Neurosyphilis.Pdf

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, Seattle, WA 98104, [email protected]. Relationship Disclosure: ABSTRACT Dr Marra receives royalties Purpose of Review: This article reviews the etiology, clinical manifestations, diag- from Wolters Kluwer Health and UpToDate, Inc, and nosis, and treatment of neurosyphilis, with a focus on issues of particular relevance 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 can develop at any time in the course of syphilis. Two neuroimaging patterns should 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- 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

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 brain and ilis come from the prepenicillin era, syphilis have serologic or clinical evi- spinal cord parenchyma. particularly the work of Houston Merritt dence of syphilis, or both, and CSF h No single specific and and colleagues. It is important to point pleocytosis, elevated protein, reactive sensitive test for out here that no single specific and sen- CSF-VDRL, or some combination of these neurosyphilis exists. The sitive test for neurosyphilis exists. The abnormalities. In addition, they are neu- diagnosis is based on diagnosis is based on clinical and CSF rologically asymptomatic. Asymptomatic clinical and CSF findings as well as clinical judgment. findingsaswellasclinicaljudgment.The neurosyphilis occurs early in infection. bottom line is that case series and re- Treatment prevents progression to h Patients with ports of patients with neurosyphilis, es- symptomatic neurosyphilis. asymptomatic pecially with ‘‘atypical forms,’’ should be Patients with symptomatic syphilitic neurosyphilis have serologic or clinical carefully evaluated with regard to accuracy meningitis present with the typical find- evidence of syphilis, or of diagnosis; just because the author of ings of aseptic meningitis, including head- both, and CSF a study thinks that the patient has neu- ache, stiff neck, nausea, and vomiting. 13 pleocytosis, elevated rosyphilis does not make it so. In re- In a large prepenicillin series, the most protein, reactive viewing the literature, I have endeavored common findings were papilledema, CSFYVenereal Disease Research Laboratory, or some combination of these abnormalities. In addition, they are neurologically asymptomatic. Asymptomatic neurosyphilis occurs early in infection. Treatment prevents progression to symptomatic neurosyphilis.

FIGURE 10-1 Natural history of neurosyphilis. Neuroinvasion occurs in at least 40% of individuals. Clearance occurs in about 70% of individuals. The remaining 30% of patients have persistent CNS infection, also called asymptomatic neurosyphilis. In the prepenicillin era, about 20% of individuals with asymptomatic neurosyphilis developed one of the symptomatic forms of neurosyphilis. In the penicillin era, the early forms (eg, symptomatic meningitis, meningovasculitis) are more common than the late forms (eg, dementia and tabes dorsalis). CNS = central nervous system. B 2015 Christina Marra, MD.

1716 www.ContinuumJournal.com December 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS convulsions, confusion, and focal and or dementia paralytica. In the prepen- h Patients with symptomatic cranial nerve abnormalities, particularly icillin era, it was most commonly seen syphilitic meningitis involving cranial nerves II, VII, and VIII. in individuals 35 to 50 years of age and present with typical Syphilitic meningitis most commonly occurred from 5 to 25 years after pri- findings of aseptic 17 occurred within a year of infection, and mary infection. Merritt stated, ‘‘The meningitis, including 7.5% of patients had concomitant sec- clinical manifestations of paretic neu- headache, stiff neck, ondary syphilis. rosyphilis are protean. Exact replicas of nausea, and vomiting. Localized syphilitic meningitis can re- every type of mental disorderI are en- There may be sult in focal mass lesions called gummas, countered. In other words, the clinical concomitant cranial which most commonly arise from the pia picture may duplicate any psychiatric nerve involvement, mater over the convexities14 and may be syndrome or disease.’’17 Early in the particularly of cranial nerves II, VII, and VIII. mistaken for tumors. Syphilitic menin- course, patients are forgetful and have gitis may uncommonly affect the spinal personality changes. With time, they may h Focal areas of syphilitic cord, causing meningomyelitis. Syphilitic develop psychiatric symptoms, such as meningitis may result in meningitis may be accompanied by mania, depression, or psychosis. How- a gumma, a mass lesion that usually arises from ocular or otologic abnormalities; vision ever, most patients simply experience the pia mater and can or hearing loss due to syphilis can also worsening of deficits in memory and mimic a tumor. be seen in isolation. A full discussion of judgment, progressing to frank demen- h these forms of syphilis is beyond the tia. In its latest stages, patients become Syphilitic meningitis may cause arteritis and scope of this article; the reader is re- immobile and incontinent and may have 15,16 stroke affecting vessels ferred to two recent review articles. seizures. The most frequent neurologic of the brain or, less Syphilitic meningitis may cause arter- examination findings are pupillary ab- commonly, the spinal itis and stroke affecting vessels of the normalities; facial and limb hypotonia; cord. This form of brain or, less commonly, the spinal cord. intention tremors of the face, tongue, neurosyphilis is termed Accordingly, this form of neurosyphilis and hands; and reflex abnormalities. Early meningovascular. is termed meningovascular. Merritt and in the course of disease, other than h Early in the course of 17 colleagues described 42 patients with cognition, the neurologic examination syphilitic dementia, brain meningovascular syphilis. Most can be normal. patients are forgetful were 30 to 50 years of age and devel- Cases of syphilitic dementia con- and have personality oped meningovascular syphilis within tinue to be reported in the modern era, changes. With time, months to years after infection, with characterized by rapidly progressive they may develop an average of 7 years.17 Stroke in the cognitive decline with or without psy- psychiatric symptoms, distribution of the middle cerebral ar- chiatric features. Zheng and colleagues22 such as mania, tery was the most common clinical find- reported a retrospective series of depression, or psychosis. ing, with hemiparesis, hemiplegia, or 116 patients with syphilitic dementia. However, most patients simply experience aphasia. Prodromal symptoms, such as All had reactive serum treponemal and worsening of deficits in headache, dizziness, and personality nontreponemal tests, 56 had CSF pleo- memory and judgment changes for days or weeks before the cytosis (the cutoff was not defined), and progressing to onset of stroke were common. Modern 100 had reactive CSF nontreponemal frank dementia. studies18 conform to the clinical descrip- tests. Ages ranged from 30 to 76 years. tions Merritt and colleagues provided Dementia, personality change, abnor- andalsoshowtheutilityofadvanced mal behavior, and emotional prob- neuroimaging techniques in identifying lems were the most common findings. syphilitic vasculitis (Case 10-1).21 Thirty-nine percent of patients had de- lusions and 16% had seizures. Of note, Late Neurosyphilis: Dementia neurosyphilis was not suspected ini- and Tabes Dorsalis tially in 36% of patients, with a delay in Syphilitic dementia is also called general diagnosis between 1 and 24 months paresis, general paralysis of the insane, (Case 10-2).22

