Tuberculous Meningitis

Epidemiology & Risk Factors

Pathogenesis

1. Hematogenous seeding of the meninges and subpial brain regions → formation of tubercles (granulomas)
2. Rupture of one or more tubercles → discharge of bacteria into the subarachnoid space → inflammatory meningitis

Pathology

• Small white tubercles scattered over the base of the cerebral hemispheres (basal predominance is hallmark)
• A thick gelatinous exudate accumulates at the base, obliterating the pontine and interpeduncular cisterns, extending to the medulla, floor of the third ventricle, optic chiasm, and undersurfaces of the temporal lobes
• Microscopically: meningeal tubercles show central caseation surrounded by epithelioid cells, giant cells, lymphocytes, plasma cells, and connective tissue
• The process extends beyond the subarachnoid space to invade underlying brain — making it a true meningoencephalitis
• Complications arising from the exudate:
  • Cranial nerve palsies (traversing nerves caught in exudate)
  • Vasculitis and arterial occlusion → infarction
  • Hydrocephalus (obstructive, from blockage of basal cisterns; up to 25% need neurosurgical shunting)
  • Arachnoid fibrosis, especially at the base of the brain (Robbins Pathology)

Clinical Features

CSF Findings

• Acid-fast smear (Ziehl-Neelsen): Sensitivity only 10–50%; increased by large volumes and multiple LPs with concentration techniques
• Culture: Gold standard but slow (3–4 weeks); rapid liquid culture <1 week with newer techniques
• PCR (nucleic acid amplification): Sensitivity ~80%; ~10% false-positive rate; multiplex PCR is more sensitive
• ADA (adenosine deaminase): Significantly elevated in TB meningitis vs. other meningitides
• Dot-ELISA (CSF antigens/antibodies): Positive in ~86% of suspected cases
• Interferon-gamma release assay (IGRA): ~90% specific for active TB infection when used in blood; also used in CSF

Imaging

• Basal meningeal enhancement on gadolinium T1 (classic finding)
• Hydrocephalus (communicating > obstructive)
• Tuberculomas — ring-enhancing lesions with central caseation
• Infarcts from vasculitis (basal ganglia, internal capsule)
• CT normal in ~30% of mild disease

Treatment

First-Line Regimen (4-drug induction)

• Induction phase: All 4 drugs for 2 months
• Continuation phase: INH + RMP for remaining 7–10 months (total 9–12 months)
• Alternative regimen: INH + PZA + high-dose RMP + moxifloxacin

• Give pyridoxine 50 mg/day with INH to prevent neuropathy (especially in alcoholics, pregnant women)
• All drugs penetrate the blood-brain barrier; INH and PZA have the best CNS penetration
• In multidrug-resistant (MDR-TB): add ethionamide (ETA) as 5th drug; doses 15–25 mg/kg/day in divided doses
• Drug-resistant organisms increasing — especially from certain geographic regions (high INH ± EMB resistance)
• Directly observed therapy (DOTS) for at least 2 months is now routine

Adjunctive Corticosteroids

• 0.4 mg/kg/day IV for 1 week, then tapered over 3–6 weeks
• A randomized trial (Thwaites et al., Vietnam) showed dexamethasone reduced mortality from 41% to 32%, though without significant effect on residual disability
• Only used in conjunction with antituberculous drugs

Neurosurgical Management

• Ventriculoperitoneal shunting required in ~25% of patients for hydrocephalus
• Tuberculomas unresponsive to medical therapy may require surgical excision
• Pott disease (spinal TB) with cord compression: surgical decompression after initial chemotherapy

Prognosis & Sequelae

• Overall mortality: ~10% in treated patients; significantly higher in HIV patients (~21%)
• Comatose patients at diagnosis: mortality approaches 50%
• 20–30% of survivors have neurologic sequelae:
  • Cognitive impairment / intellectual decline
  • Recurrent seizures
  • Visual and oculomotor disorders
  • Deafness
  • Hemiparesis
  • Psychiatric disturbances
• Early diagnosis is the single most important determinant of favorable outcome

Summary: TB Meningitis vs. Bacterial Meningitis

Clinical Features of Tuberculous (TB) Meningitis

1. Overview: The Subacute Nature

"TB meningitis, in contrast to other types of meningitis, can have a subacute or even chronic presentation, with symptoms developing months after onset of infection." — ROSEN's Emergency Medicine

2. Prodromal / Constitutional Phase (Days 1–14)

3. Meningeal Phase — Classic Signs

Headache

• The most prevalent symptom (>50% of cases)
• Becomes severe, persistent, and progressive
• Reflects raised intracranial pressure (ICP) and meningeal irritation

