculated using age-specific and Denver metropolitan population data obtained from the Colorado Department of Local Affairs, Demography Office. Colorado RSV hospitalization data are available during July 2019-December 2022. Minnesota RSV hospitalization rates are from the seven-county Twin Cities metropolitan area; rates in children and adolescents aged <18 years were calculated using age-specific and seven-county metropolitan population data obtained from CDC WONDER. Minnesota RSV hospitalization data were available during October 2018-December 2022. ** COVID-19 cases were not included because of the short period for which data were available and the variations in testing practices and surveillance catchment areas that limit the comparability of data. The figure comprises two histograms showing cases of invasive group A Streptococcus infections and hospitalization rates for influenza and respiratory syncytial virus among children and adolescents aged under 18 years in Colorado and Minnesota during January 2016-December 2022. Among the 26 (76%) iGAS cases from the recent increase period with M protein genePP (emm) typing results available, 22 (85.0%) were type 1 (nine, 34.6%) or type 12 (13, 50.0%); these were also the two most common types detected during the baseline period (55.1% type 1; 17.9% type 12). Whole genome sequencing results did not indicate changes in predicted antibiotic susceptibility (3) compared with earlier years or expansion of a single clone. Twenty-three isolates were predicted to be susceptible to all antimicrobials; one type 12 isolate was resistant to erythromycin, and two type 77 isolates were resistant to erythromycin, clindamycin, and tetracycline. The increase in pediatric iGAS cases reported during fall 2022 is important for understanding the impact of the COVID-19 pandemic on the epidemiology of iGAS (1). Increased activity of respiratory viruses, in combination with reduced exposure to GAS and associated development of protective immunity to common emm types during the COVID-19 pandemic (4), might have predisposed children to iGAS infection when pandemic restrictions were lifted. The proportion of patients with preceding or concurrent influenza infections suggests that influenza vaccination might reduce the risk for iGAS, as has been demonstrated for varicella vaccination (5). Clinicians should consider iGAS as a possible cause of severe illness in children, adolescents, and adults, particularly among patients at increased risk,*** and offer influenza and varicella vaccination to eligible persons who are not up to date. * The Emerging Infections Program is a network of 10 state health departments (program sites) funded by CDC's Division of Preparedness and Emerging Infections that collaborates with academic institutions and other public health stakeholders to address emerging infections. + (Accessed February 7, 2023). SS (Accessed January 30, 2023). P Group A Streptococcus isolated or pathogen-specific nucleic acid detected using a validated molecular test in a specimen obtained from a normally sterile body site, or group A Streptococcus isolated from a wound culture and accompanied by necrotizing fasciitis or streptococcal toxic shock syndrome. ** 45 C.F.R. part 46.102(l)(2), 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq. ++ A comparison with pandemic numbers is not provided because of the small number of cases during 2020-2021. SSSS Other respiratory pathogens detected included parainfluenza (two) and coronavirus other than SARS-CoV-2 (one). PP The M protein gene (emm) encodes the cell surface M virulence protein and forms the basis for the most widely used iGAS strain subtyping method. *** Persons at increased risk of iGAS include those aged >=65 years; American Indian or Alaska Native persons; residents of long-term care facilities; those with medical conditions such as diabetes, malignancy, immunosuppression, chronic kidney, cardiac, or respiratory disease; those with wounds or skin disease; and those who inject drugs or are experiencing homelessness. All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Ruth Lynfield reports participation on the Council of State and Territorial Epidemiologists (CSTE) Executive Board, the National Foundation of Infectious Diseases (NFID) Executive Board, the Program Committee for ID Week, and serving as associate editor of the American Academy of Pediatrics Red Book (the fee for which was donated to the Minnesota Department of Health), and receipt of support from these groups to attend CSTE, American Academy of Pediatrics Committee on Infectious Diseases, NFID, and ID Week meetings. Samuel R. Dominguez reports institutional support from Pfizer and Biofire Diagnostics, unrelated to the current work, and consulting fees (paid to his institution) from Biofire Diagnostics and Karius. Jennifer Zipprich reports that her spouse is employed by Pfizer. No other potential conflicts of interest were disclosed. References 1. Prasad N, Rhodes J, Deng L, Changes in the incidence of invasive bacterial disease during the COVID-19 pandemic in the United States, 2014-2020. J Infect Dis 2023. Epub February 1, 2023. 10.1093/infdis/jiad028 36723871 2. Herrera AL, Huber VC, Chaussee MS. The association between invasive group A streptococcal diseases and viral respiratory tract infections. Front Microbiol 2016;7 :342. 10.3389/fmicb.2016.00342 27047460 3. Fay K, Onukwube J, Chochua S, Patterns of antibiotic nonsusceptibility among invasive group A Streptococcus infections United States, 2006-2017. Clin Infect Dis 2021;73 :1957-64. 10.1093/cid/ciab575 34170310 4. Lewnard JA, Whittles LK, Rick AM, Martin JM. Naturally acquired protection against upper respiratory symptoms involving group A Streptococcus in a longitudinal cohort study. Clin Infect Dis 2020;71 :e244-54. 10.1093/cid/ciaa044 31955205 5. Hasin O, Hazan G, Rokney A, Invasive group A Streptococcus infection in children in southern Israel before and after the introduction of varicella vaccine. J Pediatric Infect Dis Soc 2020;9 :236-9. 10.1093/jpids/piz013 30927745 |
MMWR Morb Mortal Wkly Rep MMWR Morb Mortal Wkly Rep WR Morbidity and Mortality Weekly Report 0149-2195 1545-861X Centers for Disease Control and Prevention 36893048 mm7210a3 10.15585/mmwr.mm7210a3 Full Report Public Health Response to Clusters of Rapid HIV Transmission Among Hispanic or Latino Gay, Bisexual, and Other Men Who Have Sex with Men Metropolitan Atlanta, Georgia, 2021-2022 Saldana Carlos MD 1 2 * Philpott David C. MD 3 4 * Mauck Daniel E. PhD 5 Hershow Rebecca B. PhD 3 4 Garlow Eleanor MPH 5 Gettings Jenna DVM 3 5 Freeman Dorian MPH 6 France Anne Marie PhD 4 Johnson Erica N. MPA 7 Ajmal Agha MBBS PhD 4 Elimam Dena PhD 5 Reed Karrie MPH 8 Sulka Alana MPH 6 Adame Jose F. MPH 5 Andia Jonny F. PhD 4 Gutierrez Mariana MPH 4 Padilla Mabel MPH 4 Jimenez Nathalie Gonzalez MPH 4 Hayes Craig MPH 4 McClung Robert P. MD 4 Cantos Valeria D. MD 2 Holland David P. MD 1 2 Scott Jane Yoon MD 1 2 7 Oster Alexandra M. MD 4 Curran Kathryn G. PhD 4 Hassan Rashida MSPH 4 Wortley Pascale MD 5 1Fulton County Board of Health, Atlanta, Georgia; 2Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta Georgia; 3Epidemic Intelligence Service, CDC; 4Division of HIV Prevention, National Center for HIV, Viral Hepatitis, STD, and TB Prevention, CDC; 5Georgia Department of Public Health; 6Gwinnett, Newton, and Rockdale County Health Department, Lawrenceville, Georgia; 7DeKalb County Board of Health, Decatur, Georgia; 8Cobb and Douglas Public Health, Marietta, Georgia. Corresponding author: Carlos Saldana, [email protected]. 10 3 2023 10 3 2023 72 10 261264 All material in the MMWR Series is in the public domain and may be used and reprinted without permission; citation as to source, however, is appreciated. pmcDuring February 2021-June 2022, the Georgia Department of Public Health (GDPH) detected five clusters of rapid HIV transmission concentrated among Hispanic or Latino (Hispanic) gay, bisexual, and other men who have sex with men (MSM) in metropolitan Atlanta. The clusters were detected through routine analysis of HIV-1 nucleotide sequence data obtained through public health surveillance (1,2). Beginning in spring 2021, GDPH partnered with health districts with jurisdiction in four metropolitan Atlanta counties (Cobb, DeKalb, Fulton, and Gwinnett) and CDC to investigate factors contributing to HIV spread, epidemiologic characteristics, and transmission patterns. Activities included review of surveillance and partner services interview data,+ medical chart reviews, and qualitative interviews with service providers and Hispanic MSM community members. By June 2022, these clusters included 75 persons, including 56% who identified as Hispanic, 96% who reported male sex at birth, 81% who reported male-to-male sexual contact, and 84% of whom resided in the four metropolitan Atlanta counties. Qualitative interviews identified barriers to accessing HIV prevention and care services, including language barriers, deportation-related concerns, and cultural norms regarding sexuality-related stigma. GDPH and the health districts expanded coordination, initiated culturally concordant HIV prevention marketing and educational activities, developed partnerships with organizations serving Hispanic communities to enhance outreach and services, and obtained funding for a bilingual patient navigation program with academic partners to provide staff members to help persons overcome barriers and understand the health care system. HIV molecular cluster detection can identify rapid HIV transmission among sexual networks involving ethnic and sexual minority groups, draw attention to the needs of affected populations, and advance health equity through tailored responses that address those needs. Investigation and Results In February 2021, GDPH identified three HIV clusters among Hispanic MSM using molecular analysis of HIV-1 nucleotide sequence data collected through routine surveillance (1). In Georgia, clusters are inferred using a genetic distance threshold of 0.005 nucleotide substitutions per site among persons with HIV infection diagnosed during the most recent 3 years, with priority clusters defined as those that include four or more diagnoses during the most recent 12 months. This definition is consistent with evidence of rapid HIV transmission (1,3). These were the first priority clusters in Georgia comprising >=40% Hispanic persons. GDPH analysis of HIV surveillance data demonstrated that during 2014-2019, HIV diagnoses among Hispanic adolescents and adults in four metropolitan Atlanta counties increased from 38.9 to 47.1 per 100,000 persons. After demonstration of persistent growth of the clusters through early 2021, GDPH reviewed partner services interview data and attempted direct outreach to all persons in clusters, including those previously interviewed. However, response was limited, partly attributed to deportation-related concerns and limited numbers of bilingual staff members. In October 2021, CDC began providing remote assistance in analyzing epidemiologic data for investigation activities, and GDPH initiated review of medical charts of persons in clusters. Among 38 persons with available charts, 10 (26%) were primarily Spanish-speaking, and 12 (32%) were from Latin American countries; five (13%) had mental health diagnoses, including depression, anxiety, or bipolar disorder. In February 2022, GDPH requested CDC assistance in conducting a qualitative assessment with Hispanic MSM community members and service providers to identify barriers to accessing medical and social services and HIV care, as well as simplifying cluster data synthesis and visualization. CDC provided support during March-July 2022. This activity was reviewed by CDC and conducted consistent with applicable federal law and CDC policy.SS By June 30, 2022, GDPH detected two additional clusters that included >=40% Hispanic persons, with additional persons identified among all clusters throughout the investigation period . The five clusters included 75 persons with HIV, with clusters ranging in size from four to 45 persons. The median age of persons in clusters was 29 years (range = 16-54 years), 56% identified as Hispanic, 96% were assigned male sex at birth, and 81% reported male-to-male sexual contact (Table). Overall, 84% of persons lived in one of the four metropolitan Atlanta counties. Forty percent of diagnoses were from facilities with infectious disease providers who specialize in HIV care, 27% in primary or urgent care settings, 13% in inpatient or emergency department settings, and 11% at health departments. Eighty-five percent of persons in these clusters were virally suppressedP; however, new diagnoses continued to be identified throughout the investigation . FIGURE HIV diagnoses by month of diagnosis, and major events during the public health response to five HIV molecular clusters primarily among Hispanic or Latino gay, bisexual, and other men who have sex with men Metropolitan Atlanta, Georgia, February 2019-April 2022* * Persons in clusters were identified through June 30, 2022, with all identified persons having a diagnosis date of April 30, 2022, or earlier. Persons with more recently diagnosed HIV infection might not yet have been identified as part of a cluster for reasons including time needed to enter HIV care, time for HIV nucleotide sequence to be reported to health department, and molecular analysis schedule. This figure is a histogram showing the number of HIV diagnoses by month of diagnosis, and major events during the public health response to five HIV molecular clusters primarily among Hispanic or Latino gay, bisexual, and other men who have sex with men in Metropolitan Atlanta, Georgia, during February 2019-April 2022. TABLE Characteristics of persons in five HIV molecular clusters primarily among Hispanic or Latino gay, bisexual, and other men who have sex with men (N = 75) Metropolitan Atlanta, Georgia, June 2022 Characteristic No. (%) Age, yrs, median (range) 29 (16-54) Received HIV diagnosis during preceding 12 mos 22 (29) Sex at birth Male 72 (96) Female 3 (4) Race and ethnicity Black or African American, non-Hispanic 7 (9) White, non-Hispanic 15 (20) Hispanic or Latino 42 (56) Other, non-Hispanic 11 (15) County of residence at diagnosis Cobb 7 (9) DeKalb 11 (15) Fulton 10 (13) Gwinnett 35 (47) Other 12 (16) Born outside the United States 25 (33) HIV transmission category Male-to-male sexual contact 55 (73) Male-to-male sexual contact and injection drug use 6 (8) Heterosexual contact 5 (7) Unknown 9 (12) Diagnosis setting Facility with infectious diseases or HIV specialty 30 (40) Primary or urgent care 20 (27) Inpatient or emergency facility 10 (13) Health department 8 (11) Other* 7 (9) Most recent viral load test <200 HIV RNA copies/mL 64 (85) Achieved viral suppression <=365 days after diagnosis 69 (92) History of HIV PrEP use + 4 (5) STI diagnosed within 2 mos of HIV diagnosis 23 (31) STI identified during the 12 mos before HIV diagnosis 4 (5) Abbreviations: PrEP = preexposure prophylaxis; STI = sexually transmitted infection. * Includes unknown (six) and out of state (one). + HIV PrEP use ever recorded in partner services interview data. By June 30, 2022, among 52 persons in clusters eligible for partner services interviews,** 34 (65%) were interviewed, 16 (31%) could not be reached, and two (4%) declined. Among those interviewed, 20 (59%) reported meeting partners online, and four (12%) reported ever having taken HIV preexposure prophylaxis (PrEP). CDC and health department staff members conducted qualitative interviews with 28 Hispanic MSM and one transgender woman in the four counties and 28 individual or group interviews with 65 medical and social service providers who treated persons in clusters or served Hispanic MSM. Community members were recruited by provider referral, social media, and at bars and clubs. Because multiple attempts had already been made to reach persons in clusters for partner services interviews, further attempts to conduct qualitative interviews were not made for persons in clusters. Interviewed participants identified barriers to accessing medical and social services, including few Spanish-speaking staff members, limited Spanish language materials, and fear of deportation and other immigration-related concerns. Participants also reported barriers to accessing HIV prevention and care, including stigma toward MSM and persons with HIV because of sexuality-related cultural norms, low levels of awareness about HIV and other sexually transmitted infections because of limited primary care access, limited provision of HIV services in primary and urgent care settings, and limited Hispanic MSM-focused community outreach and marketing. Public Health Response Response activities have included establishing routine coordination meetings between GDPH and metropolitan Atlanta health districts and presenting reports on the investigation to HIV community advisory boards and planning councils. Health districts disseminated Spanish-language HIV prevention materials emphasizing service availability irrespective of immigration status via social media and at venues in zip codes where persons in clusters reside. GDPH established new partnerships with community-based organizations (CBOs) serving Hispanic communities and developed strategies to increase the number of bilingual staff members, including modifying job postings to prioritize hiring bilingual personnel. Health departments and CBOs partnered with academic institutions to engage in implementation science research and obtained federal funding for a culturally concordant outreach and patient navigation program for status-neutral sexual health services. A status-neutral approach provides persons with and without HIV access to comprehensive medical services, including HIV prevention and treatment, and social services depending on their needs.++ In addition, in June 2022, the local health districts launched an at-home HIV and sexually transmitted infection self-testing program.SSSS GDPH is continuing to partner with CDC to implement informatics tools to simplify cluster investigations. Discussion The detection of multiple HIV clusters among Hispanic MSM in metropolitan Atlanta provided evidence of rapid, ongoing HIV transmission and resulted in a multifaceted response involving health departments, CDC, health care providers, and CBOs. The response identified barriers to accessing HIV services among Hispanic MSM in metropolitan Atlanta. Although most persons in clusters had evidence of viral suppression, which prevents sexual HIV transmission, as of June 30, 2022, the clusters were still expanding. This finding indicates potential ongoing transmission among a larger network, which could include persons with undiagnosed HIV infection. This investigation highlighted the value of molecular HIV cluster detection and response for identifying gaps in services among networks of MSM. Although most large HIV outbreak responses in the United States have focused on persons who inject drugs, male-to-male sexual contact is the primary mode of HIV transmission in most molecular clusters (4,5). This investigation demonstrated that cluster detection and response can detect rapid HIV transmission and identify population-level gaps in systems involving MSM. Barriers to accessing HIV services among Hispanic MSM in this investigation included language barriers and deportation-related concerns; stigma toward MSM and persons with HIV, often tied to sexuality-related cultural norms; and lack of HIV prevention services in primary and urgent care settings. These findings align with studies identifying access to HIV prevention and care services, language, traditional notions of masculinity, and medical mistrust as barriers to HIV prevention among Hispanic MSM (6,7). When HIV clusters are detected, it is important to gather data to identify gaps in HIV services so that response efforts can strengthen services for affected populations. Although gaps might already be known, collaborative response efforts can clarify the most important gaps and catalyze new efforts to overcome them such as those described in this response. The findings in this report are subject to at least three limitations. First, qualitative interviews were conducted among Hispanic MSM community members; thus, findings might not directly reflect the experience of persons in the clusters. Second, because HIV testing and diagnoses substantially declined during the COVID-19 pandemic, cluster size might be underestimated (8). Finally, because surveillance and chart review data were incomplete, the proportion of persons in clusters born outside the United States or who were Spanish-speaking might also be underestimated. This investigation highlights important barriers to and inequalities in HIV prevention services experienced by Hispanic MSM in Georgia because of issues related to language, deportation-concerns, and sexuality-related cultural norms. HIV molecular cluster detection has the capability to identify rapid HIV transmission in a new demographic group and advance health equity through expanded and tailored resources for HIV prevention and care. Summary What is already known about this topic? Molecular HIV clusters provide evidence of rapid transmission. What is added by this report? In 2021, molecular HIV analysis in Georgia identified clusters of rapid HIV transmission among Hispanic or Latino (Hispanic) gay, bisexual, and other men who have sex with men (MSM) in metropolitan Atlanta. A multicomponent investigation identified factors that might limit access to HIV services, including language barriers, deportation-related concerns, and sexuality-related cultural norms. Health departments, providers, and community-based organizations collaborated to address these barriers. What are the implications for public health practice? Hispanic MSM can face important barriers to accessing HIV services. Detecting and responding to HIV clusters among MSM can mobilize resources to strengthen services and improve health equity. Acknowledgments All community members and service providers who participated in qualitative interviews; Humberto Orozco, Latino LinQ; Sergio Mendez, Gigi Pedraza, Latino Community Fund; Kayleigh McClary, Cobb and Douglas Public Health; Moja Ashanti, DeKalb County Board of Health; Terry Bolden, Sabrina Clark, Cleonecia Forbes, Darshon Herbert, Tina John, Joshua O'Neal, Fulton County Board of Health; Karem Echeverria, Sameka Orekyeh, Yazmin Silva, Gwinnett, Newton, and Rockdale County Health Department; Christine Agnew Brune, Elana Morris, Jeffery Todd, CDC; Laila Woc-Colburn, Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine. * These authors contributed equally to this report. + Partner services interviews are completed by health departments for eligible persons with a newly diagnosed HIV infection and, potentially, after a person with known HIV infection is identified as part of a cluster. Interviews are completed to ensure that persons with HIV infection are linked to care and to obtain information about their sexual partners, who can receive notification of their potential exposure and services, including testing and HIV preexposure prophylaxis. SS 45 C.F.R. part 46, 21 C.F.R. part 56; 42 U.S.C. Sect. 241(d); 5 U.S.C. Sect. 552a; 44 U.S.C. Sect. 3501 et seq. P HIV suppression is defined as HIV viral load <200 copies of HIV RNA per mL of blood in the preceding year in Georgia Department of Public Health HIV surveillance data. ** Persons who received an HIV diagnosis from a health department or entity funded by a health department are eligible for partner services interviews in Georgia. ++ SSSS All authors have completed and submitted the International Committee of Medical Journal Editors form for disclosure of potential conflicts of interest. Valeria D. Cantos reported grant support from the National Institute for Allergy and Infectious Diseases, National Institutes of Health (NIH), Gilead Sciences, and Janssen Research. Jane Yoon Scott reported grant support from the NIH's Centers for AIDS Research. No other potential conflicts of interest were disclosed. References 1. Oster AM, France AM, Panneer N, Identifying clusters of recent and rapid HIV transmission through analysis of molecular surveillance data. J Acquir Immune Defic Syndr 2018;79 :543-50. 10.1097/QAI.0000000000001856 30222659 2. Oster AM, Lyss SB, McClung RP, HIV cluster and outbreak detection and response: the science and experience. Am J Prev Med 2021;61 (Suppl 1 ):S130-42. 10.1016/j.amepre.2021.05.029 34686282 3. Kosakovsky Pond SL, Weaver S, Leigh Brown AJ, Wertheim JO. HIV-TRACE (TRAnsmission Cluster Engine): a tool for large scale molecular epidemiology of HIV-1 and other rapidly evolving pathogens. Mol Biol Evol 2018;35 :1812-9. 10.1093/molbev/msy016 29401317 4. Lyss SB, Buchacz K, McClung RP, Asher A, Oster AM. Responding to outbreaks of human immunodeficiency virus among persons who inject drugs United States, 2016-2019: perspectives on recent experience and lessons learned. J Infect Dis 2020;222 (Suppl 5 ):S239-49. 10.1093/infdis/jiaa112 32877545 5. Perez SM, Panneer N, France AM, Clusters of rapid HIV transmission among gay, bisexual, and other men who have sex with men United States, 2018-2021. MMWR Morb Mortal Wkly Rep 2022;71 :1201-6. 10.15585/mmwr.mm7138a1 36136909 6. Horridge DN, Oh TS, Alonzo J, Barriers to HIV testing within a sample of Spanish-speaking Latinx gay, bisexual, and other men who have sex with men: implications for HIV prevention and care. Health Behav Res 2019;2 . 10.4148/2572-1836.1069 31799502 7. Kimball D, Rivera D, Gonzales M 4th, Blashill AJ. Medical mistrust and the PrEP cascade among Latino sexual minority men. AIDS Behav 2020;24 :3456-61. 10.1007/s10461-020-02916-z 32405726 8. DiNenno EA, Delaney KP, Pitasi MA, HIV testing before and during the COVID-19 pandemic United States, 2019-2020. MMWR Morb Mortal Wkly Rep 2022;71 :820-4. 10.15585/mmwr.mm7125a2 35737573 |
GMS J Med Educ GMS J Med Educ GMS J Med Educ GMS Journal for Medical Education 2366-5017 German Medical Science GMS Publishing House zma001595 10.3205/zma001595 Doc13 urn:nbn:de:0183-zma0015954 Article JME has impact beyond the Impact Factor! Die Bedeutung des JME geht uber den Impact Faktor hinaus!Fischer Martin R. *12 Fabry Gotz *32 1 LMU Munchen, Klinikum der Universitat Munchen, Institut fur Didaktik und Ausbildungsforschung in der Medizin (DAM), Munich, Germany 2 GMS Journal for Medical Education (JME), editorial office, Erlangen, Germany 3 Albert-Ludwigs-Universitat Freiburg, Institut fur Medizinische Psychologie und Medizinische Soziologie, Freiburg im Breisgau, Germany *To whom correspondence should be addressed: Gotz Fabry, GMS Journal for Medical Education (JME), editorial office, Henkestr. 91, D-91052 Erlangen, Germany, E-mail: [email protected] 15 2 2023 2023 40 1 Doc1303 2 2023 03 2 2023 03 2 2023 Copyright (c) 2023 Fischer et al. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at This article is available from pmcEditorial In June 2023 the GMS Journal for Medical Education will receive an impact factor. To what extent will the impact factor change the face of the JME? Will it lead to better visibility of our articles? What developments do we as editors-in-chief of the JME expect? Let's take a look at Clarivate Analytics, the company that awards the impact factor, our partner, the Association of the Scientific Medical Societies (AWMF), our publisher German Medical Science (GMS), and the discussion of the last 10 years on impact factor and visibility of our journal. We will conclude with an outlook on where the journey might lead for the GMS Journal for Medical Education (JME) - the Open Access journal of the Society for Medical Education (GMA). On July 26, 2022, Clarivate Analytics issued a press release announcing that all journals from the Emerging Sources Citation Index (ESCI), will be included in the group of journals assigned a Journal Impact Factor (JIF) starting June 2023 ([ retrieved on 31.01.2023). In total, a staggering 9,000 new journals including the JME will receive an official impact factor as a result of this unexpected decision about the ESCI and the Arts and Humanities Citation Index (AHCI). All of these journals have met the Web of Science's strict 24 quality criteria. Overall, the proportion of quality-assured Open Access journals - to which the JME also belongs - has increased by around 8% in relation to all journals with an impact factor. So far so good. It is worth noting that Clarivate Analytics is a publicly traded company that was sold by Thomson Reuters in 2016 to Canadian and Asian investment firms for $ 3.55 billion ([ retrieved on 31.01.2023). The share price was US$ 14.25 on the New York Stock Exchange on July 26, 2022, and has fallen to US$ 11.12 by Jan. 31, 2023. From our perspective as the JME editors-in-chief, the decision-making paths of Thomson Reuters and Clarivate Analytics have been consistently difficult to follow since we took office in 2011. It was not clear for a long time why exactly Zeitschrift fur Medizinische Ausbildung (ZMA), which we then renamed Journal for Medical Education (JME) in 2015, failed in trying to get an impact factor. It's been a black box in the past and probably will continue to be. With the JME, we are part of the German Medical Science Portal (GMS), which is an interdisciplinary publication platform of the Association of the Scientific Medical Societies (AWMF). In the landscape of open access platforms, which often and sometimes primarily pursue commercial interests, GMS is an exception. It was founded with the German Institute of Medical Documentation and Information (DIMDI) and is operated in cooperation with the Federal Institute for Drugs and Medical Devices (BfArM) and ZB MED - Information Center for Life Sciences. The project was also funded by the German Research Foundation (DFG) ([ retrieved on 31.01.2023). The GMA is a member of the AWMF, which was founded in 1962 as a registered non-profit association and in which 182 scientifically working medical societies are currently organized as members and three associated societies ([ retrieved on 31.01.2023). The contrast between Clarivate Analytics, a privately held, publicly traded global information broker, and GMS, a project of nonprofit and publicly funded organizations, could hardly be greater. The JME is the flagship of the GMS Portal in terms of the number of articles published per year and the number of hits - not least because of its professionally managed editorial office. After all, three of the total 15 journals of the GMS portal including the JME are listed in the ESCI and receive the coveted Impact Factor. Critically, it should be noted that there are quite a few needs for improvement regarding the technical functionality and contemporary design of the portal, which are patiently discussed in the regular editors' meetings and pushed forward as far as possible. We, as JME editors-in-chief, together with the editorial office, regularly participate in these discussions on behalf of GMA and all JME co-editors and express our wishes. Over the last few years, we have repeatedly discussed alternatives to GMS among the editors and have rejected them up to the present day. We will critically accompany the development of GMS and, as far as possible, help to shape it and continue the discussion about the best publication channels for our articles. Then, in June 2023, we will learn for the first time from Clarivate about the Journal Impact Factor (JIF) of the JME. Again, as a reminder, the JIF is defined as the average number of citations per article based on all published articles over the past two years. So, what does this mean? As editors, we have dealt with this question time and time again. Ten years ago, when we received a repeated rejection from what was then Thomson Reuters, we wrote - referring to the state of the then increasingly critical debate on the use of the "because of the material and career incentives associated with high impact factors at both the individual and institutional levels, [...] the use of the IF is taking on a life of its own in a way that is probably doing more harm than good" . Despite the still valid and repeatedly presented criticism of the scientific community , which at the same time continues to use the JIF as the most important bibliometric parameter, from our point of view there was and still is hardly an alternative for a journal than to aim for the JIF or, in case of success, to increase it in order to be attractive for authors. We were and are convinced that the only way to achieve this is to increase the quality of our articles and our international visibility. We had therefore decided to make the English-language articles more visible and accessible on the portal and to give the editorial board a more international orientation. We hoped that this would lead to more international manuscript submissions and a broader and more differentiated focus in terms of content, without giving up the profile of the former ZMA with its clear focus on German-speaking countries . We have made good progress along this path: We have given our Editorial Board a stronger international orientation and the number of manuscripts from non-German-speaking countries is also growing steadily. A good sign of the increasing visibility of the JME is the growing number of accesses to our articles over the years and the growing number of citations in foreign-language journals. In this respect, it remains the unique selling point of the JME to be the most important medical education journal in the German-speaking world, which is nevertheless also increasingly perceived in non-German-speaking countries. We hope that the impact factor will give further impetus to this positive development. However, the fact that the impact factor or other bibliometric indices are not suitable as the sole navigation system for the orientation of a journal can be seen well in the recent development of the JME. For example, the Scopus CiteScore - an indicator comparable to the JIF that includes citations for one year and the previous three years - shows a slight deterioration for 2020 and 2021 compared to previous years (1.9 vs. 2.1). And the JME's Scimago Journal Rank also deteriorated slightly in these two years. Can we conclude from this that the quality or interest of the published articles is declining? Probably not, because during the same period, the number of accesses to the journal's articles increased significantly, as in previous years: Since 2018, the number of accesses via the PubMed server has increased from 160,000 to 221,000, and via the GMS server we have seen an increase from 80,000 to 160,000 (automated queries are already filtered out here). Therefore, the following explanation is more likely: in 2020 and 2021, due to the thematic issues on teaching and learning during the COVID-19 pandemic, many more articles were published than is normally the case. While we usually publish around 60 to 80 articles per year, there were about 120 in each of these two years, which is considerably more. However, since the number of citations did not increase in the same order of magnitude and practically all bibliometric indices relate the number of citations of a journal to the number of articles published there, we "diluted" our impact by the greatly increased number of articles. From our point of view, the two themed issues were nevertheless a great success, because the response was overwhelming and has enormously advanced the discourse, especially about digital teaching. The example thus also shows that it would be wrong to gear all the journal's activities exclusively to optimizing the impact factor, even though we as the editorial board are of course very happy to have it. We will continue to write the history of the JME with united efforts - in doing so, the quality of the contributions is the focus of our efforts, which is the indispensable prerequisite for the visibility of our articles and the fulfillment of our mission in the name of the GMA: "The GMS Journal for Medical Education aims to contribute to scientific knowledge in German-speaking countries and internationally, and thus to promote the improvement of teaching and learning as well as the evidence-based nature of education, training, and continuing education." ([ retrieved on 31.01.2023). Competing interests The authors declare that they have no competing interests. 1 Fabry G Fischer MR The ZMA and the impact factor GMS Z Med Ausbild 2013 30 3 Doc39 10.3205/zma000882 24062819 2 Fabry G Fischer MR Beyond the Impact Factor - What do alternative metrics have to offer? GMS J Med Educ 2017 34 2 Doc27 10.3205/zma001104 28584875 |
GMS J Med Educ GMS J Med Educ GMS J Med Educ GMS Journal for Medical Education 2366-5017 German Medical Science GMS Publishing House zma001594 10.3205/zma001594 Doc12 urn:nbn:de:0183-zma0015945 Article A simulation-based OSCE with case presentation and remote rating - development of a prototype Eine simulationsbasierte OSCE mit Fallprasentation und Fernbewertung - Entwicklung eines PrototypsBussenius Lisa 1 Harendza Sigrid *1 1 Universitatsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg, Germany *To whom correspondence should be addressed: Sigrid Harendza, Universitatsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Martinistr. 52, D-20246 Hamburg, Germany, Phone: +49 (0)40/7410-54167, Fax: +49 (0)40/7410-40218, E-mail: [email protected] 15 2 2023 2023 40 1 Doc1206 10 2022 10 1 2023 14 12 2022 Copyright (c) 2023 Bussenius et al. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at This article is available from Simulation-based examination formats improve the possibility to assess medical students' competences during their performance. Additionally, videotaping of simulations allows for remote rating, providing advantages for raters, students, and exam organizers. We describe a simulation-based OSCE prototype with remote rating of students' competences, developed to replace a conventional OSCE at Hamburg Medical Faculty. The assessment consists of two phases: a consultation phase with four simulated patient encounters and a case presentation phase where four students present two cases each. All encounters from the consultation and the presentation phase are to be videotaped and remotely rated by clinical raters. Advanced medical students (year 4) are to be assessed regarding their clinical knowledge as well as physician-patient-communication, clinical reasoning competence, and patient management competence. We provide detailed schedules for the simulation-based OSCE procedure and a roster for organization. When piloting the assessment, we encountered two major obstacles with respect to legal obligations regarding examination time and videotaping which allowed us to provide tips on how to successfully implement this assessment prototype. Remote rating will, when successfully implemented, help students to concentrate on their consultation or presentation tasks, reduce raters' time constraints and also allow for randomized rating. Using established instruments for competence-rating rather than OSCE checklists provides an additional feature for this simulation-based OSCE prototype. Legal issues can be avoided by using the prototype for formative assessment but should be addressed in advance when it is planned to be used as summative assessment. Simulationsbasierte Prufungsformate verbessern die Moglichkeit, Kompetenzen von Medizinstudierenden wahrend ihrer Performanz bewerten zu konnen. Zusatzlich ermoglicht die Videoaufzeichnung von Simulationen eine Bewertung ohne Anwesenheit von Prufenden (Fernbewertung), was Vorteile fur Prufende, Studierende und Prufungsorganisierende bietet. Wir beschreiben den simulationsbasierten Prototyp einer OSCE inklusive Bewertung der Kompetenzen der Studierenden ohne Anwesenheit von Prufenden, welcher entwickelt wurde, um eine konventionelle OSCE an der medizinischen Fakultat der Universitat Hamburg zu ersetzen. Die Prufung beinhaltet zwei Phasen: eine Sprechstundenphase mit vier simulierten Patient*innen und eine Fallprasentationsphase, in der vier Studierende jeweils zwei Falle vorstellen. Alle Gesprache aus der Fallprasentationsphase sollen auf Video aufgenommen und von klinischen Prufenden nach Anschauen der Videos bewertet werden. Fortgeschrittene Medizinstudierende (8. Semester) sollen hinsichtlich ihres klinischen Wissens sowie ihrer Arzt*innen-Patient*innen-Kommunikation, Clinical-Reasoning-Kompetenz und Patient*innenmanagement-Kompetenz bewertet werden. Wir stellen detaillierte Plane fur die simulationsbasierte OSCE und einen Ablaufplan fur die Organisation zur Verfugung. Bei der Pilotierung des Projektes trafen wir auf zwei grossere Hindernisse in Bezug auf rechtliche Einschrankungen hinsichtlich der Prufungsdauer und der Videoaufzeichnung. Dadurch konnen wir Tipps fur die erfolgreiche Implementierung dieses Prufungsprototyps geben. Wenn erfolgreich umgesetzt, wird eine Abwesenheit der Prufenden und spatere Bewertung der Videos den Studierenden dabei helfen, sich auf ihr Anamnesegesprach oder die Fallprasentation zu konzentrieren, die zeitlichen Einschrankungen von Prufenden reduzieren und ausserdem eine randomisierte Bewertung ermoglichen. Etablierte Instrumente fur die Kompetenzbewertung statt OSCE-Checklisten zu verwenden ist ein weiteres Merkmal dieses simulationsbasierten OSCE-Prototyps. Rechtliche Fragen konnen vermieden werden, wenn man den Prototypen als formative Prufung einsetzt, sollten aber im Vorfeld geklart werden, wenn die OSCE als summative Prufung geplant wird. assessment competence OSCE remote rating simulation pmc1. Background With the National Competence Based Catalogue of Learning Objectives for Undergraduate Medical Education , medical curricula in Germany become increasingly competence-based. This subsequently requires the development of competence-based assessment formats. Currently, objective structured clinical examinations (OSCEs) - checklist-based assessments in the presence of raters - are used to assess medical students' skills . To assess competences, simulation-based assessments with a more holistic rating approach can include greater task complexity in more authentic settings to allow expression of performance . Additionally, videotaped simulations allow for remote rating to reduce raters' influences on students' performance . Time-independent rating also allows for flexible work scheduling, which can reduce OSCE-related logistical issues and costs . To assess advanced medical students' competences in a summative exam, we developed a prototypical simulation-based OSCE including remote rating options. 2. Objectives Our main goal was to replace a traditional OSCE by a simulation-based OSCE to allow assessment of students' competences. To design an OSCE prototype for this purpose we used an evidence-based approach . Our target group were advanced medical students (year 4), who had acquired knowledge, skills, and attitudes needed to perform in a simulated setting. 3. Developing the prototype For our project, we chose an OSCE at the end of a fourth year learning module in the integrated curriculum at the University of Hamburg . At the end of this module, students must be able to communicate with patients and take detailed histories, discuss differential diagnoses based on diagnostic results, and suggest therapeutic approaches. The designated module covers medical topics around the abdomen and retroperitoneum from the clinical disciplines gastroenterology, general surgery, nephrology, and urology. The final OSCE with about 200 students takes place over two days and includes seven five-minute stations and checklists for assessment of clinical knowledge and communication skills. The aim of the OSCE redesign was to measure students' clinical knowledge and communications skills by assessing their physician-patient-communication competence, clinical reasoning competence, and patient management competence while covering the clinical content of the module. For this purpose, we designed four stations simulating physician-patient encounters (phase 1: consultations) and four stations simulating patient-case presentations in handover situations (phase 2: presentations) based on similar steps used in a validated competence-based simulation of a first day in hospital (see figure 1 (Fig. 1)). In phase 1 (consultations), eight students rotate through four 6-minute stations in two parallel courses, A and B. The students, who are randomly assigned to their starting positions, encounter different cases from each of the four clinical disciplines in the two courses. Students' assignments for each station include taking focussed histories from simulated patients and discussing test results with them, which are presented during the patient interview. All encounters are videotaped which allows for remote assessment. Besides the respective medical content correctness, clinical reasoning and physician-patient communication competences can be remotely assessed with specific questionnaires , . In phase 2 (presentation), groups A and B are combined, so that two students meet in one room for a 6-minute handover. Group B rotates in the opposite direction of group A to ensure an even mix of student pairs. Every student will present (p) and receive (r) two patients so that all four disciplines are covered in this phase (e.g., in round 1, student 1 presents (p) a gastroenterology case to student 8 who receives (r) it, while in round 2 student 8 presents (p) a nephrology case to student 3 who receives (r) it). Students' assignment includes presentation and discussion of each case to come to a management conclusion. Analogous to phase 1, all handovers will be videotaped in phase 2 which allows for remote assessment. Besides assessing students' knowledge of medical content, the presenting and the receiving student are also assessed with regard to their communication competence , , clinical reasoning , and patient management . With one minute for changing between the physician-patient encounters and between each handover and two minutes to change from phase 1 (consultation) to phase 2 (presentation), the simulation-based OSCE lasts 56 minutes. With overlapping phases (i.e. when group 1 enters the presentation phase, a new group can start with the consultation phase), 100 students can be examined in one day during normal working hours with reasonable breaks for the simulated patients (see figure 2 (Fig. 2)). With remote rating, no clinical raters need to be present and can perform the rating when they are off clinical duty. Every student will receive eight different ratings, four from phase 1 and four from phase 2, i.e. two from each discipline (see table 1 (Tab. 1)). 4. Pitfalls with and tips for implementation We piloted the simulation-based OSCE as summative assessment in July 2019 with 186 students . However, due to time constraints in the exam regulations of our medical school, we were only allowed 42 minutes to incorporate seven subjects into our assessment. Thus, we were not able to use our planned design with the two phases, which would have needed 56 minutes. Tip 1: if you wish to use this prototype with a consultation and a presentation phase including changing times, check with the exam regulations of your medical school whether there are limitations for exam time. In our case, we had to stick to the traditional OSCE format and cancel the presentation phase. Furthermore, we were not allowed to film the conversations which the students held with the simulated patients for legal reasons at our medical school. Therefore, the remote rating, a main feature of assessment in our prototype, could not take place. Tip 2: if you wish to use remote rating, check with your legal department whether it is possible to take videos of students for remote assessment. Audio tapes could be an alternative, if they are allowed. However, at least we were able to keep the core idea of our project by introducing elements of simulation into the traditional OSCE format. Students entered the examination rooms not knowing which medical content of the four clinical disciplines to expect from a certain simulated patient, which requires good history taking skills. Tip 3: Adapt the patient cases from real cases and develop them together with experienced clinicians to increase content validity . Instead of video-ratings, our examiners had to be present in the room for their ratings, but did not interfere in the student-patient-communication. Furthermore, due to the exam regulations at Hamburg Medical Faculty, which require a certain amount of points per OSCE station, the raters could not use the rating instruments for clinical reasoning and physician-patient communication competences we had planned for the consultation phase. However, instead of just rating medical content, we were at least able to integrate clinical reasoning and communication aspects in addition to medical content into our usual OSCE checklists. As an additional educational research project, raters with a background from psychosocial fields were permitted in the examination rooms to rate the students' communication competence with the Global Rating Scale . Tip 4: Before using the suggested instruments for communication competence, clinical reasoning, and patient management, check with your local exam regulations whether they will be allowed for summative assessment. Due to legal regulations at Hamburg Medical Faculty, we were not able to perform the simulation-based OSCE with competence-based remote rating as a substitute for our usual summative OSCE. However, parts of the simulation, i.e. consultations and case presentations including remote rating of clinical reasoning, communication competence, and patient management have been demonstrated elsewhere to be successfully performed , , , . The suggested prototype even works as telemedicine format which we implemented in an extended format as a formative assessment with feedback . Time-independent, remote rating works well for the assessors' work schedules. Furthermore, advantages of remote rating include that the videos can be assessed in a randomized order to prevent bias caused by order effects , and the assessors can use breaks at their own convenience to reduce rater fatigue . Furthermore, blinding students' to specific stations' content helps to prepare them for real consultations where the cause of a patient's problem is unknown. Additionally, remote rating requires less personnel on-site while the assessment takes place. When considering implementation of this OSCE format, we recommend to clarify anticipated barriers such as limited assessment time or possible legal issues with filming or data storage ahead of planning. Funding This work was supported by the Federal Ministry of Education and Research (project number: 01GK1801A). The funding body played no role in the design of the study and in collection, analysis, and interpretation of data and in writing the manuscript. Ethical approval The Ethics Committee of the Hamburg Chamber of Physicians confirmed the innocuousness of this study and its congruence with the Declaration of Helsinki (WF-047/16). The anonymity of all participants was guaranteed. Acknowledgement We thank all participating medical students, actors and actresses, raters, and the Deanery of the Medical Faculty Hamburg for their support of piloting this assessment format. Competing interests The authors declare that they have no competing interests. Table 1 Exemplary roster for organization of phase 2 (presentations) Figure 1 Rotation plans for phase 1 and 2 of the simulation-based OSCE Figure 2 Schedule for one examination day of the simulation-based OSCE 1 Fischer MR Bauer D Mohn K NKLM-Projektgruppe Finally finished! National competence based catalogues of learning objectives for undergraduate medical education (NKLM) and dental education (NKLZ) ready for trial GMS J Med Educ 2015 32 3 Doc35 10.3205/zma000977 2 Newble D Techniques for measuring clinical competence: objective structured clinical examinations Med Educ 2004 38 2 199 203 10.1111/j.1365-2923.2004.01755.x 14871390 3 Rotthoff T Kadmon M Harendza S It does not have to be either or! 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GMS J Med Educ GMS J Med Educ GMS J Med Educ GMS Journal for Medical Education 2366-5017 German Medical Science GMS Publishing House zma001589 10.3205/zma001589 Doc7 urn:nbn:de:0183-zma0015897 Article Implicit expression of uncertainty in medical students during different sequences of clinical reasoning in simulated patient handovers Impliziter Ausdruck von Unsicherheit bei Medizinstudierenden in verschiedenen Sequenzen des klinischen Argumentierens wahrend simulierter Patient*innenubergabenHarendza Sigrid *1 Bacher Hans Jakob 1 Berberat Pascal O. 2 Kadmon Martina 3 Gartner Julia 1 1 Universitatsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Hamburg, Germany 2 Technische Universitat Munchen, Fakultat fur Medizin, TUM Medical Education Center, Munchen, Germany 3 Universitat Augsburg, Medizinische Fakultat, Dekanat, Augsburg, Germany *To whom correspondence should be addressed: Sigrid Harendza, Universitatsklinikum Hamburg-Eppendorf, III. Medizinische Klinik, Martinistr. 52, D-20246 Hamburg, Germany, Phone: +49 (0)40/7410-54167, Fax: +49 (0)40/7410-40218, E-mail: [email protected] 15 2 2023 2023 40 1 Doc719 2 2022 23 11 2022 19 8 2022 Copyright (c) 2023 Harendza et al. 2023 This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 License. See license information at This article is available from Background: Dealing with medical uncertainty is an essential competence of physicians. During handovers, communication of uncertainty is important for patient safety, but is often not explicitly expressed and can hamper medical decisions. This study examines medical students' implicit expression of uncertainty in different sequences of clinical reasoning during simulated patient handovers. Methods: In 2018, eighty-seven final-year medical students participated in handovers of three simulated patient cases, which were videotaped and transcribed verbatim. Sequences of clinical reasoning and language references to implicit uncertainty that attenuate and strengthen information based on a framework were identified, categorized, and analyzed with chi-square goodness-of-fit tests. Results: A total of 6358 sequences of clinical reasoning were associated with the four main categories "statement", "assessment", "consideration", and "implication", with statements occurring significantly (p<0.001) most frequently. Attenuated sequences of clinical reasoning occurred significantly (p<0.003) more frequently than strengthened sequences. Implications were significantly more often attenuated than strengthened (p<0.003). Statements regarding results occurred significantly more often plain or strengthened than statements regarding actions (p<0.0025). Conclusion: Implicit expressions of uncertainty in simulated medical students' handovers occur in different degrees during clinical reasoning. These findings could contribute to courses on clinical case presentations by including linguistic terms and implicit expressions of uncertainty and making them explicit. Zusammenfassung Zielsetzung: Der Umgang mit medizinischer Unsicherheit ist eine wesentliche Kompetenz von Arzt*innen. Bei Ubergaben ist die Kommunikation von Unsicherheit wichtig fur die Patient*innensicherheit, wird jedoch oft nicht explizit ausgedruckt und kann medizinische Entscheidungen behindern. Diese Studie untersucht den impliziten Ausdruck von Unsicherheit bei Medizinstudierenden in verschiedenen Sequenzen des klinischen Argumentierens wahrend simulierter Patient*innenubergaben. Methodik: Siebenundachtzig Medizinstudierende im letzten Studienjahr nahmen im Jahr 2018 an Ubergaben von drei simulierten Patient*innenfallen teil, die videografiert und wortlich transkribiert wurden. Sequenzen des klinischen Argumentierens sowie Sprachverweise auf implizite Unsicherheit in Form informationsabschwachender und -verstarkender Ausdrucke wurden basierend auf einem Rahmenwerk identifiziert, kategorisiert und mit Chi-Quadrat-Anpassungstests ausgewertet. Ergebnisse: Insgesamt waren 6358 Sequenzen des klinischen Argumentierens den vier Hauptkategorien ,,Bericht", ,,Bewertung", ,,Erwagung" und ,,Schlussfolgerung" zuzuordnen, wobei Berichte signifikant (p<0,001) am haufigsten vorkamen. Abgeschwachte Sequenzen klinischen Argumentierens kamen signifikant (p<0,003) haufiger vor als verstarkte Sequenzen. Schlussfolgerungen waren dabei signifikant haufiger abgeschwacht als verstarkt (p<0,003). Bei Berichten waren Ergebnisse signifikant haufiger neutral oder verstarkt als Massnahmen (p<0,0025). Schlussfolgerung: Impliziter Ausdruck von Unsicherheit kommt in simulierten Ubergabegesprachen von Medizinstudierenden in unterschiedlicher Auspragung beim klinischen Argumentieren vor. Diese Befunde konnten dazu beitragen, in Kursen zu klinischen Fallvorstellungen sprachliche Ausserungen und implizite Ausdrucke von Unsicherheit einzubeziehen und explizit zu machen. assessment communication competence simulation handover uncertainty pmc1. Introduction In their undergraduate and postgraduate training, physicians acquire the ability to make judgments that they use in their everyday work, which is characterized by medical uncertainty, in order to reason clinically . Medical uncertainty includes both, patient-related factors such as medical history, test variability or diversity of information sources as well as physician-related factors such as communication quality, test interpretation and uncertainty tolerance . Each patient contact requires a cognitive decision-making process consisting of information acquisition, hypothesis generation, and derivation of diagnostic and therapeutic steps . This process is the basis of clinical reasoning . These aspects mentioned above are summarized in focused case presentations during patient handovers to ensure correct medical patient care . In many cases, medical uncertainty is not openly communicated . The reasons for this behavior can be found in medical socialization, where correct knowledge and good grades are held in high esteem above all other aspects , , . The expression of medical uncertainty tends to be associated with shame, as the disclosure of medical uncertainty is often interpreted as a lack of competence , and is thus also associated with one's own vulnerability in professional action . Medical students even tend to mask uncertainty . Low tolerance of uncertainty can impede medical decision-making . The accompanying communication errors can lead to unnecessary hospital admissions, can trigger unnecessary diagnostics requests, and can compromise patient safety , , . In a previous study , we elaborated the identification and distribution of implicit linguistic expressions of medical uncertainty related to patient cases (i.e., the patient-related factor of medical uncertainty ). Based on the same data, the aim of the current study was the communication of implicit uncertainty in the context of clinical reasoning (i.e., the physician-related factor of medical uncertainty ). 2. Methods 2.1. Study design and participants In 2018, 87 final-year medical students (67.4% female, 32.6% male) from three medical faculties (Hamburg, Oldenburg, TU Munich) voluntarily participated in a competence-based assessment simulating the first day of residency . The assessment included a consultation hour with three simulated patients per participant, who were handed over to other participants after collection of additional information. The patients, based on real cases from the emergency department, were portrayed by professional, trained actors and actresses. The cases were based on either a chief complaint or a chief finding (e.g., man with very severe abdominal pain: abdominal migraine; woman with elevated creatinine level: acute renal failure due to hantavirus). A detailed description of the patient cases can be found in Gartner et al. . The cases were chosen in a way that they could only be solved by analytical thinking and not by pattern recognition alone . At the end of their shift, the medical students handed three cases over to a peer who did not know these cases and discussed further diagnostics and therapy. The handovers were videotaped. 2.2. Instruments To analyze implicit uncertainty in students during the patient handovers, we used an empirically derived framework . It includes four main categories, which are each represented by a textual sample: "statement" ("I have done a urine dipstick."), "assessment" ("Stool and urine were unremarkable.") "consideration" ("[A] kidney biopsy can also be considered."), and "implication" ("At some point later [...] we should do a TTE."). In each of these main categories, the subcategories "action" ("[...] we will ask for a small blood count and an ECG.") and "result" ("[...] no known pre-existing conditions.") occur. In addition, the framework includes four types of linguistically modifying expressions, each of which either attenuates information (e.g., "maybe", "doubtful", "probably") and thus implicitly refers to increased uncertainty ("attenuated"), or strengthens information (e.g., "definitely", "of course", "absolutely") and thus implicitly refers to decreased uncertainty ("strengthened"). Furthermore, statements without these strengthening or attenuating modifiers ("plain") were found as well as statements accompanied by both, attenuating and strengthening modifiers ("mixed"). A detailed description of the linguistic expressions used and their subcategories can be found in Gartner et al. . 2.3. Data analysis The videotaped patient handovers were transcribed verbatim. Using MAXQDA Analytics Pro 2020 (Release 20.0.8, VERBI GmbH), we assigned the sequences to the four main categories and the respective subcategory. We then searched for the framework's linguistic expressions that implicitly attenuated or strengthened information . All expressions that did not literally address uncertainty were understood as implicit in this study (e.g., "I am uncertain"=explicit; "I don't know"=implicit). Possible differences in the distribution of statements across the four main categories and the three modifiers "attenuated", "plain", and "strengthened" were calculated using chi-square goodness-of-fit tests. The significance level was set at p<0.05 and set at 0.003 using the Bonferroni correction for multiple testing of 15 comparisons. The distribution of modifiers across the subcategories "action" and "result" was also analyzed using chi-square adjustment tests, and the Bonferroni-corrected significance level was set at p<0.0025 based on 20 comparisons. 3. Results In total, 6358 statements could be found and assigned to one of the four main categories that resemble sequences of clinical reasoning ("statement", "assessment", "consideration", "implication"), with "statement" being significantly (p<0.001) the most frequent (see table 1 (Tab. 1)). Overall, attenuated sequences of clinical reasoning were significantly (p<0.003) more frequent than strengthened sequences. For "statement", "implication", and "assessment", plain information occurred significantly most frequently (p<0.003). Implications were significantly more frequently attenuated than strengthened (p<0.003), while statements were significantly more frequently strengthened than attenuated (p<0.003). Table 2 (Tab. 2) shows the ratios of actions and results within the main categories of the clinical reasoning sequences and modifiers. While actions occurred significantly more frequent for "implication" than results, this was reversed for "statement" and "assessment" (p<0.0025). For "statement", results were significantly more likely to be plain or strengthened than actions (p<0.0025); for attenuated statements, there was no significant difference between results and actions. For "assessment", results were significantly (p<0.0025) more likely to be attenuated, plain, or strengthened than actions, while for "implication", actions were significantly (p<0.0025) more likely to be attenuated, plain, or strengthened than results. 4. Discussion and conclusion Plain statements occurred most frequently in the handovers, whereby stated results included significantly more implicit references to decreased uncertainty and stated actions included more implicit references to increased uncertainty. Implications, which are of particular importance in clinical reasoning, showed the highest amount of implicit references to increased uncertainty. If this uncertainty is not noticed by the persons receiving a handover, it may contribute to treatment errors in some instances. Stated actions as well as considerations and implications play a crucial role in weighting diverging hypotheses for further patient treatment. Therefore, uncertainty should be recognized and explicitly expressed in undergraduate and postgraduate training, especially in the context of patient presentations during handovers . The SNAPPS technique (S: summarize history and findings, N: narrow the differential, A: analyze the differential comparing and contrasting the possibilities, P: probe preceptors about uncertainties, P: plan management, S: select case-related issues for self-study) could be shown to support students in perceiving their uncertainty . Moreover, medical students who had attended a handover course or a clinical reasoning course were able to hand over patients in a more focused manner , . Our findings on sequences of clinical reasoning and linguistic expressions that implicitly express uncertainty could add to focusing on these linguistic expressions in such courses. This could be used to design exercises on how to make perceived implicit uncertainty explicit and discussable to improve patient safety. Recorded handovers, for example, could be watched in communication courses and, using the framework, implicit expressions of uncertainty could be explored . In a next step, medical students could consider how to express uncertainty explicitly. The effect of such reflections could be explored at the end of such a course by conducting handovers again with a focus on changes in the linguistic characteristics. Funding This study is part of the AKHOM project, funded by the German Federal Ministry of Education and Research (BMBF), grant number: 01PK1501A/B/C. Recipients of this funding were SH, POB and MK. The funders had no influence on the study design, data collection and analysis, decision to publish, or preparation of the manuscript. Ethics The Ethics Committee of the Hamburg Medical Association approved the study including written informed consent of participants and anonymized and voluntary participation (reference number: PV3649). Acknowledgement We would like to thank all the medical students who participated in this study. We thank Dr. T. Urbanowicz for her assistance in preparing the transcripts. Competing interests The authors declare that they have no competing interests. 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Ann Med Surg (Lond) Ann Med Surg (Lond) MS9 Annals of Medicine and Surgery 2049-0801 Lippincott Williams & Wilkins Hagerstown, MD 10.1097/MS9.0000000000000137 00016 3 Case Reports An Indonesian female with pulmonary cystic hamartoma: a case report and literature review Khusnurrokhman Gemilang MD [email protected] Febriani Anna MD [email protected] a Wiratama Priangga A. MD [email protected] Widyoningroem Anita MD [email protected] a Department of Pulmonology and Respiratory Medicine b Department of Anatomical Pathology c Department of Radiology, Faculty of Medicine, Universitas Airlangga - Dr. Soetomo General Academic Hospital, Surabaya, Indonesia * Corresponding author. Address: Department of Pulmonology and Respiratory Medicine, Faculty of Medicine, Universitas Airlangga - Dr. Soetomo General Academic Hospital, Jl. Mayjend Prof. Dr. Moestopo No. 6-8, Airlangga, Gubeng, Surabaya, East Java 60286, Indonesia. Tel: +62 315 501 656; fax: +6231-5501656. E-mail address: [email protected] (A. Febriani). 3 2023 6 2 2023 85 3 443446 6 9 2022 22 12 2022 Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction: Pulmonary cystic hamartoma is a rare benign cystic mass of the lung with clinical symptoms and radiological features that are not typical. Case presentation: A 43-year-old Indonesian female complained of chest and right shoulder pain, especially in the right clavicle. The patient underwent a chest X-ray and computed tomography scan thorax contrast, resulting in an anterior mediastinal tumor. The patient underwent wedge resection, and anatomical pathology showed pulmonary cystic hamartoma. The patient experienced postsurgery improvement. Discussion: Pulmonary cystic hamartoma does not have typical signs and symptoms. Pulmonary hamartoma diagnosis cannot be confirmed until a pathology anatomy examination is performed. Wedge resection is the first choice to treat pulmonary cystic hamartoma. Conclusion: Pulmonary cystic hamartoma is diagnosed with examination from pathology anatomy. Keywords: pain pulmonary cystic hamartoma oncology wedge resection OPEN-ACCESSTRUE pmcHIGHLIGHTS Preoperative diagnosis and treatment are difficult to establish in pulmonary cystic hamartoma. Wedge resection is the first choice for the management of pulmonary cystic hamartoma. Pulmonary cystic hamartoma is a rare benign cystic mass of the lung. Introduction Pulmonary cystic hamartoma is a rare benign cystic mass of the lung with no specific clinical or radiological signs. Pathological examination typically presents cysts that have grown slowly1. It is present in less than 0.5% of autopsied patients. Pulmonary hamartoma is discovered in men more often than in women by a ratio of 2 : 1, with an average age at diagnosis over 60 years old2,3. Pulmonary cystic hamartoma was first described in 1986, predominantly comprised of immature mesenchymal cells from multiple bilateral cysts and nodules. Until 2012, only 15 cases of this disease were reported in the literature4. This report study was composed based on the Surgical CAse REport (SCARE) 2020 guidelines5. Case presentation A 43-year-old Indonesian female complained of chest and right shoulder pain, especially in the right clavicle and a mass around her right shoulder that never got bigger, measuring about 2 cm. The pain around the mass did not last long. The patient's medical history showed that she had pulmonary tuberculosis 25 years ago, was triumphantly treated for 6 months, and was declared cured. She got coronavirus disease 2019 in 2020 one time. Physical examination showed a hard solid mass of about 2 cm (inspection), fixed and without pain (palpation) in the right clavicula region (sternoclavicular joint side; Fig. 1). The patient also had an increase in the jugular vein. Chest X-ray found homogenous opacity in the mediastinum region. Thoracic computed tomography scan with contrast found enhancing solid mass (35 HU) with calcification, regular border, lobulated, measurement about 3.3x2.5x5.9 cm in anterior mediastinal suggesting thymoma (Fig. 2). The tumor marker [lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and beta-human chorionic gonadotropin (b-HCG)] found no abnormality. This study performed a left thoracotomy excision on the patient, and the mass characteristic was solid and mucinous (Fig. 3). Figure 1 The right clavicula region shows a solid mass. Figure 2 Computed tomography scan thorax contrast. Figure 3 Pathological anatomy laboratory gross of the specimen shows around white and cartilaginous tissue. Postsurgery, anatomical pathology results showed the mass with a distinct multicystic area layered by columnar epithelial filled in with myxoid and more, seromucous gland, alveoli tissues, and erythrocytes inflammatory cells (Fig. 4). The conclusion from these microscopic results was pulmonary cystic hamartoma. The primary marker was the absence of a distinct boundary between the mass and lung parenchyma, and there was superior lobe hypoplasia in the left lung. The patient had a good prognosis as she had no problems with daily activities, no swelling, no pain, and no sequelae. A similar condition was also found at a follow-up 3 months later. Figure 4 Microscopic showing mostly cartilage, fibroblastic background, bronchial epithelial lining cells, hyaline cartilage, and cysts tissue. Discussion Hamartomas are caused by aberrant development of normal tissue and can occur infrequently or as part of a syndrome. Hamartoma is caused by a developmental error and may appear in several sites. It grows at the same rate as the original tissue. Some genes are involved in the pathogenesis of hamartoma development, including SMAD4, PTEN, STK1, and BMPR1A. Many hereditary syndromes are associated with hamartoma formation, including tuberous sclerosis, Cowden syndrome, PTEN hamartoma tumor syndrome, Peutz-Jeghers syndrome, and other genetic diseases of hamartoma development6,7. Most people with pulmonary hamartoma have no symptoms. However, some may experience respiratory symptoms such as hemoptysis, cough, phlegm, or chest pain11. Surgical treatment is used to treat pulmonary hamartoma. The timing and indications for surgical treatment of pulmonary hamartoma are still debatable. Guo et al. retrospectively reviewed research of a 20-year clinical history of surgical treatment for 39 patients with pulmonary hamartoma between 1985 and 2006. Wedge resection, enucleation, segmentectomy, lobectomy, and pneumonectomy were among the 40 surgeries performed on these 39 patients. Because pulmonary hamartoma is a slow-growing mass that rarely expands, this research recommends a step-by-step approach when a clinical physician decides on operative treatment. Surgical excision is justified and should be required when a solitary pulmonary lesion measured more than 2.5 cm in diameter or the probability of malignancy cannot be ruled out. In terms of surgery indications, Guo et al.8 came up with the following summary: (1) a solitary pulmonary lesion with a diameter larger than 2.5 cm; (2) heavy psychic burden making it necessary to remove the lesion; (3) a tendency for expansion or recurrence; (4) pulmonary symptoms unresponsive to drug treatment; and, most importantly, the lesion could not be distinguished from malignancy. The writer's main choice procedure was wedge resection9. Only in the following circumstances was a more aggressive lobectomy or total pneumonectomy considered: the central intrapulmonary hamartoma was located in the deep part of the pulmonary lobes and adhered severely to the hilum of the lung, the distal lung tissue was nonfunctional, and there were multiple or large tumors making wedge resection impossible. The importance of the intraoperative frozen section must be addressed to avoid disregarding any malignant lesions, and normal lung tissue should be saved as much as possible10-12. There were 23 males and 15 females in a retrospective study conducted by Erdogu et al., and lung cancer and hamartoma were found simultaneously in four cases at the time of diagnosis. Solitary pulmonary nodules with benign radiological findings were typical with pulmonary hamartoma. Although hamartomas can be related to lung cancer at the time of diagnosis or follow-up, it is essential to remember that a different nodule detected in hamartoma patients could be linked to lung cancer13. Ekinci et al.14 found 96 patients with pulmonary hamartomas, with 26 women and 70 men in the group. Malignancies were detected in 23 patients, and their results showed that patients with pulmonary hamartomas might have coexisting lung malignancies. Conclusion Pulmonary hamartoma is a rare case. Management of pulmonary hamartoma is complete resection of the pulmonary hamartoma. Pathological anatomy examination plays a vital role in determining the type of tumor. Ethical approval This case report does not require any ethical approval. Patient consent Written informed consent was obtained from the patient to publish this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Sources of funding None. Author contribution All authors contributed to data analysis, drafting and revising the paper, giving final approval of the version to be published, and agreeing to be accountable for all aspects of the work. Conflicts of interest disclosure All authors declare that they have no conflicts of interest. Research registration unique identifying number (UIN) 1. Name of the registry: NA. 2. Unique identifying number or registration ID: NA. 3. Hyperlink to your specific registration (must be publicly accessible and will be checked): NA. Guarantor Anna Febriani is the person in charge of the publication of our manuscript. Provenance and peer review Not commissioned, externally peer-reviewed. Acknowledgments We would like to thank our editor, 'Fis Citra Ariyanto.' Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online 6 February 2023 References 1 Fasanya AA Hattab Y Patel A . Mesenchymal cystic hamartoma of the lung. 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Ann Med Surg (Lond) Ann Med Surg (Lond) MS9 Annals of Medicine and Surgery 2049-0801 Lippincott Williams & Wilkins Hagerstown, MD 10.1097/MS9.0000000000000248 00005 3 Original Research Clinicodemographic profile of chronic liver disease patients at a tertiary care hospital: a retrospective analysis Shrestha Anish K. MBBS [email protected] Shrestha Anisha MBBS [email protected] Shah Sangam MBBS [email protected] Bhandari Aashna MBBS [email protected] Institute of Medicine, Tribhuvan University, Maharajgunj, Kathmandu, Nepal * Corresponding author. Address: Department of Gastroenterology, Institute of Medicine, Tribhuvan University, Maharajgunj, Kathmandu, 44600, Nepal. E-mail address: [email protected] (A. K. Shrestha). 