Tuberculous Meningitis (TBM)

Overview

Pathogenesis

1. Bacterial seeding of the meninges and subpial regions, forming discrete tubercles (part of miliary dissemination)
2. Rupture of one or more tubercles, discharging bacilli into the subarachnoid space

• Adams & Victor's Principles of Neurology, 12th Ed.

Pathological Findings

• Basal meningitis: Thick gelatinous exudate accumulates in the pontine and interpeduncular cisterns, extending to the optic chiasm, floor of the third ventricle, undersurfaces of the temporal lobes, and around the medulla
• Tubercles: Small white discrete lesions scattered over the base of the cerebral hemispheres; microscopically show central caseation surrounded by epithelioid cells, Langhans giant cells, lymphocytes, and plasma cells
• Vasculitis: Arterial inflammation and occlusion can cause cerebral infarction
• Hydrocephalus: Blockage of basal cisterns (communicating) or aqueductal obstruction (obstructive)
• Cranial nerve involvement: The inflammatory exudate engulfs cranial nerves far more often than typical bacterial meningitis
• The process is truly a meningoencephalitis - the pia and ependyma are penetrated, and the choroid plexus is studded with minute tubercles
• Adams & Victor's Principles of Neurology, 12th Ed.

MRI in TBM

Clinical Features

Presentation

• Subacute onset over 1-2 weeks (occasionally longer) - in contrast to bacterial meningitis
• Early symptoms: Low-grade fever, malaise, headache (>50% of cases), lethargy, confusion, stiff neck (~75%)
• Kernig and Brudzinski signs present
• Children/infants: Apathy, hyperirritability, vomiting, seizures; neck stiffness may be absent
• Advanced/chronic signs (present at diagnosis in ~20%): Cranial nerve palsies (especially ocular palsies, facial palsy, deafness), papilledema, hypothermia, hyponatremia
• Focal deficits: Can occur from hemorrhagic infarction (due to vasculitis)
• ~2/3 of patients have evidence of active TB elsewhere (lungs, bowel, bone, kidney, ear)

British Medical Research Council Grading

• Adams & Victor's Principles of Neurology, 12th Ed.; Tintinalli's Emergency Medicine

CSF Findings

• Large volumes of CSF from multiple lumbar punctures with concentration techniques improve sensitivity of both AFB smear and culture
• Plum & Posner's Diagnosis and Treatment of Stupor and Coma; Henry's Clinical Diagnosis

Diagnosis

Key Diagnostic Tests

1. AFB smear: Sensitivity 10-50%; low sensitivity but rapid
2. Culture (gold standard): Most specific but takes 2-6 weeks; may be negative
3. PCR (NAAT): Rapid and specific; sensitivity 25-80% with single primer; multiplex PCR (targeting multiple TB genes) has significantly higher sensitivity
4. Adenosine deaminase (ADA): Elevated levels in TBM compared to other meningitides - useful adjunct
5. Dot-ELISA for TB antigens/antibodies in CSF: 86% positivity in suspected TBM; only 5% false positives from pyogenic meningitis

Neuroimaging

• CT/MRI: May be normal in ~30% of mild cases
• Classic findings: Basal meningeal enhancement on gadolinium MRI, hydrocephalus, cerebral infarctions, tuberculomas
• Chest CT/X-ray: Evidence of pulmonary TB in ~50% of cases (miliary pattern in some)

Differential Diagnosis

• Sarcoidosis
• Leptomeningeal metastases
• Neurosyphilis
• Wegener's granulomatosis (GPA)
• Behcet's disease
• Cryptococcal meningitis (especially in HIV)
• Plum & Posner's; Henry's Clinical Diagnosis

Treatment

Antitubercular Therapy (ATT)

• If clinical/CSF response is good, PZA can be stopped at 8 weeks; EMB stopped when sensitivity confirmed
• Ethambutol has variable CNS penetration and is questionably adequate for TBM - in children, ethionamide or an aminoglycoside is often substituted (per AAP guidelines)

• Harrison's Principles of Internal Medicine 22E; Murray & Nadel's; Rosen's Emergency Medicine

Adjunctive Corticosteroids

• Murray & Nadel's; Harrison's 22E

Neurosurgical Interventions

• Ventriculoperitoneal (VP) shunt required in ~25% of patients for hydrocephalus
• Indications: Obstructive hydrocephalus, tuberculous cerebral abscess, paraparesis
• Up to 25% may require some form of neurosurgical procedure in advanced disease

Complications

Prognosis

• Untreated: Death within a few weeks
• Treated: Mortality 18-40%; neurologic disability in 10-30% of survivors
• Prognosis depends on: age, comorbidities (HIV), time to diagnosis, disease stage at presentation
• The severity of illness should always prompt TBM consideration, as early treatment is the critical determinant of outcome
• Murray & Nadel's; Rosen's Emergency Medicine; Plum & Posner's

Management: TBM + Miliary TB + Sepsis in CKD 5 on Hemodialysis with HTN & DM

IMMEDIATE PRIORITIES (First Hour - "Sepsis Bundle")

CAUTION IN CKD5/HD: Fluid resuscitation - give 30 mL/kg as per SSC protocol even in dialysis patients (do not withhold), but reassess early with ECHO or passive leg raise. Arrange urgent HD if fluid overload develops post-resuscitation.

• Mulholland's Surgery; Bailey & Love's Surgery

SEPSIS: EMPIRICAL ANTIBIOTICS

Empirical Antibiotic Regimen

• Comprehensive Clinical Nephrology, 7th Ed. (antibiotic dosing in dialysis)

De-escalate as soon as culture sensitivities available. Duration 7-10 days for sepsis (SSC guideline).

