7 Introduction Tuberculosis is a major cause of death worldwide. India has the highest TB burden, accounting for 1/5 of the global incidence and 2/3 of cases in SE Asia.Nearly 40% of population in India is affected.CNS tuberculosis occurs in up to 10% and has protean clinical manifestations.The burden of CNS tuberculosis is directly proportional to the prevalence of tuberculous infection.Tuberculous meningitis is the most devastating form of extra-pulmonary tuberculosis with 30% mortality and disabling neurological sequelae in > 25% survivors.
8 Classification of neurotuberculosis Tuberculous meningitis- Basal and spinalTuberculoma- Intracranial (parenchymal & extraparenchymal)- Spinal (parenchymal & extraparenchymal)Tuberculous abscessTuberculous encephalopathy- With or without meningitisSpinal cord involvement secondary to skeletal tuberculosisContd…
10 Causative organismCNS tuberculosis is caused by the human strain of Myobacterium tuberculosis.However in immunocompromised patients, atypical mycobacteria are an important cause of infection.They are now called non-tuberculous mycobacteria which include:Mycobacterium aviumMycobacterium intracellulare
11 PathophysiologyCNS tuberculosis is secondary to disease elsewhere in the body.Mycobacteria reach the brain by hematogenous route.Initial small tuberculous lesions (Rich foci) develop in meninges, subpial or subependymal surface of the brain or the spinal cord, and may remain dormant for years.Reactivation may be due to endogenous factors:Innate immunological and non immunological defensesLevel of function of cell mediated immunity.Tumour necrosis factor ά may have a role.
12 PathologyRelease of M tuberculosis results in a T lymphocyte dependent necrotising granulomatous inflammatory response.Thick gelatinous exudate around the sylvian fissures, basal cisterns, brainstem and cerebellum.Three processes cause most of the neurological deficits:HydrocephalousAdhesive arachnoiditisObliterative vasculitisTBM preferentially involves the meninges and basal cisterns of the brain and spinal cord.Infection starts in a subpial or subependymal cortical focus (ie, Rich focus), resulting in a granuloma that erodes into the subarachnoid space causing basal leptomeningitis.Hydrocephalus may be communicating due to obstruction of the arachnoid granulations, or it may result from obstruction of the cerebral aqueduct or fourth ventricular foramina by tuberculous exudate in the acute phase and by pachymeningitis in the chronic phase of the disease.Infarction is common (>50% of patients) in the acute phase and results from a vasculitis that involves the pontine perforator, lenticulostriate, and thalamoperforator arteries. Small infarcts are common in the basal ganglia and brainstem, where they are responsible for the morbidity associated with the disease. These infarcts can lead to mental retardation, stroke, and blindness.Spinal cord involvement rare.
13 Tuberculous brain abscess Distinct from CNS tuberculoma.4 to 7.5% of patients with CNS tuberculosis.Usually solitary, uniloculated or multiloculated of variable sizeProgresses much more rapidly than tuberculomas.Clinical features include partial seizures, focal neurological deficit and raised intracranial tension.CT and MRI show a large size lesion with marked surrounding oedema.
14 Tuberculous encephalopathy Seen in infants and children.Characterized by convulsions, stupor and coma with signs of meningeal irritation or focal neurological deficit.CSF is largely normal.Responsive to corticosteroids.
15 Tuberculoma Firm avascular spherical granulomatous mass. Usually 2-8cm in diameter.Symptoms related to their size and location.Low grade fever, headache, vomiting, seizures, focal neurological deficit, and papilloedema are the characteristic.Target sign is characteristic.
16 Spinal tuberculosis < 1% of patients. Infection starts in cancellous bone usually adjacent to an inter-vertebral disc or anteriorly under the periosteum.Thoracic (65%) lumbar (20%), cervical (10%), thoraco-lumbar (5%), and atlanto-axial region (< 1%).Two (<90%), Three (50%) vertebraeParaspinal abscess 55-90%.Local pain, tenderness over the affected spine or a gibbus associated with paravertebral muscle spasm or a palpable paravertebral abscess.Neurological deficit results from multiple causes.MyelitisPotts spine
17 Non-osseous spinal cord tuberculosis Can occur in the form of tuberculomas.Extradural tuberculomas are the most common.Intramedullary tuberculomas are rare.