Continuum (Minneap Minn) 2015;21(6):1714–1728 www.ContinuumJournal.com 1717

Case 10-1 A 46-year-old man with human immunodeficiency virus (HIV) infection reported a 2-month history of headaches and photophobia. Two to three weeks before presentation, he noticed a scaling rash on the soles of his feet. Examination showed a macular rash over his torso, coalescing scaling lesions over the dorsum of his feet, and a 2-mm erosion with surrounding edema on the dorsal surface of his penis. Serum rapid plasma reagin (RPR) was reactive at a titer of 1:1024 and serum Treponema pallidum particle agglutination assay (TPPA) was reactive. Neurologic examination was normal. CSF showed 187 white blood cells/2L (95% lymphocytes), a protein concentration of 125 mg/dL, and a reactive CSFYVenereal Disease Research Laboratory (CSF-VDRL) with a titer of 1:32. He began therapy with IM procaine penicillin G and oral probenecid for syphilitic meningitis. Five days later, he developed confusion and left-sided weakness. Brain MRI showed multiple punctate foci of restricted diffusion in the right middle cerebral and bilateral posterior cerebral artery territories (Figure 10-219). CT angiography showed critical narrowing of the right vertebral, basilar, proximal right middle cerebral, and right posterior cerebral arteries. Transcranial Doppler sonography showed severe vessel narrowing of the right middle cerebral and basilar arteries and mild narrowing of the left middle and anterior cerebral arteries. His neurosyphilis treatment was changed to high-dose IV penicillin G and aspirin 81 mg/d orally was added. Over the course of the following year, CSF abnormalities resolved. Mild left-sided weakness persisted. Comment. This case is an example of meningovascular syphilis. The patient had evidence of resolving primary syphilis (the lesion on his penis) and secondary syphilis (the rash on his torso and feet) as well as symptoms of chronic meningitis (headache and photophobia for more than 1 month). Shortly after beginning treatment for syphilitic FIGURE 10-2 Diffusion-weighted brain MRI of the patient in Case 10-1 with meningovascular meningitis, he developed symptomatic syphilis showing recent infarctions in the left meningovasculitis. His imaging studies showed thalamus, right basal ganglia, and right occipital lobe.

findings consistent with a diffuse infectious ReprintedwithpermissionfromBucherJB,etal,SexTransmDis.19 vasculitis. After therapy, his CSF normalized, journals.lww.com/stdjournal/Abstract/2011/05000/Stroke_in_a_Patient_ but he was left with mild neurologic With_Human_Immunodeficiency.17.aspx. B 2011 American Sexually Transmitted Diseases Association. abnormalities. The reason he progressed to stroke after beginning neurosyphilis treatment is a matter of speculation. The most likely explanation is that he simply became symptomatic from his already-established vasculitis. Alternatively, he may have experienced a Jarisch-Herxheimer reaction, a usually self-limited febrile response to antibiotic therapy that has been associated uncommonly with worsening neurosyphilis symptoms and signs.20

Tabes dorsalis, also called locomotor 47) years after primary infection.17 The ataxia, was the most common form of most common symptoms were pupil- neurosyphilis in the prepenicillin era. lary abnormalities, including Argyll Its frequency has declined since the Robertson pupils (strictly defined, an advent of antibiotics.18 In Merritt’s se- Argyll Robertson pupil is a small pupil ries, tabes was typically seen in pa- that does not respond to light but tients between 44 and 60 years of age contracts normally to accommodation- with onset, on average, 21 (range 3 to convergence, dilates imperfectly to

