Investigations \227\206 Mild leukocytosis \227\206 Raised inflammatory markers (CRP = 98mg/L, ESR = 66mm/h) \227\206 CXR, Fig. 13.1. Fig. 13.1 CXR. Questions 13a) Provide a differential diagnosis for this presentation. 13b) What is the most appropriate next diagnostic step? CASE HISTORIES IN RESPIRATORY MEDICINE 100 Answers 13a) Provide a differential diagnosis for this presentation. Differential diagnosis of massive effusion. Although heart failure may present with unilate ral effusion, it is unlikely to cause an effusion of this size. The main differentials to c onsider are, therefore: \227\206 TB pleuritis \200\224in an Indian presenting with progressive symptoms, large eff usion and systemic illness, this is the most likely diagnosis. TB pleuritis is usually asso ciated with small to moderate sized collections but large effusions may occur. TB pleuritis is the result of an immuno- logical reaction in the pleural space to mycobacteria, and sho uld not be confused with TB empyema \227\206 Malignancy \200\224around 70% of massive (>2/3 hemithorax) effusions are due to p rimary or secondary malignancy. Tissue types to be considered in this age group include lym phoma, germ cell tumors and testicular cancer. A systemic inflammatory reaction is not unco mmon \227\206 Parapneumonic effusion/empyema \200\224the prolonged (3-month) his- tory of sympt oms does not rule out pleural infection (especially with anaerobic organisms), which may ru n an indolent course. Such a mas- sive effusion is against the diagnosis of frank empyema ( the patient would be likely to be much more unwell). \227\206 Acute trauma and haemothorax may cause a massive effusion, but the history is too prolonged. 13b) What is the most appropriate next diagnostic step? Diagnostic pleural aspiration is the next step to narrow the differential. With a large eff usion, the initial attempt can be made \200\230blind \200\231. If pleural fluid is not obt ained at the first attempt (by an experienced operator), image guidance is required. Progress Diagnostic pleural aspiration was undertaken. Investigations \227\206 Appearance: straw-colored, no odor \227\206 Biochemistry: pH 7.43 Glucose 3.3mmol/L CASE 13 101 Protein 53g/L LDH 431IU/L (serum normal 13 \200\223250) \227\206 Cytology: Benign reactive mesothelial cells Few mature lymphocytes No malignant cells seen \227\206 Microbiology: Gram stain negative ZN stain negative. Questions 13c) Comment on the pleural fluid biochemical parameters. 13d) Comment on the pleural fluid microbiology and cytology results in terms of differential diagnosis. 13e) What is the next stage in diagnosis / management? CASE HISTORIES IN RESPIRATORY MEDICINE 102 Answers 13c) Comment on the pleural fluid biochemical parameters. Pleural fluid biochemistry: \227\206 Exudate on the basis of Light \200\231s criteria (see case 22) (assuming serum pr otein and LDH to be normal). In this situation this does not aid in narrowing the different ial diagnosis, as the main differentials are exudates. \227\206 Suggestive of an inflammatory exudate (high LDH indicative of high cell turnover). \227\206 Normal pH and glucose are strong indicators that this is not due to bacterial pleural infection. \227\206 Pleural fluid pH of <7.2 and a glucose of around 1mmol/L are usual for complicate d parapneumonic effusion or empyema (also seen in some cases of malignancy, oesophageal per foration, rheumatoid dis- ease and systemic lupus erythematosis). \227\206 Glucose level of 3.3mmol/L (low-normal) would be typical of TB pleuritis. 13d) Comment on the pleural fluid microbiology and cytology results in terms of differential diagnosis. Pleural fluid microbiology and cytology: \227\206 Negative Gram and ZN stains do not rule out bacterial or mycobacte- rial infectio n, as effusions may be mainly reactive to the presence of a few bacteria. \227\206 Up to 40% of empyemas are Gram and culture negative. \227\206 Only the minority of TB effusions are ZN positive. \227\206 Absence of malignant cells does not rule out malignancy (40% cytology negative on first aspiration). \227\206 TB pleuritis typically associated with a lymphocyte predominant cell population; up to 10% of cases are polymorph predominant. 