3 2023 17 2 2023 85 3 390393 1 10 2022 8 1 2023 Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction: With the global burden of chronic liver disease (CLD) on the rise, especially due to the rise in obesity and metabolic syndrome, a third-world country like Nepal faces a different problem. With alcohol intake being rooted in Nepalese culture, alcoholic liver disease (ALD) is the most common cause of CLD in our society. Methods: This is a retrospective observational study conducted in the inpatient ward of the Department of Gastroenterology at the University in Nepal. Ethical approval was taken from the Institutional Review Committee, and a structured questionnaire format was used to record the data retrospectively using admission log books and admission sheets. Demographic data regarding age, sex, and address were collected, while the form of decompensation during presentation was used as a source of clinical data. For statistical analysis, see SPSS 21 (IBM Corp., Released 2012. IBM SPSS Statistics for Windows, Version 21.0; IBM Corp.) was used. Results: A male-to-female ratio of 2:1 was found, with ALD the most common cause of CLD in admitted patients. Similarly, the majority of patients were admitted due to ascites, which was compounded by spontaneous bacterial peritonitis. 93.60% of patients admitted with CLD had a deranged prothrombin time, while only about a third of patients had elevated aspartate aminotransferase and/or alanine aminotransferase. Conclusion: The large burden of ALD highlights the importance of awareness programs at the community level, which have been neglected till date. Keywords: alcoholic liver disease chronic liver disease Nepal retrospective OPEN-ACCESSTRUE pmcHighlights Alcoholic liver disease contributes to an overwhelming burden of chronic liver disease patients admitted in Nepal. Ascites with spontaneous bacterial peritonitis is the most common form of decompensation for which a patient is admitted. Awareness programs need to be implemented at the community level to address this issue. The global burden of chronic liver disease (CLD) is on the rise. Based on data from the Global Burden of Disease study, the age-standardized incidence rate of CLD and cirrhosis was 20.7 per 100 000 in 2015, a 13% increase from 20001. Cirrhosis is among the top 20 causes of disability-adjusted life years2. As such, the health and economic burden of CLD with and without cirrhosis is significant globally. Mishra et al.,3 had shown alcoholic liver disease (ALD) to be the most common cause of CLD in a tertiary care center in Nepal. Our study is aimed at delineating the clinicodemographic profile and assessing the common causes of admission among CLD patients admitted to the inpatient ward of the Department of Gastroenterology at Tribhuvan University Teaching Hospital (TUTH). Methods Study design and setting This study was conducted retrospectively at TUTH, located in Maharajgunj, Kathmandu. This center was chosen for study because of its high patient flow. Ethical approval for conducting the study was taken from the Institutional Review Board (IRB) of TUTH, IOM [approval number: 164 (6-11) E2 077/078]. Inclusion criteria Patients with a diagnosis of CLD with or without cirrhosis were admitted to the inpatient ward in the Department of Gastroenterology at TUTH. Exclusion criteria Patients with acute liver disease. Sampling Nonprobability sampling. Study tools and techniques A structured proforma was used to record the data retrospectively for the admitted patients. Study variables The variables were categorized under the headings of demographic and clinical factors. Age, sex, and address of the patient were included under demographic factors. Similarly, significant alcohol consumption, as defined by greater than 80 g/day for more than 5 years4 and the form of decompensation during their presentation were recorded under clinical factors. Statistical analysis Data were compiled, edited, and checked daily to maintain consistency. The data was collected in Microsoft Excel (Ver. 2013). For statistical analysis, SPSS 21 (IBM Corp. Released 2012. IBM SPSS Statistics for Windows, Version 21.0; IBM Corp.) was used. A descriptive analysis was done to identify the clinicodemographic characteristics of patients. Results A total of 469 patients were admitted from January 2018 to December 2019 to the inpatient ward of the Department of Gastroenterology, TUTH, consisting of 303 male (64.60%) and 116 female (35.40%) patients (Table 1 and Figs 1, 2). Table 1 Demographic profile of chronic liver disease patients admitted to the inpatient ward N (%) Sex Male 303 (64.60) Female 116 (35.40) Age >60 177 (37.74) 50-59 118 (25.16) 40-49 100 (21.32) 30-39 59 (12.58) <30 15 (3.20) Province 1 54 (11.51) 2 42 (8.96) 3 243 (51.81) 4 57 (12.15) 5 51 (10.88) 6 9 (1.92) 7 13 (2.77) Figure 1 Age-wise distribution of chronic liver disease patients admitted to the inpatient ward. Figure 2 Province-wise distribution of chronic liver disease patients admitted to the inpatient ward. The majority of patients admitted were from the age group above 60 years (37.74%) and Province 3 (51.81%) of Nepal (Tables 2, 3). Table 2 Clinicolaboratory parameter of patients with CLD Cause of CLD Cause N (%) Alcohol [alcoholic liver disease (ALD) as defined by intake of >80 g/day for >5 y with CLD features] 386 (82.30) NAFLD 17 (3.62) Other causes 66 (14.07) At admission Complication/decompensation Ascites 412 (87.84) Upper gastrointestinal (UGI) bleeding 60 (12.79) Hepatic encephalopathy (HE) 90 (19.18) Hepatorenal syndrome/acute kidney injury (HRS/AKI) 51 (10.87) Spontaneous bacterial peritonitis (SBP) 186 (45.14 of ascites patients) Laboratory parameters Laboratory parameter Total bilirubin >21 mmol/l 345 (73.56) Aspartate aminotransferase (AST) (>2xULN) 156 (33.26) Alanine aminotransferase (ALT) [2xULN (upper limit of normal)] 68 (14.5) Hemoglobin (<12 g/dl) 363 (77.4) Platelets (<150 000/mm3) 333 (71) Prothrombin time (deranged, >12 s) 439 (93.60) CLD, chronic liver disease. Table 3 Laboratory parameters for patients with alcoholic liver disease Laboratory parameter N (%) AST/ALT >2 142 (36.79) AST/ALT >=1.5 205 (53.11) ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit normal. Discussion A total of 469 admitted CLD patients were analyzed, with a male-to-female ratio of 2 : 1. Patients aged over 60 years (37.74%) were the ones most commonly admitted for CLD. Since this center lies in Province 3 of Nepal, most patients admitted here were from Province 3 (51.81%), although, being a tertiary care center, a significant number of cases were from other provinces (48.19%) as well. The absolute number of CLD cases (inclusive of any stage of disease severity) is estimated at 1.5 billion worldwide1 with the most common cause being NAFLD (59%), followed by hepatitis B virus (29%), hepatitis C virus (9%), and ALD (2%)2,5. However, our analysis shows that a major proportion of patients admitted to our center with CLD were due to ALD (82.30%), with other causes contributing to only a minority of cases. The major reason for this is our cultural acceptance of alcohol. Typical presenting clinical features include jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome, or variceal hemorrhage, which are also the various forms of decompensation in CLD6. Among the CLD patients admitted, 65.45% had ascites, 12.79% had upper gastrointestinal bleeding, 19.18% had hepatic encephalopathy, 10.87% had hepatorenal syndrome or acute kidney injury, and 73.56% had jaundice. Similarly, many patients admitted due to ascites as a cause of decompensation had spontaneous bacterial peritonitis (45.14%). This higher percentage of SPB in ascitic patients is due to the rigorous criteria for their admission to the inpatient ward. In patients with ALD, the aspartate aminotransferase (AST) : alanine aminotransferase (ALT) ratio is greater than 1 in 92% of patients and greater than 2 in 70%7. In our study, however, 36.79% of the patients with ALD had an AST/ALT ratio greater than 2, while 53.11% of patients had an AST/ALT ratio greater than 1.5. This could be because of the shorter t1/2 (half-life) of AST (18 h) as compared to ALT (36 h)8. Since about 48.19% of patients come to our center from a different province, it is likely that they would have already been treated for a number of days in a different center before their referral here. Therefore, while the AST and ALT levels may be elevated, their ratio may not be greater than or equal to 2:1 over time. Further, although elevated levels of AST and ALT often signify ongoing hepatic inflammation, many patients with CLD may have normal values due to burnout9. In such cases, prothrombin time serves as a marker of hepatic function, which still remains elevated. Anemia is a common finding in CLD patients, with a prevalence ranging from 50 to 87%. The causes of anemia are varied in CLD, ranging from upper gastrointestinal bleeding to anemia of chronic disease, hypersplenism, and malnutrition10. About 77.4% of patients in our study had anemia. This study shows that ALD is the most common cause of CLD in our community reflecting upon the sociocultural acceptance of alcohol in our community. While infectious causes may contribute to a major proportion of cases of acute liver disease, they form only a minority of cases of CLD. Effective vaccination programs and therapeutic options might have contributed to this outcome, though the major contributing factor still seems to be the rampant use of alcohol in our community. The major limitation of the study is the inclusion of only the inpatient population within a single center. Since this a the retrospective study, all the data were not available. Conclusion This study shows the demographic and clinical profile of patients with CLD admitted to the inpatient ward of the Department of Gastroenterology, TUTH. The huge burden of ALD as a contribution to CLD highlights the importance of harm reduction programs that need to be implemented at a community level. Ethical approval Ethical approval was obtained from the research ethics committee of the Institutional Review Committee (IRC) of Institute of Medicine (IOM) [Ref: 164 (6-11) E2 077/078]. Consent Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Sources of funding No funding was received for the study. Conflicts of interest disclosure Authors have no conflict of interest to declare. Author contribution A.K.S., A.S., and S.S. wrote the original manuscript, reviewed, and edited the original manuscript. A.K.S., A.S., S.S., and A.B. reviewed and edited the original manuscript. Research registration unique identifying number (UIN) 1. Name of the registry: Research Registry. 2. Unique identifying number or registration ID: researchregistry8369. 3. Hyperlink to your specific registration (must be publicly accessible and will be checked): Register Now - Research Registry Guarantor Dr Anish Kumar Shrestha. Provenance and peer review Not commissioned, externally peer-reviewed. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online 17 February 2023 References 1 Moon AM Singal AG Tapper EB . Contemporary epidemiology of chronic liver disease and cirrhosis. Clin Gastroenterol Hepatol 2020;18 :2650-66.31401364 2 Asrani SK Devarbhavi H Eaton J . Burden of liver diseases in the world. J Hepatol 2019;70 :151-71.30266282 3 Mishra A Shrestha P Bista N . Pattern of liver diseases. J Nepal Health Res Counc 2009;7 :14-18. 4 Davidson SS . Davidson's medicine. Davidson's Princ Pract Med 2010;21 :498-9. 5 Sepanlou SG Safiri S Bisignano C . The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 2020;5 :245-66. 6 Moreau R Jalan R Gines P . Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology 2013;144 :1426-37.23474284 7 Cohen JA Kaplan MM . The SGOT/SGPT ratio - an indicator of alcoholic liver disease. Dig Dis Sci 1979;24 :835-38.520102 8 Botros M Sikaris KA . The De Ritis ratio: the test of time. Clin Biochem Rev 2013;34 :117.24353357 9 Lominadze Z Kallwitz ER . Misconception: you can't have liver disease with normal liver chemistries. Clin Liver Dis 2018;12 :96-99. 10 Scheiner B Semmler G Maurer F . Prevalence of and risk factors for anaemia in patients with advanced chronic liver disease. Liver Int 2020;40 :194-204.31444993 |
Ann Med Surg (Lond) Ann Med Surg (Lond) MS9 Annals of Medicine and Surgery 2049-0801 Lippincott Williams & Wilkins Hagerstown, MD 10.1097/MS9.0000000000000147 00018 3 Case Reports Large pineal parenchymal tumor of intermediate differentiation causing compression with resultant obstructive hydrocephalus: a case report Shrateh Oadi N. MD [email protected] Jobran Afnan W.M. MD [email protected] Owienah Haneen MD [email protected] Sweileh Thaer MD [email protected] Abulihya Mohand MD [email protected] Shahin Nadeem MD [email protected] Atawnah Yazan MD [email protected] Kharousha Abdalwahab MD [email protected] d Dababseh Hadi MD [email protected] Hussein Sami MD [email protected] a Faculty of Medicine, Al-Quds University, Abu-Dis, Jerusalem b Radiology Department c Pathology Department d Neurosurgery Department, Al-Istishari Arab Hospital, Ramallah, West Bank, Palestine e Neuropathology Department, Hannover Medical School, Hannover, Germany * Corresponding author. Address: Ramallah, Palestine, P620. Tel: +972 593 656 364, fax: 022 986 311. E-mail address: [email protected] (O.N. Shrateh). 3 2023 8 2 2023 85 3 451455 11 10 2022 22 12 2022 Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction: The epithalamus region contains the tiny, functionally endocrine pineal gland, which has the shape of a pinecone. Less than 1% of adult primary intracranial malignancies are pineal parenchymal tumors, which are incredibly uncommon brain tumors. A rare variety of pineal parenchymal tumors are those with intermediate differentiation. These tumors, whose namesake refers to a malignant pineal parenchymal tumor, are intermediate between pineoblastomas and pineocytomas (a benign pineal parenchymal tumor). Case Presentation: A female patient, age 13, who had been experiencing terrible headaches on and off for a month, went to the emergency room. Along with the headache, she experienced nausea, vomiting, dizziness, and blurred eyesight. A nonenhanced computed tomography scan was used for the initial brain neuroimaging, which showed a hypodense mass posterior to the midbrain and superior to the cerebellum. A heterogeneous bulk was visible on MRI. Clinical Outcome: The headache, vertigo, visual disturbance, nausea, and vomiting have all improved, according to the patient. Both postoperative MRIs with and without contrast revealed the resolution of the obstructive hydrocephalus and the absence of any residual enhancing mass. The patient was followed up for 2 months without any complications or adverse events. Conclusion: One should carefully investigate a headache as the early symptom of many illnesses and rule out any other potential causes. This would therefore enable us to create a management structure for such a very unusual malignancy. Keywords: brain neoplasms case report compression hydrocephalus pineal gland pineal parenchymal tumor OPEN-ACCESSTRUE pmcHIGHLIGHTS Pineal parenchymal tumors are rare and account for less than 1% of all central nervous system neoplasms. Patients with pineal parenchymal tumors of intermediate differentiation may present with headache and diplopia. The pineal parenchymal tumors of intermediate differentiation may be large enough to compress surrounding structures such as the cerebral aqueduct, resulting in hydrocephalus with or without signs of elevated intracranial pressure such as ataxia. Introduction Pineal tumors account for 0.5% of all central nervous system (CNS) tumors in adults, 1% in young adults (aged 20-34 years), and 2.7% in children (aged 1-12 years)1. The 2007 World Health Organization (WHO) recategorized pineal parenchymal tumors (PPTs) from two subtypes: pineocytoma (grade I) and pineoblastoma (grade IV), into four entities, including a category of tumors located between pineocytoma and pineoblastoma in histological grade termed as PPTs of intermediate differentiation (PPTIDs) grade II/III2. Because of the limited number of reported cases, the classification of PPTs, particularly PPTIDs, remains debatable3,4. The exact clinical behavior of PPTIDs is not well understood, and the optimal therapeutic option for these tumors has not yet been determined5,6. However, patients with PPTIDs may present with signs of lesion-like effects, including headache and diplopia. Parinaud's syndrome (upward gaze palsy as a result of tectal plate compression) can also be experienced7. Herein, we report a 13-year-old female patient diagnosed with a large PPTID obstructing the ventricular system with resultant obstructive hydrocephalus. This case report has been reported in line with the Surgical CAse REport (SCARE) criteria8. Case presentation A 13-year-old female patient presented to the emergency department complaining of recurrent attacks of severe headaches for 1-month duration. The headache was associated with dizziness, blurred vision, nausea, and vomiting. Despite the chronic mild headache, the patient asserted that she had never experienced pain similar to this before. The patient reported no personal and/or family history of cancer, any acute, repeated, or discontinued medications, any allergies, any genetic or psychosocial issues, and had a free past surgical history. There was no history of trauma. Upon admission, physical assessment and routine laboratory evaluation, including a complete blood count and metabolic panel, were unremarkable. The initial brain neuroimaging was performed with a nonenhanced computed tomography scan and revealed a hypodense mass located superior to the cerebellum and posterior to the midbrain. MRI showed a heterogeneous mass demonstrating low T1, high fluid-attenuated inversion recovery (FLAIR)/T2 signal, and no definite diffusion restriction measuring 3.5x2.5x3 cm, resulting in compression over the cerebral aqueduct, which appears effaced with no cerebrospinal fluid (CSF) flow through the occluded duct. MRI also revealed a moderate supratentorial ventricular dilatation with periventricular edema (Fig. 1, arrows). The pineal gland could not be clearly identified. A pineal gland tumor was suspected. MRI of the spine showed no metastatic lesions. The patient was admitted to the department of neurosurgery and underwent an endoscopic third ventriculostomy under general anesthesia. Five days later, microscopic occipital craniotomy via a supracerebellar approach for total resection of the penial gland lesion was performed. The procedure was performed by a consultant at the neurosurgery department at a private hospital. The resected lesion was sent for routine histopathology, which showed a tumor with moderate cellularity arranged in a pseudo-rosette and sheet patterns, consisting of cells that are comparatively uniform in appearance with a weak eosinophilic cytoplasm, oval nuclei, and granular chromatin. The mitotic index was low. Immunohistochemical staining showed positivity for synaptophysin and KI67 (Fig. 2). In light of these findings, a PPTID was diagnosed. Postoperative MRI showed no residues of enhancing lesions and total relief of the obstructive hydrocephalus. The patient reported significant improvement in headache, nausea, vomiting, dizziness, and visual disturbances. She was started on a radiotherapy regimen as well as platinum plus etoposide chemotherapy. The patient adhered to and tolerated the provided advice, avoiding vigorous exercise and heavy lifting. She also had a good tolerance to chemotherapy agents and was followed up for 2 months without any reported adverse events or complications. Figure 1 (A) Axial nonenhanced computed tomography scan showing a hypodense mass; (B) T1 sequence axial MRI; (C) FLAIR (fluid-attenuated inversion recovery) sequence axial MRI; (D) T2 sequence axial MRI; (E) FIESTA (fast imaging employing steady-state acquisition) sequence sagittal MRI; (F) FLAIR sequence sagittal MRI. CSF, cerebrospinal fluid. Figure 2 (A, B) Hematoxyline and eosin stains; (C) synaptophysin immunostain; (D) KI67 immunostain. Discussion Melatonin is made by the pineal gland, a tiny, pinecone-shaped midline circumventricular structure. It develops embryologically from an ependymal outpouching and is situated posterior to the third ventricle. Less than 1% of intracranial neoplasms are pineal area tumors, making them uncommon9. As a result of the mass effect on neighboring structures, they frequently exhibit symptoms. CSF blockage and hydrocephalus are caused by compression of the cerebral aqueduct. Diplopia and Parinaud syndrome are brought on by tectum involvement. Nystagmus and ataxia may be caused by larger lesions that affect the cerebellum and its peduncles. Neoplasms of the pineal gland include pineocytomas, pineoblastomas, PPTID, and papillary tumors of the pineal area. Desmoplastic myxoid tumor of the pineal area, SMARCB1-mutant (R), a rare SMARCB1-mutant tumor devoid of histological indications of malignancy, has been added to WHO CNS5 (The fifth edition of the WHO Classification of Tumors of the Central Nervous System). Pineal tumor behavior is still a subject of much debate, and histological grading standards for PPTID, papillary tumors of the pineal area, and desmoplastic myxoid tumor, SMARCB1-mutant have not yet been established10. Neoplasms in the pineal area can develop from parenchymal pineal cells, leftover stem cells, or surrounding glia. Pineal parenchymal tumors, which make up about 27% of tumors in the pineal area, are so named because they develop from these cells11. Pineocytomas are more prevalent in females and adults, respectively. Pineocytomas may spread locally; however, this seldom happens4. They only undergo surgical treatment, and the prognosis is typically very good12,13. Poorly differentiated pineoblastomas are at the other end of the range from pineal parenchymal tumors. These extremely aggressive tumors have a 25-33% metastasis rate at diagnosis, which puts them at high risk for craniospinal metastases. The majority of pineoblastomas occur in youngsters. The prognosis is inversely correlated with the age of diagnosis, and 5-year survival is only 15% for children diagnosed at age 5 or under compared to 57% for those diagnosed at age 5 or older. Surgery, craniospinal radiation, and multimodal chemotherapy, with the possibility of myeloablative chemotherapy with stem cell rescue, are all used to treat these poorly differentiated neoplasms13,14. Long known as malignant pineocytomas, pineocytomas with anaplasia, and atypical pineocytomas, these pineal parenchymal tumors are intermediately malignant between pineocytomas and pineoblastomas6. The WHO first acknowledged PPTID in 2000 after the term was coined in the 1990s15. Although formal histologic grading criteria have not yet been defined, PPTIDs are typically regarded as grade 2 or 3 tumors. There have been some suggested methods for differentiating between PPTIDs with lower and higher risks. One such system3 makes use of mitoses and antineurofilament staining, where high-grade PPTID is characterized by rare or absent antineurofilament staining or by six or more mitoses per high-power field, whereas low-grade tumors are characterized by positive neurofilament staining with fewer than six mitoses. The clinical manifestation of a PPTID seems to be similar to that of other lesions in the pineal region. Diplopia and headache are the most common symptoms. Parinaud's syndrome (abnormal vertical gaze as a result of tectal plate compression) is another frequent finding. If large enough, PPTID can cause hydrocephalus; obstructive (triventricular, noncommunicating) hydrocephalus, due to obstruction of the Sylvian aqueduct by the tumor, is the main underlying mechanism of the presenting symptoms in these patients16. Obstruction due to compression or neoplastic infiltration can be acute, subacute, or late (chronic)17. The commonest (~90%)18 presenting symptoms of pineal space-occupying lesions are, therefore, those of raised intracranial pressure, presenting as mainly new and/or severe headache, occasionally chronic and/or unilaterally located, which improves at rest. Headache has been reported in up to 100% of patients with pineal meningiomas16. For pineocytomas, surgery is frequently curative, but for pineoblastomas, severe chemotherapy (and frequently stem cell transplantation) is necessary. There is no agreement on how to treat PPTID, and many treatment paradigms that fall somewhere between these two extremes of aggression have been observed. The choice to utilize chemotherapy and radiation must be decided following the maximum safe surgical resection. The extent of the resection as well as the presence of spinal or CSF metastases, frequently play a role in this choice. The probability of craniospinal recurrence is intended to be decreased by systemic chemotherapy and more thorough ventricular radiation regimens. On the other hand, radiation and chemotherapy's long-term harmful effects must be taken into account. These factors are weighed against the highly varied survival and recurrence risk associated with PPTID. In comparison to high-grade PPTID, low-grade PPTID has an estimated 5-year overall survival rate of 74%4. Fifteen individuals first received surgical resection in Helsinki, Finland19; three of them had additional local radiotherapy since they were subtotal resections. Radiation therapy was only administered to patients on whom a complete gross resection was accomplished if the illness reappeared or if histology warranted it (pineoblastoma features or elevated MIB-1 index). No chemotherapy was administered. After conducting a thorough analysis of 29 studies involving 127 patients with PPTID, Mallick et al.20 developed an alternative protocol in which, following the maximum safe resection, the choice of local radiation, craniospinal radiation, and surveillance is based on the presence of spinal metastases or CSF positivity as well as the degree of resection. Mallick et al. suggest surveillance with radiation saved for recurrence for large complete resections without spinal and/or CSF dissemination. Local radiation is pursued in situations of subtotal resections without spinal and/or CSF dissemination. Mallick et al.20 recommend craniospinal radiation followed by chemotherapy if there is an indication of spinal and/or CSF dissemination. The combined ventricular radiation and temozolomide regimen was effectively used in the management of PPTID21. Conclusion We present the case of a 13-year-old female patient who had a big PPTID that was blocking her ventricular system and causing obstructive hydrocephalus. Physicians will be reminded of its prevalence and presentation by this case. One should carefully investigate a headache as the early symptom of many illnesses and rule out any other potential causes. This would therefore enable us to create a management structure for such a very unusual malignancy. Ethical approval Our institution has exempted this study from ethical review. Patient consent Written informed consent was obtained from the patient and family for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Sources of funding None. Author contribution O.N.S. and A.W.M.J.: writing the manuscript; H.O., O.N.S., T.S., and M.A.: imaging description; O.N.S., N.S., Y.A., A.K., H.D., and S.H.: reviewing and editing the manuscript. Conflicts of interest disclosure There are no conflicts of interest. Research registration unique identifying number (UIN) Name of the registry: none. Unique identifying number or registration ID: none. Hyperlink to your specific registration (must be publicly accessible and will be checked): none. Guarantor Oadi N. Shrateh. Provenance and peer review Not commissioned, externally peer-reviewed. Acknowledgments None. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online 8 February 2023 References 1 Dolecek TA Propp JM Stroup NE . CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2005-2009. 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Neurosurg Clin N Am 2011;22 :409-12.21801990 15 Kleihues P Louis DN Scheithauer BW . The WHO classification of tumors of the nervous system. J Neuropathol Exp Neurol 2002;61 :215-225.11895036 16 Solis OE Mehta RI Lai A . Rosette-forming glioneuronal tumor: a pineal region case with IDH1 and IDH2 mutation analyses and literature review of 43 cases. J Neurooncol 2011;102 :477-84.20872044 17 Tamburrini G Frassanito P Massimi L . Endoscopic septostomy through a standard precoronal ventricular access: feasibility and effectiveness. Acta Neurochir (Wien) 2012;154 :1517-22.22588340 18 Al-Tamimi YZ Bhargava D Surash S . Endoscopic biopsy during third ventriculostomy in paediatric pineal region tumours. Childs Nerv Syst 2008;24 :1323-6.18365207 19 Choque-Velasquez J Resendiz-Nieves JC Jahromi BR . Pineal parenchymal tumors of intermediate differentiation: a long-term follow-up study in Helsinki neurosurgery. World Neurosurg 2019;122 :e729-e739.30391615 20 Mallick S Benson R Rath GK . Patterns of care and survival outcomes in patients with pineal parenchymal tumor of intermediate differentiation: an individual patient data analysis. Radiother Oncol 2016;121 :204-8.27865543 21 Low JT Kirkpatrick JP Peters KB . Pineal parenchymal tumors of intermediate differentiation treated with ventricular radiation and temozolomide. Adv Radiat Oncol 2022;7 :100814.34746517 |
Ann Med Surg (Lond) Ann Med Surg (Lond) MS9 Annals of Medicine and Surgery 2049-0801 Lippincott Williams & Wilkins Hagerstown, MD 10.1097/MS9.0000000000000135 00014 3 Case Reports 'Man-in-the-barrel' syndrome: a case report of bilateral arm paresis following cardiac arrest Riyaz Romana [email protected] a Usaid Syed A. [email protected] Arram Niharikha [email protected] Khatroth Sumalatha [email protected] Shah Pranita [email protected] Shrestha Abhigan B. [email protected] a Shadan Institute of Medical Sciences and Research b Apollo Institute of Medical Sciences and Research c Mallareddy Medical College for Women, Suraram, Hyderabad d Prathima Institute of Medical Sciences and Research, Karimnagar, Telangana, India e M Abdur Rahim Medical College, Dinajpur, Bangladesh * Corresponding author. Address: M Abdur Rahim Medical College, Dinajpur 5200, Bangladesh. Tel: +880 1732 73 4239. E-mail address: [email protected] (A.B. Shrestha). 3 2023 8 2 2023 85 3 435438 30 8 2022 22 12 2022 Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: 'Man-in-the-barrel syndrome' (MIBS) is a neurological phenotype with brachial diplegia, normal sensation, and preserved motor function of the lower limb. Severe hypotension leading to watershed infarctions leading to this phenotype has been reported. The pathogenesis of MIBS is believed to be cerebral hypoperfusion leading to border zone infarctions between the territories of the anterior and middle cerebral arteries. Case Report and Discussion: A 49-year-old chronic alcoholic hypertensive Indian male was evaluated for barrel syndrome after a cardiac arrest. MRI confirmed hyperintensities between the territories of the anterior and middle cerebral arteries bilaterally. Conclusion: Person in barrel syndrome is a rare neurological syndrome. MIB is common after cerebral hypoperfusion and carries a poor prognosis. Identification of the underlying cause is important because the management and prognosis vary based on the etiology. Keywords: brachial diplegia cardiac arrest man-in-a-barrel syndrome OPEN-ACCESSTRUE pmcHighlights 'Man-in-the-barrel syndrome' is a rare neurological phenotype with brachial diplegia, normal sensation, and preserved motor function of the lower limb. The pathogenesis is believed to be cerebral hypoperfusion leading to border zone infarctions. Cardiac arrest can also lead to such a case; hence, prompt anticipation and management are required, as in our case described. Introduction Barrel syndrome is a rare neurological phenotype with brachial diplegia with preserved motor function of the lower limb1. It was formerly called 'Man in a barrel syndrome' (MIBS) as it resembles the aspect of a patient being constrained in a barrel1. Various names were coined to describe the same clinical phenomenon over the years, such as distal field infarction2, cruciate paralysis3, and brachial amyotrophic diplegia syndrome4. Hypertensive emergencies are one of the main causes of end-organ damage leading to systemic hypoperfusion and ischemia at the border zones of anterior cerebral artery (ACA) and middle cerebral artery (MCA), subsequently causing barrel syndrome5,6. We describe a case of 'MIBS' phenotype in a hypertensive patient following a precipitous drop in blood pressure due to cardiac arrest. This article has been delineated in accordance with the CAse REports (CARE) guideline7. Case presentation We report a case of a 49-year-old chronic alcoholic hypertensive Indian male presenting with sudden onset of breathlessness at rest for 5 h and associated with palpitations. The patient presented via ambulance in the emergency department. The patient was found to be in acute left ventricular failure. There was no history of trauma, fever, cough, and peripheral edema. On admission, a high blood pressure of 220/140 mmHg (normal: 140/90 mmHg) was observed. Shortly, he had sudden cardiac arrest, from which he was resuscitated after 15 min. Epinephrine was administered continuously as an intravenous infusion 1 mg every 3-5 min and antiedema measures like furosemide 1.0 mg/kg intravenously was injected slowly to prevent the progression of pulmonary edema. He required ventilatory support and remained unconscious and in shock for about 2 h. The blood pressure improved to 100/70 mmHg. The next day, postcardiac arrest, after regaining his consciousness completely, the patient complained of proximal upper limb weakness in the form of difficulty in abducting his arms. On neurological examination, he had normal consciousness and no abnormal speech; his cranial nerve examination was normal, with normal bilateral fundi and no facial weakness. Upper limb examination presented as reduced tone, and according to the Medical Research Council (MRC), the power of proximal muscles was 3/5 with increased deep tendon reflexes and spasticity. Distal hand motor functions were normal with the normal sensory examination. Lower limb examination was unremarkable, with normal bilateral flexor plantar response and normal sensory examination. Chest X-ray was suggestive of cardiogenic pulmonary edema. ECG showed Q waves with V3, V4, V5, and V6, suggestive of myocardial infarction. Two-dimensional echocardiography showed regional wall motion abnormality in the anterior wall with dilated left atrium and ejection fraction of 33%, without the evidence of intracardiac thrombi or valvular dysfunction. A plain MRI of the brain revealed hyperintensity areas between a bilateral ACA and MCA suggestive of watershed infarcts (Figs 1, 2). Carotid artery duplex sonography was performed in bilateral carotid arteries and excluded carotid artery stenosis. Figure 1 Plain MRI of the brain showing hyperintensity in bilateral watershed infarcts between bilateral anterior cerebral artery and middle cerebral artery territories. Figure 2 Plain MRI of the brain showing bilateral watershed infarcts between bilateral anterior cerebral artery and middle cerebral artery territories. Blood investigations were performed to rule out other comorbid conditions, as shown in Table 1, and the anticoagulation profile was normal. Liver function tests were suggestive of ischemic hepatitis. Table 1 Laboratory findings Parameters Results Units Reference values Random blood sugar 130 g/dl 80-140 High-sensitivity troponin I (Abbott Assay) 1.8 ng/l 4-10 ng/l Sodium 138 mmol/l 133-146 Potassium 3.9 mol/l 3.5-5.3 Creatinine 1.9 mg/dl 0.6-1.4 Urea 3.1 mmol/l 2.5-7.8 Total bilirubin 2.45 mg/dl 0.0-1.0 AST 187.9 U/l 0.0-50.0 ALT 92.4 U/l 0.0-45.0 Alkaline phosphatase 461.9 U/l 90.0-300.0 Total protein 5.15 g/dl 6.6-8.3 Albumin 3.7 g/dl 3.5-5.5 ALT, alanine transaminase; AST, aspartate transaminase. Further, cardioprotective management included antiplatelet agents like aspirin 75 mg, statins like atorvastatin 40 mg, and physiotherapy was advised. The blood pressure was monitored at regular intervals. The liver function returns to normal within 3-4 days with correction of the underlying cause. He was extubated on day 4 and recovered from cardiogenic shock with residual bilateral weakness in his arms. After 3 days, the patient was fully recovered and released. However, follow-up could not be maintained due to a lack of patient compliance, probably due to the economic burden he was facing. Discussion Under ACC/AHA guidelines, hypertension is diagnosed when a person's systolic blood pressure in the office or clinic is at least 140 mmHg and/or diastolic blood pressure is at least 90 mmHg8. An estimated 7.5 million deaths per year, or roughly 12.8% of all deaths, are thought to be related to high blood pressure globally9. Hypertension is associated with an increase in cardiac mortality and morbidity mainly due to a higher incidence of coronary artery disease and may also lead to left ventricular failure. During cardiac arrest, there is a sudden loss of cardiac pump function leading to a sudden drop in blood pressure and ultimately reduced cerebral perfusion. Preventing harmful arrest-related consequences on the brain is a unique challenge in cardiac arrest. More than half of individuals may experience some form of lasting brain damage if their entire circulatory arrest lasts longer than 5-8 min. Circulatory arrest lasting up to 10-15 min nearly usually results in considerable permanent loss of mental capacity. Previously only one similar case has been reported by Shaw et al.10, in which they found MIBS as a sequel to cardiorespiratory arrest. The brachial diplegia syndrome, known as 'Man-in-the-barrel syndrome' is uncommon but well-documented. The exact incidence of MIBS is unknown. In 1917, Dide and Lhermite11 gave the first description of it. The classic clinical presentation is paralysis of the upper extremity, more pronounced proximally than distally, with intact motor functions of the lower limbs. As the subject is unable to move his arms, it appears that the upper limbs are confined in a barrel1. In our case, the patient had proximal upper limb weakness but normal motor functions of distal hand muscles and lower limb muscles. Acute severe hypotension leads to hypoperfusion of the border regions of the cerebral vascular territories, which results in cell death/infarction, which is the cause of watershed strokes. Watershed strokes make up nearly 10% of all ischemic strokes 12. It usually happens between ACA and MCA. It is the place where the precentral gyrus, the motor area in charge of movement in the arm and shoulder, is located13. In our patient, an MRI of the brain revealed bilateral hyperintensities involving the watershed zones between ACA and MCA. Figure 3 shows the anatomical area of watershed zones of the brain. Figure 3 Anatomical area of the brain with watershed zones. ACA, anterior cerebral artery; MCA, middle cerebral artery; PCA, posterior cerebral artery. Other alternative etiologies might result in the phenotypic manifestation of MIBS, as well. The motor cortex-watershed infarcts due to acute systemic hypotension (most frequent cause), multiple sclerosis, metastasis, brainstem-pontine myelinolysis, and spinal cord-anterior spinal artery infarct. Anterior horn cells-motor neuron disease, cervical nerve roots-bilateral C5, C6 radiculopathies, bilateral brachial plexus injury, peripheral nerves (multifocal motor neuropathy), neuromuscular junction (myasthenia gravis), or muscles (e.g. limb-girdle muscular dystrophy) can result in MIBS1,14. The condition 'Man-in-the-barrel syndrome' is uncommonly reported and frequently goes undiagnosed by doctors. However, it might be more widespread than is generally believed. In our patient, the diagnosis is clear with a history of cardiac arrest for a prolonged time which suggests bilateral watershed infarcts as the cause of MIBS. The prognosis of this phenotype is quite variable, depending on the etiology. Some case series reported mortality up to 90% with motor neuron disease, whereas other cases point to a good recovery with minimal residual neurological deficit. Our patient had a satisfactory recovery due to timely diagnosis and treatment, along with improved weakness following physiotherapy. Conclusion MIB is common after cerebral hypoperfusion, like cardiac arrest, and carries a poor prognosis. Timely identification of the underlying cause and localization of lesion(s) is important because the management and prognosis vary based on the etiology and site of the lesion. Ethical approval Not applicable. Patient consent Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Sources of funding Not sponsored. Author contribution R.R.: conceptualization. All authors contributed equally. Conflicts of interest disclosure There are no conflicts of interest. Research registration unique identifying number (UIN) Name of the registry: not applicable. Unique identifying number or registration ID: not applicable. Hyperlink to your specific registration (must be publicly accessible and will be checked): not applicable. Guarantor Abhigan Babu Shrestha. Provenance and peer review Not commissioned, externally peer-reviewed. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online 8 February 2023 References 1 Bodle J Emmady PD . Man In A Barrel Syndrome. StatPearls Publishing; 2022. 2 Mohr JP . Distal field infarction. Neurology 1969;19 :279. 3 Bell HS . Paralysis of both arms from injury of the upper portion of the pyramidal decussation: "cruciate paralysis". J Neurosurg 1970;33 :376-80.5471927 4 Katz JS Wolfe GI Andersson PB . Brachial amyotrophic diplegia: a slowly progressive motor neuron disorder. Neurology 1999;53 :1071-6.10496268 5 Rouanet C Reges D Rocha E . 'Man in the barrel' syndrome with anterior spinal artery infarct due to vertebral artery dissection. J Stroke Cerebrovasc Dis 2017;26 :e41-e42.28065615 6 Antelo MJG Facal TL Sanchez TP . Man-in-the-barrel. A case of cervical spinal cord infarction and review of the literature. Open Neurol J 2013;7 :7-10.23407685 7 Gagnier JJ Riley D Altman DG . The CARE guidelines: consensus-based clinical case reporting guideline development. Dtsch Arztebl Int 2013;110 :603-8.24078847 8 Unger T Borghi C Charchar F . 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension 2020;75 :1334-57.32370572 9 WHO. Indicator Metadata Registry List. Accessed 25 August 2022. 10 Shaw PJ Tharakaram S Mandal SK . Brachial diplegia as a sequel to cardio-respiratory arrest: "man-in-the-barrel syndrome". Postgrad Med J 1990;66 :788. 11 Dide M Lhermite J . La diplegie brachiale spasmodique consecutive aux blessures par coups de feu de la region cervicale. Progres Med 1917;1 :1-3. 12 Torvik A . The pathogenesis of watershed infarcts in the brain. Stroke 1984;15 :221-3.6701929 13 Vanhoutte EK Faber CG van Nes SI . Modifying the Medical Research Council grading system through Rasch analyses. Brain 2012;135 :1639-49.22189568 14 Dalugama C Jayasinghe A Ralapanawa U . Too aggressive drop in blood pressure in a hypertensive male leading to "Man-in-the-Barrel Syndrome". Case Rep Neurol Med 2020;2020 :e8855574. |
Ann Med Surg (Lond) Ann Med Surg (Lond) MS9 Annals of Medicine and Surgery 2049-0801 Lippincott Williams & Wilkins Hagerstown, MD 10.1097/MS9.0000000000000230 00024 3 Case Reports Pontine and bilateral cerebellar lesion in osmotic demyelination syndrome associated with uncontrolled type II diabetes mellitus: a case report Shrestha Suraj MBBS [email protected] a Kharel Sanjeev MBBS [email protected] Gautam Sandesh MBBS [email protected] Poddar Elisha MBBS [email protected] Adhikari Sugat MBBS [email protected] Acharya Suman MBBS, MD [email protected] Pant Samriddha Raj MBBS [email protected] Jha Anamika MBBS, MD [email protected] Ojha Rajeev MBBS, MD, DM [email protected] a Maharajgunj Medical Campus, Tribhuvan University Institute of Medicine, Kathmandu b Shreegaun Primary Health Care Center, Dang Departments of c Neurology d Radiology, Tribhuvan University Institute of Medicine, Kathmandu, Nepal * Corresponding author. Address: Maharajgunj Medical Campus, Institute of Medicine, Kathmandu 14600, Nepal. Tei.: +977-9843061988 E-mail address: [email protected] (S. Shrestha). 3 2023 17 2 2023 85 3 477480 24 10 2022 25 12 2022 Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction and importance: Osmotic demyelination syndrome (ODS) as a result of the hyperosmolar hyperglycemic state is rare and can present with variable neurological manifestation due to lysis of myelin sheath. Case presentation: A 44-year diabetic male presented with complaints of sudden onset, progressive bilateral weakness in lower limbs, and slurring of speech for the past 1.5 months. Cerebellar examination showed a bilaterally impaired finger nose test, dysdiadochokinesia, impaired heel shin test, and an impaired tandem gait. MRI brain (T2 and fluid-attenuated inversion recovery sequences) showed high signal intensity in the central pons and bilateral cerebellum. With a diagnosis of ODS with poorly controlled diabetes, he was treated with insulin, metformin, and supportive measures following which his symptoms subsided gradually. Clinical discussion: A rapid correction of hyponatremia is considered the most common cause of ODS. Variations in plasma glucose levels, a rare cause of ODS, can cause an abrupt osmolality change causing pontine and extrapontine myelinolysis. Prevention of rapid correction of hyponatremia and rapid changes in plasma osmolality in vulnerable patients is the mainstay of treatment. Conclusions: Clinical features, imaging studies, and monitoring of serum osmolality, serum glucose, and electrolytes aid in diagnosis and favorable outcomes for the patient. Keywords: extrapontine myelinolysis hyperglycemia osmotic demyelination syndrome OPEN-ACCESSTRUE pmcHIGHLIGHTS Hyperosmolar hyperglycemic state can rarely cause osmotic demyelination syndrome (ODS). Clinical features and relevant MRI findings are diagnostic of the entity. Prevention of rapid changes in plasma osmolality and supportive measures are the mainstay of treatment. Introduction ODS has an unusual neurological manifestation due to damage to the myelin sheath of the brain1. The classical presentation of this syndrome is central pontine myelinolysis (CPM) involving white matter tracts of the pons, and extrapontine myelinolysis (EPM) involving extrapontine areas2. Though the exact pathogenesis remains unclear, rapid correction of hyponatremia might be the potential culprit which is a serious, however, potentially preventable central nervous system demyelinating syndrome3,4. In addition, hyperglycemic hyperosmolar syndrome along with ketosis can develop into ODS in type II diabetic patients due to infections, noncompliance with treatment, drugs, and other coexisting diseases5. The initial diagnosis of ODS is often difficult due to its variable clinical presentations. Here, we report an unusual case of ODS involving both pons and cerebellum in a chronic alcoholic with hyperglycemia and hypokalemia. The patient was diagnosed with ODS based on his clinical features, supportive laboratory studies, cerebrospinal fluid examination, and brain MRI sequences in the presence of multiple risk factors as potential triggers. This case has been reported in line with SCARE criteria6. Presentation of case A 44-year male presented with complaints of sudden onset, progressive bilateral weakness in lower limbs, and slurring of speech for the past 1.5 months. He had unsteadiness, swaying on both sides while walking, and nasal regurgitation while feeding. These symptoms were progressive for about 10 days, then became static. Owing to travel restrictions amidst the COVID-19 pandemic, the patient visited a local health center where he was prescribed some oral medications. Following the episode, he developed abdominal distension, diarrhea, polyphagia, and polydipsia for 1 month. For the past 5 days, the patient had reduced talk, increased somnolence, and occasional irrelevant talk in the evening. There was no headache, neck pain, facial weakness, fever, loss of vision, loss of consciousness, or seizure. His bowel and bladder habits were normal. Moreover, he did not give a history of any form of trauma, surgery, medicine intake, vaccination, and exposure to toxins or heavy metals. There was no family history of similar illness or any neurological disorders. The patient was diagnosed with type 2 diabetes mellitus, chronic liver disease secondary to alcohol intake with portal hypertension and ascites 1 year back. The patient was a chronic alcoholic (400 g/day for the last 20 years) and an occasional smoker, left for 2 months. He was taking insulin (glargine 34 U once daily) and linagliptin/metformin (2.5/500 mg twice a day) until 15 days before the onset of the symptoms, following which he left using insulin on his own and also missed the physician's follow-up. On examination, he was icteric and had bilateral pedal edema. While assessing the neurological status, he was cooperative and following commands, oriented to person but not to time and place. Pupils were round, regular, and reactive along with intact extraocular eye movements and normal cranial nerve examination. He had cerebellar dysarthria with scanning speech. On motor examinations, all limbs had normal tone with a power of 5/5 (Medical Research Council) across all major joints. The plantar response was bilaterally upgoing. The rest of the superficial and deep tendon reflexes were normal. Cerebellar examination showed a bilaterally impaired finger nose test, dysdiadochokinesia, impaired heel shin test, and an impaired tandem gait. There were no flapping tremors. Initially based on the history and clinical presentation our diagnoses included hepatic encephalopathy, ODS, and Wernicke's encephalopathy. On laboratory investigations, complete blood count and renal function test were in the normal range. Random blood sugar was 15 mmol/l and glycated hemoglobulin was 15.5%, corrected sodium 140 mEq/l, and potassium 3.0 mEq/l. Prothrombin time/international normalized ratio was 16.9/1.26, serum albumin 3.8 g/dl, total protein: 6.2 g/dl, alanine aminotransferase 80 IU/l, aspartate aminotransferase 152 IU/l, serum ammonia level 30 mmol/l and gamma-glutamyl transferase 323 IU/l, while viral serology markers were negative. Total, direct, and indirect bilirubin levels were normal. Vitamin B12 level was 450 pg/ml. Urine analysis showed the presence of glucose without ketone bodies. Lumbar puncture was done and the subsequent cerebrospinal fluid examination showed no abnormalities. Due to an inconclusive diagnosis clinically, an MRI brain was done. T2 and fluid-attenuated inversion recovery brain sequences showed high signal intensity in the central pons and bilateral cerebellum, small vessel disease, and mild cerebral atrophy (Figs. 1 and 2). With these features, a diagnosis of ODS with poorly controlled diabetes was made. During the hospital stay, he was treated with insulin glargine and metformin which gradually controlled his blood glucose level (Table 1). Other medications used were normal saline, methylcobalamin, and thiamine. Gait stabilization physiotherapy was regularly done. After 18 days of hospital stay, the patient was discharged with delirium fully improved, mild dysarthria, and unsteadiness but able to walk without support. On follow-up after 2 months, the patient only had a mild gait problem with no other issues. Figure 1 Fluid-attenuated inversion recovery axial images showing hyperintensity in bilateral pons and cerebellum with normal peripheral pontine and basal ganglia region. Figure 2 T2 axial images showing hyperintensity in bilateral pons and cerebellum. Table 1 Changes in parameters during the hospital stay At emergency Day 1 Day 2 At the time of discharge Reference range Glucose (mmol/l) - 15 - 8.8 3.8-7.8 Sodium (mEq/l) 130.3 129 133 135 135-146 Potassium (mEq/l) 3.0 3.0 3.2 3.9 3.5-5.2 Creatinine (mmol/l) - 61 57 71 60-115 Discussion ODS is usually depicted in only alcoholics and patients with rapid shifts in osmolarity7,8. It is a rare condition with unknown incidence and is frequently underdiagnosed. A rapid correction of hyponatremia is considered the most common cause because of the inability of the cells to readapt quickly to higher osmolarity increasing their risk of lysis mainly oligodendrocytes9. Similarly, variation in plasma glucose levels can also cause an abrupt osmolality change causing pontine and EPS10. Velver et al. 11 showed a rare association between ODS and hyperosmolar hyperglycemic state and its pathophysiological mechanism by rapid hypertonic insult. Our patient's clinical presentation along with high glycated hemoglobulin and fluctuating serum glucose suggests prolonged hyperglycemia. This suggests fluctuations in glucose concentration adjusted to normal through rapid correction by hydration and insulin therapy have caused myelinolysis of bilateral pons, cerebellum, and medulla. Hyperosmolar hyperglycemic state outweighs the rapid correction of hyponatremia in our case for causation of symptoms as rapid correction of his hyponatremia was not done. This notion is supported by patients' impaired mental status and ataxia. We suppose ODS might have developed in our patients 1.5 months back, and aggravated by hyperglycemia causing excessive sleepiness with episodes of irrelevant talk. The risk factors associated with this rare demyelinating disorder are malnutrition, chronic alcoholism, primary adrenal insufficiency, prolonged use of diuretics, hypokalemia, hyperglycemia, fluid resuscitation, hemodialysis, and liver transplant12. Our patient had multiple risk factors like chronic alcoholism, hyperglycemia, and malnutrition. However, serum ammonia level and vitamin B12 level were within normal range. The clinical features of CPM and EPM are variable. Classically, CPM has a biphasic course with seizures or encephalopathy seen initially, followed by severe deterioration causing dysarthria, dysphagia, oculomotor dysfunction, and variable degrees of quadriparesis. Rarely, locked-in syndromes have been reported2. In contrast, EPM shows various extrapyramidal symptoms and movement disorders13. In our case, the pons and cerebellum were involved causing dysarthria, dysphagia, and ataxia. Though the diagnosis of ODS can be made in the background of rapid hyponatremia correction or a hypertonic insult along with clinical and radiological features, it is important to rule out other differentials including stroke, primary brain tumors, metastases, encephalitis, meningitis, Wernicke encephalopathy, hepatic encephalopathy, and multiple sclerosis14. All these differentials were considered and ruled out before a diagnosis of ODS was made in our case. The current standard diagnostic method of ODS includes clinical features and relevant MRI features. MRI findings may not be seen in early scans and can take about 10-14 days after the onset of symptoms12. In our case, MRI was done on our patient 3 days after the admission and 1.5 months after the symptom onset. Pontine demyelination is the hallmark of this syndrome, but isolated extrapontine lesions or combined CPM and EPM have also been reported. Brain MRI typically shows hyperintense lesions in the central pons or associated extrapontine structures on T2-weighted and fluid-attenuated inversion recovery sequences with the corresponding hypointensity on T1-weighted sequences2. Extrapontine lesions of ODS often show symmetrical lesions at various sites like basal ganglia, white matter, and cerebellum15. In this case, bilateral brain lesions in the pons and cerebellum were suggestive of ODS. Due to the lack of definitive large studies, there is no proven treatment for ODS. Prevention of rapid correction of hyponatremia and rapid changes in plasma osmolality in vulnerable patients is the mainstay. Various secondary complications of neurological impairment, aspiration pneumonia, ascending urinary tract infections, venous thrombosis, and pulmonary embolism should be minimized and taken care of16,17. The increased understanding of the pathophysiology of the disease and the use of MRI has aided in early diagnosis improving the outcome of the disease17. Though treatment is supportive but additional therapies like intravenous immunoglobulin and plasmapheresis were found to be effective in some case reports18. However, the prognosis of ODS is still poor with a high mortality rate. Also, coma and irreversible sequelae may also occur in surviving patients. ODS has a variable outcome and is unpredictable from existing clinical or radiological features18,19. Conclusions ODS can have variable presentations associated with involved brain areas. Precautions taken during electrolyte balances, abstinence from the risk factors, and physician awareness of the rapid change of serum osmolality and serum glucose are important. Thus, timely diagnosis, supportive care, and prevention of complications can be a cornerstone for a favorable outcome for the patient. Ethical approval Not applicable. Consent for publication Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Sources of funding None. Authors' contribution S.S., S.K., R.O., S.G., S.A., and E.P. were involved in the study concept, data collection, and writing of the manuscript. R.O., S.R.P., and S.A. were involved in the treatment and reviewing of the manuscript. A.J. provided the necessary radiological images and reviewed the manuscript. All the authors were involved in the final review of the manuscript. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) Not applicable. Guarantor Suraj Shrestha. Provenance and peer review Not commissioned, externally peer-reviewed. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online 17 February 2023 References 1 Brown WD . Osmotic demyelination disorders: central pontine and extrapontine myelinolysis. Curr Opin Neurol 2000;13 :691-697.11148672 2 Singh TD Fugate JE Rabinstein AA . Central pontine and extrapontine myelinolysis: a systematic review. Eur J Neurol 2014;21 :1443-1450.25220878 3 George JC Zafar W Bucaloiu ID . Risk factors and outcomes of rapid correction of severe hyponatremia. Clin J Am Soc Nephrol 2018;13 :984-992.29871886 4 Gankam Kengne F Decaux G . Hyponatremia and the brain. Kidney Int Rep 2018;3 :24-35.29340311 5 Kusumoto K Koriyama N Kojima N . Central pontine myelinolysis during treatment of hyperglycemic hyperosmolar syndrome: a case report. Clin Diabetes Endocrinol 2020;6 :23.33292743 6 Agha RA Franchi T Sohrabi C . SCARE Group. The SCARE 2020 Guideline: Updating Consensus Surgical CAse REport (SCARE) Guidelines. Int J Surg 2020;84 :226-230.33181358 7 Burcar PJ Norenberg MD Yarnell PR . Hyponatremia and central pontine myelinolysis. Neurology 1977;27 :223-226.557757 8 Norenberg MD Leslie KO Robertson AS . Association between rise in serum sodium and central pontine myelinolysis. Ann Neurol 1982;11 :128-135.7073246 9 Dagur G Khan SA . Current concepts in pontine myelinolysis: review of literature. Transl Biomed 2015;6 :38. 10 Matias-Guiu JA Molino AM Jorquera M . Pontine and extrapontine myelinolysis secondary to fluctuations in glycemia [Mielinolisis pontina y extrapontina secundaria a fluctuaciones en la glucemia]. Neurologia 2016;31 :345-347.25440064 11 Rodriguez-Velver KV Soto-Garcia AJ Zapata-Rivera MA . Osmotic demyelination syndrome as the initial manifestation of a hyperosmolar hyperglycemic state. Case Rep Neurol Med 2014;2014 :652523.25431711 12 Jacob S Gupta H Nikolic D . Central pontine and extrapontine myelinolysis: the great masquerader an autopsy case report. Case Rep Neurol Med 2014;2014 :1-5. 13 Pietrini V Mozzani F Crafa P . Central pontine and extrapontine myelinolysis despite careful correction of hyponatremia: clinical and neuropathological findings of a case. Neurol Sci 2010;31 :227-230.19876589 14 Ashrafian H Davey P . A review of the causes of central pontine myelinosis: yet another apoptotic illness? Eur J Neurol 2001;8 :103-109.11430268 15 de Souza A . Akinetic-rigid syndrome due to extrapontine and pontine myelinolysis following appropriate correction of hyponatraemia. J Clin Neurosci 2011;18 :587-589.21273078 16 Barhaghi K Molchanova-Cook O Rosenburg M . Osmotic demyelination syndrome revisited: review with neuroimaging. J La State Med Soc 2017;169 :89-93.28850553 17 de Souza A . Movement disorders and the osmotic demyelination syndrome. Parkinsonism Relat Disord 2013;19 :709-716.23660544 18 Rebedew DL . Is central pontine myelinolysis reversible? WMJ 2016;115 :326-328.29095576 19 Lai CC Tan CK Lin SH . Central pontine myelinolysis. CMAJ 2011;183 :E605.21543311 |
Ann Med Surg (Lond) Ann Med Surg (Lond) MS9 Annals of Medicine and Surgery 2049-0801 Lippincott Williams & Wilkins Hagerstown, MD 10.1097/MS9.0000000000000243 00032 3 Case Reports Retroperitoneal endoscopic median arcuate ligament incision with interventional radiology: a case report and literature review Takayama Shoryu MD [email protected] Takayama Satoru MD, PhD [email protected] Kani Hisanori MD, PhD [email protected] a Tanaka Akimitu MD [email protected] Ishikawa Ken MD [email protected] Yoshimoto Nobuyasu MD, PhD [email protected] Departments of a Surgery b Cardiology, Nagoya Tokushukai General Hospital, Kasugai-Shi, Aichi Prefecture, Japan * Corresponding author. Address: Department of Surgery, Nagoya Tokushukai General Hospital, 2-52, Kozojicho-kita, Kasugai-Shi 487-0016, Aichi Prefecture, Japan, Tel:+81 586 51 8711; fax:+81 568 51 7115. E-mail address: [email protected] (S. Takayama). 3 2023 9 3 2023 85 3 514518 20 11 2022 25 12 2022 Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction and Importance: Compression of the celiac artery (CA) associated with median arcuate ligament compression syndrome can result in aneurysms at the pancreaticoduodenal arcade. If the aneurysm ruptures, treatment with interventional radiology (IVR) is recommended. Subsequently, the median arcuate ligament (MAL) should be incised to prevent the recurrence of the aneurysm. Retroperitoneal endoscopic MAL incision reduces the risk of adhesive bowel obstruction. However, there is few surgical landmark for retroperitoneal MAL incision. We used IVR to detect CA for MAL incision. Case Presentation: A 44-year-old man presented to our hospital with complaints of abdominal pain and clouding of consciousness. Contrast-enhanced computed tomography of the abdomen showed contrast leakage from pancreaticoduodenal artery aneurysm, and the CA was compressed by MAL, leading to the diagnosis of pancreaticoduodenal artery aneurysm rupture associated with median arcuate ligament compression syndrome. IVR was performed to block the blood flow to the aneurysm. After 2 months from life-saving IVR, we performed retroperitoneal endoscopic MAL incision with IVR. The patient was discharged 8 days after surgery. Echocardiography and contrast-enhanced computed tomography 2 months after discharge confirmed that the compression and flow of the CA had improved. Clinical Discussion: In retroperitoneal endoscopic MAL incision, there has been few landmark to identify MAL and CA. Retroperitoneal procedure with IVR can identify MAL easily. This is a useful technique, and it is important to accumulate more cases to standardize the technique. Conclusion: Retroperitoneal endoscopic MAL incision with IVR has not been reported, this procedure can make it easier to detect MAL. Keywords: interventional radiology median arcuate ligament compression syndrome pancreaticoduodenal artery aneurysm retroperitoneal endoscopic surgery OPEN-ACCESSTRUE pmcHIGHLIGHTS We report a case of retroperitoneal endoscopic median arcuate ligament (MAL) incision with interventional radiology (IVR). This procedure makes it easier to identify MAL and celiac artery (CA) in retroperitoneal approach. Introduction This work has been reported as in line with the SCARE 2020 criteria1. Rupture of pancreatoduodenal artery (PDA) aneurysms associated with median arcuate ligament syndrome (MALS) has been reported in many cases2,3. When an aneurysm ruptures, treatment by IVR is recommended rather than surgery4. PDA aneurysms form when the compression of the CA by the MAL changes blood flow and pressure at the pancreaticoduodenal artery arcade. Therefore, a MAL incision is performed to release the stenosis of the CA as a radical operation. Laparotomy, laparoscopic surgery, and retroperitoneal endoscopic surgery have been reported5,6. It is a relatively rare syndrome, so treatment procedure is controversial. There have been reports of failed MAL incisions because of difficulty of identification of MAL7. Even in our own cases, CA identification has been difficult. In this case, we used IVR to identify the location of the CA and performed surgery to ensure MAL incision. Case presentation A 44-year-old man with no specific medical history presented to his previous physician with a chief complaint of abdominal pain. He was transferred to our hospital on suspicion of ruptured abdominal aortic aneurysm. Two liters of transfusion was administered to maintain blood pressure. When he arrived at our emergency room, his blood pressure was 75/50 mmHg and heart rate was 110/min. His consciousness was clouded. Physical examination revealed tenderness in the pericardial area. Contrast-enhanced computed tomography (CT) of the abdomen showed contrast leakage from the PDA mass, and the CA was compressed by MAL, leading to the diagnosis of PDA aneurysm rupture associated with MALS (Fig. 1). IVR was performed to block the blood flow to the aneurysm (Fig. 2). There was no evidence of extravasation from the aneurysm after hemostasis. Abdominal distention due to intra-abdominal bleeding was prominent, and intravesical pressure was measured at 30 mmHg. There was concern about abdominal compartment syndrome, but since the patient's hemodynamics was stable and there was no evidence of organ damage, laparotomy to decompress the abdomen was not performed. After IVR embolization, the patient was still intubated and admitted to the ICU to perform decompressive laparotomy immediately when it was needed. After admitting to the ICU, continuous aspiration was performed from the nasogastric tube. Two hours after the first IVR, his intravesical pressure had dropped to 10 mmHg. The patient was extubated the day after the first IVR. Intravesical pressure had normalized. Abdominal compartment syndrome did not occur. The patient's condition stabilized and he was discharged on the ninth day of hospitalization. Therefore, the patient was admitted 2 months after treatment with IVR (Fig. 3) and underwent retroperitoneal endoscopic MAL incision (Fig. 4). There were no complications and the patient was discharged 8 days after surgery. Echocardiography and contrast-enhanced CT 2 months after discharge confirmed that the compression and flow of the CA had improved. Figure 1 Pancreatoduodenal artery aneurysm due to median arcuate ligament syndrome. Contrast-enhanced computed tomography was performed. Blood flow from the superior mesenteric artery increases with compression of the celiac artery due to median arcuate ligament syndrome (A). This causes a change in hemodynamics within the pancreaticoduodenal arcade and forms an aneurysm (B). Figure 2 Interventional radiology for ruptured pancreatoduodenal artery aneurysm. Extravasation from the pancreaticoduodenal artery aneurysm, which was noted preoperatively, was observed (A). Coil embolization was performed and adequate hemostasis was achieved (B). Figure 3 Interventional radiology and intravascular ultrasonography before and after incision of the median arcuate ligament. Interventional radiology and intravascular ultrasonography after coil embolization of pancreatoduodenal artery aneurysm (A). After coil embolization, the celiac artery was still compressed by the median arcuate ligament, and intravascular ultrasonography showed evidence of stenosis. After median arcuate ligament incision, interventional radiology and intravascular ultrasonography were performed again (B). The incision resulted in the dilation of the celiac artery and lumen of the vessel. The celiac artery was additionally balloon dilated. Interventional radiology and intravascular ultrasonography were performed after dilation (C). We determined that the hemodynamic abnormalities associated with median arcuate ligament had improved after confirming adequate celiac artery dilation. Figure 4 Laparoscopic median arcuate ligament incision via retroperitoneal approach. The median arcuate ligament incision was performed with interventional radiology. The superior mesenteric artery (arrowhead in A) and celiac artery (arrow in A) were identified. Interventional radiology was used to identify the celiac artery, and laparoscopic procedures were performed with the catheter engaged into the celiac artery (B). Thanks to this procedure, the median arcuate ligament nearby the celiac artery could be easily identified and incised. After incision, the celiac artery was balloon dilated (C). Since balloon dilation was performed while observing through the laparoscope, we were able to confirm the expansion of the celiac artery in real time. Treatment procedure Transarterial embolization for pancreaticoduodenal artery aneurysm rupture The plan was to embolize the aneurysm with IVR. The CA was to be approached from the upper extremity and the superior mesenteric artery (SMA) from the lower extremity. An arterial line was placed in the right radial artery. A 6 Fr sheath was inserted into the left brachial artery. A 7 Fr sheath was inserted into the right femoral artery. The approach was started from the upper extremity to search for the CA, but only the SMA could be approached. Contrast was injected from the SMA to identify the site of bleeding (Fig. 2A). The CA was enhanced retrograde from the SMA, and it was determined that the CA was completely occluded by the MAL, so the approach from the CA was abandoned and embolization of the aneurysm from the SMA was attempted. Digital subtraction angiography from the SMA was performed to create a road map. Then coil embolization for PDA aneurysm was completely performed (Fig. 2B). Digital subtraction angiography was performed again to confirm that there was no extravasation. The hemostasis was completed. Retroperitoneal endoscopic median arcuate ligament incision with interventional radiology IVR performed first in the supine position. We expected that the hemodynamics of the pancreaticoduodenal arcade would be altered by embolization of the aneurysm. Unlike first-time IVR, the CA was not obstructed completely and could be engaged. However, it was still highly stenotic. Intravascular ultrasonography (IVUS) was performed to evaluate the severity of the stenosis (Fig. 3A). Then the location of the CA was ascertained using the vertebral body as a marker. The catheter was removed because heparin had to be administered with the catheter in place. The patient was placed in the right lateral recumbent position, and laparoscopic surgery was started. A skin incision was made in the left lateral abdomen to make a retroperitoneal space. The retroperitoneal space was made with a balloon for dissection. Three-port retroperitoneal endoscopic surgery was started, and we attempted to identify the CA with the landmark of vertebral level, but we could not identify. Therefore, we decided to perform laparoscopic surgery with IVR, allowing for a bleeding tendency with heparin. The surgical position was left side of the abdomen tilted at 15deg. The SMA and CA were identified with IVR (Fig. 4B), and the MAL was incised (Fig. 4A). At this point, the vessel diameter had improved (Fig. 3B), but balloon dilation was performed for further dilation. The CA was observed to be dilated by balloon dilation while being observed by laparoscopy (Fig. 4C). IVUS scan confirmed that the diameter of the vessel had further improved (Fig. 3C). Total laparoscopic time was 3 h 32 min, total blood amount was 20 ml. Discussion As treatment for intra-abdominal hemorrhage, IVR and damage control surgery are controversial. There is a report of mortality rates ranging from 12 to 50% in cases treated surgically for ruptured PDA aneurysms8. There is a report of hemostasis by IVR as the first choice for ruptured PDA aneurysms4. In our hospital, similarly, IVR is the first choice for the treatment of a ruptured PDA aneurysm if the diagnosis of PDA aneurysm is made preoperatively. IVR is performed by a cardiologist. If hemostasis fails, laparotomy is performed. We have had no IVR hemostasis failures in the past 5 years, and the reason for the success of IVR hemostasis in cases of ruptured PDA aneurysms in MALS is that the location of the aneurysm is the pancreatoduodenal arcade in all cases, which makes it easier to identify the site of bleeding3. Also, unlike traumatic hemorrhage, there is basically only one aneurysm to treat, which we believe contributes to the success rate of hemostasis with IVR. Conversely, if intra-abdominal bleeding is seen, MAL should be evaluated to ensure that there is no background MALS. In our hospital, retroperitoneal endoscopic MAL incision is performed for MALS as a curative procedure, though it has been reported that incision of the MAL is not always necessary7. However, in the case we report here, the second IVR confirmed stenosis of the CA. Without incision of MAL, the hemodynamics in the pancreatoduodenal arcade can become locally hypertensive, and there is a risk of aneurysmal reformation. MAL should be incised and the CA should be released. There is recent literature arguing for the necessity of MAL incision9, and in our hospital, MAL incision is planned after life-saving IVR for ruptured aneurysms. Treatment of MALS has been reported by laparotomic incision of the MAL, removal of the spinal plexus, and patch or bypass of the CA origin if stenosis persists10. Although the results of treatment with open surgery are also good, more and more reports have been published about laparoscopic surgery5,6. The retroperitoneal approach is attractive because there is few intraperitoneal manipulation and the risk of postoperative adhesive bowel obstruction is greatly reduced. A retrospective report about the outcomes of the retroperitoneal approach described the difficulty of CA identification5, and we also had difficulty in identifying CA. This is because there is few standard landmark for CA with retroperitoneal approach. Therefore, we performed simultaneous IVR to identify the CA and performed a MAL incision. Although this was the first case, the CA was easily identified. MAL incision with IVR is an effective procedure to identify CA. In our case, we can checked the expansion of the CA. Although each report states that contrast-enhanced CT is performed after surgery, there is little evidence that the MAL was definitely incised2-7. In our case, IVR and IVUS were performed before and after MAL incision. We also performed balloon dilation of the CA and were able to observe the dilation laparoscopically. Although it is useful to be able to confirm that the MALS has been released, this is the first case and more cases need to be accumulated. Conclusion A ruptured PDA aneurysm associated with MALS was embolized with IVR for life-saving purposes. Then retroperitoneal endoscopic MAL incision was performed with IVR. MAL identification by retroperitoneal approach had been difficult in the past, but IVR made it easy. Preoperative and postoperative dilation of the CA was also confirmed at the same time. This is a useful technique, and it is important to accumulate more cases to standardize the technique. Provenance and peer review Not commissioned, externally peer-reviewed. Ethical approval Ethical approval was not required. Consent Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Sources of funding None. Authors' contribution All authors namely were involved in the management of this patient. This manuscript has been drafted by all authors. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) None. Guarantor Shoryu Takayama. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online 9 March 2023 References 1 Agha RA Franchi T Sohrabi C . For the SCARE Group. The SCARE 2020 guideline: updating consensus surgical CAse REport (SCARE) guidelines. Int J Surg 2020;84 :226-230.33181358 2 Nagasaki K Ariga H Irie T . Spontaneous retroperitoneal bleeding secondary to celiac artery compression syndrome. Clin Case Rep 2021;9 :e04158.34194757 3 Casey L Gananadha S Jones A . Ruptured pancreaticoduodenal artery aneurysm with median arcuate ligament compression: a two staged approach to management. EJVES Vasc Forum 2022;55 :42-46.35515006 4 Chivot C Rebibo L Robert B . Ruptured pancreaticoduodenal artery aneurysms associated with celiac stenosis caused by the median arcuate ligament: a poorly known etiology of acute abdominal pain. Eur J Vasc Endovasc Surg 2016;51 :295-301.26680452 5 van Petersen AS Vriens BH Huisman AB . Retroperitoneal endoscopic release in the management of celiac artery compression syndrome. J Vasc Surg 2009;50 :140-147.19563962 6 Sun Z Zhang D Xu G . Laparoscopic treatment of median arcuate ligament syndrome. Intractable Rare Dis Res 2019;8 :108-112.31218160 7 Sgroi MD Kabutey NK Krishnam M . Pancreaticoduodenal artery aneurysms secondary to median arcuate ligament syndrome may not need celiac artery revascularization or ligament release. Ann Vasc Surg 2015;29 :122.e1-7. 8 Coll DP Ierardi R Kerstein MD . Aneurysms of the pancreaticoduodenal arteries: a change in management. Ann Vasc Surg 1998;12 :286-291.9588518 9 Illuminati G Hostalrich A Pasqua R . Outcomes after open and endovascular repair of non-ruptured true pancreaticoduodenal and gastroduodenal artery aneurysms associated with coeliac artery compression: a multicentre retrospective study. Eur J Vasc Endovasc Surg 2021;61 :945-953.33762153 10 Takach TJ Livesay JJ Reul GJ Jr . Celiac compression syndrome: tailored therapy based on intraoperative findings. J Am Coll Surg 1996;183 :606-610.8957463 |