1718 www.ContinuumJournal.com December 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT Case 10-2 h Early symptoms of tabes dorsalis include A 36-year-old man (not infected with human immunodeficiency virus [HIV]) paresthesia or presented with an 18-month history of change in behavior and cognitive hyperesthesia in radicular impairment. He had been in a monogamous same-gender sexual relationship distributions, and bladder for the past 11 years and had no history of sexually transmitted diseases. While dysfunction. Later, pain, he had previously been very shy, he had become more outgoing. He had vibration, and tactile trouble with memory, often repeated himself, and had difficulty with word sensation become finding. About 3 months before presentation, he was fired from his job as impaired, and reflexes a laboratory technician because of poor work performance. He subsequently are lost. saw a psychiatrist, who diagnosed depression. As part of his psychiatric evaluation, a brain CT scan was performed and found to be normal, but serum rapid plasma reagin (RPR) was reactive at a titer of 1:128 and serum Treponema pallidum particle agglutination assay (TPPA) was reactive. CSF showed 78 white blood cells/2L, protein 120 mg/dL, and CSFYVenereal Disease Research Laboratory (CSF-VDRL) test was reactive at a titer of 1:128. On neurologic examination, he was giddy and had trouble following instructions. His score on the Mini-Mental State Examination was 24/30. A brain MRI scan was normal. He was treated for syphilitic dementia with 14 days of high-dose IV penicillin G with resolution of CSF abnormalities but only mild improvement in cognitive impairment. His partner’s serum RPR and TPPA were nonreactive. Comment. This man had syphilitic dementia. His age, rapidly progressing course, and behavioral risk factors all suggested syphilis as the etiology of his behavioral changes and cognitive impairment. As in the cases described in the prepenicillin era, he was likely infected at least 11 years before diagnosis. Treatment stopped disease progression, but he was left with significant disability. mydriatics, and does not dilate in re- of serologic tests and CSF examination. sponse to painful stimuli), optic atrophy, Neuroimaging may also be useful. lancinating pains, sensory changes, progressive ataxia, and bowel and bladder Serologic Tests Used dysfunction.17 Early sensory changes on Blood included paresthesia or hyperesthesia in Two types of serologic tests exist for radicular distributions. Later, pain, vi- syphilis. Nontreponemal tests include bration, and tactile sensation became the rapid plasma reagin (RPR) test, the impaired, and reflexes were lost. Sen- VDRL test, and the toluidine red un- sory ataxia, usually involving the lower heated serum test (TRUST). These as- more than the upper extremities, was a says measure IgG and IgM antibodies feature in 42%.17 Bladder dysfunction to a cardiolipin-lecithin-cholesterol an- occurred early, with urinary retention tigen. Results are generally expressed and overflow incontinence. As noted as a titer, with higher titers reflecting above, tabes is now an uncommon form greater disease activity. Success of ther- of neurosyphilis, but cases continue to apy is, in part, determined by decline in be described.18,23 titer, and a fourfold drop or reversion to nonreactive is evidence of treatment suc- DIAGNOSIS cess. However, even without treatment, The diagnosis of neurosyphilis is based nontreponemal titers will decline over on clinical findings and on the results time, and the proportion of patients with

Continuum (Minneap Minn) 2015;21(6):1714–1728 www.ContinuumJournal.com 1719

KEY POINT h Two types of serologic late untreated syphilis who have a noassays (EIAs) and chemiluminescent tests for syphilis exist. reactive nontreponemal blood test is immunoassays (CIAs). The FTA-ABS and Nontreponemal tests lower than in those with untreated early TPPA tests measure IgG and IgM reac- 24 include the rapid plasma disease. False-positive serum nontre- tivity to whole organisms, while the EIAs reagin (RPR) test and the ponemal tests can be seen in a variety and CIAs measure antibodies to re- Venereal Disease of clinical settings, including pregnancy, combinant T. pallidum proteins. In the Research Laboratory injection drug use, older age, and auto- United States, treponemal test results (VDRL) test. Treponemal immune disease. False-negative results are expressed qualitatively (reactive ver- tests include the can occur as a consequence of the ‘‘pro- sus nonreactive) and are used to con- fluorescent treponemal zone phenomenon,’’ in which the anti- firm a diagnosis of syphilis in a patient antibody absorption (FTA-ABS), the CSF body concentration in blood is so high with reactive nontreponemal tests. False- Treponema pallidum that the antigen-antibody ratio of the positive results for the FTA-ABS and TPPA particle agglutination test does not favor flocculation. Repeat- are rare, but are more common for the assay (TPPA), and a ing the test using a diluted sample can EIA/CIAs. Reactivity of an EIA or CIA, variety of automated identify a prozone reaction. A report of a which in many clinics is the initial test enzyme immunoassays missed diagnosis of neurosyphilis be- used for syphilis screening, needs to and chemiluminescent cause of a prozone reaction has been be confirmed by a second, different, immunoassays. published25;notethat,hadthispatient treponemal test. In addition, the trep- been screened with a serum treponemal onemal tests may be reactive in pa- test (see below), the diagnosis would tients who have been infected with likely have not been overlooked. one of the other pathogenic trepo- Treponemal tests include the fluo- nemes such as T. pallidum subspe- rescent treponemal antibody absorption cies pertenue, the organism that causes (FTA-ABS) and the Treponema pallidum yaws, a skin and bone disease that af- particle agglutination assay (TPPA) as well fects children in Central Africa, West as a variety of automated enzyme immu- Africa, Southeast Asia, and the Pacific

Case 10-3 A 54-year-old woman was referred to the neurology clinic for advice regarding the need for a lumbar puncture (LP). She emigrated from Ethiopia about 3 years earlier and lived with her son. Her medical history included treated hypertension and depression. She had no known history of syphilis or yaws. Since moving to the United States, her son had noticed that she seemed forgetful. For example, she forgot her appointments. In addition, she had little interest in family activities. Her internist was concerned that she could be developing dementia and sent syphilis serologies on blood. The serum rapid plasma reagin (RPR) was nonreactive, but the serum fluorescent treponemal antibody absorption (FTA-ABS) test was reactive. On examination, the patient was soft-spoken and deferred to her son for answers to most questions. Otherwise, her neurologic examination was normal. A brain MRI showed mild atrophy. Comment. Should this patient have an LP? Her reactive serum treponemal test could indicate previous syphilis or previous yaws, and there is no way to tell which. Her symptoms could be related to her known depression, to neurosyphilis, or to a neurodegenerative disease. Although the likelihood that this woman has syphilitic dementia is low, treatment could lead to improvement, and the morbidity of LP is low. Thus, I would recommend LP but would only treat for neurosyphilis if the criteria in Table 10-2 were met.