13e) What is the next stage in diagnosis / management? Management: \227\206 The diagnosis is not established and there is no gross respiratory embar- rassmen t, therefore complete drainage of pleural fluid (as was done here) is unnecessary and makes subsequent pleural biopsy hazardous. \227\206 There are no biochemical parameters (pH <7.2, glucose <2mmol/L) indicating pleural infection requiring drainage. CASE 13 103 \227\206 Draining a limited amount of pleural fluid for patient comfort would be reasonable. \227\206 Pleural biopsy (non-image guided, e.g. Abram \200\231s, image guided or tho- raco scopic) or contrast enhanced thoracic CT (to highlight the pleural surfaces) would be the n ext step. \227\206 Given the high likelihood of TB pleuritis, closed (e.g. Abram \200\231s) pleural biopsy would be reasonable (overall sensitivity of ZN stain or culture and histology of 80 %), although trial evidence suggests that thora- coscopy has a far higher sensitivity (appr oaching 100%). Fig. 13.2 CXR post drainage. CASE HISTORIES IN RESPIRATORY MEDICINE 104 Progress The patient was started on broad-spectrum antibiotics, a chest drain was inserted and the e ffusion freely drained for presumed pleural infection. Twenty-four hours after drain insert ion, a CXR was performed ( Fig. 13.2 ). Five days later the patient was afebrile and clinically improved. Blood cul- tures and pleu ral fluid cultures were negative and he was discharged home with out-patient follow-up in 4 weeks. One week after discharge, he was admitted to the respiratory unit with an acute illness characterized by high fevers, sweats and malaise. Investigations \227\206 White cell count, 28 \227 10 6 /ml, 90% neutrophils \227\206 Raised inflammator y markers (CRP >160mg/L, ESR, 13mm/h) Fig. 13.3 Repeat CXR. CASE 13 105 Fig. 13.4 Septated collection. \227\206 Pleural fluid parameters at this stage: Appearance, turbid Biochemistry, pH 6.9 Glucose, 1.0mmol/L Protein, 50g/L LDH 5467IU/L \227\206 Thoracic ultrasound: see Fig. 13.4 . Questions 13f) Comment on the post drainage CXR ( Fig. 13.2 ). 13g) What is the most likely diagnosis for this second presentation? 13h) Give the most important immediate steps in management. CASE HISTORIES IN RESPIRATORY MEDICINE 106 Answers 13f) Comment on the post drainage CXR ( Fig. 13.2 ). Shows a chest drain in situ in the left low er zone, some left basal consolida- tion and pleural reaction, and a bulky left hilar/aorto - pulmonary window area suggestive of lymphadenopathy. 13g) What is the most likely diagnosis for this second presentation? The most likely diagnosis for this second presentation is pleural infection (possibly iatro genic given the previous chest drain), consistent with the: \227\206 Pleural fluid biochemistry (suggestive of complicated para-pneumonic effusion) \227\206 Appearance (turbidity suggestive of above) \227\206 Radiology (septations on ultrasound). 13h) Give the most important immediate steps in management. Management of pleural infection: \227\206 Broad-spectrum antibiotics to cover likely pathogens, i.e. Gram-positive, Gram-ne gative and anaerobic bacteria, including cover in this situation for possible MRSA \227\206 Same-day chest drainage (image guided, if necessary) \227\206 TB pleuritis was not excluded on the previous admission, therefore obtaining pleural tissue should now be considered. Progress Broad-spectrum antibiotics were instituted, closed pleural biopsies performed and a chest d rain inserted. Investigations (48h later) \227\206 Pleural fluid microbiology \200\224profuse growth of coagulase-negative Staphylococcus , sensitive to flucloxacillin \227\206 Closed pleural biopsies \200\224necrotizing granulomatous inflammation but microbiologically negative ( Fig. 13.5 ). CASE 13 107 Fig. 13.5 One TB caseating granuloma (G) on pleural biopsy, H and E stain. Questions 13i) What is now your diagnosis? 13j) What antibiotics should this patient now be given? 