REVIEW ARTICLE
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C O N T I N UU M A UD I O
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CITE AS:
CONTINUUM (MINNEAP MINN)
2021;27(4, NEUROINFECTIOUS
DISEASE):1018–1039.
Address correspondence to
Dr Felicia Chow, University of
California, San Francisco at
Zuckerberg San Francisco
General Hospital, 1001 Potrero
Ave, Bldg 1, Room 101,
San Francisco, CA 94110,
felicia.chow@ucsf.edu.
RELATIONSHIP DISCLOSURE:
Dr Chow has received personal
compensation for speaking
engagements from the
University of California, San
Francisco, for the annual Recent
Advances in Neurology meeting
and for serving as an expert
physician for Grand Rounds and
has received research/grant
support from the National
Institutes of Health
(K23NS105575, R21TW010148,
R21TW011035).
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Chow reports no disclosure.
© 2021 American Academy
of Neurology.
1018
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Neurosyphilis
By Felicia Chow, MD, MAS
ABSTRACT
PURPOSE OF REVIEW: This
article focuses on the epidemiology, clinical
presentation, diagnosis, and management of neurosyphilis, with an
emphasis on clinically relevant issues faced by the practicing neurologist.
RECENT FINDINGS: The incidence of primary and secondary syphilis, the
sexually transmissible stages of infection, has been on the rise for the past
2 decades. A concerning recent trend is the surge in cases of syphilis in
women and of congenital syphilis. Neurosyphilis remains a relatively
common complication that can occur at any stage of syphilis. Along with
meningitis, meningovascular syphilis, which has been historically
described as a late presentation of neurosyphilis, now frequently occurs as
a manifestation of early infection. Late forms of neurosyphilis, including
tabes dorsalis and general paresis, are less prevalent in the era of
widespread penicillin use. As more laboratories adopt the
reverse-sequence algorithm for syphilis testing, patients with
serodiscordant results (ie, a reactive serum treponemal test with a
nonreactive nontreponemal test) may present an increasingly encountered
diagnostic challenge for neurologists. Although the CSF Venereal Disease
Research Laboratory (VDRL) remains a mainstay of diagnostic testing for
neurosyphilis, using a higher titer cutoff (greater than 1:320) for the
Treponema pallidum particle agglutination assay (TPPA) from the CSF may
improve the utility of the TPPA as a supporting criterion for the diagnosis of
neurosyphilis. Penicillin G is the treatment of choice for neurosyphilis,
although ceftriaxone may be a reasonable alternative therapy.
SUMMARY: A high index of suspicion and awareness of the variable clinical
presentations of neurosyphilis are essential to the approach to this
treatable infection. Neurologists should be mindful of the limitations of
serologic testing in the diagnosis of neurosyphilis and exercise clinical
judgment to determine the likelihood of the diagnosis.
INTRODUCTION
A
common misconception among neurologists and other health care
providers is that all presentations of neurosyphilis, an infection of
the nervous system by the spirochete Treponema pallidum
subspecies pallidum, are late, or tertiary, manifestations of
infection. In fact, neurosyphilis can occur at any stage of syphilis
and now appears to be most frequently seen in individuals with secondary
syphilis1-3; secondary syphilis, along with primary and early latent infection (ie,
asymptomatic infection acquired within the preceding 12 months), is referred to
AUGUST 2021
as early syphilis. The lack of a single, perfectly sensitive and specific test that can KEY POINTS
either definitively exclude or clinch the diagnosis of neurosyphilis requires
● Symptomatic
clinicians to use their judgment in interpreting serologic testing and the CSF neurosyphilis can occur at
profile, alongside a careful history and neurologic examination. This article any stage of syphilis and, in
reviews the epidemiology, clinical presentation, diagnosis, and management of fact, is now diagnosed most
neurosyphilis. commonly in early syphilis.

● Although the syphilis

EPIDEMIOLOGY epidemic in the
The incidence of primary and secondary syphilis, the sexually transmissible United States is centered on
stages of infection, reached an all-time low in the United States in the year 2000 young men who have sex
with 2.1 cases per 100,000 population, the lowest rate since reporting began in with men, syphilis rates are
on the rise in women and
the United States in 1941. With a year-over-year decline in rates in the 1990s, newborns.
public health officials at the turn of the 21st century considered eradication of
syphilis to be an attainable goal. The goal, however, has proven to be elusive, ● The prevalence of
with syphilis rates consistently on the rise since the nadir in 2000. Data from 2018 neurosyphilis is higher in
men, particularly men who
demonstrated a fivefold higher incidence of primary and secondary syphilis have sex with men, along
compared with data from the year 2000 at 10.8 cases per 100,000 population,4 a with people with HIV
far cry from syphilis elimination, which had seemed achievable a mere 2 decades infection.
earlier. Of the 35,063 reported primary and secondary syphilis cases in the
United States in 2018, men accounted for 86% of cases, with 53.5% in men who
have sex with men, 15.4% in men who have sex with women, and 16.7% in men
without information about the sex of sex partners. Rates were highest among
young men 20 to 34 years old.4
Although men account for the majority of syphilis cases in the United States,
an alarming trend that has surfaced more recently is the subepidemic affecting
women, with rates of primary and secondary infection in this demographic
doubling from 2014 to 2018.4,5 Substance use, including methamphetamine and
heroin use, may be driving part of the increase in infections in women.4 Other
factors, including incarceration and lack of access to health care and housing,
may also be contributing to this surge in cases in women of reproductive age and
the serious threat that it poses to newborns.6 Mother-to-child transmission and
infant mortality and neurologic disability associated with congenital syphilis,
which is entirely preventable with adequate screening and treatment of pregnant
women, are emerging public health concerns in the United States. For further
discussion of congenital syphilis, refer to the article “Congenital Infections of the
Nervous System” by Payal Patel, MD,7 in this issue of Continuum.

