CNS TB

Introduction

Tuberculosis (TB) of the central nervous system (CNS) is the most severe and life-threatening form of tuberculosis in children. It accounts for approximately 1% of all cases of TB but is responsible for a disproportionately high rate of mortality and long-term neurological morbidity. In high-burden countries like India, CNS TB remains a significant public health challenge. It encompasses three main clinical entities: Tuberculous Meningitis (TBM), Intracranial Tuberculomas, and Spinal Tuberculous Arachnoiditis. TBM is most common in children between 6 months and 4 years of age but can occur at any age.

Pathogenesis

CNS tuberculosis is almost always a result of hematogenous dissemination from a primary focus, usually in the lungs.

1. Primary Bacteremia: Following the primary infection in the lung, tubercle bacilli disseminate via the bloodstream to various organs, including the brain and meninges.
2. Formation of "Rich Focus": The bacilli deposited in the CNS form small, caseous granulomas known as "Rich foci." These are typically located in the meninges, subpial cortex, or subependymal regions.
3. Rupture and Inflammation: The onset of neurological disease occurs when a subependymal or subpial Rich focus ruptures, discharging tubercle bacilli and caseous material into the subarachnoid space or ventricular system.
4. Immunological Response: This discharge triggers a potent T-cell mediated hypersensitivity reaction, leading to the formation of a thick, gelatinous exudate.

Pathological Triad:

• Adhesive Arachnoiditis: The thick exudate accumulates primarily at the base of the brain (basal cisterns), obstructing cerebrospinal fluid (CSF) flow and absorption, leading to communicating hydrocephalus. It also encases cranial nerves (III, VI, VII, and II), causing palsies.
• Vasculitis: The exudate infiltrates the adventitia of cerebral blood vessels (infectious vasculitis), causing inflammation, spasm, thrombosis, and occlusion. This leads to cerebral infarctions (strokes), most commonly affecting the basal ganglia and internal capsule.
• Cerebral Edema: A combination of cytotoxic edema (from ischemia) and interstitial edema (from hydrocephalus) contributes to raised intracranial pressure (ICP) and brain damage,.

Clinical Manifestations

1. Tuberculous Meningitis (TBM)

The onset is usually insidious, progressing over 2–3 weeks, though it can be rapid in infants. The clinical course is classically divided into three stages, which have significant prognostic value,.

• Stage I (Prodromal Phase): Lasts 1–2 weeks. Symptoms are nonspecific and include low-grade fever, malaise, anorexia, irritability, headache, and stagnation of weight gain. Infants may show loss of developmental milestones. Sensorium is clear, and there are no focal neurological deficits.
• Stage II (Meningitic Phase): Onset is more abrupt. Signs of meningeal irritation (nuchal rigidity, Kernig’s and Brudzinski’s signs) appear. There is lethargy, drowsiness, severe vomiting, and seizures. Cranial nerve palsies (commonly VI, III, VII) and mild focal deficits (e.g., hemiparesis) may develop.
• Stage III (Paralytic/Comatose Phase): Characterized by severe clouding of sensorium, stupor, or deep coma. There are signs of severe raised ICP, decerebrate or decorticate posturing, dense hemiplegia/paraplegia, and irregular vital signs (Cushing’s triad). The prognosis in this stage is poor,.

2. Intracranial Tuberculoma

Tuberculomas are granulomatous masses that may present as space-occupying lesions. They can be solitary or multiple and are often located infratentorially (cerebellum/brainstem) in children.

• Presentation: Seizures (focal or generalized), headache, vomiting, and focal neurological signs depending on the location. Fever is often absent.
• Paradoxical Enlargement: Tuberculomas may appear or enlarge during successful anti-TB treatment (paradoxical reaction) due to immune reconstitution,.

3. Spinal Tuberculous Arachnoiditis

This is a rare complication where the gelatinous exudate encases the spinal cord, leading to nerve root compression, radicular pain, and paraplegia.

