Guideline sources The following summarized guidelines for the evaluation and management of tuberous sclerosis complex (TSC) are prepared by our editorial team based on guidelines from the Japanese Respiratory Society (JRS/ATS 2016), the Tuberous Sclerosis Complex International (TSCi 2013), and the European Respiratory Society (ERS 2010). 1 2 3 CalculatorITS diagnostic criteria for tubero Guidelines 1. Screening and diagnosis Screening of family relatives: Elicit a three-generation family history to assess for additional family members at risk of TSC. E Offer genetic testing for family counseling or when TSC diagnosis is in question but cannot be clinically confirmed. E https://web.pathway.md/diseases/recX5Cgas5NBqLFMO 1/8 6/24/23, 4:09 PM Tuberous sclerosis complex Pathway 2. Diagnostic investigations Evaluation of cerebral involvement: As per ITS 2013 guidelines, obtain brain MRI to assess for the presence of tubers, subependymal nodules, migrational defects, and subependymal giant cell astrocytoma in patients with suspected or newly diagnosed tuberous sclerosis. E Show 3 more As per ERS 2010 guidelines: Consider obtaining brain MRI as a baseline evaluation for comparison during follow-up as well as in the presence of symptoms compatible with meningioma. C Obtain brain MRI screening for meningioma in patients with lymphangioleiomyomatosis receiving progestogen therapy or planning to receive such treatment. E Evaluation of renal involvement: As per ITS 2013 guidelines, obtain MRI of the abdomen to assess for the presence of angiomyolipoma and renal cysts in patients with suspected or newly diagnosed tuberous sclerosis. E Show 2 more As per ERS 2010 guidelines, obtain abdominopelvic CT at diagnosis or during work-up to identify angiomyolipoma and other abdominal lesions in all patients with suspected or confirmed pulmonary lymphangioleiomyomatosis. B Show 3 more Evaluation of pulmonary involvement, diagnostic imaging: As per JRS/ATS 2016 guidelines, avoid using HRCT features in isolation to make a clinical diagnosis of lymphangioleiomyomatosis in patients with cystic changes on chest HRCT characteristic of lymphangioleiomyomatosis but not having additional confirmatory features of lymphangioleiomyomatosis (clinical, radiologic, or serologic). D As per ERS 2010 guidelines, do not screen asymptomatic patients for lymphangioleiomyomas during the course of the disease since a proven therapeutic intervention is not currently available for lymphangioleiomyomas. D Show 8 more Evaluation of cardiac involvement: consider obtaining fetal echocardiography to detect patients with a high risk of HF after delivery when rhabdomyomas are identified via prenatal ultrasound. E Show 2 more Evaluation of pulmonary involvement, pulmonary function testing: As per TSCi 2013 guidelines, obtain baseline pulmonary function testing (pulmonary function testing and 6-minute walk test) and chest HRCT in patients with tuberous sclerosis at risk of developing lymphangioleiomyomatosis, even if asymptomatic, typically 18 years old females. Obtain testing in adult males if symptomatic. E As per ERS 2010 guidelines: https://web.pathway.md/diseases/recX5Cgas5NBqLFMO 2/8 6/24/23, 4:09 PM Tuberous sclerosis complex Pathway Obtain spirometry, bronchodilator testing, and transfer factor for CO in the initial evaluation of patients with lymphangioleiomyomatosis (including TSC-lymphangioleiomyomatosis). B Obtain FEV1 and transfer factor for CO to assess disease progression and response to treatment. B Evaluation of pulmonary involvement (blood gas analysis): Consider obtaining blood gases in the initial evaluation of patients with lymphangioleiomyomatosis to obtain a baseline value, and in the assessment of patients with severe disease including before transplant referral. E Obtain blood gases to assess the indication for oxygen therapy in patients with advanced disease. E Evaluation of pulmonary involvement (cardiopulmonary exercise testing): Consider obtaining cardiopulmonary exercise testing to provide additional information over standard lung function tests in symptomatic patients. C Consider obtaining the 6-minute walk test in the evaluation of disability, disease progression, and response to treatment in symptomatic patients. E Evaluation of pulmonary involvement (serum VEGF-D): obtain VEGF D to establish the diagnosis of lymphangioleiomyomatosis before lung biopsy in patients