Syphilis in the Differential Diagnosis of Ascending Weakness
Neurosyphilis must be considered in the differential diagnosis of any patient presenting with neurologic disease, including ascending weakness, particularly in HIV-infected individuals. 1
When to Suspect Neurosyphilis
Neurosyphilis can occur at any stage of syphilis infection and presents with diverse neurologic manifestations including: 2, 3
- Meningitis with headache, cranial nerve palsies, or altered mental status 2
- Meningovascular syphilis causing stroke-like symptoms (hemiplegia, aphasia, focal weakness) 4
- Tabes dorsalis with ascending sensory loss and weakness
- General paresis with progressive cognitive decline and motor weakness 3
Key clinical red flags that should trigger consideration of neurosyphilis: 5
- Young patients (<50 years) with stroke-like symptoms without traditional vascular risk factors 4
- HIV-positive patients with any neurologic symptoms 1, 5
- Patients with high serum RPR titers (≥1:32) 5
- History of inadequately treated or untreated syphilis 3
Diagnostic Approach for Neurosyphilis
Essential initial workup: 1, 6
- Serum nontreponemal test (RPR or VDRL) and treponemal test (FTA-ABS, TP-PA) 6
- HIV testing (neurosyphilis risk is substantially elevated in HIV-coinfection) 1, 5
- Lumbar puncture with CSF analysis if neurologic symptoms are present 1
CSF diagnostic criteria for neurosyphilis: 1
- Reactive CSF VDRL (specific but not sensitive) 1
- Elevated CSF protein or leukocyte count with clinical symptoms consistent with neurosyphilis 1
- CSF pleocytosis (>5 WBC/μL) is the most sensitive marker 1
Important caveat: HIV-infected patients commonly have CSF abnormalities even without neurosyphilis, making interpretation challenging. However, CSF abnormalities combined with CD4 count ≤350 cells/mL and/or RPR titer ≥1:32 increase suspicion for neurosyphilis. 1
Treatment Algorithm
For confirmed or probable neurosyphilis: 6
- Aqueous crystalline penicillin G 18-24 million units per day (administered as 3-4 million units IV every 4 hours or continuous infusion) for 10-14 days 6
For penicillin-allergic patients: 1
- Skin testing to confirm penicillin allergy is essential 1
- Desensitization followed by penicillin treatment is preferred 1
- Alternative: Ceftriaxone 2 grams daily IM or IV for 10-14 days (though cross-reactivity with penicillin exists) 1
Special Considerations in HIV-Infected Patients
HIV-positive patients warrant heightened vigilance: 1, 5
- 72% of HIV-infected patients with early neurosyphilis have neurologic symptoms (headache, visual impairment, tinnitus, weakness) 5
- 28% may be asymptomatic, detected only through screening 5
- Consider lumbar puncture in HIV-infected patients with syphilis who have CD4 ≤350 cells/mL or RPR ≥1:32, even without overt neurologic symptoms 1
Treatment success monitoring: 1, 5
- Follow-up CSF examination every 6 months until CSF cell count normalizes 1
- Serum RPR should decline fourfold within 6-12 months 5
- Approximately 71-75% of patients demonstrate successful treatment response 5
Clinical Pitfalls to Avoid
Do not dismiss syphilis based on negative initial serology alone - in very early primary syphilis, serologic tests may not yet be positive. Repeat testing at 2 weeks if clinical suspicion remains high. 7
Do not assume normal CSF excludes neurosyphilis - CSF VDRL has low sensitivity; clinical presentation combined with serum serology and CSF pleocytosis guides diagnosis. 1
Do not use alternative antibiotics in pregnancy - only penicillin regimens are acceptable; penicillin-allergic pregnant women must be desensitized. 6