# Neurosyphilis and Tuberculous Meningitis

## Introduction

Neurosyphilis and tuberculous meningitis are chronic infections of the nervous system that remain clinically relevant worldwide. Both are characterized by protean neurological manifestations that can mimic many other conditions, earning syphilis the historical title of "the great imitator." Early recognition is critical because both conditions are treatable but can cause devastating and irreversible neurological damage if diagnosis is delayed.

## Neurosyphilis

### Pathophysiology and Stages

Neurosyphilis is caused by the spirochete Treponema pallidum. The organism invades the CNS within days to weeks of primary infection, and CSF abnormalities are detectable in up to 40% of patients with early syphilis. However, not all CNS invasion leads to clinical neurosyphilis, as the host immune response clears the infection in most cases.

### Clinical Forms

| Form | Timing Post-Infection | Key Features |
|---|---|---|
| Syphilitic meningitis | Months (primary/secondary) | Headache, cranial neuropathies (VII, VIII), meningismus |
| Meningovascular syphilis | 5-12 years | Endarteritis obliterans → ischemic stroke (MCA territory) |
| Ocular syphilis | Any stage | Uveitis, optic neuritis; treat as neurosyphilis |
| Otosyphilis | Any stage | Sensorineural hearing loss, tinnitus, vertigo |
| General paresis | 10-25 years | Progressive dementia, personality change, Argyll Robertson pupils |
| Tabes dorsalis | 15-25 years | Lancinating pains, sensory ataxia, Romberg+, Charcot joints, Argyll Robertson pupils |

#### Early Neurosyphilis (Months to Years)

Syphilitic meningitis presents with headache, cranial neuropathies (CN VII and VIII most commonly), and meningismus, and can occur during primary or secondary syphilis. Meningovascular syphilis is characterized by endarteritis obliterans causing ischemic stroke, typically occurring 5-12 years after primary infection with preferential involvement of the middle cerebral artery territory. Ocular syphilis manifests as uveitis, optic neuritis, or papillitis and can occur at any stage; any patient with ocular syphilis should be treated as neurosyphilis. Otosyphilis presents with sensorineural hearing loss, tinnitus, and vertigo.

#### Late Neurosyphilis (Years to Decades)

General paresis (dementia paralytica) develops 10-25 years after primary infection and presents with progressive dementia, personality changes, psychiatric symptoms, tremor, dysarthria, and Argyll Robertson pupils. Tabes dorsalis results from posterior column and dorsal root degeneration, causing lancinating pains, sensory ataxia, positive Romberg sign, loss of proprioception and vibration, bladder dysfunction, Charcot joints, and Argyll Robertson pupils; it typically develops 15-25 years post-infection. Argyll Robertson pupils are small, irregular pupils that accommodate but do not react to light and are highly characteristic of neurosyphilis.

### Diagnosis

Serum screening begins with a non-treponemal test (RPR or VDRL), and if positive, confirmation with a treponemal test (FTA-ABS, TP-PA). CSF analysis is required for neurosyphilis diagnosis. The CSF VDRL is highly specific (near 100%) but has sensitivity of only 30-70%; a positive CSF VDRL is diagnostic. The CSF FTA-ABS is highly sensitive but less specific, and a negative result effectively rules out neurosyphilis. CSF typically shows pleocytosis (5-100 lymphocytes/mcL) and elevated protein. Indications for LP include neurological or ophthalmological symptoms, treatment failure, HIV co-infection with late latent syphilis or syphilis of unknown duration, and serum RPR titer of 1:32 or greater.

### Treatment

The standard treatment is IV aqueous crystalline penicillin G at 18-24 million units daily (3-4 million units IV every 4 hours) for 10-14 days. An alternative is IM procaine penicillin 2.4 million units daily plus probenecid 500 mg orally four times daily for 10-14 days. For penicillin allergy, desensitization and treatment with penicillin is preferred; ceftriaxone 2 g IV daily for 10-14 days is an alternative. Follow-up requires repeat CSF examination every 6 months until the cell count normalizes, and CSF VDRL titer should decline. Re-treatment is indicated if CSF does not improve by 6 months.

