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Neurologists should err on the side of caution when considering the diagnosis of neurosyphilis in patients with syphilis, said Christina M. Marra, MD, Professor of Neurology at the University of Washington in Seattle, in an interview with Neurology Today. That means doing lumbar punctures in all syphilis patients with high serum Rapid Plasma Reagin (RPR) titers and in HIV-infected patients with low peripheral blood CD4+ T-cell counts.

Dr. Marra said that the conventional recommendation has been to only perform lumbar punctures in patients with syphilis who have neurological symptoms or signs and in asymptomatic patients with late syphilis, especially if they are also HIV-infected. She noted, however, that syphilis treponemes frequently invade the CNS during the early stages of infection, and that symptomatic and asymptomatic neurosyphilis can occur in any stage of syphilis, even in patients with the primary stage (See box, Stages of Syphilis).

Some people with neurosyphilis may never develop symptoms, she said, while others may develop symptomatic meningitis or stroke, or more rarely, dementia and gait problems. For all of these reasons – and new data from the largest study of neurosyphilis in the US – she recommends that serum RPR titers, rather than the stage of syphilis, be used as one of the criteria to determine whether lumbar puncture should be performed.

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“We've been studying neurosyphilis since 1996,” said Dr. Marra, “and we wanted to determine which patients with syphilis need a lumbar puncture.”

In the study published earlier this year, Dr. Marra and colleagues performed lumbar punctures on 326 patients with syphilis. Based on CSF analysis, more than 20 percent of them had neurosyphilis (J Infect Dis 2004;189:369–376). Almost three-quarters of the patients were HIV-infected.

The patients had syphilis, as defined by a reactive serum non-treponemal – Venereal Disease Research Laboratory Result (VDRL) or RPR – and treponemal – fluorescent treponemal antibody-absorbed (FTA-ABS) or T. palladium ELISA – serological tests. The investigators took a clinical history, did a neurological examination, and obtained blood and CSF samples. Neurosyphilis was defined by a CSF white blood cell count of more than 20 per microliter or a positive CSF VDRL result.

A serum RPR titer of at least 1:32 increased the odds of neurosyphilis nearly 11 times among subjects who did not have HIV and nearly six times among HIV-positive subjects. If an HIV-infected patient had a peripheral blood CD4+ T-cell count less than 350 cells per microliter, that patient was more three times more likely to have neurosyphilis than HIV-infected subjects with higher T-cell counts. When the investigators applied an even more rigorous definition for neurosyphilis, a reactive CSF VDRL test, the results were the same.



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In a separate study of 59 individuals with neurosyphilis (Clin Infect Dis 2004;38:1001–1006), the investigators saw no difference in responses to three treatment regimens: intravenous high-dose penicillin, the first-line therapy recommended by the CDC; intramuscular penicillin with oral probenecid, also recommended by the CDC; or intravenous ceftriaxone (Rocephin), which is often used for immune-compromised patients, but not routinely recommended for neurosyphilis by the CDC.

“However, people with HIV were less likely to normalize their CSF VDRL after therapy for syphilis, especially those with low peripheral blood CD4+ T-cell counts,” she said. “I'm not certain that a failure to normalize CSF-VDRL means treatment failure, but it is worrisome. The bottom line is that the combination of HIV and neurosyphilis requires careful follow-up.”

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The resurgence of syphilis may be an unfortunate byproduct of the success of HIV treatment, said Dr. Marra. “Syphilis is increasing in a big way in the United States, particularly among men who have sex with men,” she said. She noted, for example, that US cities have reported that 20 to 73 percent of men who have sex with men with syphilis are HIV-infected.

“With HIV treatment advances, people have become less concerned about becoming infected with HIV,” she said. “The risk of syphilis should be on the radar for all neurologists. We need to put aside our own discomfort and ask the necessary questions. When any physician assesses a patient with a neurological condition who may also have a sexually transmitted disease, it is important to ask about risk factors.”

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Two experts stressed that Dr. Marra's findings are a wake-up call for neurologists on several fronts: the increased prevalence of syphilis, the vulnerability to neurosyphilis of today's syphilis patients, who often also have HIV, and the need to be suspicious of neurosyphilis even in early syphilis.