Neck Stiffness (Nuchal Rigidity)

• Present in approximately 75% of cases
• Reflects irritation of spinal meninges
• May be absent in infants, the very elderly, and immunosuppressed patients — an important diagnostic pitfall

Kernig's Sign

• With the patient supine and hip flexed at 90°, extension of the knee is resisted due to pain/spasm
• Reflects meningeal and nerve root irritation

Brudzinski's Sign

• Passive flexion of the neck causes involuntary flexion of both knees
• Also reflects meningeal irritation

"Characteristically, these symptoms evolve much less rapidly in tuberculous than in bacterial meningitis, usually over a period of a week or two, sometimes longer." — Adams and Victor's Principles of Neurology

4. Cranial Nerve Involvement (Very Characteristic of TBM)

"Cranial nerves are often involved by the inflammatory exudate as they traverse the subarachnoid space, indeed, far more often than with typical bacterial meningitis." — Adams and Victor's Principles of Neurology

5. Raised Intracranial Pressure (ICP)

1. Communicating hydrocephalus — basal exudate blocks CSF resorption at the arachnoid villi
2. Obstructive hydrocephalus — ependymitis blocking the aqueduct or 4th ventricle
3. Cerebral oedema
4. Mass effect from tuberculoma(s)

Clinical signs of raised ICP:

• Severe, progressive headache (worse in morning, on Valsalva)
• Papilledema (visible on fundoscopy)
• Vomiting (without nausea = "projectile")
• Cushing's triad in severe cases (hypertension, bradycardia, irregular respirations) — late and ominous
• Altered consciousness (see next section)
• CN VI palsy (false localising sign — traction on long course of nerve)
• Up to 25% of patients ultimately require ventriculoperitoneal shunting for hydrocephalus — ROSEN's Emergency Medicine; Tintinalli's

6. Altered Consciousness & Neuropsychiatric Features

• Psychiatric disturbances may be the presenting feature, occasionally leading to initial misdiagnosis as a psychiatric disorder
• Mental confusion is listed as a cardinal symptom in multiple textbooks alongside headache and vomiting
• In untreated disease, the course is: "confusion and progressively deepening stupor and coma, coupled with cranial nerve palsies, pupillary abnormalities, focal neurologic deficits, raised ICP, and decerebrate postures; usually fatal within 4–8 weeks" — Adams and Victor's Principles of Neurology

7. Focal Neurological Deficits (Vascular Complications)

• The basal exudate envelops and invades vessel walls → obliterative endarteritis (granulomatous infiltration with marked intimal thickening)
• Vessels most commonly affected: perforating branches of the middle cerebral artery and circle of Willis → basal ganglia, internal capsule
• Aneurysm formation, thrombosis, and focal haemorrhagic infarction can result

Focal deficits arising from vascular involvement:

• Hemiplegia / hemiparesis
• Aphasia
• Hemianopia
• Basal ganglia syndromes (chorea, tremor, rigidity)
• Acute stroke-like onset — can be the initial presentation of unrecognised TB meningitis

"Tuberculous cerebral involvement is most marked at the base of the brain, and vasculitis of local arteries and veins may lead to aneurysm formation, thrombosis, and focal haemorrhagic infarction. The vessels to the basal ganglia are usually involved." — ROSEN's Emergency Medicine

8. Seizures

• Can occur at any stage; more common in children
• May be focal or generalised
• Causes include:
  • Cortical irritation from meningeal inflammation
  • Cerebral infarction
  • Hyponatraemia (a common metabolic complication — see below)
  • Tuberculoma with cortical involvement
• Recurrent seizures are one of the significant long-term sequelae in survivors

9. Metabolic & Systemic Features

Hyponatraemia

• Common and clinically important
• Mechanisms:
  • SIADH (Syndrome of Inappropriate ADH secretion) from hypothalamic involvement
  • Addisonian state — if TB affects the adrenal glands
• Can precipitate or worsen seizures, confusion, and cerebral oedema

Hypothermia

• Occasionally reported at presentation (particularly in severe/hypothalamic disease)

10. Spinal Cord & Nerve Root Features

• Radiculopathy — nerve root pain, sensory loss in dermatomal distribution
• Posterior column signs — impaired vibration and proprioception
• Lateral column signs — spasticity, upgoing plantars (myelopathy)
• Spinal block — when exudate obstructs CSF flow around the cord (protein can become extremely elevated)
• Cauda equina syndrome — if lumbosacral roots are involved

11. Features in Specific Populations

In Children and Infants:

• Prodrome is longer and more non-specific
• Neck stiffness may be absent — fontanelle bulging in infants
• Apathy, irritability, vomiting, seizures predominate
• Incidence up to 10% of all TB cases (vs ~1% in adults)