with CT findings of cystic abnormalities characteristic of lymphangioleiomyomatosis but not having clinical or extrapulmonary radiologic features of lymphangioleiomyomatosis. B Evaluation of pulmonary involvement, lung biopsy: As per JRS/ATS 2016 guidelines, consider performing transbronchial lung biopsy before surgical lung biopsy when a definitive diagnosis is required in patients with parenchymal cysts on HRCT characteristic of lymphangioleiomyomatosis but not having additional confirmatory features of lymphangioleiomyomatosis (clinical, radiologic or serologic). C As per ERS 2010 guidelines, examine pathological samples from patients with suspected lymphangioleiomyomatosis (or any diffuse parenchymal lung disease) by a pathologist experienced in lymphangioleiomyomatosis. E Show 2 more Evaluation of pulmonary involvement (screening for pulmonary hypertension): Do not screen patients with non-severe lymphangioleiomyomatosis for pulmonary hypertension. D Consider obtaining echocardiography to assess pulmonary artery pressure in patients with severe disease, requiring long-term oxygen therapy, or considered for lung transplantation. C Evaluation of pulmonary involvement (genetic testing): Refer patients with lymphangioleiomyomatosis and bilateral angiomyolipoma, and other patients where doubt remains, to a clinical geneticist for a full evaluation. B Do not obtain a routine genetic analysis in patients with sporadic lymphangioleiomyomatosis. D Evaluation of cutaneous involvement: obtain a detailed clinical dermatologic assessment (inspection and physical examination) in patients with suspected or newly diagnosed tuberous https://web.pathway.md/diseases/recX5Cgas5NBqLFMO 3/8 6/24/23, 4:09 PM Tuberous sclerosis complex Pathway sclerosis. E Evaluation of ocular involvement: obtain a complete ophthalmologic evaluation including dilated funduscopy to assess for retinal lesions and visual field deficits in patients with suspected or newly diagnosed tuberous sclerosis. E Evaluation of dental involvement: obtain a detailed clinical dental assessment (inspection and physical examination) in patients with suspected or newly diagnosed tuberous sclerosis. E Genetic testing: As per ITS 2013 guidelines, offer genetic testing and family counseling, if not done previously, in patients of reproductive age or newly considering pregnancy. E As per ERS 2010 guidelines: Screen for tuberous sclerosis, with further lymphangioleiomyomatosis screening if TSC is present, in patients with bilateral angiomyolipoma. B Refer patients with bilateral angiomyolipoma and lymphangioleiomyomatosis, and other patients where doubt remains, to a clinical geneticist for a full evaluation. B 3. Medical management Management of cerebral involvement: As per ITS 2013 guidelines: Perform surgical resection for acutely symptomatic subependymal giant cell astrocytoma. Consider creating CSF diversion (shunting). E Consider performing either surgical resection or initiating medical treatment with mTOR complex inhibitors for growing but otherwise asymptomatic subependymal giant cell astrocytoma. Include a discussion of the complication risks, adverse effects, cost, length of treatment, and potential impact on TSC-associated comorbidities in the decision-making process for determining the best treatment option. E Management of renal involvement: As per ITS 2013 guidelines: Perform embolization followed by corticosteroids as first-line therapy in patients with angiomyolipoma presenting with acute hemorrhage. Avoid performing nephrectomy. E Initiate mTOR inhibitors as first-line therapy in patients with asymptomatic, growing angiomyolipoma measuring > 3 cm in diameter. Consider performing selective embolization as second-line therapy in patients with asymptomatic angiomyolipoma. E As per ERS 2010 guidelines, consider performing embolization or nephron-sparing surgery in patients with asymptomatic renal angiomyolipomas > 4 cm or with renal aneurysms > 5 mm in diameter. E Show 3 more Management of pulmonary involvement, mTOR inhibitors: https://web.pathway.md/diseases/recX5Cgas5NBqLFMO 4/8 6/24/23, 4:09 PM Tuberous sclerosis complex Pathway As per JRS/ATS 2016 guidelines, initiate sirolimus rather than offering observation in patients with pulmonary lymphangioleiomyomatosis with abnormal/declining lung function. B As per TSCi 2013 guidelines, consider initiating mTOR inhibitors in patients