Epidemiology of Neurosyphilis
Although syphilis is a reportable condition, surveillance of neurosyphilis as a
complication of syphilis is inconsistent. As a result, population-based data on
the epidemiology of neurosyphilis are scarce. In a cross-sectional analysis of
national data on primary, secondary, and early latent syphilis (collectively
referred to as early syphilis) reported to the Centers for Disease Control and
Prevention (CDC) in 2015, 403 of 48,045 cases (0.8%) involved confirmed or
probable neurosyphilis.2 Between 2009 and 2015, the period prevalence of
neurosyphilis based on 10 states with more complete neurosyphilis reporting
was 1.8%. The annual prevalence ranged from 0.8% to 2.5%, comparable
to prevalence estimates from retrospective studies of urban US health
department records.8,9 The prevalence of neurosyphilis was nearly twofold
higher in men and in people with human immunodeficiency virus (HIV). Men

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NEUROSYPHILIS

who have sex with men were more likely to have neurosyphilis than men who
have sex with women only.
These data must be interpreted in the context of several limitations, including
ascertainment bias, passive case-based surveillance methods, and variability in
screening and diagnosis of neurosyphilis, including the threshold to obtain a
lumbar puncture. The expected effect of these limitations would be to bias
toward an underestimate of the true burden of neurosyphilis. In two
contemporary studies, the estimated prevalence of neurosyphilis was higher. In a
retrospective registry of all adults with HIV diagnosed with syphilis in
Copenhagen, Denmark, between 2004 and 2016, 6% met the criteria for
neurosyphilis.1 In a review of 567 syphilis cases in both people with HIV and
HIV-uninfected individuals from King County, Washington, between 2012 and
2013, 3.5% met the criteria for confirmed symptomatic neurosyphilis.3 When
interpreting neurosyphilis studies, the definition of neurosyphilis, which can
impact reported results, should be noted. In the former Danish study,
neurosyphilis was defined as a seroreactive test in the CSF, regardless of the
presence of symptoms, or CSF pleocytosis combined with neurologic signs and
symptoms compatible with neurosyphilis. In contrast, in the latter study in
Washington, which had a lower prevalence estimate, neurosyphilis was more
strictly defined as visual or hearing symptoms with either abnormal CSF testing
or an ophthalmologic examination consistent with ocular syphilis.
In sum, as rates of primary and secondary syphilis steadily rise nationwide,
these prevalence estimates suggest that neurosyphilis remains a relatively
common complication of the infection.

CLINICAL PRESENTATION
Neurosyphilis can occur at any stage of infection. A clinically useful approach is
to consider whether a patient is presenting early or late after primary infection,
although this critical piece of information may not always be straightforward
to ascertain.

Asymptomatic Neurosyphilis
Early in infection, T. pallidum disseminates widely throughout the body,
including in the central nervous system (CNS). Studies from the modern
treatment era using rabbit inoculation and polymerase chain reaction (PCR)
have found that 20% to 40% of individuals with untreated primary, secondary,
or early latent syphilis have detectable T. pallidum in the CSF,10,11 a proportion
comparable to studies from the pre-penicillin era. An inflammatory CSF profile,
reactive Venereal Disease Research Laboratory (VDRL), or some combination of
these CSF abnormalities may also be present. Some individuals with evidence of
early neuroinvasion have accompanying neurologic symptoms (eg, headache);
however, the majority are asymptomatic.10
Although neuroinvasion and the presence of CSF abnormalities in early
syphilis are common, their clinical and prognostic relevance in neurologically
asymptomatic individuals is unknown.12 Neuroinvasion may resolve
spontaneously, whereas for some patients, T. pallidum is not successfully
“cleared” from the CSF, and persistent inflammation may occur. HIV status does
not appear to impact the likelihood of detecting T. pallidum in the CSF in early
syphilis10,11; however, once present, HIV infection may impede the ability to
clear the infection from the nervous system. Cases of neurosyphilis have been