In HIV/Immunocompromised Patients:

• Course may be accelerated with more rapid deterioration
• Classic meningeal signs less reliable
• More frequent dissemination to extrapulmonary sites
• Higher mortality (~50% in treated HIV-positive patients with TBM)
• Less host inflammatory reaction pathologically
• May have atypical presentations with more focus on systemic symptoms

12. Concurrent Systemic TB

• Lungs (most common) — often miliary pattern on CXR
• Lymph nodes
• Small bowel, bone, kidney, ear (less common)
• Sputum cultures positive in 40–50% of TBM patients — making sputum culture a useful adjunct to diagnosis

13. Clinical Staging (British Medical Research Council — MRC Grading)

• Grade III carries mortality approaching 50%
• Grade at presentation is the strongest predictor of outcome

Summary: Clinical Feature Spectrum at a Glance

PRODROME (1–2 wk)         MENINGEAL PHASE              ADVANCED / UNTREATED
─────────────────────   ──────────────────────────   ───────────────────────────
Low-grade fever          Severe headache               Stupor → Coma
Malaise, night sweats    Neck stiffness (75%)          Decerebrate posturing
Weight loss              Kernig/Brudzinski signs       Fixed dilated pupils
Mild headache            Cranial nerve palsies (20%)   Hemiplegia
Lethargy / irritability  Papilledema                   Death (4–8 weeks)
Nausea, vomiting         Hydrocephalus signs
                         Focal deficits (vasculitis)
                         Seizures
                         Hyponatraemia

Aortic Regurgitation (AR): Clinical Features, Diagnosis & Treatment Guidelines

1. Definition & Aetiology

Primary Valve (Leaflet) Causes:

Aortic Root / Ascending Aorta Causes (now more common than primary valve disease for isolated AR requiring surgery):

2. Pathophysiology

Chronic AR — Volume Overload & Adaptive Remodelling

• LV accommodates the volume overload via eccentric hypertrophy (Laplace's law: increased wall thickness offsets the increased radius → normalised wall stress)
• This produces the largest LV end-diastolic volumes seen in any form of heart disease — cor bovinum
• Increased total stroke volume maintains forward output
• LV compliance increases → filling pressures remain near normal despite massive dilation
• The afterload excess from systolic hypertension also induces concentric hypertrophy (unlike mitral regurgitation)
• Patients remain asymptomatic for many years

• Interstitial fibrosis accumulates → compliance falls → LVEDP rises
• EF begins to fall; LVESV rises
• Forward cardiac output falls — first on exertion, then at rest
• Left atrial, pulmonary, and right heart pressures rise → pulmonary congestion

• ↑ LV mass → ↑ myocardial O₂ demand
• ↓ Aortic diastolic pressure (diastolic "runoff" into LV) + ↑ LVEDP → ↓ coronary perfusion pressure
• Reduced coronary flow reserve → angina without significant coronary artery disease

Acute AR — No Time for Compensation

• The unprepared, normal-sized LV suddenly receives a large volume overload
• LV cannot dilate acutely → LVEDP rises dramatically
• Mitral valve closes prematurely (mitral "preclosure") to protect the pulmonary circulation
• Forward stroke volume falls → cardiogenic shock
• Reflex peripheral vasoconstriction (unlike chronic AR, where resistance is reduced)
• Rapidly fatal without urgent intervention

3. Clinical Features

3A. Chronic AR — Symptoms

"Patients with severe AR often complain of an uncomfortable awareness of the heartbeat, especially in supine position lying on the left side, and thoracic discomfort caused by pounding of the heart against the chest wall." — Braunwald's Heart Disease

• Death usually within 4 years after onset of angina
• Death within 2 years after onset of heart failure
• 4-year survival in NYHA class III–IV: only ~30%

3B. Chronic AR — Physical Signs

Peripheral Vascular Signs (from wide pulse pressure):

Precordial Examination:

Auscultation:

3C. Acute AR — Clinical Features

• Gravely ill appearance: tachycardia, severe peripheral vasoconstriction, cyanosis
• Pulmonary oedema / cardiogenic shock — the dominant presentation
• Subtle peripheral signs: Pulse pressure may be only mildly widened; the dramatic eponymous signs of chronic AR are absent (no time for compensatory changes)
• Soft or absent S1 — due to premature mitral valve closure (high LVEDP closes the mitral valve before systole; only tricuspid component of S1 heard)
• Short, low-pitched early diastolic murmur (shorter than chronic AR because LV/aortic pressures equalise quickly)
• Austin Flint murmur of brief duration
• Signs of the underlying cause (endocarditis vegetations, marfanoid habitus, aortic dissection features such as unequal pulses, tearing chest pain)