## Tuberculous Meningitis

### Epidemiology and Pathogenesis

Tuberculous meningitis is the leading cause of chronic meningitis worldwide, most common in endemic areas including South and Southeast Asia and sub-Saharan Africa. It is caused by Mycobacterium tuberculosis. The pathogenesis involves hematogenous spread from a primary pulmonary or extrapulmonary focus, with subpial or subependymal caseous foci (Rich foci) rupturing into the subarachnoid space. A thick, gelatinous exudate accumulates at the base of the brain, producing basal meningitis.

### Clinical Presentation

The course is subacute to chronic, evolving over 1-4 weeks with headache, low-grade fever, malaise, and weight loss. Stage I presents with alertness and meningeal signs. Stage II involves confusion, lethargy, focal neurological deficits, and cranial nerve palsies. Stage III manifests as stupor or coma, hemiplegia, and decerebrate posturing. Cranial nerve palsies, with CN VI most commonly affected followed by CN III and CN IV, result from basal meningeal inflammation. Communicating hydrocephalus develops from obstruction of CSF absorption by basilar exudate. Vasculitis and stroke occur from inflammatory infiltration of vessels of the circle of Willis and perforating arteries, causing basal ganglia and internal capsule infarctions. Tuberculomas are granulomatous mass lesions that may present with seizures or focal deficits.

### Diagnosis

CSF analysis shows lymphocytic pleocytosis (100-500 cells/mcL), markedly elevated protein (100-500 mg/dL), low glucose (CSF:serum ratio less than 0.5, often less than 0.3), and elevated CSF adenosine deaminase (ADA) greater than 8-10 U/L. CSF AFB smear has low sensitivity of 10-30%, and large volumes with multiple samples should be examined. CSF Mycobacterium tuberculosis PCR (Xpert MTB/RIF Ultra) has sensitivity of 70-90% with rapid results within 2 hours. CSF culture is the gold standard but takes 2-6 weeks, with the advantage of allowing drug sensitivity testing. MRI with contrast shows basal meningeal enhancement, hydrocephalus, tuberculomas (ring-enhancing lesions), and infarcts in basal ganglia territory.

### Treatment

The intensive phase spans 2 months with isoniazid, rifampicin, pyrazinamide, and ethambutol (the RIPE regimen). The continuation phase lasts 7-10 months with isoniazid and rifampicin, for a total treatment duration of 9-12 months. Pyridoxine (vitamin B6) supplementation accompanies isoniazid to prevent peripheral neuropathy. Adjunctive dexamethasone at 0.3-0.4 mg/kg/day IV for 4 weeks, then tapered over 4-8 weeks, is proven to reduce mortality in all stages as demonstrated in the Thwaites trial of 2004. Monitoring for drug-induced hepatotoxicity from isoniazid, rifampicin, and pyrazinamide, and optic toxicity from ethambutol is essential.

### Complications and Prognosis

Hydrocephalus may require ventriculoperitoneal shunt placement. Vasculitic stroke may occur despite appropriate antituberculous therapy. Mortality is 20-30% with treatment and higher in Stage III disease. Neurological sequelae including cognitive impairment, cranial nerve deficits, and epilepsy occur in 20-50% of survivors.

## Clinical Pearls

Any patient with unexplained stroke in a young person should be tested for syphilis, as meningovascular syphilis is a treatable cause of ischemic stroke. A positive CSF VDRL is diagnostic of neurosyphilis; however, a negative CSF VDRL does not rule it out due to limited sensitivity. In tuberculous meningitis, treatment should not wait for culture results; empiric antituberculous therapy should be initiated based on clinical suspicion and CSF findings. Adjunctive corticosteroids reduce mortality in tuberculous meningitis and should be administered to all patients regardless of disease stage. Both neurosyphilis and TB meningitis can present with basal meningeal enhancement on MRI, and clinical context, CSF analysis, and serological testing are essential for differentiation.

## References

1. Ropper AH. Neurosyphilis. *N Engl J Med*. 2019;381(14):1358-1363.
2. Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis: more questions, still too few answers. *Lancet Neurol*. 2013;12(10):999-1010.
3. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. *N Engl J Med*. 2004;351(17):1741-1751.
4. Marra CM. Neurosyphilis. *Continuum (Minneap Minn)*. 2015;21(6):1714-1728.