What is neurosyphilis?

Neurosyphilis: Definition, Diagnosis, and Management

Neurosyphilis is a central nervous system infection caused by Treponema pallidum that can affect any part of the neuraxis, including the meninges, brain, brainstem, spinal cord, nerve roots, and cerebral and spinal blood vessels, resulting in diverse neurological and psychiatric manifestations.

Definition and Pathophysiology

Neurosyphilis occurs when the spirochete Treponema pallidum invades the central nervous system. It can develop at any stage of syphilis infection, from early to late disease, and can present with various clinical manifestations depending on the affected structures.

Clinical Presentation

Neurosyphilis can present with a wide spectrum of neurological and psychiatric manifestations:

• Meningeal involvement: Headache, meningeal signs, cranial nerve palsies
• Vascular involvement: Stroke-like symptoms
• Parenchymal involvement:
  • Cognitive impairment and dementia
  • Psychiatric symptoms (psychosis, depression-like symptoms)
  • Seizures
  • Movement disorders
• Ocular involvement: Visual loss, uveitis
• Auditory involvement: Hearing loss

Diagnosis

The diagnosis of neurosyphilis is established through a combination of clinical findings and cerebrospinal fluid (CSF) analysis 1:

1. CSF examination may reveal:

   • Mild mononuclear pleocytosis (10-200 cells/μL)
   • Normal or mildly elevated protein concentration
   • Reactive CSF-VDRL test

2. Diagnostic criteria:

   • A reactive CSF-VDRL is specific but not sensitive for neurosyphilis. A reactive test establishes the diagnosis, but a nonreactive test does not exclude it 1.
   • CSF treponemal tests (e.g., CSF FTA-ABS) are sensitive but not specific. A nonreactive test excludes neurosyphilis, but a reactive test does not confirm it 1.
   • A reactive CSF-VDRL and a CSF WBC >10 cells/μL strongly support the diagnosis 1.

3. Important diagnostic considerations:

   • HIV infection may cause mild CSF pleocytosis (5-15 cells/μL), complicating diagnosis in HIV-infected individuals 1.
   • PCR-based diagnostic methods are not currently recommended for neurosyphilis diagnosis 1.
   • If clinical suspicion is high but serologic tests are negative, other diagnostic procedures (biopsy, darkfield examination, direct fluorescent antibody staining) should be considered 1.

Treatment

The treatment of choice for neurosyphilis is intravenous aqueous crystalline penicillin G at a dosage of 12-24 million units per day, administered as 2-4 million units every 4 hours for 10-14 days 1, 2.

Additional recommendations:

• Many experts recommend supplemental therapy with benzathine penicillin G 2.4 million units IM weekly for 3 doses after completion of IV therapy 2.
• For penicillin-allergic patients, desensitization is recommended rather than using alternative antibiotics, as penicillin is the only proven effective therapy for neurosyphilis 1.
• Close follow-up is essential, particularly in HIV-infected patients, to detect potential treatment failures or disease progression 1.

Special Considerations in HIV-Infected Patients

• HIV-infected patients with syphilis should be evaluated for clinical evidence of CNS or ocular involvement 1.
• CSF examination is recommended for HIV-infected patients with:
  • Neurologic or ocular symptoms
  • Late-latent syphilis or syphilis of unknown duration
  • Treatment failure for non-neurologic syphilis
  • Some experts recommend CSF examination for all HIV-infected patients with syphilis regardless of stage, particularly with serum RPR ≥1:32 or CD4+ count <350 cells/μL 1.

Prognosis

Early diagnosis and treatment are crucial as advanced neurosyphilis may cause irreversible neurological damage 3, 4. The Jarisch-Herxheimer reaction (acute febrile reaction with headache and myalgia) may occur within 24 hours after initiating therapy 1.

Common Pitfalls and Caveats

1. Diagnostic challenges:

   • Relying solely on CSF-VDRL (may be falsely negative)
   • Basing diagnosis only on elevated CSF protein without other abnormalities
   • Failing to consider neurosyphilis in patients with psychiatric symptoms

2. Treatment pitfalls:

   • Using alternative antibiotics instead of penicillin
   • Inadequate duration of therapy
   • Insufficient follow-up, especially in HIV-infected patients

3. Special populations:

   • In HIV-infected patients, neurosyphilis diagnosis may be complicated by HIV-related CSF abnormalities
   • If neurosyphilis cannot be excluded by a nonreactive CSF treponemal test in HIV-infected persons, treatment for neurosyphilis is recommended despite diagnostic uncertainty 1.

Neurosyphilis remains an important differential diagnosis in patients with unexplained neurological or psychiatric symptoms, particularly in the context of known syphilis infection or risk factors.