13k) Comment on the negative microbiology in terms of whether treat- ment for TB should be considered. CASE HISTORIES IN RESPIRATORY MEDICINE 108 Answers 13i) What is now your diagnosis? Diagnosis: \227\206 Definite acute bacterial pleural infection (staphylococcal) \227\206 In association with TB pleuritis. 13j) What antibiotics should this patient now be given? Antibiotics: \227\206 Pleural infection is often associated with mixed bacterial pathogens \227\206 Broad-spectrum antibiotics to cover likely pathogens, i.e. Gram- positive, Gram-n egative, anaerobes, cover in this situation for possible MRSA. 13k) Comment on the negative microbiology in terms of whether treat- ment for TB should be considered. TB pleuritis: \227\206 Closed pleural biopsy (ZN stain and histology together) has a diag- nostic sensitivity of around 60% for TB pleuritis \227\206 If microbiological culture is added (waiting 6 \200\2238 weeks) this increases to around 80% \227\206 Anti-tuberculosis therapy should be started on the basis of the clinical history and the histology result, in the absence of positive microbiology. Progress Satisfactory fluid drainage was achieved. After 5 days of intravenous antibiotic therapy he was commenced on quadruple anti-tuberculosis chemotherapy, tolerating this well. He was di scharged home with an appointment in the out- patient clinic in 2 weeks to assess response. Ten days later he was re-admitted with progressive dyspnoea. A CXR showed a residual left-sided pleural effusion. A thoracic CT scan was performed ( Fig. 13.6 ). CASE 13 109 Fig. 13.6 Thoracic CT slice. Questions 13l) What are the abnormalities on the thoracic CT scan ( Fig. 13.6 )? 13m) What two diagnostic tests could be performed at this stage to confirm the diagnosis? CASE HISTORIES IN RESPIRATORY MEDICINE 110 Answers 13l) What are the abnormalities on the thoracic CT scan ( Fig. 13.6 )? Thoracic CT (Fig. 13.7): \227\206 Enhancing left pleural effusion \227\206 Two separate, non-dependant areas of gas within it, suggestive of a loculated pleural space \227\206 There is free air present in the mediastinum \227\206 This combination is suggestive of oesophageal perforation and infected pleural effusion 13m) What two diagnostic tests could be performed at this stage to confirm the diagnosis? Diagnostic tests: \227\206 Pleural fluid amylase: Raised pleural fluid amylase (i.e. greater than serum normal range) confirms the diagnosis of oesophageal perforation, caused by saliva entering the pleural space through the perfora tion Raised pleural fluid amylase levels may also be seen in acute pancreatitis and malignancy (adenocarcinoma) Left main bronchus RUL bronchus Bronchus intermedius Air in mediastinum Fig. 13.7 Enlargement of mediastinal area of thoracic CT. CASE 13 111 Fig. 13.8 Oral contrast-enhanced CT scan. Oesophageal perforation can be distinguished by conducting isoen- zyme analysis of the pleu ral fluid, revealing amylase of salivary origin \227\206 Oral contrast-enhanced thoracic CT reveals contrast in the mediasti- num (and per haps pleural fluid) confirming the diagnosis ( Fig. 13.8 ). Questions 13n) What is the differential diagnosis of this condition? 13o) How would you manage this patient? CASE HISTORIES IN RESPIRATORY MEDICINE 112 Answers 13n) What is the differential diagnosis of this condition? Causes of oesophageal perforation: \227\206 Malignant oesophageal perforation \227\206 Iatrogenic (post-OGD, post-oesophageal dilatation) \227\206 Post-upper GI surgery \227\206 Oesophageal rupture (Boerhaave \200\231s syndrome) \227\206 Malignant/necrotic mediastinal node compression. 13o) How would you manage this patient? Management of oesophageal rupture: \227\206 Surgical referral for possible repair \227\206 Upper GI rest (feeding jejunostomy or TPN) \227\206 Treat infection (mediastinitis, pleural infection). Progress \227\206 Referred for upper GI surgical opinion \227\206 Endoscopy \200\2243 \227 3cm hole in the distal esophagus, adjacent to large volume mediastinal necrotic node disease on CT \227\206 Laparotomy: omental biopsies revealed caseating granuloma and a feeding jejunostomy was inserted \227\206 Nil by mouth (6 weeks), broad-spectrum antibiotics (4 weeks) and TB quadruple therapy (6-month regime) \227\206 