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Jul22
TUBERCULOUS MENINGITIS
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
A. Meningitis Inflammatory leptomeningeal exudates
Caseous necrosis
Proiferative opticochiasmatic arachnoiditis
B. Vasculitis Arteritis
Phlebitis
C. Ependymitis and choroids plexitis
D. Encephalitis Cotical
Subepedymal
Vasculitis and infarction
Tuberculosis encephalopathy
E. Disturbance of CSF circulation and absorption (Hydrocephalus) Communicatiing
Obstructive

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 4th 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 6th 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
Stage Symptoms & Signs
I Conscious and rational , with or without neck stiffness
No focal neurological sign or hydrocephalus
Other nonspecific symptoms
II Conscious but confused or has focal signs like cranial nerve palsy or hemiparesis
Signs of meningitis
III Comatose or delirious with or without dense neurological signs. Systemic toxicity . Gross paralysis , seizure, abnormal movements.
IV Deeply comatose with decerebrate or decorticate posture.

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
. Partially - treated bacterial meningitis
. Cryptococcal meningitis
. Viral meningoencephalitis
. Carcinomatous meningitis
. Parameningeal infection
. Neurosarcoidosis
. Neurosyphilis
. Other infections due to Treponema, Brucella, Leptospirae
. Fungal infections due to Candida, Histoplasma, Aspergillus, Actinomyces
. Non infection causes due to systemic lupus erythematous, connective tissue disorder, Bechets disease, chronic benign lymphocytic meningitiss, drugs and chemicals (lodophendylate dye, Sulphonamide /Ibuprofen, Tolmentin)

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 /l, rarely exceeding 1000cells /l. 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.

4. Radiological Study:
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
. Raised intracranial pressure , cerebral oedema, stupor
. Basal meningitis with cranial nerve palsies. (II, III, IV, VI, VII and VIII)
. Focal neurological deficit and seizure ( Mental retardation , behavioral problem, organic brain syndrome, ataxia).
. Hydrocephalus
. Tuberculoma
. Tubercular abscess
. Opticochiasmatic pachymenintitis resulting in visual loss
. Tuberculosis arterites and stroke
. Endocrine disturbances like decrease growth hormone & gonadotrophin
. Hypothalamic disorder leading to loss of control of blood pressure and body temperature, delayed or precocious sexual development.
. Diabetes insipidus
. Syndrome of in appropriate ADH secretion
. Internuclear ophthalmoplegia
. Hemichorea
. Spinal block
. Spinal arachnoiditis
. Psychological or psychiatric disturbances
. Intracranial calcification
. Syringomyelia – due to vasculities of spinal arteries with ischemic myelomalacia.


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 1st 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. Hydrocephalus 3. Infarcts
3. Opticochiasmatic pachymeningitis

The dose is 60mg/day in adult and 1- 2.5 mg/kg/day in children. Contraindications of steroid specially associated fungal infection are to be ruled out before therapy. The duration is variable depending on clinical response. But usually tapered over 4 to 6 weeks.

Immunomodulators other than steroids: They are of historical interest. Intrathecal streptokinase, streptodornase, haparin though tried not beneficial. Intrathecal PPD was tried without much effect. Intathecal hyaluronidase though decreased intracranial pressure in some was not effective. Use of Thalidomide, the drug inhibiting tumor necrosis factor (TNF - ) in rabbits had some positive results. But due to adverse outcome it is not used.
2. Drug resistant TBM: The second line drugs are tried. Ethinoamide penetrate CSF adequately, so also Cycloserine. Newer aminoglycosides and Capreomycin have poor penetration in normal meninges. Fluroquinolones though effective in pulmonary TB they have poor penetration to CSF. Linezolid may be effective.
3. TBM associated with HIV infection: Treatment is same as without HIV infection. Zidovudine is well tolerated along with Anti TB medication. Antifungal drugs interact with Anti TB drugs reducing their efficacy.
4. Management of complications: Surgical intervention required in hydrocephalus, tuberculoma and tubercular abscess. Early drainage of hydrocephalus by ventriculoperitoneal or ventriculoartrial shunt is chosen. External ventricular drainage is required before shunt when CSF protein content or polymorphomuclar cell count is high. Patient of stage I, II have better outcome than stage III or IV after shunt. Tubercular abscess requires drainage. Early use of corticosteroid prevents other complications like arteritis, opticochiasmatic arachnoiditis and other endocrinal complications. A less surgically approach may be tried with medications like corticosteroid, furosemide, acetazolamide, intrathecal hyaluronidase, daily lumbar puncture to reduce hydrocephalus.