4. Diagnostic Workup

4A. ECG

• Non-specific but almost always shows left ventricular hypertrophy (LVH)
• Left axis deviation; voltage criteria for LVH (Sokolow-Lyon, Cornell)
• ST-T changes of LV strain in severe/chronic cases

4B. Chest X-Ray

• Cardiomegaly — enlarged cardiac silhouette (cor bovinum in severe chronic AR)
• Uncoiling and enlargement of the aortic root / ascending aorta
• Pulmonary venous congestion in decompensated AR or acute AR

4C. Echocardiography (Primary Diagnostic Tool)

1. Valve morphology: BAV, leaflet thickening, prolapse, flail, vegetation, perforation
2. Aortic root size and shape: proximal ascending aorta may need CT/CMR if inadequate
3. Colour Doppler: jet width in LVOT, jet area, vena contracta
4. Continuous-wave Doppler: pressure half-time (PHT); steep deceleration slope = severe (acute) AR; diastolic half-time <200ms = severe
5. Pulsed-wave Doppler: holodiastolic flow reversal in descending thoracic or abdominal aorta (abdominal reversal = severe AR)
6. LV dimensions and function: LVEDD, LVESD, LVEF, LVESV — critical for surgical timing
7. Quantitative measures: Regurgitant volume (RVol), Regurgitant fraction (RF), Effective Regurgitant Orifice Area (EROA)

4D. Cardiac MRI (CMR)

• Most accurate noninvasive technique for LVESV, LVEDV, and LV mass
• Accurate quantification of regurgitant volume and fraction from ascending aorta flow
• Preferred when echocardiographic evaluation is suboptimal
• Best for quantifying aortic root and ascending aortic dimensions (especially in BAV/Marfan)

4E. Cardiac Catheterisation / Angiography

• Rarely needed solely to diagnose AR; reserved for haemodynamic assessment when non-invasive data are discordant
• Aortography (contrast injection into aortic root at 55–60 mL, 20 mL/sec): graded I–IV
• Coronary angiography pre-operatively in patients with risk factors for CAD

5. Clinical Staging (ACC/AHA 2020 Guidelines)

6. Treatment Guidelines (ACC/AHA 2020)

6A. Medical Management

• ACE inhibitors / ARBs / dihydropyridine CCBs (e.g., nifedipine) — reduce afterload, potentially slow disease progression in patients with systemic hypertension
• When hypertension accompanies AR, treat according to standard hypertension guidelines
• Evidence for vasodilators in normotensive asymptomatic severe AR with normal LV function is less compelling and not routinely recommended as a strategy to delay surgery
• Beta-blockers: used cautiously (heart rate slowing increases regurgitant time per beat); may be useful in aortic root disease (Marfan/BAV) to reduce aortic wall stress

• Mild/moderate AR, normal LV: echocardiography every 1–2 years
• Asymptomatic severe AR, normal LV function: every 6–12 months
• Acute decompensation: urgent surgical evaluation

6B. Surgical Treatment — Indications (ACC/AHA 2020 Guidelines — Table 73.3, Braunwald's)

6C. Surgical Options

6D. Acute Severe AR — Emergency Management

1. Stabilise haemodynamically: IV vasodilators (sodium nitroprusside) to reduce afterload and forward flow; avoid beta-blockers (tachycardia is compensatory)
2. Intra-aortic balloon pump contraindicated (worsens regurgitation in diastole)
3. Urgent surgical valve replacement — mortality approaches 75% with medical management alone in acute endocarditis/dissection-related AR
4. Treat underlying cause (antibiotics for endocarditis; urgent aortic repair for dissection)

7. Prognosis

"Data compiled in the presurgical era indicate that without surgical treatment, death usually occurred within 4 years after the development of angina pectoris and within 2 years after the onset of heart failure." — Braunwald's Heart Disease

8. Summary Algorithm

AORTIC REGURGITATION
       │
  ┌────┴────┐
ACUTE      CHRONIC
  │           │
Emergency   Stage A/B (mild-moderate)
Surgery     → Serial echo, medical Rx BP
  ↑               │
Stabilise    Stage C1 (asymptomatic severe, preserved LV)
Nitroprusside → Echo every 6-12 mo
NO IABP     → Surgery if: LVEF decline to ≤55%
                          LVESD >50mm or indexed >25mm/m²
                          LVEDD >65mm (IIb)
                │
           Stage C2 (asymptomatic severe + LV dysfunction)
           → CLASS I SURGERY
                │
           Stage D (symptomatic severe)
           → CLASS I SURGERY (regardless of LVEF)