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diagnosed after people with HIV received appropriate treatment for early KEY POINTS
uncomplicated syphilis with a single IM injection of benzathine penicillin G,13
● In early neurosyphilis, the
which does not reach treponemicidal concentrations in the CSF.14 These CSF, meninges, and cerebral
examples of treatment failure suggest that immune-mediated clearance of T. blood vessels are typically
pallidum from the CSF, and by extension, the nervous system, may be impaired affected, leading to
by HIV infection, making people with HIV potentially more vulnerable to syphilitic meningitis and
meningovascular disease,
progression to symptomatic neurosyphilis. This raises the question of whether
whereas late forms of
obtaining a lumbar puncture in neurologically asymptomatic individuals with neurosyphilis tend to cause
HIV and syphilis is warranted, particularly in people with untreated HIV, lower injury to the brain and spinal
CD4+ count, and higher nontreponemal (eg, rapid plasma reagin [RPR]) titers, cord parenchyma.
which have been shown to increase the risk of neurosyphilis.15-18 However,
● Patients with
because of the lack of evidence that tailoring therapy in early syphilis based on a symptomatic early
CSF examination in neurologically asymptomatic individuals impacts long-term neurosyphilis typically
outcomes, the current CDC Sexually Transmitted Diseases Treatment Guidelines present with signs and
do not recommend routine CSF analysis in people with primary or secondary symptoms of a meningitis
(eg, headache,
syphilis, including people with HIV regardless of CD4+ count or RPR titer, unless photophobia, neck
clinical signs of neurosyphilis, ocular syphilis, or otosyphilis are present.12 Results stiffness, confusion) with or
of a clinical trial investigating whether immediate lumbar puncture followed by without cranial nerve
therapy based on CSF evaluation leads to better serologic and functional outcomes involvement.
in patients with syphilis at high risk of neuroinvasion are eagerly awaited.19

Symptomatic Neurosyphilis
Early neurologic involvement in syphilis can present concomitantly with
primary, secondary, or otherwise asymptomatic (ie, latent) syphilis and usually
occurs within the first weeks to 1 year of infection. Late neurologic
manifestations tend to present years, even decades, after infection. In early
neurosyphilis, the CSF, meninges, and cerebral blood vessels are typically
affected, leading to syphilitic meningitis and meningovascular disease, whereas
late forms of neurosyphilis more often affect the brain and spinal cord
parenchyma.

Early Neurosyphilis
Patients with symptomatic early neurosyphilis typically present with meningitis.
Cranial neuropathies, most frequently involving cranial nerves II, VII, or VIII,
may accompany the meningitis. Typical signs and symptoms include headache,
photophobia, neck stiffness, and confusion. Ocular and auditory symptoms,
including decreased visual acuity and hearing loss, are common presenting
features of neurosyphilis1 and may occur in isolation.
Syphilitic meningitis can be complicated by a vasculitis that affects both
small arteries (ie, Nissl-Alzheimer arteritis) and medium and large arteries
(ie, Heubner arteritis) of the CNS, leading to focal cerebral and, less commonly,
spinal cord infarcts.20,21 Strokes in the distribution of the middle cerebral arteries
are classically seen, although any vascular territory, including the vertebrobasilar
system, can be involved.22-25 Angiography may reveal segmental narrowing or
occlusion of one or more vessels, although radiologic evidence of vasculopathy
may be absent. High-resolution vessel wall imaging may demonstrate concentric
wall enhancement.26,27 Infarcts in multiple vascular territories,25 as often occurs
with vasculitis, can serve as an important clue to consider other causes of stroke
beyond traditional mechanisms. Although meningovascular syphilis is described
as a late form of neurosyphilis,22,28 cerebrovascular disease is now predominantly

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NEUROSYPHILIS

observed during early syphilis,29 usually weeks to months after primary

infection. Patients with meningovascular syphilis present with an acute stroke
syndrome that may follow a prodrome of symptoms of meningitis and/or
encephalitis.22,30 In some cases, infarcts are “silent” and noted incidentally on
neuroimaging obtained in a patient with meningitis (CASE 9-1).
Several studies have proposed obtaining a serum serologic test for syphilis in
all patients presenting with an acute ischemic stroke in an area where the
prevalence of syphilis is high. In a tertiary hospital in Brazil in an area with a high
prevalence of syphilis (101 cases per 100,000 people), neurosyphilis was
diagnosed in 1% to 4.7% of 1119 patients with acute stroke, depending on the
definition of neurosyphilis used.31 In a study from Thailand, also with a reported
high local prevalence of syphilis, 2.5% of 284 patients presenting with an acute
stroke were diagnosed with neurosyphilis based on serum and CSF testing; among