Monitoring therapy: Usually in TBM the CSF shows typical biochemical and cytological picture. In rest the deviation may be due to partial treatment with antibiotics and steroid. Usually after antiTB therapy the cell picture briefly become polymorphonuclear but the cell count normalize in one third in 16 months and in all cases by 3 years. In all the CSF glucose normalize after 2 months and protein level normalize within 8 months of therapy.

Clinical improvement occurs at variable period and does not correlate with CSF findings. Any clinical worsening needs neuroimaging to exclude complications. Vigilance maintained to detect drug induced hepatotoxicity, optic neuritis and vestibulopathy.

PROGNOSIS:

Though clinical and laboratory indices are variable some poor prognostic indicators are – extreme age, advanced stage of the disease, concomitant extramenigeal TB and evidence of raised intracranial pressure.

CONCLUSION:

Uncertainty and doubt dominate all aspects of TBM. The variable natural history and clinical features hinders diagnosis. Z.N. staining lacks sensitivity and culture results are often time consuming for clinical judgment. New rapid diagnostic tests are incompletely evaluated and not suitable for developing countries. The duration of chemotherapy of TBM is unclear and benefits of adjuvant corticosteroid remain doubtful. The only uncomfortable certainties lie in the fatal outcome of missed diagnosis and delayed treatment.

SUMMARY:

TBM is commonest form of extrapulmonary neurotuberculosis in developing, industrialized nations. The basic pathology is subependymal (RICH FOCUS) which later on reactivated leading to intracranial structure involvement producing meningitis, vasculitis, ependymitis, encephalitis and hydrocephalus. The clinical picture is variable and neurologically classified to 4 stages. HIV infection increases more risk. TBM is to be differentiated from other conditions keeping in mind various supportive criteria’s. Though routine tests are not specific but +ve mantoux test and classical CSF findings are helpful. Radiodiagnosis like CT/MRI are helpful to evaluate complications. Demonstration of AFB in smear or culture of CSF is confirmatory but time consuming. Immunological methods though rapid but vary in specificity and sensitivity. But PCR is most sensitive. Delay in treatment leads to complications. The treatment regimen is like pulmonary TB but differ in duration of treatment depending on clinical stage. Though role of corticosteroid in debatable its early use prevents complications. In drug resistant cases 2nd line AntiTB drugs are to be given. Surgical intervention is required in hydrocephalus, tuberculoma and abscess. If TBM is not treated prognosis is fatal.


CLINICAL FOCUS

. TBM is commonest manifestation of neurotuberculosis in children in developing countries.
. The pathological process involves various intracranial tissues leading to multifarious clinical presentation.
. For treatment and prognosis TBM is classified into 4 stages.
. It is to be differentiated from other conditions of meningitis.
. Complications and sequelae may result depending on stage, age and initiation of proper therapy.
. Though diagnosis is based on clinical, various methods are used to confirm diagnosis of which CSF study and demonstration of AFB is confirmatory.
. Various immunological methods adopted for diagnosis differ in specificity and sensitivity with various limitation factors.
. The treatment regimen is like pulmonary TB but differ in duration depending on stage of the disease.
. Role of steroid though debatable has beneficial effect .
. Co-infection with HIV does not change the clinical manifestations and outcome of TBM.
. Early diagnosis and treatment results in better outcomes and less permanent sequelae.
. However many aspects of TBM like genetic, ethnic constitution and other factors effecting resistance, early , low cost high sensitivity diagnostic method are under trial.


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