18 Tuberculous arachnoiditis Features of spinal cord or nerve involvement may predominate, but most often there is a mixed picture.Subacute paraparesis, radicular pain and bladder dysfunction.The hallmark of diagnosis is the characteristic myelographic picture, showing poor flow of contrast material with multiple irregular filling defects, cyst formation and sometimes spinal block.
19 Spinal form of tuberculous meningitis May result from rupture of Rich foci in the spinal arachnoid space.The acute form presents with fever, headache, and root pains accompanied by myelopathy.The chronic form presents with spinal cord compression.Spinal forms of tuberculous meningitis may be associated with syrinx formation.
20 Tuberculous meningitis (TBM) Commonest form of neurotuberculosis (70 to 80%) .TBM is also the commonest form of chronic meningitis.Clinical features include h/o vague ill health for 2-8 weeks prior to development of meningeal irritation.Non specific symptoms include malaise, anorexia, fatigue, low grade fever, myalgia and headache.Prodromal symptoms in infants and children include irritability, drowsiness, poor feeling, and abdominal pain..Contd…
21 Tuberculous meningitis (TBM) Contd… Meningeal irritation - neck stiffness, Kernig’s sign, Bickelle’s sign and Brudzinski’s sign.Cranial nerve palsies (20-30%), fundus - papilloedema or rarely choroid tubercles, seizures, focal neurological deficits secondary to infarction.Visual loss may be due to optic nerve involvement, optochiasmatic arachnoiditis, third ventricular compression of optic chiasma, ethambutol toxicity and occipital lobe infarction.Increasing lethargy, confusion, stupor, deep coma, decerebrate or decorticate rigidity.
22 Clinical presentation of TBM Clinical Features Children (%) Adults (%)History Tuberculosis Symptoms Headache Nausea/vomiting Apathy/behavioural changes Seizures Signs Fever Meningismus Cranial nerve palsy ComaZuger A. Tuberculosis. In: Scheld WN, Whitley RJ, Marra CM, editors. Infections of Central Nervous System. Philadelphia: Lippincott, pp
23 Staging of TBMTBM is classified into 3 stages according to the British Medical Research Council (MRC) criteriaStage I: Prodromal phase with no definite neurologicsymptoms.Stage II: Signs of meningeal irritation with slight or noclouding of sensorium and minor (cranial nervepalsy) or no neurological deficit.Stage III: Severe clouding of sensorium, convulsions, focalneurological deficit and involuntary movements.
24 Modified MRC criteriaGrade I: Alert and oriented (GCS 15) without focalneurological deficit.Grade II: GCS with or without focal neurologicaldeficit or GCS 15 with focal neurological deficit.Grade III: GCS less than 10 with or without focal
27 Investigations CSF examination CSF Smear examination: Zeihl Nelson’s, Gram’s and India Ink stain.CSF culture on solid media: Egg or agar based BACTEC systems.Adjunctive tests CSF tuberculostearic acid, adenosine deaminase, radiolabelled bromide partition test.Molecular diagnosis : Nucleic acid amplification,DNA finger printing, PCR.
28 Cerebrospinal fluid examination Predominantly lymphocytic pleocytosis, with increased proteins and low CSF/ blood glucose ratio.WBC count can be normal in presence of depressed CMI (elderly and HIV positive individuals).CSF protein (> 150 mg/dl) should always raise the suspicion of tuberculosis or fungal infection, rarely seen in viral meningitis.Smear is +ve in 10%, can be increased by examining large volume of CSF.Culture is +ve in 25-70%.
29 Cerebrospinal fluid examination Repeat CSF frequently shows a falling glucose level, a rising protein concentration and a shift to mononuclear predominance.CSF cell counts decrease by 50% during the first month but may not become normal for a year.CSF glucose becomes normal in 1 to 2 months and protein becomes normal by 12 months or longer.CSF cultures should be sterile by the first month, but PCR results may remain positive for a month.