CASE 9-1 A 41-year-old man presented to the emergency department with 1 day of
right arm and leg weakness. He endorsed several weeks of headaches
and neck stiffness. About 1 week before presentation, he noted left face
numbness and “drooping”; he was seen by his primary care provider, who
diagnosed him with Bell’s palsy and prescribed prednisone. He was on
daily tenofovir/emtricitabine for preexposure prophylaxis to prevent HIV
infection and was sexually active with men and did not use condoms.
In the emergency department, he was febrile to 39.2°C (102.5°F). He
had generalized lymphadenopathy and a mildly pruritic, maculopapular
rash on his palms and soles. His neurologic examination was notable for
left lower motor neuron facial weakness and mild weakness of the right
upper and lower extremity in a pyramidal pattern.
Brain MRI showed multiple areas of restricted diffusion (FIGURE 9-1),
including in the right basal ganglia, left caudate head, genu of the internal
capsule bilaterally, left thalamus, right anterior insula, and bilateral
corona radiata. Magnetic resonance angiography (MRA) demonstrated
irregularity and diffuse narrowing of the bilateral supraclinoid internal
carotid arteries and the proximal middle and anterior cerebral arteries.
Serum treponemal chemiluminescent immunoassay was reactive, and
serum rapid plasma reagin (RPR) was reactive at a titer of 1:128. (He had
had a nonreactive serum RPR 4 months before presentation.) HIV testing
was negative. CSF had 121 white blood cells/mm3 and an elevated protein
concentration of 94 mg/dL. CSF Venereal Disease Research Laboratory
(VDRL) was reactive at 1:8.
He was treated with a 2-week course of high-dose IV penicillin G. His
headaches resolved within 1 month of treatment, although he continued
to have mild right-sided weakness. On repeat lumbar puncture 6 months
after completing IV penicillin G, CSF pleocytosis and elevated protein
concentration were no longer present, and a CSF VDRL was nonreactive.
Serum RPR obtained at the same time as the repeat lumbar puncture was
1:16 and was nonreactive at 12 months.

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people younger than 50 years of age presenting with stroke, 4.4% met the definition
for having neurosyphilis.25 Although syphilis testing in cases of acute stroke may
not be practical for every patient population, red flags that should raise the
suspicion for meningovascular syphilis include stroke with concomitant or
preceding symptoms of meningitis or encephalitis; stroke in young, sexually
active individuals, especially in the absence of traditional cerebrovascular risk
factors32; and recurrent, unexplained strokes.33 Obtaining a detailed social
history, including sexual history, to uncover potential epidemiologic exposures is
critically important and should not be shied away from by neurologists.

Late Neurosyphilis
Widespread antibiotic use has altered the clinical landscape of neurosyphilis,
with substantially lower rates of late forms of neurosyphilis in the penicillin era.

FIGURE 9-1
Multifocal infarcts in the patient in CASE 9-1, who had meningovascular syphilis.
Hyperintense signal on axial diffusion-weighted imaging (A, B, and C) and hypointense
signal on apparent diffusion coefficient imaging (not shown) are consistent with acute
infarcts involving the right basal ganglia, left caudate head, genu of the internal capsule
bilaterally, left thalamus, right anterior insula, and bilateral corona radiata.

This was a case of meningovascular syphilis that occurred during early COMMENT
infection with clinical evidence at presentation of secondary syphilis.
Because the patient was on preexposure prophylaxis to prevent HIV
infection, he was regularly tested for sexually transmitted infections and
had had a nonreactive serum RPR 4 months before presentation. Although
cerebrovascular complications of syphilis have historically been described
as a late form of neurosyphilis, meningovascular syphilis is now often
diagnosed in early syphilis (ie, within 1 year of infection). The patient’s
young age, lack of cardiovascular risk factors, and prodrome of headaches
raised suspicion for an atypical cause of stroke, prompting serum syphilis
testing and then lumbar puncture to confirm the diagnosis of neurosyphilis.

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NEUROSYPHILIS

Tabes dorsalis, one of the prototypical late manifestations of neurosyphilis

along with general paresis, is a spinal cord disorder that results from
demyelination of the posterior columns, dorsal roots, and dorsal root ganglia. The
classic presentation of tabes dorsalis, which usually occurs decades after primary
infection, is a sensory gait ataxia with profoundly impaired proprioception,
diminished reflexes, bowel and bladder dysfunction, and lancinating pains in the
abdomen and extremities. Although tabes dorsalis was the dominant manifestation
of neurosyphilis in the prepenicillin era, it is now an uncommon diagnosis.34,35
In a series of 43 HIV-uninfected individuals with neurosyphilis seen between 1991
and 2001 in the Canary Islands, 63% had early neurosyphilis compared with 28%
with late neurosyphilis36; tabes dorsalis was observed in only one patient. In a
retrospective review of 161 patients with neurosyphilis between 1990 and 1999
in Cape Town, South Africa, only two presented with tabes dorsalis.34
General paresis, also known as syphilitic dementia or dementia paralytica, is a
chronic encephalitic form of neurosyphilis that presents with neuropsychiatric
symptoms years to decades after primary infection. Patients develop gradually
progressive personality and behavioral changes (eg, irritability, emotional
lability), cognitive impairment, psychiatric symptoms (eg, depression,
psychosis, delusions, hallucinations), seizures, and sleep disturbance.35,37,38 As
with other forms of dementia, patients can become bedbound and incontinent in
advanced disease.39 Aphasia, speech impairment, tremor, myoclonus, ataxia,
hyperreflexia, corticospinal tract signs, and primitive reflexes40-43 may be found
on examination. Argyll Robertson pupils, pupils that react poorly to light but
constrict briskly to accommodation, can be seen in both general paresis38,42 and
tabes dorsalis, although this finding is reportedly noted more frequently in
patients with tabes dorsalis.44
In late forms of neurosyphilis, CSF pleocytosis has been reported in modern
series to be absent in as many as half of cases.38,42 In one study of 85 patients
without HIV diagnosed with general paresis, 55% had a CSF pleocytosis (defined
as more than 10 white blood cells/mm3), whereas 25% had a normal CSF white
blood cell count and protein concentration (defined as protein less than
50 mg/dL).38 Atrophy, often of the frontal and temporal lobes, and subcortical
T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities may be present
on MRI,37,40,42,45 whereas in some patients neuroimaging may be normal or may
detect only minimal atrophy.45 The presence of more severe atrophy on imaging,
likely reflecting later-stage disease, portends a lower likelihood of clinical
improvement after treatment.41,45 Serologic testing for syphilis should be
considered in the evaluation of patients with new-onset neuropsychiatric
symptoms, which may be a harbinger of late neurosyphilis. In one retrospective
review of 85 patients with general paresis presenting over a 9-year period in
Zhongshan, China, 64% were initially misdiagnosed, most commonly with other
causes of dementia, primary psychiatric illnesses, or cerebrovascular disease.38

