What are the symptoms and treatment options for neurosyphilis?

Neurosyphilis: Clinical Manifestations and Treatment

Clinical Symptoms and Presentations

Neurosyphilis can present with a wide spectrum of neurological and psychiatric manifestations, ranging from asymptomatic CSF abnormalities to severe neuropsychiatric deficits, and any patient with neurologic symptoms, cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, or signs of meningitis should undergo CSF examination. 1

Neurological Manifestations

• Cognitive and psychiatric symptoms include behavioral changes, confusion, altered consciousness, memory impairment, and severe neuropsychiatric deficits that can dominate the clinical picture, particularly in late-stage disease 2, 3
• Motor and sensory deficits may present as focal weakness, with stroke-like presentations possible due to meningovascular involvement and intracranial vasculitis 4
• Cranial nerve involvement manifests as palsies affecting various cranial nerves 1
• Meningeal symptoms include headache, fever, and signs of meningitis 1

Ocular and Auditory Involvement

• Syphilitic eye disease frequently accompanies neurosyphilis and includes uveitis, neuroretinitis, and optic neuritis; these patients require treatment according to neurosyphilis protocols and ophthalmology consultation 1
• Auditory symptoms warrant treatment as neurosyphilis regardless of CSF findings, though systemic steroids as adjunctive therapy remain unproven 1

Seizures and Encephalitis

• Seizures and temporal lobe involvement can occur, with MRI showing bilateral temporal, cortical, and subcortical abnormalities that may mimic other forms of encephalitis 3
• Encephalopathy including confusion, altered consciousness, and movement abnormalities can develop, particularly with high doses or renal impairment 5

Diagnostic Approach

CSF Examination Criteria

CSF examination is mandatory for any patient with clinical evidence of neurologic involvement, ocular symptoms, or auditory symptoms. 1, 6

• CSF pleocytosis (>5 WBC/mm³) is usually present with active neurosyphilis and serves as a sensitive measure of disease activity 1
• Reactive CSF-VDRL in the absence of substantial blood contamination is diagnostic of neurosyphilis, though it may be nonreactive when neurosyphilis is present 1
• CSF protein is typically elevated but changes more slowly than cell counts 1
• CSF FTA-ABS is highly sensitive; a negative test essentially excludes neurosyphilis, but a positive test is less specific and does not confirm the diagnosis 1

Serologic Testing Considerations

• HIV testing is mandatory for all patients with syphilis, as HIV-infected patients may have atypical serologic responses with unusually high, low, or fluctuating titers 1, 6, 7
• False-negative serologic tests can occur in HIV-infected patients despite documented infection, requiring alternative diagnostic procedures if clinical suspicion is high 6

Treatment Regimens

First-Line Treatment

The only proven effective treatment for neurosyphilis is aqueous crystalline penicillin G 18-24 million units per day, administered as 3-4 million units IV every 4 hours or by continuous infusion for 10-14 days. 1, 8, 6

Alternative Regimen

• Procaine penicillin 2.4 million units IM once daily PLUS probenecid 500 mg orally four times daily for 10-14 days can be used if compliance is ensured 1, 8

Extended Treatment Consideration

• Benzathine penicillin 2.4 million units IM once weekly for up to 3 weeks may be added after completing the neurosyphilis regimen to provide comparable total duration to late syphilis treatment 1

Penicillin Allergy Management

Patients with penicillin allergy must undergo desensitization, as penicillin remains the only therapy with documented efficacy for neurosyphilis. 1, 8, 6

• Ceftriaxone 2g daily IM or IV for 10-14 days has limited data supporting its use, but cross-reactivity with penicillin exists; skin testing should be performed if available before using this alternative 1
• Skin testing for penicillin allergy should be performed when available, though minor determinants are not commercially available 1

Follow-Up and Monitoring

CSF Monitoring

• Repeat CSF examination every 6 months until cell count normalizes; CSF leukocyte count is the most sensitive measure of treatment effectiveness 1, 6
• CSF-VDRL and protein change more slowly than cell counts, and persistent abnormalities are less concerning 1
• Retreatment should be considered if cell count has not decreased after 6 months or if CSF is not entirely normal after 2 years 1

Serologic Follow-Up

• Nontreponemal tests (RPR or VDRL) should be repeated at 3,6,12, and 24 months using the same test method by the same laboratory 6, 7
• Four-fold decline in titer indicates adequate treatment response 6, 7
• Normalization of serum RPR predicts normalization of CSF parameters in immunocompetent persons and HIV-infected persons on highly active antiretroviral therapy 1

Critical Warnings and Adverse Reactions

Jarisch-Herxheimer Reaction

• Acute febrile reaction occurs within the first 24 hours after initiating therapy, accompanied by headache, myalgia, fever, sweating, chills, nausea, tachycardia, and blood pressure fluctuations 1, 8, 6, 5
• Patient counseling about this expected transient reaction is essential; antipyretics may be recommended, though no proven prevention methods exist 1
• Symptoms resolve within 10-12 hours 5

Administration Precautions

• Never administer benzathine penicillin intravenously; inadvertent IV administration has been associated with cardiorespiratory arrest and death 5
• Deep IM injection only in the upper outer quadrant of the buttock or ventrogluteal site; avoid anterolateral thigh due to risk of quadriceps fibrosis and atrophy 5

Special Populations

HIV-Infected Patients

• Same treatment regimen as HIV-negative patients, but closer monitoring is required for treatment failure or disease progression 8
• More frequent follow-up at 3-month intervals instead of 6-month intervals 7
• CSF examination should be considered for late-latent syphilis or syphilis of unknown duration in HIV-infected patients 7

Pregnancy

• Penicillin desensitization is mandatory for pregnant women with neurosyphilis who report penicillin allergy, as penicillin is the only documented effective treatment 1