TB Intensive Tyler, Texas June 2-4, 2 4 2010 Extrapulmonary TB Robert N. Longfield, MD, FACP June 2, 2010 Extra Pulmonary Tuberculosis TB Intensive Course J June 22, 2010 Robert N. Longfield, MD, FACP June 2010 Spectrum of EPTB: • CNS • Pleural – Meningitis – Tuberculoma • Skeletal – – – – Spinal Joint Osteomyelitis Myositis • Lymphadenitis – Effusion – Empyema • • • • • Genitourinary Gastrointestinal Pericardial Cutaneous Other June 2010 Schematic representation of central role of TNF-Alpha in cellular immune response to M.Tb infection The Lancet Infectious Diseases 2003;3(3):148-155 June 2010 Model of Granuloma formation. In presence of TNF-Alpha. The Lancet Infectious Diseases 2003;3(3):148-155 June 2010 Model of Granuloma formation. In absence of TNF-Alpha. The Lancet Infectious Diseases 2003;3(3):148-155 June 2010 Distribution of EPTB by site, USA, 2005 PTB: 80% EPTB + PTB: 5% EPTB Alone: 15% Co-infection Co infection with HIV has been seen in 20% of patients with EPTB in the US. June 2010 CNS Tuberculosis: • CNS TB includes: – meningitis, – and tuberculoma. • CNS infection reported frequently from high incidence countries. June 2010 INTRODUCTION • Approximately 300 to 400 cases of TB meningitis occur each year in the US. – 1% of all TB disease. • Despite effective treatment regimens, case g - 15% to 40%. fatalityy remains high June 2010 INTRODUCTION • Early recognition of TB meningitis is critical. critical • Empiric Rx should be started with: – a meningitis syndrome and – low CSF glucose, elevated protein, and lymphocytic pleocytosis and – evidence id off TB elsewhere l h in i the th body b d or – if prompt evaluation fails to establish another diagnosis. June 2010 Pathogenesis: • Post Post-primary primary infection: – infants and young children – advanced HIV infection. • Reactivation bacillemia: – – – – – – immune deficiency of aging, TNF inhibitor Rx, alcoholism, Malnutrition Malnutrition, Diabetes, malignancy. June 2010 Pathogenesis: • Tuberculin spillage into the subarachnoid space produces: – – – – – intense inflammation, most marked at the base of the brain. proliferative arachnoiditis, p vasculitis, and communicating hydrocephalus. June 2010 Basilar Meningitis: Thick grey shaggy exudate encasing cranial nerves & blood vessels: Necrotizing granulomatous inflammation of arachnoid and meningeal vessels. June 2010 CLINICAL FEATURES: 1 Prodromal phase, 1. phase 2 to 3 weeks, weeks with a) b) c) d)) insidious malaise, lassitude, headache, low-grade fever, and personalityy changes. p g 2. Meningitic phase 3. Paralytic phase June 2010 CLINICAL FEATURES: 2 Meningitic phase with 2. a) b) c) d)) e) meningismus, protracted headache, vomiting, confusion,, and varying cranial nerve and long-tract signs. June 2010 CLINICAL FEATURES: 3 Paralytic phase is the stage during which the 3. pace of illness may accelerate rapidly; confusion gives way to a) stupor and coma, b) seizures, and c) hemiparesis. June 2010 Atypical presentations: • Acute Acute, rapidly progressive, progressive syndrome suggesting acute bacterial meningitis. • Slowly progressive dementia over months or even years characterized by – – – – personality change, social i l withdrawal, i hd l loss of libido, and memory deficits. June 2010 Atypical presentations: • Encephalitis picture characterized by – stupor, – coma, and – convulsions without overt neck stiffness. June 2010 Clinical stages: • Stage I patients are lucid with no focal neurologic signs or evidence of hydrocephalus. • Stage II patients are confused or have focal signs, such as cranial nerve palsies or hemiparesis. p • Stage III represents advanced illness with delirium, stupor, coma, or dense hemiplegia. June 2010 HIV infection: • In one study study, cerebral tuberculomas were seen to be more common in the HIV-infected group (60% versus 14%). • Otherwise, HIV co-infection did not alter the clinical manifestations,, CSF findings, g , or response to therapy. June 2010 DIAGNOSIS: • Serial examination