30 Investigations CSF examination: CSF Smear examination: Zeihl Nelson’s, Gram’s and India Ink stain.CSF culture on solid media: Egg or agar based BACTEC systems.Adjunctive tests : CSF tuberculostearic acid, adenosine deaminase, radiolabelled bromide partition test.Molecular diagnosis : Nucleic acid amplification,DNA finger printing, PCR.
31 Sensitivity and specificity of adjunctive tests for the diagnosis of TBM Tests Sensitivity (%) Specificity (%) Time Required (h)BiochemicalRadiolabelled bromide partition ratioCSF adenosine deaminase level <24CSF tuberculostearic acid level <24Immunologic test (ELISA)Antigen ELISA <24Antibody ELISAKalita J, Misra UK. Tuberculosis Meningitis. In Misra UK, Kalita J (Eds) Diagnosis and Management of Neurological Disorders. Wolter Kluwers Health New Delhi 2011; pp
32 Sensitivity & specificity of various diagnostic tests for TBM ZN staining10-20%100%LJ Culture15% (25-80)BACTEC Culture55%ELISA52.3%91.6%TB PCR56%98%TST73%QTF-GOLD76%ELISPOT87%92%Menzies et al, Ann Int Med. 2007; 146:
33 Diagnostic criteria for TBM ClassDefinitionDefiniteAcid-fast bacilli seen in the cerebrospinal fluid.ProbablePatients with one or more of the following:Suspected active pulmonary TB on chest radiography.AFB found in any specimen other than the CSF.Clinical evidence of extrapulmonary tuberculosis.PossiblePatients with at least four of the following:History of tuberculosis.Predominance of lymphoytes in the cerebrospinal fluid.A duration of illness of more than six days.A ratio of CSF glucose to plasma glucose of less than 0.5.Altered consciousnessTurbid cerebrospinal fluid.Focal neurologic signs.Thwaites GE et al. Diagnosis of adult tuberculosis meningitis by use of clinical and laboratory features. Lancet 2002; 360:
34 Imaging in TBMCT/ MRI confirm the presence and extent of basal arachnoiditis, cerebral oedema, infarction, ventriculitis and hydrocephalus.Abnormalities depend upon stage of disease:I (normal in 30%), II (Normal in 10%), III (Abnormal in all).Hydrocephalus (70-85%), basal meningeal enhancement (40%), infarction (15-30%), tuberculoma (5-10%).Meningeal enhancement, tuberculoma or both have a sensitivity of 89% and specificity of 100%.Precontrast hyperdensity in basal cisterns is the most specific radiological sign.Radiological findings also help in prognostication.
35 Imaging abnormalities in TBM Picture 1. Tuberculosis, CNS. Contrast-enhanced CT scan in a patient with tuberculosis meningitis demonstrates marked enhancement in the basal cistern and meninges, with dilatation of the ventricles35
36 Search for extra CNS TBAn extra-neural focus should be sought clinically and radiologically in all patients of CNS TB as it may indicate safer and more accessible sites for diagnostic sampling e.g. X-ray chest, FNAC of the enlarged lymphnodes, abdominal USG, CT scan .77% of HIV +ve TBM patients have extra-meningeal TB compared to only 9% with HIV –ve patients.Thwaites G, et al. J Neurol Neurosurg Psychiatry 2000;68:
37 Principles of treatment of TBM Treatment should be started early in suspected TBM.Multiple antimicrobial drugs are required.Drugs must adequately cross the blood-CSF barrier to achieve therapeutic concentrations in CSF.Drugs should be taken on a regular basis for a sufficient period to eradicate the CNS infection.Intrathecal therapy is not required.No general consensus regarding the choice of drug, doses and duration of treatment.