with lymphangioleiomyomatosis with moderate-to-severe lung disease or rapid progression. E As per ERS 2010 guidelines, do not use sirolimus routinely for pulmonary lymphangioleiomyomatosis outside clinical trials. Encourage patients with lymphangioleiomyomatosis to participate in clinical trials whenever possible. D Show 2 more Management of pulmonary involvement, hormone therapy: As per JRS/ATS 2016 guidelines, avoid using hormonal therapy for the treatment of patients with pulmonary lymphangioleiomyomatosis. D As per ERS 2010 guidelines, do not use oral or intramuscularly progesterone routinely in patients with lymphangioleiomyomatosis. D Show 4 more Management of pulmonary involvement (inhaled bronchodilators): offer a trial of inhaled bronchodilators in patients with airflow obstruction and continue if a response is observed. B Management of pulmonary involvement (doxycycline): avoid using doxycycline for the treatment of patients with pulmonary lymphangioleiomyomatosis. D Management of pulmonary involvement, management of pneumothorax: As per JRS/ATS 2016 guidelines, consider offering ipsilateral pleurodesis after the initial pneumothorax episode rather than waiting for a recurrent pneumothorax before intervening with a pleural symphysis procedure in patients with lymphangioleiomyomatosis. C As per ERS 2010 guidelines, manage pneumothorax in lymphangioleiomyomatosis ideally jointly by a chest physician and thoracic surgeon. B Show 2 more Management of pulmonary involvement, management of chylothorax: As per JRS/ATS 2016 guidelines, consider initiating sirolimus before invasive management in patients with pulmonary lymphangioleiomyomatosis with symptomatic chylous fluid accumulations. C As per ERS 2010 guidelines: Decide on the decision to intervene and the choice of technique for symptomatic chylous pleural effusions on an individual basis based on clinical evaluation, including the amount of chyle collected, recurrence of chylothorax, respiratory condition of the patient, and consideration of future lung transplantation. E Consider offering a fat-free diet with supplementation of mid-chain triglycerides in patients with chylothorax. E Management of pulmonary involvement, lung transplantation: As per JRS/ATS 2016 guidelines, avoid viewing previous unilateral or bilateral pleural procedures (pleurodesis or pleurectomy) as a contraindication to lung transplantation in patients https://web.pathway.md/diseases/recX5Cgas5NBqLFMO 5/8 6/24/23, 4:09 PM Tuberous sclerosis complex Pathway with pulmonary lymphangioleiomyomatosis. D As per TSCi 2013 guidelines, recognize that patients with TSC with lymphangioleiomyomatosis are candidates for lung transplantation but TSC comorbidities may impact transplant suitability. E As per ERS 2010 guidelines, offer lung transplantation in patients with NYHA functional class III or IV with hypoxemia at rest, severe impairment in lung function, and exercise capacity (VO2 max < 50% of predicted). B Show 9 more Management of pulmonary involvement (pulmonary rehabilitation): consider offering pulmonary rehabilitation in patients with pulmonary lymphangioleiomyomatosis limited by dyspnea. E Management of pulmonary involvement, general counseling: As per TSCi 2013 guidelines, counsel adolescent and adult female patients on smoking risks and estrogen use. E As per ERS 2010 guidelines, inform patients with both sporadic and TSC- lymphangioleiomyomatosis, including patients with no or minimal symptoms, of the risk of pneumothorax and advise them to seek urgent medical attention in the event of symptoms of pneumothorax. B Show 4 more Management of pulmonary involvement (routine immunizations): offer influenza and pneumococcal vaccination in patients with pulmonary lymphangioleiomyomatosis. E Management of pulmonary involvement (pregnant patients): counsel all patients with pulmonary lymphangioleiomyomatosis, including patients with few or no symptoms, that there is a greater risk of pneumothorax and chylous effusion during pregnancy. E Show 5 more Management of cutaneous involvement: treat rapidly changing, disfiguring, or symptomatic TSC-associated skin lesions as appropriate for the lesion and clinical context, using approaches such as surgical excision, lasers, or possibly topical mTOR inhibitor. E Management of dental involvement: perform surgical excision or curettage for the treatment of symptomatic or deforming