Ann Med Surg (Lond) Ann Med Surg (Lond) MS9 Annals of Medicine and Surgery 2049-0801 Lippincott Williams & Wilkins Hagerstown, MD 10.1097/MS9.0000000000000193 00021 3 Case Reports Guillain-Barre syndrome following the second dose of COVID AstraZeneca vaccine in a 78-year-old male: a case report from Nepal Acharya Bimarsh MBBS [email protected] KC Sabin MBBS [email protected] Karki Shailendra MBBS [email protected] Thapa Pratima MBBS [email protected] KC Pooja MBBS [email protected] d a KIST Medical College and Teaching Hospital, Lalitpur, Gwarko b Gandaki Medical College, Pokhara c Kathamandu Medical College, Sinamangal, Kathmandu d Pokhara Academy of Health and Science, Pokhara, Nepal * Corresponding author. Address: KIST Medical College and Teaching Hospital, Lalitpur 44700, Gwarko, Nepal. Tel.: +977-9867261599. E-mail address: [email protected] (B. Acharya). 3 2023 17 2 2023 85 3 466469 11 10 2022 25 12 2022 Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction and Importance: Guillain-Barre syndrome (GBS) is a rare acute idiopathic demyelinating polyneuropathy that causes bilateral, symmetrical, and progressive weakness of muscles. AstraZeneca vaccine is a genetically modified spike glycoprotein vaccine of an adenovirus vector. GBS following the second dose of the AstraZeneca vaccine dose is rare and not frequently noted. Case Presentation: A 78-year-old male presented to the hospital with complaints of bilateral weakness of the lower limbs over 4 days following the second dose of the AstraZeneca vaccine. On examination, the power and tone of the limbs were diminished. The sensitivity pinprick test revealed low sensitivity in the right lower limb than in the left lower limb. Nerve conduction studies revealed acute inflammatory demyelinating polyneuropathy and the patient was diagnosed with GBS. After admission, the patient was successfully treated with intravenous immunoglobulins along with physiotherapy. Clinical Discussion: GBS can be diagnosed clinically with nerve conduction studies and Brighton's criteria. The robust causal relationships between COVID-19 infections, COVID-19 vaccination, and GBS are still unclear. The evaluation of the potential association and risk of GBS with vaccines warrants the need for precise post-vaccination surveillance measures and results. Conclusion: Only a few cases of GBS following the second dose of AstraZeneca are reported so far and there is a need for strong and accurate diagnosis of the disease and proper post-vaccination surveillance for the evaluation of risk associated with COVID vaccines. Keywords: AstraZeneca case report Guillain-Barre syndrome post-COVID-19 vaccination OPEN-ACCESSTRUE pmcHIGHLIGHTS Guillain-Barre syndrome (GBS) is a rare disease that causes bilateral, symmetrical progressive weakness of the muscles. Reports of GBS following AstraZeneca COVID vaccination warrants the need for post-vaccination surveillance globally. Nerve conduction studies and Brighton's criteria can be used to diagnose GBS. GBS can be successfully managed with Intravenous immunoglobulin therapy. Introduction AstraZeneca is a recombinant, nonreplicative Spike (S) glycoprotein vaccine created using chimpanzee adenovirus vector, in a genetically modified human embryonic kidney (HEK 293) cell lines, with reported efficacy of 70.4%. after two standard doses1. Cerebral venous sinus thrombosis; thrombocytopenia, GBS, and acute transverse myelitis have been reported following the AstraZeneca vaccine2. About 18.6 million people took the first dose and 7.24 million people have completed two standard doses in Nepal by the September of 2022. To our knowledge, there is the first case of GBS following the second dose of the COVID-19 AstraZeneca vaccine from Nepal. This case report has been reported in line with the SCARE Criteria3. Case presentation Our 78-year-old male presented with the complaint of bilateral lower limb swelling, weakness, and tingling sensation of finger and toes for 4 days, following 15 days after the second dose of AstraZeneca vaccination. Weakness was acute in onset and gradually progressed to the upper limbs within a week and was associated with difficulty in sitting, standing, and walking activities. He had no history of trauma, headache, photophobia, double vision, abnormal body movements, loss of consciousness, bowel or bladder incontinence, and respiratory or gastrointestinal illness. However, there is a past history of Hashimoto thyroiditis, hypertension, diabetes mellitus, and chronic obstructive pulmonary disease, and have been taking medicines for these conditions. On examination vitals were stable (blood pressure 160/80 mm, respiratory rate 18/min, pulse rate 86 bpm, and SpO2 96%). The Glasgow Coma Scale was recorded at 15/15 and all cranial nerves were intact. Muscle bulk was normal but the tone and power were diminished. Power of both the shoulder and elbow 3/5, left: wrist flexor 2/5, extensor 3/5, handgrip strength 50% and right: wrist flexor 2/5, extensor 2/5, handgrip strength 60%, left: hip flexor, abductor, and extensor 2/5, knee flexor and extensor 3/5, dorsal flexion, plantar flexion, and great toe 1/5, right: hip flexor abductor and extensor 2/5, knee flexor 2/5, extensor 3/5, dorsiflexion and plantar flexion 1/5 and great toe 1/5. Sitting balance test: static was good and dynamic was fair and reflexes were preserved. The sensation was decreased on the right lower limb more than on the left lower limb to the pinprick test. Laboratory investigation showed hemoglobin (12.7 g/dl), packed cell volume (38.7%), increased C-reactive protein (66.6 mg/l), hypoalbuminemia (2.90 g/dl), aspartate aminotransferase (103 U/l), and elevated alkaline phosphatase (488 U/l). The patient was hyperkalemic (5.40 mmol/l) and his serum urea was 47 mg/dl. Also, the random blood sugar was 175 mg/dl and free T3 was 1.70 pg/ml. Cerebrospinal fluid showed adenosine deaminase 2.86 Ul, glucose 60 mg/dl, and total protein of 53 mg/dl. No significant findings on the computed tomography scan. Nerve conduction findings were consistent with acute inflammatory demyelinating polyneuropathy. Nerve conduction study tables show the electrophysiological evidence of sensorimotor axonomylenic polyneuropathy of a severe degree along with the abnormal motor, sensory, and F-wave patterns in Figures 1 and 2, respectively. Figure 1 Motor nerve conduction (MNC). Figure 2 Sensory nerve conduction (SNC). With the help of clinical findings and nerve conduction findings, Brighton's criteria patient was diagnosed with GBS and was admitted to the Mediciti Hospital Kathmandu. Five doses of Intravenous immunoglobulin were commenced from the day of admission and his condition gradually improved afterward. Along with the medical treatment patient also underwent physiotherapy. He was discharged after 10 days following the treatment with immunoglobulins. With three follow-ups in between and 6 months later, he finally recovered with no neuromotor or sensory dysfunction at the time. Our patient believes that his conditions were due to COVID vaccination and also satisfied with the treatment provided in Figure 3. Figure 3 F wave. Discussion Along with other parts of the world, Nepal has also been one of the prime victims of the COVID pandemic. A total of 12 016 deaths were recorded from 3 January 2020 to September 2022, and more than 9000 cases have been recorded. Overall, 22 324 933 (76.61%) of the population have been fully vaccinated throughout this time4. Our patient developed the symptoms of bilateral limb weakness 15 days after following the second dose with AstraZeneca (ChAdOx1 nCoV-19). There have been reports of GBS following AstraZeneca and other post-COVID vaccinations5,6. Reporting of such cases should be scrutinized with accurate diagnosis and strong post-vaccination surveillance systems for the proper evaluation of risk. The known etiopathogenesis of GBS is molecular mimicry of pathogen-borne antigens, which results in the formation of antiganglionic cross-reactive antibodies and activation of a complement system that targets the gangliosides. The type of infection and the specific antiganglioside antibody defines the subtype of GBS. Our electrophysiological findings were consistent with acute inflammatory demyelinating polyneuropathy which results due to the invasion of myelin by macrophages due to activation of the complement system and membrane attack complex formation on the outer surface of Schwann cells7. Some evidence suggests that individuals with T-cell glycolipid CD1 polymorphisms are more susceptible to GBS8. GBS by vaccine virus or vaccine-associated products occurs possibly due to the insertion of virus-specific polypeptides from neighboring cells into host cell membranes damaged by the virus resulting in the humoral or cell-mediated mechanism against myelin antigen in circulations There is only a little evidence of vaccine-associated GBS with Swine flu vaccine 1976, older formulation Rabies vaccines cultured in mammalian brain tissues, Quadrivalent conjugate meningococcal vaccine (MCV4)9. Vaccine-associated GBS is considered a relevant diagnosis if received up to 4 weeks before the onset of symptoms10. Also, the Brighton criteria is significant to diagnose GBS in clinical settings11. Our patient was observed at the level of 4 as per the criteria. According to a nerve conduction study (n=93), 70% of Hadden's and 38% of Rajabally's criteria had primary demyelinating characteristics for GBS12. Our case also follows the same results as shown in Figure 1. In two different case series regarding GBS following post-COVID vaccination, all patients were in their fifth to seventh decade of life and the common presentations occurring within 3 weeks of vaccination were bifacial weakness with paresthesia's variants5,6,13. It took 6 months for our patient to return to his normal activities. A systematic review of GBS in association with COVID-19 vaccination reveals 85% partial recovery among the affected individuals14. Although 900-2200 per billion people are expected to develop GBS within 6 weeks of receiving the first dose of vaccine and 1500-3700 per billion within a 10-week period from following the second dose of vaccination, no significant relation between COVID vaccines and GBS is established from available data15. Conclusion Vaccines have proven to be our most important tool to fight the COVID pandemic and very few cases of GBS following the second dose of AstraZeneca and other vaccines are reported so far. Our case was presented with acute onset of bilateral limb weakness which was treated with the help of intravenous immunoglobulin and physiotherapy. More studies and evidence are required to signify the causality among the reported cases which would eventually assist to prevent the further burden of the COVID pandemic. Provenance and peer review Not commissioned, externally peer-reviewed. Ethical approval Since this is a case report. Ethical approval is not required. Consent Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Sources of funding None. Authors' contribution B.A. wrote the manuscript and edited the manuscript. S.K.C. worked on data collection and also took written consent for the publication of the case report from the patient. S.K., P.T., and P.K.C. were involved in the review process of the literature and preparation of the manuscript. All the authors individually did the final proofreading of the manuscript before submission. Conflicts of interest disclosure All authors declare that they have no any conflicts of interest. Research registration unique identifying number (UIN) None. Guarantor Bimarsh Acharya. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online 17 February 2023 References 1 Voysey M Clemens SAC Madhi SA . Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomized controlled trials in Brazil, South Africa, and the UK. Lancet 2021;397 :99-111.33306989 2 Garg RK Paliwal VK . The spectrum of neurological complications following COVID-19 vaccination. Neurol Sci 2022;43 :3-40.34719776 3 Agha RA Franchi T Sohrabi C . The SCARE 2020 Guideline: Updating Consensus Surgical CAse REport (SCARE) Guidelines. Int J Surg 2020;84 :226-230.33181358 4 World Health Organization. Nepal: WHO Coronavirus Disease (COVID-19) dashboard with vaccination data. 2022. Accessed 25 September 2022. 5 Maramattom BV Krishnan P Paul R . Guillain-Barre syndrome following ChAdOx1-S/nCoV-19 vaccine. Ann Neurol 2021;90 :312-314.34114256 6 Hanson KE Goddard K Lewis N . Incidence of Guillain-Barre syndrome after COVID-19 vaccination in the Vaccine Safety Datalink. JAMA Netw Open 2022;5 :e228879.35471572 7 van den Berg B Walgaard C Drenthen J . Guillain-Barre syndrome: pathogenesis, diagnosis, treatment and prognosis. Nat Rev Neurol 2014;10 :469-482.25023340 8 Geleijns K Laman JD van Rijs W . Fas polymorphisms are associated with the presence of anti-ganglioside antibodies in Guillain-Barre syndrome. Journal of neuroimmunology 2005;161 :183-189.15748958 9 Haber P Sejvar J Mikaeloff Y . Vaccines and Guillain-Barre syndrome. Drug safety 2009;32 :309-323.19388722 10 Shahrizaila N Lehmann HC Kuwabara S . Guillain-Barre syndrome. Lancet (London, England) 2021;397 :1214-1228.33647239 11 Ghazanfar H Qazi R Ghazanfar A . Significance of Brighton criteria in the early diagnosis and management of Guillain-Barre syndrome. Cureus 2020;12 :e8318.32607301 12 Rath J Schober B Zulehner G . Nerve conduction studies in Guillain-Barre syndrome: influence of timing and value of repeated measurements. J Neurol Sci 2021;420 :117267.33352506 13 Allen CM Ramsamy S Tarr AW . Guillain-Barre syndrome variant occurring after SARS-CoV-2 vaccination. Annals of neurology 2021;90 :315-318.34114269 14 Abolmaali M Rezania F Behnagh AK . Guillain-Barre syndrome in association with COVID-19 vaccination: a systematic review. Immunol Res 2022;70 :752-764.36098903 15 Marquez Loza AM Holroyd KB Johnson SA . syndrome in the placebo and active arms of a COVID-19 vaccine clinical trial: temporal associations do not imply causality. Neurology 2021;96 :1052-1054. |
Ann Med Surg (Lond) Ann Med Surg (Lond) MS9 Annals of Medicine and Surgery 2049-0801 Lippincott Williams & Wilkins Hagerstown, MD 10.1097/MS9.0000000000000256 00036 3 Case Reports Adult-onset Still's disease as the first manifestation of acute myeloid leukemia: a case report Ibrahim Ranim MD [email protected] Drie Tasneem MD [email protected] Shahada Zienab MD [email protected] a Al Halabi Hayat MD [email protected] Kudsi Maysoun MD [email protected] a Department of Rheumatology, Al-Mouwasat University Hospital b Departmen of Rheumatology, Damascus University/Syrian Private University, Damascus, Syria * Corresponding author. Address: Department of Rheumatology, Al-Mouwasat University Hospital, Damascus, Syria. E-mail address: [email protected] (R. Ibrahim). 3 2023 17 2 2023 85 3 532535 17 9 2022 8 1 2023 Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction and importance: The association between adult-onset Still's disease (AOSD) and malignancy has previously been observed. However, only a limited number of cases described a combination of AOSD and leukemia, none of which reported AOSD-related symptoms as the first manifestation of acute myeloid leukemia (AML). This presentation might represent a paraneoplastic syndrome or leukemic arthritis mimicking AOSD. Case presentation: Here the authors report a case of a 23-year-old female who fulfilled the Yamaguchi criteria for an AOSD diagnosis. She presented with complaints of polyarthritis, sore throat, and daily fever spikes with the appearance of a nonpruritic maculopapular salmon-colored rash. Her laboratory work showed marked pancytopenia, which led to a bone marrow examination and an AML diagnosis. The patient started receiving chemotherapy with considerable improvement in the AOSD-related symptoms. Clinical discussion: Patients with underlying malignancies could present with systemic features compatible with AOSD, which necessitates excluding malignancy in any patient with this presentation, specifically in light of some warning signs like pancytopenia. Conclusion: This case interprets a rare association between AOSD and AML. In addition, it highlights how crucial it is to be aware of the signs that should warn the clinician of a possible underlying malignancy in any patient presenting with AOSD-related symptoms. Keywords: adult-onset Still's disease AOSD-associated leukemia case report leukemic arthritis paraneoplastic syndrome OPEN-ACCESSTRUE pmcHighlights Patients with underlying malignancies could present with adult-onset Still's disease (AOSD) symptoms. Clinicians should be aware of the warning signs in AOSD patients. Leukemic arthritis could mimic AOSD. AOSD-associated leukemia might represent a paraneoplastic syndrome. Introduction First coined by EG Bytwars in 1971, the term 'adult-onset Still's disease' (AOSD) is used to refer to a rare systemic condition categorized as a multigenic autoinflammatory disorder1. It primarily affects young patients between 16 and 35 years. Rarely, a delayed onset after the age of 50 can also occur2. There is no specific test for the diagnosis of AOSD. However, there are several proposed classification criteria sets, of which the Yamaguchi criteria are the most commonly used ones (Table 1). To consider the diagnosis of AOSD, five or more criteria (two or more majors) are required3. Table 1 Yamaguchi classification criteria for adult-onset Still's disease (AOSD) Major criteria 1. Fever of at least 39degC for at least 2 weeks 2. Arthralgia or arthritis for at least 2 weeks. 3. Nonprutitic salmon-colored rash on trunk/extremeties. 4. Granulocytic leukocytosis (10 000/ml or greater) Minor criteria 1. Sore throat 2. Lymphadenopathy, hepatomegaly, or splenomegaly 3. Abnormal liver function tests 4. Negative tests for antinuclear antibody (ANA) and rheumatoid factor (RF) Exclusion criteria Infections Malignancies (mainly malignant lymphoma) Other rheumatic disease (mainly systemic vasculitides) Even though the association between AOSD and malignancy has previously been observed, the relationship underlying this association is not entirely understood4. Here we present the case of a young female diagnosed with acute myeloid leukemia (AML) masquerading as AOSD. This presentation might represent a paraneoplastic syndrome or leukemic arthritis mimicking AOSD. This case report has been reported in line with the SCARE 2020 criteria5. Case presentation A 23-year-old female presented to the rheumatology clinic with a 2-month complaint of symmetric polyarthritis involving the elbows, wrists, knees, and ankles, accompanied by a daily fever and significant weight loss. She reported that her symptoms were first associated with a sore throat, which had improved about 2 weeks before the presentation. She had no past morbidities or prior surgeries and did not smoke tobacco or drink alcohol. Her family history revealed that her younger brother was diagnosed with neuroblastoma at the age of four. She had received paracetamol for the past 2 months before the presentation and reported a resolution of her fever upon taking the medicine but no improvement in her pain. On examination, her heart rate was 117 beats per minute, her respiratory rate was 17 breaths per minute, and her blood pressure was 100/70 mm Hg. The patient was pale, irritable, and looked in pain. Her cardiac and pulmonary examinations were within normal limits. Her joint examination was positive for swelling and tenderness in her wrists, knees, and ankles. There was no lymphadenopathy, hepatomegaly, or splenomegaly. She was admitted to the rheumatology department for observation and further investigation. Her temperature chart showed a daily fever spike twice a day, with peaks reaching 40degC. On the second day of the admission, she developed a nonpruritic maculopapular salmon-colored rash during the febrile episodes (Fig. 1). The rash appeared mainly on the patient's legs and upper extremities and was disappearing as the fever resolved. Figure 1 Shows the left swollen knee joint as well as the maculopapular salmoncolored rash. Laboratory data at the time of presentation are summarized in Table 2. It showed marked pancytopenia with high inflammatory markers, high ferritin, and low albumin. Antinuclear antibody, rheumatoid factor, anti-Cyclic Citrullinated Peptide, hepatitis B surface antigen, antihepatitis C virus, parvovirus antibodies, and blood cultures were all negative. The glycosylated ferritin level could not be tasted since it was not available. Computed tomography scan of the chest, abdomen, and pelvis was done and did not show any findings suggesting a potential malignancy. The diagnosis of AOSD was considered appropriate because the patient fulfilled the Yamaguchi criteria. However, the presence of pancytopenia made it crucial to perform a bone marrow examination to exclude other disorders, including macrophage activation syndrome. It revealed a hypercellular marrow with an excess of immature blasts but no hemophagocytosis. The diagnosis of acute myelomonocytic leukemia (FAB classification M4) was made according to the immunophenotyping. A cytogenetic study was performed, and a translocation between chromosomes 6 and 9 with breakpoints at p22 and q34, respectively, was found. The patient started receiving chemotherapy with considerable improvement in the AOSD-related symptoms. Table 2 Laboratory values at presentation Laboratory parameter Patient laboratory value at presentation Reference range Leukocyte count 2900/mm3 4500-11 000/mm3 Segmented neutrophils 66% 54-62% Hemoglobin 6.5 g/dl 12.0-16.0 g/dl Platelet count 100 000/mm3 150 000-400 000/mm3 Prothrombin time 12 s 11-15 s Partial thromboplastine time 40.5 s 25-40 s Erythrocyte sedimentation rate (ESR) 98 mm/h 0-20 mm/h protein (CRP) 34 mg/dl Up to 0.5 mg/dl Albumin 2.8 g/dl 3.5-5.5 g/dl Ferritin 5000 ng/ml 12-150 ng/ml Alanine aminotransferase (ALT) 10 U/l 10-40 U/l Aspartate aminotransferase (AST) 13 U/l 12-38 U/l Lactate dehydrogenase (LDH) 322 U/l 140-280 U/l Creatinine 0.6 g/dl 0.6-1.2 g/dl Uric acid 3.6 mg/dl 3-6 mg/dl Discussion The association between AOSD and malignancy has previously been observed. A solid tumor was diagnosed in half of the reported cases, with breast, lung, and thyroid cancers being the most frequent types6-8. The rest of the patients were diagnosed with a hematopoietic malignancy, prominently lymphoma9, with two cases of chronic myelogenous leukemia10,11, two cases of acute lymphoblastic leukemia4,12, and one case of myelodysplastic syndrome with later progression to AML13. These cases showed that the diagnosis of malignancy could precede, concur with, or follow AOSD. However, it followed the presentation of AOSD-related symptoms in the vast majority of the cases, with a median interval of nine months. To our knowledge, this is the first reported case of concurrent diagnoses of AOSD and AML. AOSD-associated leukemia is rare and its cause remains unclear. The temporal relationship between these two entities plays a significant role in predicting the etiology underlying this association. Nakagawa and Sugawara published two cases of AOSD-associated leukemia, in which the diagnosis of AOSD preceded the diagnosis of leukemia by 2 and 6 years, respectively. They both suggested that the cyclosporine used in AOSD treatment might have induced the development of leukemia10,13. We report concurrent diagnoses of AOSD and AML with marked improvement in the AOSD-related symptoms after chemotherapy. This presentation could represent a misinterpretation of leukemia's symptoms and signs as AOSD. Leukemic cells can infiltrate into synovial tissue, causing symptoms and signs of arthritis. It has been widely observed that leukemic arthritis could mimic Still's disease in children with acute lymphoblastic leukemia14. However, it is far less common in adults and more likely to present as seronegative reactive arthritis or rheumatoid arthritis rather than the AOSD-like disease15,16. Another possible explanation for this presentation is that it represents a paraneoplastic syndrome. Nevertheless, AOSD has not been listed as a true paraneoplasia as there was not enough evidence in the previously reported cases4. Most of the AOSD classification criteria share the requirement of excluding malignancy before the final diagnosis. However, there are no obvious guidelines regarding how strict the application of this exclusion criterion should be. Hofheinz et al.4 published a review on AOSD-associated malignancy and identified several signs that should warn the clinician of a possible underlying malignancy in any patient presenting with AOSD, including the first presentation at a higher age than usual, atypical features of the skin rash, high levels of lactate dehydrogenase, and high concentrations of the soluble interleukin-2 receptor. The presence of pancytopenia, in our case, oriented us toward a bone marrow examination and an AML diagnosis. This finding may also suggest an accompanying macrophage activation syndrome, which can affect about 12-15% of AOSD patients17,18. However, this diagnosis was ruled out since it usually presents in severely ill patients with a number of specific features, such as unremitting fever, organomegaly, coagulopathy, hypertriglyceridemia, hypofibrinogenemia (indicated by a normal or low erythrocyte sedimentation rate), and the presence of hemophagocytosis in the bone marrow examination18. Our approach was limited by the unavailability of both the cytokine tests and the glycosylated ferritin level test, which is a more specific marker for AOSD than serum ferritin19 Conclusion We report a case in which a presumptive diagnosis of AOSD was made with simultaneous detection of AML and demonstrated the significance of further investigation in any patient with AOSD-related symptoms in order to exclude any underlying malignancy, specifically in light of some warning signs like pancytopenia. Ethical approval None. Consent Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Sources of funding None. Author contribution R.I.: literature review, manuscript writing and editing, review and approval of the final manuscript. T.D.: obtaining informed written consent, clinical follow up, manuscript writing, and approval of the final manuscript. Z.S. and H.A.: manuscript writing and approval of the final manuscript. M.K.: mentor and approval of the final manuscript. Conflicts of interest disclosure All authors declare no conflict of interest. Research registration unique identifying number (UIN) This case report do not detail a new surgical technique or new equipment/technology, this registration was not required. Guarantor Ranim Ibrahim. Provenance and peer review Not commissioned, externally peer-reviewed. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online 17 February 2023 References 1 Gerfaud-Valentin M Jamilloux Y Iwaz J . Adult-onset Still's disease. Autoimmun Rev 2014;13 :708-22.24657513 2 Mollaeian A Chen J Chan NN . Adult onset Still's disease in the elderly: a case-based literature review. BMC Rheumatol 2021;5 :12.33875007 3 Yamaguchi M Ohta A Tsunematsu T . Preliminary criteria for classification of adult Still's disease. J Rheumatol 1992;19 :424-30.1578458 4 Hofheinz K Schett G Manger B . Adult onset Still's disease associated with malignancy - cause or coincidence? Semin Arthritis Rheum 2016;45 :621-6.26581485 5 Agha RA Franchi T Sohrabi C . for the SCARE Group. The SCARE 2020 Guideline: Updating Consensus Surgical Case Report (SCARE) Guidelines. Int J Surg 2020;84 :226-30.33181358 6 Fukuoka K Miyamoto A Ozawa Y . Adult-onset Still's disease-like manifestation accompanied by the cancer recurrence after long-term resting state. Mod Rheumatol 2019;29 :704-7.27846765 7 Bosch-Barrera J Montero A Lopez-Picazo JM . Adult onset Still's disease after first cycle of pemetrexed and gemcitabine for non-small cell lung cancer. Lung Cancer 2009;64 :124-6.19008012 8 Tirri R Capocotta D . Incidental papillary thyroid cancer diagnosis in patient with adult-onset Still's disease-like manifestations. Reumatismo 2019;71 :42-5.30932443 9 Smaali J Khattabi AE Qatni ME . Maladie de Still de l'adulte et lymphome: une association rare [Adult onset Still's disease and lymphoma: a rare association]. Pan Afr Med J 2020;36 :55.32774630 10 Nakagawa Y Furusyo N Taniai H . Chronic myelogenous leukemia that occurred two years after the diagnosis of adult Still's disease. Intern Med 2005;44 :994-7.16258220 11 Nagasaki Y Miyamoto T Henzan H . Longstanding remission of adult onset Still's disease under imatinib therapy in a patient with chronic myelogenous leukemia. J Rheumatol 2009;36 :1349-51.19509096 12 Benitez Velazco A Gonzalez Garcia FM Albala Gonzalez MD . Gammagrafia osea con 99mTc-MDP en un paciente con leucemia aguda linfoblastica diagnosticado inicialmente de enfermedad de Still [Bone scintigraphy with 99mTc-MDP in a patient with acute lymphoblastic leukemia initially diagnosed of Still's disease]. Rev Esp Med Nucl 2005;24 :319-21.16194464 13 Sugawara T Tsukada T Wakita Y . A case of myelodysplastic syndrome progressing to acute myelocytic leukemia in which adult-onset Still's disease had occurred 6 years before. Int J Hematol 1993;59 :53-7.8161735 14 Marwaha RK Kulkarni KP Bansal D . Acute lymphoblastic leukemia masquerading as juvenile rheumatoid arthritis: diagnostic pitfall and association with survival. Ann Hematol 2010;89 :249-54.19727722 15 Silverstein MN Kelly PJ . Leukemia with osteoarticular symptoms and signs. Ann Intern Med 1963;59 :637-45.14082717 16 Gur H Koren V Ehrenfeld M . Rheumatic manifestations preceding adult acute leukemia: characteristics and implication in course and prognosis. Acta Haematol 1999;101 :1-6.10085431 17 Arlet JB Le TH Marinho A . Reactive haemophagocytic syndrome in adult-onset Still's disease: a report of six patients and a review of the literature. Ann Rheum Dis 2006;65 :1596-601.16540551 18 Hot A Toh ML Coppere B . Reactive hemophagocytic syndrome in adult-onset Still disease: clinical features and long-term outcome: a case-control study of 8 patients. Medicine (Baltimore) 2010;89 :37-46.20075703 19 Fautrel B Le Moel G Saint-Marcoux B . Diagnostic value of ferritin and glycosylated ferritin in adult onset Still's disease. J Rheumatol 2001;28 :322-9.11246670 |
Ann Med Surg (Lond) Ann Med Surg (Lond) MS9 Annals of Medicine and Surgery 2049-0801 Lippincott Williams & Wilkins Hagerstown, MD 10.1097/MS9.0000000000000140 00017 3 Case Reports Unusual initial presentation of childhood acute lymphoblastic leukemia as massive ascites and pleural effusion in post-COVID-19 setting: a case report Shrateh Oadi N. MD [email protected] Jobran Afnan W.M. MD [email protected] Owienah Haneen MD [email protected] Adwan Rabee MD [email protected] c Dwikat Yasmin MD [email protected] Najajreh Mohammad MD [email protected] a Al-Quds University-School of Medicine, Abu-Dis, East Jerusalem b Radiology Department c Infectious Department d Pediatric Department e Pediatric Hematology and Oncology Department, Al-Istishari Arab Hospital, Ramallah, West Bank, Palestine * Corresponding author. Address: Ramallah, Palestine. fax: 02 298 6311. E-mail address: [email protected] (O.N. Shrateh). 3 2023 9 3 2023 85 3 447450 13 9 2022 22 12 2022 Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction: Acute lymphoblastic leukemia (ALL) in children typically presents with nonspecific manifestations such as fever, fatigue, lethargy, joint and bone pain, and bleeding diathesis. Ascites and pleural effusion as an initial presentation of ALL, although described, is exceedingly rare. However, this unusual initial presentation becomes much rarer in the post-coronavirus disease 2019 (COVID-19) setting. Herein, we aim to highlight such a rare initial presentation of childhood ALL that warrants clinical attention. Case Presentation: Two months following a COVID-19 infection, a 3-year-old male patient presented to the hospital with severe abdominal distention associated with occasional dyspnea. Physical assessment revealed a critically ill and pale patient with a distended abdomen and decreased air entry on the right side of the chest. Laboratory testing showed pancytopenia. Imaging studies confirmed the presence of massive ascites and pleural effusion. Bone marrow aspiration revealed CD10-positive pre-B-cell ALL. The patient was treated with chemotherapy and achieved complete remission. Conclusion: Rare manifestations of relatively common diseases create a barrier to prompt and effective detection and medical intervention. Although ascites and pleural effusion are rare conditions in ALL children patients, the occurrence of these pathologies in this particular patient, especially following COVID-19 infection, is an exceedingly rare event. Keywords: acute lymphoblastic leukemia ascites case report COVID-19 infection pleural effusion OPEN-ACCESSTRUE pmcHighlights Pleural effusions are a common feature of nearly all hematological malignancies during the course of the disease, but they only sporadically manifest in this way. Severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019) infection has a detrimental effect on the prognosis of cancer patients. Rarity of initial presentation of childhood acute lymphoblastic leukemia as synchronous massive ascites and pleural effusion in post-coronavirus disease 2019 setting. Introduction Acute lymphoblastic leukemia (ALL) is a malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood, and extramedullary sites. The vast majority of ALLs occur in children's age group with a percentage of 80% of all childhood leukemias. ALL is the most frequent childhood malignancy, with an overall estimated incidence of 34 cases per million individuals in the United States1,2. Although ALL occurs primarily as a de novo neoplasm, Down syndrome, Fanconi anemia, Bloom syndrome, neurofibromatosis type I, and ataxia telangiectasia have all been identified as genetic syndromes that predispose to a minority of ALL cases in the pediatric population. Furthermore, ionizing radiation exposure, pesticides, and certain viruses, including Epstein-Barr virus and HIV, have also been linked to a higher risk of childhood leukemia3. Pleural involvement with leukemic cells is a frequent finding at postmortem autopsy but is rarely emergent throughout life4. However, ALL was reported to cause an isolated unilateral pleural effusion as an initial presentation5. Besides that, ALL can present initially with ascites, pleural effusion, and confusion in the adult age group6. This report highlights the unusual initial presentation of childhood ALL in a 3-year-old patient presented with massive ascites concomitant with pleural effusion following coronavirus disease 2019 (COVID-19) infection. Case presentation A.Z., a previously healthy 3-year-old male child was brought to the pediatric outpatient clinic with a 6-day history of nonproductive cough associated with fever and hypoactivity. One of his family members had a COVID-19 infection 1 week ago. The patient was tested for COVID-19 and was positive. The general medical condition of the child was significantly improved and the symptoms completely disappeared. Two months later, the patient came to the emergency department of the hospital with complaints of severe abdominal distention associated with occasional dyspnea. The patient had no fever, cough, abdominal pain, jaundice, or weight loss. He had no significant past medical, surgical, psychosocial, or drug history. No family history of genetic disorders. Upon admission, the physical assessment revealed a pale and critically ill child with multiple palpable submetacentric cervical lymph nodes. The heart sounds and jugular venous pressure were normal, but diminished breath sounds were noted at the level of the lung base on the right side. The abdomen was significantly distended with mild tenderness and a positive shifting dullness. The liver and spleen were not palpable. A purpuric rash was seen in the right lower quadrant region. Examination of lower limbs showed no pedal edema. Vital signs were normal except for a respiratory rate of 23 breaths per minute. No other remarkable findings were noted on examination. Laboratory evaluation was normal except for pancytopenia (Table 1). Imaging studies revealed the presence of massive ascites with mild liver enlargement and pleural effusion on the right side (Fig. 1a-c). No other prominent pathologic findings were seen. Analysis of pleural fluid demonstrated glucose of 90 mg/dl, protein of 3800 mg/dl, and lactate dehydrogenase of 235 IU/ml. In all, 1.5 l of the ascitic fluid were aspirated and subjected to biochemical and cytological assessment. This showed hemorrhagic content and prominent lymphocytic infiltrate with few atypical lymphocytes. Malignancy was suspected and bone marrow aspiration was performed. This, in turn, revealed more than 85% of bone marrow cells were lymphoblasts, and flow cytometry testing confirmed the diagnosis of CD10-positive pre-B-cell ALL. The patient was given intravenous fluid, fresh frozen plasma, platelets and started therapy according to the BFM-AIEOP (Berlin-Frankfurt-Munich - Associazione Italiana Ematologia Oncologia Pediatrica) 2009 protocol combined with methylprednisolone. The patient was also started on nystatin and trimethoprim-sulfamethoxazole. At the 3-month period of follow-up, lymphadenopathy was subsidized, and ascites and pleural effusion were significantly improved without recurrence. The patient achieved complete remission with less than 5% blasts in the bone marrow, a normal peripheral blood count, and no other symptoms of the disease. He also had no immunophenotypic evidence of minimal residual disease. According to the patient's parents, their child showed good adherence and tolerability to the provided therapy without any noticeable adverse events. Table 1 Laboratory results at the presentation Laboratory parameter The value Reference range Complete blood count Hb (g/dl) 7.1 13.5-17.5 WBC (x103)/ml 1.5 6-18 PLT (x103)/ml 60 142-450 Inflammatory markers CRP (mg/dl) 0.7 0-6 ESR (mm/h) 4 0-15 LDH (IU/l) 157 135-225 Liver studies AST (U/l) 17 8-33 ALT (U/l) 21 7-55 GGT (U/l) 10 10-70 Total bilirubin (mg/dl) 1.2 1-1.2 Albumin (g/dl) 4.8 3.4-5.4 ALP (U/l) 162 40-130 Kidney function CRE (mg/dl) 0.8 0.72-1.25 BUN (mg/dl) 14 5-18 UA (mg/dl) 3.8 3-7 Coagulation studies PT (s) 14.4 11-13.5 INR 1.1 1.1-1.2 Others Serum amylase Normal Urinalysis Normal Serum and urine electrolytes Normal Blood cutlers Negative Brucella serology Negative ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; CRE, creatinine; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; GGT, gamma-glutamyl transferase; Hb, hemoglobin; INR, international normalized ratio; LDH, lactate dehydrogenase; PLT, platelet; PT, prothrombin time; UA, uric acid; WBC, white blood cell. Figure 1 Computed tomography scan of (A) the chest showing right-sided pleural effusion, (B) the abdomen showing massive amounts of ascitic fluid, and (C) the abdomen showing hepatomegaly. Discussion All body organs and tissues are affected by leukemia, a disease that affects the entire body. Fever, pallor, and lethargic symptoms are frequent clinical manifestations. Rarely are acute leukemias with pleural infiltrations of malignant cells discovered during a person's lifetime, but are a frequent discovery at autopsies7. Childhood acute leukemia, which accounts for one-third of all cases and has a fluctuating incidence rate of 10-45 cases per 106 children per year and a cumulative risk of 1 in 2000 up to the age of 15 years, is the most prevalent pediatric malignancy in developed cultures. ALL, the most prevalent form of pediatric leukemia, is an essentially fatal malignancy, as shown by a uniformly poor clinical prognosis prior to the development of effective therapy. To date, however, cure rates for ALL utilizing combination chemotherapy hover around 90%8, making this one of oncology's true success stories. There are numerous environmental factors that may be connected to ALL, but these links are frequently shaky, contradictory, or lack biological plausibility. A more conducive framework for studying this subject has been made available by large, multidisciplinary national research or multinational consortia9. At present, ionizing radiation is the only recognized causative factor for ALL, albeit in extreme situations10. By employing biological knowledge of cancer itself as the basis for developing, testing, and confirming hypotheses, it may be possible to understand the etiology of ALL most effectively. Pleural effusions are a common feature of nearly all hematological malignancies during the course of the disease, but they only sporadically manifest in this way. This most frequently happens when the illness worsens, mostly in Hodgkin's and non-Hodgkin's lymphomas11. The rarity of childhood ALL manifesting as massive ascites and pleural effusion following COVID-19 infection in the literature4 is why this case deserves to be mentioned. When pleural fluid cytology is unable to identify the etiology of the effusion, closed biopsy or thoracoscopic biopsy is usually the next steps in the diagnosis of the fluid's malignant origin. A total of 77% of malignant effusions with varied etiologies get positive results from these tests. Positive cytology is observed in 14-88% of individuals with lymphomatous effusions. However, the number of cancer cells in pleural specimens may be so low that even skilled cytologists cannot make a conclusive diagnosis12. As is highlighted in this research, a General Blood Picture in conjunction with a bone marrow biopsy can reliably confirm the diagnosis in all of these cases when a lymphoreticular condition is the underlying cause. Thus, a General Blood Picture must be performed on all individuals with effusions while the source of the condition is being investigated. With mortality rates of over 20%, Severe acute respiratory syndrome coronavirus 2 (COVID-19) infection has a detrimental effect on the prognosis of cancer patients13. This is especially important in people with hematologic neoplasia and those undergoing allogeneic hematopoietic stem cell transplant, where the fatality rate exceeds 30%14. Four patients who are currently undergoing severe chemotherapy or immunotherapy as well as those with active illness are particularly at risk. This high mortality rate is a result of several variables, including advanced age, poor general health, and neutropenia, in addition to the disease itself. The mortality rates of the various hematologic neoplasia vary dramatically, with acute myeloblastic leukemia and lymphoproliferative disorders having the greatest mortality rates15. There is little available data on the prevalence and prognosis of COVID-19 infection in patients with ALL. Reports typically group patients with other hematologic malignancies due to the low prevalence of ALL in adulthood. One study on ALL found that patients with Philadelphia chromosome-positive (Ph+) ALL had a low incidence of COVID-19 infection. The study also suggested that tyrosine kinase inhibitors may be helpful in preventing patients from contracting the infection. This study was conducted in Italy during the first peak of the pandemic16. Conclusion Ascites and pleural effusion can occur in approximately all hematological malignancies such as childhood ALL, during the disease process, but they only occur infrequently and rarely as the initial manifestations. This unusual and seldom presentation becomes much rarer during post-COVID-19 period. Ethical approval Our institution has exempted this study from ethical review. Patient consent Written informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Sources of funding The authors declare that writing and publishing this manuscript was not funded by any organization. Author contribution O.N.S. and A.W.M.J.: writing the manuscript; H.O. and O.N.S.: imaging description; R.A., M.N., Y.D., O.N.S., and A.W.M.J.: reviewing and editing the manuscript. Conflicts of interest disclosure The authors declare that there are no conflicts of interest regarding the publication of this article. Research registration unique identifying number (UIN) Name of the registry: none. Unique identifying number or registration ID: none. Hyperlink to your specific registration (must be publicly accessible and will be checked): none. Guarantor Oadi N. Shrateh. Provenance and peer review Not commissioned, externally peer-reviewed. Acknowledgments None. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online 9 March 2023 References 1 Howlader N Noone AM Krapcho M . SEER Cancer Statistics Review (CSR) 1975-2014. National Cancer Institute; 2021. 2 Siegel DA Henley SJ Li J . Rates and trends of pediatric acute lymphoblastic leukemia - United States, 2001-2014. MMWR Morb Mortal Wkly Rep 2017;66 :950-954.28910269 3 Onciu M . Acute lymphoblastic leukemia. Hematol Oncol Clin North Am 2009;23 :655-674.19577163 4 Dix DB Anderson RA McFadden DE . Pleural relapse during hematopoietic remission in childhood acute lymphoblastic leukemia. J Pediatr Hematol Oncol 1997;19 :470-472.9329473 5 Mishra AK Kumar S Babu S . Rare initial presentation of ALL as pleural effusion. Egypt J Chest Dis Tuberc 2015;64 :615-616. 6 Roushan N Shahi F Mirzazadeh A . Acute leukemia presenting with ascites and confusion. Leuk Lymphoma 2007;48 :1234-1236.17577793 7 Parkin DM Stiller CA Draper GJ . The international incidence of childhood cancer. Int J Cancer 1988;42 :511-520.3170025 8 Inaba H Greaves M Mullighan CG . Acute lymphoblastic leukaemia. Lancet 2013;381 :1943-1955.23523389 9 UK Childhood Cancer Study Investigators. The United Kingdom Childhood Cancer Study of exposure to domestic sources of ionising radiation: 1: radon gas. Br J Cancer 2002;86 :1721-1726.12087456 10 Preston DL Kusumi S Tomonaga M . Cancer incidence in atomic bomb survivors. Part III: Leukemia, lymphoma and multiple myeloma, 1950-1987. Radiat Res 1994;137 (2 suppl ):S68-S97.8127953 11 Berkman N Breuer R Kramer MR . Pulmonary involvement in lymphoma. Leuk Lymphoma 1996;20 :229-237.8624461 12 Lossos IS Intrator O Berkman N . Lactate dehydrogenase isoenzyme analysis for the diagnosis of pleural effusion in haemato-oncological patients. Respir Med 1999;93 :338-341.10464900 13 Lee LYW Cazier J-B Starkey T . COVID-19 prevalence and mortality in patients with cancer and the effect of primary tumour subtype and patient demographics: a prospective cohort study. Lancet Oncol 2020;21 :1309-1316.32853557 14 Vijenthira A Gong IY Fox TA . Outcomes of patients with hematologic malignancies and COVID-19: a systematic review and meta-analysis of 3377 patients. Blood 2020;136 :2881-2892.33113551 15 Pinana JL Martino R Garcia-Garcia I . Risk factors and outcome of COVID-19 in patients with hematological malignancies. Exp Hematol Oncol 2020;9 :21.32864192 16 Foa R Bonifacio M Chiaretti S . Philadelphia-positive acute lymphoblastic leukaemia (ALL) in Italy during the COVID-19 pandemic: a Campus ALL study. Br J Haematol 2020;190 :e3-e5.32368790 |
Ann Med Surg (Lond) Ann Med Surg (Lond) MS9 Annals of Medicine and Surgery 2049-0801 Lippincott Williams & Wilkins Hagerstown, MD 10.1097/MS9.0000000000000212 00030 3 Case Reports Successful surgical resection of a complicated left ventricular diverticulum in a neonate presented with unexplained anemia: a case report Shrateh Oadi N. MD [email protected] Abusamra Muttaz M.M. MD [email protected] Abudaoud Majdi A. MD [email protected] Srour Moayad A. MD [email protected] Hijjeh Nizar MD [email protected] Haymouni Nidal MD [email protected] Sbeitan Iyad MD [email protected] Abdelraziq Samer MD [email protected] Abutaqa Mohammed MD [email protected] b a Al-Quds University School of Medicine b Department of Pediatric Cardiology, Al-Makassed Islamic Charitable Hospital, Jerusalem, Palestine * Corresponding author. Address: Ramallah P620, Palestine, Tel: +970 259 365 6364, fax: +970 02 298 6311. E-mail address: [email protected] (O.N. Shrateh). 3 2023 9 3 2023 85 3 501505 3 10 2022 25 12 2022 Copyright (c) 2023 The Author(s). Published by Wolters Kluwer Health, Inc. 2023 This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction: Congenital left ventricular diverticulum (LVD) is a rare congenital cardiac anomaly and may be complicated by fatal adverse events such as diverticulum rupture. Most LVD cases are asymptomatic and often discovered incidentally. Herein, we describe an unusual and peculiar clinical presentation with felicitous surgical management of ruptured LVD. Case presentations: A 10-day-old male infant presented with severe, intractable, and unexplained anemia associated with respiratory distress. Upon admission, the patient was clinically shocked with a hemoglobin level of 6.0 g/dl. As chest imaging showed cardiomegaly, echocardiography was performed and revealed a 9x10 mm diverticulum arising from the posterolateral wall of the left ventricle along with blood and clot collection in the pericardium. The patient underwent an urgent surgical resection of the diverticulum. He was followed up for 2 years without any readmissions or cardiac complaints. Clinical discussion: Systemic thromboembolism, heart failure, infarction, and tachyarrhythmias have all been reported as complications of LVD. The most serious complication is diverticulum rupture, which can result in death. As a result, this congenital defect should be discovered early to determine the potential risks and plan appropriate treatment. Conclusion: Congenital heart defects such as LVD should be suspected in neonates presenting with unexplained and intractable anemia. To avoid the diagnosis confusion and risk of serious complications in LVD patients, such as spontaneous rupture of the diverticulum, we advocate immediate surgical management of LVD in children. Keywords: case report congenital heart defects diverticulum rupture left ventricular diverticulum surgical resection unexplained anemia OPEN-ACCESSTRUE pmcHIGHLIGHTS Congenital left ventricular diverticulum (LVD) is a rare congenital cardiac anomaly. Severe, intractable, and unexplained anemia in neonates may indicate a serious underlying congenital heart anomalies such as LVD. Most cases are asymptomatic but may be complicated by fatal adverse events. The most serious complication is diverticulum rupture, which can result in death. We advocate that surgical resection of all LVD is a more convenient and safe option compared with conservative management. Introduction Congenital LVD is a rare congenital anomaly with an overall incidence of 0.4%, or three in 750 autopsies of congenital heart defects1. The diverticulum of the left ventricle is defined as a swollen structure that contains the endocardium, myocardium, and pericardium and exhibits normal systolic contractility2,3. Since it is commonly associated with other cardiac and midline thoracoabdominal malformations, LVD is frequently diagnosed in early infancy4. The vast majority of LVD cases are clinically silent and are often encountered incidentally on physical assessment for other reasons. Although these anomalies are usually benign, rare fatal complications such as thromboembolism, cardiac arrhythmia, heart failure, and diverticulum rupture have been reported5. Therefore, prompt recognition and early surgical intervention are critical, as delayed diagnosis and treatment of such complications may be associated with poor prognostic outcomes. Herein, we report a case of a 10-day-old infant who presented with severe, intractable, and unexplained anemia who was found to have a ruptured congenital LVD. The patient underwent a felicitous and successful surgical resection of the diverticulum with an uneventful 2-year postoperative follow-up period. This case report has been reported in line with the SCARE Criteria6. Case presentation A 10-day-old male infant was referred to our hospital for the assessment of severe, intractable, and unexplained anemia associated with respiratory distress. The patient's parent reported that their child has no personal and/or family history of cancer, any acute, repeat, or discontinued medications, any allergies, any genetic or psychosocial issues, and has a free past surgical history. Upon admission to the hospital, the patient was in apparent respiratory distress and clinically shocked with a hemoglobin level of 6.0 g/dl, which was treated by packed red blood cells administration in the transferring hospital without significant improvement. Physical assessment was normal except for tachycardia without heard murmurs and hypotension. When a plain chest roentgenogram was performed and demonstrated cardiomegaly, a transthoracic echocardiogram was planned. The echocardiography carried out in our hospital revealed the presence of pericardial effusion of 5-8 mm in diameter with scattered blood clots and a diverticulum with dimensions of nearly 9x10 mm arising from the posterolateral wall of the left ventricle near the base of the heart (Fig. 1). We suspected that microperforation of the diverticulum was the reasonable source of the blood and clots in the pericardium. A color Doppler study demonstrated pulsatile flow in the diverticulum. An enhanced computed tomography scan performed before surgery revealed a 9 mm contrast-filled left ventricular outpouching (Fig. 2). The patient was diagnosed with congenital LVD complicated by rupture. The imaging diagnosis was confirmed further during intraoperative exploration. The patient was arranged for emergent surgical resection of the ruptured diverticulum. The procedure was performed by a consultant at the department of pediatric cardiac surgery and congenital heart defects at a tertiary referral hospital. The patient was followed up for 2 years without any readmissions or cardiac complaints and the parents adhered to and tolerated the provided advices. Figure 1 Echocardiography showing the left ventricular diverticulum (arrows in A-C), and hemopericardium with blood clots (in D-F). Figure 2 Enhanced computed tomography scan showing a contrast-filled left ventricular outpouching (arrows); with in an axial view (A), in a coronal view (B), and in an oblique view (C). Operative and postoperative course The patient underwent single-lumen intubation. An arterial line, right internal jugular central venous line, nasogastric tube, and Folly's catheter were inserted. Midline sternotomy and thymectomy were performed. Upon opening of the pericardium, huge clots surrounding the heart were observed. Heparin was infused; cannulation of the aorta and right atrium; institution of cardiopulmonary bypass; aortic clamp; and anterograde custodial cardioplegia were done. After that, the hemopericardial collection was evacuated. Elevation of the inferoposterior surface of the heart disclosed the LVD. Ligation and excision of the diverticulum (Fig. 3) were carried out. Histopathologic assessment of the excised specimen confirmed the diagnosis. Rewarming, smooth heart rebate, deairing off cardiopulmonary bypass, decannulation, and insertion of one mediastinal drain were performed. The sternum and skin were closed with vicryl and monocryl, respectively. Figure 3 The resected left ventricular diverticulum. The patient was transferred intubated to the pediatric cardiac intensive care unit. The patient was hemodynamically stable with no need for pressor support. A cardiac echocardiogram on the postoperative day 1 showed normal global function and geometry with no residual outpouching, pericardial effusion, or vegetation. A postoperative cardiac computed tomography scan revealed that the LVD had completely disappeared and that the morphology was normal. The patient was extubated on postoperative day 2, breastfeeding was restarted on the same day, and the mediastinal chest tube was removed on postoperative day 3 with significant improvement in respiratory distress. The patient was re-examined at 1, 3, 6 months, 1 year, 18 months, and 2 years in a 2-year postoperative period during which an ECG showed no arrhythmias. There were no readmissions to the hospital due to cardiac complaints, and no other adverse events occurred. Discussion The LVD is a rare congenital left ventricle malformation. It is described as a bulging structure in the left ventricle containing all three layers of the cardiac wall, including the endocardium, myocardium, and pericardium, and exhibits synergistic function with the left ventricular contraction. This diverticulum is connected to the ventricular wall by a narrow neck ~1 cm2,7. A meta-analysis study found 453 cases of LVD between the first description in 1816 and January 2012. There have only been a few reported cases of LVD since O'Bryan8 first identified it as a rare congenital heart defect in 1838, and the majority of them are in neonates and children9. The estimated incidence of LVD is 0.4%, or three in 750 autopsies of congenital heart defects2. Although the exact etiopathogenesis of the LVD is unclear, it is currently thought to occur as a consequence of impaired endocardial tube development during the fourth week of embryologic growth10. Some authors categorize LVD as either muscular or fibrous. Others classified it into two types based on the diverticulum's anatomical location: apical, which is usually associated with other congenital cardiac anomalies, and nonapical, which is mostly isolated. The LVD is also divided into congenital and acquired3,5,11. Our patient had a congenital, fibrous, and nonapical LVD. Because it is commonly associated with other heart and thoracoabdominal abnormalities, LVD is most often detected in early childhood12,13. Cantrell syndrome is defined as a constellation of congenital malformations including LVD, congenital cardiac defects, midline congenital anomalies, substernal abnormalities, diaphragmatic defects, and incomplete formation of pericardium14. However, isolated LVD may occur in up to 30% of cases15. Although they are exceptionally rare, it is important to distinguish LVD from other left ventricular outpouchings (bulge or pseudoaneurysm) in terms of location, structure beneath the ventricle's three layers, lack of contraction, or paradoxical contraction in comparison with ventricle muscle5,13. Given the rarity of congenital LVD, its natural history has not been thoroughly studied. The majority of cases are asymptomatic and were identified incidentally during a physical assessment for other reasons, a few of which can be discovered prenatally using echocardiography15,16. A four-chamber view of the heart can be used to make a prenatal diagnosis of such ventricular defect, especially if it is large. There are few reported clinical reports enumerating the defect, so information on the natural course of ventricular diverticulum identified during fetal life is limited17. In comparison to diverticuli, fetal ventricular aneurysms detected in early pregnancy may have a poor prognosis, according to the size and advancement of the lesion18. Two out of three fetuses with left ventricular aneurysm developed hydrops and died in utero in a study of seven fetuses with ventricular diverticula or aneurysms. Three of the four cases with diverticula had significant pericardial effusion. After 8-24 months of postnatal follow-up, one baby with aneurysm and all infants with diverticula remained symptomless19. The vast majority of diverticula have very few but may be fatal complications. According to a comprehensive study evaluating the clinical sequalae of LVD, 2.9% of 453 cases had cerebral or peripheral vascular complications, 9.9% had cardiac arrhythmias, 6.8% had complications of heart failure, and 4.2% of cases had rupture of the diverticulum, with the vast majority of ruptured cases (90%) occurring in children under the age of 1815. Although there is no consensus on the optimal way to manage LVD, some scholars presume that asymptomatic LVD can be monitored without requiring immediate surgery. Notwithstanding, other scholars believe that surgical resection of all LVD is a more convenient and safe option compared with conservative management, considering the possibility of a left ventricular rupture and other devastating complications, including systemic thromboembolism, or compromised ventricular function, and tachyarrhythmias10,20-22. A case series included 12 neonates with LVD, who were managed conservatively, noticed that ten patients had at least one adverse consequence, including two cases of spontaneous diverticulum rupture23. Here, we report a case of a patient with isolated congenital LVD who presented with an unusual and enigmatic clinical manifestation as a severe, intractable, and unexplained anemia. The patient also experienced shock with respiratory distress. After a thorough investigatory process, he was found to have a complicated LVD by rupture with a resultant hemopericardium that explained the underlaying mechanism of the patient's anemia. The patient successfully underwent subsequent surgical resection of the LVD with an unremarkable postoperative period. Conclusion LVD is a rare type of congenital cardiac outpouchings that's often incidentally detected. Although it's rarely symptomatic, LVD may present with an unusual and peculiar manifestation such as unexplained anemia, as in our case. Most cases of LVD have a few or no complications. However, some can result in irreversible and/or lethal consequences, including thromboembolism, arrhythmia, heart failure, or even rupture of the diverticulum. Accordingly, our experience, in this case, affirms the significance of elective surgical resection of all identified LVD, even if they are asymptomatic. Ethical approval Our institution has exempted this study from ethical review. Consent Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Sources of funding None. Authors' contribution O.N.S.: writing the manuscript. O.N.S., M.M.M.A., M.A.A., M.A.S., N.H., I.S.: Imaging description. O.N.S., N.H., S.A., and M.A.: reviewing and editing the manuscript. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) None. Guarantor Oadi N. Shrateh. Provenance and peer review Not commissioned, externally peer-reviewed. Mutaz M.M. Abusamra, Majdi A. Abudaoud, Moayad A. Srour, Nizar Hijjeh, Nidal Haymouni, Iyad Sbeitan, Samer Abdelraziq, Mohammed Abutaqa are co-authors. Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article. Published online 9 March 2023 References 1 Walton-Shirley M Smith SM Talley JD . Left ventricular diverticulum: case report and review of the literature. Cathet Cardiovasc Diagn 1992;26 :31-33.1499060 2 Makkuni P Kotler MN Figueredo VM . Diverticular and aneurysmal structures of the left ventricle in adults: report of a case within the context of a literature review. Tex Heart Inst J 2010;37 :699.21224951 3 Pedraza-Jimenez R Alanis-Naranjo JM Morelos-Guzman M . Diverticulo ventricular congenito izquierdo aislado en adulto: un hallazgo inusual en infarto de miocardio asociado a cocaina. Cardiovasc Metab Sci 2021;32 :105-109. 4 Hamaoka K Onaka M Tanaka T . Congenital ventricular aneurysm and diverticulum in children. Pediatr Cardiol 1987;8 :169-175.3124083 5 Halpern L Garabedian C Worrall NK . Congenital ventricular diverticulum or aneurysm: a difficult diagnosis to make. 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World J Nucl Med World J Nucl Med 10.1055/s-00052852 World Journal of Nuclear Medicine 1450-1147 1607-3312 Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 10.1055/s-0042-1759615 WJNM-22-9-0001 Case Report Hurthle Cell Thyroid Carcinoma with Liver and Paraaortic Abdominal Nodal Metastasis: Progression on Sorafenib Therapy after Initial Disease Stabilization Loharkar Sarvesh 12 Basu Sandip 12 1 Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Parel, Mumbai, Maharashtra, India 2 Homi Bhabha National Institute, Mumbai, Maharashtra, India Address for correspondence Sandip Basu, MBBS, DRM, DNB, MNAMS Radiation Medicine Centre (BARC), Tata Memorial Hospital AnnexeJerbai Wadia Road, Parel, Mumbai, 400012, [email protected] 20 12 2022 3 2023 1 12 2022 22 1 7074 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hurthle cell thyroid carcinoma (HCTC) demonstrates inferior prognosis compared with other types of differentiated thyroid cancer (DTC), along with radioiodine refractoriness and relatively poor 131 I concentrating ability. We herein report a case of a middle-aged lady presenting with neck swelling for years, who on pre-surgery work-up was diagnosed to harbor metastatic nodal and lung lesions. Post-thyroidectomy and neck dissection, she was diagnosed with HCTC. Post-surgery, none of the lesions concentrated radioactive-iodine (RAI) sufficiently but showed FDG avid lesions as mediastinal nodes, lung nodules, solitary lytic sternal lesions, and unusual bilateral paraaortic abdominal nodes. She was put on tyrosine kinase inhibitor (sorafenib) and showed disease stabilization for the initial 3 years, but multiple toxicity symptoms while on sorafenib therapy that needed multiple dose adjustments. Over the period of the subsequent year, she developed significant disease progression with liver involvement. She was shifted to lenvatinib, which she tolerated well. The functional imaging profile with unusual metastatic sites, the aggressive clinical presentation and disease course of RAI refractory HCTC over 4 years on tyrosine kinase inhibitor therapy, and the role of molecular FDG-PET/CT imaging in disease monitoring and clinical management of such case is presented. Keywords Hurthle cell thyroid carcinoma 18 F-FDG-PET/CT tyrosine kinase inhibitors para-arotic lymphadenopathy sorafenib lenvatinib radioiodine-refractory pmcIntroduction HCTC, earlier designated as a rare subtype of follicular thyroid carcinoma (FTC), is now classified it as a distinct tumor type by the 2017 WHO classification owing to significant histopathological and molecular differences with FTC. It is estimated to comprise 3 to 7% of DTCs. 1 The histopathological examination of HCTC shows the predominance of the characteristic oncocytic cells. Multiple large series have proven its adverse prognosis compared with other forms of DTCs, especially papillary thyroid cancer, and more recurrences and poorer survival rates than pure FTC population. The lesser fraction of these tumors (estimated at 10% of HCTC metastases) concentrates RAI. Compared with FTCs these commonly involve regional lymph nodes while also showing a greater propensity for distant metastases. 2 Thus, HCTC patients may present with symptomatic metastases and adequate preoperative staging using a cross-sectional imaging (CT scan) is often advocated. After surgery, RAI ablation therapy is considered next-line management and in metastatic disease, it has shown improved survival rates in RAI concentrating tumors. For RAI refractory thyroid cancer, especially in grossly metastatic and symptomatic cases, the tyrosine kinase inhibitors (TKIs) form a mainstay of treatment, including HCTCs. TKIs stabilize the disease and prolong PFS; however, bear multiple toxic effects and have limited long-term follow-up data at present. 3 Herein, we present a patient of HCTC with RAI-refractory features and FDG-avid distance metastases. Unusual paraortic nodal and liver metastases and progression after initial 3 years of disease stabilization on TKI therapy (sorafenib) are other findings noteworthy in the case. Case Report A 56-years-old female patient presented with a large neck mass that gradually increased in size over the 8 years. The USG-guided FNAC from thyroid tissue turned out to be of Bethesda category IV. She underwent a staging CT scan that revealed a large heterogeneously enhancing lesion in the left lobe of thyroid, multiple metastatic pulmonary nodules, and metastatic mediastinal nodes were also noted. She underwent total thyroidectomy, bilateral central compartment, and selective neck dissection along with mediastinoscopy, the histopathology was suggestive of Hurthle cell variant of differentiated thyroid cancer (HCTC), with gross extrathyroidal extension and metastasis to left sided neck nodes. A biopsy from the largest right sided lung nodule turned out as metastatic thyroid carcinoma with Hurthle cell change. She underwent an RAI scan ( Fig. 1A ) that showed low-grade uptake in the chest region slightly above background only followed by high-dose RAI therapy with 181 mCi dose. The post-therapy scan also showed very low-grade uptake in the chest region; a non-contrast-enhanced 18 F-FDG-PET/CT ( Figs. 1B, D ) revealed FDG avid bilateral lung nodules, mediastinal nodal mass, and bilateral abdominal soft tissue lesions and solitary lytic bone lesion in the sternum. Initially, these abdominal masses were suspected of bilateral adrenal metastases but contrast-enhanced CT undertaken later confirmed these to be para-aortic nodal masses ( Fig. 1C, D ). The repeat whole body scan using 131 I at 6 months following 131 I treatment demonstrated no iodine avid focus in the whole body survey, with stimulated serum Tg level over 300 ng/mL. Fig. 1 ( A ) Baseline radioiodine planar gamma camera scan showing diffuse low-grade uptake in chest region. ( B ) 18 F-FDG PET/CT (MIP image) post-thyroidectomy showing metabolically active multiple mediastinal nodal masses, lung nodules, and bilateral abdominal soft tissue density masses, which on ( C ) shows contrast-enhanced CT scan labeled as paraaortic nodal masses ( dotted arrow ) adjacent to adrenal glands ( yellow solid arrow ). Considering her symptomatic status for breathing difficulties and RAI-refractory status she was started on tablet Sorafenib 400 mg twice daily, the dose reduced within a month of treatment initiation in view of grade 3 hand-foot syndrome (HFS) and diarrhea, to 200 mg twice daily for 6 months and subsequently gradually escalated to 400 mg twice daily in next 6 months. Post-1-year response evaluation PET/CT showed stable disease and a 50% decrease in her symptoms and she continued sorafenib for further 2 years with no significant toxicity and progression ( Fig. 2 ). The 3 year treatment response evaluation 18 F-FDG-PET/CT showed a new right-sided tiny cervical lesion, some increase in FDG uptake, size, and number of pulmonary nodules, mediastinal nodes, sternal lesion, though some decrease in FDG uptake of para-aortic nodes was noted. Considering the COVID-19 pandemic and patient-related logistic issues, multidisciplinary team decided to continue the same regimen of TKI. Again, she developed grade-2 HFS, hypertension, and low platelet counts, for which a lower dose regimen was titrated. The following response evaluation 18 F-FDG-PET/CT demonstrated disease progression with new FDG-avid liver lesion and increase in the FDG uptake, size, and number of other lesions (lung nodules, mediastinal and abdominal nodes, lytic sternal lesion) ( Figs. 2 and 3 ). The serum thyroglobulin (Tg) value (with suppressed TSH) on all occasions were more than 300 ng/mL. Additionally, the patient complained of pyrexia of unknown origin for 1 month for which all serological, microbiological workup and 18 F-FDG PET/CT did not reveal any obvious cause and was suspected as disease-related fever. Meanwhile, she underwent next-generation sequencing (NGS) for RET, NTRK, ALK, BRAF, etc, for any actionable mutations, but revealed only positive Tier III (variant of unknown significance) missense mutation in exon 3 of the HRAS gene. She was switched over to tablet lenvatinib 18 mg, which she is tolerating well at present and recorded a reduction in episodes of fever spikes also. Fig. 2 Serial 18 F-FDG PET/CT MIP images showing initial stabilization of lesions for 3 years up to 2021, which progressed further in 2022 when there was increase in the size and metabolism of mediastinal and abdominal nodal masses and newly seen liver lesion. Fig. 3 18 F-FDG-PET/CT fused transaxial images (scan done in 2021 on left and in 2022 on right side) showing increase in size and FDG uptake of ( A ) left-sided cervical level III node, ( B ) lytic sternal lesion and mediastinal nodal mass, ( C ) multiple lung nodules in bilateral lungs, and ( D ) bilateral para-aortic nodal masses with newly seen liver lesion. Discussion Long-standing palpable neck mass is the most common presentation for HCTCs followed by pressure symptoms such as dyspnea, both of them were the only symptoms present in our case. Residual tumors after surgery and the presence of distant metastases are considered important prognostic factors. Among distant metastases, the lung is most commonly reported followed by bone and mediastinum. 4 Similar was followed in our case but the liver and abdominal nodal metastases are rare. Only a few such reports exist in the literature: (i) Meyer et al 5 reported pelvic nodal mass in insular carcinoma, while (ii) anaplastic transformation of papillary thyroid cancer in form of mesenteric mass was reported by Hosoda et al 6 ; but our case showed the unique observation of bilateral paraaortic nodal metastases in HCTC. As noted in this case, lack of adequate RAI concentration, a common observation in HCTCs precludes the use of powerful RAI therapy. 18 F-FDG-PET/CT has proven its added role over RAI scan and CECT in assessing metastatic disease, especially in cases with low RAI concentration. Furthermore, such as other tumors, high-grade 18 F-FDG uptake is considered an indicator of poor prognosis. Similar was noted in our case as she showed almost no RAI concentration and high FDG concentration in metastatic lesions eventually progressed despite all standard of care. It is imperative that all cases of metastatic HCTC or with high-serum thyroglobulin level, irrespective of RAI concentration status at baseline be evaluated using 18 F-FDG-PET/CT. 7 In radioiodine refractory thyroid carcinoma, systemic therapy with TKIs has currently evolved as the treatment of choice. Though improved survival has been documented both in retrospective and prospective data, adverse effects are a major concern with their use. Even our case showed multiple symptoms such as HFS, diarrhea, thrombocytopenia, and hypertension with sorafenib but almost all were manageable with dose modifications. Our patient showed an initial response (disease stabilization) for 3 years on sorafenib but progressed subsequently. Also reported initial flare phenomenon and rapid progression after discontinuing TKIs. 8 Many groups such as Aydemirli et al have highlighted the utility of genomic sequencing and using targeted treatments too in HCTC. 9 This was followed in our case but remained unsuccessful due to lack of targetable mutation. Conclusion HCTCs are aggressive and can be commonly observed as RAI refractory and metastatic. 18 F-FDG PET/CT is a promising imaging modality for staging, disease burden assessment, and also for treatment assessment, especially in systemic metastatic disease. TKI though currently considered a mainstay in metastatic and symptomatic RAI-refractory thyroid cancer patients, should be used cautiously considering their multiple toxicities and monitored for long-term disease control. Authors' Contributions Conflict of Interest None declared. Dr Sarvesh Loharkar and Dr Sandip Basu have given substantial contributions to the conception or the design of the manuscript. All authors have participated to drafting the manuscript and revised it critically. All authors read and approved the final version of the manuscript. References 1 Goffredo P Roman S A Sosa J A Hurthle cell carcinoma: a population-level analysis of 3311 patients Cancer 2013 119 03 504 511 22893587 2 Bhattacharyya N Survival and prognosis in Hurthle cell carcinoma of the thyroid gland Arch Otolaryngol Head Neck Surg 2003 129 02 207 210 12578450 3 Liu J W Chen C Loh E W Tyrosine kinase inhibitors for advanced or metastatic thyroid cancer: a meta-analysis of randomized controlled trials Curr Med Res Opin 2018 34 05 795 803 28812918 4 Besic N Schwarzbartl-Pevec A Vidergar-Kralj B Crnic T Gazic B Marolt Music M Treatment and outcome of 32 patients with distant metastases of Hurthle cell thyroid carcinoma: a single-institution experience BMC Cancer 2016 16 162 26921186 5 Meyer-Rochow G Y McMullen T P Gill A J Sywak M S Robinson B G Intra-abdominal insular thyroid carcinoma metastasis Thyroid 2009 19 05 527 530 19415999 6 Hosoda K Kusama K Yanagisawa N Anaplastic transformation of thyroid cancer in mesentery metastases presenting as intestinal perforation: a case report Surg Case Rep 2020 6 01 194 32748087 7 Pryma D A Schoder H Gonen M Robbins R J Larson S M Yeung H W Diagnostic accuracy and prognostic value of 18F-FDG PET in Hurthle cell thyroid cancer patients J Nucl Med 2006 47 08 1260 1266 16883003 8 Yamazaki H Sugino K Matsuzu K Rapid disease progression after discontinuation of lenvatinib in thyroid cancer Medicine (Baltimore) 2020 99 11 e19408 32176066 9 Aydemirli M D Corver W Beuk R Targeted treatment options of recurrent radioactive iodine refractory Hurthle cell cancer Cancers (Basel) 2019 11 08 1185 31443247 |
