TUBERCULOUS MENINGITIS

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INTRODUCTION

            Neurological Tuberculosis comprises 10 to 15% of cases of extrapulmonary tuberculosis and occur frequently in children. Tuberculous meningitis (TBM) accounts for 70 to 80% of cases of neurological tuberculosis. It is common in developing countires, including India. A delay in diagnosis and treatment  results in fatal outcome. So physician’s responsibility rests on the promptness of instituting adequate therapy considering the predisposing factors, proper diagnosis by adopting various diagnostic methods, associated conditions, treatment of complications and prevention. The resurgence of tuberculosis in industrialized modern India with HIV epidemic , atypical clinical presentation and increase in multidrug resistant tuberculosis (MDR – TB) is a significant health problem.

PATHOGENESIS

             The Organism responsible is commonly Mycobacterium tuberculosis. Rarely M. boovis, M. avium, M. ulcerans, M. africans, M. intracellular are documented to cause meningitis.

            The observation of pathogenesis discussed by Mc Cordock and Rich are still accepted . The CNS involvement occurs in a stepwise manner. In the bacteraemic phase of primary lung infection the metastatic foci get established in the subependyma (RICH-FOCUS) like seedling in any other organ. It is still a dispute that the subependymal foci may develop during primary lung infection or due to secondary haematogenous spread from extracranial extrapulmonary site. Then after a latent phase varying from weeks to years a stimulus , either immune or trauma leads to release of organism and antigen contained in the tubercle to the subarachnoid space causing the disease.

            Conditions which lead to reactivation are intercurrent viral infection, advanced age, alcoholism, malnutrition, corticosteroid use, immunosuppresant drugs, HIV infection and other immunocompromised status. However in most cases no such condition may be found.

PATHOLOGY

            The pathological process involves various intracranial tissues leading to multifarious presentation.

TABLE – I

Serofibrinous exclude collect between pia and arachnoid intermixed with caseous necrosis. The exudates contain mainly lymphocytes and plasma cells with few giant and epitheloid cells. Mycobacteria are present in variable number. Anti TB treatment induces further caseation of the exudates. With successful treatment the exudates resolve leaving residual tubercles, foci of caseation and fibrosis. Proliferative arachnoiditis commonly at the base of the brain involve the area of optic chiasma. As the process becomes chronic it encircles the brain stem involving other cranial nerves.

The terminal portion of internal carotid artery and proximal middle cerebral artery in the Sylvian fissure are commonly involved by vasculitis with inflammation, spasm, constriction and thrombosis. Inflammatory cells infiltrate all layers of vessels and tubercles form first in advertitia and then in media and intima. With progress the media layer fibrose, the intima thickens and vessel lumen shrinks in a necrotising vasculitis reminiscent of periarteritis nodosa. The meningeal veins traversing the inflammatory exudates show varying degrees of phlebitis and thrombosis.

Ependymitis is always a feature of TBM and becomes more severe than meningeal reaction. The choroids plexus shows varying degree of inflammation.

The brain parenchyma underlying the meningeal exudate and subepednymal region show variable degree of oedema, perivascular inflammation and microloglial reaction. Infarction occurs in the territory of middle cerebral artery. Occasionally diffuse cerebral oedema, demyelination and haemorrhagic leukoencephalopathy are identified, mostly in children, attributed due to hypersensitivity reaction to tuberculoproteins. Atrophy of gray and white maters are induced by hydrocephalus .

Hydrocephalus develops in most  symptomatic cases within 2-3 weeks. Commonly it is communicating type due to blockage of the basal cistern by exudates in acute stage or adhesive leptomeningitis in chronic. Less commonly it is obstructive type due to narrowing or occlusion of aqueduct by ependymal inflammation or tuberculoma or due to obstruction at the outlet foramina of 4^th ventricle. Hydrocephalus is common and severe in children than adult.

CLINICAL FEATURES

The clinical  manifestations of TBM are protean. The presentation varies in different series and countries. The most determinant factor is age. In developing countries TBM is disease of childhood with highest incidence in first 3 years of life. The disease is usually a subacute or chronic onset, rarely acute (Children – 50%, Adult 14%). A history of TB can be elicited in child (50%) and adult (10%).