“We need to keep people worrying about neurosyphilis,” said David B. Clifford, MD, Feay Professor of Clinical Neuropharmacology in Neurology at Washington University in Saint Louis, MO, in a telephone interview. Dr. Clifford, who specializes in the neurologic complications of HIV, is the principal investigator of the Neurologic AIDS Research Consortium, which is funded by the NIH.



“Dr. Marra's work emphasizes that this problem hasn't gone away,” he said. “Her study, which involved a large number of syphilis patients, showed neurologic involvement in 20 percent. We need to remain vigilant, particularly with HIV-infected patients.”

The findings should remind neurologists to obtain complete histories from all patients, particularly “good sexual histories in a way that gets as honest a response as possible,” he said. “We need to be watch out for syphilis because it is such a treatable problem.”

Because of the risk of neurosyphilis, neurologists have a particular responsibility to watch for possible risk factors, said Kenneth L. Tyler, MD, Reuler-Lewin Family Professor of Neurology at Colorado University Health Sciences Center in Denver, where he is also a Professor of Medicine and Microbiology and Immunology.

“In the last five to six years, we've seen an increase in syphilis and other sexually-transmitted diseases in gay men,” Dr. Tyler said in a telephone interview. He agreed with Dr. Marra that the availability of new anti-retroviral drugs has reduced some of the fear regarding HIV, and that this complacence has led to less safe sexual practices.

“Additionally, there's a pathological linkage between syphilis and HIV,” he said. The development of chancres can provide a route of entry by disrupting the integrity of the skin and mucosa that typically form barriers against HIV.''

“Dr. Marra has tried to help us by bringing an understanding of patients with syphilis to the modern era,” he said. “She has helped us determine who is at risk of neurosyphilis, and when we need to order lumbar punctures so that we can conduct a CSF analysis. Therefore, we know a lot about the epidemiology of neurosyphilis, and which patients should be considered for lumbar puncture.”

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Part of the problem, he said, is the lack of universally accepted laboratory criteria for the diagnosis of neurosyphilis – so there is no real gold standard to which to compare the CSF-VDRL results. The presence of a negative CSF FTA-ABS essentially excludes the diagnosis of neurosyphilis, he said. But unfortunately, a positive test does not establish the diagnosis – as positive CSF FTA-ABS can be found in patients with syphilis but not neurosyphilis.

In July, Dr. Marra and colleagues reported that in HIV-positive patients – with and without syphilis – the CSF-FTA-ABS and unabsorbed version of the test, the FTA, were sensitive, but not specific for the diagnosis of neurosyphilis (Neurology 2004;63:85–88).

“Neurologists need to be active in screening these patients,” Dr. Tyler said. “This is a treatable disease. We can reduce the risk of neurosyphilis and prevent progression to devastating late forms.”

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Stages of Syphilis

  • Primary Syphilis: The first signs, chancres, of syphilis infection appear. The disease can be passed to another person when sores are present. If not treated, the disease continues to the second stage.
  • Secondary Syphilis: Signs and symptoms include a skin rash. As in the first stage, the disease can be passed to another person when signs and symptoms are present. If not treated, the disease progresses to the next stage.
  • Latent Syphilis: There are no symptoms or signs. In late latent syphilis (more than 1–2 years after primary infection), the disease is no longer contagious and cannot be passed to another person. Some people with latent syphilis have no further symptoms or problems.
  • Tertiary Syphilis: Damage to body organs, including neurosyphilis, develops as well as other serious complications.
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• Golden MR, Marra CM, Holmes KK. Update on syphilis: resurgence of an old problem. JAMA 2003;290:1510–1514.
    • Marra CM, Maxwell CL, Smith SL, et al. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis 2004;189:369–376.
      • Rowland LP, Stefanis L, eds. Spirochete infections: neurosyphilis. In: Rowland LP, ed. Merritt's Neurology. 10th ed. Philadelphia, PA. Lippincott Williams & Wilkins. 2000:182–188.
        ©2004 American Academy of Neurology