World J Nucl Med World J Nucl Med 10.1055/s-00052852 World Journal of Nuclear Medicine 1450-1147 1607-3312 Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 10.1055/s-0042-1757281 WJNM-22-2-0005 Case Report Is Further Evaluation of Areas with Faint MDP Uptake Needed in Individuals with Oligo-Metastatic Prostatic Adenocarcinoma? Sharma Anshul 1 Dwivedi Ankur 2 1 Department of Nuclear Medicine, Homi Bhabha Cancer Hospital and Research Centre, Punjab, India 2 Department of Radiodiagnosis, Homi Bhabha Cancer Hospital and Research Centre, Punjab, India Address for correspondence Anshul Sharma, MD Department of Nuclear Medicine, Homi Bhabha Cancer Hospital and Research Centre (TMC)Punjab, [email protected] 28 10 2022 3 2023 1 10 2022 22 1 4042 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A 42-year-old male patient with high-risk prostate adenocarcinoma underwent baseline 99m Tc-methylene diphosphonate skeletal scintigraphy, which revealed two skeletal metastases and an area of faint radiotracer uptake in the left femoral shaft. In view of oligo-metastatic nature of the disease in the bone scan and the young age of the patient, he was a candidate for metastases-directed treatment. Single photon emission computed tomography (SPECT)/CT was performed to further characterize this lesion. It was revealed to be a small soft tissue density lesion within the fatty bone marrow density, suggesting bone marrow involvement. A more sensitive evaluation of such areas with faint radiotracer uptake may be needed in high-risk prostate cancer patients where access to advanced modalities is limited. Their significance will also need reassessment as their detection will improve with technological advancements. Keywords high-risk prostate cancer 99m Tc-MDP skeletal scintigraphy bone marrow metastasis oligometastatic disease pmcIntroduction Prostatic adenocarcinoma is the second commonest cancer in men. 1 Survival in these patients is a function of metastatic burden, with patients diagnosed at an earlier stage showing longer survival. 2 Optimum treatment and prognostication are dependent on accurate staging. This is especially important in the case of oligo-metastatic disease where more aggressive options are available. 3 4 To this end, the European Association of Urology (EAU) recommends metastatic screening in high-risk patients with localized/locally-advanced disease, 5 which includes cross-sectional imaging and bone scan. Though recent studies have proven prostate specific membrane antigen-positron emission tomography (PSMA-PET/CT) to be superior to a bone scan, particularly in the detection of marrow metastases 6 ; its higher cost and lower availability are significant limitations. This is especially true in low-income countries. Still, a bone scan is not entirely helpless in case of marrow lesions as some reactive uptake is expected in the surrounding regions. With the advancements in image processing, camera technology, and machine learning, such areas with low-intensity uptake will be picked up at a higher rate. The present case is one example of the importance of such low-intensity uptake where access to more advanced modalities was limited. Case A 42-year-old male patient with recently diagnosed prostate adenocarcinoma was referred to the department of Nuclear Medicine for baseline 99m Tc-methylene diphosphonate skeletal scintigraphy ( 99m Tc-MDP). Gleason score was (5 + 4) and serum PSA was 102 ng/mL. The patient was found to have locally advanced disease in magnetic resonance imaging (MRI). Planar 99m Tc-MDP scintigraphy revealed intense radiotracer uptake in the C6-7 vertebral region and the sacrum, which was indicative of osteoblastic skeletal metastases. Thus, the patient was categorized as having oligo-metastatic disease and a candidate for metastases-directed therapy. In addition to these findings, an area of faint radiotracer was noted in the mid-shaft region of the left femur ( Figs. 1A , B and enhancement with gamma correction C , D ) . Due to the oligo-metastatic nature of the disease, the reporting nuclear medicine physician decided to confirm his suspicion of suspected bone marrow involvement. However, the patient could not undergo a repeat MRI (of the thigh) or 68 GaPSMA PET/CT due to financial reasons. Therefore, regional single photon emission computed tomography (SPECT)/CT of the thigh was acquired, which confirmed increased radiotracer uptake in the left mid-femoral region ( Fig. 1E ). A small soft tissue density lesion within the bone marrow was noted in the corresponding CT images ( Fig. 1F ). This lesion was surrounded by the fatty density. The two bony lesions and one marrow lesion, along with the young age of the patient, allowed the patient to avail metastases-directed therapy to improve his survival and prognosis. Fig. 1 Planar whole body ( A [anterior]), ( B [posterior]); regional spot (window adjusted; C [anterior], D [posterior]); SPECT/CT ( E ) and CT ( F ) images in a 42-year-old male patient with proven prostatic adenocarcinoma, PSA of 102 ng/mL and Gleason score of (5 + 4). Planar images showed an area of faint radiotracer uptake in the left mid-femoral shaft ( A , C arrows ) and soft tissue density lesion in the corresponding region in SPECT/CT ( E , F arrows ). Discussion The European Association of Urology recommends metastatic screening with cross-sectional imaging and skeletal scintigraphy in only those patients, who present with high-risk localized/locally advanced prostatic adenocarcinoma. 5 Increasingly 68 Ga-PSMA (prostate-specific membrane antigen) PET (positron emission tomography)/CT has been filling in the role of cross-sectional imaging. 7 Recent studies have shown it to be comparable to skeletal scintigraphy in the detection of skeletal metastases 6 and superior to the latter in the detection of marrow and osteolytic lesions. 8 With increasing importance being given to the diagnosis and aggressive treatment of oligo-metastatic prostatic cancer, correct identification of all metastatic sites has become important and PSMA PET/CT has become the preferred modality. 3 Despite the fact that the best possible modality should be used to correctly identify all lesions before opting for aggressive treatment of oligometastatic disease, the limited availability and higher cost of PSMA PET/CT means that many centers continue to use the combination of regional cross-sectional imaging and skeletal scintigraphy for baseline staging. Therefore, in this limited scenario, as seen in the presented case, we may need to attach greater significance to the areas of faint radiotracer uptake in baseline skeletal scintigraphy. While marrow lesions by themselves do not show increased uptake on the bone scan, there are reactive changes in the surrounding bone, which may be picked up. In our opinion, with the advancements in image post-processing, camera technology, and machine learning, such areas with low-intensity uptake are expected to further increase in number. Even a simple act of changing the gamma, as seen in Fig. 1C , D can help us to better delineate this lesion. 9 The issue of false positives can be addressed with the judicious use of SPECT/CT while taking note of the impact on patient management. Judicious use of SPECT/CT incorporates disease stage, risk classification, and serum PSA, which can aid calculation of pre-test probability of finding distant metastases and consequently a need for such sensitive analysis. The drawback of this approach in the discussed case was the likelihood of missing other lesions, but the decision to offer aggressive treatment was influenced by the age of the patient, the locally advanced but operable primary disease, and restricted access to advanced diagnostic modalities. Finally, we must emphasize that we are not recommending this approach to replace the need for the best available modality, that is, PSMA-PET/CT or MRI. Instead, we are trying to show that with technical improvements, we will be able to see a higher number of such lesions and therefore we will need to address the significance we assign to them. Future studies are needed to address these questions. Conclusion In patients undergoing a bone scan, areas with low avidity should be carefully examined in the context of their likely impact on patient management. With the advancements in image processing, camera technology, and machine learning, such areas with very low-intensity uptake will be picked up at a higher rate and therefore their significance and drawbacks will need to be reassessed, especially in the context of restricted availability of other advanced modalities. Informed Consent Conflict of Interest None declared. Permission was taken from the patient before submitting this case study. References 1 Rawla P Epidemiology of prostate cancer World J Oncol 2019 10 02 63 89 31068988 2 Cancer of the Prostate - Cancer Stat Facts [Internet]SEER. [cited 2022 Feb]. Assessed August 18, 2022, at: 3 Broughman J R Fleming C W Mian O Y Stephans K L Tendulkar R D Management of oligometastatic prostate cancer Appl Radiat Oncol 2020 9 03 6 10 33134438 4 Tosoian J J Gorin M A Ross A E Pienta K J Tran P T Schaeffer E M Oligometastatic prostate cancer: definitions, clinical outcomes, and treatment considerations Nat Rev Urol 2017 14 01 15 25 27725639 5 Professionals S-O EAU Guidelines: Prostate Cancer [Internet]Uroweb. [cited 2022 Feb]. Assessed August 18, 2022, at: 6 Raju S Sharma A Patel C Is there a utility of adding skeletal imaging to 68-Ga-prostate-specific membrane antigen-PET/computed tomography in initial staging of patients with high-risk prostate cancer? Nucl Med Commun 2020 41 11 1183 1188 32796451 7 Corfield J Perera M Bolton D Lawrentschuk N 68 Ga-prostate specific membrane antigen (PSMA) positron emission tomography (PET) for primary staging of high-risk prostate cancer: a systematic review World J Urol 2018 36 04 519 527 29344682 8 Lengana T Lawal I O Boshomane T G 68 Ga-PSMA PET/CT replacing bone scan in the initial staging of skeletal metastasis in prostate cancer: a fait accompli? Clin Genitourin Cancer 2018 16 05 392 401 30120038 9 Sharma A Pandey A K Khichi D Kumar R Methylene diphosphonate bone scan scintigraphic image enhancement using gamma correction and optimizing the value of gamma Indian J Nucl Med 2020 35 01 21 27 31949365 |
World J Nucl Med World J Nucl Med 10.1055/s-00052852 World Journal of Nuclear Medicine 1450-1147 1607-3312 Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 10.1055/s-0042-1757288 WJNM-22-5-0008 Case Report Metastatic Hepatocellular Carcinoma Masquerading as an Expansile Osteolytic Lesion in Scapula: A Rare Case of Isolated Appendicular Skeletal Metastatic Involvement of Hepatocellular Carcinoma at Initial Presentation John Arun Ravi 1 Dwivedi Surjeet 2 Varghese Jeenu 3 Walia Gurpreet Kaur 3 1 Department of Nuclear Medicine, Command Hospital Air Force, Bengaluru, Karnataka, India 2 Department of Surgical Oncology, Command Hospital Air Force, Bengaluru, Karnataka, India 3 Department of Pathology, Command Hospital Air Force, Bengaluru, Karnataka, India Address for correspondence Arun Ravi John, MBBS, DNB Department of Nuclear Medicine, Command Hospital Air ForceBengaluru, 560007, [email protected] 31 10 2022 3 2023 1 10 2022 22 1 5558 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hepatocellular carcinoma (HCC) is known to be the most common primary tumor of the liver and is also the fifth most common cancer in the world. Chronic hepatitis B and C along with type 2 diabetes mellitus and alcoholic liver disease are quite well-known risk factors for HCC, and it is uncommon in the noncirrhotic liver. HCC favors spreading as multifocal intrahepatic lesions and potential vascular invasion, and extrahepatic spread is uncommon. Skeletal metastasis from HCC occurs infrequently compared to other cancers and is common in the axial skeleton. Metastatic involvement of the appendicular skeleton is a rare entity, and the initial presentation of HCC as metastatic involvement of the appendicular skeleton is even rarer. We report a case of HCC with incidentally detected cirrhosis and chronic hepatitis B infection presenting with pain in the left shoulder. Keywords appendicular skeletal metastasis chronic Hepatitis B FDG PET-CT hepatocellular carcinoma triple phase CECT pmcIntroduction Liver cancer is an increasingly significant contributor to the global cancer burden. Hepatocellular carcinoma being the principal histologic type of liver malignancy accounts for a large majority of the disease burden. The age-adjusted incidence rate of hepatocellular carcinoma (HCC) in India for men ranges from 0.7 to 7.5 and for women 0.2 to 2.2 per 100,000 of the population per year. 1 The most common risk factors for HCC worldwide include cirrhosis of the liver, HBV infection, HCV infection, alcohol consumption, and aflatoxin exposure. In addition to the above, non-alcoholic fatty liver disease (NAFLD) and diabetes mellitus are also being increasingly recognized as risk factors in the Indian population. 1 HCC generally tends to spread as multifocal intrahepatic lesions, with an increase in size and potential vascular invasion. 2 Extrahepatic metastases of HCC are known to be relatively rare at the time of initial diagnosis. 3 The most frequent site of extrahepatic metastasis are the lungs, followed by lymph nodes, bones, and adrenal gland. 4 5 The most common location of bone metastasis is the axial skeleton with the most frequently involved sites being the lumbosacral vertebrae, followed by thoracic vertebrae and cervical vertebrae. 6 We present a rather unusual case wherein an unsuspected case of HCC with incidentally detected cirrhosis and chronic hepatitis B infection initially presented with shoulder pain and was found to have an expansile lytic lesion in the scapula on further imaging. Case Presentation A 72-year-old male patient with no known comorbidities presented with a history of progressive pain in his right shoulder of 2 months duration. Radiography of the right shoulder revealed an ill-defined osteolytic lesion epicentered in the glenoid process of the right scapula. The lesion showed a poor zone of transition with chondroid matrix and no evidence of periosteal reaction. A differential diagnosis of plasmacytoma, chondrosarcoma, and metastasis was provided. A subsequent magnetic resonance imaging (MRI) scan revealed a well-defined lobulated expansile osteolytic lesion measuring 8 AP x 6 TR x 8 CC cm epicentered in the neck of the right scapula. The lesion was involving the inferolateral aspect of the spine of the scapula, upper one-third of the medial border including the infra-glenoid tubercle and glenoid process, relatively sparing the supraglenoid tubercle. The right coracoid and acromion process were spared by the lesion. T2 hyperintensity was noted in the anterosuperior aspect of the head of the right humerus; however, no obvious infiltration of the above lesion was noted. There was an associated large soft tissue component within the lesion, which appeared isointense on T1-weighted images and intermediate to high-signal intensity in T2 and proton density fat suppressed (PDFS) sequences. The lesion showed restriction of diffusion, and in the post-contrast study, there was a relatively homogenous enhancement. Based on the above findings, the differential diagnoses were metastasis, plasmacytoma, chondrosarcoma (mesenchymal variant), and telangiectatic osteosarcoma. In view of the MRI findings and a higher suspicion of metastasis, the patient was further subjected to PET-CT using 18 F-fluorodeoxyglucose (FDG). The PET-CT scan also revealed a metabolically active expansile lytic lesion with a soft tissue component in the right scapula. In addition, another FDG avid hypodense lesion was detected in segment VII of the liver ( Fig. 1 ). In view of the above, two differential diagnoses were provided, firstly osteosarcoma or chondrosarcoma with liver metastasis and secondly a hepatocellular carcinoma with bone metastasis in the scapula. A biopsy ( Fig. 2 ) was obtained from the osteolytic lesion in the right scapula that revealed a malignant tumor arranged in diffuse sheets and a vague acinar and trabecular pattern. The tumor cells were large, polygonal with abundant eosinophilic granular cytoplasm and prominent nucleoli with brisk mitoses one to two per high power field, and many cells also showed intranuclear inclusions. The tumor was seen infiltrating into the surrounding skeletal muscle. Areas of hemorrhage and necrosis were also noted. Immunohistochemistry revealed Hep Par 1 positivity. CK 7, CK 20, S 100, CD 68, and CD 99 were found to be negative. In view of the above, the lesion was diagnosed to be a metastatic deposit from hepatocellular carcinoma. In view of the PET-CT and biopsy findings, the patient was further subjected to a triple-phase CT with an ill-defined nonhomogenous hypodense lesion in segment VII of the liver, which was heterogeneously hyper-enhancing in the late arterial phase and showed a rapid washout in the portal venous phase. The lesion was hypoenhancing in the delayed phase. An enhancing capsule was also noted in the portal venous phase. Signs of portal hypertension were also noted in the form of a prominent portal vein (14 mm) with a few lienorenal, gastroesophageal junction, and perisplenic collaterals. On USG correlation, the liver also appeared enlarged, hyperechoic, and cirrhotic. The patient was a social drinker who used to consume less than one drink daily. Clinical examination revealed no stigmata of chronic liver disease. His laboratory workup revealed normal bilirubin levels with elevated aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) (80 U/L), alanine aminotransferase/serum glutamate pyruvate transaminase (ALT/SGPT) (176 U/L), and normal alkaline phosphatase levels (140 U/L). The patient was found to be HBsAg positive with elevated HBV DNA levels. Alpha feto protein (AFP) was elevated (33.85 ng/mL). Other tumor markers including carbohydrate antigen 19.9 (CA19.9) and carcinoembryonic antigen (CEA) were negative. The patient was finally diagnosed with a case of metastatic hepatocellular carcinoma in a background of cirrhosis and chronic hepatitis B with a good performance score (Eastern Cooperative Oncology Group Performance Status-1 [ECOG PS-1]). The patient was treated with radiotherapy to the bone lesion, followed by bisphosphonates, sorafenib, and entecavir. Fig. 1 ( A ) A maximum intensity projection image of an 18 F-FDG PET-CT study revealing increased tracer uptake in the right shoulder region (black arrow) along with a focal lesion in the liver ( black arrow ). ( B ) A coronal-fused 18 F-FDG PET-CT image showing a metabolically active expansile lytic lesion involving the right scapula. ( C ) An axial-fused PET-CT image showing a metabolically active expansile lytic lesion involving the right scapula. ( D ) An axial-fused PET-CT image showing a metabolically active hypodense lesion involving segment VII of the liver. Fig. 2 ( A ) (hematoxylin and eosin, 40 x ) Image showing tumor arranged in thick trabeculae and sheets. ( B ) (hematoxylin and eosin, 400 x ) Polygonal-shaped tumor cells with moderate eosinophilic cytoplasm, pleomorphic nuclei, and prominent macro nucleoli. ( C ) Immunohistochemistry image (400 x ) showing strong granular cytoplasmic Hep Par 1 positivity in the tumor cells. Discussion It is a recognized fact that almost all kinds of cancers can spread to the bones; however, the most commonly encountered primary cancers that metastasize to the bones are from the prostate, breasts, kidneys, lungs, and thyroid. In contrast to intrahepatic metastasis, extrahepatic metastasis of HCC is relatively uncommon with a reported incidence of about 15 to 17%. 7 Risk factors for metastatic involvement especially extrahepatic metastasis include advanced tumors, index tumor size greater than 5 cm, multifocal lesions or infiltrative lesions, and vascular invasion. 8 9 The most frequent location for metastatic HCC is the lungs, followed by the lymph nodes and bones. Although bone metastases from HCC or initial presentation with bone metastasis are not very uncommon, the presentation of HCC as an isolated appendicular skeletal metastasis is extremely rare 2 with very few cases reported in the literature. The typical location of bone metastases is in the axial skeleton with the most common site being the vertebral column. Metastasis to the bones occurs through portal vein-vertebral vein plexuses, thus explaining the more frequent craniospinal and pelvic bone metastases. 10 Skeletal metastasis appears to be relatively unique among various hematogenous metastases of HCC because it can occur before clinical manifestations of chronic liver disease and is usually symptomatic, as in our present case. The pulmonary and systemic circulation is thought to be the main route of metastasis to the skeletal system. Bone metastases from HCC usually present as expansile osteolytic lesions with soft tissue components. This phenomenon can be explained by the premetastatic niche theory where tumor-released soluble factors enter the bloodstream and induce microenvironment changes including matrix remodeling, which support subsequent cancer cell engraftment. The likely molecules involved in this mechanism include CXCL12, interleukin (IL-6), annexin II, and vascular endothelial growth factor (VEGF), as they contribute to both hematopoietic stem cell homing to the bone marrow and cancer cell infiltration and survival. In this way, cancer cells occupy the original hematopoietic stem cell niche and further colonize the site. The replacement of hematopoietic stem cells with cancer cells in the niche promotes metastatic tumor progression. 11 The histopathological diagnosis of metastatic HCC is made from cellular morphology and supporting immunohistochemistry. Although these neoplasms correspond to poorly differentiated carcinomas, they are focally trabecular with an acinar pattern. The nuclei have nuclear inclusions in the cytoplasm, and a pigment compatible with brown bile is observed. With these microscopic findings and positivity for Hep Par-1, the histopathological diagnosis of HCC is made. Hep Par-1 (human hepatocyte paraffin-1) is an antigen that reflects hepatocyte differentiation in approximately 90% of HCCs and is considered positive, the staining must be granular and cytoplasmic. 12 Conclusion We report a rare presentation of HCC in a background of cirrhosis caused by chronic hepatitis B infection wherein appendicular skeletal metastasis involving the scapula causing shoulder pain was the initial presentation even before any feature of chronic liver disease could be detected. Through this case report and literature review, we seek to focus on and identify the uncommon osseous metastatic sites of HCC and reappraise the role of imaging including triple-phase CT and PET-CT in detecting such rare extrahepatic sites of metastasis initially at the time of diagnosis to further guide the treating clinicians in clinching the diagnosis. Acknowledgments We acknowledge the Departments of Radiology, Pathology, and Malignant Diseases Treatment Centre, Command Hospital Air Force, Bengaluru, Karnataka, India, for their help in preparing this manuscript. Authors' Contributions Conflict of Interest None declared. Arun Ravi John contributed to manuscript preparation, Surjeet Dwivedi contributed to reviewing of manuscript, Jeenu Varghese contributed to manuscript preparation and histopathological image preparation, and Gurpreet Kaur Walia contributed to reviewing the manuscript including histopathology report. The manuscript has been read and approved by all the authors, the requirements for authorship as stated earlier in this document have been met, and each author believes that the manuscript represents honest work. References 1 (The INASL Task-Force on Hepatocellular Carcinoma) Kumar A Acharya S K Singh S P The Indian national association for study of the liver (INASL) consensus on prevention, diagnosis and management of hepatocellular carcinoma in India: the puri recommendations J Clin Exp Hepatol 2014 4 03 S3 S26 25755608 2 Lasagna A Cuzzocrea F Maccario G Mahagna A Sacchi P U. Mondelli M Bone metastases and hepatocellular carcinoma: some food for thought Future Oncol 2021 17 29 3777 3780 34313153 3 Bae S Y Kim H J Oh H H Multiple bone metastases as the first manifestation of hepatocellular carcinoma in patient with noncirrhotic liver Case Rep Oncol Med 2015 2015 512849 26635983 4 Katyal S Oliver J H III Peterson M S Ferris J V Carr B S Baron R L Extrahepatic metastases of hepatocellular carcinoma Radiology 2000 216 03 698 703 10966697 5 Becker A K Tso D K Harris A C Malfair D Chang S D Extrahepatic metastases of hepatocellular carcinoma: a spectrum of imaging findings Can Assoc Radiol J 2014 65 01 60 66 24239313 6 Nottebaert M von Hochstetter A R Exner G U Schreiber A Metastatic carcinoma of the spine. a study of 92 cases Int Orthop 1987 11 04 345 348 3440653 7 Takahashi K Putchakayala K G Safwan M Kim D Y Extrahepatic metastasis of hepatocellular carcinoma to the paravertebral muscle: a case report World J Hepatol 2017 9 22 973 978 28839518 8 Monteserin L Mesa A Fernandez-Garcia M S Gadanon-Garcia A Rodriguez M Varela M Bone metastases as initial presentation of hepatocellular carcinoma World J Hepatol 2017 9 29 1158 1165 29085559 9 Yokoo T Patel A D Lev-Cohain N Singal A G Yopp A C Pedrosa I Extrahepatic metastasis risk of hepatocellular carcinoma based on a-fetoprotein and tumor staging parameters at cross-sectional imaging Cancer Manag Res 2017 9 503 511 29081671 10 Ayan A K Seven B Orsal E Demirci E Evaluation of bone metastasis as the first presentation of hepatocellular carcinoma using 18-fluorodeoxyglucose positron emission tomography-computed tomography Indian J Nucl Med 2013 28 03 171 172 24250027 11 Zhuyan J Chen M Zhu T Critical steps to tumor metastasis: alterations of tumor microenvironment and extracellular matrix in the formation of pre-metastatic and metastatic niche Cell Biosci 2020 10 89 32742634 12 Ruiz-Morales J M Dorantes-Heredia R Chable-Montero F Vazquez-Manjarrez S Mendez-Sanchez N Motola-Kuba D Bone metastases as the initial presentation of hepatocellular carcinoma. Two case reports and a literature review Ann Hepatol 2014 13 06 838 842 25332273 |
World J Nucl Med World J Nucl Med 10.1055/s-00052852 World Journal of Nuclear Medicine 1450-1147 1607-3312 Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 10.1055/s-0042-1750401 11721 Case Report Synchronous Bilateral Multifocal Warthin's Tumor Mimicking Primary Malignancy on 18 F-FDG Whole Body PET/CT in a Case of Metastatic Cervical Lymph Nodes from Unknown Primary Malignancy Basheer Shyma 1 Satish Alamelu 1 Vallonthaiel Archana George 1 Sarma Manjit 1 1 Department of Nuclear Medicine & Molecular Imaging, Amrita Institute of Medical Sciences, Kochi, Kerala, India Address for correspondence Shyma Basheer, MD Department of Nuclear Medicine & Molecular Imaging, Amrita Institute of Medical Sciences (AIMS)Ponekkara, Kochi, 682041, [email protected] 09 9 2022 3 2023 1 9 2022 22 1 2225 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Warthin's tumor is a benign and frequently encountered salivary gland neoplasm. Bilaterality and multifocality are rare in Warthin's tumor. Synchronous cervical lymph nodal metastasis with unknown primary in a case of Warthin's tumor can raise a suspicion of primary malignancy of the parotid gland. We present a case of bilateral multifocal Warthin's tumor with synchronous squamous cell carcinoma metastasis to the cervical lymph node. 18 F-fluorodeoxyglucose whole body positron emission tomography/computed tomography imaging showed hypermetabolic bilateral multifocal parotid lesions and metastatic cervical lymph node with unknown primary malignancy. Keywords Warthin's tumor metastatic cervical lymph node with unknown origin 18 F-FDG PET/CT Funding None. pmcKey Messages Warthin's tumor shows intense FDG uptake on 18 F-FDG whole body PET/CT and can be multifocal and bilateral. Coexistent cervical lymph nodal metastasis should be investigated thoroughly for aerodigestive malignancies and can also present as malignancy of unknown origin. Introduction Warthin's tumor is the second most common parotid gland tumor after pleomorphic adenoma. Although unifocal Warthin's tumor is common, multifocality and bilaterality are rare. Squamous cell carcinoma cervical lymph nodal metastasis in a patient with Warthin's tumor can raise a suspicion for primary malignancy in the parotid gland. This is a unique case report of metastatic cervical lymph node and 18 F-fluorodeoxyglucose ( 18 F-FDG) whole body positron emission tomography/computed tomography (PET/CT) showed metabolically active bilateral parotid gland lesions and a right cervical lymph node with no possible primary site of malignancy. Case History A 70-year-old male, a chronic smoker, presented with complaints of swelling of the cheek for the last 6 years. Ultrasound showed hyperechoic well-defined lesions with similar echotexture and vascularity seen in both lobes of parotid gland and enlarged lymph nodes in bilateral level II nodal stations. Ultrasound-guided fine-needle aspiration (FNA) from bilateral parotid gland was suggestive of Warthin's tumor. However, right cervical lymph node showed well-differentiated squamous cell carcinoma. Indirect laryngoscopy and upper gastrointestinal endoscopy were normal. 18 F-FDG whole body PET/CT imaging ( Fig. 1 ) showed metabolically active multiple metabolically active lesions in the bilateral parotid gland and metabolically active bilateral level II lymph nodes. No other possible site of primary malignancy was seen. Minimal tracer uptake was seen in the right lobe of thyroid gland and diffuse uptake in stomach walls, with no corresponding lesions on CT images. No suspicious nodules or significant mediastinal lymph nodes were seen in lung parenchyma on inspiratory lung CT images. Patient subsequently underwent repeat biopsy from the right parotid lesion having the maximum standardized uptake value (14.6). The repeat biopsy( Fig. 2 ) was also suggestive of Warthin's tumor. The patient subsequently underwent radiotherapy for cervical lymph nodal metastasis. Fig. 1 Axial section on computed tomography (CT), positron emission tomography (PET), and fused PET-CT showing intense fluorodeoxyglucose (FDG) uptake in the parotid region corresponding to multiple enhancing nodules in both lobes of parotid gland on axial CT ( above ) and FDG avid right level II lymph node ( below ). 18 F-FDG PET maximal intensity projection image shows multiple foci of increased abnormal uptake of FDG seen bilaterally in the neck. Minimal tracer uptake in the right lobe of thyroid gland and diffuse uptake in stomach walls are also seen, with no corresponding lesions on CT images. Physiological tracer uptake is seen in the brain, kidneys, and urinary bladder. Fig. 2 Micrograph of cytology from bilateral parotid swellings showing monolayer cells of oncocytic epithelium with round nucleus and inconspicuous nucleoli with background of lymphocytes and proteinaceous material which is suggestive of Warthin's tumor ( above and below left ). Specimen from right cervical lymph node ( above right ) shows atypical squamous cells with orangeophilic cytoplasm round to angular hyperchromatic nucleus suggestive of squamous cell carcinoma ( below right ). Discussion Warthin's tumor is benign neoplasm of the major salivary glands. It is the second most common parotid gland tumor after pleomorphic adenoma accounting for approximately 15% of all parotid epithelial tumors. 1 Unilateral metabolically active lesion of parotid gland on PET/CT imaging can occur from a large spectrum of benign or malignant, such as adenoma, Warthin's tumor, oncocytic neoplasm, lymphoma, and primary or secondary malignancy of the gland. Bilateral multifocal Warthin's tumor is less common. 2 Metastatic cervical lymph node with unknown primary malignancy is a metastatic disease in the lymph nodes of the neck without any evidence of a primary tumor after appropriate investigation. In patient initially presenting with cervical lymph nodal metastasis, 2 to 10% patients account for the unknown primary malignancy after a routine clinical workup. 3 The pathophysiology that allows a primary tumor to remain hidden after the development of metastases is yet not known. Various theories include regression or involution of the primary and development of the malignancy of unknown origin in stem cells with capacity to differentiate into multiple cell lines to the liver, muscles, skin, or even the cells of the gastrointestinal tract. Proper recognition of clinical presentation, CT or magnetic resonance imaging and PET/CT, may guide to the diagnosis of primary malignancy. Direct laryngoscopy and careful endoscopy of the nasopharynx and biopsy of the suspicious areas are also warranted. Ultrasound-guided FNA or histologic biopsy from the initial occult site should be obtained for initial tissue diagnosis. Histologic biopsy should be obtained, preferably from the occult primary site. Tonsillectomy and lingual tonsillectomy may also be indicated to identify a possible primary site. Immunohistochemistry is used to define the cell differentiation and identify the primary tumor in approximately 25 to 30% cases. Squamous cell carcinoma is the most common cytopathological finding in metastatic cervical lymph nodes. Salivary gland cancers, well-differentiated thyroid malignancies, and nonsquamous malignancies originating from skin are the other common histologies in the neck. Metastasis to cervical lymph nodes is developed more often from the upper aerodigestive tract primary malignancies. 3 4 As Warthin's tumor is more commonly seen in smokers, it may be mistaken for malignancy when associated aerodigestive tract cancer is present. The clinicians should be aware of the possibility of Warthin's tumor masquerading as malignancy in these patients. Further evaluation by FNA, ultrasound-guided FNA, or technetium-99 salivary scintigraphy can confirm the diagnosis and, in such cases, surgery can be avoided for the benign lesion. 5 The studies on FDG PET/CT in salivary gland tumors are limited. Although Warthin's tumor is of benign nature, it has been shown to concentrate FDG with uptake similar to the malignant salivary gland tumors, thereby reducing the sensitivity of PET to discriminate benign and malignant tumors. 6 This case after PET/CT imaging, a repeat FNA from the most metabolically active lesion in the parotid gland, was suggestive of Warthin's tumor. Squamous cell carcinoma occurring de novo from the parotid gland is a rare cancer comprising of less than 1% of all salivary gland neoplasms. 7 But in this case of cervical nodal biopsy showing squamous cell carcinoma, hypermetabolic activity in Warthins's tumor with no lesions elsewhere can be mistaken for primary malignancy and should be excluded. In conclusion, the coexistence of bilateral multifocal Warthin's tumor with cervical lymph nodal metastasis can misguide the clinician to suspect primary malignancy from the salivary gland. In a smoker, where incidence of Warthin's tumor and aerodigestive malignancies are more often, the synchronous presentation of bilateral multifocal Warthin's tumor and metastasis of unknown origin can exist together and complete clinical examination and investigations should be performed to identify the primary site of malignancy. Conflict of Interest None declared. References 1 Chulam T C Noronha Francisco A L Goncalves Filho J Pinto Alves C A Kowalski L P Warthin's tumour of the parotid gland: our experience Acta Otorhinolaryngol Ital 2013 33 06 393 397 24376295 2 Nguyen V X Nguyen B D Ram P C Bilateral and multifocal Warthin's tumors of parotid glands: PET/CT imaging Clin Nucl Med 2012 37 02 175 177 22228345 3 Karapolat I Kumanlioglu K Impact of FDG-PET/CT for the detection of unknown primary tumours in patients with cervical lymph node metastases Mol Imaging Radionucl Ther 2012 21 02 63 68 23487242 4 Qaseem A Usman N Jayaraj J S Janapala R N Kashif T Cancer of unknown primary: a review on clinical guidelines in the development and targeted management of patients with the unknown primary site Cureus 2019 11 09 e5552 10.7759/cureus.5552 31695975 5 Rassekh C H Cost J L Hogg J P Hurst M K Marano G D Ducatman B S Positron emission tomography in Warthin's tumor mimicking malignancy impacts the evaluation of head and neck patients Am J Otolaryngol 2015 36 02 259 263 25523505 6 Dua S G Purandare N C Shah S Rangarajan V Bilateral synchronous and multifocal Warthin's tumor mimicking metastases from lung cancer: A rare cause of false positive flourodeoxy glucose positron emission tomography/computed tomography Indian J Nucl Med 2012 27 02 139 140 23723595 7 Akhtar K Ray P S Sherwani R Siddiqui S Primary squamous cell carcinoma of the parotid gland: a rare entity BMJ Case Rep 2013 2013 bcr2013009467 10.1136/bcr-2013-009467 |
World J Nucl Med World J Nucl Med 10.1055/s-00052852 World Journal of Nuclear Medicine 1450-1147 1607-3312 Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 10.1055/s-0042-1757287 WJNM-22-5-0004 Case Report 18 F-FDG PET Brain Findings in a Case of Idiopathic Benign Rolandic Epilepsy of Childhood Vankadari Kousik 1 Kumar Rajender 2 Mittal Bhagwant Rai 2 Sankhyan Naveen 3 1 Department of Nuclear Medicine, Yashoda Hospital, Secunderabad, Telangana, India 2 Department of Nuclear Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, India 3 Department of Pediatric Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, India Address for correspondence Bhagwant Rai Mittal, MD Department of Nuclear Medicine and PET/CT, Postgraduate Institute of Medical Education and ResearchChandigarh, [email protected] 28 10 2022 3 2023 1 10 2022 22 1 5254 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Idiopathic benign rolandic epilepsy, also known as benign childhood epilepsy with centrotemporal spikes (BCECTS), is one of the commonly seen electroclinical epilepsy syndromes of childhood with a generally favorable long-term prognosis. We describe a 5-year-old female child who presented with recurrent focal seizures involving right side of face since the age of 6 months. She had no perinatal or postnatal insults, had normal development, and her neurological examination was unremarkable. Electroencephalogram showed rolandic spikes, suggesting BCETCS. Her seizures remained refractory to two appropriately dosed antiepileptic drugs. Magnetic resonance imaging of the brain did not reveal any structural lesion. Interictal fluorodeoxyglucose 18 F-positron emission tomography brain showed hypometabolism in the left lower rolandic region. Keywords 18 F-FDG BCECTS rolandic epilepsy centrotemporal spikes childhood epilepsy Funding None. pmcIntroduction Benign rolandic epilepsy (BRE) is a commonly seen focal childhood epileptic disorder of probable genetic origin in view of family history of either febrile seizures or epilepsy in approximately 25% of pediatric children affected with this disorder. 1 It is named as rolandic epilepsy as seizures originate from cortex surrounding the central sulcus of brain that is called as centrotemporal area or rolandic area. Case Report A 5-year-old female child presented with recurrent drug-resistant focal motor seizures involving right side of face with preserved awareness since age of 6 months. Initially she had 1 to 2 episodes/year that gradually increased to 4 to 5 episodes per week. Most of the seizures were early in the morning and were preceded by an aura of altered taste sensation and a feeling of the face being move to one side followed by clonic activity of right side of the face and drooling of saliva from the angle of the mouth associated with slurring of speech. The overt seizure episode lasts for approximately 1 minute with preserved consciousness. She was born at term and had a smooth perinatal transition. She was developmentally normal and did not suffer any postnatal brain insult. Her social behavior was age-appropriate and continued to show a good scholastic performance. Her intelligence quotient (by the Malin's Intelligence Scale for Indian Children) was 105 that was normal. Sleep electroencephalogram (EEG) revealed frequent bilateral (right > left) frontotemporal interictal epileptiform discharges with tangential dipoles (rolandic spikes) of benign childhood epilepsy with centrotemporal spikes (BCECTS). Since her seizures were refractory to maximal doses of two appropriate antiepileptic drugs (oxcarbazepine and levetiracetam), she was evaluated with radiological and function brain imaging to rule out a structural lesion amenable to surgical intervention. Fluorodeoxyglucose 18 F ( 18 F-FDG, 148 MBq) was intravenously administered to the patient. Thereafter child was allowed to rest in quiet, dim-lit room for 45 minute and static brain acquisition was done under positron emission tomography (PET) scanner. Transaxial, sagittal, and coronal interictal 18 F-FDG PET brain images done 72 hours following last seizure episode reveal hypometabolism in the left lower rolandic motor cortex representing facial region ( Fig. 1A - C ) with no structural abnormality in the corresponding region on transaxial magnetic resonance imaging (MRI) brain image ( Fig. 1D ). In addition to visual analysis, semiquantitative analysis was done by drawing an equal sized region of interest (ROI) on bilateral lower Rolandic cortices and maximum standardized uptake value (SUVmax) measured showed significant difference between right and left lower rolandic cortices with right to left asymmetry index measuring 18%. Fig. 1 Interictal fluorodeoxyglucose 18 F-positron emission tomography images showing hypometabolism in the left lower rolandic motor cortex representing facial region ( A - C ; arrows ) with no significant morphological abnormality in the corresponding magnetic resonance imaging brain image ( D ; arrow ). Discussion BRE is a common focal idiopathic childhood epilepsy syndromes characterized by abnormal neuronal activity in the rolandic region of brain. 2 It is also referred to as benign childhood epilepsy with centrotemporal spikes (BCECTS) due to hallmark presence of rolandic spikes in centrotemporal region on EEG. 3 Seizures can start anywhere between 1 and 14 years (peak between 7 and 10 years), with an atypical presentation (earlier age of onset) seen in the index case. 4 The exact cause for epileptogenesis remains unknown, but literature suggests genetic disturbances in neurotransmission and delayed cortical maturation in the affected regions. 5 6 Most of the children usually have seizures in first few hours of sleep, but minority present with early morning seizures in wakefulness as seen in this case. Seizures associated with this syndrome are usually unilateral and manifestations include orofacial clonic movements, numbness/stiffness/tingling sensation of the face and throat, pharyngolaryngeal involvement, leading to guttural sounds, hypersalivation, and speech arrest or slurring of speech. 7 Occasionally facial numbness/twitching associated with the seizure disorder can spread to ipsilateral arm, ipsilateral leg, and to contralateral side, leading to full-blown generalized seizure. Most of the children affected with this disorder become seizure-free by the age of 15 to 16 years. 8 Even though children affected with this syndrome over the years have shown excellent long-term neurocognitive outcome, recent emerging studies report higher risk of developing subtle learning deficits and behavioral disorders. 9 10 Rarely BRE can be early manifestation of other epileptic syndromes. For lateralizing the seizure onset zone through interictal PET, concordance of visual asymmetric hypometabolism with electroclinical features plays important role. However, accuracy of visual interpretation can be further improved by deriving age-matched normalized Z score using statistical parametric mapping (SPM) and semiquantitative assessment of asymmetric hypometabolism using ROI-based SUVmax. Although SPM is a commonly used technique for the lateralization of seizures in adult patients, it is rarely applied to childhood studies due to the lack of validation of the spatial normalization procedure in children of different age groups. 11 Few studies reported in literature mentioned semiquantitative assessment of hypometabolism using SUVmax for seizure analysis and asymmetry index greater than 15% between affected and contralateral sides was considered to be significant. 12 To the best of our knowledge, this is the first case reporting interictal 18 F-FDG PET findings in BRE. The findings in our case suggest 18 F-FDG PET can be used as a complementary imaging modality to EEG, clinical features, and MRI brain to diagnose and confirm BRE in cases of discordant electroclinical and structural imaging results. Informed Consent Conflict of Interest None declared. Appropriate patient consent is obtained for publishing the images and clinical information regarding the patient without revealing patient identity. References 1 Vears D F Tsai M H Sadleir L G Clinical genetic studies in benign childhood epilepsy with centrotemporal spikes Epilepsia 2012 53 02 319 324 22220564 2 Loiseau P Beaussart M The seizures of benign childhood epilepsy with Rolandic paroxysmal discharges Epilepsia 1973 14 04 381 389 4521094 3 Gregory D L Wong P K Topographical analysis of the centrotemporal discharges in benign rolandic epilepsy of childhood Epilepsia 1984 25 06 705 711 6510378 4 Kramer U Nevo Y Neufeld M Y Fatal A Leitner Y Harel S Epidemiology of epilepsy in childhood: a cohort of 440 consecutive patients Pediatr Neurol 1998 18 01 46 50 9492091 5 Xiong W Zhou D Progress in unraveling the genetic etiology of rolandic epilepsy Seizure 2017 47 99 104 28351718 6 Siripornpanich V Visudtibhan A Kotchabhakdi N Chutabhakdikul N Delayed cortical maturation at the centrotemporal brain regions in patients with benign childhood epilepsy with centrotemporal spikes (BCECTS) Epilepsy Res 2019 154 124 131 31129368 7 Beaussart M Benign epilepsy of children with Rolandic (centro-temporal) paroxysmal foci. A clinical entity. Study of 221 cases Epilepsia 1972 13 06 795 811 4509173 8 Loiseau P Duche B Cordova S Dartigues J F Cohadon S Prognosis of benign childhood epilepsy with centrotemporal spikes: a follow-up study of 168 patients Epilepsia 1988 29 03 229 235 3371279 9 Matos M Bara T Clark S Zeigelboim B S Marques J M Liberalesso P BN Benign rolandic epilepsy of childhood and central auditory processing disorder: a noncasual neurophysiological association Epilepsy Behav 2018 89 55 58 30384100 10 Karalok Z S Ozturk Z Gunes A Cortical thinning in benign epilepsy with centrotemporal spikes (BECTS) with or without attention-deficit/hyperactivity (ADHD) J Clin Neurosci 2019 68 123 127 31326285 11 Delbeke D Lawrence S K Abou-Khalil B W Blumenkopf B Kessler R M Postsurgical outcome of patients with uncontrolled complex partial seizures and temporal lobe hypometabolism on 18FDG-positron emission tomography Invest Radiol 1996 31 05 261 266 8724123 12 Muzik O Chugani D C Juhasz C Shen C Chugani H T Statistical parametric mapping: assessment of application in children Neuroimage 2000 12 05 538 549 11034861 |
World J Nucl Med World J Nucl Med 10.1055/s-00052852 World Journal of Nuclear Medicine 1450-1147 1607-3312 Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 10.1055/s-0042-1757285 WJNM-22-3-0006 Case Report The Outcome of Progressive Uterine Sarcoma with Potential Bone Involvement Al-Ibraheem Akram 1 Abdlkadir Ahmed S. 1 1 Department of Nuclear Medicine, King Hussein Cancer Center, Amman, Jordan Address for correspondence Akram Al-Ibraheem, MD Department of Nuclear Medicine, King Hussein Cancer CenterQueen Rania Street, Al Jubeiha, Amman, Jordan [email protected] 28 10 2022 3 2023 1 10 2022 22 1 4851 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. High-grade endometrial stromal sarcoma (HGESS) is a very rare kind of uterine tumor that accounts for less than 2% of all uterine cancers. The usual sites of metastasis are the abdomen and lung, while bone metastasis is very rare, with only a few cases reported till now. We present a case of HGESS with bone metastasis and review the literature. Keywords endometrial stromal sarcoma uterine sarcoma bone metastasis nuclear medicine pmcIntroduction Endometrial stromal sarcoma (ESS) is a rare uterine malignancy that arises from endometrial stromal cells. It accounts for less than 2% of all uterine malignancies. 1 It is, nevertheless, the second most frequent kind of uterine interstitial tumor. 1 2 Based on clinical, pathological features, and molecular genetic studies of ESS, the World Health Organization classified ESS into three types as follows: (1) low-grade ESS (LGESS), (2) high-grade ESS (HGESS), and (3) undifferentiated uterine sarcoma (UUS). 3 The limited clinical data on the symptoms of HGESS and the lack of biomarkers contribute to the delayed diagnosis. Moreover, the overlapping symptoms of uterine fibroids may often lead to misdiagnosis. Case Report In January 2021, a 58-year-old female patient presented to the gynecologic department with postmenopausal vaginal bleeding for 9 days. Pelvic magnetic resonance imaging (MRI) showed multiple uterine fibroids with cystic degeneration and heterogeneous enhancement distorting the uterine cavity. She was misdiagnosed and treated as a case of uterine fibroids. Symptoms began to progress over time, and on further gynecologic consultation, it was decided that the patient should have surgical intervention. She underwent a total abdominal hysterectomy with bilateral salpingooophorectomy in April 2021. Pathology showed HGESS, limited to the uterine wall with no involvement of the parametrium or cervix. The tumor was pathologically staged as pT1aNx. In July 2021, the patient started complaining of pain on the right side of the pelvis along with symptoms of abdominal pain and distention that began to progress over time, affecting hip joint movement and causing severe anorexia for the patient. Whole-body computed tomography (CT) scan showed large multiloculated fluid collections within the pelvis with enhancing walls, raising the possibility of abscess. This was associated with evidence of bone and abdominal lymph node metastasis ( Fig. 1 ). In August 2021, the patient was referred to the nuclear medicine department to further assess the bone pain. A whole-body bone scan showed evidence of an active bone lesion within the right ischium, suspicious of a metastatic bone lesion ( Fig. 2 ). Chemoradiotherapy was planned but delayed due to rapid disease progression. Unfortunately, the patient developed obstructive uropathy, mandating admission to the intensive care unit. A follow-up CT scan at that time interval revealed that the previous multiloculated mass had grown in size, exerting pressure on adjacent structures and causing obstructive uropathy ( Fig. 3A, B ). The right ischial osteolytic lesion had also become more prominent since the previous scan ( Fig. 3C ). Subsequently, the patient developed urosepsis with multiple organ failure and succumbed 4 months after surgery. Fig. 1 CT scan of the pelvis showing destructive lesion involving the right ischial tuberosity representing A metastatic deposits. CT, computed tomography. Fig. 2 Whole body bone scan ( A ) anterior and posterior views. ( B ) Anterior spot view of pelvis. ( C ) Posterior spot view of pelvis. Images revealed active bone lesion within the right ischium highly suspicious for metastatic bone lesion. Fig. 3 Abdominopelvic CT scan without contrast. ( A ) Axial view with soft tissue window, ( B ) sagittal view with soft tissue window, ( C ) axial view with bone window. All images demonstrate progression in size of the previously known pelvic mass lesion exerting pressure on urinary bladder and causing obstructive uropathy ( arrow heads ) along with more prominent osteolytic destructive right ischial bone lesion ( arrows ). CT, computed tomography. Discussion The incidence of high-grade stromal sarcoma is extremely rare. The average age group of the presentation is between 40 and 55 years of age. 2 So, having this type of tumor at the age of 58 years with progressive involvement of the bone is a very rare clinical presentation of that tumor that has been reported only in a few cases before. HGESS symptoms are frequently atypical, leading to misinterpretation and misdiagnosis, as it can overlap and mimic uterine fibroid symptoms. Vaginal bleeding, abdominal pain, abdominal distention, and pelvic mass are the most common clinical features associated with HGESS. Initially, the patient was misdiagnosed as having a uterine fibroid, but surgery confirmed the diagnosis with HGESS. Three months after surgery, the patient had right hip discomfort which was attributed to a prolapsed intervertebral disc rather than taken in the context of the underlying disease. This was actually due to bone metastasis from her malignant uterine tumor which was later confirmed by a whole-body bone scan. The usual surgical intervention performed for such cases consists of total abdominal hysterectomy with bilateral salpingooophorectomy and systemic pelvic and para-aortic lymph node dissection which should not be performed in cases of unremarkable lymph node involvement. 4 At first, the patient was pathologically staged as T1Nx, but with distant metastasis discovered later on, the International Federation of Gynecology and Obstetrics (FIGO) staging for this tumor is IVB. 2 Because HGESS has a high risk of recurrence and metastasis, postoperative adjuvant therapy is mandatory. Pelvic external radiotherapy has been widely used as an adjuvant therapy to help reduce the risk of pelvic recurrence after surgery. It has not been shown to improve overall survival which may be because of extra-pelvic metastases. 4 Pautier et al concluded that the API regimen (doxorubicin, ifosfamide, and cisplatin) of chemotherapy resulted in a statistical increase of 3-year disease-free survival rate in 81 patients with uterine sarcoma who received four cycles of chemotherapy of the API regimen followed by radiotherapy as compared with a control group of 18 patients managed only with postsurgical radiotherapy. 5 Gemcitabine combined with docetaxel or doxorubicin/ifosfamide, doxorubicin/dacarbazine, gemcitabine/dacarbazine, and gemcitabine/vinorelbine are the most commonly used adjuvant chemotherapy for HGESS. 6 Targeted treatment for ESS is still controversial due to a lack of a large-scale clinical database. Pazopanib is a multitarget tyrosine kinase inhibitor used in systemic therapy of sarcoma. 6 On the other hand, apatinib is an oral vascular endothelial growth factor (VEGFR-2) intracellular inhibitor that inhibits neovascularization in tumor cells via highly selective competition for the VEGFR-2 ATP binding site in affected cells. It carries potential antitumor effects and has been shown to be a promising therapeutic option in the near future. 7 Metastatic bone lesions in HGESS cases are extremely rare and have been reported in very few cases till now. 8 9 Metastasis to bone can definitely increase the rates of mortality and morbidity and needs careful evaluation and follow-up. Huang et al reported a rare case of ESS with bone metastasis that also involved the right pelvic bone, skull, and multiple vertebrae and was treated with chemoradiation after surgery followed by L3 laminectomy and subtotal tumor resection in the vertebrae. It was concluded that any musculoskeletal complaints should raise the suspicion of tumor involvement to avoid misinterpretation and achieve the best outcome. 9 Date et al reported a case of metastatic ESS to the skull 1 year after tumor diagnosis and concluded that close follow-up and observation for patients with metastatic ESS should be performed periodically to assess this aggressive tumor and achieve the best outcome possible. 8 Conclusion Patients with ESS are prone to misdiagnosis due to tumor rarity and a lack of typical and specific clinical features. Even though bone metastasis is rare, it is important to note that any musculoskeletal complaints should raise the suspicion of tumor involvement to avoid misinterpretation and achieve the best possible outcome. Acknowledgment We would like to acknowledge all supportive staff of Nuclear Medicine Department of King Hussein Cancer Center, Amman, Jordan. Informed Consent Ethical Approval Author's Contributions Conflict of Interest None declared. Consent to participant and consent for publication were obtained properly. All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the Helsinki declaration as revised in 2013 and its later amendments or comparable ethical standards. All authors have contributed in writing the manuscript and collecting the required materials. References 1 Ali R H Rouzbahman M Endometrial stromal tumours revisited: an update based on the 2014 WHO classification J Clin Pathol 2015 68 05 325 332 25595274 2 Prat J Mbatani N Uterine sarcomas Int J Gynaecol Obstet 2015 131 04 S105 S110 26433666 3 Carcangiu M L Kurman R J Carcangiu M L Herrington C S WHO Classification of Tumours of Female Reproductive Organs Lyon, France International Agency for Research on Cancer 2014 4 Denschlag D Thiel F C Ackermann S Sarcoma of the uterus. Guideline of the DGGG (S2k-Level, AWMF registry No. 015/074, August 2015)[published correction appears in Geburtshilfe Frauenheilkd. 2015 Oct;75(10):e3]Geburtshilfe Frauenheilkd 2015 75 10 1028 1042 26640293 5 Pautier P Floquet A Gladieff L A randomized clinical trial of adjuvant chemotherapy with doxorubicin, ifosfamide, and cisplatin followed by radiotherapy versus radiotherapy alone in patients with localized uterine sarcomas (SARCGYN study). A study of the French Sarcoma Group Ann Oncol 2013 24 04 1099 1104 23139262 6 National Comprehensive Cancer Network Koh W J Greer B E Abu-Rustum N R Uterine sarcoma, version 1.2016: featured updates to the NCCN guidelines J Natl Compr Canc Netw 2015 13 11 1321 1331 26553763 7 Li F Liao Z Zhang C Apatinib as targeted therapy for sarcoma Oncotarget 2018 9 36 24548 24560 29849960 8 Date I Yagyu Y Bukeo T Endometrial stromal sarcoma metastatic to the skull-case report Neurol Med Chir (Tokyo) 1986 26 07 571 574 2430224 9 Huang M I Debernardo R L Rodgers M Hart D J Endometrial stromal sarcoma metastasis to the lumbar spine and sphenoid bone Rare Tumors 2011 3 03 e27 22066034 |
World J Nucl Med World J Nucl Med 10.1055/s-00052852 World Journal of Nuclear Medicine 1450-1147 1607-3312 Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 10.1055/s-0042-1758804 WJNM-22-7-0006 Case Report Tenosynovial Giant Cell Tumor of Foot in a Patient with Radioiodine-Refractory Thyroid Cancer: Imaging Findings on FDG-PET/CT, MRI, and Radioiodine Scan Loharkar Sarvesh 12 Basu Sandip 12 1 Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Parel, Mumbai, Maharashtra, India 2 Homi Bhabha National Institute, Mumbai, Maharashtra, India Address for correspondence Sandip Basu, MBBS, DRM, DNB, MNAMS Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe buildingJerbai Wadia Road, Parel, Mumbai, 400012, [email protected] 20 12 2022 3 2023 1 12 2022 22 1 6366 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We herein illustrate a case of benign tenosynovial giant cell tumor, which was incidentally detected as FDG-avid lesion on PET/CT in a patient with radioiodine refractory thyroid cancer, with predominantly non-iodine concentrating disease. The lesion was followed up clinically and with local MRI annually for subsequent 3 years. The utility of hybrid PET-CT imaging, the non-iodine concentration of the tumor along with clinical knowledge, and findings on other imaging and pathological modalities in answering and diagnosing incidental benign musculoskeletal tumors in a patient with known thyroid malignancy are presented here. Keywords benign tenosynovial giant cell tumor 18 F-FDG-PET/CT benign bone tumor radioiodine refractory thyroid cancer thyroglobulin elevated negative iodine scintigraphy differentiated thyroid carcinoma pmcIntroduction Patients with radioactive-iodine refractory (RAIR) thyroid cancer and thyroglobulin elevated negative iodine scintigraphy (TENIS) are considered as therapeutic challenges and possess guarded prognosis compared to their DTC counterparts. FDG-PET/CT has become a pivotal imaging tool in these cases, its sensitivity and is positively correlated with serum thyroglobulin (Tg) levels and plays a prognostic indicator in this patient subset. 1 2 The false-positive uptake of FDG in multiple other neoplastic as well as non-neoplastic forms warrants careful interpretation, which may also be observed in benign bone neoplasms. Additionally, DTCs have been incidentally detected with other malignancies and vice versa, the most common being breast cancers. 3 These facts warrant clinical correlation and cautiousness while labeling FDG uptake as part of metastatic disease involvement in such cases. Here we discuss a case of RAIR thyroid cancer, which was imaged using an FDG-PET/CT scan and found to have FDG-avid benign tenosynovial giant cell tumor (BTSGCT) of the foot. Case Report A 50-year-old male patient, diagnosed with differentiated papillary thyroid carcinoma (classical type), with extensive capsular invasion and extra-thyroidal extension and bilateral neck lymph node, and lung metastasis (on preoperative evaluation with regional CT scan), had undergone total thyroidectomy with bilateral central compartment clearance with bilateral modified neck dissection. The strap muscles also showed metastatic deposits, and multiple resected nodes were positive for metastases and showed extra-nodal extension. His RAI scan ( Fig. 1A ) showed only a small focus of uptake in the neck, following which he received high-dose RAI therapy with the traditional protocol of TSH elevation following thyroid hormone withdrawal (the pre-treatment TSH level was 36 mIU/mL). He received a therapeutic dose of 7,326 MBq of 131 I as per the institutional protocol, and the post-RAI therapy scan ( Fig. 1B ) showed neck uptake and faint bilateral chest uptake. The TSH stimulated serum Tg was 432.21 ng/mL before therapy and he was considered for whole-body FDG-PET/CT, especially in view of that preoperatively noted lesions were not well visualized on RAI scan. FDG-PET/CT showed multiple nodular lesions in bilateral lungs, many of which showed intense FDG concentration ( Fig. 2A , left column of C and D). One FDG avid subcutaneous soft tissue lesion was noted in the right ankle region, just superior to the calcaneus measuring 3.4 x 3.0 cm with an SUVmax value of 12.07; subtle cortical erosion of the underlying calcaneus bone was also noted ( Fig. 2A , right columns of C and D). Fig. 1 1-mCi radioactive iodine planar scan ( A ) showing tracer uptake in the midline neck region (thyroid bed), and ( B ) post-radioiodine therapy scan showing focal tracer concentration in the neck, chest, and low-grade diffuse chest uptake. Fig. 2 FDG-PET/CT at baseline ( A ) and 2 years of treatment ( B ) showing FDG concentrating tiny multiple bilateral lung nodules, increased in number ( dotted arrow ). FDG avid subcutaneous soft tissue density lesion at the right ankle ( solid arrow ). On the right panel, the lung and foot lesions are demonstrated with their enlarged coronal views, at pre-treatment and at 2 years following sorafenib therapy. Of these, the left column shows CT chest images (lung window) coronal section ( C ) and ( E ); PET/CT coronal chest fused images ( D ) and ( F ). Right column CT images coronal section at foot level ( C ) and ( E ); and corresponding fused PET/CT images ( D ) and ( F ) at baseline and 2 years of treatment are also illustrated. The patient was asymptomatic except for some local swelling; on local examination, there was soft to firm swelling without skin fixity over the Achilles tendon of the right ankle, which, according to the patient, was stable over last 18 months and was non-tender. A local ultrasonographic examination done showed a heterogeneous soft tissue lesion in the subcutaneous plane superficial to the Achilles tendon in the dorsal aspect of the right ankle measuring 2.9 x 2 x 0.6 cm. The lesion was further elucidated with a local MRI done after RAI therapy ( Fig. 3 ). This revealed irregular soft tissue lesion in subcutaneous region of the posterior aspect of foot, just superior to the calcaneus, encasing the tendon Achilles without infiltration. It was seen abutting the cortex of the calcaneum with no appreciable erosion. MR characteristics of lesion were isointense on T1, intermediate on T2, and hyperintense on STIR, with minimal restricted diffusion and homogenous post-contrast enhancement. Though these MRI characteristics were not typical for metastasis, considering the diagnosis of malignancy in the patient, FNAC was planned. The FNAC showed scattered osteoclastic giant cells, numerous histiocytes, and lymphocytes and was labeled as a BGCTS. Retrospectively, post-therapy whole body RAI scans ( Fig. 1B ) also did not reveal any radioiodine concentration in this lesion. This lesion was followed up clinically and local MRI every 12 months. Fig. 3 MR image of the right foot and ankle showing ( A ) T1-weighted sagittal section image demonstrating T1 isointense soft tissue lesion in the subcutaneous region of the posterior aspect of the foot superior to the calcaneum, encasing the Achilles tendon without infiltration. ( B ) T2-weighted sagittal section image showing intermediate intensity of the lesion with no obvious erosions; ( C and D ) dynamic post (gadolinium) contrast T1-weighted images showing homogenous post-contrast enhancement in the lesion. In his further course, he developed non-radioiodine concentrating disease and elevated serum Tg with FDG concentrating multiple bilateral lung nodules and started on tyrosine kinase inhibitor (lenvatinib) therapy. At nearly 2 years down the line, follow-up FDG-PET/CT study ( Fig. 2B, E, F ) demonstrated some increase in his metabolically active lung metastatic lung lesions but almost stable metabolically active right-sided ankle lesion. Discussion BTSGCT is one of the rare benign bone tumors usually affecting adults and are limited to specific joint areas. A few case reports have reported this to be FDG avid, and FDG-PET/CT along with MRI is useful in evaluating its local extent and the response to CSF1-targeting therapies. Nervo et al recently performed an extensive study on bone disease in thyroid cancer and suggested the rare possibility of benign bone tumors in such setting and the utility of MRI, especially the DWI sequence, in their diagnosis. 4 The same is evidenced in the present case, differentiating it from the metastatic spread, and confirmed on minimally invasive FNAC technique and follow-up scans. To the best of our knowledge, this is the first such case reported in a patient having metastatic DTC. Pallas et al have reported similar such FDG avid BGCTS tumor mimicking melanoma metastases. 5 In the literature, there are descriptions of benign tumors concentrating radioiodine. This includes (1) parotid tumors such as Warthin's tumor or oncocytoma, (2) meningioma, (3) cavernous angioma, (4) cystic mesothelioma, (5) hepatic hemangioma, (6) breast fibroadenoma, (7) uterine myoma, (8) struma cordis and struma ovarii along with other types of ovarian tumors and teratoma. These findings have been related to NIS-dependent uptake or other mechanisms 6 and potentially may cause false-positive results in routine RAI scans. There are other reports of incidental findings of various types of BTSGCT showing uptake on FDG-PET/CT acquired for other indications, mostly in oncology patients. This case uniqueness was in the incidence of this benign tumor in a patient with thyroid cancer imaged and treated with radioactive iodine. Despite the known uptake of RAI in certain other benign tumors, this lesion was cold on the RAI scan and hence underscored the non-radioiodine concentrating property of BTSGCT. A confounding scenario in this patient was high serum Tg values, which could be explained by FDG-avid extensive bilateral pulmonary metastases. Conflict of Interest None declared. References 1 Ozdemir E Yildirim Poyraz N Polat S B Turkolmez S Ersoy R Cakir B Diagnostic value of 18F-FDG PET/CT in patients with TENIS syndrome: correlation with thyroglobulin levels Ann Nucl Med 2014 28 03 241 247 24379008 2 Ranade R Kand P Basu S Value of 18F-FDG PET negativity and Tg suppressibility as markers of prognosis in patients with elevated Tg and 131I-negative differentiated thyroid carcinoma (TENIS syndrome) Nucl Med Commun 2015 36 10 1014 1020 26049373 3 Murray S E Schneider D F Bauer P S Sippel R S Chen H Synchronous and antecedent nonthyroidal malignancies in patients with papillary thyroid carcinoma J Am Coll Surg 2013 216 06 1174 1180 23522438 4 Nervo A Ragni A Retta F Bone metastases from differentiated thyroid carcinoma: current knowledge and open issues J Endocrinol Invest 2021 44 03 403 419 32743746 5 Pallas A Hagge R Borys D Hunter J Intense FDG uptake in an intra-articular localized giant-cell tumor of the tendon sheath (pigmented villonodular synovitis) mimics metastatic melanoma Radiol Case Rep 2015 4 04 343 27307839 6 Oh J R Ahn B C False-positive uptake on radioiodine whole-body scintigraphy: physiologic and pathologic variants unrelated to thyroid cancer Am J Nucl Med Mol Imaging 2012 2 03 362 385 23133823 |
World J Nucl Med World J Nucl Med 10.1055/s-00052852 World Journal of Nuclear Medicine 1450-1147 1607-3312 Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 10.1055/s-0042-1757289 WJNM-22-7-0001 Case Report "Stocking Pattern Metabolic Captivity" of Legs on 18 F-FDG PET-CT in Necrotizing Fasciitis: Potential Complimentary Role in Differential Diagnosis and Assessment of Disease Extent in a Life-Threatening Condition Sonavane Sunita Nitin 12 Basu Sandip 12 1 Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital, Mumbai, Maharashtra, India 2 Homi Bhabha National Institute, Mumbai, Maharashtra, India Address for correspondence Sandip Basu, MBBS, DRM, Diplomate NB, MNAMS Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial HospitalAnnexe building, Jerbai Wadia Road, Parel, Mumbai, Maharashtra, [email protected] 28 10 2022 3 2023 1 10 2022 22 1 5962 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A rare and fatal life-threatening case of necrotizing fasciitis (initially presenting with skin-deep superficial lesions and clinical suspicion of paraneoplastic syndrome) is described, who was finally diagnosed with the help of fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) as more extensive infectious process. A 36-year-old male presented with bilaterally symmetrical cutaneous lesions involving lower limbs that rapidly progressed to ulcerative lesions and pancytopenia. In view of suspicion of paraneoplastic manifestation, the patient underwent 18 F-FDG-PET/CT to rule out any underlying malignancy. The FDG-PET/CT findings confirmed hypermetabolism circumferentially along the fasciae of bilateral lower extremities while sparing muscles and subcutaneous fat from below the knee till toe with diffused hypermetabolic marrow, and no evidence of focal disease suggesting malignancy. Biopsy turned out to be superficial necrolytic fasciitis. The patient's condition deteriorated and, 20 days following the scan, the patient succumbed secondary to severe pancytopenia and hypotension. The case raises the importance of high degree of suspicion and prompt diagnosis of this condition, where FDG-PET/CT imaging can play a valuable complimentary role. Such awareness could be lifesaving due to early optimal treatment in the disease course. Keywords FDG PET-CT necrotizing fasciitis paraneoplastic syndrome pmcIntroduction Necrotizing fasciitis (NF) is a rapidly progressing and potentially life-threatening infectious process of the fascia, perifascial planes, and can also cause a secondary involvement of the overlying and underlying skin, soft tissue, and muscle. 1 2 Polymicrobial infections can occur because of a combination of gram-negative and anaerobic involvement. 3 NF affects about 0.4 in every 100,000 people per year in the United States, while in some parts of the world, it is as common as one in every 100,000 people. 4 The present report describes the clinical presentation, molecular fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) imaging, and microbiological characteristics of this condition and discusses the determinants of mortality associated with this uncommon surgical emergency. 5 Case Report A 36-year-old nondiabetic wheelchair-bound male, with previous history of weight loss and herpes simplex virus 2 infection, presented with bilaterally symmetrical predominantly cutaneous lesions involving extensor aspects of the lower limbs which began as multiple desquamating plaques that rapidly progressed to vesicles, bullae, and ulcers, and was suspected of pyoderma gangrenosum with peripheral neuropathy and pancytopenia. The biochemical and blood work revealed normal blood glucose but presence of anemia with hemoglobin of 6.7 g/dL, platelets of 0.9 lac/mm 3 , normal serum ferritin levels 84.4 (normal 20-250 ng/mL), high aspartate aminotransferase of 185 (5-40 units per liter), and preserved renal function with serum creatinine of 0.6 mg/dL (normal 0.7-1.2 mg/dL). The patient was referred for a whole body 18 F-FDG-PET/CT to rule out underlying malignancy considering the skin lesions as suspicious paraneoplastic syndrome. A whole-body 18 F-FDG-PET/CT ( Figs. 1 and 2 ) was undertaken 60 minutes after intravenous injection of 6.5 mCi of 18 F-FDG, using a whole-body full-ring dedicated three-dimensional PET-CT scanner (Gemini TF; 250 mAs, 120 kVp, noncontrast CT scan with 2 mm slice thickness). 18 F-FDG-PET/CT revealed circumferential hypermetabolism along the fasciae of bilateral lower extremities while sparing muscles and subcutaneous fat extending from below knee level till dorsum of feet (standardized uptake value [SUV]max 4.75). Linear increased FDG uptake was noted in psoas muscles bilaterally (right > left) (SUVmax 6.15) ( Figs. 1 and 2 ). Hypermetabolism accompanied by fat stranding was noted around the site of intramedullary nail insertion in diaphysis of right femur (SUVmax 3.96). Diffuse hypermetabolic bone marrow was noted (SUVmax 5.55). Non-FDG avid minimal right-sided pleural effusion with pleural thickening and adjacent infective consolidatory changes showing mild FDG uptake (SUVmax 3.19). Rest of the whole-body survey was unremarkable and showed physiological tracer distribution. Thus, there was no definite scan evidence of any focal lesion suspicious of malignancy. A diffuse increased metabolic captivity was seen from the region of proximal leg to dorsum of feet bilaterally, suggestive of active infective process; skin biopsy was performed which revealed dermal infiltrating aggregates in skin, fascia, and subcutaneous tissue mixed with lymphocytes and abundant neutrophils, small vessel vasculitis, extensive dermal glands, and fat necrosis, favoring diagnosis of superficial NF. The patient in subsequent days developed progressive extensive skin involvement extending proximally and succumbed secondary to severe pancytopenia and hypotension 20 days thereafter, raising the importance of prompt diagnosis and treatment (i.e., surgery, antibiotics, and hyperbaric chamber) of this life-threatening infection. Fig. 1 ( A , B ) Maximum intensity projection (MIP) positron emission tomography (PET) image anterior and posterior; Computed tomography (CT), PET, and fused PET/CT axial ( C - E ), coronal ( F - H ), and sagittal ( I - K ) images showing diffusely increased metabolic captivity along the fasciae sparing muscles and subcutaneous fat from the region of proximal leg to dorsum of feet bilaterally (standardized uptake value [SUV]max: 4.75). MIP ( A , B ) images reveal linear hypermetabolism in bilateral psoas muscles (right > left) (SUVmax: 6.15). Low-grade hypermetabolism accompanied by fat stranding was noted around the site of intramedullary nail insertion in diaphysis of right femur (SUVmax: 3.96). Diffuse hypermetabolic bone marrow was noted in the axial skeleton (SUVmax: 5.55). Rest of the whole-body survey was unremarkable and showed physiological tracer distribution. Fig. 2 ( A , E ) Anterior maximum intensity projection (MIP) images. ( A - D ) Attenuation corrected (AC) fluorodeoxyglucose-positron emission tomography (FDG-PET) images; ( E - H ) nonattenuation corrected (NAC) FDG-PET images (MIP, transaxial, coronal, and sagittal slices, respectively) reveal diffusely increased metabolic captivity along the fasciae from the region of proximal leg to dorsum of feet bilaterally. Discussion Marszal and Bielecki reported NF as mixed infection of skin and subcutaneous tissue with a characteristic clinical and pathological appearance, caused by aerobic, anaerobic, and mixed bacterial flora or may be polymicrobial with wide variety of infections, making it an increasing problem in medical and surgical practice. 6 Kihiczak et al termed NF as life-threatening condition, consisting of a soft-tissue infection that is rapidly progressive, with widespread fascial necrosis. 7 Wong et al highlighted the paucity of cutaneous findings early in the course of the disease makes the diagnosis at times difficult. 5 These investigators studied 89 patients with NF, among which diagnosis was available in 13 patients, the most common cause being streptococcus, and the most common associated comorbidity was diabetes mellitus (70.8%), advanced age, and two or more associated comorbidities. Multivariate analysis showed that only a delay in surgery of more than 24 hours was correlated with increased mortality ( p < 0.05; relative risk = 9.4). 5 Case reports in the literature have illustrated necrotizing dermatitis as paraneoplastic syndrome and association with multiple malignancies like chronic lymphocytic leukemia, 8 Hodgkin's lymphoma, 9 myelodysplastic syndrome, 10 metastatic endometrial cancer, 11 rectal cancer, 12 colon cancer, 13 breast carcinoma, 14 and glucagonoma. 15 In the present case, however, we were unable to delineate any malignant focus on FDG-PET/CT. On ruling out malignancy, other conditions like immunosuppression and aplastic anemia-related association of NF is also known. Ugarte-Torres et al reported the difficult-to-treat organisms having significant implications in both clinical and public health settings. A similar case as our patient, a 37-year-old Caucasian male with immunosuppression due to aplastic anemia being treated with cyclosporine, presented to the hospital with relapsed disease, he subsequently developed overwhelming sepsis secondary to bilateral lower extremity NF. 16 The NF was caused by a multidrug-resistant strain of Aeromonas hydrophila . Despite broad-spectrum antibiotics and aggressive surgical debridement, he succumbed to this severe invasive infection. Kim et al in their reported case of eosinophilic fasciitis in a 37-year-old woman with a 3-month history of progressive stiffness involving her forearms and lower legs, highlighted the role of FDG-PET/CT images, FDG uptake was increased along the fasciae of bilateral upper and lower extremities while sparing muscles and subcutaneous fat, similar pattern as in the case presented in this report. Biopsy and histological examination confirmed diagnosis of eosinophilic fasciitis. The report stated FDG-PET/CT may be helpful in the diagnosis of eosinophilic fasciitis as it could clearly illustrate anatomical involvement of the disease. 17 Another PET tracer like 68 Ga-DOTATATE PET/CT can have diagnostic role delineating suspected glucagonoma 18 or active inflammatory processes where macrophages and leukocyte do express SSTR2 receptors. 19 With regard to considering the optimal management, Khalid et al reported necrotizing soft tissue infections being associated with considerable morbidity and mortality, and delayed recognition and treatment can have severe implications. 20 As stated previously, Kihiczak et al have reported that prompt diagnosis and treatment are essential, with surgical debridement and antibiotic therapy are the primary treatment options. 7 Marszal and Bielecki stated early and radical surgical excision of all affected tissue is the treatment of choice. 6 Adjuvant hyperbaric oxygen appeared to be important in refractory progressive bacterial gangrene. A combination of hyperbaric oxygen, surgical treatment, and antibiotics gives the lowest mortality and morbidity in gas gangrene compared with other treatment modifications. 6 Conclusion In summary, NF is a rapidly progressive and potentially lethal infectious condition, and delay in diagnosis can be life-threatening and a high index of suspicion and prompt management with aggressive early surgical debridement along with antibiotics as early as 24 hours of diagnosis are the most important treatment options, which can reduce mortality among these patients. The present case illustrates a young patient's irrecoverable, debilitating condition secondary to NF with illustration of a characteristic FDG-PET/CT finding in this condition. Conflict of Interest None declared. References 1 Kim Y H Ha J H Kim J T Kim S W Managing necrotising fasciitis to reduce mortality and increase limb salvage J Wound Care 2018 27 (Sup9a):S20 S27 2 Lange J H Cegolon L Comment on: early clinical manifestations of vibrio necrotising fasciitis Singapore Med J 2018 59 08 449 30175372 3 Erichsen Andersson A Egerod I Knudsen V E Fagerdahl A M Signs, symptoms and diagnosis of necrotizing fasciitis experienced by survivors and family: a qualitative Nordic multi-center study BMC Infect Dis 2018 18 01 429 30153808 4 Fernando S M Tran A Cheng W Necrotizing soft tissue infection: diagnostic accuracy of physical examination, imaging, and LRINEC score: a systematic review and meta-analysis Ann Surg 2019 269 01 58 65 29672405 5 Wong C H Chang H C Pasupathy S Khin L W Tan J L Low C O Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality J Bone Joint Surg Am 2003 85 08 1454 1460 12925624 6 Marszal M Bielecki K Martwiczezapalenieskory, tkankipodskornej, powieziglebokiejorazmiesni: klasyfikacja i leczenie [Necrotizing dermatitis, infections of soft tissue and deep fascia: classification and treatment] Wiad Lek 1998 51 (1-2):64 70 9608834 7 Kihiczak G G Schwartz R A Kapila R Necrotizing fasciitis: a deadly infection J Eur Acad Dermatol Venereol 2006 20 04 365 369 16643131 8 Spadaro S Berselli A Marangoni E Aeromonas sobria necrotizing fasciitis and sepsis in an immunocompromised patient: a case report and review of the literature J Med Case Reports 2014 8 315 9 Tabata M M Novoa R A Martires K J Paraneoplastic granulomatous dermatitis in a patient with Hodgkin's disease: a diagnostic pitfall BMJ Case Rep 2018 2018 bcr2018224961 10 Niscola P Tendas A Cupelli L Necrotizing fasciitis in myelodysplastic syndrome: an exceptionally rare occurrence Support Care Cancer 2013 21 02 365 366 22960853 11 Hendrickson S Bystrzonowski N Kokkinos C Butler P Necrotising fasciitis caused by metastatic endometrial cancer: a rare cause of a life-threatening condition Ann R Coll Surg Engl 2017 99 02 e72 e74 27869494 12 Liu S Y Ng S S Lee J F Multi-limb necrotizing fasciitis in a patient with rectal cancer World J Gastroenterol 2006 12 32 5256 5258 16937546 13 Sato K Yamamura H Sakamoto Y Necrotizing fasciitis of the thigh due to penetrated descending colon cancer: a case report Surg Case Rep 2018 4 01 136 30478748 14 Suresh Kumar D Viswanathan M P Navin Noushad S Necrotizing fasciitis of cancer breast: case report and literature review Indian J Gynecol Oncolog 2020 18 58 15 Makan R Van Vuuren C Necrotising migratory erythema leading to the diagnosis of a metastatic glucagonoma without diabetes. J Endocrinol Metabolism Diabetes South Africa 2020 25 03 80 81 16 Ugarte-Torres A Perry S Franko A Church D L Multidrug-resistant Aeromonas hydrophila causing fatal bilateral necrotizing fasciitis in an immunocompromised patient: a case report J Med Case Reports 2018 12 01 326 17 Kim H J Lee S W Kim G J Lee J H Usefulness of FDG PET/CT in the diagnosis of eosinophilic fasciitis Clin Nucl Med 2014 39 09 801 802 24152641 18 Mavi M E Tuncel M Treatment of glucagonoma-related necrolytic migratory erythema with peptide receptor radionuclide therapy Clin Nucl Med 2021 46 12 1002 1003 34034327 19 Hofman M S Lau W F Hicks R J Somatostatin receptor imaging with 68Ga DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in interpretation Radiographics 2015 35 02 500 516 25763733 20 Khalid M Dattani M Bowley D Necrotizing fasciitis: expect the unexpected Int J Surg Case Rep 2020 76 199 201 33039782 |