History of lowering resistance like bacterial or viral infection  may be elicited. The disease evolves over 2-6 weeks. The prodromal phase lasting for 2-3 weeks may have vague ill health, apathy, irritability, anorexia and behavioral  changes. With onset of meningitis headache , vomiting and fever occur. Focal neurological deficit and features of raised intracranial pressure (papilloedema) may preceed meningitis. Convulsion (focal or generalized) are seen in 20-30% cases during course. Cranial nerve palsies occur in 20-30% (commonly 6^th cranial nerve). Complete or partial loss of vision is a major complication. The contributing factors for visual impairment are opticochiasmatic exudate, arteritis, hydrocephalus or tuberculoma compressing anterior visual pathway and Ethambutol toxicity. Other clinical presentation may be hemiplegia, facial nerve palsy, optic atrophy, abnormal movement, oculomotor nerve palsy and choroid tubercles.

In untreated cases consciousness deteriorate, pupillary abnormalities and pyramidal signs are seen due to increasing hydrocephalus and tentorial herniation. Terminally  deep coma, decerebrate or decorticate posture occur. Without treatment death occurs in 5-8 weeks.

According to severity and neurological findings TBM is categorized into 4 stages which is useful for treatment and prognosis.

TABLE – 2:CLINICAL STAGING OF TBM

The  paresis reflects ischemic infarction from vasculitis. It may be induced or exacerbated by hydrocephalus.

The picture of TBM has changed in some developed countries with atypical presentation like acute meningitis syndrome, progressive dementia, status epilepticus, psychosis, stroke syndrome, locked in state, trigeminal neuralgia, infantile spasm and movement disorder. The factors responsible are delay in the age of onset of primary infection, immunization, immigrant population  and HIV infection.

HIV infection – CNS involvement are 5 times more in HIV + patients . HIV status does not alter the clinical manifestions, CSF findings and response to ATT. It has been observed that intravenous drug abusers having AIDS exhibit increased risk of CNS tuberculosis and tubercular brain abscess.

DIFFERENTIAL DIAGNOSIS:

TBM should be differentiated from other conditions of  subacute or chronic meningitis.

TABLE – 3 Differential Diagnosis of TBM

            Diagnosis of TBM is fraught with difficulties as demonstration of M. tuberculosis in CSF is difficult and time consuming. Diagnosis is based on neurological symptoms and signs, CSF findings, radiological evidence of exudate, hydrocephalus, infarction, tuberculoma. Evidence of tuberculosis outside CNS with positive Mantoux test, history of contact  and response to treatment are supportive features of tuberculosis etiology.

DIAGNOSIS  - BASED ON VARIOUS TESTS:

1. ROUTINE TESTS: Rarely helpful to establish diagnosis. Raised ESR, anaemia and lymphocytosis are seen in majority of cases. WBC count may be high, normal or low. Occasionally metamyelocytes and nucleated RBC may be seen.
2. MANTOUX TEST: The delayed hypersensitivity skin test using purified protein derivative (PPD) is found positive in Western Countries. (Adults 40-65%, children 85-90%. But PPD lacks specificity in developing countries due to BCG vaccination and sensitization to environmental mycobacteria.
3. CSF Study:  (Clear CSF with moderately raised cells and protein and low glucose is classical)

(a)     Cytology: In TBM the leucocyte count is between 100-500 cells /ml, rarely exceeding 1000cells /ml. Lymphocyte usually predominant. In acute stage polymorphonuclear  cells are usual. Occasionally cell count may be normal. Rarely CSF may be haemorrhagic due to fibrinoid necrosis of vessels. Malignant cells are not found.

(b)    Biochemical:

Protein: Value ranges from 100 to 200mg/dl . In cases of spinal block it may exceed 1gm/dl and xanthochromic. If  allowed to stand a pellicle or cobweb may form indicating presence of fibrinogen which is highly suggestive of TBM. Protein may be normal in some cases of AIDS and TBM.

Glucose: In majority cases less than 40% of corresponding blood sugar level, with a median value between 18 t0 45 mg/dl. Unlike pyogenic meningitis it is never undetectable level.

Chloride: Low chloride level is a non-specific marker reflecting coexisting hypochloraemia. It is unhelpful in discriminating TBM, Bacterial and viral meningitis.

(c)     Microbiological Test:

A negative Gram stain, India inkstain and sterile culture for bacteria and fungi are usual. Demonstration of acid fast bacilli (AFB) in the smear and culture usually confirmatory. The number of bacteria must be more than 10⁴/ml to detect in smear or culture. The smear is stained by Ziehl – Neelsen and auramine (positive in 4-40%). Centrifuging CSF (10-20 ml for 30 minutes) and thick smear from pellicle and repeated CSF smear enhance detection rate.