1720 www.ContinuumJournal.com December 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS Islands. This cross-reactivity can prove 0% to 100% of individuals with neurosy- h Nontreponemal tests troublesome in evaluating patients philis; the generally accepted sensitivity is may become nonreactive from these geographic areas who have 30% to 70%. The CSF-VDRL test is very spe- in late syphilis, while cognitive symptoms (Case 10-3). Tre- cific, although false-positive results may treponemal tests remain ponemal tests generally remain reac- be seen when the CSF is visibly blood- reactive for life in patients tive for life in patients with treated or tinged in patients with high serum VDRL or with all forms of syphilis, untreated syphilis and are a good indi- RPR titers, and rarely otherwise (Case 10-4). even after treatment. h cator of previous infection. Patients Thus, a reactive CSF-VDRL establishes CSF white blood cell with reactive treponemal tests but the diagnosis of neurosyphilis, but a non- concentration in neurosyphilis is generally nonreactive nontreponemal tests have reactive test does not exclude it. greater than 10/2L either very early syphilis (generally the Because the CSF-VDRL test is not treponemal tests become reactive be- with a lymphocytic available worldwide, the use of alter- predominance. fore the nontreponemal tests), treated native nontreponemal tests on CSF has h The CSFYVenereal syphilis, or late untreated syphilis. been investigated. We showed that the Disease Research CSF-RPR was significantly more spe- Cerebrospinal Fluid Laboratory (CSF-VDRL) cific than the CSF-VDRL for the diag- test is considered to be A summary of CSF abnormalities from nosis of symptomatic neurosyphilis, the gold standard test 17 26 Merritt’s series is shown in Table 10-1 . butthattheCSF-RPRwasnegativein for neurosyphilis 27 CSF white blood cell (WBC) concentra- 36% of CSF-VDRLYreactive samples. diagnosis. However, the tion in neurosyphilis is generally greater A large study from China found that CSF-VDRL may be than 10/2Lwithalymphocyticpredom- qualitative results of the CSF-VDRL and reactive in only 30% to inance. Higher cell counts are seen in the CSF-TRUST were the same 97% of 70% of patients with early compared to late neurosyphilis; the time. However, 11% of CSF-VDRLY neurosyphilis. Thus, a patients with tabes dorsalis, the latest reactive samples were CSF-TRUST nonreactive CSF-VDRL occurring form of neurosyphilis, may some- reactive.28 Thus, the problem of low establishes the diagnosis of neurosyphilis, but a times have entirely normal CSF as may diagnostic sensitivity of the CSF-VDRL nonreactive test does not patients with brain gumma. The CSF-VDRL is likely greater for the CSF-RPR and exclude it. is considered to be the gold standard test CSF-TRUST tests. h for diagnosis of neurosyphilis. However, In contrast to the CSF-VDRL, CSF tre- In contrast to the CSFYVenereal Disease depending upon the diagnostic criteria ponemal tests are generally sensitive, Research Laboratory but not specific, for the diagnosis of chosen, the CSF-VDRL may be reactive in test, CSF treponemal tests are generally TABLE 10-1 Cerebrospinal Fluid Profiles in the Different Forms of sensitive, but not Neurosyphilis in the Prepenicillin Eraa specific, for the diagnosis of neurosyphilis. Form of White Blood Protein Reactive CSF Neurosyphilis Cells (per 2L) (mg/dL) Wassermann Testb Asymptomatic 0Y100 G45Y100 84% Meningeal 200Y400 100Y200 91% Meningovascular 11Y100 100Y200 81% Paresis 25Y75 50Y100 100% Tabes dorsalis 10Y50 45Y75 72%

CSF = cerebrospinal fluid. a Reprinted with permission from Marra CM, Wolters Kluwer Health.26 B 2014 Wolters Kluwer Health. b The Wassermann test is the predecessor of the Venereal Disease Research Laboratory (VDRL) test and, for the purposes of these data, can be considered equivalent to it.

Continuum (Minneap Minn) 2015;21(6):1714–1728 www.ContinuumJournal.com 1721

Case 10-4 A 59-year-old woman presented to a specialty multiple sclerosis clinic with a remote history of optic neuritis and more recent episodic imbalance. As part of her evaluation, CSF studies were sent, including a CSFYVenereal Disease Research Laboratory (CSF-VDRL) test, which was reactive at a titer of 1:4. However, serum rapid plasma reagin (RPR) and Treponema pallidum particle agglutination assay (TPPA) tests were negative. She had no history of syphilis. Comment. Although rare, false-positive CSF-VDRLs do occur. As with any test, a false-positive result is more common when the test is performed when the likelihood of disease is low. The patient’s negative serum treponemal test rules out a diagnosis of syphilis and neurosyphilis. She should not be treated for neurosyphilis. The laboratory repeated the test on a saved specimen, and it was nonreactive, suggesting that the false-positive test in this instance was due to laboratory error.

neurosyphilis. Sensitivity is highest malities,29 suggesting that nonreactive when the diagnosis of neurosyphilis is CSF treponemal tests can exclude the di- based on CSF rather than clinical abnor- agnosis of asymptomatic neurosyphilis

FIGURE 10-3 Axial fluid-attenuated inversion recovery (FLAIR) (A) and contrast-enhanced T1-weighted sagittal (B) MRI of a cerebral syphilitic gumma showing edema in the left temporal lobe (white arrows) with nodular surface enhancement (yellow arrows). The left anterior temporal lobe was resected and Treponema pallidum DNA was amplified from paraffin embedded tissue. Courtesy of Sky Blue, MD. B 2015 Sky Blue, MD.