World J Nucl Med World J Nucl Med 10.1055/s-00052852 World Journal of Nuclear Medicine 1450-1147 1607-3312 Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 10.1055/s-0042-1757253 12521 Case Report Crossed Cerebellar Diaschisis in Thalamic Lymphoma on 18 F-FDG PET/CT Bhoil Amit 1 RacuAmoasii Igor 2 Vinjamuri Sobhan 1 1 Department of Nuclear Medicine, The Royal Liverpool University Hospital NHS Trust, Liverpool, United Kingdom 2 Haemato-oncology Diagnostic Service, Liverpool Clinical Laboratories, Liverpool, United Kingdom Address for correspondence Amit Bhoil, MD Department of Nuclear Medicine, The Royal Liverpool University Hospital NHS TrustLiverpool L7 8XPUnited [email protected] 09 9 2022 3 2023 1 9 2022 22 1 2932 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Primary central nervous system lymphomas (PCNSLs) are extranodal variant forms of non-Hodgkin lymphoma arising within the brain parenchyma, leptomeninges, or spinal cord. PCNSL can present with varied neurological symptoms and imaging findings, making diagnosis without biopsy difficult. PCNSLs are highly aggressive, causing rapid deterioration, but are responsive to chemotherapy and radiotherapy making early diagnosis important. Crossed cerebellar diaschisis (CCD) is mostly seen with cerebral cortex vascular insults and is rarely reported with thalamic lesions and even rarer with thalamic lymphoma. However, CCD has also been described in other brain tumors (including primary glioma), chronic subdural hematoma, congenital insults, intracranial infections, and various dementia subtypes. We present a rare case of thalamic lymphoma evaluated with positron emission tomography/computed tomography that showed hypermetabolism of thalamus and associated hypometabolism in ipsilateral cerebral cortex and contralateral cerebellum representing CCD. Keywords PCNSL thalamic lymphoma DLBCL crossed cerebellar diaschisis (CCD) PET/CT Funding None. pmcIntroduction Primary central nervous system lymphoma (PCNSL) is a rare neoplasm, accounting for 0.5 to 2% of all primary brain tumors and 1 to 3% of all non-Hodgkin lymphoma, with approximately 95% of PCNSLs being diffuse large B cell lymphomas (DLBCLs). PCNSL is a "whole-brain disease" from a pathological point of view, with involvement of the brain, eye, leptomeninges, and rarely spinal cord with subacute presentation in form of typical symptoms as cognitive decline or personality changes without evidence of systemic involvement. 1 The PCNSL is a vasocentric neoplasm with an infiltrative tumor extending beyond the primary lesion, with multifocality in more than 50% cases. Focal neurological deficits with involvement of the parenchyma or leptomeninges needing rapid imaging are seen in approximately 70% of the patients. 1 2 Case Report A 65-year-old male presented with a history of lethargy, memory loss, and hemiparesis of right lower limb. Gadolinium-enhanced T1-weighted magnetic resonance axial ( Fig. 1A ) and coronal images ( Fig. 2A ) showed enhancing mass in the left thalamus, internal capsule, and lentiform nucleus extending into cerebral peduncle. Fig. 1 ( A ) Gadolinium-enhanced T1-weighted MR axial and 18 F FDG PET and fused 18 F FDG PET/CT axial ( B, C ) showed enhancing mass in the left thalamus, internal capsule and lentiform nucleus with hypometabolism of ipsilateral parietotemporal region. Fig. 2 ( A ) Gadolinium-enhanced T1-weighted MR and 18 F FDG PET and fused 18 F FDG PET/CT ( B, C ) coronal images showed enhancing mass in the left thalamus, internal capsule and lentiform nucleus extending into cerebral peduncle with hypometabolism of contralateral cerebellar hemisphere suggestive of crossed cerebellar diaschisis (CCD). Biopsy showed diffuse proliferation of medium-to-large lymphoid cells ( Fig. 3A , hematoxylin and eosin, x100). The neoplastic cells revealed diffuse and strong expression of CD20 (B), BCL-6, BCL-2, and MUM-1 with a very high proliferation fraction demonstrated by K i 67 stain (D) and absent expression of CD3 (C) and CD10. The phenotype in combination with morphology was supportive of a diagnosis of DLBCL type of PCNSL. Fig. 3 ( A ) Biopsy showed diffuse proliferation of medium to large lymphoid cells ( A , H&E x 100).The neoplastic cells revealed diffuse and strong expression of CD20 ( B ), BCL-6, BCL-2, and MUM-1 with a very high proliferation fraction demonstrated by Ki 67 stain ( D ) and absent expression of CD3 ( C ) and CD10. 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET) and fused 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) axial ( Fig. 1B and C ) and coronal images ( Fig. 2B and C ) showed hypermetabolic left thalamic lesion with ipsilateral hypometabolism of parietotemporal region ( Fig. 1B and C ) and contralateral cerebellar hemisphere suggestive of crossed cerebellar diaschisis (CCD). The whole body 18 F-FDG PET/CT imaging showed no evidence of systemic disease. The progressive imaging showed partial response to chemotherapy in the thalamic lesion. Discussion The PCNSLs are commonly seen with a median age of 60 year in immune-competent patients and at a younger age in immune-compromised patients. 3 The site of PCNSL lesion determines the patients' clinical presentation. These could be focal neurological deficit signs, seizures, or neuropsychiatry symptoms as memory deficit, slowed thinking or confusion, with or without the symptoms of increased intracranial symptoms. PCNSL primarily starts with a diffuse pattern involving the deep hemispheric periventricular white matter, corpus callosum, and basal ganglia. The isolated thalamic lymphomas are a rarer cause of PCNSL, together involving the thalamus and basal ganglia. 4 The subcortical structures as the striatum are rich in mitochondria, vascular supply, neurotransmitter, and chemical content compared with other regions of the brain, making them vulnerable to metabolic anomalies and disease processes. 5 18 F-FDG-PET has an important role in PCNSL staging at diagnosis or in the follow-up, as it can diagnose systemic disease with higher sensitivity than conventional imaging. CCD is defined as decreased neuronal activity by focal structural lesions or disturbance remotely from the structures likely due to interruption of afferent and efferent pathways. CCD is a well-recognized phenomenon after cerebral infarction and reported contralateral to the focal supratentorial lesion likely due to disruption of the cortico-ponto-cerebellar tract. 6 The severity of CCD is an important prognostic marker for assessment of recovery and treatment response. 7 Vascular insult of the subcortical structures is rarely reported cause of CCD, as basal ganglia or thalamus is not usually connected to the cortico-ponto-cerebellar tract and the remote effect is usually not observed. Deep-seated thalamic infarcts have been reported to cause CCD due to their direct effect on cerebellar efferent pathways or indirect effect from the affected cerebral cortex. 8 Basal ganglia hematoma has been seen to cause CCD directly due to interruption of inhibitory GABAergic axons to globus pallidus and to thalamus through cerebellar efferent pathways resulting in reduced regional cerebral blood flow in cerebellum 9 or indirectly from interruption of dopaminergic pathways 10 or hypoperfusion of the cerebral cortex. 11 In the case of thalamic hematomas, the major anatomical pathways associated with CCD are due to the interruption of the efferent pathways from the cerebellum involving ascending cerebello-thalamo-cortical systems or due to interruption of cortico-ponto-cerebellar tract by compression of posterior limb of internal capsule or due to hypoperfusion of cerebral cortex while causing compression of cortico-ponto-cerebellar system. 8 Similar to thalamic hematomas, the mass effect due to thalamic lymphoma may cause direct or indirect interruption of the cortico-ponto-cerebellar tract and be the likely cause of CCD, although rarely reported. Similar mass effect resulting in CCD has also been described in other brain tumors (including primary glioma), chronic subdural hematoma, congenital insults, intracranial infections, and various dementia subtypes. 6 12 13 14 15 This case is a rare demonstration of PCNS thalamic lymphoma with ipsilateral cerebral hypoperfusion and contralateral CCD likely due to the compression effect of posterior limb of internal capsule and interruption of cortico-ponto-cerebellar tract. Conclusion The 18 F-FDG PET plays an important role in diagnosis of patients who cannot undergo brain biopsy due to surgical risks, older age, or comorbidities, with PET/magnetic resonance imaging having good accuracy for the assessment of inoperable PCNSL. 16 Whole body staging with imaging along with bone marrow biopsy to rule out the systemic diseases with secondary CNS involvement should be performed once CNS lymphoma is confirmed as outlined by International PSNSL Collaborative group. 17 Note Conflict of Interest None declared. The manuscript has been read and approved by the author that the requirements for authorship as stated earlier in this document have been met, and that author believes that the manuscript represents honest work, if that information is not provided in another form References 1 Fine H A Mayer R J Primary central nervous system lymphoma Ann Intern Med 1993 119 11 1093 1104 8239229 2 Traweek S T Nervous system involvement by lymphoma, leukemia and other hematopoietic cell proliferations London Arnold Press 1998 195 237 3 Gerstner E R Batchelor T T Primary central nervous system lymphoma Arch Neurol 2010 67 03 291 297 20212226 4 Eichler A F Batchelor T T Primary central nervous system lymphoma: presentation, diagnosis and staging Neurosurg Focus 2006 21 05 E15 5 Finelli P F DiMario F J Jr Diagnostic approach in patients with symmetric imaging lesions of the deep gray nuclei Neurologist 2003 9 05 250 261 12971836 6 Lim J S Ryu Y H Kim B M Lee J D Crossed cerebellar diaschisis due to intracranial hematoma in basal ganglia or thalamus J Nucl Med 1998 39 12 2044 2047 9867139 7 Sobesky J Thiel A Ghaemi M Crossed cerebellar diaschisis in acute human stroke: a PET study of serial changes and response to supratentorial reperfusion J Cereb Blood Flow Metab 2005 25 12 1685 1691 15931159 8 Forster A Kerl H U Goerlitz J Wenz H Groden C Crossed cerebellar diaschisis in acute isolated thalamic infarction detected by dynamic susceptibility contrast perfusion MRI PLoS One 2014 9 02 e88044 24505372 9 Barbara F W Eduado E B Jasper R D Thomas J R Burton A S Medical Neurosciences, Motor System. 3rd edition Boston Little Brown & Co. 1994 193 195 10 Snider R S Maiti A Snider S R Cerebellar pathways to ventral midbrain and nigra Exp Neurol 1976 53 03 714 728 1001395 11 Hoover J E Strick P L Multiple output channels in the basal ganglia Science 1993 259 (5096):819 821 7679223 12 Sebok M van Niftrik C HB Halter M Crossed cerebellar diaschisis in patients with diffuse glioma is associated with impaired supratentorial cerebrovascular reactivity and worse clinical outcome Cerebellum 2020 19 06 824 832 32737798 13 Demir Y Surucu E Cilingir V Bulut M D Tombul T Dyke-Davidoff-Masson syndrome with cerebral hypometabolism and unique crossed cerebellar diaschisis in 18F-FDG PET/CT Clin Nucl Med 2015 40 09 757 758 26164180 14 Agarwal K K Tripathi M Karunanithi S Das C J Suri V Nalwa A Crossed cerebellar diaschisis in cerebral toxoplasmosis demonstrated on 18 F-FDG PET/CT Rev Esp Med Nucl Imagen Mol 2014 33 06 397 398 25043772 15 Franceschi A M Clifton M A Naser-Tavakolian K FDG PET/MRI for visual detection of crossed cerebellar diaschisis in patients with dementia AJR Am J Roentgenol 2021 216 01 165 171 33170738 16 Chiavazza C Pellerino A Ferrio F Cistaro A Soffietti R Ruda R Primary CNS lymphomas: challenges in diagnosis and monitoring BioMed Res Int 2018 2018 3.60697E6 17 International Primary CNS Lymphoma Collaborative Group Abrey L E Batchelor T T Ferreri A JM Report of an international workshop to standardize baseline evaluation and response criteria for primary CNS lymphoma J Clin Oncol 2005 23 22 5034 5043 15955902 |
World J Nucl Med World J Nucl Med 10.1055/s-00052852 World Journal of Nuclear Medicine 1450-1147 1607-3312 Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 10.1055/s-0042-1757282 WJNM-22-1-0002 Case Report Use of 99m Tc-DTPA Scintigraphy in Evaluation of Ureteral Laceration Due to Transurethral Lithotripsy in a Patient with Nephrolithiasis Gharepapagh Esmaeil 1 Fakhari Ashraf 1 Zomorrodi Afshar 2 Dabiri Oskuei Shahram 1 1 Medical Radiation Sciences Research Team, Tabriz University of Medical Sciences, Tabriz, Iran 2 Department of Urology, Tabriz University of Medical Sciences, Tabriz, Iran Address for correspondence Ashraf Fakhari, PhD Medical Radiation Sciences Research Team, Tabriz University of Medical SciencesP.O. Box: 5166614756, [email protected] 28 10 2022 3 2023 1 10 2022 22 1 4347 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Transurethral lithotripsy (TUL) procedure via ureteroscopy as an invasive method for nephrolithiasis treatment would lead to urinary tract injuries. In this reported case, the procedure caused severe damage to the left ureter that was detected by 99m Tc-diethylenetriaminepentaacetic acid ( 99m Tc-DTPA) scan. Generally, the TUL procedure through the ureter scope is used to manage urinary tract stones. In this case, the TUL was performed on a patient with a history of nephrolithiasis. Following that, she was accompanied with abdominal pain and discomfort, so 99m Tc-DTPA scintigraphy was performed to evaluate the urinary tract system. The scintigraphy showed a severe damage to the left ureter that finally resulted in autotransplantation. The control 99m Tc-DTPA scintigraphy performed 3 weeks after revealed no visible urinary leakage. In this case, the 99m Tc-DTPA scan prevented the patient from dangerous complications. So, 99m Tc-DTPA scan could be performed after TUL and ureteroscopy to detect probable risks. Keywords radiopharmaceutical scan 99m Tc-DTPA renal scintigraphy nephrolithiasis transurethral lithotripsy ureteroscopy pmcIntroduction Nephrolithiasis, making of calculi in the kidneys or urinary tract, is one of the common kidney disorders (problems). About 9% of women and 19% of men are involved with nephrolithiasis during their lifetime. There are two common complications associated with nephrolithiasis including UTI (urinary tract infection) and CKD (chronic kidney disease). 1 TUL (transurethral lithotripsy) is a procedure to break up stones of ureters through the urethra by a ureter scope (ureteroscopy). The TUL is classified into three types including flexible, rigid, and semirigid ureteroscopes. 2 The complications of ureteroscopy are considered as major and minor types. 3 99m Tc-diethylenetriaminepentaacetic acid ( 99m Tc-DTPA) renal scintigraphy is used to assay urinary excretion and drainage in addition to the glomerular filtration rate (GFR) estimation, because 90 to 95% of 99m Tc-DTPA is filtrated by the glomerulus. According to functional characteristic of 99m Tc-DTPA scintigraphy, renal excretory disorders especially ureteral leakage could be detected during this procedure. 4 Case Report In this report, a 56-year-old female patient with a history of kidney and ureteral stones who was referred to TUL procedure via ureteroscopy, presented with severe abdominal pain due to device manipulation. For this reason, the 99m Tc-DTPA renal scintigraphy was performed to evaluate the urinary tract system. The renal scintigraphy by i.v. injection of 555 MBq of 99m Tc-DTPA revealed mild-to-moderate decreased perfusion and function for both kidneys, especially of the left side. Moreover, an abnormal retention of radioactive urine was detected during the excretory phase of scintigraphy in the left hemiabdomen and pelvis because of left ureter urinary leakage. The urinary leakage was more considerable after i.v. injection of 0.3 mg/kg furosemide ( Fig. 1 ). According to the dynamic phase of the scan, the curve of renogram showed mild decreased perfusion and uptake of kidneys with near to normal excretory function especially after injection of a diuretic. Moreover, the renogram curves showed that there was a normal pattern of excretion on the left side despite ureteral damage, and there was mildly decreased GFR for both the kidneys ( Fig. 2 ). It should be mentioned that in spite of unsuccessful TUL, the normal urine excretion of the left kidney was related to the urine leakage into the retroperitoneal cavity that would have caused peritoneal or systemic infection. After detection of severe ureteral damage, the patient was referred to the left kidney autotransplantation surgery in the left iliac fossa and the results were evaluated by control 99m Tc-DTPA renal scintigraphy 3 weeks after surgery. The control scintigraphy showed the normal drainage of urine from pelvic left kidney to the bladder without evidence of urinary leakage ( Figs. 3 and 4 ). Based on this study, it is distinguished that 99m Tc-DTPA scintigraphy will be beneficial just after TUL procedure via ureteroscopy for early detection and treatment of probable complications. Fig. 1 ( A ) The perfusion phase of scintigraphy (for 60 seconds after injection of 99m Tc-DTPA) shows mild decreased perfusion of both the kidneys. ( B ) The excretory phase reveals normal excretion of activity from the right kidney to the bladder and remarkable urinary leakage around the left ureter. Fig. 2 The angiogram curves illustrate mild-to-moderate decreased perfusion of both the kidneys, and the renogram curves show normal excretory function of both the kidneys despite severe ureteral damage on the left side. Fig. 3 The control 99m Tc-DTPA renal scintigraphy shows normal pattern of excretion in both the kidneys with no evidence of urinary leakage in the left side. Fig. 4 The control angiogram and renogram curves illustrate mild-to-moderate decreased perfusion and uptake and normal excretory function of both the kidneys without any evidence of urinary leakage. Discussion Kidney stone is defined as the deposition of minerals in the renal parenchyma especially in calyces and pelvis. There are some types of stones including calcium oxalate, calcium phosphate, struvite, uric acid, and cysteine. 5 The TUL and SWL (shock wave lithotripsy) are modalities for the treatment of large and smaller ureteral stones, respectively. 6 According to potential risks of ureteroscopy, the urinary tract study is so important for early prognosis and treatment of complications, especially perforation and avulsion. Some diagnostic methods, for instance, ultrasound, computed tomography, magnetic resonance imaging, and renal scintigraphy could be used for kidney evaluation. 7 Among them, renal scintigraphy and functional MRI are considered as a functional imaging method. Beatrice et al showed that there are not significant differences between the two functional imaging methods in patients with drainage. 8 Renal scintigraphy, which is classified into static and dynamic imaging, has been used with different indications. 9 In this case, the TUL via ureteroscopy was used for the treatment of the patient with nephrolithiasis. Because the ureteroscopy is accompanied by some complications, the evaluation of the urinary tract could be recommended after this procedure. For this purpose, renal radiopharmaceuticals could be useful (through excretion or filtration) for the diagnosis of every ureteral damage as well as ureter perforation and avulsion. Dynamic scintigraphy by glomerular ( 99m Tc-DTPA, 99m Tc-GH) and tubular ( 99m Tc-EC, 99m Tc-MAG3) radiopharmaceuticals, has been used for kidney functional study. 10 The 99m Tc-DTPA, a radiopharmaceutical filtered by glomerulus, was used for this case. Based on the passage of radioactive urine, the ureters abnormalities such as obstruction, dilatation, tortuosity, and leakage are diagnosed in the excretory phase of the study. The distribution of radioactive urine around the ureter in the retroperitoneal cavity is considered as ureteral leakage. In this case, 99m Tc-DTPA scintigraphy showed the distribution of radiotracer in the mid-portion of the left ureter due to ureteroscopic manipulation. The results revealed that there is a risk of ureteral injury that leads to serious complications including perforation, laceration, and even avulsion. Following that, the patient was referred to autotransplantation surgery, and then control 99m Tc-DTPA scintigraphy. The 99m Tc-DTPA scintigraphy is more beneficial to early diagnosis and treatment of probable risks due to urinary tract invasive producers, so many related complications especially pelvic and systemic infections could be prevented. For this patient, the 99m Tc-DTPA scan confirmed a serious injury in the left ureter that led to kidney autotransplantation. According to the results, if the 99m Tc-DTPA scan was performed just after ureteroscopy, the necessary treatments could promptly be used before serious threatening signs. So, evaluation via control 99m Tc-DTPA scan just after ureteroscopy is firmly recommended to prevent probable complications. Also, it is suggested to include the radionuclide study in the urological guideline as a complementary step. Because of some complications during TUL via ureteroscopy, it was concluded that performing 99m Tc-DTPA renal scintigraphy is useful for the detection of probable damage. Also, based on glomerular filtration of 99m Tc-DTPA, there is a chance to evaluate perfusion-function and GFR for manipulated kidneys. Acknowledgments The authors thank Imam Reza Hospital and Tabriz University of Medical Sciences, Tabriz, Iran, for their official support. Authors' Contributions Conflicts of Interest None declared. Fakhari organized the investigation and was a major contributor to writing the manuscript. Gharepapagh interpreted scintigraphy regarding the 99m Tc-DTPA renal scan. Afshar Zomorrodi performed auto-transplantation surgery. Shahram Dabiri Oskuei reviewed the manuscript. References 1 Sorokin I Pearle M S Medical therapy for nephrolithiasis: State of the art Asian J Urol 2018 5 04 243 255 30364650 2 Basillote J B Lee D I Eichel L Clayman R V Ureteroscopes: flexible, rigid, and semirigid Urol Clin North Am 2004 31 01 21 32 15040398 3 Taie K Jasemi M Khazaeli D Fatholahi A Prevalence and management of complications of ureteroscopy: a seven-year experience with introduction of a new maneuver to prevent ureteral avulsion Urol J 2012 9 01 356 360 22395832 4 Taylor A T Radionuclides in nephrourology, part 1: radiopharmaceuticals, quality control, and quantitative indices J Nucl Med 2014 55 04 608 615 24549283 5 Khan S R Pearle M S Robertson W G Kidney stones Nat Rev Dis Primers 2016 2 16008 27188687 6 Rabani S M Moosavizadeh A Management of large proximal ureteral stones: a comparative clinical trial between transureteral lithotripsy (TUL) and shock wave lithotripsy (SWL) Nephrourol Mon 2012 4 03 556 559 23573485 7 Durand E Chaumet-Riffaud P Grenier N Functional renal imaging: new trends in radiology and nuclear medicine Semin Nucl Med 2011 41 01 61 72 21111860 8 Damasio M B Bodria M Dolores M Comparative study between functional MR urography and renal scintigraphy to evaluate drainage curves and split renal function in children with congenital anomalies of kidney and urinary tract (CAKUT) Front Pediatr 2020 7 527 32047727 9 Mettler F Guiberteau M Essentials of Nuclear Medicine and Molecular Imaging 7th ed. Philadelphia Elsevier 2019 287 10 Chervu L R Blaufox M D Renal radiopharmaceuticals-an update Semin Nucl Med 1982 12 03 224 245 6289454 |
World J Nucl Med World J Nucl Med 10.1055/s-00052852 World Journal of Nuclear Medicine 1450-1147 1607-3312 Thieme Medical and Scientific Publishers Pvt. Ltd. A-12, 2nd Floor, Sector 2, Noida-201301 UP, India 10.1055/s-0042-1757254 13321 Case Report An Uncommon Presentation of Leptomeningeal Metastases in Breast Carcinoma Detected by F-18 FDG PET/CT Surya Gavini 1 Ajit Nimmagadda 1 Priya Rallapeta Ramya 1 Hemalatha Dhamarcherla S. 1 Devi Bodagala Vijayalakshmi 2 Kalawat Tekchand 1 1 Department of Nuclear Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India 2 Department of Radiology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India Address for correspondence Tekchand Kalawat, DRM, DNB Department of Nuclear Medicine, Sri Venkateswara Institute of Medical SciencesTirupati, 517507, Andhra [email protected] 09 9 2022 3 2023 1 9 2022 22 1 3639 The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( ) 2022 The Author(s). This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Leptomeningeal carcinomatosis is a manifestation in which tumor cells migrate into meninges. Breast carcinoma presenting with leptomeningeal metastases is a rare phenomenon that can occur in an isolated form as well as with coexistent parenchymal brain metastases. The gold standard for diagnosis is cerebrospinal fluid analysis, while contrast-enhanced magnetic resonance imaging is the most commonly used imaging modality. Nuclear medicine imaging with flourine-18-fluorodeoxyglucose positron emission tomography/computed tomography has proved to be useful in detecting leptomeningeal metastases and, at times, even before anatomical changes occur. Here, we present a case of breast carcinoma presenting with both pachymeningeal and leptomeningeal metastases 10 years after treatment. Keywords breast cancer F-18 FDG PET/CT leptomeningeal metastases pmcIntroduction Leptomeningeal carcinomatosis is a late-stage manifestation of systemic cancers where tumor cells invade leptomeninges containing pia, arachnoid matter, and subarachnoid space. It can occur through direct invasion, venous dissemination, hematogenous spread, or through neural route. 1 Leptomeningeal metastases are commonly associated with breast cancer, lung cancer, and malignant melanoma. Rarely, it is also seen in certain gastrointestinal, primary brain tumors, and hematological malignancies. 2 Patients generally present with clinical features related to increase in intracranial pressure and cerebrospinal fluid (CSF) obstruction such as headache, nausea, vomiting, radiculopathy, and decreased level of consciousness. CSF analysis is considered as the gold standard for diagnosis. Magnetic resonance imaging (MRI) is indicated in clinically suspicious cases and with negative cytology where it can detect nodularity and leptomeningeal enhancement. CSF flow studies by indium-111 (In-111) DTPA can sometimes be useful in detection of obstruction of CSF flow. Flourine-18-fluorodeoxyglucose positron emission tomography computed tomography (F-18 FDG PET/CT) is known to help in detection of leptomeningeal involvement of both intracranial and extracranial structures, as in this case report of a carcinoma right breast with leptomeningeal metastases. Case Report A 65-year-old female patient with invasive lobular carcinoma of right breast underwent right modified radical mastectomy, and adjuvant chemotherapy with six cycles of paclitaxel and carboplatin and subsequently remained event free for 6 years; later she was diagnosed with skeletal metastases and underwent palliative radiotherapy and was maintained on hormonal therapy with tab. tamoxifen for 4 years. Later, she complained headache and giddiness without associated nausea or loss of consciousness and was evaluated for the same. Contrast-enhanced MRI using T1-weighted and T2-weighted sequences was performed that revealed nodular thickening along with leptomeningeal enhancement in bilateral cerebral hemispheres and bilateral cerebellar regions in concurrent with cerebral metastases in right frontal cortex. One week later, F-18 FDG PET/CT was performed that showed widespread multiple FDG-avid sclerotic bone lesions in vertebral column, ribs, long bones and metabolically active hypodense lesions in both lobes of liver along with mediastinal lymphadenopathy ( Fig. 1 ). Brain images showed isodense area of non-FDG-avid lesion in right frontal cortex with surrounding diffuse disproportionate edema and mass effect on right side basal ganglia and anterior horn of right lateral ventricle. There are multiple focal and diffuse leptomeningeal thickening with increased metabolic activity in bilateral cerebral hemispheres, predominantly in right frontal, left parietal convexity, and bilateral cerebellar regions ( Fig. 2 ). All findings are suggestive of progressive disease with late sequela of brain parenchymal and pachymeningeal deposits. Fig. 1 F-18 FDG PET CT maximum intensity projection (MIP) image ( A ) and sagittal CT ( B ) and fused PET CT ( C ) images showing no abnormal metabolic activity at primary treated site and moderately increased FDG concentration at leptomeninges, liver and multiple sclerotic lesions in skeletal system. Fig. 2 Transverse CT ( A, B ) and fused PET CT ( C, D ) images showing moderately increased FDG concentration in leptomeninges of right frontal, temporal cortex and bilateral cerebellar regions along with parenchymal lesion in right frontal cortex with disproportionate edema. Discussion Leptomeningeal metastases in breast cancer are a rare presentation that constitute up to 3 to 5% of overall metastases. 3 Lobular type of breast carcinoma has more propensity for leptomeningeal metastases than others. 4 The deficiency of E-cadherin complex, a crucial factor for maintenance of normal cytoarchitecture, is a favorable factor for metastases invasion. 5 Triple-negative subtype of breast carcinoma constitutes major proportion in those progressing to leptomeningeal metastases and tends to decrease median time of onset of metastases from onset of primary. 6 Existing bone metastases particularly vertebral and paravertebral lesions can infiltrate leptomeninges by spreading along perivascular spaces of venous plexus . Most common clinical feature is headache and other features are focal neurological deficits, visual disturbances, diplopia, and radiculopathy depending on neuronal structure involved by malignant cells; these cells can grow and obstruct the flow of CSF leading to symptoms of obstructive hydrocephalus such as nausea, vomiting, and positional headaches. 7 CSF examination can demonstrate tumor cells has sensitivity of up to 90% after three successive lumbar punctures. 8 Other nonspecific parameters include elevation of biomarkers and cytokines, elevated CSF pressure, increased protein levels, leukocytosis, and decreased glucose levels. 9 However, in our case, the patient did not undergo CSF analysis. MRI with gadolinium contrast is more sensitive than CT and should be performed in patients with clinical suspicion and should cover entire brain and spinal cord, as leptomeningeal carcinomatosis can involve entire neuronal axis. Pial enhancement and nodularity can involve cerebral convexities, tentorium, ventricular ependymal surfaces, and cauda equina. 10 CSF flow studies by In-111 DTPA can detect site of obstruction and provide guide for focused radiotherapy. 11 F-18 FDG PET/CT imaging is a known as an efficient modality in detecting metastases. Also, whole-body survey for primary tumor, local recurrence, metastases, and evaluation of treatment response can be done in a single sitting. However, it has certain limitations in structures with high background activity such as brain. In literature, several reports suggested the utility of F-18 FDG PET/CT in detection of both extracranial leptomeningeal metastases. 12 13 Short et al reported a case of leptomeningeal metastases, where lesions were seen on F-18 FDG PET/CT with normal MRI findings. 14 In our case, F-18 FDG PET/CT not only detected leptomeningeal metastases but also detected brain, liver, and skeletal metastases along with mediastinal lymphadenopathy. Treatment options for leptomeningeal metastases include intrathecal radiotherapy, radiotherapy, and systemic chemotherapy. 15 Despite all the treatment modalities available, leptomeningeal metastases in breast carcinoma have a poor prognosis with median survival time of 3.5 months and 1 year survival rate is almost 20%. 16 Conclusion Leptomeningeal metastases are a late and rare presentation in breast carcinoma with poor prognosis. Even though early detection may not significantly improve survival, it can help in planning of palliative management. As illustrated in our case report, F-18 FDG PET/CT detected leptomeningeal metastases along with other metastatic lesions in brain, skeleton, and liver. Conflict of Interest None. References 1 Pellerino A Brastianos P K Ruda R Soffietti R Leptomeningeal metastases from solid tumors: recent advances in diagnosis and molecular approaches Cancers (Basel) 2021 13 12 2888 34207653 2 Wasserstrom W R Glass J P Posner J B Diagnosis and treatment of leptomeningeal metastases from solid tumors: experience with 90 patients Cancer 1982 49 04 759 772 6895713 3 Le Rhun E Taillibert S Chamberlain M C Carcinomatous meningitis: leptomeningeal metastases in solid tumors Surg Neurol Int 2013 4 (4, Suppl 4):S265 S288 23717798 4 Niwinska A Rudnicka H Murawska M Breast cancer leptomeningeal metastasis: propensity of breast cancer subtypes for leptomeninges and the analysis of factors influencing survival Med Oncol 2013 30 01 408 23322521 5 Corso G Pravettoni G Galimberti V Veronesi P Clinical implication of E-cadherin deficiency in lobular breast cancer Breast Cancer Res Treat 2019 173 03 751 752 30448898 6 Yust-Katz S Garciarena P Liu D Breast cancer and leptomeningeal disease (LMD): hormone receptor status influences time to development of LMD and survival from LMD diagnosis J Neurooncol 2013 114 02 229 235 23756727 7 Balm M Hammack J Leptomeningeal carcinomatosis. Presenting features and prognostic factors Arch Neurol 1996 53 07 626 632 8929170 8 Glantz M J Cole B F Glantz L K Cerebrospinal fluid cytology in patients with cancer: minimizing false-negative results Cancer 1998 82 04 733 739 9477107 9 Straathof C S de Bruin H G Dippel D W Vecht C J The diagnostic accuracy of magnetic resonance imaging and cerebrospinal fluid cytology in leptomeningeal metastasis J Neurol 1999 246 09 810 814 10525979 10 Nayar G Ejikeme T Chongsathidkiet P Leptomeningeal disease: current diagnostic and therapeutic strategies Oncotarget 2017 8 42 73312 73328 29069871 11 Mason W P Yeh S D DeAngelis L M 111Indium-DTPA cerebrospinal fluid flow studies predict distribution of intrathecally administered chemotherapy and outcome in patients with leptomeningeal metastases Neurology 1998 50 02 438 444 9484369 12 Intriago B Danus M Ananos M Trampal C Montero M Calvo N 18F-FDG PET detection of spinal leptomeningeal metastases from cerebral glioblastoma multiforme Eur J Nucl Med Mol Imaging 2011 38 07 1392 21394504 13 Ortapamuk H Demir M K Intracranial leptomeningeal carcinomatosis in three cases from breast cancer demonstrated on F-18 fluorodeoxyglucose positron emission tomography/computerized tomography Indian J Nucl Med 2017 32 01 16 18 28242978 14 Short R G Bal S German J P Poelstra R J Kardan A Potential of F-18 PET/CT in the detection of leptomeningeal metastasis Neuroradiol J 2014 27 06 685 689 25489891 15 Franzoi M A Hortobagyi G N Leptomeningeal carcinomatosis in patients with breast cancer Crit Rev Oncol Hematol 2019 135 85 94 30819451 16 Morikawa A Jordan L Rozner R Characteristics and outcomes of patients with breast cancer with leptomeningeal metastasis Clin Breast Cancer 2017 17 01 23 28 27569275 |
Case Rep Anesthesiol Case Rep Anesthesiol CRIA Case Reports in Anesthesiology 2090-6382 2090-6390 Hindawi 10.1155/2023/1558183 Case Report Peripheral Nerve Stimulation for the Treatment of Phantom Limb Pain: A Case Series Pagan-Rosado Robert 1 Smith Brandon J. 1 Smither Fantley C. 1 Pingree Matthew J. 2 D'Souza Ryan S. [email protected] 2 1Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA 2Department of Anesthesiology and Perioperative Medicine, Division of Pain Medicine, Mayo Clinic Hospital, Rochester, MN, USA Academic Editor: Serkan Tulgar 2023 6 3 2023 2023 155818331 10 2022 1 2 2023 11 2 2023 Copyright (c) 2023 Robert Pagan-Rosado et al. 2023 This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. This case series aims to highlight the efficacy of peripheral nerve stimulation (PNS) in the treatment of phantom limb pain, as well as provide an alternative method for the treatment of this pain syndrome. In this report, we describe three amputee patients with severe phantom limb pain who obtained substantial analgesia and improvement in physical functionality after implantation of a temporary PNS device. Future studies should assess predictors of successful response or poor response to PNS therapy, such as mental health, environmental stressors, coping skills, and procedural factors. These factors may facilitate an individualized approach for each patient to ensure appropriate candidacy for PNS and better prognosis. Considering that patients in our cohort did not achieve long-lasting benefit after removal of temporary PNS, future research should assess if patients with phantom limb pain would benefit from permanent PNS, rather than temporary PNS. NevroSaol Therapeutics pmc1. Introduction Nearly 200,000 extremity amputations are performed annually in the United States . Despite advances in the field of pain medicine, nearly 70% of post-amputee patients experience long-term chronic pain and discomfort following the amputation . Prolonged and uncontrolled pain is associated with multiple negative consequences including poor quality of life and functionality. Post-amputation pain is generally categorized as either phantom limb pain (PLP) and/or residual limb pain (RLP). PLP is pain originating in the lost limb that is no longer present to generate sensory input and is believed to have both central and peripheral components. There are a variety of descriptors for PLP including burning, stabbing, itching, or muscular contractions and spasms . First-line treatment for PLP typically begins with evaluating prosthetic fit and wound healing and also includes mirror therapy and desensitization. Commonly utilized pharmacologic agents include gabapentinoids and selective norepinephrine reuptake inhibitors. Despite these measures, many patients with PLP fail to achieve adequate analgesia , which has resulted in growing interest in the use of neuromodulation to address this pain. Specifically, peripheral nerve stimulation (PNS) has recently emerged as a neuromodulation intervention that can be utilized to treat refractory manifestations of chronic pain, including post-amputation pain . This case series aims to highlight the efficacy of PNS in three patients with phantom limb pain from a single tertiary academic center as well as propose a treatment algorithm for phantom limb pain that incorporates the use of PNS. 2. Patient Information, Therapeutic Intervention, and Outcomes 2.1. Case 1 A 68-year-old female with a history of left transhumeral amputation, end-stage renal disease on hemodialysis, hypertension, type 2 diabetes mellitus, and anxiety presented to the pain clinic for phantom limb pain. Her left transhumeral amputation was due to a planned surgical resection due to necrotizing fasciitis two years ago. Her main complaint was severe phantom limb pain based around the area where her thumb, dorsal hand, and wrist were previously located. She reported constant shooting and burning pain with intermittent "lightning bolt" sensations. She also described residual nociceptive limb pain which was less intense compared to the phantom limb pain. She had previously trialed gabapentin 100 mg twice a day, nortriptyline 10 mg daily, 5 mg oxycodone four times daily, lidocaine patches, ice application, and mirror therapy without success. A median nerve neuroma was identified during examination with ultrasound, and thus, the decision was made to perform PNS of the left median nerve for pain relief. A diagnostic block with 2% lidocaine at the left median nerve resulted in 80% pain relief. A temporary stimulator (SPRINT, SPR Therapeutics, Cleveland, OH, USA) was implanted under ultrasound guidance in close proximity to the left median nerve. A Sonosite linear ultrasound transducer (15-6 MHz) was used to identify the left median nerve (neuroma). A short-axis, in-plane approach was used to place the stimulating needle in close proximity to the neuroma . The introducer needle was advanced to near the left median nerve (neuroma) and stimulation was carried out with the patient stating that she was feeling paresthesia in the phantom limb (thumb and index finger). After the stimulating needle exhibited optimal spread of coverage, a PNS lead was advanced through the stimulating needle. The external portion of the lead was secured to the skin with Dermabond (Ethicon, Inc., Somerville, NJ) and Tegaderm (3M, Inc., Saint Paul, MN). At the 2-week follow-up after implantation, the patient reported a 40% improvement in both pain and physical functionality, with a subsequent 60% improvement in both outcomes at the 6-weekfollow-up period. Further, she reported substantially lower frequency of pain flares and great satisfaction with PNS. After completion of the 60-day PNS treatment and removal of the device, her pain returned to its baseline within 3 months. No complications were reported during or after the procedure. 2.2. Case 2 A 77-year-old female has a history of hypertension, diabetes, chronic kidney disease, depression, and a high-grade spindle cell sarcoma that resulted in a left transfemoral amputation. She reported phantom limb pain diffusely around the area of the left foot. She had previously tried gabapentin, duloxetine, tramadol, intra-articular hip steroid injections, and mirror therapy without any significant relief. The pain was described as severe 10/10 pain exacerbated by weather changes, and intermittent radiation to the residual stump. She underwent a left femoral and sciatic nerve ultrasound-guided diagnostic block with 2% lidocaine which provided significant pain relief (100%) for 4-6 hours. Two months later, she underwent a temporary PNS device placement targeting the left femoral and sciatic nerves. A Sonosite linear ultrasound transducer (15-6 MHz) was used to identify the left femoral and sciatic nerve at the inguinal and subgluteal region, respectively. A short-axis, in-plane approach was used to place the stimulating needle in close proximity to the nerves. The subcutaneous tissue layers were identified, and local anesthetic was infiltrated in the subcutaneous tissue. The introducer needle was first advanced to near the left femoral nerve and stimulation was carried out with the patient stating that she was feeling paresthesia in the left femoral nerve distribution. We then inserted the lead and re-performed stimulation and then styleted the lead. We repeated these same steps for the left sciatic nerve. After the stimulating needle exhibited optimal spread of coverage, a PNS lead was advanced through the stimulating needle. The external portion of the lead was secured to the skin with Dermabond (Ethicon, Inc., Somerville, NJ) and Tegaderm (3M, Inc., Saint Paul, MN). At the 2-week follow-up visit, the patient reported a 100% improvement for both pain intensity and physical functionality, with a sustained 100% improvement in both measures at the 6-week follow-up visit. She reported lower frequency of pain flares and greater satisfaction with PNS therapy compared to baseline. After severe recurrence of pain was noted at day 45, ultrasound evaluation revealed migration of the PNS lead. The PNS settings were re-programmed, and efficacy was achieved again with 75% improvement in pain intensity. After removal of the PNS device 60 days post-implant, she had a relapse of phantom limb pain in 2 months that was 50% less intense than pre-implant pain intensity. No other complications were reported. 2.3. Case 3 A 16-year-old male reported a history of chronic left lower extremity pain in the setting of refractory erythromelalgia and left transtibial amputation secondary to severe pain and recurrent infection. After amputation, he began experiencing severe phantom limb pain at the left foot about three weeks after amputation. A diagnostic nerve block at the sciatic nerve provided 80% pain relief, and therefore, a temporary PNS stimulator was implanted under ultrasound guidance to stimulate the sciatic nerve. A Sonosite linear ultrasound transducer (15-6 MHz) was used to identify the left sciatic nerve at the subgluteal region. A short-axis, in-plane approach was used to place the stimulating needle in close proximity to the nerve. The subcutaneous tissue layers were identified, and local anesthetic was infiltrated in the subcutaneous tissue. The introducer needle was advanced to near the left sciatic nerve and stimulation was carried out with the patient stating that he was feeling paresthesia in the left sciatic nerve distribution. We then inserted the lead and repeated stimulation and then styleted the lead. After the stimulating needle exhibited optimal spread of coverage, a PNS lead was advanced through the stimulating needle to the optimal site of stimulation. The external portion of the lead was secured to the skin with Dermabond (Ethicon, Inc., Somerville, NJ) and Tegaderm (3M, Inc., Saint Paul, MN). At the 2-week follow-up visit, the patient reported pain intensity was 2/10 compared to 10/10 at baseline. At the 6-week follow-up visit, pain intensity was 5/10. He reported less frequent pain flares and great satisfaction. After removal of his PNS device at 60 days, his pain intensity subsequently increased to 10/10 within one month following removal. No complications were reported. 3. Discussion We report a case series of post-amputee patients with severe phantom limb pain who obtained substantial analgesia and improvement in physical functionality after implantation of a temporary PNS device. Reduced frequency of pain flares, good patient satisfaction, and no adverse events were reported. However, after removal of the temporary PNS device, pain intensity worsened in all patients and regressed completely back to pre-implant baseline levels in two patients. This small case series highlights that temporary PNS provides substantial short-term pain relief and improved physical functionality, although this therapeutic effect is temporary and does not extend long-term after device removal. The mechanism in which patients experience PLP is not entirely delineated but likely has both central and peripheral components. Central components include somatosensory cortical reorganization of the area representing the amputated limb, as well as spinal reorganization in the dorsal horns after deafferentation from a peripheral nerve . Peripheral components such as increased ectopic nociceptive afferent inputs, axonal nerve inflammation, and regenerative sprouting may also contribute to PLP . PNS is also believed to have both peripheral and central mechanisms contributing, which would lay the foundation for a plausible mechanism of PLP improvements with PNS. Central alterations with PNS include the activation of afferent non-nociceptive fibers which alter dorsal horn interneurons that are needed in the processing of nociceptive stimuli. PNS may also modulate wide dynamic range neurons in the dorsal horns and can act peripherally by altering local micro-environments of nociceptive afferent fibers and reducing ectopic discharges . PNS likely results in improvements in PLP by altering both the central and peripheral mechanism contributing to PLP. Our results are concordant with the literature, which highlights efficacy of PNS in treatment of post-amputation pain . Our data are also consistent with superior analgesia and clinical outcomes from PNS treatment of both acute and chronic pain syndromes in the back, upper extremity, lower extremity, and head . However, PNS studies utilizing temporary PNS lead placement highlight persistent pain relief up to a year after removal of the PNS device. Our small case series contradicts this finding because all patients in our series reported significant worsening of pain intensity within a month after PNS device removal. Potential explanations for this include comorbid psychiatric and medical comorbidities in all three patients, which may have amplified their pain intensity and affected their response to PNS. Moreover, prior literature on PNS for post-amputation pain excluded certain patients, such as those with diabetes, bleeding disorders, autoimmune disorders, and depression, which may explain the differences in outcomes between our case series and the results of prior studies . Interestingly, patient #3 in this series had a history of erythromelalgia, which may be an additional factor leading to treatment-resistant and refractory pain, given its interplay with the peripheral vasculature and peripheral nervous system. Additional clinical studies are needed to further assess the efficacy of PNS in the treatment of phantom limb pain. The current literature suggests that PNS therapy may provide clinically significant pain relief and improvement in the quality of life of patients with chronic neuropathic post-amputation pain, which usually includes both residual limb pain and phantom limb pain . When evaluating post-amputee patients who are experiencing phantom limb pain, the first step should be to assess prosthetic fit and ensure proper wound healing if amputation occurred recently. If none of these are sources of pain, referral to a physical therapist would be warranted to work on multiple exercises and pain management modalities. Pharmacologic treatment with oral gabapentinoids, selective norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs), followed with a formal biopsychologic evaluation, should be the next step in cases where pain is refractory to rehabilitation and alternative therapies. Neuromodulation techniques such as PNS and spinal cord stimulation may be considered for those patients who do not obtain benefit from conservative and pharmacologic treatment. Additionally, other procedural interventions such as dorsal root entry zone ablation, peripheral nerve blocks, and radiofrequency ablations can also be considered. In some cases, surgical intervention may be necessary if none of the aforementioned interventions improve the patients' pain and quality of life. Future studies should assess predictors of successful response or poor response to PNS therapy, such as mental health, environmental stressors, coping skills, and procedural factors. These factors may facilitate an individualized approach for each patient to ensure appropriate candidacy for PNS and better prognosis. Considering that patients in our cohort did not achieve long-lasting benefits after removal of temporary PNS, future research should assess if patients with phantom limb pain would benefit from permanent PNS, rather than temporary PNS. Acknowledgments Ryan D'Souza receives investigator initiated funding from Nevro Corp and Saol Therapeutics. Ethical Approval This case series conforms to all CARE guidelines and reports the required information accordingly. This case series was deemed exempt from institutional board review. Consent Informed consent was obtained from patients. Conflicts of Interest All authors are full time employees at May Clinic, Rochester, MN. Authors' Contributions Robert Pagan-Rosado drafted the original and subsequent versions of the manuscript including its format and intellectual content, before preparing it for submission. Brandon J. Smith drafted the original and subsequent versions of the manuscript including its format and intellectual content, before preparing it for submission. Fantley C. Smither contributed important intellectual content to the manuscript and approved the final version. Matthew J. Pingree contributed important intellectual content to the manuscript and approved the final version. Ryan D'Souza conceived and led the development of this project, drafted the original and subsequent versions of the manuscript including its format and intellectual content, before preparing it for submission. Figure 1 Transverse sonographic view of the median nerve proximal to the left antecubital fossa, with an in-plane stimulator needle superior to the median nerve. Due to poor quality, the sonographic images of the other two cases were not included. 1 Ziegler-Graham K. MacKenzie E. J. Ephraim P. L. Travison T. G. Brookmeyer R. Estimating the prevalence of limb loss in the United States: 2005 to 2050 Archives of Physical Medicine and Rehabilitation 2008 89 3 422 429 10.1016/j.apmr.2007.11.005 2-s2.0-39449127714 18295618 2 Ehde D. M. Czerniecki J. M. Smith D. G. Chronic phantom sensations, phantom pain, residual limb pain, and other regional pain after lower limb amputation Archives of Physical Medicine and Rehabilitation 2000 81 8 1039 1044 10.1053/apmr.2000.7583 2-s2.0-0033863146 10943752 3 McCormick Z. Chang-Chien G. Marshall B. Huang M. Harden R. N. Phantom limb pain: a systematic neuroanatomical-based review of pharmacologic treatment Pain Medicine 2014 15 2 292 305 10.1111/pme.12283 2-s2.0-84893839175 24224475 4 Gilmore C. Ilfeld B. Rosenow J. Percutaneous peripheral nerve stimulation for the treatment of chronic neuropathic postamputation pain: a multicenter, randomized, placebo-controlled trial Regional Anesthesia and Pain Medicine 2019 44 6 637 645 10.1136/rapm-2018-100109 2-s2.0-85066353412 30954936 5 Albright-Trainer B. Phan T. Trainer R. J. Peripheral nerve stimulation for the management of acute and subacute post-amputation pain: a randomized, controlled feasibility trial Pain Management 2021 11 p. 11 6 Kew J. J. Ridding M. C. Rothwell J. C. Reorganization of cortical blood flow and transcranial magnetic stimulation maps in human subjects after upper limb amputation Journal of Neurophysiology 1994 72 5 2517 2524 10.1152/jn.1994.72.5.2517 2-s2.0-0027939139 7884476 7 Hsu E. Cohen S. P. Postamputation pain: epidemiology, mechanisms, and treatment Journal of Pain Research 2013 6 121 136 10.2147/jpr.s32299 2-s2.0-84874751853 23426608 8 Papuc E. Rejdak K. The role of neurostimulation in the treatment of neuropathic pain Annals of Agricultural and Environmental Medicine: AAEM 2013 1 14 17 9 Strand N. H. D'Souza R. Wie C. Mechanism of action of peripheral nerve stimulation Current Pain and Headache Reports 2021 25 7 p. 47 10.1007/s11916-021-00962-3 10 Cohen S. P. Gilmore C. A. Rauck R. L. Percutaneous peripheral nerve stimulation for the treatment of chronic pain following amputation Military Medicine 2019 184 7-8 e267 e274 10.1093/milmed/usz114 2-s2.0-85068898218 31111898 11 Wilson R. D. Gunzler D. D. Bennett M. E. Chae J. Peripheral nerve stimulation compared with usual care for pain relief of hemiplegic shoulder pain: a randomized controlled trial American Journal of Physical Medicine and Rehabilitation 2014 93 1 17 28 10.1097/phm.0000000000000011 2-s2.0-84891784176 24355994 12 Gilmore C. A. Kapural L. McGee M. J. Boggs J. W. Percutaneous peripheral nerve stimulation (PNS) for the treatment of chronic low back pain provides sustained relief Neuromodulation 2018 18 10.1111/ner.12854 2-s2.0-85054415893 |
Case Rep Crit Care Case Rep Crit Care CRICC Case Reports in Critical Care 2090-6420 2090-6439 Hindawi 10.1155/2023/3472718 Case Report Full-Term Delivery and Complete Lung Recovery following VV ECMO Support Midpregnancy in a Patient with COVID-19 ARDS Leong Shelley 1 2 Moreno Guillermo 1 3 Fayed Mohamed 1 2 Tallman Crystal Ives [email protected] 1 2 1University of California San Francisco, Fresno, USA 2Department of Pulmonary and Critical Care Medicine, University of California San Francisco, Fresno, USA 3Department of Obstetrics, University of California San Francisco, Fresno, USA Academic Editor: Minesh Khashu 2023 6 3 2023 2023 347271827 3 2022 16 9 2022 9 1 2023 Copyright (c) 2023 Shelley Leong et al. 2023 This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Pregnant women are especially vulnerable to coronavirus disease 2019 (COVID-19). We present a twin pregnancy case with acute respiratory distress syndrome following COVID-19 infection at 19 weeks. The patient's ARDS was successfully managed with veno-venous extracorporeal membrane oxygenation (VV ECMO). She recovered completely and delivered healthy twins. pmc1. Introduction Maternal immunologic adaptations to pregnancy are known to increase the risk of severe respiratory disease from viral infections. Pregnancy is a risk factor for severe COVID-19 [1-4]. In one Italian study, one out of five pregnant women admitted with COVID-19 was delivered urgently for respiratory compromise or was admitted to the ICU . After adjusting for other risk factors, pregnant women with COVID-19 are three times more likely to require mechanical ventilation than nonpregnant women . Veno-venous extracorporeal membrane oxygenation (VV ECMO) is a rescue strategy for severe ARDS that has been used successfully in pregnant women during the COVID-19 Pandemic [5-10]. This support is not undertaken lightly, however, as ECMO support is associated with increased complications, including moderate to severe bleeding and intracranial hemorrhage . We present a case of severe ARDS secondary to COVID-19 requiring VV ECMO during midpregnancy. To our knowledge, this is the first case of VV ECMO support during twin gestation for this indication, with complete recovery of lung function. 2. Case Presentation A 39-year-old woman with twin pregnancies presented at 19 weeks two days of gestation with worsening shortness of breath. She tested positive for COVID-19 a week before the presentation. She reported a productive cough and loss of appetite for one week and was admitted for acute hypoxia with 82% oxygen saturation on room air. She was evaluated the day before in the emergency department for her symptoms and advised admission. On admission, she was placed on two litres oxygen via nasal cannula. On day three, she alternated between noninvasive positive airway pressure and high-flow nasal cannula support. Due to ongoing oxygen demand, she was transferred to the ICU for further monitoring. She was treated with dexamethasone (6 mg daily), remdesivir (200 mg once, then 100 mg daily), one dose intravenous methylprednisolone (80 mg), and vitamins C, D, and Zinc. The patient developed severe ARDS in the ICU and was then transferred to an ECMO centre for further evaluation. Her lung condition deteriorated with worsening hypoxia, and she was intubated on day six. The perinatology team evaluated her at the ECMO centre. A bedside ultrasound confirmed normally developing twins. She remained intubated with fluctuating FiO2 support until day 13. On day 13, her ventilatory and sedative demands were significantly increasing. A chest X-ray confirmed the progression of her lung disease . She did not respond to prone therapy. Her tidal volumes increased to greater than 7 mL/kg, and peak ventilatory pressure the next day was 36 cmH2O. With the loss of lung protective ventilation and her rapid clinical decline, she underwent VV ECMO cannulation on hospital day 14 at 21 weeks and 1-day gestation. A 28 Fr Crescent dual lumen catheter was placed in the right internal jugular vein. During ECMO cannulation, the patient received a weight-based heparin bolus and anticoagulation was maintained with a heparin drip titrated to anti-Xa levels. Following VV ECMO initiation, the patient's ventilator support was quickly weaned to extreme lung protective ventilation parameters in an effort to reduce the potential for lung damage and complications. This included even more protective parameters beyond ARDSnet protocol. By day two of VV ECMO support, ventilator settings were as follows: pressure control ventilation with tidal volumes < 6 cc/kg IBW, FiO2 of 50%, inspiratory pressure of 15, positive end-expiratory pressure of 10, and respiratory rate of 6. On day four of VV ECMO support, her ventilator settings had been weaned further, and FiO2 was 35%. While supported by VV ECMO, daily awakening trials were performed, but her course was complicated by hyperactive delirium. Enteral quetiapine and diazepam allowed her to be calm and awake. On day eight of VV ECMO treatment, she could sit up at the edge of the bed with physical therapy. She required VV ECMO support for nine days due to refractory hypercapnia from her COVID-19 infection and was decannulated on hospital day 22. She was extubated on hospital day 24 to a high-flow nasal cannula and remained in the ICU until hospital day 28. She required four litres nasal cannula at the time of her downgrade to the medicine floor. Routine fetal monitoring was initiated once she reached 23 weeks gestation. From 23 weeks to 23 weeks and six days, fetal heart rates were monitored daily. Unfortunately, the patient's hospital course was then complicated by altered mental status. An MRI of the head on day 32 confirmed a right-sided intraparenchymal hemorrhage that was 2.6 x 3.4 x 3.3 cm in size . The patient was transferred to the Neuro ICU for 24 hours for frequent neurologic checks. No additional bleeding or ECMO-related complications were identified. Both twins reached a viability period of 24 weeks. Electronic fetal monitoring of both the twins was carried out until 24 + 1 weeks. Parents expressed that they would like full intervention, including cesarean delivery if needed. A biophysical profile (BPP) was performed every 2-3 days to check fetal well-being. Subsequent MRA of the head did not show any abnormalities. Other than her altered mental status, her neurologic exam was normal. The neurosurgery team recommended monitoring with a repeat MRI of the head. She was transferred back to the medicine floor the next day. The patient was discharged to acute rehabilitation on hospital day 40. She was there for nine days before she was discharged home without any need for supplemental oxygen. Repeat head MRI showed an interval decrease of her known intraparenchymal hemorrhage. Her mental status remained normal. The rest of her pregnancy was uncomplicated with regular twice-weekly follow up in a high-risk pregnancy clinic. She was admitted to the hospital at 37 weeks and 3 days for planned cesarean delivery and delivered healthy twins. Baby A had an uncomplicated neonatal course, spending two days in the NICU. Baby A's birthweight was 3005 g. APGARS at the time of delivery were 8 and 9 at 1 and 5 minutes, respectively. Baby B also had an uncomplicated neonatal course, spending two days in the NICU. The baby's birthweight was 2675 g, and APGARS were 8 and 8 at 1 and 5 minutes, respectively. No COVID-19 testing was done on either infant. Postnatal follow-up, six months after delivery, showed complete resolution of the patient's COVID-19 disease. Her CT chest demonstrated a normal appearance of the lung parenchyma, and her pulmonary function tests had returned to normal . 3. Discussion Pregnant women are especially vulnerable to COVID-19. Pregnant women are more likely to require intensive care and mechanical ventilation for COVID-19 ARDS than non-pregnant women . The successful use of VV ECMO as a rescue therapy in pregnant women with COVID-19 ARDS has been documented in a handful of case reports [5-10]. In these case reports, these pregnant women required emergent delivery before, during, or immediately after VV ECMO support [5-10]. More recent case reports have documented successful treatment of COVID-19 ARDS with VV ECMO in pregnant women, allowing for full-term deliveries . Our patient is unique in that following VV ECMO support she delivered healthy, full-term twins and had complete recovery of her lung function. Our patient had a longer hospital course compared to other case reports of pregnant women with COVID-19 ARDS treated with VV ECMO, due to other complications such as her right-sided intraparenchymal brain hemorrhage. Despite this complication, the patient had a very good outcome from a neurologic, respiratory, and pregnancy perspective. Rates of complications in pregnant women requiring ECMO support are similar to other patients requiring ECMO support. These complications include mild to moderate bleeding in 18%, severe bleeding requiring surgical intervention in 13%, and intracranial neurologic morbidity in 5% . There were likely multiple factors contributing to her successful, full-term pregnancy. Early transfer to an ECMO centre with an obstetrics team familiar with high-risk pregnancies was essential to her care. Once lung protective ventilator support was no longer possible, ECMO cannulation was likely beneficial to allow her lungs to heal. Aggressive awakening trials and physical therapy supported by VV ECMO probably also added to her complete recovery. 4. Conclusion A few case reports have documented VV ECMO rescue therapy in pregnant women with ARDS from COVID-19 infection. However, this is the first case demonstrating successful VV ECMO support during twin pregnancy with full-term delivery of twins. In addition, this case also demonstrates complete lung function recovery. Consent Written and informed consent for publication was obtained from the patient. Conflicts of Interest The authors declare no conflicts of interest. Figure 1 (a) Bilateral infiltrates on initial portable chest X-ray at her first ED visit. (b) Progression of bilateral infiltrates on portable chest X-ray on hospital day 12. Figure 2 Intraparenchymal hemorrhage of the right frontal lobe on axial T2 flare MRI. Figure 3 Resolution of disease seen on serial axial cuts of noncontrast chest CT six months after initial presentation. Figure 4 Normal spirometry, lung volumes, and diffusing capacity six months after initial presentation. 1 Savasi V. M. Parisi F. Patane L. Clinical findings and disease severity in hospitalized pregnant women with coronavirus disease 2019 (COVID-19) Obstetrics and Gynecology 2020 136 2 252 258 10.1097/AOG.0000000000003979 32433453 2 Vogel J. P. Tendal B. Giles M. Clinical care of pregnant and postpartum women with COVID-19: living recommendations from the national COVID-19 clinical evidence taskforce The Australian & New Zealand Journal of Obstetrics & Gynaecology 2020 60 6 840 851 10.1111/ajo.13270 33119139 3 Kayem G. Lecarpentier E. Deruelle P. A snapshot of the Covid-19 pandemic among pregnant women in France Journal of Gynecology Obstetrics and Human Reproduction 2020 49 7, article 101826 10.1016/j.jogoh.2020.101826 4 Zambrano L. D. Ellington S. Strid P. Update: characteristics of symptomatic women of reproductive age with laboratory-confirmed SARS-CoV-2 infection by pregnancy status United States, January 22-October 3, 2020 MMWR. Morbidity and Mortality Weekly Report 2020 69 44 1641 1647 10.15585/mmwr.mm6944e3 33151921 5 Fiore A. Piscitelli M. Adodo D. K. Successful use of extracorporeal membrane oxygenation postpartum as rescue therapy in a woman with COVID-19 Journal of Cardiothoracic and Vascular Anesthesia 2021 35 2140 2143 10.1053/j.jvca.2020.07.088 32888800 6 Hou L. Li M. Guo K. First successful treatment of a COVID-19 pregnant woman with severe ARDS by combining early mechanical ventilation and ECMO Heart & Lung 2021 50 1 33 36 10.1016/j.hrtlng.2020.08.015 32948334 7 Douglass K. M. Strobel K. M. Richley M. Maternal-neonatal dyad outcomes of maternal COVID-19 requiring extracorporeal membrane support: a case series American Journal of Perinatology 2021 38 1 082 087 10.1055/s-0040-1718694 8 Larson S. B. Watson S. N. Eberlein M. Simmons J. S. Doerschug K. C. Leslie K. K. Survival of pregnant coronavirus patient on extracorporeal membrane oxygenation The Annals of Thoracic Surgery 2021 111 3 e151 e152 10.1016/j.athoracsur.2020.09.004 33039361 9 Barrantes J. H. Ortoleva J. O'Neil E. R. Successful treatment of pregnant and postpartum women with severe COVID-19 associated acute respiratory distress syndrome with extracorporeal membrane oxygenation ASAIO Journal 2020 67 10.1097/MAT.0000000000001357 10 Tambawala Z. Y. Hakim Z. T. Hamza L. K. Al R. M. Successful management of severe acute respiratory distress syndrome due to COVID-19 with extracorporeal membrane oxygenation during mid-trimester of pregnancy BML Case Reports 2021 14 2, article e240823 10.1136/bcr-2020-240823 33541967 11 Naoum E. E. Chalupka A. Haft J. Extracorporeal life support in pregnancy: a systematic review Journal of the American Heart Association 2020 9 13, article e016072 10.1161/JAHA.119.016072 32578471 |