CSF culture in Lowenstein-Jensen (LJ) media takes 4-8 weeks due to slow growth. Positivity ranges from 25-75% and Indian reports mostly less than 19%. The yield can be enhanced by using liquid culture media like Septic-Chek AFB system and Middle brook 7H9. Isolation rate is higher from cisternal and ventricular CSF than lumbar. In milliary tuberculosis sputum and bone marrow may be positive.

A.            Chest X-ray:  Finding consistent with pulmonary tuberculosis is seen in 25 to 50% of case TBM in adult and 50-90% in children.

B.           Skull X-ray:  Acute TBM does not show any change. In hydrocephalus signs of raised intracranial pressure are seen. Flecks of calcification are seen along basal cistern or course of major vessels. Obliterative endarteritis leading to collateral channels results in enlarged vascular grooves.

C.           Neuroimaging: (CT or MRI, Angiography): Reveal thickening and enhancement of meninges (60%) due to exudates seen at basal cisterns, supracellar cistern and Sylvian fissure. The exudates may be mild, moderate and severe. Hydrocephalus is seen 50-80% cases, the degree correlate with duration of disease. Cerebral infarction (28%) commonly in middle cerebral artery tertiary, edema (periventricular) and mass lesion like tuberculoma (10%) and tubercular abscess are seen. Vasculitis and thrombosis are seen as multiple hypodensity areas on CT. Serial CT is helpful to assess the progress and complications. Contrast enhanced MRI is superior to contrast CT to detect diffuse or focal granulomatous lesion, focal infarction and associated  brainstem lesion. With effective treatment pathologic findings usually resolve but differ in patients and lesion to lesion in same patient. Eventually there may be permanent encephalomalacia , persistent of meningeal granuloma and at times calcification.

Angiography is useful only to differentiate tumor from tuberculoma by absence of “tumor vascularity”. For knowledge purpose in TBM angiography may show ventricular dilatation, narrowing of basal  vessels and cerebral arteritis.

5. Immunological Methods:  Due to variable and nonspecific feature of CSF in TBM a reliable rapid test is a need. In India TBM picture always confuse with partially treated pyogenic meningitis. Several tests which measure directly the components (antigen) of M. tuberculosis and indirectly the host response (antibody) have been tried. They vary in their specificity and sensitivity.

a)     Antibody detection: Antibodies against variety of antigens maybe detected in CSF. They are more sensitive than specific as they are compromised by low level, circulating, cross reactive antibodies. Antibodies to soluble Mycobacteria extract earlier detected in 68% of TBM. But also showed false +ve in pyogenic meningitis probably due to previous exposure and latent infection. Recently antibodies to a  variety of purified antigens including Bacilli Calmette Guerin (BCG), PPD , antigen 5 , 14kD antigen, lipoarabinomannan (LAM) have been  detected by ELISA , RIA and dotimmunobinding assay. In different study the sensitivity  varies from 61-90% and specificity varies from 58-100%. Antibody against M.tuberculosis antigen has a better sensitivity than PPD or BCG. Assay to detect CSF cells secreting antimycobacterial antibodies though technically demanding are less useful. One study detected cells secreting antiBCG antibodies in 96% and anti PPD antibodies in 90% of TBM.

b)     Antigen Detection: There are many reports of mycobacterial antigen assay using latex agglutination, radioimmunoassay, ELISA, inhibition ELISA, immunoblotting , reverse passive hemagglutination, rabit IgG against BCG, culture filtrate antigen, antigen- 5 and immunoabsorbent affinity column-purified antigen have been used. Antigen detection has been more specific than antibody assay. The combined assay of antigen and antibody improve the accuracy.

c)      Circulating Immune Complexes: From serum and CSF these complexes isolated by ELISA and studied for  presence of antigen and antibody. The antigen component decline during the treatment . For formation of immune complex antigen - 5 is required. The detection may vary from 60-82%

d)     Other indirect measures of host response: Adenosine deaminase an enzyme produced by T-lymphocytes is elevated in CSF of 60 –100% cases of TBM. But false +ve results are found in other meningitis. CSF lymphocyte transformation assay, detecting antiBCG secreting cells in CSF, leucocyte migration inhibition  assay and T-cell immunoblotting are other tests. Bromide partition test, measuring the ratio of serum to CSF bromide after a loading dose (< 1.6 is seen in TBM) can be false +ve in other meningitis and not used now a days.