Syphilitic Gummas
Syphilitic gummas are granulomatous lesions that can develop in any tissue,
including in the CNS. These intracranial and spinal mass lesions46 typically arise
from the pia mater, most commonly in the region of the cerebral convexities,47
and are often mistaken for tumors because of direct extension into the
parenchyma. Presenting symptoms (eg, headache, seizures, focal weakness) are
related to the location of the lesion and associated mass effect and

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inflammation.47 On MRI, gummas are typically T1 hypointense and T2 hyperintense KEY POINTS
with associated contrast enhancement and perilesional edema. Gummas are
● Red flags that should
traditionally described as a tertiary manifestation of syphilis, although they can raise the suspicion for
occur in early infection, including in HIV-uninfected individuals.48,49 meningovascular syphilis
include stroke with
The “Great Imitator” concurrent or preceding
symptoms of meningitis or
If all cases of neurosyphilis followed these textbook presentations, it would not
encephalitis and stroke in
live up to its well-deserved reputation as the “great imitator.” In daily practice, young, sexually active
the wide-ranging clinical presentations of this treatable infection, including individuals, especially in the
with lesser-known manifestations such as syphilitic amyotrophy (CASE 9-2) or a absence of traditional
cerebrovascular risk
pure cerebellar ataxia,52 or atypical presentations of more classic syndromes
factors.
(eg, general paresis masquerading as Parkinson disease53) argue for
maintaining a high index of suspicion and low threshold for testing for syphilis. ● Late forms of
However, as with any testing, before ordering syphilis testing, careful neurosyphilis (eg, tabes
consideration of the pretest probability for neurosyphilis and how test results dorsalis and general paresis)
are much less common in
will inform decision making is essential, particularly in light of challenges in the the era of penicillin.
interpretation of diagnostic testing, as outlined in CASE 9-3.
● The classic presentation
DIAGNOSIS of tabes dorsalis, which
usually occurs decades after
The diagnosis of neurosyphilis relies on interpretation of serologic testing from
primary infection, is a
the serum and CSF, along with the CSF profile, the patient’s exposure and sensory gait ataxia with
treatment history, current symptoms, and neurologic examination. Because of profoundly impaired
the limitations of culture and methods to detect T. pallidum directly from lesion proprioception, diminished
reflexes, bowel and bladder
exudate or tissue, serologic testing, which refers to detection of antibodies, is the
dysfunction, and lancinating
mainstay of the laboratory diagnosis of syphilis. All patients with neurosyphilis pains in the abdomen and
should have evidence of current or previous syphilis with reactive serologic extremities.
testing from serum (ie, a reactive serum treponemal test at a minimum; most will
have both a reactive serum treponemal and nontreponemal test) (FIGURE 9-3). ● General paresis is a
chronic encephalitic form of
Although serologic testing from CSF is crucial, no one test can definitively neurosyphilis that presents
confirm or exclude the diagnosis of neurosyphilis. The highly specific CSF VDRL is with neuropsychiatric
erroneously regarded as a gold standard test, but its low sensitivity limits symptoms years to decades
its utility in ruling out neurosyphilis in individuals with a high pretest probability. after primary infection.
In contrast, CSF treponemal tests are less specific than the VDRL and do not
● All patients with
distinguish between previously treated neurosyphilis and active infection. neurosyphilis should have
evidence of current or
Serum Nontreponemal Tests previous syphilis with a
reactive serum treponemal
Serologic testing for syphilis is divided into nontreponemal and treponemal tests.
test.
Both types of tests are required to make a presumptive diagnosis of syphilis, and
either can serve as an initial screen followed by the other as a confirmatory test. ● Serologic testing for
Nontreponemal tests, including the RPR and VDRL tests, measure nonspecific syphilis is divided into
antibodies made in response to a synthetic cardiolipin, cholesterol, and lecithin nontreponemal and
treponemal tests. Both
antigen complex. The sensitivity of nontreponemal testing varies by stage of types of tests, one as an
syphilis (TABLE 9-154-58), with higher false-negative rates from serum in primary initial screen followed by
and late (ie, tertiary and late latent) syphilis.54 False-negative results have also the other as a confirmatory
been reported in people with HIV59 and with the prozone phenomenon, which is test, are required to make a
presumptive diagnosis of
most common in secondary syphilis and occurs when a high antibody syphilis.
concentration interferes with flocculation. In cases of the prozone reaction, the
reactive test will be missed unless the sample is diluted. Serum false-positive tests
can be seen in a variety of clinical situations, including in HIV infection,
autoimmune disorders, pregnancy, and injection drug use.60 These false-positive