Case Rep Dermatol Med Case Rep Dermatol Med CRIDM Case Reports in Dermatological Medicine 2090-6463 2090-6471 Hindawi 10.1155/2023/9467084 Case Report Confluent and Reticulated Papillomatosis Successfully Treated with Topical Vitamin A Derivative Alsulami Manal [email protected] 1 Alharbi Bader 2 Alotaibi Yaser 2 Alghamdi Fadi 2 Alsantali Adel 2 1College of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia 2Department of Dermatology, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia Academic Editor: Hristo Dobrev 2023 6 3 2023 2023 94670842 11 2022 2 2 2023 6 2 2023 Copyright (c) 2023 Manal Alsulami et al. 2023 This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Confluent and reticulated papillomatosis (CARP) is a rare dermatosis that typically develops in adolescents and young adults. Clinical characteristics include hyperkeratotic papules that coalesce centrally with a reticulated pattern peripherally on the central and upper trunk, neck, and axilla. Its etiology is not precisely known, and disordered keratinization has been postulated as one of the etiologies. Treatment options of the disease include systemic (such as antibiotics, antifungals, and retinoids) and topical treatments (such as lactic acid, antifungals, retinoids, salicylic acid, urea, tacrolimus, and vitamin D analogs). We report a case of a 17-year-old boy, otherwise healthy, presented with a new onset of asymptomatic, persistent, and slowly progressing brownish skin lesions over the trunk for 6 months. The diagnosis was revised to CARP based on clinical and histopathological examination. Treatment with topical tretinoin 0.025% cream once daily was begun. There was complete resolution of his lesions at the end of 8 weeks of therapy. There has been no relapse at 2 months follow-up. The effectiveness of tretinoin in this patient supports the theory that CARP is a keratinization disorder. Initiating treatment with topical tretinoin when no limitations for its use would be reasonable as it can provide a safer alternative to systemic therapy. pmc1. Introduction Confluent and reticulated papillomatosis (CARP) is a rare dermatosis originally described by Gougerot and Carteaud and also called Gougerot-Carteaud syndrome . It is characterized by hyperkeratotic or verrucous grey-brownish papules that coalesce into confluent plaques centrally with a reticulated pattern peripherally . It is commonly distributed on the central and upper trunk, neck, and axilla in adolescents and young adults . The diagnosis is largely made on a clinical basis but the role of histopathology remains an important measure to exclude other dermatoses. Its etiology remains uncertain, which explains the diversity of therapy options with variable outcomes . Treatment options for the disease include systemic and topical treatments. Systemic treatment includes antibiotics (such as minocycline, doxycycline, tetracycline, and azithromycin), antifungals, and retinoids (isotretinoin and acitretin). Topical treatment includes lactic acid, antifungals, retinoids, salicylic acid, urea, tacrolimus, and vitamin D analogs . Herein, we describe a case of CARP that was successfully treated with topical tretinoin. 2. Case Report A 17-year-old boy, otherwise healthy, presented with a new onset of asymptomatic, persistent, and slowly progressing brownish skin lesions over the trunk for 6 months. Past medical history, drug history, and family background were noncontributory. Examination revealed hyperpigmented, hyperkeratotic, confluent macules, and papules that coalesce into reticulated plaques over the upper trunk . No fluorescence was observed under a Wood's light examination. Rubbing the lesion with 70% isopropyl alcohol was unrevealing. Oral and nail examinations were unremarkable. A skin biopsy showed marked hyperkeratosis with papillomatosis in the epidermis and numerous fungal organisms (yeasts) in the corneal layer. A very scant chronic perivascular inflammatory infiltrate was noted in the dermis with edema and fibrosis . Based on the clinical and histopathological findings, a diagnosis of CARP was made. The patient was unwilling to start oral minocycline. Therefore, we initiated treatment with topical tretinoin 0.025% cream once daily. In 5 weeks, the patient started to notice a marked improvement with the flattening and fading of the papules and plaques. Within 8 weeks, the condition was almost completely resolved . No recurrence was noted at 2 months follow-up . 3. Discussion CARP is a rare skin disorder that preferentially affects young adults without particular sex predilection . Its pathogenesis is not precisely known, but there are various theories. It was thought to be caused by Malassezia furfur as CARP clinically resembles tinea versicolor. Still, studies have not been consistent with the detection of yeasts in patients with CARP. The current infectious theory is that CARP is caused by the bacteria, Dietzia papillomatosis. Disordered keratinization has been postulated as an etiology that is either familial or acquired . Reports of cases that were successfully treated with vitamin A derivatives support this theory [5-7]. Other etiologies include diabetes, obesity, ultraviolet light, and amyloidosis . In regard to the diagnosis of CARP, Davis et al. proposed the following criteria: (i) clinical findings include scaling brown macules and patches, at least part of which appear reticulated and papillomatosis; (ii) involvement of the upper trunk and neck; (iii) fungal staining of scales is negative for fungus; (iii) fungal staining of scales is negative for fungus; (iv) no response to antifungal treatment; and (v) excellent response to minocycline . Histopathologically, the most common findings are hyperkeratosis, papillomatosis, and acanthosis. The dermis may contain perivascular lymphocytic infiltrates, mild dilatation of superficial dermal blood vessels, beading of elastic fibers, and hypermelanosis of the basal layer . Our case was compatible with these typical features of CARP. In our case, we considered tinea versicolor, terra firma-forme dermatosis, Dowling-Degos disease, and Darier disease as differential diagnoses. Tinea versicolor was unlikely considering the absence of fluorescence on Wood's light examination. We swabbed the lesion with 70% isopropyl alcohol but it did not remove it, thus ruling out terra firma-forme dermatosis. Dowling-Degos disease was not favored as it usually presents as reticulated hyperpigmentation without papules or plaques and presents with a family history of similar lesions. Darier disease was ruled out due to the absence of oral, nail, palmoplantar changes, and the lack of suprabasal acantholysis and dyskeratotic cells in histopathology, in addition to the absence of family history . Numerous treatment modalities have been used for CARP. Antibiotics such as minocycline, which was considered the first-line treatment, were reported to yield good results. Despite the successful response seen in patients treated with minocycline, relapse is common after discontinuation, and long-term treatment with antibiotics has its associated risks . Doxycycline, tetracycline, and azithromycin are three other antibiotics that have been shown to be effective in treating some patients. The effectiveness of these antibiotics is mainly attributed to their anti-inflammatory properties . Topical selenium sulphide was found to be beneficial in a variety of cases . It has both keratolytic and antifungal properties, and its effect could be due to its keratolytic effect rather than its antifungal properties . Topical (tretinoin) and oral (isotretinoin and etretinate) vitamin A derivatives have also been used with success [5-7, 13, 14], whereas other studies have not shown improvement with topical tretinoin treatment . Other topical therapies that have been used successfully include lactic acid, urea, salicylic acid, calcipotriol, and tacrolimus . Our patient responded very well to topical tretinoin (0.025% cream once daily). Continuing the treatment for a longer period is recommended to see if there is a possibility to taper the medication without causing a relapse of CARP. The major limitation of using topical tretinoin is that its application is cumbersome when extensive areas are involved and areas hard to reach in self-application (such as the back) are affected. Therefore, if a patient is able to apply the medication as the lesion is localized and easy to reach in self-application, similar to our case, topical tretinoin may provide a safer alternative to systemic therapy. 4. Conclusion CARP is an uncommon and curable dermatosis. The effectiveness of tretinoin in this patient supports the theory that CARP is a keratinization disorder. Initiation of treatment with topical tretinoin when there are no limitations on its use would be reasonable, as it can provide a safer alternative to systemic therapy. Acknowledgments The authors would like to thank Dr. Daliah Anwar Abdulhafeez, Consultant Pathologist at King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia, for her valuable contribution in histopathological imaging analysis and interpretation. Data Availability The data used to support the findings of this study are included within the article. Consent Informed consent was obtained from the patient for publication of the case description and accompanying images. Conflicts of Interest The authors declare that they have no conflicts of interest. Figure 1 Hyperpigmented, hyperkeratotic, confluent macules, and papules that coalesce into reticulated plaques over the upper trunk. Figure 2 A skin biopsy showing marked hyperkeratosis with papillomatosis in the epidermis and numerous fungal organisms (yeasts) in the corneal layer. A very scant chronic perivascular inflammatory infiltrate was noted in the dermis with edema and fibrosis. Figure 3 Resolution of the lesion within eight weeks of treatment. Figure 4 No recurrence at two-month follow-up. 1 Le C. Bedocs P. M. Confluent and reticulated papillomatosis StatPearls 2022 USA, StatPearls Publishing Treasure Island (FL) 2 Scheinfeld N. Confluent and reticulated papillomatosis a review of the literature American Journal of Clinical Dermatology 2006 7 5 305 313 10.2165/00128071-200607050-00004 2-s2.0-34347235162 17007541 3 Lee S. W. Loo C. H. Tan W. C. Confluent and reticulated papillomatosis: case series of 3 patients from Kedah, Malaysia and literature review Medical Journal of Malaysia 2018 73 5 338 339 30350820 4 Chong W. S. Lim J. H. L. Tey H. L. Confluent and reticulated papillomatosis: diagnostic and treatment challenges Clinical, Cosmetic and Investigational Dermatology 2016 9 217 223 10.2147/ccid.s92051 2-s2.0-84991765452 27601929 5 Solomon B. A. Laude T. A. Two patients with confluent and reticulated papillomatosis: response to oral isotretinoin and 10% lactic acid lotion Journal of the American Academy of Dermatology 1996 35 4 645 646 10.1016/s0190-9622(96)90703-3 2-s2.0-0030479217 8859306 6 Kagi M. K. Trueb R. Wuthrich B. Burg G. Confluent and reticulated papillomatosis associated with atopy. Successful treatment with topical urea and tretinoin The British journal of dermatology. England 1996 134 381 382 7 Schwartzberg J. B. Schwartzberg H. A. Response of confluent and reticulate papillomatosis of Gougerot and Carteaud to topical tretinoin Cutis 2000 66 4 291 293 11109153 8 Davis M. D. P. Weenig R. H. Camilleri M. J. Confluent and reticulate papillomatosis (Gougerot-Carteaud syndrome): a minocycline-responsive dermatosis without evidence for yeast in pathogenesis. A study of 39 patients and a proposal of diagnostic criteria British Journal of Dermatology 2006 154 2 287 293 10.1111/j.1365-2133.2005.06955.x 2-s2.0-33644883642 16433798 9 Tamraz H. Raffoul M. Kurban M. Kibbi A.-G. Abbas O. Confluent and reticulated papillomatosis: clinical and histopathological study of 10 cases from Lebanon Journal of the European Academy of Dermatology and Venereology 2013 27 1 e119 e123 10.1111/j.1468-3083.2011.04328.x 2-s2.0-84872855943 22050084 10 Amatya B. Sharma R. Syed M. A. Rajbhandari A. Confluent and reticulated papillomatosis of Carteaud and Gougerot in a young Nepali male Nepal Journal of Dermatology, Venereology & Leprology 2020 18 1 64 66 10.3126/njdvl.v18i1.25594 11 Nordby C. A. Mitchell A. J. Confluent and reticulated papillomatosis responsive to selenium sulfide International Journal of Dermatology 1986 25 3 194 200 10.1111/j.1365-4362.1986.tb02219.x 2-s2.0-0022634178 3699967 12 Friedman S. J. Albert H. L. Confluent and reticulated papillomatosis of Gougerot and Carteaud: treatment with selenium sulfide lotion Journal of the American Academy of Dermatology. United States 1986 14 280 282 13 Bruynzeel-Koomen C. A. de Wit R. F. Confluent and reticulated papillomatosis successfully treated with the aromatic etretinate Archives of Dermatology 1984 120 9 1236 1237 10.1001/archderm.120.9.1236 6476862 14 Hodge J. A. Ray M. C. Confluent and reticulated papillomatosis: response to isotretinoin Journal of the American Academy of Dermatology 1991 24 4 p. 654 10.1016/s0190-9622(08)80164-8 2-s2.0-0025760650 |
Case Rep Surg Case Rep Surg CRIS Case Reports in Surgery 2090-6900 2090-6919 Hindawi 10.1155/2023/5738806 Case Report Surgical Management of Atraumatic Rupture of Splenic Artery Aneurysm with Spleen Preservation in a Regional Australian Hospital Hamilton Emma Jane [email protected] 1 2 Ngugi Samuel 1 Kotakadeniya Rasika 1 1Department of General Surgery, Bundaberg Base Hospital, Bundaberg, QLD, Australia 2University of Queensland, St Lucia, QLD, Australia Academic Editor: Dimitrios Mantas 2023 6 3 2023 2023 573880615 11 2022 18 2 2023 20 2 2023 Copyright (c) 2023 Emma Jane Hamilton et al. 2023 This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A 41-year-old male presented to the emergency department of a regional Australian hospital with chest and abdominal pain. He became rapidly haemodynamically unstable and was diagnosed with a ruptured splenic artery aneurysm and large volume hemoperitoneum. Due to the regional location of our small hospital, endovascular services are not available and the patient required emergency laparotomy. At laparotomy, a 2 L hemoperitoneum was evacuated, and the bleeding splenic artery aneurysm was identified and controlled. The aneurysm was approached with a unique technique via division of the gastro colic omentum to enter the lesser sac. This allowed adequate exposure of the splenic artery and proximal and distal control of the vessel was achieved. Adequate perfusion to the spleen was preserved by this surgical technique and splenectomy was therefore not required. This study details the management of this patient, details of the interoperative technique, and a discussion regarding splenic artery aneurysms. Splenic artery control and ligation without splenectomy may be considered in appropriate patients and splenectomy is therefore not always required in cases of hemodynamic instability where open surgical management is performed. pmc1. Case Report A 41-year-old male presented to the emergency department of a regional Australian hospital with sudden onset severe chest and abdominal pain. On arrival, the patient was haemodynamically stable, but became rapidly unresponsive with oxygen saturations of 85%, tachycardia to 140 beats per minute, unrecordable blood pressure, and a Glasgow Coma Scale of 8 (eyes 3 points, voice 1 point, and motor 4 points). Bedside, ultrasound scan yielded intra-abdominal free fluid in the left upper quadrant. The patient was resuscitated sufficiently to allow prompt computerized tomography (CT) angiogram. He had no history of trauma, falls, pancreatitis, or known hypertensive crisis, and no knowledge of any previous aneurysms. CT angiogram demonstrated a large left upper quadrant intraperitoneal and retroperitoneal haematoma with dense peritoneal free fluid consistent with hemoperitoneum . A splenic artery aneurysm at least 28 mm x 16 mm was seen with active contrast extravasation . In our regional centre, there are no interventional radiology or endovascular services available; hence, the patient underwent emergency laparotomy where a 2 L hemoperitoneum was evacuated. The bleeding splenic artery aneurysm was approached via division of the gastro colic omentum and reflection of the stomach superiorly to allow exposure of the lesser sac. This allowed adequate visualisation of the length of the splenic artery and the ruptured aneurysm mid-way along the artery was easily seen. Following this exposure, control of the splenic artery vessel at two points was achieved via suture ligation: the splenic artery proximal to the aneurysmal sac and distal to the aneurysmal sac were both secured, resulting in ligation of the artery at these two points. This was sufficient to achieve haemostasis. Due to the exposure technique via division of the gastro colic omentum, the short gastric and left gastro epiploic arteries were undisturbed and left intact allowing collateral circulation to the spleen to persist despite ligation of the splenic artery. Perfusion to the spleen appeared preserved and splenectomy was not required to be performed. The patient was admitted to the intensive care unit postoperatively for monitoring and made an unremarkable recovery. A surgical drain placed into the left upper quadrant of the abdomen at the time of operation had minimal output with no evidence of ongoing bleeding and was able to be removed day 2 postoperatively. On post-operative day 3, the patient remained very well and was fit for discharge home after an ultrasound scan confirmed continuing splenic perfusion and organ viability, though noted some surrounding residual haematoma. Three weeks postoperatively, the patient remained well and underwent surveillance CT angiogram, which confirmed ongoing sufficient collateral perfusion of the spleen and viability of the organ, with a resolving peri-splenic haematoma also seen . The differential diagnosis for the cause of the peri-splenic haematoma includes inadequate evacuation of haematoma at time of operation, iatrogenic damage to collateral vessels resulting in minor bleeding postoperatively, or inadequate control of the splenic artery. The post-operative drain had minimal output and the haematoma was reduced in size on repeat imaging; therefore, inadequate evacuation of an already formed clot from the time of operation is the most likely cause. At review 6 months post-procedure, the patient remained well with no latent complications. 2. Discussion Visceral artery aneurysms can be either true aneurysms or pseudoaneurysms that affect any branch of the abdominal aorta defined as an abnormal dilation of the artery 50% greater than the baseline or normal vessel diameter . 60% of visceral artery aneurysms arise from the splenic artery, 20% from the hepatic artery, 5-8% from the superior mesenteric artery, 4% from the coeliac artery, 2-4% gastric or gastroepiploic, and 2-3% jejunal, ileal, and colic artery aneurysms . In addition, whilst splenic artery aneurysms are the most common site of visceral artery aneurysm it overall remains a rare condition with incidence in the general population believed to be around 0.8% . Splenic artery aneurysms have an annual rate of rupture between 2% and 10% in asymptomatic patients increasing to 76-83% in symptomatic patients . Mortality from spontaneous rupture of a splenic artery aneurysm in non-pregnant patients ranges from 25% to 40% with higher mortality rates in pregnant women . The aetiological cause is not able to be established in all cases, but contributing factors include atherosclerosis, multiple pregnancies, portal hypertension, acute or chronic pancreatitis, vasculitis, and congenital anomalies including fibromuscular dysplasia or collagen vascular diseases . A literature review of all documented splenic artery aneurysm cases at the time by Tessier et al. found that chronic pancreatitis was the presumed cause in 46% of patients, trauma the cause in 29% of patients, and the next most common cause was unknown or no reported cause occurring in 14% of the documented cases . Splenic artery aneurysms can occur as true aneurysms, whereby the arterial wall is weakened by a number of potential causes including atherosclerosis (32%), medial degeneration or dysplasia (24%), abdominal trauma (10%), hypertension, connective tissue disease, or necrotizing vasculitis . Pseudoaneurysms of the splenic artery have a different aetiology, whereby there is rupture of vessel intima and media resulting in a periarterial haematoma contained by the adventitia surrounding the vessel. These are more commonly caused by iatrogenic trauma or inflammatory processes, such as chronic pancreatitis . Emergency management of rupture can be via endovascular vessel embolization or splenectomy via emergency laparotomy. A study by Martinelli et al. published in 2019 recommended that endovascular approach should be considered first line even in emergency settings ; however, in our small Australian regional town endovascular management is not available with the nearest capable centre being 295 km away. The patient was deemed too unstable to await interhospital transfer; therefore, surgical management was the only readily available appropriate option in this case. The spleen is a well perfused organ with extensive collateral circulation via the superior mesenteric, pancreatic, and left gastric arteries as well as via the short gastric arteries. An anterior approach to splenectomy will require ligation of the left gastro-epiploic and short gastric arteries, which will eliminate most of the collateral circulation once the splenic artery is controlled; therefore, necessitating splenectomy . These patients who undergo splenectomy will have modified immunological function and require long term antibiotics, vaccinations, and are at increased risk of overwhelming post-splenectomy infections. There is no available literature detailing potential long-term complications post-spleen preserving open splenic artery ligation. There is however many cases detailing endovascular ligation of splenic artery aneurysms (angioembolization), which retains the spleen in situ. Complications associated with this procedure include infarction of the spleen, splenic abscess formation, pseudocyst formation, vascular injury, pancreatitis, or intestinal perforation . These complications that are secondary to splenic hypoperfusion, due to alteration in blood supply are theoretically possible in the described case though no such complications had arisen by 6 months post-procedure. In this case, the splenic artery was approached in the lesser sac at the upper border of the pancreas by dividing the gastro colic omentum. Direct ligation of the splenic artery allowed haemorrhage control whilst preserving collateral perfusing vessels. The spleen was thus able to remain situ, which is a unique approach in a haemodynamically unstable patient. Splenic artery control and ligation without splenectomy may be considered in appropriate patients and splenectomy is therefore not always required in cases of haemodynamic instability. Data Availability Data supporting this research article are available from the corresponding author or first author on reasonable request. Conflicts of Interest The author(s) declare(s) that they have no conflicts of interest. Figure 1 Large volume hemoperitoneum with active contrast extravasation from splenic artery on abdominal CT angiogram. Figure 2 Splenic artery aneurysm with active contrast blush on abdominal CT angiogram. Figure 3 CT angiogram confirming adequate collateral perfusion of the spleen 3 weeks post-laparotomy. 1 Kassem M. Gonzalez L. Splenic artery aneurysm StatPearls 2022 StatPearls Publishing [Updated 2022 July 18], [Internet], Available from: 2 Obara H. Kentaro M. Inoue M. Kitagawa Y. Current management strategies for visceral artery aneurysms: an overview Surgery Today 2020 50 1 38 49 10.1007/s00595-019-01898-3 31620866 3 Moon D. Lee S. Hwang S. Characteristics and management of splenic artery aneurysms in adult living donor liver transplant recipients Liver Transplantation 2009 15 11 1535 1541 10.1002/lt.21885 19877249 4 Mattar S. Lumsden A. The management of splenic artery aneurysms: experience with 23 cases The American Journal of Surgery 1995 169 6 580 584 10.1016/S0002-9610(99)80225-6 7771620 5 Abdulrahman A. Shabkah A. Hassanain M. Aljiffry M. Ruptured spontaneous splenic artery aneurysm: a case report and review of the literature International Journal of Surgery Case Reports 2014 5 10 754 757 10.1016/j.ijscr.2014.08.021 25240215 6 Tessier D. Stone W. Fowl R. Andrews J. Bower T. Gloviczki P. Clinical features and management of splenic artery pseudoaneurysm: case series and cumulative review of literature Journal of Vascular Surgery 2003 38 5 969 974 10.1016/S0741-5214(03)00710-9 14603202 7 Martinelli O. Giglio A. Irace L. Di Girolamo A. Gossetti B. Gattuso R. Single-center experience in the treatment of visceral artery aneurysms Annals of Vascular Surgery 2019 60 447 454 10.1016/j.avsg.2019.01.010 31009733 8 Al-Habbal Y. Christophi C. Muralidharan V. Aneurysms of the splenic artery a review The Surgeon 2010 8 4 223 231 10.1016/j.surge.2009.11.011 20569943 9 Crichton J. Naidoo K. Yet B. Brundage S. Perkins Z. The role of splenic angioembolization as an adjunct to nonoperative management of blunt splenic injuries: a systematic review and meta-analysis Journal of Trauma and Acute Care Surgery 2017 83 5 934 943 10.1097/TA.0000000000001649 29068875 |
Case Rep Cardiol Case Rep Cardiol CRIC Case Reports in Cardiology 2090-6404 2090-6412 Hindawi 10.1155/2023/9335392 Case Report Spontaneous Closure of a Coronary Artery Bypass Graft Pseudoaneurysm Embedded in a Mediastinal Hematoma Hess Daniel L. [email protected] 1 Horde Gaither W. 1 Sarode Karan 2 Morgan William S. 3 Kamal Salmaan Z. 1 Watts Jubal R. 3 Chapman Gregory D. 4 1Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA 2Division of Cardiology, Department of Internal Medicine, Texas Tech University Health Sciences Center El Paso, El Paso, TX, USA 3Department of Radiology, University of Alabama at Birmingham, Birmingham, AL, USA 4Division of Cardiology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA Academic Editor: Ertugurul Ercan 2023 6 3 2023 2023 93353923 8 2022 22 12 2022 23 1 2023 Copyright (c) 2023 Daniel L. Hess et al. 2023 This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Coronary artery bypass graft (CABG) pseudoaneurysms are a rare but often unrecognized clinical entity. They are prone to rupture and hemodynamic compromise and should therefore be on the differential in the appropriate patient. We present a case of a gentleman with a recent CABG surgery who presented with acute onset dyspnea and a large pleural effusion. Imaging revealed a saphenous vein graft pseudoaneurysm embedded in a mediastinal hematoma. Four weeks later, prior to planned stenting, the pseudoaneurysm had spontaneously closed. This case highlights an unusual acute presentation of a CABG pseudoaneurysm and a multidisciplinary approach to its management. pmc1. Introduction Pseudoaneurysms of coronary artery bypass graft (CABG) vessels are rare, estimated to develop in <0.1% of grafts . Pseudoaneurysms, or false aneurysms, are disruptions of the vessel wall that remain bounded by the outermost adventitial layer, with formation of a hematoma at the site of disruption. This is in contrast with true aneurysms, which are disruptions of all three layers of the vessel wall (intima, media, and adventitia). Because they lack the smooth muscle cell-rich medial layer that provides vascular wall integrity, pseudoaneurysms are more prone to rupture than aneurysms . Because of their rarity, there is no consensus on optimal treatment modality of CABG pseudoaneurysms. Here, we present a case of a gentleman who presented with acute onset dyspnea, who was found to have a CABG pseudoaneurysm leading to a mediastinal hematoma and hemothorax. 2. Case Presentation A 73-year-old male with a medical history of heart failure with reduced ejection fraction (40%), diabetes mellitus, atrial fibrillation (on apixaban), chronic obstructive pulmonary disease, and three vessel CABG [saphenous vein (SV) aorta-right posterior descending artery (rPDA), SV aorta-obtuse marginal, and left internal mammary artery-proximal left anterior descending] approximately six months prior to presentation, presented with the acute onset of dyspnea while walking up a ramp at his home. The dyspnea continued for two days until his presentation to the emergency department. On admission physical examination, he had increased work of breathing and decreased breath sounds over the left lung base. Labs were significant for anemia (hemoglobin 8.5 g/dL) and undetectable serial troponins. Initial chest X-ray showed bibasilar opacities. Subsequent computed tomography (CT) chest without contrast showed a soft tissue density within the anterior mediastinum and pericardial cavity as well as a loculated left-sided pleural effusion. A thoracostomy tube was inserted, and pleural studies were consistent with an exudative effusion with over 2.5 million red blood cells but no malignant cells or infectious process. The chest tube output totaled approximately 3 L of bloody fluid over the next 5 days before the output stopped, and the chest tube was able to be removed. CT chest with contrast was then obtained, which showed a 1.5 cm blush of contrast at the level of the SV aorta-rPDA graft that was embedded in the same mediastinal mass seen on prior CT and 1(b)). This suggested a pseudoaneurysm arising from the CABG graft that was embedded within a mediastinal hematoma. Subsequent left heart catheterization confirmed a pseudoaneurysm arising from the SV aorta-rPDA graft measuring approximately 1.5 cm in diameter ; Video 1). This led to consultation with our cardiology and cardiothoracic surgery colleagues. The most likely explanation for the patient's presentation was a disruption in the SV graft pseudoaneurysm leading to a mediastinal hematoma and hemothorax. The patient was not a good surgical candidate given relatively recent CABG and his multiple medical co-morbidities. Ultimately, we decided to proceed with placement of an off-label covered stent across the site of the pseudoaneurysm. However, placement of an off-label covered stent required Institutional Review Board approval for emergent use. Although there was concern the pseudoaneurysm could further expand, the halted output from the chest tube as well as the patient's hemodynamic stability suggested that the pseudoaneurysm was contained. Because of this and the time required for approval of the stent, the patient was discharged with strict return precautions with plan for direct admission in three weeks for repeat left heart catheterization and placement of a covered stent across the pseudoaneurysm. The only medication change made on discharge was continuing to hold his apixaban for his atrial fibrillation given the risk of further expansion of his mediastinal hematoma. Repeat left heart catheterization three weeks after discharge showed a patent SV aorta-rPDA with spontaneous resolution of the pseudoaneurysm ; Video 2), thus precluding use of the stent. Intravascular ultrasound confirmed closure of the pseudoaneurysm, although a minimal remnant pseudoaneurysm could be seen. The patient was doing well at cardiology follow-up approximately two months later. Cardiac CT with three-dimensional angiography approximately three and a half months after initial presentation showed persistent resolution of the pseudoaneurysm, with a hematoma that had decreased in both size and density ). 3. Discussion Treatment approaches for CABG pseudoaneurysms include open surgical repair, endovascular interventions such as placement of covered stents, or observation . There is no consensus on optimal treatment because there is limited data and no randomized controlled trials comparing one approach versus another. Previous literature suggests that they should be considered for repair if large (e.g. >1 cm) or if associated with symptoms . In our case, we concluded that the patient's presenting symptoms were related to the pseudoaneurysm, after ruling out other potential etiologies. Since the pseudoaneurysm was embedded in a mediastinal hematoma, there was an initial disruption in the wall of the pseudoaneurysm, with hemostasis later achieved by tamponade from accumulating hematoma. When the SV was harvested during surgery, clips were placed on the branches to promote hemostasis. The most likely cause of the bleed was a dislodgement of a clip on one of the SV branches, leading to blood loss from the midportion of the graft. While it seems most likely that dislodgement of a clip led to the bleed, the patient was also on apixaban chronically for atrial fibrillation. We cannot rule out that apixaban contributed to expansion of the bleed, though apixaban was held throughout the hospitalization and on discharge. Additionally, because the epicardial layer is stripped during bypass graft operations, it is possible a communicating tract formed between the mediastinum and pleural space, leading to the patient's hemothorax. Indeed, there have been descriptions of CABG pseudoaneurysms causing complications including expanding to the point of compression of the right atria, ventricle, or main pulmonary artery . Another report describes a patient with chest pain who went for cardiac catheterization which showed a pseudoaneurysm with active extravasation. The patient died of cardiogenic shock before procedural intervention could be performed . In our case, given the pseudoaneurysm was embedded in hematoma, indicative of prior bleed, it seemed most appropriate to intervene, especially given its size and risk of potential expansion and/or rupture. Successful closure of a SV graft pseudoaneurysm using a covered stent has previously been reported . In our case, it was fortunate the pseudoaneurysm spontaneously closed, but there were no indications or data to suggest it would. The rate of spontaneous closure of CABG pseudoaneurysms is unknown, both because of their rarity and because many likely go undetected given lack of symptoms. However, to our knowledge, this is only the second report of the spontaneous closure of a CABG pseudoaneurysm . In the end, diagnosis and management of this rare clinical entity required a multidisciplinary approach and ultimately resulted in an equally rare outcome. Acknowledgments The authors acknowledge and thank all providers and ancillary staff that participated in the care of the patient. Abbreviations CABG: Coronary artery bypass graft SV: Saphenous vein PDA: Posterior descending artery. Data Availability Original figures and videos related to the case can be made available after publication, upon request. Disclosure JRW is on the speaker's bureau for Boehringer Ingelheim Pharmaceuticals. Conflicts of Interest The author(s) declare(s) that they have no conflicts of interest. Figure 1 Pseudoaneurysm arising from a CABG graft. (a) and (b) A blush of contrast consistent with a potential pseudoaneurysm could be seen arising from the SV aorta-rPDA graft. It was embedded in a mediastinal hematoma. (c) Left heart catheterization confirmed the presence of a pseudoaneurysm arising from the SV aorta-rPDA graft. Figure 2 Spontaneous closure of pseudoaneurysm. (a) During left heart catheterization approximately four weeks after initial presentation, there was no detectable pseudoaneurysm, consistent with spontaneous closure. (b) On follow-up CT imaging approximately three and a half months after initial presentation, there was again no detectable pseudoaneurysm and the mediastinal hematoma had decreased in size. 1 Smer A. Alla V. Chandraprakasam S. Saphenous venous graft pseudoaneurysm: a review of the literature Journal of Cardiac Surgery 2015 30 1 70 73 25363741 2 Hulten E. A. Blankstein R. Pseudoaneurysms of the heart Circulation 2012 125 15 1920 1925 22508841 3 Sareyyupoglu B. Schaff H. V. Ucar I. Surgical treatment of saphenous vein graft aneurysms after coronary artery revascularization Annals of Thoracic Surgery 2009 88 6 1801 1805 10.1016/j.athoracsur.2009.07.048 2-s2.0-71649109800 19932238 4 Duran Crane A. Newtown E. Cremer P. Conservative vs. invasive treatment of aortocoronary saphenous vein graft aneurysms: treatment algorithm based upon a large series Cardiovascular Surgery 2003 11 6 507 513 14627974 5 Thayse K. Baldassarre S. Carlier S. Ruptured pseudoaneurysm of coronary artery bypass graft European Heart Journal Case Reports 2021 5 2 10 11 6 Jehangir Q. Lambert C. Sawar A. Saphenous vein graft pseudoaneurysm repair with GraftMaster(r) Cureus 2018 10 11 1 8 7 Abe T. Terada T. Noda R. Spontaneous disappearance of a saphenous vein graft pseudoaneurysm after coronary artery bypass grafting Annals of Thoracic Surgery 2013 95 1 345 346 10.1016/j.athoracsur.2012.05.088 2-s2.0-84871876038 23272859 |
Case Rep Infect Dis Case Rep Infect Dis CRIID Case Reports in Infectious Diseases 2090-6625 2090-6633 Hindawi 10.1155/2023/2619785 Case Report A Rare Case of Acute Pancreatitis as Dengue Complication Nguyen Tuy Hong Thi 1 Nguyen Hien Quang [email protected] 2 1Tam Anh Hospital, Ho Chi Minh City, Vietnam 2University of Medicine and Pharmacy, Ho Chi Minh City, Vietnam Academic Editor: Bhim Gopal Dhoubhadel 2023 6 3 2023 2023 261978510 1 2023 16 2 2023 21 2 2023 Copyright (c) 2023 Tuy Hong Thi Nguyen and Hien Quang Nguyen. 2023 This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. A 31-year-old male was admitted to the hospital because of fever for 2 days. He also had chills, headaches, muscle aches, fatigue, and diarrhea. His vital signs were stable. Dengue virus nonstructural protein 1 (NS1) antigen was positive. Laboratory tests were significant for thrombocytopenia of 67.000/mm3 and high hematocrit of 45%. On the fifth day of the onset of fever, he experienced sudden epigastric pain. Laboratory results showed elevated serum amylase and lipase. Noncontrast abdominal CT findings were consistent with acute pancreatitis, Balthazar grade D. The patient was managed with supportive care and bowel rest. Two days later, his condition became stable, and he was discharged without complications. pmc1. Introduction Dengue is a viral disease, transmitted by Aedes species mosquito, endemic to parts of Asia and South America, among which Vietnam is one of the countries carrying the highest burden, reaching more than 100,000 caseson average every year. The highest incident was 320,331 casesin 2019, with 53 fatalities. There are four serotypes of the virus belonging to the Flaviviridae family that cause dengue. The majority of dengue virus infection cases are asymptomatic or present with mild symptoms. However, dengue also can manifest as a severe illness, including hemorrhage or shock syndrome, and in rare cases, it is fatal [1-3]. Although the diagnosis of dengue is not difficult, especially in the endemic areas, and in the season when the disease surges, early recognition of severe conditions is paramount in treatment and prognosis. We report a severe dengue case, complicated with acute pancreatitis, a very rare and atypical clinical association. 2. Case Presentation A 31-year-old male patient with no prior medical history presented to the emergency room with high-grade fever for 2 days. He also had chills, headaches, muscle aches, fatigue, and diarrhea. He used over-the-counter acetaminophen to control his symptoms. On admission, the patient was oriented. His temperature was 38degC, blood pressure was 130/90 mmHg, pulse was 92 bpm, respirations were 20 bpm, and oxygen saturation was 98%. Physical examination showed no abdominal pain, no organomegaly, a negative Murphy's sign, and no evidence of mucocutaneous bleeding. Laboratory tests were significant for thrombocytopenia with platelet count of 67.000/mm3, high hematocrit (45%), hemoglobin level of 15.2 g/dL, leukocyte count of 3.310/mm3, and a positive NS1 antigen test. His liver enzymes were mildly elevated, AST was 89 U/L, and ALT was 69 U/L; serum HbsAg and HCV antibody were negative. Serum creatinine and C-reactive protein were within normal limits. Abdominal ultrasound showed normal liver and pancreas sizes, thickening gallbladder wall (8 mm), and no intraperitoneal fluid was noted. Chest X-ray was unremarkable. In the hospital, his diarrhea was worsening, more than 5 times a day. On the fifth day after the onset of fever, he started to have burning-like abdominal pain, which was localized in the epigastrium and radiated to the back. He had 2-3 episodes of nausea and vomiting per day. He also developed petechiae over his lower limbs. Laboratory results showed elevated serum amylase (174 U/L) and lipase (606 U/L). Platelet count decreased to 10.000/U, hematocrit was 51%, leukocyte count was 5.200/mm3, and serum triglyceride was 3.81 mmol/L (Table 1). Plain abdominal computed tomography revealed an enlarged pancreas, peripancreatic fat stranding, and peripancreatic fluid collection (Balthazar score D) along with a minimal right pleural effusion . He was managed with intravenous fluids, analgesics, antacid, and bowel rest. Two days later, his clinical condition became stable, he started to be afebrile, the abdominal pain was resolved, and his platelet cell count was trending up. Subsequently, he was discharged without complications. 3. Discussion This case report emphasizes the notability of the diagnosis of acute pancreatitis in patients with dengue who abruptly develop severe abdominal pain. Our patient was admitted to the hospital with fever and severe thrombocytopenia. A positive NS1 test result confirmed dengue. During hospitalization, he developed sudden onset of abdominal pain along with elevated amylase and abnormal abdominal CT, which indicated the presence of pancreatitis. This association is unusual, with only a few cases were represented in the literature . The two most common etiologies associated with acute pancreatitis are gallstones and alcohol consumption. Cholelithiasis is seen in approximately 40-70% of cases, while alcoholism is present in 25-35% of cases. Less frequent causes include trauma, medications, autoimmune diseases, congenital abnormalities, hypercalcemia, or infections . There are many organisms associated with infectious pancreatitis, including parasites, bacteria, and viruses. A notable pathogen in the tropical areas is Ascaris lumbricoides, which induces pancreatitis by obstruction of the biliary and pancreatic duct. In particular, viruses are the most common microbes that account for infectious pancreatitis, including hepatitis viruses, Coxsackie virus, mumps, varicella-zoster virus, CMV, EBV, HSV, and HIV . The mechanism of viral-induced pancreatitis is still controversial. Many researchers have provided different hypotheses. Pancreatic islet cells can be destroyed directly by viruses, as well as by inflammatory reactions, or cellular edema in response to viral infection. This hypothesis is supported by autopsies showing that HBV antigen present in the cytoplasm of exocrine pancreatic cells. Pancreatic enzymes from injured cells can be leaked and can provoke pancreatic necrosis. Another explanation is that the ampulla of Vater or the pancreatic duct has gotten edema, leading to the obstruction of the outflow of pancreatic fluid . It is reasonable that multiple mechanisms can contribute to pancreatitis at the same time, as we believe in our case of dengue. However, it can be challenging to definitively determine whether pancreatitis is a complication of dengue or merely a coincidence. The association between the two is rarely reported to establish a statistically significant correlation. Nonetheless, as we mentioned, there is a reasonable hypothesis about how viruses can induce pancreatitis, and therefore, a causative relationship between the two clinical presentations is believed to exist. Imaging has indispensable values in the assessment of organ involvement in dengue. On ultrasonography, gallbladder wall thickening (GBWT) can be a useful screening finding for dengue as well as a predictive factor for severity and prognosis. GBWT is an indicator of increased capillary permeability, the pathophysiology of dengue. A GBWT of more than 3 mm has a high sensitivity for detecting dengue. GBWT greater than 3 mm is associated with more severe cases, and patients with GBWT above 5 mm increase risk of developing hypovolemic shock . Our patient with GBWT of 8 mm had a higher risk of severe complications. Performing ultrasonography of the pancreas in patients with dengue hemorrhagic fever, Setiawan reported an enlarged pancreas was found in 29% of cases, 14% of whom had mild and 44% of whom had severe clinical presentations. The pancreas was hyperechoic compared with the liver in 25% of cases, isoechoic in 69%, and hypoechoic in 6% of cases . Therefore, when a patient with dengue presents with abdominal pain, it is important to perform imaging studies such as ultrasonography and CT scans, if available, to detect early organ involvement and enable effective management. It is noteworthy that in dengue-endemic countries of South and Southeast Asia, many clinical centers may not have access to CT scans. In these situations, diagnosis may rely on clinical signs, including typical abdominal pain and elevated pancreatic enzymes. Treatment of dengue-induced pancreatitis is similar to that in other etiologies, with primary management being supportive and bowel rest. Our patient had mild pancreatitis and recovered 2 days after the onset of epigastrium pain. To date, no predisposing factors have been identified to predict the onset of pancreatitis in patients with dengue. This complication may occur unpredictably, emphasizing the importance of early detection and providing adequate supportive treatment, which plays the most crucial and effective role. 4. Conclusions Acute pancreatitis should be considered in patients with dengue, who presents with sudden new onset of severe abdominal pain. Pancreatic imaging and amylase levels are the next steps in management. Appropriate early intervention plays a vital role in treatment and recovery. Data Availability The data used to support the findings of this study are included within the article. Consent Written informed consent for publication of the patient's clinical details and images was obtained from the patient prior to submission. A copy of the signed consent form is available for review by the editor of the journal. Conflicts of Interest The authors declare that they have no conflicts of interest. Figure 1 Noncontrast abdominal CT showing an enlarged pancreas, peripancreatic fat stranding, and peripancreatic fluid collection, consistent with Balthazar score D. Table 1 Clinical and laboratory results on admission and 3 days after hospitalization. On admission 3 days after hospitalization Clinical signs (i) Fever (day 2) (i) Fever (day 5) (ii) Diarrhea (ii) Diarrhea worsening (iii) Chills, headaches, muscle aches, and fatigue (iii) Chills, headaches, muscle aches, and fatigue continuing (iv) Sudden epigastric pain, nausea, and vomiting Plt (k/mL) 67 10 Hct (%) 45 51 HGB (g/dL) 15.2 17.4 WBC (k/mL) 3.31 5.2 Others (i) NS1 : positive (i) Serum amylase: 174 U/L (ii) AST: 89.1 U/L (ii) Serum lipase: 606.6 U/L (iii) ALT: 69.7 U/L 1 Agrawal A. Jain N. Gutch M. Shankar A. Acute pancreatitis and acute respiratory distress syndrome complicating dengue haemorrhagic fever Case Reports 2011 2011 1 bcr1020114891 10.1136/bcr.10.2011.4891 2-s2.0-81455143197 2 Jain V. Gupta O. Rao T. Rao S. Acute pancreatitis complicating severe dengue Journal of Global Infectious Diseases 2014 6 2 76 78 10.4103/0974-777x.132050 2-s2.0-84901405020 24926168 3 Seetharam P. Rodrigues G. 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This guideline will provide a practical roadmap for management of SSc that builds upon the previous treatment guideline to incorporate advances in evidence-based treatment and increased knowledge about assessment, classification and management. General approaches to management as well as treatment of specific complications will be covered, including lung, cardiac, renal and gastrointestinal tract disease, as well as RP, digital vasculopathy, skin manifestations, calcinosis and impact on quality of life. It will include guidance related to emerging approved therapies for interstitial lung disease and account for National Health Service England prescribing policies and national guidance relevant to SSc. The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol. This development process to produce guidance, advice and recommendations for practice has National Institute for Health and Care Excellence accreditation. scleroderma SSc pulmonary fibrosis guideline management British Society for Rheumatology pmc NICE has accredited the process used by BSR to create its clinical guidelines. The term began on 27 February 2012 and the current renewed accreditation is valid until 31 December 2023. More information on accreditation can be viewed at www.nice.org.uk/accreditation. Why the guideline is needed The current British Society for Rheumatology (BSR) guideline for SSc was published in 2016 and represented an important step forward for management of this complex disease with high morbidity, mortality and unmet medical need. It provides a roadmap for best practice management to try and harmonize treatment and investigation of SSc and defines key quality and audit standards that can be used to assess practice and improve outcomes. Updating the guideline is now required to conform to the National Institute for Health and Care Excellence accreditation process that applies to BSR guidelines and has important implications for application and implementation across National Health Service (NHS) England. The guideline will be developed using the methods and processes outlined in Creating Clinical Guidelines: Our Protocol . Moreover, there have been important new trials and evidence-based therapies (e.g. nintedanib, tocilizumab and soon rituximab for lung fibrosis) as well as changes in NHS England prescribing policies (e.g. digital ulcers) that mean the present guideline no longer reflects current best practice and does not reflect all the available high-quality evidence that can underpin management of SSc. The previous guideline did not include children and young people. In line with other BSR guidelines and equality considerations, we feel it is important to also represent the needs of children and young people and update the guideline to include all ages of people affected by SSc. Key facts and figures SSc affects 1-2 in 10 000 of the UK population and is complex and diverse, with limited treatment options . It has the highest mortality of any of the autoimmune rheumatic diseases, with approximately half of people affected by SSc eventually dying as a direct result of the disease or a related complication . Approximately 1 in 3 people with SSc develops lung fibrosis and 1 in 10 may develop pulmonary hypertension, and these are currently the most frequent direct causes of SSc-related death . Of people with SSc, 1 in 5 develops overlap connective tissue diseases, which require specific management in parallel with SSc. It is plausible that vigilant screening for organ-based complications and routine use of disease-modifying immunosuppression in dcSSc have improved overall survival, and this is supported by single-centre observational cohort analysis . Current practice Current management is generally centred on rheumatology clinics in a secondary care setting with appropriate involvement and cross-referral to other specialties including dermatology, respiratory medicine, gastroenterology and others. There are important shared care links with other specialists. Treatment may include centres commissioned for specialized rheumatology and may also involve national designated centres for specific complications such as pulmonary hypertension. There are many management challenges that will be considered in the BSR treatment guideline to harmonize care and define auditable standards. More systematic approaches to investigation and treatment of major complications such as scleroderma renal crisis or pulmonary arterial hypertension (PAH) likely explain this better outcome. The availability of a series of best practice recommendations that were published by the UK Systemic Sclerosis Study Group, together with evidence-based recommendations from EULAR/EUSTAR that were published in 2009 and updated in 2015 , have helped to harmonize management across expert centres. The BSR treatment guideline provides a template for management within the UK NHS since it was published in 2016 . Some available treatments such as autologous haematopoietic stem cell transplantation need very specialist centres and a framework of multidisciplinary and multiprofessional care is required. Challenges in current practice are early diagnosis, timely referral to secondary care, integrated management with shared care, including appropriate tertiary centres and specialists, and ongoing management of disease burden and non-lethal morbidity. Recent studies suggest a treatment landscape of supportive or symptomatic treatment in most patients diagnosed with SSc, but also highlight the challenge of delayed diagnosis in those patients with milder or less complete disease that may fulfil proposed criteria for very early diagnosis of SSc . Another challenge is those presenting with a major organ-based complication such as thrombotic microangiopathy, PAH or interstitial lung disease (ILD) but who have not yet been diagnosed with SSc although they may fulfil the 2013 ACR/EULAR classification criteria . For dcSSc skin disease, most people are treated with immunosuppression along the lines explored in the large European Scleroderma Observational Study with MMF, MTX or sometimes intravenous CYC. Immunosuppression is also routinely used for SSc-ILD based on expert opinion and published clinical trial data. Recent clinical trials have confirmed or suggested the benefit of other approaches to SSc-ILD, including nintedanib, tocilizumab and rituximab . These will be reviewed in the scope of the updated BSR guideline. Who the guideline is for This guideline is for: rheumatologists, dermatologists, respiratory physicians and other clinicians involved in management of people with SSc; specialist nurses and allied healthcare professionals involved in caring for people with SSc; people with SSc and primary care clinicians. Equality considerations All ages and ethnicities are affected by scleroderma, but the need for high-quality education, long-term community-based management and the use of specialized treatments and ongoing screening means that language and cultural barriers to equitable and excellent care need to be considered and addressed. What the guideline will cover Who is the focus? Groups that will be covered The guideline will cover people of all ages with SSc. Relevance to young people with SSc will also be considered with inclusion of relevant paediatric rheumatology expertise in the working group and dissemination of the guideline to all stakeholders. This will include lcSSc, dcSSc, SSc sine scleroderma and overlap SSc fulfilling classification criteria (EULAR/ACR 2013) . Groups that will not be covered Treatment of localized scleroderma (morphoea) and of 'scleroderma-like' conditions (e.g. scleroedema, scleromyxedema, fasciitis, nephrogenic systemic fibrosis) will not be considered in this guideline. Settings Settings that will be covered Settings that will be covered include SSc in hospital-based settings including secondary care rheumatology, other specialized care including tertiary hospital settings and in communities of shared care and primary care settings. Key areas that will be covered We will look at evidence in the following areas when developing the guideline, but it may not be possible to make recommendations in all the areas: early diagnosis, classification and stratification of risk; global management of SSc; treatment of organ-based complications of SSc, both drug and non-drug; and organizations or services for SSc within the NHS, including paediatric services and transition of paediatric patients to adult services. Related guidance Related guidance includes the published BSR guideline (2016) , EULAR recommendations (published 2009; updated 2016) , European Dermatology Forum Guideline (Part 1, 2017) , UKSSG best practice recommendations (gastrointestinal complications, cardiac disease, renal crisis, digital vasculopathy) [14-17] and the Single Hub and Access point for paediatric Rheumatology in Europe recommendations on juvenile SSc . Key issues and draft questions The working group has identified the following key issues and draft questions related to them. The key issues and draft questions will be used to develop more detailed review questions, which will guide the systematic review of the literature. Proposed updated guideline structure General approach to SSc management The working group recognizes the importance of timely diagnosis of SSc and that there have been advances in understanding early identification of the disease. Delays in diagnosis should be minimized. As previously, it is appropriate that early dcSSc is a particularly important diagnosis because of the early risk of severe internal organ complications and the need for specialist referral and initiation of disease-modifying treatment with immunosuppression. Current priorities and approach What is the best approach to timely diagnosis and specialist referral? How can people with SSc be classified for stratified medicine and management? What are the best treatments for early dcSSc? When and how should people with SSc be screened for concurrent malignant disease? What non-pharmacological treatments are supported by evidence, including vitamins, supplements, massage (manual lymph drainage) and psychological support for early new diagnosis and established disease? Key therapies and treatment of organ-based disease in SSc This section will update and expand the management and treatment recommendations included in the previous BSR guidelines. Trials for several new treatments have been published for complications such as SSc-ILD and PAH. In addition, new approaches to treatment with established therapies are likely to be considered, including autologous haematopoietic stem cell transplantation. These topics will be considered in the following questions: Autologous stem cell transplantation Which people with SSc should be considered for autologous stem cell transplantation, taking into account the risks as well as potential long-term benefits? Cardiopulmonary complications How should ILD in SSc be managed and treated, taking into account new approved drugs such as nintedanib with emerging evidence supporting the use of targeted biological agents? What is the best evidence-based management and treatment for pulmonary hypertension, including PAH? What is the best evidence-based management and treatment for cardiac involvement? Digital vasculopathy What is the best evidence-based management and treatment for Raynaud's phenomenon (RP)? What is the best evidence-based management and treatment for digital ulceration? What is the best evidence-based management and treatment for critical digital ischaemia? Gastrointestinal tract disease What is the best evidence-based management and treatment for gastrointestinal complications, including nutrition, oropharyngeal and dental aspects (sicca syndrome)? Renal complications What is the best evidence-based management and treatment for scleroderma renal crisis? Skin complications What is the best evidence-based management and treatment for skin manifestations in addition to skin thickening and fibrosis such as telangiectasis and pruritis? What is the best evidence-based management and treatment for calcinosis in SSc? Neurological complications What is the best way to manage and treat neurological complications of SSc, including peripheral neuropathy, allodynia, cranial neuropathy and neuralgia? Musculoskeletal disease, fatigue and quality of life What is the best way to manage and treat musculoskeletal manifestations of SSc, including soft tissue loss, contractures, arthritis and bone health? What is the best evidence-based management and treatment for pregnancy and reproductive health problems, including male and female sexual dysfunction? What are the best interventions for general impact of SSc on health status and quality of life, including fatigue? Service organization and delivery within NHS England and devolved nations The working group recognizes that there are challenges delivering high-quality equitable care for SSc across England and the devolved nations. This reflects the infrequency of SSc in primary and secondary care and its clinical diversity, as well as the need for comprehensive multispecialist and interdisciplinary clinical care. In addition, while treatment options are increasing, it is recognized that clinical impact can be limited, and even with optimal management there is a significant unmet medical need for people with SSc. The group will provide feasible and appropriate ways of benchmarking delivery of care and assessing standards so that audits of service delivery as well as patient-specific evaluations can be undertaken in a robust and standardized way. It is likely that SSc will provide a template that may be relevant to other uncommon multisystem autoimmune rheumatic diseases managed across the NHS. Approaches to audit of the guideline What are reasonable key quality standards? How can an audit of the guideline be best performed to assess service delivery and to undertake a patient-specific audit? The guideline is expected to be published in 2024. Guideline working group Chris Denton (chair), Voon Ong (rheumatologist), Ariane Herrick (rheumatologist), Maresa Carulli (rheumatologist), Francesco del Galdo (rheumatologist and EUSTAR guideline liaison), Elizabeth Renzoni (respiratory physician), John Pauling (rheumatologist), Emma Derrett-Smith (rheumatologist), Jeremy Royle (rheumatologist), Muditha Samaranayaka (rheumatologist), Nuala O'Donoghue (dermatologist), Michael Hughes (rheumatologist), Athiveeraramapandian Prabu (rheumatologist), Karen Douglas (rheumatologist), Bridget Griffiths (rheumatologist), Maya Buch (rheumatologist), Clare Pain (paediatric rheumatologist), Julia Spierings (autoimmune disease stem cell transplant expert), Luke Gompels (rheumatologist), Caroline Cotton (BSR Standards, Audit and Guidelines Working Group liaison), Aoife Tynan (pharmacist), Kim Fligelstone (patient representative), Georgina Pantano (patient representative), Begonya Alcacer-Pitarch (allied healthcare representative), Louise Warburton (general practitioner), Emma Blamont and Sue Farrington (Scleroderma & Raynaud's UK patient organization), Nina Goldman (respiratory medicine fellow), Enrico De Lorenzi (rheumatology fellow) and Elen Roblin (rheumatology fellow). Data availability No new data were generated in support of this work. Authors' contributions C.P.D. and V.O. drafted this article. All authors contributed to developing the guideline scope, provided critical manuscript editing and revision, and approved the final submitted version. Funding This work was supported by the British Society for Rheumatology. Disclosure statement: C.P.D. has received research grants or consulting fees from Arxx Therapeutics, Roche, Janssen, GlaxoSmithKline, Bayer, Sanofi, Galapagos, Boehringer Ingelheim, CSL Behring, Acceleron, Horizon and Corbus. The remaining authors have declared no conflicts of interest. |
Cureus Cureus 2168-8184 Cureus 2168-8184 Cureus Palo Alto (CA) 10.7759/cureus.34875 Gastroenterology A Case of Refractory Gastric Antral Vascular Ectasia Treated Successfully With Distal Gastrectomy and Billroth II Reconstruction Muacevic Alexander Adler John R Itagaki Hideya 1 Suzuki Katuhiko 2 Endo Tomoyuki 1 1 Department of Emergency and Disaster Medicine, Tohoku Medical and Pharmaceutical University Hospital, Miyagi, JPN 2 Surgery, Honjoudaiichi Hospital, Yurihonjou, JPN Hideya Itagaki [email protected] 11 2 2023 2 2023 15 2 e3487511 2 2023 Copyright (c) 2023, Itagaki et al. 2023 Itagaki et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. This article is available from Gastric antral vascular ectasia is a rare cause of upper gastrointestinal bleeding and an important cause of transfusion dependence. Although surgery should be considered when patients with gastric antral vascular ectasia become transfusion-dependent even after endoscopic treatment, surgery for such patients with cirrhosis on dialysis has not been reported. Our patient, a 62-year-old man with a history of cirrhosis and chronic kidney failure, experienced recurrent bloody stool. Upper endoscopic findings indicated a diagnosis of gastric antral vascular ectasia; therefore, we initiated therapy with argon plasma coagulation. Anemia developed, and despite a second argon plasma coagulation treatment, it remained difficult to control. During the six weeks of hospitalization, the patient received more than 40 units of red blood cells. The gastroenterologist determined that further treatment with argon plasma coagulation would increase the risk of gastric perforation; therefore, we performed distal gastrectomy with Billroth II reconstruction. The patient was discharged from the hospital 15 days after surgery and had no signs of anemia for more than one year after discharge. The case of our patient shows that although endoscopic therapy is the usual treatment for gastric antral vascular ectasia, surgery should be considered when anemia is difficult to control. upper gastrointestinal(ugi) bleeding distal gastrectomy argon plasma coagulation diffuse antral vascular ectasia gastric antral vascular ectasia The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus. pmcIntroduction Gastric antral vascular ectasia (GAVE) was first described by Rider et al. in 1953, but its pathophysiological features remain largely unexplored . This disease is a rare but important cause of upper gastrointestinal bleeding because affected patients can become transfusion dependent . Although endoscopic treatment is considered the "gold standard" for GAVE, surgery is considered a last resort in refractory cases . We report the case of a patient with GAVE who twice underwent argon plasma coagulation (APC), an endoscopic treatment, but in whom GAVE recurred and transfusion-dependence developed; therefore, we performed pyloric gastrectomy with Billroth II reconstruction to control bleeding. Case presentation A 62-year-old man visited our hospital emergency department because of anemia and bloody stool. The patient had been admitted to our gastroenterology department approximately three weeks earlier for anemia (hemoglobin [Hb]: 6.6 g/dL). After admission, upper endoscopy revealed hemorrhagic gastritis, and the patient underwent a blood transfusion and was discharged two weeks later. However, bleeding started immediately after discharge, and a blood test performed at his local doctor's office the day before his visit to the emergency department revealed that his Hb level had dropped to 4.0 g/dL. Therefore, a recurrence of gastrointestinal bleeding was suspected, and the patient was referred to our emergency department the next day. The patient had no related family history, but his medical history included diabetes, chronic kidney failure (treated with hemodialysis), prostate cancer, chronic hepatitis B, and cirrhosis; his Child-Pugh score was B. He was taking rosuvastatin, cinacalcet hydrochloride, voglibose, alogliptin benzoate, glimepiride, enzalutamide, and vonoprazan fumarate (a potassium-competitive acid blocker) , all of which had been prescribed at other hospitals. Physical examination on the patient's arrival at our department revealed normal vital signs and no abdominal tenderness; however, the digital rectal examination revealed tarry stool. Blood test results indicated severe anemia (Hb: 4.0 g/L); therefore, we performed an emergency upper endoscopy on the day of his arrival. During this procedure, we observed blood clots circumferentially adherent to the pyloric region of the stomach . Figure 1 Blood clots circumferentially adherent to the pyloric region of the stomach. Hemostasis was achieved with thrombin therapy, and the patient underwent upper endoscopy again on the third day of hospitalization. Because diffuse redness was present circumferentially in the pyloric region , the patient was diagnosed with diffuse antral vascular ectasia (DAVE), which is considered to be the same disease as GAVE. Figure 2 Diffuse redness is visible circumferentially in the pyloric region of the stomach. The patient then underwent APC. Bleeding from the mucosa was observed during an upper endoscopic examination on the fifth day of hospitalization, and APC was repeated. Bleeding secondary to DAVE was observed again during upper endoscopy on the 10th day of hospitalization. The gastroenterologist determined that further APC treatment would increase the risk of perforation at many points; therefore, the patient was prescribed an oral proton-pump inhibitor and monitored thereafter. However, he required frequent red blood cell transfusions, and by the sixth week of hospitalization, he had received more than 40 units. Despite the two APC treatments and proton-pump inhibitor therapy, he became transfusion dependent because of refractory anemia. We, therefore, performed distal gastrectomy with Billroth II reconstruction on day 45 of hospitalization . Figure 3 Separated pyloric region of the stomach Findings in the pyloric region resolved after blood vessels were removed to prepare a specimen. The histological examination revealed moderate to severe edema of the mucosa and submucosa and moderate to severe dilation of capillaries and veins, mainly in the gastric antrum, which led to the pathological diagnosis of GAVE . Figure 4 Histopathology of the gastric antrum Findings revealed moderate to severe edema of the mucosa and submucosa, and moderate to severe dilatation of capillaries and veins. On the first postoperative day, the Hb level was 6.9 g/dL. Four units of red blood cells were transfused, and the Hb level rose to 9.0 g/dL. Thereafter, the patient's Hb level remained at 9.1 g/dL, and further no red blood cell transfusion was performed; he was discharged 15 days after surgery. For more than one year after surgery, no signs of tarry stool or anemia were observed, but one and a half years after surgery, his right femoral neck was fractured in a fall, and he underwent surgery. His liver function deteriorated postoperatively, and he died of liver failure on the 16th day after the surgery. Discussion In our patient, who had cirrhosis and chronic renal failure, GAVE and refractory anemia developed even after two APC treatments, and he underwent surgery. Surgical treatment of patients with cirrhosis is rare, and we have found no reports of surgical treatment of such patients with chronic renal failure who are on dialysis. GAVE, first described as "gastritis characterized by veno-capillary ectasia" by Rider et al. in 1953, is characterized by radial longitudinal vasodilatation of the gastric antrum and is an endoscopic finding known as "watermelon stomach" . Diffuse petechial hemorrhages in the gastric wall, known collectively as "DAVE," is an endoscopic finding known as a "honeycomb stomach" . However, GAVE and DAVE is considered the same disease because the pathological findings are identical . Among patients with GAVE, the incidence of iron deficiency anemia is 88%, and the incidence of hematochezia is 42%. Oral iron supplements are inadequate for the treatment of anemia, and 60%-70% of affected patients require blood transfusions . The cause of GAVE is still unknown, but the disease is associated with cirrhosis, chronic renal failure, diabetes, autoimmune diseases, hypothyroidism, and cardiac disease . In particular, cirrhosis is found in up to 30% of patients with GAVE, and it is estimated that 2.5% of patients with end-stage liver disease have GAVE . The prevalence of chronic kidney disease in patients with GAVE is not known, but vascular ectasia is a predominant cause of gastrointestinal bleeding in patients with chronic kidney disease, whereas it is not in patients with normal renal function . In our patient, diffuse petechial hemorrhage in the pyloric region led to the diagnosis of DAVE, but cirrhosis of the liver and chronic renal failure may have predisposed the patient to vascular ectasia. GAVE is typically seen in the gastric antrum and rarely seen in other regions; duodenum, jejunum, and rectum . It is necessary to distinguish GAVE from portal hypertensive gastropathy and antral gastritis. Unlike GAVE, the lesions associated with portal hypertensive gastropathy are usually observed endoscopically in the gastric body and fundus. Additionally, GAVE is histologically characterized by capillary dilation and fibrosis of the lamina propria and the presence of fibrin emboli; a differential diagnosis of GAVE is possible based on these observations . In our patient, the endoscopic findings were consistent with GAVE because of diffuse petechial hemorrhage in the gastric antrum. Pathological findings also revealed moderate to severe edema of the mucosa and submucosa and moderate to severe dilatation of capillaries and veins, mainly in the gastric antecubital area, and this was pathologically diagnosed as GAVE. The "gold standard" of treatment for GAVE is endoscopic therapy, mainly thermocoagulation, including APC . Usually, multiple APC treatments are required; according to one study, two or more APC treatments, on average, are necessary to achieve a therapeutic effect in patients with DAVE . Other endoscopic treatments include RFA (radiofrequency ablation) and EBL (Endoscopic Band Ligation). RFA is considered an alternative to APC, but to date, no randomized controlled trials have compared RFA to APC. RFA catheters are used to achieve adequate contact with tissue, and there are through-the-scope catheters with ablation areas of 1.2 cm2, 1.5 cm2, and 2.6 cm2, respectively: HALO60 and HALO90 . Although the treatment success rate for RFA is reported to be up to 90%, persistent gastrointestinal bleeding can occur even after complete resection with the HALO90 ablation system, and 13.3%-40% of GAVE patients remain in need of blood transfusion after RFA . Next, EBL has a treatment success rate of 77.8%-100%, but 15.4%-55.6% of GAVE patients require transfusion after EBL, with a recurrence rate of 8.3%-48.1% . However, in a randomized controlled trial of 88 patients with GAVE assigned to either the APC or EBL group, the EBL group required fewer treatments and fewer blood transfusions . These results suggest that RFA and EBL may be superior to APC in terms of hemostasis, treatment frequency, and recurrence, but the optimal endoscopic treatment for GAVE has not yet been adequately confirmed in high-quality randomized controlled trials, so at present, APC is the first choice for endoscopic treatment of GAVE. APC is currently the first choice for the endoscopic treatment of GAVE. When anemia is difficult to control with endoscopic treatment, surgery should be considered. Our patient required transfusions with 14 and 26 units of blood before and after the second APC treatment, respectively, and he remained transfusion dependent, which necessitated surgery because the bleeding could not be controlled. Surgical treatment for GAVE is usually an antrectomy because the lesion is located primarily at the pylorus . However, it is very difficult to determine the appropriate extent of resection during surgery because the pyloric lesion disappears after the vessels have been excised . We performed a Billroth II pyloric gastrectomy to adequately resect the lesion, after which it did not recur. However, surgery in patients with GAVE is highly risky. According to one report of four patients with a history of cirrhosis who underwent pyloric gastrectomy, two died within 30 days of the procedure . The four patients had undergone transjugular intrahepatic pressure shunting, and their portal hypertension did not improve after surgery, which suggests that these patients had extremely advanced cirrhosis. If the portal vein pressure is considerably elevated, clinicians should consider whether surgery is indicated. Prospective studies with larger numbers of patients are needed to determine the ideal protocol for similar patients. Conclusions To our knowledge, surgical treatment in patients with GAVE, chronic renal failure, and cirrhosis who are on dialysis has not been reported previously. Because such patients are prone to bleeding, surgery should be carefully considered when bleeding is difficult to control endoscopically; and patients become transfusion dependent. Human Ethics The authors have declared that no competing interests exist. Consent was obtained or waived by all participants in this study References 1 Gastritis with veno-capillary ectasia as a source of massive gastric hemorrhage Gastroenterology RI JA KL AP KI JB 118 123 24 1953 13052170 2 Watermelon stomach: pathophysiology, diagnosis, and management J Gastrointest Surg Novitsky YW Kercher KW Czerniach DR Litwin DE 652 661 7 2003 12850679 3 Successful treatment of refractory gastric antral vascular ectasia by distal gastrectomy: a case report World J Gastroenterol Jin T Fei BY Zheng WH Wang YX 14073 14075 20 2014 25320549 4 Diffuse antral vascular ectasia Gastrointest Endosc Lee FI Costello F Flanagan N 87 90 30 1984 6714608 5 Gastric antral vascular ectasia. 