1722 www.ContinuumJournal.com December 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT with a high degree of certainty, but a sequences and isointense or high in- h Two neuroimaging negative result is less able to exclude tensity on T2-weighted MRI sequences; patterns should alert symptomatic neurosyphilis. Specificity enhance homogenously, sometimes the neurologist to a may be improved by excluding sam- with a nodular component and often diagnosis of neurosyphilis: 30 ples with blood contamination. Two with a dural tail; and have associated (1) cerebral gummas, studies have shown that using a titer edema (Figure 10-3).14 Second, MRI may pial-based lesions that cutoff of greater than 1:320 improves mimic herpes encephalitis, with high can mimic meningiomas; Y the diagnostic specificity of the CSF signal intensity on T2-weighted or and (2) high signal Treponema pallidum hemagglutina- diffusion-weighted images in one or both intensity on T2-weighted tion (CSF-TPHA) test, a treponemal test 35 or diffusion-weighted medial temporal lobes (Figure 10-4). that is not available in the United States, MRI in one or both for clinical and laboratory diagnoses Synthesizing the Diagnosis medial temporal lobes of neurosyphilis.31,32 that can mimic Establishing a diagnosis of neurosyphilis, In the United States, syphilis is most herpes encephalitis. especially the diagnosis of syphilitic dem- common in men who have sex with men, many of whom are HIV infected. entia, can be a frustrating experience In addition, HIV infection may in- for neurologists. As noted above, the crease the risk of neurosyphilis. No diagnosis is based on clinical findings, data suggest that CSF nontreponemal CSF abnormalities, and clinical judg- or treponemal tests perform differ- ment. The greatest experience comes ently in individuals who are HIV from the prepenicillin era, to which many infected compared to those who are of us turn for guidance. However, the not HIV infected. However, mild CSF accuracy of some of these data has been pleocytosis is common in individuals disputed, mostly based on results of se- who are HIV infected but do not have rum and CSF serologic tests. For exam- syphilis, particularly in those who are ple, Simon suggested that erroneous relatively immunocompetent. For example, Marshall and colleagues33 showed that 16% of CSF samples from 649 individuals who were HIV infected had greater than 10 WBC/2L, with progressive decline in CSF WBC concentration with more advanced stages of disease. We showed that CSF pleocytosis due to HIV is most common in patients with peripheral blood CD4+T cells greater than 200/2L, in those not taking antiretroviral medications, and in those who have detectable plasma HIV RNA.34 Neuroimaging While a variety of neuroimaging find- FIGURE 10-4 Axial fluid-attenuated ings have been described in neuro- inversion recovery (FLAIR) syphilis, two patterns should alert the MRI showing increased in the medial left temporal lobe in a neurologist to a diagnosis of neuro- patient with syphilitic dementia. Reprinted with permission from Lee JW, et al, syphilis. First, cerebral gummas are cir- 35 Neurology. www.neurology.org/content/65/11/1838. cumscribed pial-based mass lesions that short. B 2005 American Academy of Neurology. are low intensity on T1-weighted MRI

Continuum (Minneap Minn) 2015;21(6):1714–1728 www.ContinuumJournal.com 1723

KEY POINT h All patients given a diagnoses of syphilitic meningitis and neurosyphilis, and, of these, the diagno- diagnosis of meningovasculitis in individuals with sis was confirmed by the authors based neurosyphilis should nonreactive serum and CSF serologies, on history, physical examination find- have evidence of current respectively, were made in individuals ings, and serologic tests in 157. The 13 or past syphilis as who, in reality, had viral meningitis or ‘‘false positives’’ were attributed to neg- indicated by a reactive nonsyphilitic cerebrovascular disease.36 ative serum serologic tests, ‘‘false- serum treponemal test. Similarly, Patterson and colleagues1 positive’’ serum or CSF serologic tests, reviewed 5270 discharge records from and lack of clinical correlation. These the Boston City Hospital (the source of reports emphasize the role of clinical judgment. In my mind, the interpretation Merritt’s series17) from 1930 to 1979, of of nonreactive CSF serologic tests, espe- which, 253 patients were discharged with cially in suspected syphilitic dementia, a diagnosis of neurosyphilis. On review, is the most vexing problem. The CSF- 170 had symptoms consistent with late VDRL can be nonreactive in syphilitic dementia, as is well documented in a case reported by Lee and colleagues35 of an TABLE 10-2 Suggested Neurosyphilis Diagnostic Criteria individual who was not HIV infected, with progressive cognitive impairment, b Asymptomatic Neurosyphilis whose CSF-VDRL was negative on two Reactive serum treponemal test separate occasions 6 months apart. AND CSF WBCs were normal on the first Reactive CSF-VDRL assessment, but the protein concentra- If CSF-VDRL is negative: tion was elevated at 97 mg/dL; serum syphilis serologic tests were not Reactive CSF-treponemal test obtained. At the time of the second AND CSF examination, serum RPR, TPPA, 1. In a patient not infected with HIV: CSF WBCs 95/2Lor and FTA-ABS were reactive; CSF CSF protein 945 mg/dL showed 41 WBC/2L; and CSF protein 2. In a patient who is HIV infected with peripheral was 88 mg/dL. T. pallidum DNA was blood CD4+ T cells G200/2L and undetectable plasma amplified from a temporal lobe biopsy. 9 2 HIV RNA and on antiretroviral therapy: CSF WBCs 5/ L Suggested neurosyphilis diagnostic 3. In a patient who is HIV infected with peripheral blood criteria are shown in Table 10-2. They CD4+ T cells 9200/2L or detectable plasma HIV RNA or not taking antiretroviral medications: reactive differ by HIV status as well as within CSF-FTA-ABS and CSF WBCs 920/2L patients infected with HIV based on b Symptomatic Neurosyphilisa immunologic and HIV treatment status. Reactive serum treponemal test All patients given a diagnosis of neurosyphilis should have evidence of cur- AND rent or past syphilis as indicated by Symptoms and signs of neurosyphilis a reactive serum treponemal test. In AND the absence of neurologic symptoms Reactive CSF-VDRL and signs (asymptomatic neurosyphilis), OR diagnosis is based exclusively on CSF CSF WBCs 95/2L or CSF protein 945 mg/dL abnormalities, including CSF-VDRL reactivity, CSF pleocytosis, or elevated CSF CSF = cerebrospinal fluid; FTA-ABS = fluorescent treponemal antibody absorption; HIV = human immunodeficiency virus; RNA = ribonucleic acid; protein concentration. Because HIV alone VDRL = Venereal Disease Research Laboratory; WBCs = white blood cells. may cause CSF pleocytosis, particularly a Please see text for additional information. in patients who have high peripheral blood CD4+ T-cell counts or detectable