dental lesions, oral fibromas, and bony jaw lesions. E 4. Follow-up and surveillance Follow-up of cerebral involvement: obtain MRI of the brain every 1-3 years in asymptomatic patients with TSC aged < 25 years to monitor for the new occurrence of subependymal giant cell astrocytoma. Obtain MRI more frequently in patients with large or growing subependymal giant cell astrocytoma or with subependymal giant cell astrocytoma causing ventricular enlargement but yet remaining asymptomatic, and educate their families regarding the potential of new symptoms. Continue obtaining imaging periodically in adult patients with asymptomatic subependymal giant cell astrocytoma diagnosed in childhood to ensure there is no growth. E https://web.pathway.md/diseases/recX5Cgas5NBqLFMO 6/8 6/24/23, 4:09 PM Tuberous sclerosis complex Pathway Show 2 more Follow-up of renal involvement: As per ITS 2013 guidelines: Obtain MRI of the abdomen to assess for the progression of angiomyolipoma and renal cystic disease every 1-3 years throughout the lifetime of patients with possible or definite tuberous sclerosis. E Assess renal function (including determination of GFR) and BP at least annually in patients with possible or definite tuberous sclerosis involving kidneys. E As per ERS 2010 guidelines, do not treat patients with asymptomatic renal angiomyolipoma < 4 cm, rather obtain annual ultrasound assessments unless symptoms occur. Obtain CT or MRI if ultrasound measurements are unreliable due to technical factors. D Show 3 more Follow-up of pulmonary involvement: As per ITS 2013 guidelines, obtain clinical screening for lymphangioleiomyomatosis symptoms, including exertional dyspnea and shortness of breath, at each clinic visit of patients with tuberous sclerosis. Review counseling regarding smoking risk and estrogen use at each clinic visit of patients at risk of lymphangioleiomyomatosis. E Show 2 more As per ERS 2010 guidelines, consider repeating lung function tests at 3-6 monthly intervals during the first year following diagnosis, and at 3-12 monthly intervals thereafter depending on the severity and progression of the disease. C Show 6 more Follow-up of cardiac involvement: Obtain every 1-3 years in asymptomatic pediatric patients until regression of cardiac rhabdomyomas is documented. Consider obtaining more frequent or advanced diagnostic assessments in symptomatic patients. E Obtain ECG every 3-5 years in asymptomatic patients of all ages to monitor for conduction defects. Consider obtaining more frequent or advanced diagnostic assessments, such as ambulatory and event monitoring, in symptomatic patients. E Follow-up of cutaneous involvement: obtain a detailed clinical dermatologic assessment (inspection and physical examination) annually. E Follow-up of ocular involvement: obtain annual ophthalmologic evaluation in patients with previously identified ophthalmologic lesions or vision symptoms at baseline. Do not obtain more frequent assessments, including in patients treated with vigabatrin, unless new clinical concerns arise. E Follow-up of dental involvement: obtain a detailed clinical dental assessment (inspection and physical examination) at minimum every 6 months and panoramic radiographs by age 7 years, if not obtained previously. E https://web.pathway.md/diseases/recX5Cgas5NBqLFMO 7/8 6/24/23, 4:09 PM Tuberous sclerosis complex Pathway References 1. Darcy A Krueger, Hope Northrup, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex surveillance and management: recommendations of the 2012 International Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013 Oct;49 4 255 65. Open 2. S R Johnson, J F Cordier, R Lazor et al. European Respiratory Society guidelines for the diagnosis and management of lymphangioleiomyomatosis. Eur Respir J. 2010 Jan;35 1 14 26. Open 3. Francis X McCormack, Nishant Gupta, Geraldine R Finlay et al. Official American Thoracic Society/Japanese Respiratory Society Clinical Practice Guidelines: Lymphangioleiomyomatosis Diagnosis and Management. Am J Respir Crit Care Med. 2016 Sep 15;194 6 748 61. Open 4. Hope Northrup, Darcy A Krueger, International Tuberous Sclerosis Complex Consensus Group. Tuberous sclerosis complex diagnostic criteria update: recommendations of the 2012 Iinternational Tuberous Sclerosis Complex Consensus Conference. Pediatr Neurol. 2013 Oct;49 4 243 54. Open https://web.pathway.md/diseases/recX5Cgas5NBqLFMO 8/8