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Int J Surg Case Rep Int J Surg Case Rep International Journal of Surgery Case Reports 2210-2612 Elsevier S2210-2612(23)00097-4 10.1016/j.ijscr.2023.107969 107969 Case Series Clinicopathological report on epidermoid cysts of the brain: A case series and literature review from an African perspective Khaba Moshawa Calvin [email protected] a* Dube Nomthandazo Amanda b a Department of Anatomical Pathology, Dr George Mukhari Academic Laboratory, National Health Laboratory Service, Sefako Makgatho Health Sciences University, Ga-Rankuwa, South Africa b Department of Neurosurgery, Dr George Mukhari Academic Hospital, Sefako Makgatho Health Sciences University, Ga-Rankuwa, South Africa * Corresponding author at: Department of Anatomical Pathology, Sefako Makgatho Health Sciences University, Molotlegi Road, Ga-Rankuwa, 0208, Ga-Rankuwa, South Africa. [email protected] 10 3 2023 4 2023 10 3 2023 105 10796927 12 2022 27 2 2023 1 3 2023 (c) 2023 The Author(s) 2023 This is an open access article under the CC BY license ). Introduction Epidermoid cysts are rare benign lesions of the central nervous system which accounts for approximately 1-2 % of all intracranial tumours. They are commonly located in the parasellar region, cerebellopontine angle; however, brain parenchyma origin is rare. We report clinicopathological features of these rare lesions. Method and material This is a retrospective study of epidermoid cyst of the brain diagnosed between 01 January 2014 and 31 December 2020. Results The four patients had mean age of 30,8 years (range: 3-63), one male and 3 females. All four patients presented with headache and one associated with seizures. Radiological images showed two posterior fossa; each occipital and temporal locations. All tumours were successfully removed and histopathological assessment confirmed epidermoid cysts. All patients showed clinical improvement and were discharged home. Conclusion Epidermoid cysts of the brain are rare and still remain a preoperative clinico-radiological conundrum as they may be indistinguishable from other intracranial tumours. Therefore, collaboration with histopathologists is advised in the management of these cases. Highlights * Epidermoid cysts of the brain are usually rare. * They are a clinical and radiological challenge, especially in experience hands. * Accurate management is associated with good clinical outcome. * Epidermoid cysts of the brain in Africa are underreported. Keywords Brain Epidermoid Keratinous cyst Africa pmc1 Introduction Epidermoid cysts (EC) are rare benign lesions of the brain which are estimated below 2 % of all brain tumours , , . These lesions are usually considered congenital as they are formed around the 3rd and 5th weeks of intrauterine life due to abnormal trapping of ectodermal cells. This eventually develops in to the epidermis within the nervous tissue during neural tube closure. Around this period of embryogenesis, the otic and optic vesicles are also being formed. Therefore, the inclusion of ectodermal cells within these structures has been attributed to the cerebellopontine angle and parasellar region being the common site of epidermoid cyst of the brain , , . Other sites of EC include parapontine region, middle cranial fossa, parapituitary region, diploe, and spinal canal while pure intracerebral epidermoids are rare , , . Accurate preoperative radiological diagnosis remains problematic because of the close similarity to more common intracranial cystic tumours. Moreover, the accurate preoperative diagnosis of intraparenchymal ECs is more important because they may result in chemical meningitis during or after operation. Based on the literature search, only 7 cases have been described from the African continent exclusively from three countries , , , , , . This case series has been reported in line with PROCESS guideline . 2 Methods and material This is a retrospective study of cases diagnosed with epidermoid cyst of the brain for a period of 6 years (01 January 2014-31 December 2020) in our centre. Departmental and hospital records of these patients were accessed, where available, to record clinical details age (gender, age, race, clinical presentation and clinical outcomes). Radiological investigations where available and haematoxylin and eosin (H&E) stained sections were retrieved and reassessed. 3 Results See Table 1 for clinicopathological findings.Table 1 Clinicopathological features. Table 1Case Age (years) Gender Clinical presentation Imaging Histopathological diagnosis Outcome 1 63 Male Headache and seizures with associated hydrocephalus Cerebellopontine angle Epidermoid cyst Asymptomatic on follow-up visits 2 30 Female Headache and inability to walk 4th ventricular tumour Epidermoid cyst Asymptomatic on follow-up visits 3 27 Female Headache and seizures. Cerebral tumour in the temporal lobe Epidermoid cyst Asymptomatic on follow-up visits 4 3 Female Headache and seizures with loss of weight Cerebral tumour in the occipital lobe Epidermoid cyst Asymptomatic on follow-up visits The study consisted of four patients composed of one male and 3 females with a mean age of 30,8 years (range: 3-63). All four patients presented with headache. From this, only one patient has associated seizures. Imaging reports were accessed on 3 cases and was not possible to review the images (case1-3). Based on brain imaging, 2 patients had posterior fossa, 1 had occipital and 1 had temporal tumours (Fig. 1). Two patients with posterior fossa tumours had associated hydrocephalus. All tumours were successfully removed and histopathological assessment confirmed epidermoid cysts (Fig. 2). All patients showed clinical improvement and were discharged from the neurosurgical unit to their respective homes.Fig. 1 A-D: MRI of the brain (case 4) show a well circumscribed cystic lesion in the posterior fossa which causes splaying of the superior sagittal sinus and transverse sinuses bilaterally. Fig. 1 Fig. 2 A-D show brain cyst. Brain (black star); Keratin (red arrow); stratified squamous epithelium (black arrow). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.) Fig. 2 4 Discussion Although they are considered congenital, they do not manifest until the 2nd to the 6th decades of life due to their slow growth. Their increase in size is due to accumulation of keratin and cholesterol arising from the desquamation of epithelial cells. Furthermore, their late presentation may be attributed to the absence of mass effect due to these tumours having propensity to grow along available cisternal spaces , . This is evident in this study as three patients presented from the second decade of life to the 6th decade. However, one patient that presented early at 3 years. The size the tumour at 3 years gives an impression that it had accelerated growth. This is very uncommon and was highlighted by only 1 paediatric case been reported from Africa to date (Table 2) , , , , , . Most of the reported cases from Africa are single case reports with Balogun et al., 2018 having reported 2 cases. To date, this study has the largest cohort from the African continent.Table 2 Reported cases in Africa. Table 2Authors Year Number of cases Location Age Outcome Country Aggouri et al., 2009 2010 1 Fourth ventricle Adult Morocco Hassani et al., 2014 2014 1 Pineal gland Adult Morocco El Mghari et al., 2017 2017 1 Sella turcica Adult Morocco Balogun et al., 2018 2018 2 Cerebella vermian Adult Nigeria Africha et al., 2019 2019 1 Extradural Adult Morocco Labuschagne et al., 2020 2020 1 Brain stem Paediatric South Africa Epidermoid cysts are extra-axial lesions, commonly found in the posterior fossa, with the cerebellopontine angle cistern being the most common location . All four cases in this study had different locations including with only one arising from the cerebellopontine angle. While the cerebellopontine angle might not be the common location in this study, the limitation of this study and exististing African literature is the small sample size and one cannot comment on the statistical significance. Due to their slow growth, clinical symptoms of BEC are usually due to insidious mass effect with or without cranial nerves involvement which happen after many years of life. Mass effect is responsible for most symptoms as the cyst contents accumulation may cause direct compression of the brain structures , . The common symptom is headache followed by seizures, cranial nerve abnormalities, cerebellar symptoms and raised intracranial pressure in no particular order. Hydrocephalus has also been described in other reports , , . Headache was present in all the cases in this study (Table 1). Radiological imaging is instrumental in establishing the diagnosis of EC with computed tomography (CT) and magnetic resonance imaging (MRI) the preferred choice. However, MRI is the imaging modality of choice in these lesions . The CT scan show a well-defined lobulated mass which is hypodense while on MRI is hypointense on T1-weighted and hyperintense on T2-weighted and DWI , . The retrospective nature of this study made it difficult to access all the radiological data needed, therefore, precluding accurate reporting and/or interpretation of the radiological images and/or findings (Fig. 1). Histopathological assessment is an essential tool in establishing the exact origin of the brain cysts. Grossly, EC are well-circumscribed tumours with a shiny nodular surface with keratinous contents on cut surface and occasional calcifications 11. Microscopically, they are lined by stratified squamous epithelium with granular cell layer and luminal keratin 9. In case of cyst rupture, foreign body giant cell reaction, inflammation and/or abscess formation may be seen 9. The cyst lining and wall compositions are important in the differentiating them from the other cysts. The following cysts should be considered in the differential diagnosis of brain EC: colloid cysts, arachnoidal cysts, dermoid cysts, neurocystocercosis, neuroenteric cyst. Cystic tumours of the brain and hamartomatous lipomas should also be considered. These tumours can be differentiated by imagining and confirmed by histopathology . Radiology and histopathology are important in reaching the correct diagnosis which will allow the surgeons to plan for adequate and/or definitive management. The primary goal of treatment is to completely remove the cyst and its contents. EC are very troublesome to completely remove as they growth into different spaces and cisterns. Furthermore, they tend to engulf cranial nerves and vessels making it difficult for radical excision . The location and the extent of the lesion usually determine the neurosurgical approach to be taken. Some of the approaches include suboccipital retrosigmoid, retromastoid and subtemporal . Suboccipital retrosigmoid approach is the most preferred as it allows to remove enough tumour and capsule and therefore allow the delay in recurrence of symptoms , . Failure to completely remove the cyst will lead to multiple recurrence and cause resurgence of the initial symptoms coupled multiple surgeries. Moreover, incomplete resections have been associated with malignant transformation of EC to squamous cell carcinoma. While this is very rare, it has been described; especially in recurrent EC. The malignant transformation either be suggested by rapid growth or enhancement after contrast administration , . Spillage of the cyst contents during surgery may cause chemical meningitis. While steroid is used to treat this, it is usually transient and self-limiting. Furthermore, irrigation of with hydrocortisone solution during the operation and delayed withdrawal of steroids in the post-operative period have been advocated as possible measures for preventing chemical meningitis. This was done in all the cases included in this study. Communicating hydrocephalus can develop as a result of meningitis and might require CSF diversion procedures , . 5 Conclusion Epidermoid cysts of the brain are rare and still remain a preoperative clinico-radiological conundrum as they may be indistinguishable from other intracranial tumours. "A multidisciplinary approach to these cases is important to improve patient's outcome. One of the challenges in the African continent which may lead to under-reporting of these cases could be access to health care facility, especially neurosurgical services and access to radiological imaging. This study will further assist in improving the awareness of these inracranial cysts by the neurosurgeons and radiologists from the African continent." Patient (parent's) consent Written informed consent was obtained from the patients and patient's parents for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request. Ethical approval Ethical Approval was provided by the authors institution. Sources of funding N/A. Author contribution M.C.K. conceptualized the report. M.C.K. and N.A.D and wrote the manuscript. All authors have read and approved the submitted version of this manuscript. Guarantor MC Khaba. Research registration N/A. Provenances and peer review Not commissioned, externally peer reviewed. Declaration of competing interest N/A. References 1 Labuschagne J. Mutyaba D. Koranteng P. Intrinsic brainstem epidermoid: case report and literature review Wits J. Clin. Med. 2 3 2020 199 2 Gopalakrishnan C.V. Dhakoji A. Nair S. Epidermoid cyst of the brainstem in children: case-based update J. Child Neurol. 27 1 2012 105 112 21862831 3 Czernicki T. Kunert P. Nowak A. Wojciechowski J. Marchel A. Epidermoid cysts of the cerebellopontine angle: clinical features and treatment outcomes Neurol. 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Cerebellar vermian epidermoid tumor: a report of 2 cases World Neurosurg. 112 2018 153 157 10.1016/j.wneu.2018.01.128 Available from: 29410035 10 Africha T. Boulahroud O. Giant extradural epidermoid cyst Pan Afr. Med. J. 33 2019 1 2 11 Agha R.A. Borrelli M.R. Farwana R. Koshy K. Fowler A.J. Orgill D.P. The PROCESS 2018 statement: updating consensus preferred reporting of CasE series in surgery (PROCESS) guidelines Int. J. Surg. 60 October 2018 279 282 10.1016/j.ijsu.2018.10.031 Available from: 30359781 12 Chowdhury F. Haque M. Sarker M. Intracranial epidermoid tumor; microneurosurgical management: an experience of 23 cases Asian J. Neurosurg. 8 1 2013 21 23741259 13 Hasegawa M. Nouri M. Nagahisa S. Yoshida K. Adachi K. Inamasu J. Cerebellopontine angle epidermoid cysts: clinical presentations and surgical outcome Neurosurg. Rev. 39 2 2016 259 267 26566990 14 Jamjoom D.Z. Alamer A. Tampieri D. 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Front Pediatr Front Pediatr Front. Pediatr. Frontiers in Pediatrics 2296-2360 Frontiers Media S.A. 10.3389/fped.2023.1083168 Pediatrics Case Report Chemotherapy-induced cavitating Wilms' tumor pulmonary metastasis: Active disease or scarring? A case report and literature review Zarfati Angelo 1 2 Martucci Cristina 1 * + Crocoli Alessandro 3 Serra Annalisa 4 Persano Giorgio 3 Inserra Alessandro 1 1 General Surgery Unit, Department of Surgery, Bambino Gesu Children's Hospital IRCCS, Rome, Italy 2 Department of Surgery, University of Rome Tor Vergata, Rome, Italy 3 Surgical Oncology Unit, Department of Surgery, Bambino Gesu Children's Hospital IRCCS, Rome, Italy 4 Hematology/Oncology Unit, Department of Pediatric Hematology/Oncology Cell and Gene Therapy, Bambino Gesu Children's Hospital IRCCS, Rome, Italy Edited by: Luca Pio, St. Jude Children's Research Hospital, United States Reviewed by: Joanna Stefanowicz, Medical University of Gdansk, Poland Tianqi Zhu, Huazhong University of Science and Technology, China Sofia Vasconcelos-Castro, Centro Hospitalar Universitario de Sao Joao (CHUSJ), Portugal * Correspondence: Cristina Martucci [email protected] + ORCID Cristina Martucci orcid.org/0000-0002-0037-4534 Specialty Section: This article was submitted to Pediatric Surgery, a section of the journal Frontiers in Pediatrics 28 2 2023 2023 11 108316828 10 2022 01 2 2023 (c) 2023 Zarfati, Martucci, Crocoli, Serra, Persano and Inserra. 2023 Zarfati, Martucci, Crocoli, Serra, Persano and Inserra This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. The second most common abdominal tumor in children is Wilms' tumor, and the lung is where it most often metastasizes. The typical metastases are multiple, peripherally located, round, and variable-sized nodules. Atypical patterns are also possible and may create diagnostic challenges, especially in patients treated with chemotherapy. Among these, cavitating metastases are an anecdotal type of atypical secondary lung lesions. Here, we report a case of a chemotherapy-induced cavitating Wilms' tumor pulmonary metastasis discovered during the follow-up for an anaplastic nephroblastoma in a 6-year-old girl. Furthermore, we conducted a review of the existing literature on this exceedingly rare radiological pattern to establish its best management. cavitation atypical metastasis nephroblastoma Wilms' tumor pulmonary metastasis lung metastasis computed-tomography chemotherapy pmcIntroduction Wilms' tumor, the second most frequent extracranial malignant solid tumor in children, most commonly metastasizes to the lung (1). The most common radiologic appearance of lung metastases is multiple, spherical, and variable-sized nodules associated with diffuse interstitial thickening (2). However, atypical aspects of pulmonary localization of cancer may occur, and they could be more difficult to identify (3). Furthermore, treatments, as well as the biology of the tumor itself, may change the radiologic appearance of the metastasis and cause it to mimic other diseases, making a diagnosis difficult (2, 3). Early detection of pulmonary metastases in individuals with a known cancer may be essential for the design of a successful treatment plan (2). Only a few reports in the literature have described cavitation as an unusual evolution of pulmonary metastasis of the Wilms' tumor (4). Here, we report the case of a patient with known pulmonary metastasis secondary to Wilms' tumor in whom there was chemotherapy-induced cavitation of the metastasis itself and review the existing literature in this regard to establish the best management. Case description A 4-year-old girl was referred to our institution for a palpable mass in the right quadrants of the abdomen; a CT scan revealed a localized Wilms' tumor arising from the right kidney. After initial staging, the patient was enrolled in the SIOP Umbrella 2016 protocol and started on a two-drug regimen (vincristine-actinomycin) for localized disease. After the first course, the patient experienced hemoperitoneum secondary to tumor rupture and underwent an urgent laparotomy and right nephrectomy. The histology confirmed the diagnosis of high-risk Wilms' tumor III c, according to the UMBRELLA protocol, SIOP-RTSG 2016, with a blastemal predominance. The patient was started on adjuvant therapy according to a high-risk protocol (cyclophosphamide, doxorubicin, etoposide, and carboplatin) and whole abdomen irradiation (19.5 Gy, starting 30 days after surgery). She tolerated the treatment well and started the follow-up. During follow-up at 2 years after the initial diagnosis and 18 months after the last cycle of chemotherapy, a right ovular expansive pulmonary lesion and bilateral axillary lymphadenopathy were detected . The patient underwent preoperative chemotherapy with the vincristine (1.5 mg/m2)-irinotecan (50 mg/m2)-pazopanib (450 mg/m2) regimen. After the completion of three courses, a CT scan showed a persistency of the metastasis, which presented an unusual cavitating aspect . After consultations with the Institutional Tumor Board, the indication for surgical resection was established. She underwent segmentectomy of the superior segment of the right lower lobe by thoracotomy. No surgical complication occurred. The histology confirmed the diagnosis of Wilms' tumor metastasis with a blastemal predominance, without any signs of anaplasia, and a residual vitality of 30%-40%. She was started on adjuvant therapies as per the UMBRELLA protocol with chemotherapy by following the vincristine/irinotecan/pazopanib regimen (nine postoperative courses) and lung irradiation (15 Gy from the 14th to 29th of June 2022). Two weeks after the surgery, a control CT did not rule out the disease's persistence, and therefore, the treatment was continued. The patient is currently in adjuvant treatment and in good clinical condition. The main clinical events are summarized in Table 1. Figure 1 (A,B) At chest CT, a right 46 x 30 x 35 mm ovular, expansive pulmonary lesion and bilateral axillary lymphadenopathy was detected: the lesion showed non-uniform contrast enhancement. Figure 2 (A,B) After adjuvant therapy, a CT scan showed a persistency of the metastasis, which presented an unusual cavitating aspect. Table 1 Time frame of the relevant clinical events. February 22 February-April 22 April 22 May 22 May-October 22 CT detection of a right ovular expansive lung lesion during the second year of follow-up Three courses of vincristine (1.5 mg/m2) - irinotecan (50 mg/m2) - pazopanib (450 mg/m2) CT showed a persistency of the metastasis, which presented an unusual cavitating aspect Segmentectomy of the superior segment of the right lower lobe by thoracotomy. The histology confirmed a viable metastasis Nine courses of vincristine - irinotecan -pazopanib and lung irradiation (15 Gy) Discussion We presented an exceptional case of chemotherapy-induced cavitation of a pulmonary metastasis of nephroblastoma. Wilms' tumor is the pediatric cancer most frequently associated with lung metastasis (3, 4). It usually appears as single or multiple, round, and well-defined nodules (4). Cavitation is an atypical presentation of Wilms' lung metastases, rarely reported in the literature (5-8). In the literature, a pulmonary consolidation with a relatively thick wall (more than 4 mm) or within an adjacent infiltrate or mass that was detected during a radiological examination is referred to as a "cavity," while a space containing air that is surrounded by a relatively thin wall (less than 4 mm) is referred to as a "cyst" (9). The causes of lung cavitary lesions cover a broad spectrum, from benign to malignant pulmonary disorders of congenital or acquired origin, as well as numerous infections (10). Due to the fact that they are typically created pathologically by necrotic tissue produced by an underlying lesion, cavity-forming pulmonary lesions are uncommon in the absence of a concurrent disease (9). Cavitation of malignancies may be caused by internal cyst formation, treatment-related necrosis, or internal desquamation of tumor cells followed by liquefaction (3, 9). Excavation of solid nodules with ejection of necrotic material within the tumor is the most likely etiology for cystic metastasis. Cystic dilation caused by a ball-valve obstruction in small bronchioles driven by tumor infiltration is another potential mechanism (3). In the literature, only five cases of treatment-induced cavitation of pulmonary metastasis in patients affected by nephroblastoma have been reported (Table 2) (5-8). In all these patients, cavitation seemed to be induced by adjuvant chemotherapy associated with lung irradiation, while the presented patients did not undergo any lung irradiation before the cavitation appeared. Similarly to our patient, most cases of those reported in the literature had a single cavitating lesion, and a histological examination, when performed, always confirmed the diagnosis of a viable metastasis of Wilms' tumor. Table 2 Summary of cases reported in the literature. Author, year Cases Chemotherapy Chest radiotherapy Number Histology Deck, 1959 1 Not reported + (30 Gy) Multiple Not performed Coussement, 1973 1 + (Actinomycin D) + (Dose not reported) Single Viable tumor Kassner, 1976 2 + (Actinomycin D, vincristine) + (10.5 Gy) Single Viable tumor, with no anaplasia and predominant sarcomatous component + (Actinomycin D, vincristine) + (16 Gy) Multiple Not performed Daneman 1978 1 + (Actinomycin D, vincristine, adriamycin) + (19.5 Gy) Multiple Not performed Controversy exists regarding the interpretation of the etiology and role of therapy-induced cavitating lesions. According to Seo et al., if the metastasis fails to shrink after appropriate treatment, it is usually constituted by a necrotic lesion (with or without fibrosis), lacking in live tumor cells (2). The only radiological difference between these "sterilized" nodules and a remnant live tumor seems to be the stable appearance of their size (2). Instead, according to Kassner, these alterations in metastatic lesions can be caused by tumor development rather than a side effect of treatment (8). This is in line with the findings in the present and the other reported cases, in which histologic examination invariably revealed a viable tumor in the pulmonary lesions (5, 6, 8). Several preoperative factors influence the prognosis of patients with relapsed Wilms' tumor with pulmonary metastases, including the persistence of pulmonary nodules after chemotherapy (16.7%-16.7% in 5-year-overall and event-free survival vs. 79.4%-66.5% in partial remission and 90.6%-79.4% in complete remission) and high-risk histology of the primary tumor (5-year-overall and event-free survival 44.4%-39.0% vs. 89.2%-75.9% in intermediate risk and 100%-93.3% in low risk, respectively) (11). According to the SIOP UMBRELLA 2016 protocol, the first treatment for relapsed metastatic disease is second-line chemotherapy; surgery for pulmonary metastases is indicated if a response to chemotherapy is apparent and when all persisting sites of the disease are amenable to complete excision (12). After local treatment, the presence of a viable tumor in the pulmonary nodules after chemotherapy and the persistence of lung metastases after local therapy (i.e., R1/R2 status after surgery or detectable metastases after radiotherapy) have also been associated with poorer survival in patients affected by metastatic and relapsed Wilms' tumor (11). Patients who present with cavitating lesions on CT scan after chemotherapy, such as the patient in our case, pose a clinical challenge since the radiological appearance of pulmonary lesions in these patients does not reliably predict malignant behavior (13, 14). These patients need both histological confirmation of the vitality of the pulmonary metastases and complete resection of the residual disease to establish a subsequent treatment strategy and improve survival rates (11-13). Surgical removal of suspect lesions is, therefore, warranted (15). Conclusions Chemotherapy-induced cavitating Wilms' tumor pulmonary metastases are anecdotal atypical lung lesions that may create diagnostic challenges. In the presented case and in all cases previously reported, a histological exam confirmed the presence of a viable tumor in these lesions. Treatment-induced cavitating nephroblastoma lung metastases should be considered an active disease and removed for diagnostic and therapeutic purposes. Data availability statement The raw data supporting the conclusions of this article will be made available by the authors without undue reservation. Ethics statement Written informed consent was obtained from the individual(s) and minor(s)' legal guardian/next of kin for the publication of any potentially identifiable images or data included in this article. Author contributions AZ and CM conceived the study and wrote the first draft of the manuscript. AI worked on the drafts and re-edits of the manuscript. All authors contributed to the article and approved the submitted version. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. 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JA Clin Rep JA Clin Rep JA Clinical Reports 2363-9024 Springer Berlin Heidelberg Berlin/Heidelberg 606 10.1186/s40981-023-00606-y Case Report Venoarterial-extra corporeal membrane oxygenation-assisted parathyroidectomy for hypercalcemic crisis due to parathyroid carcinoma complicated by severe circulatory and respiratory failure: a case report Enomoto Yuria Matsuda Yuko Nagamine Yusuke [email protected] Goto Takahisa grid.470126.6 0000 0004 1767 0473 Department of Anesthesiology and Critical Care Medicine, Yokohama City University Hospital, 3-9 Fukuura, Kanazawa-Ku, Kanagawa 236-0004 Yokohama, Japan 14 3 2023 14 3 2023 12 2023 9 1428 12 2022 4 3 2023 7 3 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Background Hypercalcemia crisis is a rare but severe form of hypercalcemia complicated by multiple organ failure. Hypercalcemia crisis due to hyperparathyroidism is commonly caused by a parathyroid tumor, which often requires surgical resection. However, there are no clear recommendations on when the surgery should be performed. Case presentation A 64-year-old female patient developed hyperparathyroidism due to a parathyroid tumor and hypercalcemic crisis, which was complicated by severe circulatory and respiratory failure refractory to medical therapy, and an emergent surgery was planned to resect the parathyroid tumor. To prevent intraoperative circulatory and respiratory collapse, venoarterial-extra corporeal membrane oxygenation (VA-ECMO) was introduced, resulting in a safe operation and anesthetic management. Conclusions In patients with hypercalcemic crisis complicated by severe circulatory and respiratory failure, induction of prophylactic VA-ECMO was useful for safe anesthetic management. Surgical resection should be performed as soon as the diagnosis is made before VA-ECMO is required. Keywords Hypercalcemic crisis Hyperparathyroidism Parathyroidectomy Venoarterial-extra corporeal membrane oxygenation VA-ECMO issue-copyright-statement(c) The Author(s) 2023 pmcBackground Hypercalcemia crisis is a rare but severe form of hypercalcemia complicated by multiple organ failure. The most common cause of hypercalcemia crisis is primary hyperparathyroidism caused by a parathyroid tumor, which often requires surgical resection . However, there are no clear recommendations on when the surgery should be performed. Although there have been case reports of venoarterial-extra corporeal membrane oxygenation (VA-ECMO) support after cardiac arrest due to hypercalcemia crisis , there have been no reports of prophylactic VA-ECMO for circulatory and respiratory failure during surgical treatment of hypercalcemia crisis. In this report, we describe a case in which prophylactic VA-ECMO was used to safely manage circulatory and respiratory failure during parathyroid tumor resection with hypercalcemic crisis due to parathyroid cancer. The patient's informed consent was obtained for this case report. This manuscript adheres to the CARE guidelines . Case presentation A 64-year-old female (152 cm, 42.4 kg) with a history of ureteral stone was referred to our hospital for asymptomatic hematuria. She was alert, SpO2 was 94% in room air, and body temperature was 36.4 C on admission. The blood pressure was 78/50 mmHg, and the heart rate were 100/min with sinus rhythm but marked QT prolongation (corrected QT interval, 695 ms) (Fig. 1a). Chest XP demonstrated no abnormal findings (Fig. 2), computed tomography (CT) showed a 40 x 30 mm mass on the left thyroid gland and an enlarged pancreas (Fig. 1b, c). Blood test was remarkable for calcium 21.9 mg/dL, phosphorus 4.6 mg/dL, potassium 2.2 mmol/L, magnesium 1.0 mg/dL, blood urea nitrogen 57 mg/dL, creatinine 2.42 mg/dL, and prothrombin time international normalized ratio of 1.44. Of note, serum lipase was 499 U/L (normal range: 14-54 U/L) and parathyroid hormone (PTH) was 2204 pg/mL (normal range: 15-65 pg/mL). She received fluid infusion and calcitonin with a diagnosis of hyperparathyroidism due to parathyroid tumor and secondary acute pancreatitis. Parathyroidectomy was planned after improvement of the general condition at this time.Fig. 1 Electrocardiogram (a) and neck and abdominal CT images (b and c) on admission. Electrocardiogram demonstrated marked QT prolongation (corrected QT interval, 695 ms) (a). CT images showed a 40 x 30 mm mass on the left side of the thyroid gland (b). Enlarged pancreas with increased fat concentration (c) (white arrows) Fig. 2 Chest radiograph, P/F ratio = PaO2/FiO2 ratio On day 2, continuous hemodiafiltration and infusion of noradrenaline 0.05 mg/kg/min was started for acute kidney injury, for remarkably increased serum calcium level of 22.3 mg/dL and persistent hypotension (Fig. 3). On day 3, the patient was endotracheally intubated and admitted to the intensive care unit (ICU) because of hypoxia with arterial partial oxygen pressure (PaO2)/fractional inspired oxygen concentration (FiO2) ratio of 212 mmHg due to acute respiratory distress syndrome (ARDS). Besides noradrenaline 0.2 mg/kg/min, adrenaline 0.04 mg/kg/min and vasopressin 0.02 unit/min, administration of etelcalcetide for regulating PTH secretion and denosumab, an anti-receptor activator of NF-kB ligand (RANKL) antibody for inhibiting osteoclast activation was started. The respiratory condition worsened further to a PaO2/FiO2 ratio of 76.7 mmHg with rapid progressing bilateral lung infiltrate shadow (Fig. 2). Emergent parathyroidectomy under VA-ECMO was planned for possible fatal arrhythmias caused by severe hypercalcemia resulting from surgical maneuver of the tumor on day 4.Fig. 3 Clinical course, corrected, and ionized serum calcium concentrations. Serum-corrected calcium concentration (mg/dL) = measured calcium concentration (mg/dL) + 4-albumin (g/dL) General anesthesia was induced and maintained with propofol, fentanyl, and remifentanil with continuous infusion of adrenaline <= 0.05 mg/kg/min, noradrenaline <= 0.2 mg/kg/min, and vasopressin <= 0.03 units/min under monitoring of arterial pressure, central venous pressure, and transesophageal echocardiography. No intracardiac or pulmonary emboli were detected; continuous hemodiafiltration was continued intraoperatively. After insertion of drainage and return catheters to the right atrium through the right femoral vein and to the right femoral artery, respectively, ECMO was started at a flow rate of 3.5 L/min. Nafamostat mesilate was infused for maintaining activated coagulation time approximately 200 s. Surgical resection of the left parathyroid tumor and combined left lobe of thyroid were completed uneventfully. Duration of surgery and anesthesia was 177 and 284 min, respectively. Intraoperative blood loss was 202 mL, and we transfused 840 ml of red blood cells, 720 mL of fresh frozen plasma, and 200 mL of the platelet. The patient was returned to the ICU with ECMO support. PTH was markedly decreased to 31 pg/mL, and the serum calcium level decreased to 15.2 mg/dL on postoperative day 1 (day 5). Vasoactive drug requirements were reduced in response to improved cardiac function, and the patient was weaned from ECMO on day 6. She was discharged from the ICU on day 8 with a serum calcium level of 11 mg/dL and an ionized calcium level of 1.14 mmol/L (Fig. 3). Pathological findings of the excised tumor suggested a parathyroid carcinoma. After discharge from the ICU, she developed further complications, including pneumothorax, ventilator-associated pneumonia, and sepsis associated with a relapse of pancreatitis, resulting in a long hospital stay. The patient was transferred to a rehabilitation hospital with a tracheostomy on day 104. Discussion Hypercalcemic crisis is a rare but potentially fatal condition with multiple organ damage . Its incidence is 6.7% among patients undergoing parathyroidectomy , and the most common cause is primary hyperparathyroidism by a parathyroid tumor . Although no clear diagnostic criteria have been established, it is defined as a rapid increase in serum calcium level above 15 mg/dL, oliguria or elevated urea nitrogen, and acute onset of gastrointestinal, circulatory, or central nervous system symptoms . Hypercalcemic crisis triggers numerous symptoms , from mild ones such as gastrointestinal symptoms, urinary tract stone, dehydration, muscular, and neurological symptoms to serious complications including cardiorespiratory failure requiring venovenous (VV)-ECMO and VA-ECMO . Acute pancreatitis as observed in our case is more common in patients with severe crisis . It causes abnormal electrocardiogram and cardiac dysfunction. The action potential phase 2 shortens due to increased extracellular calcium concentration, and shortening of the ST and QT portions is common ECG findings. In our case, the ECG findings reflected a QT prolongation, fusion of T and U waves, and an enhancement of U wave, observed in hypokalemia. Intracellular hypercalcemia causes impaired diastolic relaxation due to impaired myocardial repolarization , and myofibrillar hypercontraction and subsequent myocardial necrosis . Hypercalcemic crisis patients with impaired cardiac function should be monitored for the development of intracardiac thrombi. Chan et al. reported a case of intracardiac thrombi in a patient with hypercalcemic crisis under VA-ECMO . Hyperparathyroidism and hypercalcemia have been reported to induce activation of coagulation factors and increased platelet aggregation, which may trigger various type of thrombosis . Hypercalcemic crisis in patients with an impaired cardiac function requiring VA-ECMO may be more susceptible to intracardiac thrombosis due to procoagulant stimuli by exposure to ECMO circuits , requiring strict monitoring for intracardiac thrombosis. In this case, two potential etiologies are postulated as causes of respiratory failure and ARDS. First, pulmonary edema due to infusion overload for hypercalcemia symptoms. Infusion overload due to acute renal failure or acute pancreatitis may also act in an additive manner. Second, animal studies have shown that hypercalcemia causes pulmonary edema via activation of inducible nitric oxide synthase and increased nitric oxide production and inflammatory cytokines . There is much debate regarding the timing of surgical treatment in cases of hypercalcemic crisis, varying from emergency to elective surgery after correction of electrolytes , although the timing of surgery was not associated with the long-term prognosis . In our case, the patient's symptoms progressed very rapidly, and the tumor resection was performed when the patient's circulatory and respiratory status had collapsed. If the surgery had been performed at the initial stage, a non-invasive and safe anesthetic management could have been performed before the progression to multiple organ failure. In cases of the severe form of hypercalcemic crisis complicated by circulatory and respiratory failure, we believe that urgent surgical intervention should be performed as soon as the diagnosis is made. In conclusion, we experienced parathyroid tumor resection in a patient with hypercalcemic crisis complicated by severe circulatory and respiratory failure. We performed the surgery after introducing prophylactic VA-ECMO for intraoperative circulatory and respiratory collapse. In patients with the most severe form of hypercalcemic crisis, surgical resection should be performed as soon as the diagnosis is made. Abbreviations ARDS Acute respiratory distress syndrome CT Computed tomography ICU Intensive care unit FiO2 Fractional inspired oxygen concentration PaO2 Arterial partial pressure of oxygen P/F ratio PaO2/FiO2 ratio PTH Parathyroid hormone RANKL Receptor activator of NF-kB ligand VA-ECMO Venoarterial-extra corporeal membrane oxygenation VV-ECMO Venovenous-extra corporeal membrane oxygenation Acknowledgements Not applicable. Authors' contributions YE helped conceive the study, acquire and interpret the data, and draft and revise the manuscript. YM helped conceive the study, acquire and interpret the data, and draft and revise the manuscript. YN helped conceive the study, acquire and interpret the data, and draft and revise the manuscript. GT helped conceive the study, interpret the data, and draft and revise the manuscript. The authors read and approved the final manuscript. Funding Not applicable. Availability of data and materials Not applicable. Declarations Ethics approval and consent to participate Not applicable. Consent for publication Consent to publish was obtained from the patient. Competing interests The authors declare that they have no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Ahmad S Kuraganti G Steenkamp D Hypercalcemic crisis: a clinical review Am J Med 2015 128 239 245 10.1016/j.amjmed.2014.09.030 25447624 2. Knoll K Kurowski V Schunkert H Sager HB Management of hypercalcaemia-induced heart failure using mechanical circulatory support Eur J Cardiothorac Surg 2018 54 784 785 10.1093/ejcts/ezy139 29617917 3. Gagnier JJ Kienle G Altman DG The CARE guidelines: consensus-based clinical case report guideline development J Clin Epidemiol 2014 67 46 51 10.1016/j.jclinepi.2013.08.003 24035173 4. 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Payne JE Jr Tanenberg RJ Hyperparathyroid crisis and acute necrotizing pancreatitis presenting as diabetic ketoacidosis Am J Surg 1980 140 698 703 10.1016/0002-9610(80)90062-8 6776834 10. Kho C Lee A Hajjar RJ Altered sarcoplasmic reticulum calcium cycling-targets for heart failure therapy Nat Rev Cardiol 2012 9 717 733 10.1038/nrcardio.2012.145 23090087 11. Schmittinger CA Dunser MW Torgersen C Histologic pathologies of the myocardium in septic shock: a prospective observational study Shock 2013 39 329 335 10.1097/SHK.0b013e318289376b 23376953 12. Koufakis T Antonopoulou V Grammatiki M The relationship between primary hyperparathyroidism and thrombotic events: report of three cases and a review of potential mechanisms Int J Hematol Oncol Stem Cell Res 2018 12 175 180 30595818 13. Chen HI Yeh DY Kao SJ The detrimental role of inducible nitric oxide synthase in the pulmonary edema caused by hypercalcemia in conscious rats and isolated lungs J Biomed Sci 2008 15 227 238 10.1007/s11373-007-9211-1 17906944 14. Lew JI Solorzano CC Irvin GL 3rd Long-term results of parathyroidectomy for hypercalcemic crisis Arch Surg 2006 141 696 9 10.1001/archsurg.141.7.696 16847243 |
Mol Cell Pediatr Mol Cell Pediatr Molecular and Cellular Pediatrics 2194-7791 Springer International Publishing Cham 155 10.1186/s40348-023-00155-5 Correspondence Umbilical catheter placement aided by coronary guidewires Gendera Katarzyna 1 Georgiev Stanimir 1 Ewert Peter 1 Eckstein Stefan 2 Fusch Christoph 34 Rochow Niels [email protected] 345 1 grid.6936.a 0000000123222966 Department of Pediatric Cardiology and Congenital Heart Defects, German Heart Center Munich, Technische Universitat Munchen, Munich, Germany 2 Eckstein Design, Munich, Germany 3 grid.511981.5 Department of Pediatrics, Paracelsus Medical University, Breslauer Str. 201, 90471 Nuremberg, Germany 4 grid.25073.33 0000 0004 1936 8227 Department of Pediatrics, McMaster University, Hamilton, Ontario Canada 5 grid.413108.f 0000 0000 9737 0454 Department of Pediatrics, University Medical Center Rostock, Rostock, Germany 14 3 2023 14 3 2023 12 2023 10 124 10 2022 26 2 2023 (c) The Author(s) 2023 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit Catheterization of the umbilical vessels has proven to be an effective and relatively rapid method for gaining central vascular access in neonates. However, it can be technically difficult, the procedure may last 30 min or longer, and it can be associated with complications in some patients. We suggest using a coronary guidewire during catheterization of umbilical vessels to support the placement of umbilical catheters and significantly reduce a risk for complications. We tested the proposed technique in 6 successful ex vivo bench tests of catheterization of the umbilical vessels in stillborn piglets immediately after birth. We are confident that using coronary guidewire as a guiding tool during catheterization of the umbilical vessels is a rapid and safe method. We expect that it allows to obtain a vascular access with lower risk for dangerous procedural complications, which could be a lifesaving in critically ill patients. However, the approach needs to be validated in a comparative study in neonates. Keywords Umbilical vessels Coronary guidewire Neonatology issue-copyright-statement(c) The Author(s) 2023 pmcMain text Catheterization of the umbilical vein and arteries has proven to be an effective and relatively rapid method for gaining central vascular access in neonates. However, catheterization of the umbilical vessels can be technically difficult, takes more than 30 min, and can be associated with vascular complications and misplaced catheters in some patients [1-4]. The presence of anatomical narrowing at the level of curved junction of umbilical arteries between the abdominal wall and the peritoneum following the umbilical stump increases the risk for false passage and dissection. Furthermore, the U-turn-like trajectory of the umbilical artery between its origin from the iliac artery and the fundus of the urinary bladder represents another potential obstacle when aiming cannulation. Due to the stiffness of umbilical catheters, these tend to move forward in a straight-line direction. Particularly, the outer wall of an empty urinary bladder does not have enough resistance to ensure the normal anatomical course of the umbilical arteries during mechanical manipulation. The vascular passage could kink or even perforate. Finally, accidental/iatrogenic perforations of the internal iliac artery just below the bifurcation of the common iliac artery were described. Originally developed for interventions inside coronary arteries, but currently also commonly employed in other percutaneous interventions, coronary guidewires are used to navigate within vessels with a high risk for injury throughout the body. Accordingly, coronary guidewires have flexible and soft tips to minimize the risk of vessel dissection or perforation. We propose a modified procedure for umbilical vessel cannulation by using a coronary guidewire during catheterization of umbilical arteries and the umbilical vein to support the placement of umbilical catheters and significantly reduce vessel injuries. We have tested the proposed technique in 6 successful ex vivo bench tests of catheterization of the umbilical arteries and umbilical veins in stillborn piglets immediately after birth. Abbott BMW Wire Hi-Torque Balance Middleweight UniversalTM Guide Wire 0.014'', 190 cm (Abbott Laboratories, Illinois), and polyurethane umbilical catheter with a rounded tip (Umbili CathTM, Utah Medical Products Inc., Midvale, Utah) were used (Fig. 1A,B). In all performed experiments, it was feasible to safely achieve a fast and secure vascular access through the umbilical vessels without perforation. Based on this experience, we suggest novel guided placement of the umbilical catheter.Fig. 1 Coronary guidewire and umbilical catheter. A Guidewire loop and umbilical catheter with luer-lock connector. B Tip soft end of guidewire and umbilical catheter The procedure of placing umbilical artery and umbilical vein catheters is modified from recent publications [5-7], and the following steps will be added and adjusted:An umbilical catheter will be loaded with a coronary guidewire. The guidewire's tip of the "soft" end will be kept inside the tip of the umbilical catheter. It should be noted that coronary guide wires have a length of up to 190 cm. For reasons of practicability, the "stiff" end could remain in the packaging or alternatively be shortened. A fine dilator or fine forceps will be used to gently ease introducing the umbilical catheter into the dilated entrance of the vessel at the umbilical stump. The position of the umbilical catheter inside the stump should be secured and the tip of the coronary wire ought to be gently pushed forward moving the tip distal out of the umbilical catheter. The soft tip of the guidewire will pass the umbilicus, move inferiorly inside the umbilical artery, then in the anterior division of the internal iliac artery, into the common iliac artery, and subsequently into the aorta (Fig. 2A-C). Following the guidewire, the umbilical catheter will be pushed into the umbilical artery over the wire. The tip of the catheter should be placed ideally at high position at T6 to T10 level (Fig. 2C-F). The low position at the L3 to L5 level would be acceptable. The placement of the guidewire could be confirmed by ultrasound. Alternatively, the guidewire could be marked at a certain length, e.g., with a torque device, to prevent from deep insertion. The guidewire will be removed and the catheter flushed with saline, e.g. The position of the catheter should be confirmed using either ultrasound or x-ray. Fig. 2 Placement of umbilical artery catheter (UAC). A, B Coronary guidewire (CGW) passing through the umbilicus. C CGW reaching the descending aorta and the umbilical catheter sliding through the umbilicus. D-F UAC passing over the CGW towards thoracic and descending aorta The coronary guidewire-aided placement of umbilical catheter could be adopted for the umbilical vein. A similar technique could be applied while the guidewire and catheter would generally pass directly superiorly following the umbilical vein. The tip should be placed at the junction of the inferior vena cava with the right atrium. Coronary wire-aided placement for umbilical catheters allows us to gently pass the narrowed and angled segments of umbilical vessels. With this approach, it could be possible to avoid invasive alternative approaches for vascular access . Indication for umbilical catheter placement has become restrictive in the recent time. As a result, safety aspects have become even more relevant. In conclusion, using coronary guidewire as a guiding tool and additional support during catheterization of the umbilical vessels is feasible. Successful, fast, and safe umbilical vessel access can be achieved by avoiding dangerous procedural complications, which could be a lifesaving in critically ill patients. However, future studies need to prove our results in clinical trials. Authors' contributions S.G., N.R. and K.G. performed the experiments, K.G. and N.R. wrote the main manuscript text. S.G., P.E., S.E., C.F. reviewed the manuscript. All authors have read and approved the manuscript. Funding This work was supported by Medical Valley Award, M4-2007-0010. Availability of data and materials All data supporting our findings were included in this manuscript. Declarations Ethics approval consent to participate N/A Consent for publication N/A Competing interests The authors declare no competing interests. Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. References 1. Puvabanditsin S Vessel perforation and false tracking resulting from umbilical artery catheterization: a case report and literature review Pediatr. Dev. Pathol 2017 20 5 426 431 10.1177/1093526616686454 28812467 2. Molanus D van Scherpenzeel M Derikx J van den Dungen F Umbilical artery perforation: a potentially life-threatening complication of umbilical artery catheterisation BMJ Case Rep. 2017 2017 bcr-2017-222664 10.1136/bcr-2017-222664 29141932 3. Miller D Kirkpatrick BV Kodroff M Ehrlich FE Salzberg AM Pelvic exsanguination following umbilical artery catheterization in neonates J. Pediatr. Surg. 1979 14 3 264 269 10.1016/s0022-3468(79)80482-0 480088 4. Ar D, Dv P, Sm N, P. N, and N. As (2017) Umbilical venous catheter versus peripherally inserted central catheter in neonates: a randomized controlled trial. J. Trop. Pediatr. 63(5). 10.1093/tropej/fmw099 5. Shukla H Ferrara A Rapid estimation of insertional length of umbilical catheters in newborns Am. J. Dis. Child 1986 140 8 786 788 10.1001/archpedi.1986.02140220068034 3728405 6. K. Lewis and P. W. Spirnak, "Umbilical vein catheterization," in StatPearls, Treasure Island (FL): StatPearls Publishing, 2022. Accessed: 4 Jul 2022. [Online]. Available: 7. V. Dumpa and I. D. Avulakunta, "Umbilical artery catheterization," in StatPearls, Treasure Island (FL): StatPearls Publishing, 2022. Accessed: 04 Jul 2022. [Online]. Available: 8. Clark JM Jung AL Umbilical artery catheterization by a cutdown procedure Pediatrics 1977 59 6 Pt 2 1036 1040 10.1542/peds.59.6.1036 865957 |
Background and Aims A pandemic has posed a major challenge to health systems all over the world. All countries have realized that the only way to get real growth and development and solve their problems is to use what they have learned from research. Methods A descriptive and analytic type of study was conducted with the help of experts in the field of health research. The components affecting the research system were obtained via process approach and content analysis methods, and then the position of each component was identified by the Mic Mac technique. Results Seventeen influential structural components in the health research system were identified. The leadership and management components had the most direct and indirect influence among other components. The health promotion component had a greater dependency than the other components. Conclusion All health systems need to provide adequate financial resources and manpower to provide a useful research system. Human resources are the most important inputs to such a system. Components such as the research process, research sustainability, quality, or innovation in research can play a balancing role. Having the right infrastructures for creating, transferring, developing, and getting access to knowledge makes it possible to do systematic science. It is hoped that this science will be used in other results of the health research system, like improving the effectiveness or promoting health. COVID-19 health system need assessment pandemic research system Shiraz University of Medical Sciences 10.13039/501100004320 source-schema-version-number2.0 cover-dateMarch 2023 details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.2.6 mode:remove_FC converted:14.03.2023 Kharazmi E , Ostovar S , Ahmadi Marzaleh M . The need to reorganize health research systems in pandemic crisis: a prospective study. Health Sci Rep. 2023;6 :e1146. 10.1002/hsr2.1146 pmcAbbreviations MDI Matrix of Direct Influences MII Matrix of Indirect Influences MPDI Matrix of Potential Direct Influences MPII Matrix of Potential Indirect Influences 1 INTRODUCTION A pandemic has posed a major challenge to health systems around the world. 1 Current prevention and treatment methods that have been effective for other infectious diseases cannot be effective enough for this epidemic, and health systems are forced to discover new ways to prevent and treat the epidemic. 2 One of the most obvious indicators of the growth and development of a country is its technological capabilities and scientific research, so any action to clarify the status of research and the obstacles facing it is important. 3 Conducting research studies and producing science are crucial in today's world, such that the number of articles submitted, the number of researchers, and the volume of investment in the research sector are considered the main indicators of development in evaluating the scientific record of a country. 4 All countries have realized that they have no choice but to invest in and use research findings to achieve real growth and development and solve social, health, and economic problems; without research and using its results, they may not achieve sustainable development in its true sense. 5 The research sector has attracted the attention of individuals in charge of health systems for various reasons. This is because the results of the health research sector are very effective in ensuring and promoting good health for a society, and ignoring them could put people's lives at risk. 6 Numerous studies on health systems show that different research systems have been formed in most countries of the world 7 , 8 , 9 ; however, most of these research systems are not effective enough for health systems for various reasons, one of which is the inconsistency and divergence of research in many research systems. 10 , 11 Another reason is the lack of a general and coordinated policy for conducting research in these systems. 12 , 13 In many cases, research systems may not be effective due to a lack of financial resources or specialized human resources. 14 , 15 The so-called reasons show how important it is for every health system in the world to have an integrated research system. In Iran, after the emergence of the Corona crisis, there was an urgent need to review the research system, and the managers and professors of the universities of the Health Ministry have tried to design a suitable system through several meetings and sessions. Universities of medical sciences in Iran have similar organizational structures, and there is no difference between universities in different provinces of Iran. Each university of medical sciences, in addition to providing health services, also provides educational and research services. Due to the similar organizational structure of Iranian universities of medical sciences, the results of this study can be generalized to the whole country of Iran. The present study set out to design an integrated pattern for the health research systems and use appropriate quantitative and qualitative methods. 2 METHODS A descriptive and analytic study was conducted; using the opinions of experts in the field of health research, the components affecting the research system were identified, and then the position of each component in the whole system was identified by Mic Mac analysis. 2.1 Participants The statistical population of this study consisted of administrators and professors of Iranian Medical Universities. Reviewing the studies, an initial list of components was prepared to identify the proper components, and this list was then provided to experts. In semistructured interviews, the collective views of 30 key and expert people in the field of health research were extracted, including the heads and deputies of medical sciences universities, the deans and deputies of the faculties of these universities, and professors of health services' management and health information management. The so-called individuals were selected based on a purposive sampling method and the following criteria: Having at least 5 years of executive experience in health research management Publication of at least 10 articles in first index journals in which they were the corresponding author Membership in one of the research centers of medical sciences universities Having a specialized doctoral degree in one of the specialized fields of the medical sciences universities Individuals who were reluctant to participate in the study or whose access was difficult due to distance or a busy schedule were excluded from the study and replaced by new individuals. Sampling of experts continued until the theoretical saturation of the data was reached, so 30 experts participated in this study (Table 1). Table 1 Demographic characteristics of the participants in the study. Variable Number (%) Age range 40-50 12 (40) 51-60 12 (40) 61-70 6 (20) Sex Woman 3 (10) Man 27 (90) Marital status Married 30 (100) Single 0 (0) Management experience 5-10 6 (20) 11-15 14 (46) 16-20 5 (17) 21-25 5 (17) Level of education PhD 17 (57) MD 13 (43) Scientific rank Assistant professor 8 (27) Associate professor 13 (43) Full professor 9 (30) John Wiley & Sons, Ltd. 2.2 Data collection The final list of components of the health research system was obtained using the process approach and content analysis method. In this step, the six-step Clarke and Braun method was used, including familiarity with the data, creating initial codes, searching for themes, forming subthemes, defining and naming the main themes, and preparing the final list. Expert opinions were identified at three levels of conceptual, structural, and basic components. Naming structural components were done specifically based on the function of these components. Because the primary goal of this study was to develop an integrated model of the health research system during the pandemic crisis, the third-level (basic) components were excluded from the analysis, and only the second-level components were used to develop the final model. Third-level components can be used in the operational plans of the research system. For final review and validation, the list of components was given to two scientific experts who were not part of the research sample. Based on their opinions, any changes that needed to be made were made. 2.3 Data analysis After identifying and classifying the effective components in the health research system, Mic Mac analysis was used to determine the position, influence, effectiveness, and stability of the designed system. The identified components were placed in the n x n matrix, and the variables' effectiveness or influence was scored 0-3 by the experts. Mick Mac matrices were made in four different ways, and then the outputs of the matrices were sorted and analyzed using Mic Mac graphs and maps: 2.4 Matrix of Direct Influences (MDI) (1) Matrix of Indirect Influences (MII) (2) Matrix of Potential Direct Influences (MPDI) (3) Matrix of Potential Indirect Influences (MPII) 3 RESULTS The demographic characteristics of the study participants are shown in Table 1. In this study, 17 influential structural components in the health research system were identified. Table 2 shows the categories and titles of these components. Table 2 second-level components of the health research system in pandemic crisis. First-level: conceptual components title Second-level: structural components title Third-level: basic components frequency Enhancers Leadership and management 5 Hhuman resources 7 Information systems and databases 8 Financing 5 Research process 5 Primary outputs Knowledge management and science production 8 Efficiency 2 Quality 7 Sustainability 3 Innovation 4 Satisfaction 4 Decision making 6 Final outputs Responsiveness to community needs 7 Health promotion 5 Culturalization 4 Equity 5 Effectiveness 3 John Wiley & Sons, Ltd. Although the third-level components were not used in modeling, for more information, the frequency of these components is listed in Table 3. Table 3 Influence/dependence matrix of health research system factors in pandemics. No. Label Direct influence Direct dependence Indirect influence Indirect dependence 1 Leadership and management 1420 170 2612 158 2 Information systems and databases 1306 397 2307 206 3 Human resources 909 397 899 317 4 Financing 909 170 1861 101 5 Knowledge management and science producing 909 795 771 512 6 Research process 795 454 1394 281 7 Quality 738 568 3 379 8 Sustainability 681 568 0 399 9 Satisfaction 625 795 1 591 10 Decision making 568 625 1 395 11 Efficiency 511 738 0 457 12 Innovation 397 227 144 202 13 Responsiveness to community needs 113 965 0 1301 14 Equity 56 852 0 1268 15 Effectiveness 56 909 0 1367 16 Health promotion 0 1022 0 1578 17 Culturalization 0 340 0 481 John Wiley & Sons, Ltd. With the entry of the second-level components into Mic Mac, the position of each component in relation to other components and also their role were determined. The leadership and management components have the most direct and indirect influence among other components. The health promotion component has a greater dependence than the other components. Management and leadership, systems and databases, financing, human resources, and research process components were identified as input components in the health research system. Innovation, sustainability, and culturalization components are located in the position of independent components of the research system. Knowledge management and science production are the linkage components. Other components act as outputs for the research system. Figure 1 shows the status and position of the components relative to each other. The system under review is stable as only one component is located in the first quarter of the map. Figure 1 Map of direct and indirect influence of effective components on the integrated health research system. Drawing graphs of the influence of the components in both direct and indirect modes shows the intensity of the relationships between the studied components. In the direct mode, there are strong relationships between the components, while in the indirect mode, a strong relationship can only be observed between the components of management and leadership and health promotion. 4 DISCUSSION Pandemics have had profoundly short-term and long-term effects on all aspects of health systems. 16 , 17 , 18 , 19 Meanwhile, research systems have also been affected by the coronavirus epidemic. 20 , 21 In many cases, most resources and facilities of health systems have focused on the treatment sector, and other sectors, such as research, have encountered shortcomings due to the criticality of this epidemic. 22 , 23 However, due to the nature and scientific background of the medical profession, from the very beginning of the COVID-19 crisis, various countries have tried to fight against this epidemic by paying attention to research activities, especially in the field of vaccine production. 24 , 25 In this study, professors and administrators interested in research examined various aspects of this epidemic during various sessions and tried to keep this part of the health system active and effective by creating a conceptual model of the health research system. In this research, the so-called conceptual model has been developed using the opinions of academic experts and appropriate operational research techniques. The components identified in the health research system can take on different roles depending on their effectiveness or influence as well as their relationships with other components. Management and leadership, systems and databases, financing, human resources, and research process components are located in the second quarter of the Mic Mac direct influence map. These components are the inputs of the health research system and are mainly influenced by events outside this system. Therefore, they can also be called environmental variables. Some changes in these components can completely affect the system under review, and even in some cases, defects in these components can lead to a crisis in the entire health research system. Since the research process component is located near the coordinate center, it can play a regulatory role in the research system. 26 The components of innovation, sustainability, and culturalization are located in the third quarter of the map. According to Mic Mac maps, these variables are considered independent and have little effect on the research system. The sustainability component is near the coordinate center, just like the research process component, so it is one of the regulators of the research system. 27 , 28 The knowledge management and science-producing component is a linkage component, that is, it has a high influence and dependence on the research system. This component is located in the first quarter of Mic Mac coordinates and can therefore play the role of an important and intermediate goal in the research system. Studies show that in many research systems, science production and knowledge management are the basic functions of these systems. 29 , 30 , 31 The components of decision making, efficiency, satisfaction, effectiveness, equity, health promotion, and responsiveness to community needs, are among the outputs of the research system. However, paying attention to the position of these components shows that the dependency of components on health promotion and responsiveness to community needs is greater than other components of this quarter. 32 , 33 Considering that some of the studied components are located near the coordinate center and play a regulatory role, the research experts developed a conceptual model of the health research system, using the outputs of Table 1 and Figure 2. In this model, the basic concepts of the process are used. To achieve the real position of each component, direct and indirect influence numbers related to each component have been used. The model presented in Figure 3 can provide a clearer analysis of the role and position of the components. Figure 2 Graph of direct and indirect influence of effective components on the integrated health research system. Figure 3 Conceptual model of integrated health research system components. To create a useful research system, it is necessary to provide sufficient and appropriate financial and human resources . Human resources are the most important input of such a system, and other inputs are formed based on the needs of this component. 34 , 35 As a rule, the existence of an effective database is one of the requirements of any research system, and to guide these three components, a management and leadership system is needed. The mentioned components constitute the inputs of the research system in the health system. It is very important to pay attention to the role of regulators in this model. Components such as research process, research sustainability, and quality or innovation in research can keep research systems balanced in the health sector and ensure the survival of such systems. 36 Also, the sustainability of such a system requires culturalization in each of the health systems. Classifying research system outputs into three categories of outputs, outcomes, and impacts can be very helpful in policy-making, planning, and evaluation of research systems. Science production and knowledge management are, in fact, the primary outputs of any research system. 37 If research systems have appropriate infrastructures to create, transfer, develop, and access knowledge, it is possible to produce systematic science in those systems, and it can be hoped that this science will be used in other outputs of the health research system such as effectiveness or health promotion. 38 5 CONCLUSION In epidemic crises, health systems must focus their scientific efforts on identifying the causes of outbreak and prevalence and prevention and treatment methods of the epidemic. The COVID-19 pandemic has challenged health systems recently, and research systems must identify and discover its causes and solutions. Combining a process model with qualitative techniques such as content analysis and quantitative methods such as Mic Mac can be beneficial in designing such systems. One of the essential inputs in such a system is the component of management and leadership, which can improve health in communities in the long run, along with other elements. AUTHOR CONTRIBUTIONS Erfan Kharazmi: Conceptualization; data curation; formal analysis; investigation; resources; supervision; validation; visualization. Sedigheh Ostovar: Conceptualization; data curation; formal analysis; methodology; resources; supervision; writing review and editing. Milad Ahmadi Marzaleh: Conceptualization; data curation; methodology; project administration; resources; supervision; validation; writing original draft; writing review and editing. CONFLICT OF INTEREST STATEMENT The authors declare no conflict of interest. ETHICS STATEMENT This study is derived from a research project approved with code 24176 and the ethical code IR.SUMS.NUMIMG.REC.1400.034 by Shiraz University of Medical Sciences. After obtaining the necessary permission from the Deputy of Research, the researchers presented the research samples, introduced themselves to the participants, explained the objectives of the research, and reassured them that all the recorded issues would be kept confidential. Afterward, the participants who were willing to participate in the study were selected, and they were also assured that they could withdraw from the interview process at any stage. Other ethical considerations included: (1) obtaining written consent from the experts, (2) assuring participants that the study's results would be provided to them if they so desired, (3) observing the ethical considerations in terms of confidentiality of the data, (4) acknowledging and appreciating all the people who cooperated in the research, and (5) obtaining approval from the ethics committee. TRANSPARENCY STATEMENT The lead author Milad Ahmadi Marzaleh affirms that this manuscript is an honest, accurate, and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned (and, if relevant, registered) have been explained. ACKNOWLEDGMENTS We would like to thank all participants and experts in this research. The financial resources received had no influence on the data collection, analysis of data, writing of the report and dissemination of information. DATA AVAILABILITY STATEMENT Not applicable. |