38 List of antitubercular drugs First-Line Drugs Second-Line DrugsINH Cycloserine Rifampicin Ethionamide Rifapentine Levofloxacin* Rifabutin* Moxifloxacin* Ethambutol Gatifloxacin* Pyrazinamide p-aminosalicylic acid** Streptomycin** Amikacin/Kanamycin* Capreomycin* Not approved by U.S. FDA** Included in second-line drugs due to toxicity, limited efficacy or difficulty inadministration.
39 TreatmentCNS tuberculosis is categorised under TB treatment category I by WHO.Initial phase therapy ( 2 mths) with isoniazid, rifampicin, pyrazinamide and streptomycin or ethambutol followed by continuation phase (7 mths) with isoniazid and rifampicin.The BTS and IDSA/ATS recommend 9-12 months of ATT. Therapy should be extended to 18 months in patients who do not tolerate pyrazinamide.Short duration therapy (6 mths) might be sufficient if the likelihood of drug resistance is low.However as the emergence of neurological deficit has been seen in some of the studies so a minimum of 12 months treatment would be worthwhile.
40 What is the best anti-tuberculous drug regimen? Isonaizid, rifampicin and pyrazinamide are considered mandatory at the beginning of TBM treatment.Isoniazid penetrates the CSF freely and has potent early bactericidal activity.Rifampicin penetrates the CSF less well (maximum concentrations around 30% of plasma), but the high mortality from rifampicin resistant TBM has confirmed its central role in the treatment of CNS disease.There is no conclusive evidence to demonstrate that pyrazinamide improves outcome of CNS tuberculosis, although it is well absorbed orally and achieves high concentration in the CSF.Thwaites GE et al. J Neurol Neurosurg Psychiatry 2000; 68: ;Lancet Neurol 2005; 4:
41 Choice of the fourth drug No data from controlled trials.Most authorities recommend either streptomycin or ethambutol, although neither penetrates the CSF well in the absence of inflammation.Streptomycin should not be given to those who are pregnant or have renal impairment.Ethambutol should be avoided where optic neuropathy is a concern.The fluoroquinolones may represent an effective fourth agent, although data concerning their CSF pharamacokinetics and safety during prolonged therapy are limited.Others-Ethionamide, prothionamide.
42 Adjunctive steroid therapy The use of corticosteroids as adjunctive therapy in the treatment of CNS tuberculosis began as early as the 1950s.The rationale behind the use of steroids includes the reduction of inflammation within the subarachnoid space.The largest RCT in TBM recommends dexamethasone treatment in patient with TBM for 6-8 weeks.Thwaites GE et al. N Engl J Med 2004; 351: ;Lancet Neurol 2007; 6:
43 Adjunctive steroid therapy A recent Cochrane review and meta-analysis of 7 randomised controlled trials involving 1140 participants (with 411 deaths) concluded that corticosteroids improved outcome in HIV-negative children and adults with TBM, but the benefit in HIV infected individuals remains uncertain.Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008;(1):CD
44 Role of surgery in CNS tuberculosis Hydrocephalus, tuberculous cerebral abscess and vertebral tuberculosis with paraparesis are all indications for neurosurgical referral (A,II).Early ventriculo-peritoneal shunting should be considered in those with non-communicating hydrocephalus (A,II) and in those with communicating hydrocephalus falling medical management (B,II).Communicating hydrocephalus may be treated initially with frusemide (40 mg/24 h adults, 1 mg/kg children) and acetazolamide (10-20 mg/kg adults, mg/kg children) (B,II) or repeated lumbar punctures (B,III).Urgent surgical decompression should be considered in all those with extra-dural lesions causing paraparesis (A,II).
45 TBM in HIV positive patients The optimal regimens have not been clearly established, should be same as in HIV –ve individuals.Four drug regimen including pyrazinamide is recommended.Initiation of HAART depends upon CD 4 counts.Infection with NTM (M avium/M intracellulare).Current recommendations include using azithromycin ( mg/day) and clarithromycin ( mg/day) in combination with ethambutol (15mg/kg/day) or clofazimine (100 mg/day).Alternative regimens include the use of ciprofloxacin and rifampicin.Rifabutin is recommended in place of rifampicin for those taking protease inhibitors.
