BASICS
DESCRIPTION
- A chronic, systemic, infectious disease with any involvement of the CNS at any stage of syphilitic Treponema pallidum infection (primary, secondary, tertiary, and latent)
- Transmitted sexually, via the maternal " “fetal route, and via blood infusions
- Early manifestations:
- Asymptomatic neurosyphilis: presence of CSF abnormalities in the absence of neurologic signs/symptoms; peak incidence 12 to 18 months after infection
- Meningeal syphilis: signs and symptoms of meningitis; may be associated with gummas; onset within 12 months after initial infection
- Meningovascular syphilis: Meningitis with CNS vascular involvement, resulting in thrombosis, ischemia, and infarction; onset 5 to 12 years after initial infection.
- Ocular syphilis: ocular symptoms with or without meningitis; usually occurs in early infection
- Otologic syphilis: hearing loss with/without meningitis; can occur at any time
- Late manifestations: parenchymatous syphilis
- General paresis: Also known as dementia paralytica; onset is 15 to 20 years after initial infection but may be as early as 2 years after initial infection.
- Tabes dorsalis: Also known as progressive locomotor ataxia; onset is 20 to 25 years after initial infection but may be as early as 3 years after initial infection.
EPIDEMIOLOGY
Incidence
See "Syphilis. " ť Since 2005, the Centers for Disease Control and Prevention (CDC) no longer classifies/reports neurosyphilis as a distinct stage. ‚
Prevalence
More common in the preantibiotic era and now most often seen in patients with HIV, with predominance of early neurosyphilis compared with late neurosyphilis ‚
ETIOLOGY AND PATHOPHYSIOLOGY
- T. pallidum, spirochete
- Meningeal and meningovascular syphilis: lymphocytic infiltration of the meninges and perivascular spaces with diffuse thickening
- General paresis: atrophy of the frontal and temporal lobes with sparing of the motor, sensory, and occipital cortex
- Tabes dorsalis: degeneration of posterior roots and column of the spinal cord
RISK FACTORS
- High-risk sexual behavior
- Multiple sex partners
- Men having sex with men
- Transplacental transmission
- Exposure to infected body fluids
- Inmates at adult correctional facilities
- IV drug use (rare)
GENERAL PREVENTION
- Routinely obtain the patient 's sexual history.
- Educate and counsel persons at risk on ways to avoid sexually transmitted infections (STIs) through changes in sexual behaviors.
- Recommend abstinence, a reduction of the number of sex partners, and the use of male condoms.
COMMONLY ASSOCIATED CONDITIONS
- HIV infection
- Hepatitis B
- Other STIs
DIAGNOSIS
HISTORY
Previous sexual contact with partner with known infection, or partner with high-risk sexual behavior, maternal transmission ‚
PHYSICAL EXAM
- Many neurosyphilitic patients are asymptomatic.
- Signs/symptoms depend on type:
- Meningeal neurosyphilis: fever, meningismus, headache, photophobia, nausea, vomiting, cranial nerve palsies (II " “VIII); occasional seizures
- Meningovascular syphilis: early prodrome of headache, vertigo, insomnia, emotional lability, and personality changes with acute/subacute onset of stroke symptoms, with middle cerebral artery the most common site of thrombosis (contralateral hemiplegia, hemianesthesia, homonymous hemianopsia)
- Ocular syphilis: posterior uveitis (diminished vision) most common; also anterior uveitis, cranial nerves II " “VI abnormalities, optic neuritis, papillitis, perineuritis
- Otologic syphilis: hearing loss, tinnitus, vertigo
- General paresis
- Early symptoms: irritability, forgetfulness, personality changes, headaches, changes in sleep habits
- Late symptoms: emotional lability, impaired memory and judgment, disorientation, confusion, delusions, occasional seizures
- Psychiatric manifestations: depression, delirium, mania, psychosis
- Neurologic signs: pupillary abnormalities (late); dysarthria; tremors of facial, lingual, and hand muscles; rarely, optic atrophy and ocular muscle palsies
- Tabes dorsalis:
- Ataxia; dysuria (bladder hypotonia), lower extremity lightning pains, also paresthesias and decreased vision (optic atrophy)
- Exam triad of Argyll Robertson pupils (accommodate, but do not react, to light), areflexia, loss of proprioception; also ocular palsies and Charcot joints
DIFFERENTIAL DIAGNOSIS
- HIV infection
- HIV-related CNS lesions (e.g., toxoplasma, lymphoma, progressive multifocal leukoencephalopathy, cytomegalovirus)
- Herpes simplex virus encephalitis
- Acute/subacute stroke
- Primary neuropsychiatric disease
- Parkinson or Huntington disease
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
- Laboratory diagnosis of neurosyphilis usually depends on various combinations of reactive serologic test results, CSF cell count/protein, and a reactive CSF-Venereal Disease Research Laboratory (VDRL), with/without, clinical manifestations (1)[B].