1724 www.ContinuumJournal.com December 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS plasma HIV RNA or in patients who are penicillin G with oral probenecid is an h Penicillin G is the 9 not taking antiretroviral medications, these alternative (Table 10-3). For patients recommended treatment factors influence CSF diagnostic crite- who are allergic to penicillin and can- for neurosyphilis. ria for asymptomatic neurosyphilis. CSF not undergo desensitization or who Ceftriaxone may be an protein concentration is also increased cannot take penicillin for other reasons, acceptable alternative. in patients who are HIV infected, but ceftriaxone, 2 g/d IV, may be an accept- h The success of the association with clinical or labora- able alternative to penicillin based on neurosyphilis treatment 37,38 tory features of HIV is less clearly defined. small studies. However, ceftriaxone is determined by In the setting of clear symptoms and is not recommended by the CDC for resolution or stabilization signs of neurosyphilis, the influence of neurosyphilis treatment. The 2008 of clinical abnormalities HIV on CSF abnormalities is not as European39 and 2008 United Kingdom40 and by normalization of rigorously considered. syphilis guidelines recommend doxycy- CSF abnormalities. The exceptions related to intracra- cline 200 mg orally 2 times a day for Clinical abnormalities are more likely to resolve nial gumma and tabes dorsalis should 28 days as an alternative neurosyphilis treatment regimen in selected instances; in early than in be noted here. While serum treponemal late neurosyphilis. tests will be reactive in both these forms this regimen is not recommended in 41 of neurosyphilis, the CSF profile may the 2014 European guidelines and is uncommonly be normal. In the case of not recommended by the CDC. gumma, neuroimaging is integral to es- The success of neurosyphilis treat- tablishing the diagnosis. In the case of ment is determined by resolution or tabes, diagnosis may need to be based stabilization of clinical abnormalities and solely on highly characteristic clinical by normalization of CSF abnormalities. findings, keeping in mind that normal Clinical abnormalities are more likely to CSF is the exception, not the rule. resolve in early than in late neurosyphilis. Patients with syphilitic meningitis TREATMENT and intracranial gummas completely The Centers for Disease Control and recover. In contrast, in patients with Prevention (CDC) recommends high- meningovascular syphilis, meningeal dose IV penicillin G as the first-line ther- symptoms and signs will resolve, but apy for neurosyphilis; IM procaine there will be residual stroke symptoms

TABLE 10-3 Treatment of Neurosyphilis

b Recommended Regimensa Aqueous crystalline penicillin G 18Y24 million units/d IV, given as 3Y4 million units IV every 4 hours or as a continuous IV infusion for 10Y14 days OR Procaine penicillin G 2.4 million units IM once per day, plus probenecidb 500 mg orally 4 times/d, both for 10Y14 days b Nonstandard Regimensa Ceftriaxone 2 g IV once per day for 10Y14 days Doxycycline 200 mg orally 2 times/d for 28 days

IM = intramuscular; IV = intravenous. a Some experts recommend 3 weekly doses of 2.4 million units of benzathine penicillin G IM, which is the treatment for uncomplicated late latent syphilis, after completion of neurosyphilis treatment. b Probenecid is contraindicated for patients with serious allergy to sulfa-containing medications.