of the CSF by AFB stain and culture is the best diagnostic approach. • Smears and cultures may yield positive results days to weeks after therapy has been initiated. June 2010 DIAGNOSIS CSF Examination : • • • • Diagnosis (Dx) can be difficult difficult. Proper CSF specimens are critical for early Dx. Maintain a high degree of suspicion. Initiate empiric therapy promptly. June 2010 DIAGNOSIS CSF Examination : • Typical CSF formula shows – elevated protein – lowered glucose and – a mononuclear pleocytosis. • CSF protein ranges from 100 to 500 mg/dL. • Hydrocephalus with subarachnoid block may have protein levels of 2 to 6 g/dL, xanthochromia and a poor prognosis. June 2010 DIAGNOSIS CSF Examination : • Early in the course of illness illness, the cellular reaction may be atypical with – only a few cells or – with a PMN predominance. • Usually changes rapidly to a lymphocytic predominance. June 2010 DIAGNOSIS AFB smears: • Repeated, d careful f l CSF examination i i andd culture l for M. tuberculosis cannot be overemphasized. • In one series, only 37% of cases were diagnosed on the basis of an initial positive AFB smear. • The Th yield i ld increased i d to t 87% when, h ddespite it therapy, up to 4 serial specimens were examined. June 2010 DIAGNOSIS AFB smears: • A minimum of 3 lumbar punctures should be performed at daily intervals. • Empiric therapy should not be delayed. June 2010 DIAGNOSIS AFB smears: • The sensitivity of the AFB smear may be enhanced by: – Using the last fluid removed at lumbar puncture. – Removing a large volume (10 to 15 mL) of CSF. – Examining g a smear of the clot or centrifuged g sediment (cyto-centrifuge). June 2010 DIAGNOSIS AFB smears: • 200 to 500 HPF should be examined methodically (approximately 30 minutes), preferably by more than one observer. June 2010 NOT! June 2010 Molecular Diagnosis of TB Meningitis Thwaites, J Clin Micro, 2004; 42: 996 73 patients with TM vs. 79 without TM AFB (Z/N) Staining C/W Gen-Probe Amplified Mycobacterium Direct Test (MTD) Z/N MTD C bi d Combined Sensitivity Specificity 52% (2% after Rx) 100% 38% (28% after Rx) 99% 68% (83% with ith repeated t d samples) l ) Before Treatment: Careful bacteriology is as good as, or better than, the commercial NAA assays. June 2010 PCR • Nevertheless Nevertheless, submit CSF specimens for PCR testing whenever clinical suspicion is high and initial AFB stains are negative! • A negative test result does not exclude the diagnosis g or remove the need for continued empiric treatment! June 2010 Neuroradiology • Contrast CT defines the presence and extent of – basilar meningitis, – cerebral edema and infarction, and – hydrocephalus. June 2010 Multiple p tuberculomas along enhanced dural reflections: June 2010 Basilar Enhancement & Hydrocephalus: June 2010 Tuberculoma & Hydrocephalus: June 2010 Neuroradiology • Compatible clinical features, features CT evidence of basilar meningeal enhancement AND any degree of hydrocephalus is strongly suggestive of TB meningitis. • Hydrocephalus y p combined with marked basilar enhancement is indicative of advanced disease and carries a poor prognosis. June 2010 Neuroradiology • Marked basilar enhancement correlates well with vasculitis and, therefore, with a risk for basal ganglia infarction. • MRI is superior to CT in defining lesions of the basal gganglia, g , midbrain,, and brain stem and for evaluating all forms of suspected spinal TB. June 2010 Other Conditions Mimicking TB Meningitis Radiographically: • • • • • • Cryptococcal Meningitis Coccidioides Meningitis Viral Encephalitis Sarcoidosis Meningeal Metastases Lymphoma June 2010 THERAPY Recommended regimens: • Drug resistance should be considered in individuals – from areas of the world where TB is prevalent, – in those with a history of prior TB treatment, and – in those with exposure p to drug-resistant g source. June 2010 Duration of therapy • There are no randomized trials to establish the optimal duration of therapy. • It is recommended that