Neurosyphilis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-In-Chief: Lakshmi Gopalakrishnan, M.B.B.S. [2]

Overview

• Neurosyphilis refers to a site of infection involving the central nervous system (CNS).

• Neurosyphilis may occur at any stage of syphilis.

• Before the advent of antibiotics, it was typically seen in 25-35% of patients with syphilis.

• Neurosyphilis is now most common in patients with HIV infection. Reports of neurosyphilis in HIV-infected persons are similar to cases reported before the HIV pandemic. The precise extent and significance of neurologic involvement in HIV-infected patients with syphilis, reflected by either laboratory or clinical criteria, have not been well characterized. Furthermore, the alteration of host immunosuppression by antiretroviral therapy in recent years has further complicated such characterization.

Clinical presentation: Four clinical types

• The late forms of neurosyphilis (tabes dorsalis and general paresis) are seen much less frequently since the advent of antibiotics.
• The most common manifestations today are asymptomatic or symptomatic meningitis.

1. Asymptomatic meningitis

• Asymptomatic neurosyphilis usually has no signs or symptoms and is diagnosed exclusively with the presence or absence of CSF abnormalities notably pleocytosis, elevated protein, decreased glucose.

2. Symptomatic meningitis

• develops within 6-months to several years of primary infection
• typical meningitis symptoms: headache, nausea, vomiting, photophobia
• Acute syphilitic meningitis usually occurs within the first year of infection; 10% of cases are diagnosed at the time of the secondary rash.
• Patients present with headache, meningeal irritation, and cranial nerve abnormalities, especially the optic nerve, facial nerve, and the vestibulocochlear nerve.
• Rarely, it affects the spine instead of the brain, causing focal muscle weakness or sensory loss.

3. Meningovascular syphilis

• Meningovascular syphilis occurs a few months to 10 years (average, 7 years) after the primary syphilis infection.

• Meningovascular syphilis can be associated with prodromal symptoms lasting weeks to months before focal deficits are identifiable.

• Prodromal symptoms include:

• unilateral numbness,
• paresthesias,
• upper or lower extremity weakness,
• headache,
• vertigo,
• insomnia, and
• psychiatric abnormalities such as personality changes.

• The focal deficits initially are intermittent or progress slowly over a few days.

• However, it can also present as an infectious arteritis and cause an ischemic stroke, an outcome more commonly seen in younger patients.

• Angiography may be able to demonstrate areas of narrowing in the blood vessels or total occlusion.

4. Parenchymatous neurosyphilis

• develops 15-20 years after primary infection
• argyll robertson pupil: small irregular pupil
• clinical presents as general paresis or tabes dorsalis with resultant ataxia

• General paresis, otherwise known as general paresis of the insane, is a severe manifestation of neurosyphilis.

• It is a chronic dementia which ultimately results in death in as little as 2-3 years.

• Patients generally have progressive personality changes, memory loss, and poor judgment.

• More rarely, they can have psychosis, depression, or mania.

• Imaging of the brain usually shows atrophy.

Diagnosis

• Clinical signs of neurosyphilis (i.e., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, and auditory or ophthalmic abnormalities) warrant further investigation and treatment for neurosyphilis.

• Approximately 35% to 40% of persons with secondary syphilis have asymptomatic central nervous system (CNS) involvement, as demonstrated by any of these on cerebrospinal fluid (CSF) examination:

• An abnormal leukocyte cell count, protein level, or glucose level
• Demonstrated reactivity to Venereal Disease Research Laboratory (VDRL) antibody test

• Laboratory testing is helpful in supporting the diagnosis of neurosyphilis; however, no single test can be used to diagnose neurosyphilis in all instances.

CSF analysis

• Cerebrospinal fluid (CSF) abnormalities are common in persons with early syphilis.

• Diagnosed by finding high numbers of leukocytes in the CSF or abnormally high protein concentration in the setting of syphilis infection.

• VDRL in cerebrospinal fluid (CSF-VDRL), which is highly specific but insensitive, is the standard serologic test for CSF. Although some advocate using the FTA-ABS test to improve sensitivity.

• When reactive in the absence of substantial contamination of CSF with blood, it is considered diagnostic of neurosyphilis; however in early syphilis, it can be of unknown prognostic significance.

• Most other tests are both insensitive and nonspecific and must be interpreted in relation to other test results and the clinical assessment. Therefore, the laboratory diagnosis of neurosyphilis usually depends on various combinations of reactive serologic test results, CSF cell count or protein, and a reactive CSF-VDRL with or without clinical manifestations.

HIV Co-infection

• There is anecdotal evidence that the incidence of neurosyphilis is higher in HIV patients, and some have recommended that all HIV-positive patients with syphilis should have a lumbar puncture to look for asymptomatic neurosyphilis.

• Among persons with HIV infection, the CSF leukocyte count usually is elevated (>5 white blood cell count [WBC]/mm3); using a higher cutoff (>20 WBC/ mm3) might improve the specificity of neurosyphilis diagnosis.

• The CSF-VDRL might be non-reactive even when neurosyphilis is present.

• Therefore, additional evaluation using FTA-ABS testing on CSF can be considered. The CSF FTA-ABS test is less specific for neurosyphilis than the CSF-VDRL but is highly sensitive; neurosyphilis is highly unlikely with a negative CSF FTA-ABS test.