Continuum (Minneap Minn) 2015;21(6):1714–1728 www.ContinuumJournal.com 1725

and signs. Similarly, treatment of pa- CSF-VDRL reactivity with a high degree tients with dementia or tabes may arrest of certainty, except in patients infected disease progression but is unlikely to with HIV who are not taking antiretro- reverse dementia or sensory ataxia.18 viral agents. The CDC guidelines state that CSF WBC count should decline at 6 months CONCLUSION and all CSF abnormalities should resolve Neurosyphilis can develop at any time by 2 years after treatment.9 My approach in the course of syphilis. Diagnosis re- differs, with the first follow-up lumbar lies on consideration of clinical find- puncture performed 3 months after ings and CSF abnormalities as well as therapy because the median time for clinical judgment, which is based on a normalization of CSF WBC, CSF-VDRL, sound understanding of the spectrum and serum RPR was approximately of disease and the strengths and lim- 42 4 months in our prospective study. Ce- itations of diagnostic tests. Penicillin G rebrospinal protein concentration is slow remains the first-line treatment for neu- to normalize and may remain elevated rosyphilis, but ceftriaxone may be an ac- even after normalization of other CSF ceptable alternative. Success of treatment 42,43 and clinical abnormalities, thus, the is judged by resolution or stabilization decision to re-treat should not be based of clinical abnormalities and by normal- solely on failure of CSF protein con- ization of CSF abnormalities. Clinical centration to normalize. If CSF abnor- abnormalities are more likely to resolve malities persist at 3 months (excluding in early than in late neurosyphilis. elevated protein concentration), CSF should be reexamined at 6 months REFERENCES after therapy and at 12 months if ple- 1. Patterson D, Vilensky JA, Robertson WM, ocytosis and CSF-VDRL reactivity persist Berger J. Treatment and diagnostic accuracy of neurosyphilis at Boston City Hospital’s at 6 months. Failure of the CSF WBC Neurological Unit, 1930-1979. J Neurol Sci 2012; count to decrease 6 months after ther- 314(1Y2):1Y4. doi:10.1016/j.jns.2011.11.007. apy or failure of CSF-VDRL to decline 2. Musher DM. Syphilis, neurosyphilis, penicillin, fourfold (or to nonreactive if the initial and AIDS. J Infect Dis 1991;163(6):1201Y1206. titer is less than 1:2) 1 year after therapy 3. Centers for Disease Control and Prevention, are indications for retreatment. Serum Department of STD Prevention. Sexually transmitted disease surveillance 2013. www. nontreponemal tests should be ob- cdc.gov/std/stats13/surv2013-print.pdf. Published tained at 3, 6, and 12 months after ther- December 2014. Accessed October 7, 2015. apy. Failure of the serum RPR or VDRL 4. World Health Organization. Global incidence to decline fourfold (or to nonreactive if and prevalence of selected curable sexually transmitted diseasesV2008. www.who.int/ the initial titer is less than 1:2) at 1 year reproductivehealth/publications/rtis/ after therapy is an additional indica- stisestimates/en/. Published 2012. Accessed tion for retreatment. Keep in mind that October 7, 2015. RPR and VDRL titers are usually not 5. Taylor MM, Aynalem G, Olea LM, et al. A equivalent in the same serum sample consequence of the syphilis epidemic among men who have sex with men (MSM): (the RPR titer is usually 2 to 4 times neurosyphilis in Los Angeles, 2001-2004. higher than the VDRL titer). Thus, titers Sex Transm Dis 2008;35(5):430Y434. should be compared within RPRs or doi:10.1097/OLQ.0b013e3181644b5e. within VDRLs, not RPR to VDRL or vice 6. Daey Ouwens IM, Koedijk FD, Fiolet AT, et al. versa. Normalization of serum RPR after Neurosyphilis in the mixed urban-rural community of the Netherlands. Acta neurosyphilis therapy (as defined above) Neuropsychiatr 2014;26(3):186Y192. doi:10. predicts normalization of CSF WBCs and 1017/neu.2013.53.

1726 www.ContinuumJournal.com December 2015

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 7. Lukehart SA, Hook EW 3rd, Baker-Zander SA, neurosyphilis in immunocompetent patients. et al. Invasion of the central nervous system Eur Neurol 2004;52(1):29Y35. doi:10.1159/ by Treponema pallidum: implications for 000079391. diagnosis and treatment. Ann Intern Med 19. Bucher JB, Golden MR, Heald AE, Marra CM. 1988;109(11):855Y862. doi:10.7326/ Stroke in a patient with human 0003-4819-109-11-855. immunodeficiency virus and syphilis treated 8. Rolfs RT, Joesoef MR, Hendershot EF, et al. with penicillin and antiretroviral therapy. A randomized trial of enhanced therapy for Sex Transm Dis 2011;38(5):442Y444. early syphilis in patients with and without doi:10.1097/OLQ.0b013e3181ffa5d0. human immunodeficiency virus infection. 20. Davis LE, Oyer R, Beckham JD, Tyler KL. The Syphilis and HIV Study Group. N Engl J Elevated CSF cytokines in the Jarisch-Herxheimer Med 1997;337(5):307Y314. doi:10.1056/ reaction of general paresis. JAMA Neurol NEJM199707313370504. 2013;70(8):1060Y1064. doi:10.1001/ 9. Workowski KA, Bolan GA; Centers for jamaneurol.2013.2120. Disease Control and Prevention (CDC). Sexually transmitted diseases treatment 21. Bauerle J, Zitzmann A, Egger K, et al. The guidelines, 2015. MMWR Recomm Rep great imitatorVstill today! A case of 2015;64(RRY03):1Y137. meningovascular syphilis affecting the posterior circulation. J Stroke Cerebrovasc 10. Marra CM, Sahi SK, Tantalo LC, et al. Toll-like Dis 2015;24(1):e1Ye3. doi:10.1016/j. receptor polymorphisms are associated with increased neurosyphilis risk. Sex Transm Dis jstrokecerebrovasdis.2014.07.046. 2014;41(7):440Y446. doi:10.1097/OLQ. 22. Zheng D, Zhou D, Zhao Z, et al. The 0000000000000149. clinical presentation and imaging 11. Centers for Disease Control and Prevention manifestation of psychosis and dementia in (CDC). Symptomatic early neurosyphilis among general paresis: a retrospective study of HIV-positive men who have sex with menVfour 116 cases. J Neuropsychiatry Clin Neurosci cities, United States, January 2002YJune 2004. 2011;23(3):300Y307. doi:10.1176/ MMWR Morb Mortal Wkly Rep 2007; appi.neuropsych.23.3.300. 56(25):625Y628. 23. Pandey S. Magnetic resonance imaging of 12. Marra CM, Sahi S, Tantalo LC, et al. Enhanced the spinal cord in a man with tabes dorsalis. molecular typing of treponema pallidum: J Spinal Cord Med 2011;34(6):609Y611. geographical distribution of strain types doi:10.1179/2045772311Y.0000000041. and association with neurosyphilis. J Infect Dis 2010;202(9):1380Y1388. 24. Larsen SA, Steiner BM, Rudolph AH. doi:10.1086/656533. Laboratory diagnosis and interpretation of tests for syphilis. Clin Microbiol Rev 13. Merritt HH, Moore M. Acute syphilitic 1995;8(1):1Y21. meningitis. Medicine (Baltimore) 1935;14: 119Y183. 25. Lessig S, Tecoma E. Perils of the prozone reaction: neurosyphilis presenting as an 14. Fargen KM, Alvernia JE, Lin CS, Melgar M. RPR-negative subacute dementia. Neurology Cerebral syphilitic gummata: a case presentation 2006;66(5):777. doi:10.1212/01.wnl. and analysis of 156 reported cases. Neurosurgery 2009;64(3):568Y575. doi:10.1227/ 0000201187.17578.49. 01.NEU.0000337079.12137.89. 26. Marra CM. Neurosyphilis. In: Scheld WM, 15. Moradi A, Salek S, Daniel E, et al. Clinical Whitley RJ, Marra CM, eds. Infections of the features and incidence rates of ocular central nervous system. 4th edition. Philadelphia, complications in patients with ocular syphilis. PA: Wolters Kluwer Health, 2014. Y Am J Ophthalmol 2015;159(2):334 343.e1. 27. Marra CM, Tantalo LC, Maxwell CL, et al. The doi:10.1016/j.ajo.2014.10.030. rapid plasma reagin test cannot replace 16. Phillips JS, Gaunt A, Phillips DR. Otosyphilis: the venereal disease research laboratory test a neglected diagnosis? Otol Neurotol 2014; for neurosyphilis diagnosis. Sex Transm Dis 35(6):1011Y1013. doi:10.1097/MAO. 2012;39(6):453Y457. doi:10.1097/OLQ. 0000000000000361. 0b013e31824b1cde. 17. Merritt HH, Adams RD, Solomon HC. 28. Gu W, Yang Y, Wu L, et al. Comparing the Neurosyphilis. New York, NY: Oxford University performance characteristics of CSF-TRUST Press, 1946. and CSF-VDRL for syphilis: a cross-sectional 18. Conde-Sendin MA, Amela-Peris R, Aladro-Benito Y, study. BMJ Open 2013;3(2). pii: e002204. Maroto AA. Current clinical spectrum of doi:10.1136/bmjopen-2012-002204.