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NEUROSYPHILIS

results are generally low titer (less than 1:8)61 and underscore the importance of
obtaining a confirmatory treponemal test in all patients with a reactive serum
nontreponemal test (FIGURE 9-462,63).
Nontreponemal test results are reported as a titer that largely correlates
with disease activity. Titers of nontreponemal tests decline in response
to treatment but can wane over time even in the absence of treatment.

CASE 9-2 A 33-year-old man presented to neurology clinic with a 2-year history of
slowly progressive bilateral weakness and gradual wasting of his hand
muscles. He denied sensory changes, neck or shoulder pain, bowel/
bladder incontinence, or bulbar symptoms.
Three years before presentation, he had a reactive serum rapid plasma
reagin (RPR) but was lost to follow-up. Two years before presentation, he
noted decreased visual acuity of the right eye. Six months before
presentation, he reported progressive vision loss. Ophthalmologic
examination revealed bilateral panuveitis with chronic retinal
detachments. A serum RPR was reactive at 1:256. HIV testing was
negative. CSF demonstrated 80 white blood cells/mm3, protein
concentration of 60 mg/dL, and reactive CSF Venereal Disease Research
Laboratory (VDRL) at 1:4. He was treated at that time with high-dose IV
penicillin G for 14 days. His past medical history was notable for
methamphetamine use disorder.
On examination, he had marked atrophy of the intrinsic hand muscles
with associated weakness. Reflexes were preserved in the upper and
lower extremities. Sensation was intact to all modalities in the hands. Gait
was normal, and Romberg testing was negative.
Spine MRI demonstrated abnormal cervical cord signal from C6 to C7,
with focal T2 hyperintensities in the ventral gray matter (FIGURE 9-2).
Repeat RPR titer (6 months after completing treatment with IV penicillin
G) was 1:64. CSF demonstrated 4 white blood cells/mm3, protein
concentration of 57 mg/dL, and nonreactive CSF VDRL. Herpes simplex
and varicella-zoster virus testing from CSF was negative, as was West Nile
and human T-cell lymphotropic virus types I and II. Vitamin B12 level was
normal. Nerve conduction studies and EMG showed chronic reinnervation
changes in bilateral C7, C8, and T1 innervated muscles with preserved
sensory responses, localizing most likely to the nerve roots and/or
anterior horn cells.
His symptoms and neurologic examination remained stable over 3 years
of follow-up. Repeat RPR titer 3.5 years after IV penicillin G was 1:16, down
from 1:256 before treatment.

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A minimum fourfold decrease in titer, which represents a change of two dilutions
(eg, from 1:32 to 1:8), is one criterion used to demonstrate a successful response
to treatment. RPR and VDRL test results are not interchangeable; because the
two results are not comparable, the same testing method (ideally performed in
the same laboratory) should be used for successive testing to gauge treatment
response.

FIGURE 9-2
Cervical spinal cord involvement in the patient in CASE 9-2, with late neurosyphilis. A,
Sagittal T2-weighted image showing hyperintense cord signal abnormality spanning C6 to
C7 with mild cord volume loss. B, Axial T2-weighted image demonstrates that the cord
signal abnormality predominantly affected the ventral gray matter, also known as the
owl-eyes sign in which bilaterally symmetric ovoid foci of T2 hyperintensity are observed
in the anterior horn cells. The cervical cord lesion did not enhance after administration of
gadolinium on T1-weighted MRI (not shown).

This case was thought to be an example of syphilitic amyotrophy (ie, muscular COMMENT
atrophy due to syphilis).50 Progressive degeneration of anterior horn cells
results in insidious onset of muscular atrophy, typically of the hands, shoulder
girdle, or legs.50 Other lower motor neuron signs, including hypotonicity,
decreased tendon reflexes, and fasciculation potentials, may be observed. As
with this patient, syphilitic amyotrophy is a motor-predominant syndrome.
Weakness is the chief presenting symptom, followed by neck or shoulder
pain.50 Bulbar symptoms are uncommon, and sensation remains intact.
Syphilitic amyotrophy is a form of late neurosyphilis that can present with
tabes dorsalis or general paresis but often occurs in isolation.50,51 The
duration of syphilis was unknown when this patient began to develop hand
weakness 2 years before he presented for evaluation. Although his
presentation was consistent with syphilitic amyotrophy, no test can establish
the diagnosis with complete confidence. However, the lack of progression or
development of new neurologic symptoms over the 3 years after IV penicillin
G treatment supported the diagnosis of syphilitic amyotrophy.