therapy be administered for 12 months in the usual case of drug-sensitive infection. June 2010 Duration of therapy • If PZA is omitted or cannot be tolerated, tolerated treatment should be extended to 18 months. • There are no guidelines for the duration of therapy in patients with MDR-TB. • The duration of therapy may be extended to 18 to 24 months, based on severity of illness, clinical response, and the pt’s immune status. June 2010 CSF Penetration of TB Drugs GOOD FAIR POOR Isoniazid * Rifampin * Streptomycin * Pyrizimamide Ethambutol Capreomycin * Ethionamide Quinolones * Amikacin * y Cycloserine Linezolid * * Can Be Given IV June 2010 Adjunctive Corticosteroids: • There is substantial data that adjunctive corticosteroid therapy is beneficial. • A randomized, double-blind trial in Vietnam compared 6 to 8 weeks of dexamethasone with pplacebo in 545 patients p over 14 years y of age. g June 2010 Adjunctive Corticosteroids: Mortality (%) Stage I: Stage II: Stage III: Total: Steroid Group: 17 31 55 32 NonSteroid: 20 40 60 41 NS June 2010 Adjunctive Corticosteroids: • There was no reduction in residual neurologic deficits and disability among surviving patients at nine months. • I.e., Morbidity not improved by steroids. June 2010 Adjunctive Corticosteroids: • The survival benefit associated with steroid therapy may have been in part due to a reduction in severe adverse events (9.5 versus 16.6%), particularly hepatitis that necessitated changes in TB drug regimens. • No mortality benefit from dexamethasone was seen in 98 HIV-infected patients included in the study. June 2010 Adjunctive Corticosteroids: • Adjunctive corticosteroid therapy is recommended for all children and adults treated for TB meningitis. June 2010 Adjunctive Corticosteroids: • Specific clinical indications include: – Acute "encephalitis" with high CSF pressure or cerebral edema. – Worsening signs after start of therapy. – Spinal block or incipient block (CSF protein >500 mg/dL and rising). – CT evidence of marked basilar enhancement. – Patients with symptomatic tuberculoma(s). June 2010 Adjunctive Corticosteroids: • Be aware that concurrent treatment with Rifampin may reduce effective levels of corticosteroids by induction of the hepatic cytochrome P-450 system. June 2010 Recommended Corticosteroid regimens: • Children — Prednisone 2 to 4 mg/kg per day tapered over 4wks. • Adults either: – Prednisone 60 mg per day tapered gradually over six weeks, or – Dexamethasone De amethasone IV ffor th the fi firstt 3 weeks k (i (initially iti ll 0.4 mg/kg per day, tapering to 0.1 mg/kg per day) followed by oral 4 mg per day, tapered over 3 - 4 weeks. June 2010 Surgery • Hydrocephalus may require urgent shunting. shunting • Serial LP and steroid therapy may suffice for Stage I pts awaiting response to antibiotics. • Shunting should not be delayed in patients with stupor coma or progressive neurologic signs. stupor, signs June 2010 Skeletal Tuberculosis: • • • • Vertebral Osteomyelitis – Pott Pott’ss Disease Arthritis Myositis Osteomyelitis June 2010 History: • 39 yy.o. o undocumented Hispanic male presented with F, wt. loss & upper back pain which was worse with cough. • No prior TB Hx or treatment. • Pt found to have far advanced TB on CXR CXR. • Sputum AFB heavily positive, PCR – MTb. June 2010 History 2: • CT spine and MRI spine revealed discitis discitis, vertebral osteo. and epidural abscess at T2 – 4. • Sterile pyuria, anemia and hyponatremia also noted. • Patient treated with RIPE RIPE. June 2010 Exam: • T 102.0 102 0oF, F HR 88 88, BP 84/42 84/42, 55’3” 3 , 111 lbs lbs. • Lungs – occ. faint upper lobe crackles. • Neurologic: – – – – Strength 4/5 BLE, weak ankle dorsiflexors. Sensory numbness below T8 T8. DTR’s 3/4. Plantar flexor reflex on Left, equivocal on Right. BUL, F Far Advanced, Cavvitary TB. June 2010 June 2010 June 2010 June 2010 June 2010 Hospital Course: • Pt continued with daily fevers fevers. • He had decreased LE strength and was transferred