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Neurosyphilis Review Article Address correspondence to Dr Christina M. Marra, University of Washington, Neurosyphilis Harborview Medical Center, 325 9th Avenue, Department Christina M. Marra, MD, FAAN of Neurology, Box 359775, 12/20/2018 on dEGITNzRJOxEH7LJrfJp2vgWAS2vVD9/MC7qX9EmfnPnugaqPjRkQ0NfrThjRVURTR2GnqJvWOdHFRx5vURyK63cYMd3A7NuDM02v8dmVhInRHL2ucyx2He/bKgb2lW4 by https://journals.lww.com/continuum from Downloaded Seattle, WA 98104, [email protected]. Downloaded Relationship Disclosure: ABSTRACT Dr Marra receives royalties Purpose of Review: This article reviews the etiology, clinical manifestations, diag- from Wolters Kluwer Health from and UpToDate, Inc, and nosis, and treatment of neurosyphilis, with a focus on issues of particular relevance https://journals.lww.com/continuum receives research support to neurologists. from the National Institutes Recent Findings: The number of cases of infectious syphilis in the United States of Health. has steadily increased since 2000. The highest rates are among men who have sex Unlabeled Use of Products/Investigational with men, and approximately half of these individuals are infected with human Use Disclosure: immunodeficiency virus (HIV). Neurosyphilis is a serious complication of syphilis that Dr Marra discusses the by can develop at any time in the course of syphilis. Two neuroimaging patterns should dEGITNzRJOxEH7LJrfJp2vgWAS2vVD9/MC7qX9EmfnPnugaqPjRkQ0NfrThjRVURTR2GnqJvWOdHFRx5vURyK63cYMd3A7NuDM02v8dmVhInRHL2ucyx2He/bKgb2lW4 unlabeled/investigational use of antibiotics, including ceftriaxone alert the neurologist to a diagnosis of neurosyphilis: cerebral gummas, which are dural- and doxycycline, for the based lesions that can mimic meningiomas, and medial temporal lobe abnormalities treatment of neurosyphilis. that can mimic herpes encephalitis. Penicillin G is the recommended treatment for * 2015, American Academy of Neurology. neurosyphilis, but ceftriaxone may be an acceptable alternative. Summary: The diagnosis of neurosyphilis can be challenging. A sound understanding of the clinical manifestations and the strengths and limitations of diagnostic tests are essential tools for the neurologist. Continuum (Minneap Minn) 2015;21(6):1714–1728. INTRODUCTION lems in the first half of the 1900s. With Neurosyphilis can develop at any time theadventofpenicillin,theincidence in the course of syphilis. Because no of syphilis and the prevalence of neu- 1 single highly sensitive and specific diag- rosyphilis declined. However, at the nostic test exists, the diagnosis relies beginning of the acquired immunodefi- on consideration of clinical findings ciency syndrome (AIDS) epidemic, cases and CSF abnormalities as well as clinical of neurosyphilis were noted in patients judgment. While diagnosis is relatively infected with human immunodeficiency straightforward when patients present virus (HIV) who had been adequately 2 with symptomatic meningitis or stroke treated for early syphilis, drawing at- in the setting of known untreated syph- tention to the possibility of increased ilis or strongly reactive syphilis serologic risk of neurosyphilis in this population, tests, deciding whether patients with non- but also reminding clinicians of a pre- on 12/20/2018 specific cognitive complaints, reactive viously underrecognized disease. treponemal but nonreactive nontrep- Syphilis is a reportable disease in the onemal tests, and nonspecific CSF ab- United States. The number of cases of normalities have neurosyphilis can be a primary and secondary syphilis in the challenge. This article reviews the clinical United States has steadily increased manifestations, diagnosis, and treatment since 2000; in 2013, the number of cases of neurosyphilis, with a focus on issues was the most recorded since 1995. Rates of particular relevance to neurologists. were highest among men, and 75% of patients were men who have sex with EPIDEMIOLOGY men; approximately half of these in- In the United States, syphilis and neuro- dividuals were HIV infected.3 World- syphilis were major public health prob- wide, the incidence of syphilis is high. 1714 www.ContinuumJournal.com December 2015 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS The World Health Organization (WHO) from 21% of 134 neurologically asymp- h In the United States, the estimates that there were 10.6 million tomatic patients with untreated early incidence of syphilis has incident cases of syphilis in 2008, of syphilis (unpublished data). steadily increased since which 60% were from Africa and South- Studies from the prepenicillin era 2000. In 2013, rates of 4 east Asia. also demonstrated that the proportion syphilis were highest In contrast to syphilis, neurosyphilis of patients with ‘‘neuroinvasion’’ (based among men, in particular is not a reportable disease in the United on CSF analysis) exceeded the number men who have sex with States or elsewhere. A retrospective study that developed symptomatic neurosyph- men. Approximately half conducted in Los Angeles, California, be- ilis, leading to the hypothesis that of these individuals were tween 2001 and 2004 showed that the T. pallidum is cleared from the CSF human immunodeficiency Y rate of neurosyphilis in patients with and, by analogy, the central nervous virus infected. early syphilis was 2.1% in individuals system in some individuals. Those in h In the developed world, who were HIV infected and 0.6% in whom clearance failed were deemed to male gender, younger those not infected with HIV.5 Aretro- have ‘‘asymptomatic neurosyphilis’’ and age, men who have sex spective study from the Netherlands were at risk for progression to symptom- with men, and human immunodeficiency found that between 1999 and 2010, the atic neurosyphilis, with those with the virus infection are mean annual incidence of neurosyphilis most abnormal CSF at greatest risk. Then features associated was 0.7 per 100,000 in men and 0.2 per and now, patients with asymptomatic neu- with neurosyphilis. 100,000 in women, with median ages of rosyphilis are treated with a neurosyphilis h Neurosyphilis can occur 47 and 54 years, respectively.6 The re- regimen to prevent this progression. at any time in the sults of both of these studies should be Today, the value of identifying CSF course of infection and interpreted carefully given the retrospec- abnormalities in neurologically asymp- should not be considered tive design and limited information re- tomatic patients with syphilis remains to be solely a ‘‘tertiary’’ 9 garding diagnostic criteria. Nonetheless, debated. The likelihood of CSF abnor- manifestation of syphilis. they point out features that can help malities decreases after treatment for identify those at greatest risk for neu- uncomplicated syphilis,10 and currently, rosyphilis: male gender, younger age, no means exist of identifying those indi- men who have sex with men, and those viduals who are destined to clear CSF who are infected with HIV. abnormalities versus those who will not. Persons who are HIV infected may ETIOLOGY be the exception, with well-documented Syphilis is caused by the bacterium Trep- instances of development of early neu- onema pallidum subspecies pallidum, rosyphilis after recommended antibiotic a pathogenic treponeme that cannot be treatment of uncomplicated syphilis,2,11 cultured in vitro. In the prepenicillin era, a phenomenon that is not described in CSF was commonly analyzed in all pa- individuals not infected with HIV. Other tients with syphilis, demonstrating that factors increase risk of CSF abnormali- T. pallidum invaded the CSF early in the ties in patients with syphilis, including course of disease. This finding has been bacterial strain type12 and host genetic confirmed in the modern era: 25% to 40% polymorphisms that influence the im- of untreated neurologically asymptomatic mune response,8 but their clinical rele- patients with primary, secondary, or early vance remains to be determined. latent syphilis have CSF pleocytosis and 20% to 30% have a reactive CSFYVenereal CLINICAL MANIFESTATIONS Disease Research Laboratory (CSF-VDRL) Neurosyphilis can occur at any time in test.7,8 In our ongoing study of CSF abnor- the course of infection, thus, it should malities in patients with syphilis, T. pallidum not be considered to be solely a ‘‘ter- was identified by reverse transcriptase tiary’’ manifestation of syphilis. The early polymerase chain reaction (RT-PCR) in CSF forms of neurosyphilis occur within Continuum (Minneap Minn) 2015;21(6):1714–1728 www.ContinuumJournal.com 1715 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Neurosyphilis KEY POINTS h The early forms of months to the first few years after pri- to restrict my comments to studies for neurosyphilis occur mary infection and affect the meninges which individual patient diagnoses meet within months to the and blood vessels, while the late forms the criteria described below. first few years after occur years to decades after primary infection and affect the infection and also affect the brain and Early Neurosyphilis: meninges and blood spinal cord parenchyma (Figure 10-1). Asymptomatic Syphilitic vessels, while the late Because syphilis and neurosyphilis Meningitis, Symptomatic forms occur years to were so common in the first half of the Syphilitic Meningitis, and decades after infection 1900s, much of what is known about Meningovascular Neurosyphilis and also affect the clinical manifestations of neurosyph- Patients with asymptomatic neuro- the
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