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NEUROSYPHILIS

Serum Treponemal Tests

In general, treponemal tests are more sensitive than nontreponemal tests but lack
specificity for active syphilis. Manual treponemal tests, which include the T.
pallidum particle agglutination assay (TPPA) and the fluorescent treponemal
antibody absorption (FTA-ABS) test, measure antibodies to T. pallidum organisms,
whereas automated enzyme and chemiluminescent immunoassays measure
antibodies to recombinant T. pallidum proteins. Similar to nontreponemal tests, the
sensitivity of treponemal tests differs by syphilis stage (TABLE 9-1). The majority of
treponemal assays performed on serum have greater than 95% sensitivity when
considering all stages of syphilis combined.64 Unlike nontreponemal tests,
treponemal test positivity tends to persist for life, even after treatment, making it
less specific for active syphilis infection. However, in individuals treated early in
infection and in those with advanced HIV infection, seroreversion of treponemal
testing to nonreactive has been observed.64-67

Serodiscordant Results
In the traditional syphilis testing algorithm, a nontreponemal test (eg, RPR) is
used as the initial screen followed, as needed, by a confirmatory treponemal test.
The diagnosis for patients with primary or latent syphilis may be missed by the
traditional algorithm because of the lower sensitivity of nontreponemal tests for
those stages of syphilis (TABLE 9-1).68 Given the growing availability and

CASE 9-3 An 82-year-old woman with hypertension presented to clinic with a

3-year history of mild cognitive decline. As part of the evaluation, a serum
treponemal enzyme immunoassay was obtained, which was reactive,
whereas the confirmatory serum rapid plasma reagin (RPR) was
nonreactive. A serum Treponema pallidum particle agglutination assay
(TPPA) sent to resolve the discrepancy was reactive. The patient denied a
previous history of syphilis exposure, diagnosis, or treatment. She had
never traveled outside the United States. Her neurologic examination was
normal, aside from mild impairment on delayed recall memory testing.

COMMENT This is a fairly common clinical scenario that neurologists may encounter. If
the patient has no history of previously treated syphilis, the question arises
as to whether her cognitive decline is due to untreated late neurosyphilis
with a spontaneous decline in RPR over time. In general, neurosyphilis is
unlikely, albeit not impossible, in this scenario. To evaluate further, most
neurologists, including this author, would continue on the diagnostic
pathway for possible untreated neurosyphilis and perform a CSF examination
to rule out neurosyphilis. Although cognitive changes due to late neurosyphilis
may be permanent, treatment could prevent further cognitive decline. The
primary issue with CSF examination is that no test can definitively exclude
neurosyphilis if the clinical suspicion is high. However, in this case, given the
low pretest probability, this author would be reassured by a bland CSF profile
and nonreactive CSF Venereal Disease Research Laboratory (VDRL). If the
history, neurologic examination, or an abnormal CSF profile raised the pretest

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affordability of automated treponemal testing, a reverse-sequence algorithm
may also be used, in which an automated treponemal immunoassay is the initial
screen followed by a nontreponemal test. The reverse algorithm can lead to
serodiscordant results, whereby a patient has a reactive treponemal
immunoassay but a nonreactive nontreponemal test. In these situations, a
second, usually manual treponemal test is used to adjudicate serodiscordant
results, with the more sensitive and specific TPPA preferred over the
FTA-ABS.64 If the second treponemal test is also reactive, confirming the
serodiscordant results, one of three scenarios is most likely: (1) previously treated
syphilis with the expected fall in nontreponemal titers to nonreactive, (2)
previously untreated late syphilis with a decline in nontreponemal titers over
time, or (3) early infection before nontreponemal antibodies have developed
(FIGURE 9-4). Serodiscordant results may also be seen in patients with other
treponemal infections, such as yaws (endemic in Asia, Africa, and Central and
South America) or pinta (endemic predominantly in Central and South America
and the Caribbean).
As more laboratories adopt the reverse-sequence algorithm, patients with
serodiscordant results present an increasingly common diagnostic challenge
(CASE 9-3). The probability of neurosyphilis in people with serodiscordant
serologies (ie, reactive serum treponemal test and confirmatory treponemal test
with a nonreactive RPR) is thought to be low overall, although it has been

probability for neurosyphilis, then this author would obtain a CSF treponemal
test if the CSF VDRL were nonreactive.
If the pretest probability for neurosyphilis is low in an older patient
presenting with mild cognitive impairment and no other neuropsychiatric
symptoms, some clinicians may be less inclined to pursue a CSF examination,
in part because of the risks of lumbar puncture, low as they may be. Infectious
disease physicians in this camp may opt instead to treat for late latent syphilis
with three doses of weekly IM benzathine penicillin G followed by close
observation. This rationale highlights the importance of consideration of the
pretest probability for neurosyphilis before sending syphilis testing, which
could circumvent unnecessary testing. Finally, some clinicians might make the
argument that no further evaluation or treatment is warranted. With the
traditional screening algorithm, syphilis would have been ruled out by a
nonreactive serum RPR and, additional testing (eg, CSF examination) would
only have been pursued if a high pretest probability were present, which was
not the case with this patient.
Ultimately, the likelihood of neurosyphilis in a patient with serodiscordant
results presenting with cognitive decline or another nonspecific neurologic
symptom should be considered on a case-by-case basis, taking into account
the clinical presentation, indication for lumbar puncture and other workup,
the results of these evaluations, and the plausibility of other diagnoses. In this
case, the patient had a lumbar puncture with a bland CSF profile and
nonreactive CSF VDRL, which were felt to be adequate to exclude
neurosyphilis. She was treated with three doses of weekly IM benzathine
penicillin G for presumed late latent syphilis.