Treatment

• CNS involvement can occur during any stage of syphilis. However, CSF laboratory abnormalities are common in persons with early syphilis, even in the absence of clinical neurological findings. No evidence exists to support variation from recommended treatment for early syphilis for patients found to have such abnormalities.

• If clinical evidence of neurologic involvement is observed (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis), a CSF examination should be performed.

• Syphilitic uveitis or other ocular manifestations frequently are associated with neurosyphilis and should be managed according to the treatment recommendations for neurosyphilis. Patients who have neurosyphilis or syphilitic eye disease (e.g., uveitis, neuroretinitis, and optic neuritis) should be treated with the recommended regimen for neurosyphilis; those with eye disease should be managed in collaboration with an ophthalmologist. A CSF examination should be performed for all patients with syphilitic eye disease to identify those with abnormalities; patients found to have abnormal CSF test results should be provided follow-up CSF examinations to assess treatment response.

• For patients diagnosed with neurosyphilis including ocular or auditory syphilis with or without positive CSF results, aqueous crystalline penicillin G is the treatment of choice.

• The recommended regimen is intravenous treatment every 4 hours or continuously for 10-14 days
• If intravenous administration is not possible, then procaine penicillin is an alternative (administered daily with probenecid for two weeks).
• Procaine injections are painful, however, and patient compliance may be difficult to ensure.
• To approximate the 21-day course of therapy for late latent disease and to address concerns about slowly dividing treponemes, most experts now recommend 3 weekly doses of benzathine penicillin G after the completion of a 14-day course of aqueous crystalline or aqueous procaine penicillin G] for neurosyphilis.

• No oral antibiotic alternatives are recommended for the treatment of neurosyphilis. The only alternative that has been studied and shown to be effective is intramuscular ceftriaxone daily for 14 days.

CDC Recommendations: Pharmacotherapy [3]

“

Recommended Regimen 1. 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. Alternative Regimen 1. Procaine penicillin 2.4 million units IM once daily, plus probenecid 500 mg orally four times a day, both for 10-14 days.

”

• If compliance with therapy can be ensured, the following alternative regimen might be considered.

• The durations of the recommended and alternative regimens for neurosyphilis are shorter than the duration of the regimen used for late syphilis in the absence of neurosyphilis. Therefore, benzathine penicillin, 2.4 million units IM once per week for up to 3 weeks, can be considered after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy.

Other Management Considerations

• Other considerations in the management of patients who have neurosyphilis are as follows:

• All persons who have syphilis should be tested for HIV.
• Although systemic steroids are used frequently as adjunctive therapy for otologic syphilis, such drugs have not been proven to be beneficial.

Special Considerations

Penicillin Allergy

• Limited data suggest that ceftriaxone 2 g daily either IM or IV for 10-14 days can be used as an alternative treatment for patients with neurosyphilis.

• However, the possibility of cross-reactivity between ceftriaxone and penicillin exists.

• Other regimens have not been adequately evaluated for treatment of neurosyphilis. Therefore, if concern exists regarding the safety of ceftriaxone for a patient with neurosyphilis, skin testing should be performed (if available) to confirm penicillin allergy and, if necessary, desensitize the patient.

Pregnancy

Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin.

Follow-up

• If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal.

• Follow-up CSF examinations also can be used to evaluate changes in the CSF-VDRL or CSF protein after therapy; however, changes in these two parameters occur more slowly than cell counts, and persistent abnormalities might be less important.

• The leukocyte count is a sensitive measure of the effectiveness of therapy. If the cell count has not decreased after 6 months or if the CSF cell count or protein is not normal after 2 years, retreatment should be considered.

• Limited data suggest that in immunocompetent persons and HIV-infected persons on highly active antiretroviral therapy, normalization of the serum RPR titer predicts normalization of CSF parameters.

Neurosyphilis Among HIV-Infected Persons

Treatment

HIV-infected patients with neurosyphilis should be treated according to the recommendations for HIV-negative patients with neurosyphilis.

Special considerations

• HIV-infected, penicillin-allergic patients who have neurosyphilis should be managed according to the recommendations for penicillin-allergic, HIV-negative patients with neurosyphilis.

• Several small observational studies conducted in HIV-infected patients with neurosyphilis suggest that ceftriaxone 1-2 g IV daily for 10-14 days might be effective as an alternate agent.

Follow-up

• If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal.

• Follow-up CSF examinations also can be used to gauge response after therapy.

• Limited data suggest that changes in CSF parameters might occur more slowly in HIV-infected patients, especially those with more advanced immunosuppression.

• If the cell count has not decreased after 6 months or if the CSF is not normal after 2 years, retreatment should be considered.

Related chapters

• Syphilis
• Congenital syphilis

Resources

• UCSF HIV InSite Knowledge Base Chapter: Syphilis and HIV
• "A New Gold Standard For Syphilis?" Poster Presentation for European Academy of Dermatology and Venereology 2004 Spring Symposium
• Syphilis Pictures and Information
• Kipkeepers, Pox and Gleet Vendors: A Rapid History of Syphilis
• POX: Genius, Madness, and the Mysteries of Syphilis
• Syphilis Informational resource
• Secrets of the Dead (PBS): The Syphilis Enigma
• Syphilis and AIDS: Lessons from history
• "Syphilis fact sheet" from the Center for Disease Control
• The treatment of dementia paralytica by malaria inoculation (A Nobel Prize lecture, December 13, 1927)
• National Institute of Allergy and Infectious Diseases Factsheet
• New study blames Columbus for syphilis spread from Reuters Jan 15, 2008

References

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