Diagnosis

Diagnosis of pediatric CNS TB is challenging due to the paucibacillary nature of the disease and nonspecific symptoms. A high index of suspicion is required.

1. Clinical Criteria and History

• History of contact with an adult TB case is a critical clue but may be absent in up to 50% of cases.
• Presence of symptoms >5 days, focal deficits, or optic disc changes.

2. Cerebrospinal Fluid (CSF) Analysis

Lumbar puncture is the cornerstone of diagnosis (contraindicated if there are signs of impending herniation).

• Appearance: Usually clear or slightly opalescent ("ground glass"). A fibrin web (cobweb) may form on standing.
• Cytology: Pleocytosis (usually 10–500 cells/mm³). Predominantly lymphocytes, though neutrophils may predominate in the very early stage.
• Biochemistry:
  • Protein: Significantly elevated (100–500 mg/dL), often >1 g/dL if spinal block is present.
  • Glucose: Hypoglycorrhachia is a hallmark. CSF glucose is <40 mg/dL or CSF:Blood glucose ratio is <0.5 (often <0.3).

3. Microbiological Confirmation

• Smear Microscopy (ZN Stain): Sensitivity is low (<10–15%) in children. Examining large volumes of CSF (5–10 mL) and centrifuging can improve yield.
• Culture (MGIT/LJ): The gold standard but takes weeks.
• Nucleic Acid Amplification Tests (NAAT):
  • Cartridge-Based NAAT (CBNAAT/GeneXpert/TrueNat): NTEP guidelines recommend Upfront NAAT on CSF for all suspected TBM cases.
  • Sensitivity is moderate (~30–60%) but Specificity is very high (98–100%). A positive Xpert result confirms TBM and detects Rifampicin resistance. However, a negative NAAT does not rule out TBM,.

4. Neuroimaging

Contrast-Enhanced CT (CECT) or MRI of the brain is essential. MRI is more sensitive than CT,.

• Basal Meningeal Enhancement: Thick, enhancing exudates in the basal cisterns. This is a pathognomonic feature,.
• Hydrocephalus: Communicating type (ventricular dilatation with basal exudates).
• Infarcts: Typically in the "tubercular zone" (basal ganglia, thalamus, internal capsule) due to lenticulostriate arteritis.
• Tuberculomas: Ring-enhancing lesions with perilesional edema.
  • Differentiation from Neurocysticercosis (NCC): Tuberculomas are usually larger (>2 cm), irregular, have thick enhancement, and may show a "lipid peak" on MR Spectroscopy. NCC lesions are smaller (<2 cm), round, thin-walled, and may show a scolex.

5. Supportive Evidence

• Mantoux Test (TST): Positive in ~50% of cases; a negative test does not exclude TBM (anergy is common in severe disease).
• Chest X-ray: Abnormal in 20–50% of cases (primary complex, miliary TB).
• Gastric Aspirate: Should be sent for CBNAAT/Culture to seek bacteriological confirmation from the lungs, even if CSF is negative.

Diagnostic Algorithm (NTEP)

If a child presents with insidious fever and neurological symptoms:

1. Perform Lumbar Puncture (CSF analysis + NAAT) and Neuroimaging.
2. If CSF NAAT Positive: Treat as Confirmed TBM.
3. If CSF NAAT Negative: Evaluate based on criteria:
   • Clinical features (>5 days symptoms, focal deficits).
   • CSF findings (Lymphocytosis, Low sugar, High protein).
   • Imaging (Basal enhancement, Hydrocephalus, Tuberculoma).
   • Risk factors (Contact history, HIV, SAM).
   • If $\ge$ 2 criteria met (or strong clinical suspicion): Start TBM Treatment.

Differential Diagnosis

• Partially Treated Pyogenic Meningitis: CSF may show lymphocytes and low sugar, but glucose is usually not as low as TBM, and gram stain/culture may help.
• Viral Meningoencephalitis: CSF sugar is usually normal. Onset is more acute. MRI shows temporal lobe involvement (HSV) or thalamic lesions (JE),.
• Cryptococcal Meningitis: In immunocompromised children; India ink/Antigen test positive.
• Neurocysticercosis: Differentiated by neuroimaging features (scolex, size) and serology.