for neurosurgical assessment. • Neuro exam revealed anti-gravity strength Rt > Lt weak right ankle dorsiflexor, Lt, dorsiflexor numbness below nipples, and intact toe position sense. June 2010 Laminectomy T2 – T5: • • • • Posterior laminectomy. laminectomy No discrete epidural mass encountered. The surgeon decompressed the thecal sac. Corticosteroids were given during the early post operative phase then later tapered & stopped. stopped June 2010 Further Management: • Pt returned to TCID on P P.O.D. O D 10 10, afebrile with improved cough. • He was able to do transfers with improved L.E. strength. • Pt completed a 1 year course with prolonged continuation phase (INH & RIF). • He was able to walk at discharge. June 2010 Potts Disease: June 2010 Potts T10 & T11: Potts Paravertebral Abscess: June 2010 24 yo Nigerian Female with 1 yr history of b k pain: back i June 2010 Psoas Abscess: June 2010 Needle Biopsy of Vertebral Osteomyelitis under CT guidance: June 2010 TB Osteomyelitis Distal Femur: June 2010 June 2010 TB Arthritis of the wrist: June 2010 TREATMENT • Duration of therapy — • Traditionally, 12 to 18 months of therapy has been advocated. • At issue: drug penetration into necrotic bone. • Several studies recommended shorter treatment. treatment June 2010 TREATMENT • Many specialists, specialists continue to advise at least nine months Rx for skeletal TB. • Longer treatment regimens (at least 12 months) are recommended for patients – with advanced or extensive disease,, – concern for vital adjacent structures (spinal cord) or – if the response to therapy is uncertain. June 2010 Role of surgery • When available available, surgery is useful for: – abscess drainage, – debridement of infected material, – decompression and stabilization of vital structures such as the spinal cord, and – reconstruction or replacement of joints (usually after extensive antibiotic treatment). June 2010 Lymphadenitis: • Cervical – Scrofula • Peripheral • Visceral June 2010 June 2010 June 2010 Peripheral Tuberculous Lymphadenitis Polesky, Medicine, 2005; 84:350 106 Patients with TB lymphadenitis (Santa Clara Co., CA, 1994-1999) Female Mean Age Foreign Born Years in US HIV Seropositive 66% 34 years 92% (Vietnam 60%) 5.2 (mean) 5% June 2010 Necrotic Lymph Node by CT: June 2010 Immune Reconstitution TB LAD: 43 y.o. HIV+ (CD4=46) Pulmonary TB Started on RIPE Started on HAART – AZT/3TC/efavirenz 17 Days later…. June 2010 TB LAD: June 2010 Role of Surgery: • Diagnostic aspiration or biopsy enlarged LN. LN – Exclude co-existing malignancy. • Drain fluctuant lymph nodes. • Resect chronic draining fistulae. June 2010 Pleural Tuberculosis: • • • • • Exudate Empyema Empyema necessitans Broncho-pleural Fistula P Pneumothorax h June 2010 PLEURAL TUBERCULOSIS • TB is the most common cause of pleural effusion in most areas of the world. • In the US, 1/30 patients with PTB have effusion. • True incidence unknown. • Higher incidence in HIV (+) patients patients. • Frequent manifestation of primary TB. June 2010 June 2010 June 2010 Therapy of Pleural TB: • Standard RIPE therapy advised for PTB(S). • AVOID CHEST TUBE – for f simple i l exudates. d t • NO DECORTICATION FOR 3-4 MONTHS – Pleural thickening often decreases with time. – Entrapped lung occasionally requires surgery. June 2010 Tb Empyema: June 2010 Empyema Necessitans: June 2010 June 2010 June 2010 Therapy of Pleural TB: • BP FISTULA (air-fluid level in pleural space): – Does not heal spontaneously. – 90-120 days therapy before decortication. June 2010 Role of Surgery: • Tube thoracostomy management of pneumothorax or empyema. • Decortication of thickened pleura. • Release of entrapped lung. • Closure of BP fistulae with persistent air leak. leak • Resection of necrotic pulmonary tissue. • Muscle flap placement to fill voids. June 2010 Pericardial Tuberculosis: • Effusive • Constrictive • Calcific June 2010 Effusive: June 2010 Pericardial Calcification: June 2010 Chronic Pericarditis: Constrictive Pericarditis: Fibrinous Pericarditis: June 2010 June 2010 TB Pericarditis: • Large pericardial effusion and inversion of the right atrium, caused by elevated pericardial pressure, in late diastole and early systole. • A parasternal short-axis view shows that the right ventricular t i l outflow tfl tract t t is i compressed in diastole because of the elevated pericardial pressure. June 2010 Nardell E. N Engl J Med 2004; 351:1804-1805 NORMAL HEMODYNAMICS: TAMPONADE: June 2010 Role of corticosteroids • In a series reported in 1948, 1948 constrictive pericarditis occurred in 16 of 18 untreated patients. • Constriction now occurs in only 10 to 20% of treated cases. • A trial from South Africa found that corticosteroids gi en for the first 11 weeks given eeks of Tb therap therapy red reduced ced mortality and the need for subsequent pericardiocentesis. June 2010 Role of corticosteroids • The following benefits were noted in the prednisolone group: – – – – More rapid reduction in pulse rate and JVP Improved functional status Lower mortalityy duringg follow-up p (4% ( versus 11%)) Lower need for pericardiectomy (21% versus 30%) June 2010 Role of corticosteroids • Mortality with effusion drainage, drainage TB therapy and prednisolone was 3%. • Mortality with drainage and TB therapy was 14%. June 2010 Role of corticosteroids • The ATS, ATS CDC, CDC and IDSA joint guidelines recommend corticosteroids as an adjunct during the first 11 weeks of therapy for TB pericarditis. June 2010 Role of corticosteroids • The recommended regimens are as follows: – For adults, prednisone 60 mg/day for 4 weeks, • 30 mg/day for 4 weeks, • 15 mg/day for 2 weeks, then • 5 mg/day for week 11. – For children, prednisone 1 mg/kg daily as the initial dose for 4 weeks, with a decreasing dose over time as described for adults. June 2010 Surgical Pericardiectomy: • Reserved for recurrent effusions or elevated CVP after 4 to 6 weeks of combination therapy. • “Early” surgery - more easily accomplished with lower mortality. • The procedure less beneficial with end end-stage stage constriction. June 2010 Pericardiectomy Preferred technique via a left anterior thoracotomy thoracotomy. Pericardium is removed from the level of the left pulmonary veins to the right side of the mediastinum. The left phrenic nerve is preserved. June 2010 Genitourinary Tuberculosis: • Renal • Ureters & Bladder • Genital June 2010 June 2010 June 2010 Ureteral U t l TB with stenosis. June 2010 Blunting of the calyces (caliectasis) and two long ureteral strictures (arrows) are seen. seen Although the caliceal changes can be seen in other disorders (such as reflux nephropathy), the concurrent ureteral abnormalities b li i are virtually i ll diagnostic of tuberculosis. June 2010 GU & Male Genital TB June 2010 TB Prostate: A 46-year-old man presented with features of prostatism, lower urinary tract symptoms, and painless intermittent hematuria. TRUS showed a markedly enlarged prostate containing a large hypoechoic mass protruding from the base and d f deforming i the h capsule. l Urine U i culture l was positive for Mycobacterium tuberculosis. The patient had no evidence of pulmonary TB. June 2010 TB Testis: June 2010 Laparoscopic views in genitourinary tuberculosis. (a) Free and loculated ascites and fine fibrous adhesions. June 2010 Laparoscopic views in genitourinary tuberculosis.. (b) Miliary nodular exudate in the anterior wall. June 2010 Diagnosis of Renal Tb: • Supported by the presence of AFB in the urine. urine • Dysuria, sterile pyuria, hematuria, and characteristic imaging findings support the diagnosis. • Urine TB culture is the gold standard – Three to six first morning midstream specimens. – Bacilli are shed into the urine intermittentlyy – Only 30% to 40% of single specimens are positive. June 2010 Role of Surgery: • Relief of urinary obstruction. obstruction • Urinary diversion. – Temporary. – Permanent. • Nephrectomy on rare occasions. occasions • Drainage of prostatic abscesses. June 2010 