Note on CNS penetration: Meropenem has good CSF penetration. Avoid imipenem in TBM patients as it lowers seizure threshold.

ANTI-TUBERCULAR THERAPY (ATT) - DOSE-ADJUSTED FOR HD

Standard 4-Drug Regimen Modified for CKD5/HD

Key rules:

• INH and RIF: full daily doses unchanged - both primarily hepatobiliary; rifampicin is highly protein-bound, lipophilic, and not significantly dialyzed
• EMB: MUST dose-reduce - renally excreted; accumulates → visual toxicity (optic neuritis) if given daily in CKD5. Change to 3x/week and give after HD. Monitor visual acuity and color vision monthly.
• PZA: HD removes pyrazinamide and its metabolite pyrazinoic acid accumulates in renal failure - give after HD, 3x/week
• Give all drugs 4-6 hours before HD or after HD completion to prevent dialytic removal before adequate tissue levels are achieved (applies mainly to EMB and PZA)

• Comprehensive Clinical Nephrology 7th Ed.; Katzung's Pharmacology 16th Ed.; BTS Guidelines (web); Queensland Health TB in Renal Disease Guidelines

Duration of Treatment for TBM

• Intensive phase: 2 months (HRZE)
• Continuation phase: INH + RIF for 7-10 additional months (total 9-12 months for TBM)
• Miliary TB: Treat same duration as TBM (most severe form)

ADJUNCTIVE DEXAMETHASONE

IMPORTANT - DM + Dexamethasone interaction:

• Dexamethasone will markedly worsen hyperglycemia in a known diabetic
• Intensify insulin regimen from day 1 of steroids
• Monitor capillary blood glucose every 4-6 hours
• Target glucose: 140-180 mg/dL (ICU range per ADA)
• Use sliding scale insulin + basal insulin (dose adjustment for CKD - insulin clearance also reduced)
• Dexamethasone does NOT require dose adjustment in renal failure

MANAGEMENT OF COMORBIDITIES IN THIS PATIENT

1. CKD 5 on Hemodialysis

• Continue regular HD schedule (typically 3x/week)
• Schedule HD to optimize ATT pharmacokinetics - administer EMB and PZA after each HD session
• Watch for: fluid overload post-sepsis resuscitation → may need extra HD session
• Avoid nephrotoxins strictly: aminoglycosides (streptomycin, kanamycin, amikacin) are CONTRAINDICATED as 4th drug substitute in this patient - will worsen/eliminate residual renal function
• Monitor: BUN, creatinine, potassium, bicarbonate, phosphate at each HD

2. Hypertension

• BP management complicated by:
  • Vasopressors for septic shock (norepinephrine first-line)
  • Rifampicin induces CYP3A4 - reduces levels of many antihypertensives (CCBs like amlodipine, nifedipine significantly affected)
  • May need to increase CCB/ARB doses or switch to drugs with less interaction
  • Avoid ACE inhibitors/ARBs in the acute sepsis phase (risk of hypotension and hyperkalemia in CKD5)
  • Post-sepsis: amlodipine is less affected by rifampicin than most; dose adjustment may be needed
• Continue HD for fluid management as antihypertensive

3. Diabetes Mellitus

• Dexamethasone: aggressive glucose monitoring and insulin titration (see above)
• Rifampicin may reduce metformin levels (enzyme induction) - however, metformin is CONTRAINDICATED in CKD5 (lactic acidosis risk) - ensure it is stopped
• Insulin clearance is reduced in CKD - risk of hypoglycemia; reduce doses carefully
• Diabetic patients have higher TB risk and worse TBM outcomes - tight glucose control is important

4. Hyponatremia (commonly seen in TBM - SIADH from hypothalamic involvement)

• Check serum sodium urgently
• If SIADH present: fluid restrict to 800-1000 mL/day
• Correct cautiously - no faster than 8-10 mEq/L per 24 hours (risk of osmotic demyelination)
• HD can be used for sodium correction if severe

NEUROSURGICAL CONSIDERATIONS

MONITORING PROTOCOL

DRUGS TO AVOID / USE CAUTION

SUMMARY TREATMENT PLAN AT A GLANCE

SEPSIS:
  → Meropenem 500 mg IV q12h (after HD)
  → Vancomycin 1 g IV post-HD (level-guided)
  → Norepinephrine if MAP <65 despite 30 mL/kg crystalloid
  → Blood cultures × 2, lactate, CBC, LFT before antibiotics
  → De-escalate at 48-72h based on cultures

TBM + MILIARY TB:
  → INH 300 mg oral daily (no change)
  → Rifampicin 600 mg oral daily (no change)
  → Pyrazinamide 25-30 mg/kg oral 3×/week AFTER HD
  → Ethambutol 15-25 mg/kg oral 3×/week AFTER HD
  → Pyridoxine (B6) 25-50 mg oral daily (mandatory)
  → Dexamethasone 0.4 mg/kg/day IV (taper over 6 weeks)
  Total duration: 9-12 months

COMORBIDITIES:
  → Continue HD schedule; add sessions if fluid-overloaded
  → Intensify insulin for dexamethasone-induced hyperglycemia
  → Stop metformin (already contraindicated in CKD5)
  → Adjust antihypertensives (rifampicin lowers levels of CCBs)
  → Monitor eyes monthly (EMB), LFTs 2-weekly, electrolytes each HD
  → Neurosurgery consult for hydrocephalus monitoring