- Serologic testing: Confirm T. pallidum infection:
- Nontreponemal tests (VDRL and rapid plasma reagin [RPR]): for screening and correlation with disease activity
- Treponemal tests (fluorescent treponemal antibody absorbed, T. pallidum particle agglutination assay, syphilis immunoglobulin (Ig) G, microhemagglutination assay for T. pallidum antibodies, and T. pallidum immobilization test: for confirmation of positive nontreponemal screen
- CSF testing:
- Recommended for the following:
- Serologic evidence of syphilis with neurologic signs or symptoms (including ocular or auditory) in any stage of syphilis
- Latent syphilis with evidence of active tertiary syphilis (e.g., aortitis and gumma)
- Treatment failure in any stage of syphilis
- Asymptomatic HIV patients with late latent or latent syphilis of unknown duration
- The CDC does not recommend testing asymptomatic HIV patients with early (primary or secondary) syphilis, but some recommend doing so when the CD4 is ≤350 cells/mL and/or the RPR titer is ≥1:32 (1,2)[C].
- Children with syphilis, after the newborn period, to rule out neurosyphilis
- CSF abnormalities:
- Lymphocytic pleocytosis (>5 WBC per high-power field, >20 in HIV-infected patients), low glucose (<2/3 serum glucose), and elevated protein (>45 mg/dL); entirely normal levels may occur in up to 4% of patients with symptomatic neurosyphilis.
- CSF-VDRL (gold standard): Positive result is diagnostic of neurosyphilis, but a negative result does not rule it out; false-positive findings from bloody tap, tuberculosis, pyogenic/aseptic meningitis
- CSF-RPR: not used because it is less specific than CSF-VDRL
- CSF-FTA: Very sensitive but not specific; consider using to rule out neurosyphilis in HIV patients with CSF pleocytosis and nonreactive CSF-VDRL.
TREATMENT
GENERAL MEASURES
All patients with neurosyphilis should be tested for HIV. ‚
MEDICATION
First Line
Aqueous crystalline penicillin G 18 to 24 million U/day, administered as 3 to 4 million U IV q4h or 24 million U daily as a continuous infusion, for 10 to 14 days (1)[B] ‚
Second Line
- Procaine penicillin: 2.4 million U IM OD PLUS probenecid 500 mg PO QID, both for 10 to 14 days (1)[B]
- Penicillin allergy: Skin testing and treatment with penicillin after desensitization is optimal, but ceftriaxone (monitor for cross-reactivity) 2 g daily, either IM or IV, for 10 to 14 days OR oral doxycycline 200 mg BID for 21 to 28 days can be used as an alternative (2)[C].
- Children (after newborn period): aqueous crystalline penicillin G 200,000 to 300,000 U/kg/day IV divided every q4 " “6h , for 10 to 14 days; OR procaine penicillin: 50,000 U/kg IM daily for 10 to 14 days (1)[B]
- Pregnancy: Dosage schedules same as for nonpregnant patients; penicillin-allergic patients require penicillin desensitization and treatment, as there are no proven alternatives during pregnancy (1)[B].
- HIV-infected patients: Dosage schedules same as for HIV-negative patients; consider penicillin desensitization and treatment for penicillin-allergic patients, although ceftriaxone may be effective (1)[B].
- Contraindication: penicillin allergy
- Precautions:
- Benzathine penicillin G does not reach detectable levels in the CSF and should not be used.
- CSF laboratory abnormalities are common in early syphilis; there is no variation from the recommended treatment for early syphilis in the absence of clinical neurologic findings.