46 Treatment of multi-drug resistant TBM The treatment of multi drug resistant TBM should abide by the principles of treatment of multi drug resistant pulmonary tuberculosis.Never add a single drug to a failing regimen.Use at least three previously unused drugs, one of which should be a fluoroquinolone.Streptomycin resistance does not confer resistance to other aminoglycosides, therefore amikacin or kanamycin can be used.Treatment should be given for at least 18 months.
47 PrognosisVirtually all patients with no focal deficits and only minor lethargy recover, most-without sequelae.Comatose patients have a mortality of 50% and a high incidence of residual disability.The incidence of residual neurological deficits after recovery from TBM varies from 10-30%.Late sequelae include cranial nerve deficits, gait disturbance, hemiplegia, blindness, deafness, learning disability, dementia and various syndromes of hypothalamic or pituitary dysfunction.
48 Poor prognostic factors Stage of disease.Presence of miliary diseaseSevere disease on admissionDelay in initiation of treatmentExtremes of age, preexistence of a debilitating conditionVery abnormal CSF (very low glucose or elevated protein)
49 ConclusionCNS tuberculosis is a common, eminently treatable disorder with protean manifestations.Early diagnosis requires a high index of suspicion.Careful bacteriology of CSF is as good as or better than molecular method before starting treatment.CT or MRI showing basal meningeal enhancement with any degree of hydrocephalus is strongly suggestive of TBM.Clinical outcome depends greatly on the stage of disease at which therapy is initiated.
50 1. Spinal tuberculosis is classically thought to begin in which portion of the vertebral body: Antero inferiorAntero superiorPostero superiorPostero inferior
51 1. Spinal tuberculosis is classically thought to begin in which portion of the vertebral body: Antero inferiorAntero superiorPostero superiorPostero inferior
52 2. A decreased CSF glucose concentration is not seen in Tuberculous meningitisFungal meningitisViral meningitisNeuro-Sarcoidosis
53 2. A decreased CSF glucose concentration is not seen in Tuberculous meningitisFungal meningitisViral meningitisNeuro-Sarcoidosis
54 3. For a positive smear on Zeihl-Neelsen staining, the bacterial load (in AFB/ml) required is 10×1010×10210×10310×104
55 3. For a positive smear on Zeihl-Neelsen staining, the bacterial load (in AFB/ml) required is 10×1010×10210×10310×104
56 4. Which of the following adjunctive tests has the highest sensitivity and specificity for the diagnosis of TBMRadiolabelled bromide partition testCSF adenosine deaminase levelCSF tuberculostearic acid levelCSF antigen ELISA
57 4. Which of the following adjunctive tests has the highest sensitivity and specificity for the diagnosis of TBMRadiolabelled bromide partition testCSF adenosine deaminase levelCSF tuberculostearic acid levelCSF antigen ELISA
58 5. Maximum CSF concentration occurs with: INHRifampicinPyrazinamideEthambutol
59 5. Maximum CSF concentration occurs with: INHRifampicinPyrazinamideEthambutol
60 6. In a patient with antitubercular therapy, if the primary elevation is in bilirubin and alkaline phosphatase, the most likely offending drug is,IsoniazidRifampicinEthambutolPyrazinamide
61 6. In a patient with antitubercular therapy, if the primary elevation is in bilirubin and alkaline phosphatase, the most likely offending drug is,IsoniazidRifampicinEthambutolPyrazinamide
62 7. Which of the following quinolone antibiotics has highest CSF penetration LevofloxacinMoxyfloxacillinGatifloxacinOfloxacin
63 7. Which of the following quinolone antibiotics has highest CSF penetration LevofloxacinMoxyfloxacillinGatifloxacinOfloxacin
64 8. Chemoprophylaxis for tuberculosis is indicated in persons with high risk medical conditions, if the tuberculin reaction size (in mm) is,<5≥5≥10≥15
65 8. Chemoprophylaxis for tuberculosis is indicated in persons with high risk medical conditions, if the tuberculin reaction size (in mm) is,<5≥5≥10≥15