e)     Biochemical detection of mycobacterial products: Tuberculostearic acid, a structural component of M.tuberculosis is detected (sensitivity 75%, specificity 96%) . But cost is a limitation for wide application. The 3-(2-ketohexyl) indoline detection is another evidence.

f)        Molecular methods: Amplification of mycobacterium tuberculosis- specific DNA sequence by polymerase chain reaction (PCR) is used for rapid diagnosis . There  are many methods of PCR assay of which few are simple and others cumbersome. One step amplification used as conventional method has low sensitivity. Two step nested amplification is several fold sensitive. PCR has advantage of confirmation beside AFB smear on the same day. In some studies PCR is more sensitive than culture. PCR is not affected by other infecting bacteria. However in some false –ve results may be due to treatment effect, low bacterial number, small volume of CSF, method of extracting DNA.  False +ve may be due to contamination with other samples like sputum. However in different studies PCR , antibody assay or immunocomplex assay the sensitivity varies.

COMPLICATIONS

            Various complications and sequelae may result depending on the stage  of presentation , response to treatment,  age of the  patients and side effect of the drugs.

TABLE – 4

TREATMENT

            Delay in starting therapy is to be minimized. Though confirmation of diagnosis by PCR or immunological method is not possible in every case in disease prevalent countries, other indirect evidences like  clinical diagnosis of chronic meningitis, history of pulmonary TB, exposure to open cases, chest X-ray findings, raised ESR, positive Mantoux test, CT/MRI evidence of basal meningitis or its sequelae should raise the high suspicion of TBM. A CSF study is mandatory. Prior to initiation factors like age, coexisting hepatic or renal disease and pregnancy are to be considered.

            The Following are the different situations for treatment:

1. Uncomplicated TBM: Before initiation of therapy clinical staging is required and usual drugs are 1^st line antitubercular drugs. Meningeal permeability is increased by non-ionisation of drugs , small molecular weight, low protein binding, high lipid solubility. Isoniazid is  non protein bound and rapidly crosses the Blood brain barrier giving > 30 times MIC (minimum inhibitory concentration). Rifampicin is highly protein bound and 20% penetrate CSF, but it reaches  above MIC  and equally effective in TBM. Pyrizinamide penetrate CSF excellently and recommended highly in TBM due to sterilizing property and reduction of relapse. Ethambutol penetrates in inflamed meninges only posing accurate CSFconcentration measurement. Ethionamide crosses both healthy and inflamed meninges and produce high MIC. But this drug is not used due to poor outcome. Streptomycin concentration varies with severity and meningeal inflammation and slightly above MIC level. Intrathecal route of Streptomycin though produce better CSF concentration is not used due to poor outcome.

Treatment Dose

Isoniazid                      - 10mg/kg                                Rifampicin                   - 10mg/kg

Pyrizinamide               - 40mg/kg/day                         Ethambutol                  - 15mg/kg/day

Ethionamide                - 250mg/day                            Streptomycin               - 750mg/day

Treatment Regimen:            Though many regimens are tried but four drug regimen comprising Isoniazid, Rifampicin, Ethambutol or Streptomycin and Pyrizinamide are to be followed. Ethambutol is better than Streptomycin due to better CSF penetration. This regimen is highly effective unless there is drug resistence. After 2 months Isoniazid and Rifampicin are continued. Pyridoxine (Vt B₆) usually co-prescribed to avoid Isoniazid induced peripheral neuropathy.

Duration of treatment:Though longer duration of treatment lower relapse rate, the cost factor , toxicity and drug compliance are greater. Though 18-24 months was recommending in past but 6-12 month treatment is adequate. For clinical stage I, II treatment for  9-12 months and for Stage III , IV treatment for 12-18 months are adequate.

Role of Steroid:  The role of corticosteroid is debatable. Different studies found that it reduces mortality in stage II, III, morbidity  and complications in stage I on early administration. However the possible rational use is in complications. Indications of steroid are :-

Clinical

1. Stage II and above  2.  Evidence of increased intracranial pressure

3. Focal neurological deficit due to arteritis    4.  Stupor        5. Spinal block

Radiological

1.   Cerebral /perilesional oedema      2.