ADDITIONAL THERAPIES
Topical and oral glucocorticoids are often used as adjunctive therapy, respectively, for ocular and otologic syphilis, but no evidence indicates benefit (1,2)[C]. ‚
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- T. pallidum cannot be grown in the laboratory, and there is no microbiologic test of cure.
- Neurologic and CSF examination at 3 to 6 months and every 6 months thereafter until normalized:
- Consider retreatment for neurosyphilis if CSF WBC count does not decline within 6 months or if CSF abnormalities persist after 2 years.
- CSF-VDRL and protein also may be followed, but change more slowly, and persistence may be less important.
- A 4-fold decline in serologic RPR titers may predict CSF resolution in non " “HIV-infected patients and HIV-infected patients on highly active antiretroviral therapy.
PATIENT EDUCATION
No sexual contact until a 4-fold serologic titer drop. ‚
PROGNOSIS
- Early meningeal syphilis: usually quick resolution of symptoms
- Late syphilis: Clinical abnormalities may persist after treatment, especially if tissue damage has occurred.
- HIV-infected patients have higher rates of progression from asymptomatic to symptomatic neurosyphilis and may have higher rates of serologic treatment failure; close follow-up is required.
COMPLICATIONS
- A Jarisch-Herxheimer reaction (headache, myalgia, fever) may occur within 24 hours after therapy initiation. The 2008 WHO guidelines for treatment of syphilis in Europe recommends prednisone 20 to 60 mg daily for 3 days, starting the day before antitreponemal treatment (3)[C].
- Persistence of neurologic and psychiatric symptoms
REFERENCES
11 Workowski ‚ KS, Berman ‚ S. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59(RR-12):1 " “110.22 Marra ‚ CM. Update on neurosyphilis. Curr Infect Dis Rep. 2009;11(2):127 " “134.33 French ‚ P, Gomberg ‚ M, Janier ‚ M, et al. IUSTI: 2008 European guidelines on the management of syphilis. Int J STD AIDS. 2009;20(5):300 " “309.
ADDITIONAL READING
- Berger ‚ JR, Dean ‚ D. Neurosyphilis. Handb Clin Neurol. 2014;121:1461 " “1472.
- Chahine ‚ LM, Khoriaty ‚ RN, Tomford ‚ WJ, et al. The changing face of neurosyphilis. Int J Stroke. 2011;6(2):136 " “143.
- Ghanem ‚ KG. Review: neurosyphillis: a historical perspective and review. CNS Neurosci Ther. 2010;16(5):157 " “168.
CODES
ICD10
- A52.3 Neurosyphilis, unspecified
- A52.2 Asymptomatic neurosyphilis
- A52.13 Late syphilitic meningitis
- A52.11 Tabes dorsalis
- A52.14 Late syphilitic encephalitis
- A52.17 General paresis
- A52.10 Symptomatic neurosyphilis, unspecified
- A52.15 Late syphilitic neuropathy
- A52.12 Other cerebrospinal syphilis
- A52.19 Other symptomatic neurosyphilis
- A52.16 Charcot 's arthropathy (tabetic)
ICD9
- 094.9 Neurosyphilis, unspecified
- 094.3 Asymptomatic neurosyphilis
- 094.2 Syphilitic meningitis
- 094.0 Tabes dorsalis
- 094.87 Syphilitic ruptured cerebral aneurysm
- 094.1 General paresis
- 094.81 Syphilitic encephalitis
- 094.82 Syphilitic parkinsonism
- 094.83 Syphilitic disseminated retinochoroiditis
- 094.84 Syphilitic optic atrophy
- 094.86 Syphilitic acoustic neuritis
- 094.89 Other specified neurosyphilis
- 094.85 Syphilitic retrobulbar neuritis
SNOMED
- Neurosyphilis (disorder)
- Asymptomatic neurosyphilis (disorder)
- Syphilitic meningitis
- Tabes dorsalis (disorder)
- Syphilitic encephalitis
- General paresis - neurosyphilis
CLINICAL PEARLS
- CNS involvement can occur at any stage of syphilis infection.
- Procaine penicillin is the gold standard for treatment. Benzathine penicillin G does not reach detectable levels in the CSF and should not be used.
- All patients with syphilis should be tested for HIV.