Continuum (Minneap Minn) 2015;21(6):1714–1728 www.ContinuumJournal.com 1727

29. Harding AS, Ghanem KG. The performance 36. Simon RP. Neurosyphilis. Arch Neurol 1985; of cerebrospinal fluid treponemal-specific 42(6):606Y613. doi:10.1001/archneur. antibody tests in neurosyphilis: a systematic 1985.04060060112021. Y review. Sex Transm Dis 2012;39(4):291 297. 37. Marra CM, Boutin P, McArthur JC, doi:10.1097/OLQ.0b013e31824c0e62. et al. A pilot study evaluating ceftriaxone 30. Chan Y, Yeung KH, Ho HF, et al. Use of and penicillin G as treatment agents cerebrospinal fluid enzyme immunoassay for neurosyphilis in human immunodeficiency virus-infected for diagnosis of neurosyphilis. Int J STD AIDS individuals. Clin Infect Dis 2013;25(8):571Y578. doi:10.1177/ 2000;30(3):540Y544. doi:10.1086/313725. 0956462413515452. 38. Shann S, Wilson J. Treatment of neurosyphilis 31. Luger AF, Schmidt BL, Kaulich M. Significance with ceftriaxone. Sex Transm Infect of laboratory findings for the diagnosis of 2003;79(5):415Y416. doi:10.1136/sti.79.5.415. neurosyphilis. Int J STD AIDS 2000;11(4): 224Y234. doi:10.1258/0956462001915750. 39. French P, Gomberg M, Janier M, et al. IUSTI: 2008 European guidelines on 32. Levchik N, Ponomareva M, Surganova V, et al. the management of syphilis. Int J STD Criteria for the diagnosis of neurosyphilis in AIDS 2009;20(5):300Y309. doi:10.1258/ijsa. cerebrospinal fluid: relationships with 2008.008510. intrathecal immunoglobulin synthesis and blood-cerebrospinal fluid barrier dysfunction. 40. Kingston M, French P, Goh B, et al. UK Sex Transm Dis 2013;40(12):917Y922. national guidelines on the management of doi:10.1097/OLQ.0000000000000049. syphilis 2008. Int J STD AIDS 2008;19(11): 729Y740. doi:10.1258/ijsa.2008.008279. 33. Marshall DW, Brey RL, Cahill WT, et al. 41. Janier M, Hegyi V, Dupin N, et al. 2014 Spectrum of cerebrospinal fluid findings in European guideline on the management of various stages of human immunodeficiency syphilis. J Eur Acad Dermatol Venereol 2014; virus infection. Arch Neurol 1988;45(9): 28(12):1581Y1593. doi:10.1111/jdv.12734. 954Y958. doi:10.1001/archneur.1988. 00520330032007. 42. Marra CM, Maxwell CL, Tantalo L, et al. Normalization of cerebrospinal fluid 34. Marra CM, Maxwell CL, Collier AC, et al. abnormalities after neurosyphilis therapy: Interpreting cerebrospinal fluid pleocytosis does HIV status matter? Clin Infect Dis in HIV in the era of potent antiretroviral 2004;38(7):1001Y1006. doi:10.1086/382532. therapy. BMC Infect Dis 2007;7:37. doi:10.1186/1471-2334-7-37. 43. Marra CM, Maxwell CL, Tantalo LC, et al. Normalization of serum rapid plasma reagin 35. Lee JW, Wilck M, Venna N. Dementia due to titer predicts normalization of cerebrospinal neurosyphilis with persistently negative fluid and clinical abnormalities after treatment CSF VDRL. Neurology 2005;65(11):1838. of neurosyphilis. Clin Infect Dis 2008;47(7): doi:10.1212/01.wnl.0000187082.92497.95. 893Y899. doi:10.1086/591534.

1728 www.ContinuumJournal.com December 2015