Astrocytes show unique anatomical, morphological, and metabolic features to take up substrates from the blood and metabolize them for local delivery to active synapses to sustain neuron function. In the present review, we specifically focus on key molecular aspects of energy and redox metabolism that facilitate this astrocyte-neuronal coupling in a controlled manner. Basal glycolysis is co-ordinated by the anaphase-promoting complex/cyclosome (APC/C)-Cdh1, a ubiquitin ligase that targets the proglycolytic enzyme 6-phosphofructokinase-2,6-bisphosphastate-3 (PFKFB3) for degradation. APC/C-Cdh1 activity is more robust in neurons than in astrocytes, which determine that PFKFB3 abundance and glycolytic rate are weaker in neurons. The low PFKFB3 activity in neurons facilitates glucose-6-phosphate oxidation via the pentose-phosphate pathway, which promotes antioxidant protection. Conversely, the high PFKFB3 activity in astrocytes allows the production and release of glycolytic lactate, which is taken up by neurons that use it as an oxidizable substrate. Importantly, the mitochondrial respiratory chain is tighter assembled in neurons than in astrocytes, thus the bioenergetic efficiency of mitochondria is higher in neurons. Because of this, the production of reactive oxygen species (mROS) by mitochondrial complex I is very low in neurons and very high in astrocytes. Such a naturally occurring high abundance of mROS in astrocytes physiologically determines a specific transcriptional fingerprint that contributes to sustaining cognitive performance. We conclude that the energy and redox metabolism of astrocytes must complementarily match that of neurons to regulate brain function and animal welfare. animal welfare astrocytes metabolic coupling neurons redox homeostasis pmcIntroduction The high-energy supply required for neuronal activity has been classically related to the use of glucose as the brain's main energy substrate , along with the consumption of almost 20% of inhaled O2 . These high-energy costs depend closely on metabolic involvement with astrocytes for energy control and redox homeostasis , given their role as essential partners for neurotransmission and behavior . To do this, astrocytes form a syncytium by establishing cellular processes to contact blood capillaries with neuronal soma and synapses. Together with abundant gap junctions, such processes account for an abundant exchange of intermediates that cover the energetic and metabolic demands in the nervous system . This astrocyte-neuron metabolic coupling is clearly observed during glutamatergic neurotransmission, where astrocytes efficiently take up neuronal-derived glutamate from the synaptic space through Na+-dependent active transporters . Therefore, glutamate uptake is energy-costly for astrocytes and occurs at the expense of ATP, used to restore the Na+ gradient by the Na+/K+ ATPase pump . In astrocytes, intracellular glutamate may follow at least two distinct metabolic fates, its conversion to a-ketoglutarate for oxidation within mitochondria through the tricarboxylic acid cycle (TCA), or its conversion in glutamine by glutamine synthetase, absent from neurons, to be released and taken up by neighboring neurons, which convert it back to glutamate by glutaminase. Importantly, the activation of the Na+/K+ ATPase pump is paralleled by an increase in glucose uptake and coupled with glycolysis in astrocytes . Brain glycolysis is mainly regulated by the E3 ubiquitin ligase anaphase-promoting complex/cyclosome (APC/C)-Cdh1, which targets the key regulatory glycolytic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphastate-3 (PFKFB3) for proteasomal degradation . In contrast with neurons, the low APC/C-Cdh1 activity in astrocytes triggers PFKFB3 stabilization and a high glycolytic activity to provide lactate as a bioenergetic substrate to neurons . These findings have been confirmed worldwide by many laboratories, both in primary cells and in vivo, and their importance in health and disease have been established [16-20]. Conversely, the mitochondrial respiratory chain is tighter assembled in neurons than in astrocytes. Thus, neurons depend mainly on the mitochondrial oxidative phosphorylation (OXPHOS) to fulfil their energy demands, while astrocytes mostly rely on glycolysis for energy production [21-24]. Nevertheless, astrocytic mitochondria are important organelles both for energy and signaling purposes . Consequently, the redox homeostasis in both neurons and astrocytes is different, although they are tightly coupled to sustain neurotransmission. Moreover, astrocytes provide antioxidant defence to neurons, which is essential to prevent neurodegeneration . Thus, the bioenergetics and redox cooperation between neurons and astrocytes regulate neuronal survival, brain function, and animal welfare, which might provide new therapeutic targets to fight against neurodegenerative diseases. Glycolysis is complementarily regulated in astrocytes and neurons Glycolysis is mainly regulated by the enzymatic activities of hexokinase, 6-phosphofructo-1-kinase (PFK1), and pyruvate kinase (PK). In astrocytes, PFK1-specific activity is approximately fourfold than found in neurons, and the levels of PFK1 powerful allosteric activator, fructose-2,6-bisphosphate (F2,6P2) is twofold . F2,6P2 synthesis is controlled in astrocytes mainly by the isoform 3 of the PFKFB enzyme (PFKFB3) . Interestingly, PFKFB3 has a high, approximately 700-fold kinase versus bisphosphatase ratio . Hence, PFKFB3 levels are directly proportional to F2,6-P2-synthesizing activity. PFKFB3 knockdown abolishes the ability of astrocytes to up-regulate glycolysis upon mitochondrial inhibition, suggesting that PFKFB3 is important to maintain the glycolytic phenotype of astrocytes . However, PFKFB3 is virtually absent from neurons, because of the continuous destabilization by the ubiquitin-proteasome pathway . Thus, only the PFKFB3 isoform contains a 142Lys-Glu-Asn (KEN) box that targets it for ubiquitination by APC/C-Cdh1 , which is an E3 ubiquitin ligase known for its role in the regulation of mitosis, meiosis , tumor suppression, and genome stability . APC/C-Cdh1 regulates important functions in neurons, such as axonal growth [30-32], cortical neurogenesis , and survival [34-36]. In cortical neurons, Cdh1 knockdown leads to PFKFB3 accumulation, which is sufficient to increase glycolysis . This was the first observation to describe a role for a cell cycle-related protein (APC/C-Cdh1) in metabolism, mimicked by PFKFB3 full-length cDNA overexpression . In contrast, Cdh1 protein levels and APC/C-Cdh1 ubiquitylating activity are very low in astrocytes, which explains their high levels of PFKFB3 and glycolytic activity . In neurons, the index of glucose that is oxidized in the TCA cycle after having been converted into pyruvate, analyzed as the rate of [6-14C] glucose incorporated into 14CO2, is negligible when compared with astrocytes . In addition, glycolysis, assessed as the rate of 3H2O formation from [3-3H] glucose and thus accurately reflecting the flux of glucose through glycolysis , is approximately fivefold slower in neurons than in astrocytes . It seems, therefore, that the neuronal capacity to perform glycolysis is limited. Interestingly, the overactivation of glutamatergic receptors, which inhibits APC/C-Cdh1 via cyclin-dependent kinase-5 (Cdk5)-p25 , stabilizes PFKFB3 and other substrates, as cyclin B1 and Rock2 , causing neuronal metabolic switch and apoptotic death . Altogether, these results suggest that full activation of glycolysis is dangerous for neurons. In contrast, glycolysis flux is strongly up-regulated in astrocytes, either upon inhibition of mitochondrial respiration by, e.g., nitric oxide or cyanide via 5'-AMP-activated protein kinase (AMPK)-mediated activation of PFKFB3 , or upon nitric oxide-dependent hypoxia-inducible factor-1a (HIF1a) activation, which causes enhanced expression of most glycolytic enzymes including PFKFB3 . Figure 1 The metabolism of astrocytes matches that of neurons Glycolysis is regulated, amongst other factors, by the ubiquitin ligase APC/C-Cdh1, which targets the proglycolytic enzyme PFKFB3 for proteasomal degradation in neurons. In astrocytes, APC/C-Cdh1 activity is low, allowing PFKFB3 stabilization and higher glycolysis. In neurons, low glycolysis allows glucose conversion into PPP to sustain antioxidant protection, whereas in astrocytes, high glycolysis releases lactate that may be used by neurons. Neuronal function depends on astrocytic glucose metabolism Astrocytes store glycogen , which, after glycogenolysis, serves to supply lactate as an energy substrate for neurons; in contrast, lactate oxidative utilization is comparatively less efficient in astrocytes . Astrocytes lack the mitochondrial aspartate/glutamate carrier, which reduces the ability of these cells to use the malate/aspartate shuttle to transfer NADH-reducing equivalents to mitochondria as a mechanism to recover cytosolic NAD+. Therefore, in these cells, the pyruvate-to-lactate conversion becomes a predominant system to regenerate the cytosolic NAD+ via lactate dehydrogenase isoform-5 (LDH5), needed to keep active the glycolytic flux . Neurons, in contrast, are more efficient cells to converting lactate to pyruvate through the LDH1 isoform. Altogether, these metabolic differences between astrocytes and neurons help explaining their adaption to couple their metabolism and to transferring lactate from the glial to the neuronal compartment , sustaining the bases for the astrocyte-neuron lactate shuttle (ANLS) model . In vivo evidence for the occurrence of ANLS strongly suggests that it constitutes an evolutionarily well-preserved mechanism of neuronal survival . Importantly, altered ANLS that occurs with dysfunctional monocarboxylate transporter-4 and -2 (MCT4 and MCT2), responsible for the lactate release from astrocytes or uptake by neurons, and lactate content in the brain has been described in Alzheimer's disease . Thus, memory formation requires energy, which is provided by learning-dependent regulations of glucose metabolism pathways [48-51]. Interestingly, glucose metabolism shifts as the brain matures . While the adult hippocampus preferentially employs glycogenolysis and astrocyte-neuronal lactate-mediated coupling, the juvenile hippocampus selectively requires, in addition to higher astrocyte-neuronal lactate transport, a direct neuronal glucose transport and a functional PFKFB3 in neurons . Furthermore, the expression of APC/C-Cdh1 in juvenile hippocampal neurons was inverse when compared with adult neurons . This substantial increase in neuronal glucose metabolism may explain the significantly higher levels of excitability, synaptogenesis, and synapse pruning during development and may protect them from death that could be otherwise caused by their high rate of oxidative phosphorylation . Redox control of neurons depends on their own glucose metabolism The phenomenon of neurotransmission not only is a highly energetically expensive process but it is associated with a high production of reactive oxygen species (ROS) derived from different sources, which generally involves Ca2+ influx and glutamatergic stimulation . For this reason, the antioxidant systems of neurons must be effective in dealing with these high levels of ROS to which they are subjected. To do this, unlike astrocytes, neurons derive a substantial proportion of glucose consumption through the pentose phosphate pathway (PPP), responsible for regenerating the levels of NADPH necessary for the efficient reduction in glutathione (GSH), the most abundant antioxidant in the brain . GSH is mostly synthesized in astrocytes by two steps, catalyzed by glutamate-cysteine ligase (GCL) and glutathione synthetase (GSS) . Neurons also use this biosynthetic machinery to resynthesize GSH, although with a lower abundance, by capturing amino acid precursors resulting from the degradation of astrocytic GSH [55-57]. The loss of a robust antioxidant capacity in neurons is related to the cognitive impairment associated with certain neurodegenerative diseases that concur with the loss of GSH . Interestingly, a proportion of Parkinson's disease (PD) patients harbor gene mutations that encode for the PTEN-induced kinase 1 (PINK1)-Parkin axis, which is critical to regulate mitophagy . Loss of PINK1 activity induces ROS that may lead to the stabilization of HIF1a, a master up-regulator of glycolysis . While high glycolytic rates are related to increased growth and proliferation of astrocytes in patients with PD , a greater glycolytic flow in neurons leads to a detriment of the PPP and reduced GSH . This metabolic switch could help explaining neuronal death in PD and other neurodegenerative diseases coursing with impairment mitophagy, such as Batten disease . Given the need to maintain proper GSH levels to preserve neuronal function, increasing GSH concentration may therefore be a strong strategy to provide neuroprotection . This occurs, even if complete conversion to GSH is not achieved, and its immediate precursor, g-glutamylcysteine can still be used by glutathione peroxidase (GPx) to confer protection against neuronal loss and motor impairment . The astrocyte-neuron glutathione shuttle couples neurotransmission with neuronal antioxidant protection The master regulator of the antioxidant response in the brain is the transcriptional activator of nuclear erythroid-related factor 2 (Nrf2) [66-69]. Nrf2 governs the transcription of a wide spectrum of antioxidant enzymes, not only those required for the GSH pathway, such as GCL and GPx, but other enzymes such as heme oxygenase-1 (HO-1), thioredoxin (Trx), NAD(P)H dehydrogenase quinone (Nqo-1), and enzymes involved in NADPH regeneration [70-72]. The poor antioxidant response and increased susceptibility of neurons to ROS are largely due to the continued degradation and destabilization of Nrf2 by the Cullin3-Kelch-like ECH-associated protein 1 (Cul3-KEAP1) complex. Under basal conditions, Nrf2 binds to the redox sensor KEAP1, which, in the absence of ROS, allows the interaction of Nrf2 with E3 ubiquitin ligase Cul3, for its polyubiquitination and subsequent proteasomal degradation. After the accumulation of ROS, the oxidation of key cysteine residues in KEAP1 takes place to induce a conformational change in the Cul3-KEAP1 complex, allowing nuclear translocation and transcriptional activity of Nrf2 . Here, Nrf2 induces the expression of genes whose promoters contain its binding site, referred to as the antioxidant response element (ARE) . In neurons, levels of Nrf2 decline by a mechanism involving the epigenetic repression of the Nrf2 promoter leading to histone hypoacetylation around the Nrf2 transcription start site, making these cells especially vulnerable to ROS . However, Nrf2 is more stabilized in astrocytes making them primarily responsible for the removal of ROS in the nervous system, since antioxidants are not only mainly synthesized in astrocytes but have also been shown to supply them to adjacent neurons in both in vitro and in vivo models . For this reason, astrocytes are key to providing antioxidant capacity to neurons, although neurons are also able to induce the expression of antioxidant genes in an Nrf2-independent manner through the interpretation of Ca2+ signals [77-79]. In astrocytes, the activation of glutamatergic receptors (GluR), mainly N-methyl-D-aspartate receptors (NMDAR), triggers a signal transduction pathway involving phospholipase C mediated by the release of Ca2+ from the endoplasmic reticulum and the subsequent activation of protein kinase Cd (PKCd). The activation of this kinase promotes, by phosphorylation, the stabilization of p35, a cofactor of Cdk5. In the cytosol, the active Cdk5-p35 complex phosphorylates Nrf2 on the residues Thr395, Ser433, and Thr439, which is enough to promote the translocation of Nrf2 to the nucleus and induce the expression of the antioxidant machinery . This astrocytic pathway provides an antioxidant reserve that neurons use for ROS detoxification. The increase in intracellular Ca2+ produced, following excessive activation of NMDARs by glutamate, is known as an excitotoxic response that could lead to neuronal death when unresolved . The neuronal activity involves an astrocyte response that entails, among other antioxidant mechanisms, de novo biosynthesis of GSH and its release to neurons through the astrocyte-neuron glutathione shuttle (ANGS) . Therefore, this intercellular communication via NMDAR couples neurotransmission with neuronal survival, as demonstrated during ischemic preconditioning . The mitochondrial energy efficiency of astrocytes impacts on redox signaling and organismal welfare In recent years, numerous findings have changed the current view of how neural cells produce ROS and what are their function within the nervous system. Despite being considered deleterious by-products, ROS have now been shown to be essential for proper metabolic and redox coupling. To understand this issue, we should look at the regulation of the OXPHOS. One of the main differential characteristics between neurons and astrocytes is that neurons depend mainly on OXPHOS to fulfil their energy requirements, while astrocytes mainly rely on glycolysis for energy production [21-24]. Mitochondria are considered the main producers of ROS within the cell . Thus, along with other enzymatic sources within mitochondria , increased ROS production emerges from electron transfer through mitochondrial complexes during OXPHOS . To account for an efficient function of the electron transport chain (ETC) and ATP production from respiration, respiratory complexes are assembled into quaternary structures called respiratory supercomplexes (RSCs) . Surprisingly, astrocytes barely assemble CI to CIII and CIV to form RSCs, presenting most of the CI disassembled. However, neurons have most of their complexes assembled in RSC, housing CI, CIII, and CIV . The less active, free CI of astrocytes, accounts for less efficient respiration along with a significant increase in ROS production . In free CI, the flavin mononucleotide containing the NDUFV1 subunit is more available to interact with O2 . In this scenario, the generation of superoxide anion (O2*-) is carried out since the ETC is in an oxidized state , with a low efficiency to consume O2 from NADH substrates in astrocytes, compared with neurons. In a model of targeted expression of catalase to the mitochondria, astrocytic ROS was attenuated in vivo and was shown to regulate brain metabolism, neuronal function, and organismal behavior . Moreover, the impact of astrocytic mitochondrial ROS on behavior was also confirmed in a different biological environment. Thus, the production of astrocytic mitochondrial ROS can be reduced in vivo by the activation of cannabinoid-1 receptors that are present in mitochondria (mtCB1) . This decrease in astrocytic mitochondrial ROS, by down-regulating HIF1a, attenuates the glycolytic flow and lactate release to neurons, causing neuronal bioenergetic deficit and social impairment . Therefore, these concepts are in line with hormesis, defined as the process of adaptive response to a persistent, but not lethal, stressful stimulus that generates in the cell resistance to such stress, probably due to a greater antioxidant capacity [89-91]. This fact could explain how astrocytes are prepared to efficiently manage oxidative stress and how redox homeostasis constitutes a clear example of compartmentalization of neural cells that is closely related to brain metabolism . Figure 2 Astrocytic mitochondrial ROS physiologically regulates metabolism and behavior The mitochondrial respiratory chain is poorly assembled in astrocytes, which determines a low bioenergetic efficiency, but a high mitochondrial ROS (mROS) production. The high abundance of mROS in astrocytes actively promotes a transcriptional program that contributes to sustaining energy and redox metabolism, impacting on mouse cognitive performance. In contrast, the higher assembly of the mitochondrial respiratory chain in neurons determines higher energy efficiency and lower mROS production in these cells. Summary Ubiquitin ligase APC/C-Cdh1 co-ordinates astrocyte-neuron metabolic coupling by promoting PFKFB3 destabilization and attenuation of glycolysis in neurons, facilitating PPP activity for antioxidant protection. In astrocytes, APC/C-Cdh1 activity is very low resulting in PFKFB3 stabilization and higher basal glycolytic rate and lactate release. The mitochondrial respiratory chain is tighter assembled in neurons than in astrocytes, which determines higher bioenergetic efficiency and lower mROS production in the neurons. The weaker assembly of the mitochondrial respiratory chain in astrocytes determines lower bioenergetic efficiency and higher mROS production in these cells. Astrocytic mROS promote a transcriptional signature that contributes to sustaining the metabolic and redox metabolism and brain function. Acknowledgements The authors acknowledge Dr. Jesus Agulla for his help in designing the figures. Competing Interests The authors declare that there are no competing interests associated with the manuscript. Funding This work was supported by the Agencia Estatal de Investigacion [grant numbers PID2019-105699RB-I00/AEI/10.13039/501100011033, PDC2021-121013-I00, RED2018-102576-T (to J.P.B.)]; Plan Nacional de Drogas [grant number 2020I028 (to J.P.B.)]; Instituto de Salud Carlos III [grant numbers PI21/00727, RD21/0006/0005 cofunded by the European Union (to A.A.)]; and Junta de Castilla y Leon [grant number CS/151P20 cofunded by P.O. FEDER (to A.A.)]; Apoyo Regional a la Competitividad Empresarial, [grant number ICE 04/18/LE/0017 (to J.P.B.)]; and Escalera de Excelencia [grant number CLU-2017-03 (to J.P.B. and A.A.)]. D.J.B. is a recipient of a Juan de la Cierva-Incorporacion contract [grant number IJC2020-044230-I]. Author Contribution A.A. and J.P.B. defined the review focus. D.J.B. collected data from the literature and wrote the manuscript. A.A. and J.P.B. designed the artwork and reviewed the manuscript draft. All the authors edited and approved the submitted version of the manuscript. Abbreviations AMPK 5'-AMP-activated protein kinase ANGS astrocyte-neuron glutathione shuttle ANLS astrocyte-neuron lactate shuttle APC/C anaphase-promoting complex/cyclosome ARE antioxidant response element CB1 cannabinoid-1 receptor Cdk5 cyclin-dependent kinase-5 Cul3 Cullin3 ETC electron transport chain F2,6P2 fructose-2,6-bisphosphate GCL glutamate-cysteine ligase GluR glutamatergic receptor GPx glutathione peroxidase GSH reduced glutathione GSS glutathione synthetase HIF1a hypoxia-inducible factor-1a HO-1 heme oxygenase-1 KEAP1 Kelch-like ECH-associated protein 1 LDH lactate dehydrogenase MCT monocarboxylate transporter mROS mitochondrial reactive oxygen species NMDA N-methyl-D-aspartate Nqo-1 NAD(P)H dehydrogenase quinone Nrf2 nuclear erythroid-related factor 2 OXPHOS mitochondrial oxidative phosphorylation PD Parkinson's disease PFK1 6-phosphofructo-1-kinase PFKFB3 6-phosphofructo-2-kinase/fructosa-2,6-bisphosphastate-3 PINK1 PTEN-induced kinase 1 PK protein kinase PPP pentose phosphate pathway RSC respiratory supercomplex TCA tricarboxylic acid cycle Trx thioredoxin |
Front Pediatr Front Pediatr Front. Pediatr. Frontiers in Pediatrics 2296-2360 Frontiers Media S.A. 10.3389/fped.2023.1115788 Pediatrics Case Report Staphylococcus aureus bacteremia complicated with non-traumatic mediastinal abscess in children: A case report Li Yiyuan Zhu Yu Wan Chaomin Wen Yang * Key Laboratory of Women and Children Diseases, Department of Pediatrics, West China Second University Hospital, Sichuan University, Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China Edited by: Nada Harik, Children's National Hospital, United States Reviewed by: Chiara Minotti, University of Modena and Reggio Emilia, Italy Farhan A. Rashid Shaikh, Rainbow Children's Hospital, India * Correspondence: Yang Wen [email protected] Specialty Section: This article was submitted to Pediatric Infectious Diseases, a section of the journal Frontiers in Pediatrics 28 2 2023 2023 11 111578804 12 2022 13 2 2023 (c) 2023 Li, Zhu, Wan and Wen. 2023 Li, Zhu, Wan and Wen This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Background Staphylococcus aureus bacteremia complicated with non-traumatic mediastinal abscess rarely occurs in children. Herein, we report a case of S. aureus bacteremia in a previously healthy 15-month-old boy, which was complicated with a non-traumatic mediastinal abscess, followed by recovery without surgery Case presentation A previously healthy 15-month-old boy presented to the hospital with a high fever, accompanied by chills, lethargy, tachycardia, tachypnea, and slight cough. Contrast-enhanced computerized tomography revealed mediastinal abscess and blood culture analysis showed the presence of S. aureus which was methicillin-susceptible. With prompt initiation of antibiotic treatment, with appropriate duration, the patient successfully recovered without surgical drainage upon discharge. Conclusions Staphylococcus aureus bacteremia complicated with non-traumatic mediastinal abscess is rare in children, and early recognition and appropriate management are essential for a successful outcome. Staphylococcus aureus bacteremia non-traumatic mediastinal abscess pediatric healthy children bacteria with unknown origin pmcBackground Staphylococcus aureus is a major pathogen responsible for invasive infections such as bacteremia, endocarditis, osteomyelitis, arthritis, and pneumonia (1). Staphylococcus aureus bacteremia (SAB) is associated with high mortality and morbidity despite the availability of adequate treatments (2, 3). Intravascular catheters, implants, chronic diseases, nasal colonization, and intravenous drug use are the main risk factors for SAB (2, 4-6). Patients with SAB frequently experience high fever, sepsis, toxic shock syndrome, and other symptoms associated with the source of infection, including osteomyelitis, arthritis, endocarditis, and pneumonia. The most common complications of SAB are necrotizing pneumonia, pulmonary bullae, pleural effusion, and empyema; however, mediastinal abscess (MA) is relatively rare in children with SAB. MA is rarely observed in healthy children, and usually occurs as a complication of esophageal perforation, thoracic trauma, or thoracic surgery (7, 8). MA due to a non-traumatic etiology is extremely infrequent in pediatric population and tends to result either from direct extension along contiguous anatomic pathways and fascial planes or by hematogenous or lymphatic spread from distant sites of infection (9, 10). In this report, we describe a case of a 15-month-old boy who presented with SAB further complicated with non-traumatic MA. The patient had a successful recovery after prompt antibiotic therapy, without resorting to surgical drainage. Case presentation A 15-month-old boy was admitted to the hospital because of prolonged and persistent fever for fifteen days. The patient was delivered at full term weighing 3,100 g and did not require admission to the neonatal intensive care unit (NICU). He was previously healthy without recurrent respiratory infections, cough, wounds, admissions, or surgeries. Additionally, he was up-to-date with vaccinations. The patient experienced fever for fifteen days before he visited the pediatric infectious department of our hospital. He had initially developed a high fever of 39degC, two or three times daily, without chills, lethargy, cough or vomit. The patient was treated at home with only oral antipyretic drugs. He was admitted to the local hospital four days later as he developed a high fever of 42degC, two or three times daily, accompanied by chills, lethargy, decreased appetite, tachycardia, tachypnea, and mild cough. Physical examinations revealed enlarged tonsils with yellow discharge, 0.5 cm x 2 cm lymphadenopathy on the right side of the neck and few rales in bilateral lungs. Laboratory tests showed a normal white blood cell count (WBC, 9.82 x 109/L; normal range, 4-10 x 109/L) and elevated levels of C-reactive protein (CRP, 206.6 mg/L; normal range, <0.5 mg/L) and procalcitonin (PCT, 10.831 ng/ml; normal range, <0.5 ng/ml). The first sample of blood culture collected on admission was negative for bacterial growth. Radiograph of the chest revealed bilateral bronchopneumonia. The doppler echocardiography was normal and ultrasound of the neck did not find any obvious mass or liquid anechoic area. Even after intravenous administration of cefuroxime (25 mg/kg, q6h) for two days and cefoperazone sodium and sulbactam sodium (20 mg/kg, q6h) for three days (Table 1), the patient's fever persisted. Subsequently, the second sample of blood culture, collected five days after admission, revealed the growth of S. aureus which was demonstrated to be methicillin-susceptible. Computed tomography (CT) of the chest showed bilateral scattered infiltrates in lungs , an enlarged mediastinum, some pleural effusion, and pericardial effusion . Moreover, the WBC count and CRP levels increased to 14 x 109/L and 295.1 mg/L, respectively. Physicians considered the occurrence of SAB and modified the antibiotic treatment to intravenous vancomycin (50 mg/kg, q6h) after excluding central nervous infection. The symptoms alleviated after four days of intravenous vancomycin therapy. Nine days after admission to the local hospital, contrast-enhanced CT of the chest revealed scattered infiltrates in the bilateral lungs and encapsulated MA , and the patient was transferred to the pediatric surgery unit of another hospital for abscess incision and drainage. Figure 1 CT scan of chest. (A) The lung window showing scattered infiltrates in the bilateral lungs. (B) The mediastinal window showing an enlarged mediastinum (red arrow), some pleural effusion (blue arrow), and pericardial effusion (yellow arrow). Figure 2 Contrast-enhanced CT scan of chest. (A). CT showing scattered infiltrates in the bilateral lungs. (B). CT showing partial encapsulated changes of mediastinum (red arrow) revealing the possibility of mediastinal abscess, some pleural effusion (yellow arrow), and pericardial effusion (white arrow). (C). CT showing mediastinal abscess disappeared when the patient was discharged. Table 1 Clinical course of the patient. Hospitals Day Antibiotic Dose Clinical course Hospital 1 Day 1-2 cefuroxime 25 mg/kg, q6h Fever with lethargy, tachycardia, tachypnea, elevated CRP and PCT. Hospital 1 Day 3-5 cefoperazone sodium and sulbactam sodium 20 mg/kg, q6h Persistence of symptoms, an enlarged mediastinum, increase of CRP Hospital 1 Day 6-9 vancomycin 10 mg/kg, q6h Detection of MSSA, discovery of MA, improvement of symptoms Hospital 2 Day 10-21 Vancomycin oxacillin 10 mg/kg, q6h 50 mg/kg, q6h Fever subsidence, decrease of CRP, partial absorption of MA Hospital 3 Day 22-35 oxacillin 50 mg/kg, q6h Recovery MA, mediastinal abscess; MSSA, methicillin-susceptible Staphylococcus aureus. The patient received intravenous oxacillin (50 mg/kg, q6h) and vancomycin (10 mg/kg, q6h) treatment in the surgical ward before surgery. With this therapy regimen, the symptoms improved gradually and contrast-enhanced CT of the chest obtained after eleven days suggested partial absorption of MA. Afterwards, the patient was transferred to our hospital for continuous conservation treatment. Physical examination of the patient at our hospital on admission revealed the vital signs were normal. He had pharyngeal hyperemia, with bilateral tonsil hypertrophy without exudate. The rest of the physical parameters were normal. Laboratory tests showed that the WBC count was 6.6 x 109/L and the CRP level was less than 0.5 mg/L. Tests for immune function and tuberculosis yielded normal results. The patient was diagnosed to be septic, by methicillin-susceptible S. aureus (MSSA) and non-traumatic MA. After fourteen consecutive days of intravenous oxacillin (50 mg/kg, q6h) treatment, the blood culture was negative for MSSA twice, and MA disappeared . The patient fully recovered and was discharged. He did not show any untoward symptom during the one-month follow-up. Discussion and conclusions Staphylococcus aureus is one of the leading pathogens causing community-acquired and hospital-acquired bacteremia. Most children diagnosed with SAB manifest symptoms such as local infective lesions related to osteomyelitis, arthritis, skin and soft tissue infections, pneumonia, and intravascular catheter infections. The ratio of patients diagnosed with SAB without focused infection only accounts for 5%-7% (5, 11). However, in this case, the patient showed no signs of local infective lesions. The respiratory system manifestations, including a mild cough, few fixed rales, and scattered infiltrates in the bilateral lungs could not be correlated with S. aureus pneumonia. Therefore, the origin of SAB was unclear. Non-traumatic MA, which can be caused by hematogenous or lymphatic spread from distant sites of infection, or direct extension along contiguous anatomic pathways and fascial planes such as peritonsillar or retropharyngeal abscess (12), odontogenic infection, mediastinal lymph node tuberculous abscess (13) and S. aureus pneumonitis (14), is rare in children. The most common etiology identified in non-traumatic mediastinitis is S. aureus (9, 10), manifesting as disseminated staphylococcal infection (15). Non-traumatic MA related to SAB was uncommon among the pediatric population. Smith et al. reported a case that SAB originating from septic arthritis lead to an anterior mediastinal abscess in a 11-year-old boy who recovered by surgical drainage and antibiotic therapy (16). In this case, the patient had no surgeries, wounds or clues of descending infection. As lack of symptoms including swallowing disorders, pain, or impaired movement of the neck, the clinical evidence for pharyngeal or cervical infection is insufficient despite the patient had tonsil hypertrophy and lymphadenopathy on the right side of neck. In addition, the ultrasound of the neck did not reveal any obvious mass or liquid anechoic area. Hence, the MA was considered to be a result of SAB. After antibiotic therapy for MSSA, the MA absorbed completely. Early diagnosis and aggressive treatments of SAB and MA are essential for decreasing mortality and morbidity. Contrast-enhanced CT scan is indispensable to confirm the presence of loculations, the extent of the MA, and its relationship with surrounding organs. Treatment of acute MA is based on the administration of antibiotics and control of the source of infection by surgical debridement (8). The time of antibiotic administration is recognized to be the main determinant of SAB outcomes (17, 18). Empirical antibiotic treatment for children with suspected SAB depends on comprehensive considerations including the source of infection, severity, community-related or hospital-related origin, and the prevalence of methicillin-resistant S. aureus (MRSA) in the community. For children with life-threatening infection with suspected SAB, empirical therapy consists of vancomycin plus nafcillin/oxacillin (19, 20), which can cover both MRSA and MSSA in most cases. Vancomycin is the primary choice for hospital-related S. aureus infection and community-acquired MRSA infection. However, once S. aureus is confirmed to be methicillin-susceptible, the antimicrobial regimen should be modified (16). In this case, the patient with SAB received empirical vancomycin treatment in order to cover MRSA. Despite MSSA, oxacillin and vancomycin were applied in the surgical unit, probably in consideration of severe infection or insufficient experience in treating children diagnosed with SAB complicated with non-traumatic mediastinal abscess. The antibiotic was adjusted to oxacillin based on the drug susceptibility of S. aureus when the patient was transferred to the pediatric infection department of our hospital. Immediate antibiotic treatment and surgical drainage are both indispensable for MA. Sanchez et al. reported a severe case of community-acquired MRSA pericarditis with extension to the mediastinum and carotid sheath in a previously healthy 8-month-old infant who was successfully treated with surgical interventions and antibiotics (9). Lira et al. also reported a case of mediastinitis in a five-year-old child, successfully treated with 4 weeks of intravenous antibiotics. The patient in the case also recovered well without surgical involvement. The potential reason was unclear. Maybe it was related to prompt initiation of antibiotic treatment and appropriate duration. In conclusion, physicians should pay attention to MA among children with SAB. Early diagnosis and treatment were essential to acquiring a satisfying outcome. Some patients can recover well without surgery. Data availability statement The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s. Ethics statement Written informed consent was obtained from the patient's parents for publication of their child's personal or clinical details, along with any identifying images in this study. Author contributions YL conducted the data collection, performed literature review, drafted and edited the manuscript. YZ and CW revised the manuscript. YW revised the manuscript and performed literature review. All authors contributed to the article and approved the submitted version. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Clinical characteristics and outcomes of Staphylococcus aureus implant-associated infections in children. Pediatr Infect Dis J. (2019) 38 (8 ):808-11. 10.1097/INF.0000000000002349 31033905 5. Hamdy RF Dona D Jacobs MB Gerber JS . Risk factors for complications in children with Staphylococcus aureus bacteremia. J Pediatr. (2019) 208 :214-20. e212. 10.1016/j.jpeds.2018.12.002 30879729 6. Jacobsson G Dashti S Wahlberg T Andersson R . The epidemiology of and risk factors for invasive Staphylococcus aureus infections in western Sweden. Scand J Infect Dis. (2007) 39 (1 ):6-13. 10.1080/00365540600810026 17366006 7. Latif A Selim M Kapoor V Ali M Mirza MM Stavas JM . Successful percutaneous computed tomography guided drainage of mediastinal abscess in esophageal perforation. Intractable Rare Dis Res. (2019) 8 (3 ):221-3. 10.5582/irdr.2019.01080 31523604 8. 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Front Psychiatry Front Psychiatry Front. Psychiatry Frontiers in Psychiatry 1664-0640 Frontiers Media S.A. 10.3389/fpsyt.2023.1115357 Psychiatry Editorial Editorial: Comorbidity in bipolar disorder, volume II De Berardis Domenico 1 2 3 * Fornaro Michele 4 Carmassi Claudia 5 1Department of Psychiatry, Azienda Sanitaria Locale 4, Teramo, Italy 2School of Nursing, University of L'Aquila, L'Aquila, Italy 3International Centre for Education and Research in Neuropsychiatry, Samara State Medical University, Samara, Russia 4School of Medicine and Surgery, University of Naples Federico II, Naples, Italy 5Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Edited and reviewed by: Andrea Fagiolini, University of Siena, Italy *Correspondence: Domenico De Berardis [email protected] This article was submitted to Mood Disorders, a section of the journal Frontiers in Psychiatry 28 2 2023 2023 14 111535703 12 2022 13 2 2023 Copyright (c) 2023 De Berardis, Fornaro and Carmassi. 2023 De Berardis, Fornaro and Carmassi This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial on the Research Topic Comorbidity in bipolar disorder, volume IIbipolar (affective/mood) disorders comorbidity anxiety ADHD substance use disorder posttraumatic stress disorder (PTSD) dissociative symptoms overweight/obese pmcBipolar disorder (BD), with a lifetime prevalence of about 2 per cent in the general population and a recurrent course tending toward chronicity, represents one of the most severe, frequent and costly psychiatric disorders, characterized by significant rates of disability, a high incidence of suicidality and multiple medical and psychiatric comorbidities (1). In addition, literature reviews estimate that at least 50 per cent of BD patients meet the criteria for other mental or organic disorders, with obvious repercussions on diagnostic framing, treatment and healthcare costs (2). The presence of comorbidities, a concept that originated in general medicine in the 1970s but which finds its fullest expression in psychiatry, becomes fundamental for any in-depth study of the etiopathogenic hypotheses, the prognostic judgement and, above all, for the relevant therapeutic strategies (3). Alarming data on the co-presence of other disorders in bipolar patients come from both large community epidemiological studies and those conducted on clinical samples. For example, the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), conducted in 2001-2002, confirmed that substance use and psychiatric disorders continue to be highly comorbid, and, in particular, bipolar disorder was steadily associated with panic disorder, agoraphobia, posttraumatic stress disorder, and borderline, schizotypal and antisocial personality disorders (4). The National Comorbidity Survey Study (NCS) and various clinical studies also reported high rates of comorbidity in BD patients (5-7). The works carried out by the Stanley Foundation Bipolar Treatment Outcome Network on about 300 patients with BD-I and BD-II showed that 65% of these subjects had met the diagnostic criteria for at least one other Axis I disorder at some point in their lives, with an earlier onset of affective symptoms and a worse prognosis (8, 9). On the other hand, Strakowski et al. (10), in a famous study of inpatients suffering from DB, showed psychiatric comorbidity of about 40 per cent and general medical comorbidity of 20 per cent, with a higher frequency in the female sex. The psychiatric disorders most commonly associated with BD are anxiety disorders, eating disorders, attention deficit hyperactivity disorder and substance (SUD) and alcohol abuse (2). It remains to be clarified whether substance abuse is a cause or a consequence of BD. Still, the association between the two pathologies leads to increased affective mood swings, prolonged intervallic phases, a higher prevalence of physical disorders and suicide attempts, and worse adherence to treatment (11). Concerning the main theme of the Research Topic, Aguglia et al. conducted a cross-sectional study involving 556 patients with a primary diagnosis of BD (376 without SUD, 101 with SUD, and 79 with Polysubstance Use Disorder [polySUD]). They found that younger age, male gender, early age at onset, psychotic and residual symptoms, positive family history of psychiatric disorders, and use of benzodiazepines were significantly associated with polySUD in patients with BD. Interestingly, patients with BD and polySUD were more likely to take four or more medications, particularly benzodiazepines and other drugs. The Authors pointed out that particular attention on this specific subtype of patients with BD may help implement personalized pharmacological and psychosocial therapies integrating the different professional roles. Following the line of substance abuse and intoxication, Swoboda et al. aimed to compare intoxications due to a suicide attempt with an antidepressant (AD) and antipsychotic (AP) agents, or both with those of other medications and alcohol to illustrate the toxicity potential of these substances in a general population treated for intoxication. They conducted a retrospective and naturalistic one-year registry study that included 105 patients treated for oral intoxication at the University Department of Emergency Medicine in Vienna, Austria. AD/AP intoxications were present in 26 patients, while in the control group (n = 79), non-AD/AP drugs (n = 54) and exclusively alcohol (n = 25) were the toxic agents. In addition, they found that patients with AD/AP intoxication were significantly more often transferred to the psychiatric department, while discharge to home was more likely in the control group. Luckily, study results suggested that the risk of a potentially life-threatening outcome in intoxication with AD/AP wasn't substantially higher than in other readily available toxic agents, in line with the advantageous risk/benefit ratio of newer ADs and APs. Two papers on the Research Topic addressed the problem of comorbidity between ADHD and BD. In a perspective paper, Comparelli et al. focused on specific clinical and developmental dimensions to recognize and/or differentiate the pattern of ADHD across the course of BD from a nosological perspective. They concluded that treating concurrent ADHD and BD remains an unresolved challenge regardless of the phase of illness. From a developmental perspective, such treatment might require a staged approach. By staging the introduction of treatments, it's possible to reduce the risk of overmedicating patients, better assessing the effect of each treatment. On the other hand, in the case of real comorbidity, a hierarchical approach to treatment should be followed: BD should be treated first. In contrast, ADHD should be treated by combining ADHD medications and mood stabilizers after mood stabilization. Besides, proper mood stabilizing therapy can reduce the chance of positive mood episodes that might arise if psychiatrists only use ADHD-specific medications. That is why a hierarchical approach should be followed. In another interesting study, Nunez et al. evaluated demographic, clinical, treatment, and genetic differences between BD with and without ADHD comorbidity, extending this comparison to consider the onset of attention deficits. Among patients with BD (N = 2,198) enrolled in the Mayo Clinic Bipolar Biobank, the researchers identified those with ADHD diagnosed in childhood (BD + cADHD; N = 350), those with adult-onset attention deficit symptoms (BD + aAD; N = 254), and those without ADHD (N = 1,594). A subset of the clinical sample had genotype data available. They found that attention deficits are more prevalent in men and associated with lower employment rates. In line with previous studies, they found a higher prevalence of ADHD in the offspring of BD patients. In addition, BD+ ADHD patients showed significantly higher rates of family history of affective disorders and a higher prevalence of substance use disorders. Specifically, it was observed increased rates of alcohol use disorder and stimulant use. Besides a higher prevalence of anxiety and depression disorders in patients with attentional deficits and, in terms of treatment response to mood stabilizers, the BD + cADHD group had a significantly poorer response to lithium and lamotrigine. Study results showed that BD + cADHD was associated with more significant comorbidities and reduced response to mood-stabilizing treatments. The higher ADHD polygenic risk scores (PRSs) for the BD + cADHD group may reflect a more powerful influence of genetic factors on the early presentation of ADHD symptoms. Studies have found that traumatic events that occurred during childhood, adolescence and adulthood are associated with an increased risk of developing BD, with a significant likelihood of suicide and psychotic evolution (12-14). As dissociative disorders are an influential group of trauma-related disorders, the co-occurrence of dissociative disorders (DD) and symptoms (DS) in bipolar disorder has been relatively understudied. Still, there is some evidence that this comorbidity may have significant mechanistic and clinical implications. Rajkumar wrote an interesting scoping review on the frequency and correlates of DS and DD in BD. He pointed out that a significant minority of patients (10-20%) with bipolar disorder might experience important DS, even during the euthymic phase. The overall severity of DS was higher in BD than in healthy controls and major depression but lower in BD compared to "trauma spectrum disorders" such as DD, complex PTSD and borderline personality disorder. The presence of DS might be associated with psychotic symptoms, suicide attempts, and a poorer response to treatment. DS also appeared to be related to the severity of childhood trauma in patients with BD. Thus, assessing DD and DS in a patient affected by BD would be helpful in everyday clinical practice to adequately address the treatment. On the other hand, Hogg et al. started from the assumption that post-traumatic stress disorder (PTSD) is an established comorbidity in BD. They conducted a multi-center study comprising 79 adult participants with BD with a history of psychological trauma and reported baseline data from a trial registered in Clinical Trials ref: NCT02634372). Study findings provided further evidence of the lack of difference in how trauma symptoms were presented across BD subtypes and provided essential data regarding the high levels of trauma symptoms in BD subjects, even when criteria for a PTSD diagnosis weren't met. However, the evidence showed that there were few differences in clinical BD severity between the subjects with full PTSD and subsyndromal PTSD, although they found a possible tendency for appositive correlation between full PTSD and psychotic symptoms, as well as between sexual abuse and rapid cycling, which can be clinically helpful in the identification and treatment of both. In conclusion, the study findings highlighted the proper investigation to understand the impact of comorbidity with a history of psychological trauma in BD patients, including subsyndromal PTSD symptoms and underlined the importance of screening for psychological trauma in the BD population. Recently, some studies have suggested a higher risk of developing metabolic syndrome in BD than in the general population, increasing the risk of cardiovascular morbidity (15, 16). Furthermore, BD patients are at high risk of being overweight and obese, suffer more frequently from type II diabetes mellitus, and have higher cardiovascular mortality rates than the general population (17). Yi et al. conducted a retrospective, cross-sectional study to investigate the prevalence and associated factors of obesity and overweight in a sample of 1,169 inpatients with BD in China. They found that the prevalence rates of obesity and overweight were 21.0% and 32.2%, respectively, and the duration of BD was significantly associated with obesity. Besides, in a binary logistic regression analysis, the duration of BD and the levels of uric acid, ALT, triglycerides, and LDL cholesterol were identified as predictors for obesity. In contrast, male sex and uric acid level were associated with a higher frequency of overweight. The results of the present study show a need to implement early screening, prevention and interventions for obesity and overweight in patients with BD. Finally, from a mixed psychopathological and translational perspective, gastrointestinal (GI) symptoms are widespread in BD patients but relatively understudied. Guo et al. recruited 59 BD patients that were divided into two groups. Each group was assessed with the 24-item Hamilton Depression Rating Scale (HAMD-24) according to the presence or absence of GI symptoms and compared with healthy controls. Differential metabolites were identified and further analyzed using Metabo Analyst 3.0 to identify associated metabolic pathways. The results showed that BD patients with GI symptoms experience more severe symptoms than the metabolic pathways related to GI symptoms, which may be risk factors for gastrointestinal symptoms in BD patients. Moreover, researchers found that the total HAMD-24 scores in the GI symptoms group were more significant than that of the non-GI symptoms group, consistent with past research findings. Based on metabolomic analysis results, it was also found that the common disturbances metabolic pathways of both groups of patients jointly exhibited disorders of ketone body metabolism: ketone body metabolism might be involved in the inflammation, and oxidative stress may be one of the pathogeneses of BD. Besides, the unique disturbances in metabolic pathways of BD patients with GI symptoms were fatty acid biosynthesis and tyrosine metabolism. One can argue that the abnormalities of these two metabolic pathways may be related to the disturbance of the gut microbiome, and the gut microbiome has been implicated in multiple human chronic GI disorders. In conclusion, this Research Topic has shed light on the problem of comorbidity and BD, and researchers have profound a remarkable effort to address this topic. We would thank all of them for this and hope that the new forthcoming issue on Frontiers in Psychiatry entitled "Comorbidity in Bipolar Disorder and Schizophrenia Volume III" will further contribute to the understanding of comorbidity issues in severe psychiatric disorder, this time also in schizophrenia. Finally, all the Guest Editors wish to dedicate the current Research Topic to Professor Gianna Sepede, MD PhD, a gifted psychiatrist whose kind manners and bright scientific and clinical skills inspired many of us as colleagues, friends, and trainees before her premature departure. Author contributions All Authors have contributed to the present Editorial with equal efforts. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 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Nierenberg: Childhood trauma and treatment outcomes during mood-stabilising treatment with lithium or quetiapine among outpatients with bipolar disorder. Acta Psychiatr Scand. (2022) 145 :615-27. 10.1111/acps.13420 35243620 13. Wrobel AL Jayasinghe A Russell SE Marx W Alameda L Dean OM . Turner: The influence of childhood trauma on the treatment outcomes of pharmacological and/or psychological interventions for adolescents and adults with bipolar disorder: a systematic review and meta-analysis. J Affect Disord. (2022) 296 :350-62. 10.1016/j.jad.2021.09.103 34606813 14. Cogan CM Paquet CB Lee JY Miller KE Crowley MD Davis LJ . Differentiating the symptoms of posttraumatic stress disorder and bipolar disorders in adults: Utilizing a trauma-informed assessment approach. Clin Psychol Psychother. (2021) 28 :251-60. 10.1002/cpp.2504 32822516 15. Schuster MP Borkent J Chrispijn M Ioannou M Doornbos B Burger H . Haarman: increased prevalence of metabolic syndrome in patients with bipolar disorder compared to a selected control group-a Northern Netherlands LifeLines population cohort study. J Affect Disord. (2021) 295 :1161-8. 10.1016/j.jad.2021.08.139 34706429 16. Grover S Mehra A Chakravarty R Jagota GS . Sahoo: Change in prevalence of metabolic syndrome in patients with bipolar disorder. Asian J Psychiatr. (2020) 47 :101876. 10.1016/j.ajp.2019.101876 31756556 17. Gimenez-Palomo A Gomes-da-Costa S Dodd S Pachiarotti I Verdolini N Vieta E . Does metabolic syndrome or its component factors alter the course of bipolar disorder? A systematic review. Neurosci Biobehav Rev. (2022) 132 :142-53. 10.1016/j.neubiorev.2021.11.026 34800584 |
Front Plant Sci Front Plant Sci Front. Plant Sci. Frontiers in Plant Science 1664-462X Frontiers Media S.A. 10.3389/fpls.2023.1143653 Plant Science Editorial Editorial: Breeding for intercropping Rubiales Diego 1 * Enjalbert Jerome 2 Hohmann Pierre 3 Anten Niels P.R. 4 Weih Martin 5 1 Institute for Sustainable Agriculture, CSIC, Cordoba, Spain 2 AgroParisTech, UMR GQE-Le Moulon, Institut National de Recherche pour l'agriculture, l'alimentation et l'environnement (INRAE), Gif-sur-Yvette, France 3 BETA Technological Center, University of Vic, Vic, Spain 4 Centre for Crop Systems Analysis, Wageningen University and Research, Wageningen, Netherlands 5 Department of Crop Production Ecology, Swedish University of Agricultural Sciences, Uppsala, Sweden Edited and Reviewed by: Valerio Hoyos-Villegas, McGill University, Canada *Correspondence: Diego Rubiales, [email protected] This article was submitted to Plant Breeding, a section of the journal Frontiers in Plant Science 28 2 2023 2023 14 114365313 1 2023 16 2 2023 Copyright (c) 2023 Rubiales, Enjalbert, Hohmann, Anten and Weih 2023 Rubiales, Enjalbert, Hohmann, Anten and Weih This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Editorial on the Research Topic Breeding for intercropping plant breeding intercropping selection modelling quantitative prediction pmcIntercropping, also known as mixed cropping, consists on simultaneously growing more than one species on a field. It has a great potential for enhancing nutrient-use efficiency and improving plant productivity, yield stability and resilience to biotic and abiotic stress, including those triggered by climate change. Despite their manifold benefits, the practice of intercropping has not risen above its niche status in many regions of the world. The selection of varieties specifically adapted to intercropping remains a major practical challenge to its widespread deployment. This Research Topic hosted at Frontiers in Plant Sciences entitled "Breeding for intercropping" gathers a series of articles covering new insights in the areas of quantitative genetics, ecology, ecophysiology and agronomy integrating theoretical, experimental as well as participatory approaches. Why is specific breeding needed for intercrops? Moutier et al. showed that the performance of genotypes grown in pure stand as monocrops is not necessarily a good indicator for their performance grown in intercrops. In this research performed in France, eight wheat genotypes and five legume testers (three pea and two faba bean varieties) were field-grown as monocrops and in all possible binary intercrops in nine contrasting environments for three years. The mixing abilities of the varieties investigated was evaluated in terms of their ability to maintain or exceed their monocrop yield when grown in intercropping (producer effect); and their ability to benefit the yield of the companion crop (associate effect). Mixing abilities varied greatly between the investigated varieties, both for the wheat and the legume testers, implying that the choice of the legume tester is important for better discriminating the producer or associate effects of the wheat genotype that it is intercropped with. The authors conclude that both the wheat varietal choice and the identity of the legume tester variety are key issues in the breeding for intercropping. They also note that the breeding should consider the mixing ability in terms of both the producer and the associate effects. In their review, Moore et al. provide an overview of three case studies, identifying relevant considerations for plant breeding efforts. Forage mixtures are the most mature among the cropping systems discussed. However, there is a need to accelerate efforts to breed for mixture systems, e.g., through genomic selection and/or selection of both component species. Breeding for perennial groundcover systems and winter oilseed systems is much less developed. In both cases, there is an opportunity to design a breeding pipeline that incorporates intercropping systems as one of its primary goals. Although nascent, breeding for intercropping systems holds great potential for improving intercropping systems and realizing the potential of this crop diversification strategy for addressing sustainability challenges. Bourke et al. highlight the need for re-designing breeding programs to accommodate inter-specific interactions, as genotypes bred for monoculture are not the best adapted to intercropping systems. They summarize how to decipher plant interactions in intercropping, studying trait plasticity or plant-microbiome interactions, or exploring its ecophysiological basis using a functional structural plant model (FSPM). They then identify two general breeding strategies, either i) ideotype-driven (i.e., "trait-based" breeding) or ii) quantitative genetics-driven (i.e., "product-based" breeding), and they highlight the interest of the theoretical framework of direct genetic effect (DGE, equivalent to producer effect) and indirect genetic effects (IGE, equivalent to associate effect). They propose a "Powerful Troika", combining the two strategies, for example coupling FSPM modelling with genomic-assisted selection and analysis of indirect genetic effects. Current breeding programs do not select for enhanced general mixing ability (GMA) and neglect biological interactions within species mixtures. To address this issue, Haug et al. proposed a model framework for general and specific mixing ability (GMA and SMA). Incomplete factorial designs show the potential to drastically improve genetic gain by providing similar estimates for GMA and SMA variances compared with a two commonly used full factorial designs that employ the same amount of resources. This model was extended to the producer and associate concept to exploit information on fraction yields and allowed to characterise genotypes for their contribution to total mixture yield. Correlations between Producer/Associate effects and plant traits allowed to describe biological interaction functions (BIF) such as commensalism, competition and others. BIF can be used to optimize species ratios at harvest as well as to extend our understanding of competitive and facilitative interactions in a mixed plant community. This study provides an integrative methodological framework to promote breeding for mixed cropping. Timaeus et al. evaluated intraspecific diversity intercropping 15 wheat cultivars with one winter pea cultivar under organic conditions. Mixtures increased cereal grain quality, weed suppression, resource-use efficiency, yield gain, and reduced lodging. Under higher nutrient availability, entry-based variation was reduced in both systems, and pea was suppressed. Heterogeneous populations were more stable than line cultivars. Trait analysis revealed a possible link between harvest index and reduced competition in mixture, which can increase yield performance in specific line cultivars. They conclude that while cultivar breeding for mixtures can be successful in monocultures, high environmental variation highlights the necessity of evaluating cultivars in mixtures. In addition, use of intraspecific diversity within interspecific mixed cropping systems can be a valuable addition to further improve mixture performance and its stability under increasing environmental stresses due to climate change. Which suits of traits are most important in the breeding for intercropping? The primary focus of the work by Kiaer et al. is the importance of the end use in the evaluation of potential beneficial effects of intercrops. Thus, this perspective paper evaluated breeding targets for genotypes to be grown in intercropping in a supply chain perspective, using three case studies of intercropped legume and cereal species for human consumption to identify crop traits that could be desirable for different actors along the corresponding supply chains. The authors concluded that the widespread adoption and integration of intercrops will only be successful if all supply chain actors are included and collaborate; if the breeding approach takes into account the relative complexity of intercrop supply chains; and if diversification strategies are implemented in every process from field to fork. Morphological and functional plant traits involved in species interactions were addressed by Peng et al., who evaluated the effects of intercropping on the medicinal plant Atractylodes lancea on various morphological traits including growth and volatile oil content. In their field study carried out in a subtropical environment in China, the authors have grown A. lancea plants in monocrop and intercropped with with Zea mays, Tagetes erecta, Calendula officinalis, Glycine max, or Polygononum hydropiper as mixing component. Significantly enhanced growth and accumulation of some volatile oils was found especially when A. lancea was mixed with Z. mays, T. erecta or C. officinalis. However, large and significant variation in all measured traits was found also between the two years of this study, and the effects of the mixing treatments on the assessed traits partly varied greatly between the two years; suggesting strong management (here mixing partner) by environment interaction. Kammoun et al. hypothesized that the grain yield achieved by a cultivar in low nitrogen input durum wheat-grain legume intercrops could be estimated using a few simple variables: (i) the yield of the wheat cultivar at full density in monocrop, (ii) the yield of the legume cultivar at half density in monocrop, and (iii) an indicator of legume cultivar response to interspecific competition that reveals cultivars' competitive abilities and tolerance to competition. Such a competition index appeared less predictable for the legume than for the durum wheat. Further studies on more diverse genotypes and growing conditions are needed to improve the predictive quality of the model. Moreover, further mechanistic understanding is required to better evaluate the links between the tolerance to interspecific interactions and the plant phenotype characteristics (traits). Land Equivalent Ratio (LER), is a classical agronomical index used for comparing the performance of species when intercropped, taking as reference their yields in monocrops. Tavoletti and Merletti. proposed to use LER to identify best performing varieties. They explored the yield response to intercropping of durum wheat (Triticum turgidum ssp. durum) and faba bean (Vicia faba), using, respectively, 13 and 3 varieties of the two species. They focussed on a factorial design of 24 mixtures (12 wheat x 2 faba varieties), recording yield in a field trial performed over two years. They observed contrasting performances between the two years, with LER significantly higher than 1 only in the first year. To better discriminate the varietal performances in intecropping, the authors performed principal component and cluster analyses for total yield, LERtotal, i.e. LERw + LERfb, and ln(LERratio), i.e. (LERw/LERfb). This multivariate analysis provides a way to identify the best variety combinations, while the authors propose to use principal component scores as indices of selection within breeding programs aimed to simultaneously improve intercropped species. Demie et al. reviewed how the performance of cereal/legume intercropping depends on the genotypes used. Over 69 publications analysed, a subset of 35 of them reported land equivalent ratio (LER), with a mean LER of 1.26. Genotype x cropping system (monocrop/intercrop) interactions were tested in 71% of the 69 publications, and reported significant in 75%, of the studies. Interestingly, the different species analysed exhibited different land-use efficiencies in the different design types with finger millet having the highest land-use efficiency for cereals. In most of the studies, the link between traits and intercropping performance were not properly addressed, even if some key traits for intercropping performance, such as earliness, plant height, or growth habit, were also critical in intercropping. The lack of data on traits and genotypes effects on intercropping performance calls for additional experimental efforts, including more genotypes, to improve breeding and blending designs for intercropping systems. Can crop growth models and quantitative predictions assist breeding for intercropping? In a perspective paper, Weih et al. revisited the challenges associated with breeding for intercropping, and gave an outlook on the application of crop growth models to assist breeding for intercropping. Previous approaches using crop models to assist plant breeding were mostly based on the performance and properties of monocrops. For models to be effective in assisting breeding for intercropping, they need to (i) incorporate the relevant plant features and mechanisms driving interspecific plant-plant interactions in the model; (ii) rely on parameters that are closely linked to the traits that breeders would select for; and (iii) be calibrated and validated with field data that are assessed in intercrops. In addition, due to their lower complexity and much reduced parameter requirement, the authors consider minimalist crop growth models to be more likely to incorporate the above elements than comprehensive and parameter-rich crop growth models. Firmat and Litrico. point out that obtaining reliable community level quantitative predictions for diverse crop systems empirically is limited by the size and complexity of experiments that would be needed. Breeding strategies should instead be compared using theoretically informed qualitative predictions. To this end, they reviewed different approaches arising from the field of evolutionary ecology focusing on: (i) the community heritability approach, (ii) the joint-phenotype approach and (iii) the community trait genetic gradient approach. They suggest research strategies related to each of these approaches. To explore the interest of genomic selection for intercrop breeding, Bancic et al. proposed an elegant study based on stochastic simulation, where they compared four breeding programs implementing genomic selection and one breeding program based on phenotype only. The different breeding schemes were sized according to a constant budget, using realistic steps as double-haploid production, or intercropping evaluation using testers. Three different genetic correlations (0.4, 0.7, and 0.9) between monocrop and intercrop grain yield were assumed, and only GMA was simulated. Under these three scenarios, all four simulated breeding programs using genomic selection produced significantly more intercrop genetic gain than the phenotypic selection program (~1.3-2.5 times), but at the cost of genetic variance. Under low genetic correlations, the Grid-GS program, which employed an incomplete factorial instead of using testers, was the most efficient. Authors suggest a genomic selection strategy which combines monocrop and intercrop trait information, using a selection index that includes economic weights, in order to increase selection accuracy. Annicchiarico et al. studied efficiency of several phenotypic or genomic selection strategies in pea breeding for intercropping with cereals. The efficiency of an indirect selection index including onset of flowering, plant height, and grain yield in monocrops was comparable to that of pea yield selection in intercrops. Genomic selection for pea yield in monocrop displayed an efficiency close to that of phenotypic selection for pea yield in intercrop, and nearly two-fold greater efficiency when also taking into account its shorter selection cycle and smaller evaluation cost. Instead of breeding to improve monoculture yield of single crops in isolation, Wolfe et al. propose optimizing multiple interacting species and genotypes by enabling joint-selection to improve the performance of the cropping system across time and space. Genomic and phenomic prediction poses an exciting opportunity to develop a multi-tiered selection scheme. There are multiple levels or "tiers" of selection, which when considered jointly enact agroecosystem improvement. The objective at Tier 1 is intraspecific population improvement, which is addressed simultaneously across each species to affect co-adaptation of the germplasm pools. At Tier 2, selection is focused on predictions of performance of the combination over space and time. The practice of wheat variety mixtures is spreading. However, there are few blending rules to design variety mixtures, and not any based on plant architecture. As the high dimensionality of trait combinations in intercopping is hardly compatible with field experiments, Blanc et al. proposed to use the FSPM WALTer to simulate wheat cultivar mixtures and try to better understand how key traits driving the aerial architecture can influence mixture performance. However, most FSPM are slow to run and do not allow to explore the combinatorics of their numerous parameters. Hence the authors combined two original methods: i) they used a metamodel of WALTer, i.e. an approximation of the FSPM outputs, to speed up computation, and ii) they then performed a sensitivity analyses based on both mean and differences in architectural trait values of the mixed components (binary and balanced mixtures). These analyses highlighted the impact of the leaf dimensions and the tillering capability on the performance of the simulated mixtures. Identifying the best performing mixtures revealed original combinations of ideotypes with contrasting tillering abilities and leaf dimensions, asking for experimental confirmations. Author contributions All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. |
Front Cardiovasc Med Front Cardiovasc Med Front. Cardiovasc. Med. Frontiers in Cardiovascular Medicine 2297-055X Frontiers Media S.A. 10.3389/fcvm.2023.1144849 Cardiovascular Medicine Editorial Editorial: Emerging roles of miRNAs in cardiovascular disease Santovito Donato 1 2 3 * Fan Yuhua 4 Elia Leonardo 5 6 Tan Joanne T. M. 7 8 van der Vorst Emiel P. C. 1 2 9 * 1 Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximillians-Universitat (LMU), Munich, Germany 2 German Center for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany 3 Institute for Genetic and Biomedical Research, Unit of Milan, National Research Council, Milan, Italy 4 Department of Basic Medical College, Harbin Medical University (Daqing), Daqing, China 5 IRCCS Humanitas Research Hospital, Rozzano, MI, Italy 6 Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy 7 Vascular Research Centre, Lifelong Health Theme, South Australian Health and Medical Research Institute, Adelaide, SA, Australia 8 Adelaide Medical School, The University of Adelaide, Adelaide, SA, Australia 9 Aachen-Maastricht Institute for CardioRenal Disease (AMICARE), Interdisciplinary Center for Clinical Research (IZKF) and Institute for Molecular Cardiovascular Research (IMCAR), RWTH Aachen University, Aachen, Germany Edited and Reviewed by: Masanori Aikawa, Harvard Medical School, United States * Correspondence: Donato Santovito [email protected] Emiel P. C. van der Vorst [email protected] Specialty Section: This article was submitted to Atherosclerosis and Vascular Medicine, a section of the journal Frontiers in Cardiovascular Medicine 28 2 2023 2023 10 114484915 1 2023 15 2 2023 (c) 2023 Santovito, Fan, Elia, Tan and van der Vorst. 2023 Santovito, Fan, Elia, Tan and van der Vorst This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. miRNA cardiovascular disease macrophages biomarker acute coronary syndrome Center for Clinical ResearchRWTH Aachen University 10.13039/501100007210 EPCvdV is funded by a grant from the Interdisciplinary Center for Clinical Research within the faculty of Medicine at the RWTH Aachen University. pmcEditorial on the Research Topic Emerging roles of miRNAs in cardiovascular disease MicroRNAs (miRNAs) are short sequences of single-stranded non-coding RNAs involved in RNA-dependent gene silencing by directing the RNA-induced silencing complex (RISC) toward target messenger RNAs to promote their translational repression or decay (1). Since their original discovery in C. elegans, hundreds of conserved miRNAs have been identified, and their contribution to regulating genes that are crucially involved in cell biology is supported by strong mechanistic evidence (1). As such, miRNAs feature key contributions in developmental and homeostatic processes, as well as in the pathogenesis of several diseases (1, 2). In particular, miRNAs are crucial for homeostasis and function of the cardiovascular system, and genetic deletion of Dicer1, encoding for the rate-limiting enzyme for miRNA biosynthesis, in mice inhibits angiogenesis and results in embryonic lethality (3). Similarly, the postnatal inhibition of the miRNA biosynthesis pathway either by conditional deletion of Dicer1 in cardiomyocytes or vascular cells or by blocking proper RISC assembly results in failure of the cardiovascular function with the development of pathological phenotypes (i.e., dilatative cardiomyopathy or susceptibility to atherosclerosis) (4). Fueled by these observations, multiple studies have already investigated the role of miRNAs in cardiovascular disease and identified feasible therapeutic opportunities moving toward clinical translation, as shown by the completion of recent phase I clinical trials on inhibitors of miR-132-3p and miR-92a-3p for the treatment of heart failure (2, 5, 6). Yet, knowledge about the exact role of miRNAs in cardiovascular disease is far from reaching its completeness, and evidence from the last few years has also highlighted the relevance of unconventional mechanisms of miRNA functions, as well as their contribution to paracrine/endocrine cell communication upon release in the extracellular space, and their potential relevance as a biomarker of cardiovascular disease with potential clinical applications (7-10). The articles in this Research Topic further extend our knowledge on the roles and possible translational applications of miRNAs in cardiovascular disease. Macrophages play important roles in cardiovascular disease. For example, macrophages are involved already in the early phases of atherogenesis, when they accrue modified lipoproteins and differentiate into foam cells, one of the hallmarks of atherosclerosis (11). However, macrophages are characterized by high phenotypical plasticity and, while they can perpetuate inflammatory responses to favor atheroprogression, their alternative activation may result in protective phenotypes (12). Among them, higher expression of ATP-binding cassette transporter A1 (ABCA1) prevents the formation of foam cells by aiding cholesterol efflux and reverse cholesterol transport, thus exerting protective roles against atherosclerosis (12). The ABCA1 transcript is characterized by a remarkably long 3'UTR (>3.3 Kb) that binds to several miRNAs. Mechanistic studies as well as correlative analyses in humans revealed the importance of miRNAs in regulating ABCA1 (e.g., miR-33, miR-144, miR-758, and others) (13-15), and Aranda et al. further strengthen this evidence by showing the contribution of miR-199a-5p in regulating ABCA1 and cholesterol efflux in macrophages. Notably, miR-199a-5p is downregulated by hypoxia and hyperlipidemia, possibly implying the involvement of this pathway in cardiovascular pathophysiology, where cholesterol alterations and hypoxia play important roles. Besides their intracellular regulatory role, miRNAs can be packaged for release in the extracellular space within vesicles (e.g., exosomes, microparticles), plasma lipoproteins, or associated with proteins (e.g., AGO2) (2, 10, 16). Notably, miRNAs can be reliably detected in most biological fluids (e.g., plasma, serum, urines) and studies have identified changes in their expression pattern with disease, highlighting their prospective use as diagnostic biomarkers (2, 9, 10). In their research article, Gager et al. report the results of a monocentric prospective study revealing a negative association between circulating miR-125b and all-cause mortality in patients with acute coronary syndrome (ACS). Moreover, circulating miR-125b was lower in patients suffering from ST-elevation ACS and directly correlated with plasma levels of inflammatory biomarkers (i.e., C-reactive protein). Furthermore, Venugopal et al. aimed to prioritize the choice of miRNAs as biomarkers for patients with ACS. In their study, they explored two already available datasets and integrated the data with algorithms to predict affected target genes and pathways. Their analyses identified four miRNAs (i.e., let-7b-5p, let-7c-5p, miR-342-3p, and miR-4505) as possible biomarkers for ACS, with involvement in pathways relevant to response to ischemia and cardiac disease, to be validated and tested in future prospective studies. While these findings will require independent replication in multicenter prospective clinical trials and while the prompt introduction of circulating miRNAs as biomarkers in clinical practice is still limited by multiple aspects (e.g., lack of universal consensus in the analytical/normalization approach) (2), these studies open up new avenues for future research with the ultimate endeavor of identifying new biomarkers for a better risk assessment and management of patients with ACS. Finally, the Research Topic includes two critical review articles summarizing the current evidence on the role of miRNAs as biomarkers of site-specific atherosclerosis and pulmonary artery hypertension (PAH). Indeed, Teixeira et al. review the circulating miRNAs associated with atherosclerosis in distinct arterial districts, specifically aiming to identify a common circulating signature associated with a stable atherosclerotic phenotype independent of the affected artery. Moreover, Rogula et al. summarize the evidence on the possible applications of circulating miRNAs as diagnostic tools for distinguishing the different etiologies of PAH and as prognostic markers of disease severity. Finally, they conclude their overview by discussing miRNAs as potential therapeutic targets in PAH. In conclusion, this Research Topic aims to provide a standpoint for further research focusing on miRNAs with the ultimate goal of identifying new diagnostic and prognostic markers for cardiovascular disease as well as new therapeutic targets. The successful accomplishment of this future research would contribute to increasing the standard of care for patients with cardiovascular disease, still representing the first cause of death worldwide. Author contributions DS and EPCvdV wrote the manuscript. YF, LE and JTMT revised the manuscript. All authors contributed to the article and approved the submitted version. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Publisher's note All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. References 1. Bartel DP . Metazoan MicroRNAs. Cell. (2018) 173 :20-51. 10.1016/j.cell.2018.03.006 29570994 2. Peters LJF Biessen EAL Hohl M Weber C van der Vorst EPC Santovito D . Small things matter: relevance of MicroRNAs in cardiovascular disease. Front Physiol. (2020) 11 :793. 10.3389/fphys.2020.00793 32733281 3. Yang WJ Yang DD Na S Sandusky GE Zhang Q Zhao G . Dicer is required for embryonic angiogenesis during mouse development. J Biol Chem. (2005) 280 :9330-5. 10.1074/jbc.M413394200 15613470 4. Santovito D Weber C . Non-canonical features of microRNAs: paradigms emerging from cardiovascular disease. Nat Rev Cardiol. (2022) 19 :620-38. 10.1038/s41569-022-00680-2 35304600 5. Taubel J Hauke W Rump S Viereck J Batkai S Poetzsch J Novel antisense therapy targeting microRNA-132 in patients with heart failure: results of a first-in-human phase 1b randomized, double-blind, placebo-controlled study. Eur Heart J. (2021) 42 :178-88. 10.1093/eurheartj/ehaa898 33245749 6. 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Santovito D Weber C . Zooming in on microRNAs for refining cardiovascular risk prediction in secondary prevention. Eur Heart J. (2017) 38 :524-8. 10.1093/eurheartj/ehw259 27371715 11. Weber C Noels H . Atherosclerosis: current pathogenesis and therapeutic options. Nat Med. (2011) 17 :1410-22. 10.1038/nm.2538 22064431 12. Barrett TJ . Macrophages in atherosclerosis regression. Arterioscler Thromb Vasc Biol. (2020) 40 :20-33. 10.1161/ATVBAHA.119.312802 31722535 13. Rayner KJ Suarez Y Davalos A Parathath S Fitzgerald ML Tamehiro N MiR-33 contributes to the regulation of cholesterol homeostasis. Science. (2010) 328 :1570-3. 10.1126/science.1189862 20466885 14. Mandolini C Santovito D Marcantonio P Buttitta F Bucci M Ucchino S Identification of microRNAs 758 and 33b as potential modulators of ABCA1 expression in human atherosclerotic plaques. Nutr Metab Cardiovasc Dis. (2015) 25 :202-9. 10.1016/j.numecd.2014.09.005 25445880 15. Ramirez CM Rotllan N Vlassov AV Davalos A Li M Goedeke L Control of cholesterol metabolism and plasma high-density lipoprotein levels by microRNA-144. Circ Res. (2013) 112 :1592-601. 10.1161/CIRCRESAHA.112.300626 23519695 16. Garcia-Martin R Wang G Brandao BB Zanotto TM Shah S Kumar Patel S MicroRNA sequence codes for small extracellular vesicle release and cellular retention. Nature. (2022) 601 :446-51. 10.1038/s41586-021-04234-3 34937935 |
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