Gastrointestinal Tuberculosis: • Peritoneal • Hollow Viscus • Hepatosplenic June 2010 June 2010 Tuberculosis Peritonitis: • Sx: Acute or chronic pain pain, swelling, swelling constitutional symptoms, intestinal obstruction. • Doughy abdomen – rare. • Ascitic fluid: Exudate, 150-400 WBC, lymphocytic (can be neutrophilic). • (+) ( ) MTB culture l <20%. • Elevated ascitic fluid adenosine deaminase (ADA). • Laparoscopy and biopsy offer best approach to Dx. June 2010 Peritoneal Tb: Laparoscopic view ie of multiple peritoneal tubercles. June 2010 Peritoneal Tb. Laparoscopic L i view of peritoneal ‘‘spider web’’ adhesions Note adhesions. the ascitic fluid at the right bottom corner. June 2010 Hollow Viscus Tuberculosis: • Chronic pain (R L Q) Q), weight loss, loss anorexia fever • Colitis (ulcerative, hypertrophic) with predilection for ileocecum. • Strictures. • Perforation. • Endoscopic findings are not definitive, – full thickness biopsy with AFB smear and culture. June 2010 Esophageal Tuberculosis: A 25 25-y.o woman, India I di immigrant, presented with substernal chest pain and dysphagia for 4 days. She reported 2.5-kg weight loss in the past 3 months. Esophagoscopy showed a deep linear ulcer in the esophagus. Biopsy showed necrotizing granulomas and cultures grew M. tuberculosis complex. The American Journal of Medicine (2007) 120, e1-e2 June 2010 Duodenal TB (Miliary Case): June 2010 June 2010 June 2010 June 2010 June 2010 June 2010 •TB Splenic Flexure at onset of treatment. June 2010 •TB Splenic Flexure after 10 weeks of Rx. June 2010 84 y.o. WM with change in bowel habits and an normal CXR. June 2010 Anatomic distribution of GI TB: Site: Autopsy %: Clinical % Esophageal 0.14 0.3 Stomach 0.69 2 Duodenum 2.5 0.3 Ileocecal 66.1 42 Colon 53.8 12 Anorectum 11.9 7 June 2010 Hepatic or Splenic TB: June 2010 Surgical Considerations: • Laparascopic biopsy to Dx peritonitis peritonitis. • Management of strictures, fistulae and perforation which do not respond to medical therapy. June 2010 ENT Tuberculosis: • Laryngitis • Otitis • Mastoiditis June 2010 June 2010 TB Otitis Media: June 2010 Extensive Mastoiditis on L June 2010 Surgery: • • • • • • Tracheostomy for respiratory compromise. compromise Correction of tracheal stenosis. Biopsy to exclude malignancy. Abscess drainage (i.e., mastoid Tb). D Decompression i off the h facial f i l nerve. Treatment of Tb extension into the CNS. June 2010 Other EPTB: • • • • • Adrenal Thyroid Myocardium Retina – choroidal tubercles Ski – Lupus Skin L vulgaris l i June 2010 Adrenal Calcifications from Tb: June 2010 Adrenal tuberculosis in 49-year-old man of 2 months duration. Contrast-enhanced CT shows the bilateral mass-like enlargement with peripheral enhancement. June 2010 Choroidal Tubercles: June 2010 Lupus vulgaris Reddish-brown plaque. Note nodular infiltration, scaling of the helix, and atrophic scarring in the center of the plaque. June 2010 16 y.o. male with PTB & Skin TB x 5yrs: June 2010 June 2010 Miliary TB: • Wide dissemination throughout the body. body • Tiny size of the lesions. • Distinctive pattern seen on chest X-ray. – With or without other types of infiltrates. • Appearance similar to millet seeds, seeds thus the term "miliary" tb. June 2010 Miliary TB: June 2010 June 2010 June 2010 Guidelines for EPTB Treatment: • In general, general EPTB can be treated with the same regimens as pulmonary disease. • Evidence suggests that 6- to 9-month regimens that include INH and RIF are effective. • If PZA cannot be used in the initial phase, phase continuation phase must be increased to 7 months. June 2010 Guidelines for EPTB Treatment: • For disseminated TB and TB meningitis, meningitis 9--12 months of treatment is recommended. • Prolongation of therapy also should be considered for TB in any site that is slow to respond. • The Th adjunctive dj i corticosteroids ti t id are recommended for TB pericarditis and TB meningitis. June 2010
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