Chest drain remained in situ for 2 weeks, no further pleural fluid accumulation \227\206 Discharged at 6 weeks on a normal diet and completed TB therapy without complication \227\206 Now fully recovered and working again. Final diagnosis TB pleuritis, subsequent iatrogenic empyema and subsequent oesophageal perforation secondar y to necrotic TB mediastinal lymph nodes. Case 14 A 78-year-old man was referred for continuous positive airway pressure (CPAP) therapy. He h ad developed snoring and witnessed apnoeas over the past 5 years (having had an unsuccessfu l uvulopalatopharyngoplasty), along with excessive daytime sleepiness over the last year (E pworth Sleepiness Score, 16/24). He had lost 5kg (BMI of 21). Three years previously he had an ineffec- tive prostatectomy for urinary retention and dribbling. He had started shout- ing during sleep and thrashing around in bed. His wife thought that he had \200\230slowed up \200\231 over the last year. He was now finding it difficult to play the piano, but put this down to his being 78. On more direct questioning he described dizziness on getting out of bed in the mornings, after meals and if he got out of a chair too quickly. He had been impotent for several years and noticed he no longer sweated. He was taking no medications. A sleep study was performed recording oxygen saturation, pulse rate, sound levels ( Fig. 14 .1 ) along with a video-recording available for reviewing, if necessary. Start of night (a) End of night Start of night (b) End of night Start of night (c) End of night Fig. 14.1 Overnight sleep study. (a) Eight sequential hours of overnight oximetry (each sca le 70 \200\223100% SaO 2), starting top-left and ending bottom-right. (b) Eight sequential hours of overnight pulse rate (each scale 50 \200\223170BPM), starting top-left and ending bottom-right. (c) Eight sequential hours of overnight snoring (each scale 30 \200\22380dB), starting top-left and ending bottom-right. CASE 14 115 Analysis \227\206 Oximetry: Mean level, 91.1 % \227\217 >4% SaO 2 dips/h, 13.1 \227\217 Lowest SaO 2 , 77 % \227\206 Pulse: Mean level, 66BPM Standard deviation, 4.1BPM \227\206 Sound: Time>70dB, 361min. Questions 14a) Do the tracings ( Fig. 14.1 ) show obstructive sleep apnoea/hypopnoea, if so, how severe is it? 14b) Why is the heart rate tracing unusual for obstructive sleep apnoea? 14c) What is the diagnosis and why, what further information would have been available from listening to the video? CASE HISTORIES IN RESPIRATORY MEDICINE 116 Answers 14a) Do the tracings ( Fig. 14.1 ) show obstructive sleep apnoea/hypopnoea, if so, how severe is it? The oximetry tracing shows oscillating SaO 2 , which could be due to a variety of causes, both central and obstructive. On this tracing alone further differe ntiation is not possible with any confidence. The noise tracing (once verified as snoring) would of course strongly support obstructive sleep apnoea/hypopnoea, and this could be furt her verified by watching and listening to a segment of the video. The fact that he is not o bese reduces the probability of conventional OSA. The severity is considerable as it extend s throughout most of the night; however, because the size of the dips often does not reach the >4% threshold to be counted, the oxygen desaturation index (ODI) is only 13.1/h and mar k- edly understates the severity of the sleep apnoea. This usually occurs when a patient wi th OSA is thin. The rate at which the SaO 2 falls during an apnoea depends on lung stores of oxygen and the rate at which oxygen is consumed \200\224in thin people, the FRC is proportionately larger than in obese individuals, and their meta- bolic rate is proportionately lower. This means that in the more obese, the SaO 2 falls faster during an apnoea and vise versa. Thus a neg ative screening sleep study, particularly if relying on computer derived indi- ces, rather than looking at the tracing, will be more likely to be falsely negative in thinner individu als. In contrast, false positive screening oximetry tracings are more likely if someone is obese, and/or the starting SaO 2 baseline is low (<93%, e.g. at altitude or with COPD), as it is easier to drop the SaO 2 by 4% with more minor oscillations in ventila- tion if you a re already on the steep part of the hemoglobin dissociation curve. 