Management

1. Antitubercular Chemotherapy

Treatment must be started immediately on clinical suspicion without waiting for culture results. Delay in treatment is the most significant factor predicting mortality and sequelae.

Regimen for Drug-Sensitive TBM (NTEP 2022 Guidelines): The total duration of treatment is 12 months.

• Intensive Phase (IP): 2 months of HRZE (Isoniazid, Rifampicin, Pyrazinamide, Ethambutol).
• Continuation Phase (CP): 10 months of HRE (Isoniazid, Rifampicin, Ethambutol).
  • Note: The CP contains 3 drugs (HRE) instead of 2 (HR) to prevent resistance amplification,.
  • Daily therapy is mandatory.

Dosages (Daily):

• Isoniazid (H): 10 mg/kg (Max 300 mg)
• Rifampicin (R): 15 mg/kg (Max 600 mg)
• Pyrazinamide (Z): 35 mg/kg (Max 2000 mg)
• Ethambutol (E): 20 mg/kg (Max 1200 mg).

Drug-Resistant TBM: If Rifampicin resistance is detected (by CBNAAT), the child should be managed as per DR-TB guidelines (MDR/RR-TB regimen) involving second-line drugs like Levofloxacin, Linezolid, Bedaquiline (if age >5y), etc., for 18–20 months.

2. Corticosteroids

Steroids are strongly recommended in TBM and Tuberculomas with edema.

• Rationale: They reduce meningeal inflammation, vasculitis, and intracranial pressure, thereby reducing mortality and severe neurological sequelae,,.
• Indication: TBM Stages II and III (and often Stage I), spinal block, raised ICP.
• Regimen:
  • Prednisolone: 2 mg/kg/day (or Dexamethasone 0.6 mg/kg/day).
  • Duration: Given for 4 weeks, then tapered over the next 4–8 weeks.

3. Management of Complications

• Hydrocephalus:
  • Medical: Acetazolamide/Furosemide may be tried for mild communicating hydrocephalus (limited efficacy).
  • Surgical: Ventriculoperitoneal (VP) shunt is indicated for non-communicating hydrocephalus or failure of medical management. It significantly improves outcomes.
• Raised Intracranial Pressure (ICP): Mannitol or hypertonic saline, head elevation, and ventilatory support if comatose.
• Hyponatremia: Common due to SIADH (Syndrome of Inappropriate ADH secretion) or CSW (Cerebral Salt Wasting).
  • SIADH: Fluid restriction.
  • CSW: Aggressive fluid and salt replacement. Correct identification is vital as treatments are opposite,.
• Seizures: Treat with anticonvulsants (Levetiracetam is preferred; Phenytoin/Carbamazepine induce hepatic enzymes and may lower Rifampicin levels, requiring dose adjustments).

4. General Care

• Nutritional support (Nasogastric feeding for comatose children).
• Prevention of bedsores and aspiration.
• Physiotherapy for motor deficits.

Prognosis and Sequelae

The outcome depends primarily on the stage of disease at the start of treatment.

• Stage I: nearly 100% cure with minimal sequelae.
• Stage III: High mortality (up to 50%) and high morbidity.
• Sequelae: Occur in 1/3rd of survivors.
  • Neurological: Hemiplegia, quadriplegia, dystonia, cranial nerve palsies.
  • Sensory: Blindness (optic atrophy), deafness (drug toxicity or disease).
  • Cognitive: Intellectual disability, behavioral problems, ADHD,.

Prevention

• BCG Vaccination: Provides significant protection (up to 80%) against severe forms of childhood TB like TBM and miliary TB.
• TB Preventive Treatment (TPT): Contact tracing of all pulmonary TB patients. Children <5 years exposed to active TB must receive TPT (Isoniazid) after ruling out active disease to prevent progression to TBM,.