14b) Why is the heart rate tracing unusual for obstructive sleep apnoea? Normally the heart rate rises with every arousal following an apnoeic/ hypopnoeic event. Th is is because the obstructive event is terminated by activation of the brainstem by the aro usal stimuli, which increases pha- ryngeal muscle tone and simultaneously activates the aut onomic centers. Usually the arousal then spreads through the cortex, to a varying degree, p roducing the sleep fragmentation. On inspection, his heart-rate tracing shows very little o scillation (as also evidenced by the very low standard deviation, <10%). Often this is due to the patient taking blockers, which was not the case here. CASE 14 117 14c) What is the diagnosis and why, what further information would have been available from listening to the video? The diagnosis is Shy \200\223Drager syndrome (or multi-system atrophy); the sound tracing o f the sleep study must be listened to in order to identify laryngeal obstruction (stridulou s), as opposed to the more common pharyngeal obstruction (usual snoring). Multi-system atrophy is a rare condition producing multiple neurologi- cal abnormalities. P atients sometimes present with Parkinsonian-like symptoms (the probable cause of the patien t \200\230slowing up \200\231), and an auto- nomic neuropathy (hence the postural hypotens ion, bladder problems unresponsive to prostatectomy, impotence and absent sweating). On for mal testing, his systolic BP fell 35mmHg on standing, and his diastolic fell 25mmHg, with n o perceptible rise in pulse rate. The stridulous breathing at night, either continuous or frank obstructive sleep apnoea, is due to a specific atrophy and weakness of laryngeal abductors. Sometimes the stridor is evi dent during wakefulness, or can be provoked by a rapid inspiration or exercise. The brainst em nuclei supplying these muscles seem to degenerate early. With the general loss of muscle tone occurring at sleep onset, the larynx may critically narrow. Sudden nocturnal death is reported in this condition, and fatal closure of the larynx is postulated. Continuous posi tive airway pressure (CPAP) works in this condition and is able to splint open the cords. T hus CPAP should probably be offered, even if daytime sleepiness is not trouble- some. Alter native surgical solutions, such as an arytenoidectomy or tracheostomy, are available. In addition he had features to suggest REM sleep behavior disorder (when dreams are physica lly acted out). REM behavior disorder is also a feature of both Parkinson \200\231s and Shy \200\223Drager syndrome, occurring when the area of the brainstem responsible for paralyzi ng most muscles during REM sleep (Jouvet \200\231s center) is damaged, thus allowing the mo tor activity associated with dreaming to be reflected in muscle activity. This varies from a general waving about of the arms and legs with shouting, through to highly aggressive and dangerous behavior, often centered on fighting off attackers in the dream. REM behavior di sorder is also seen in some other brain degenerative disorders such as dementia with Lewy b odies. During a sleep study, with video, it may be obvious that there are abnor- mal movements and shouting. If these are not overt during the sleep study, then a polysomnographic study may demonstrate an attenuation CASE HISTORIES IN RESPIRATORY MEDICINE 118 of the normal degree of dropout of submental EMG activity during REM sleep. REM behavior di sorder can occur many years before the features of Parkinson \200\231s or Shy \200\223Drage r syndrome declare themselves. Progress CPAP was initiated with full resolution of the stridulous breathing at night and partial im provement of the ESS (to 11/24). Clonazepam suppressed the REM behavior disorder, but the o ther symptoms of multi-system atrophy have continued to progress. Further reading Chokroverty S ( 1996 ). Sleep and degenerative neurologic disorders . Neurol Clin ; 14 : 807 \200\223 826 .