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NEUROSYPHILIS

KEY POINTS

● The sensitivity of
nontreponemal and
treponemal testing varies by
stage of syphilis.

● Serum false-positive
nontreponemal tests, which
are usually low titer (less
than 1:8) can be seen in a
variety of clinical situations,
including in HIV infection,
autoimmune disorders,
pregnancy, and injection
drug use.

● Nontreponemal test
results are reported as a
titer that correlates with
disease activity. A minimum
fourfold decrease in titer,
which represents a change
of two dilutions (eg, from
1:32 to 1:8), is one criterion
used to demonstrate a
successful response to
treatment.
● Treponemal tests
typically remain positive for
life, even after appropriate
treatment, making them less
specific for active infection.
● The probability of
neurosyphilis in people with
serodiscordant serologies
(ie, reactive serum
treponemal test with a
nonreactive RPR) is thought
to be low overall.
● The CSF pleocytosis in
early neurosyphilis tends to
be more robust than in late
neurosyphilis.
FIGURE 9-3
Approach to the diagnosis of symptomatic neurosyphilis.
CSF = cerebrospinal fluid; c/w = consistent with; VDRL = Venereal Disease Research Laboratory;
WBC = white blood cells.
a
Most patients with neurosyphilis will have a reactive serum treponemal and nontreponemal test. See the
text (Serodiscordant Results) for additional discussion, including the approach to serodiscordant results (ie,
reactive serum treponemal test with a nonreactive treponemal test).
b
Human immunodeficiency virus (HIV) itself can cause a CSF pleocytosis up to 20 WBCs/mm3, especially in
people not on antiretroviral therapy, with detectable HIV RNA, or with CD4+ greater than 200 cells/mm3.
This should be considered when interpreting the CSF profile of a person with HIV, although it is less relevant
when making a diagnosis of symptomatic (in contrast to asymptomatic) neurosyphilis.
c
In some situations of a nonreactive CSF VDRL with a CSF pleocytosis or elevated protein in which the
clinical suspicion for neurosyphilis is only moderate (eg, an alternative explanation for the CSF abnormalities is
available), a CSF treponemal test may help guide the diagnostic decision making.
d
A reactive CSF treponemal test does not distinguish between active and previously treated neurosyphilis.
e
In very rare cases in which the clinical suspicion is extremely high, a nonreactive CSF treponemal test may
not rule out symptomatic neurosyphilis.
reported in data of variable quality.69 A retrospective analysis of patients
identified by at least one reactive serum treponemal test who had paired serum
and CSF syphilis testing found that the 43 patients who met laboratory criteria
for neurosyphilis all had a reactive serum nontreponemal test. Furthermore,
none of the 265 patients (including both people with HIV and HIV-uninfected
individuals) with a negative serum nontreponemal test met the criteria for
neurosyphilis, leading the authors to conclude that neurosyphilis in patients with
serodiscordant results is extremely unlikely.15 In a retrospective single-center
chart review of patients with serodiscordant results who underwent lumbar
puncture, no definitive cases of neurosyphilis were identified.69 These limited
data provide some reassurance that neurosyphilis is unlikely in people with a
reactive treponemal assay and nonreactive RPR. Ultimately, the probability of
neurosyphilis in patients with serodiscordant results has to be determined on an
individual basis, taking into account the presenting neurologic signs and
symptoms, whether a lumbar puncture and neuroimaging are indicated and, if
so, their respective results, alongside the weight of alternative diagnoses.

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CSF Testing
In most forms of symptomatic neurosyphilis, the CSF profile demonstrates a
mild to moderate (greater than 5 white blood cells/mm3) lymphocyte-
predominant pleocytosis with elevated protein. The pleocytosis in early
neurosyphilis tends to be more robust than in late neurosyphilis. Interpretation
of the CSF profile can be confounded by HIV co-infection (FIGURE 9-3), as a mild
CSF pleocytosis (up to 20 white blood cells/mm3) is common in people with HIV
without neurosyphilis, especially in those with untreated HIV infection,
detectable plasma HIV RNA, and CD4+ greater than 200 cells/mm3.70
One question that arises in clinical practice is the likelihood of neurosyphilis
in the setting of bland CSF. Certainly, up to half of individuals with ocular

Performance Characteristics of Syphilis Serologic Tests From Serum TABLE 9-1

and CSFa

Nontreponemal test Treponemal test

Sensitivity Specificity Sensitivity Specificity

Serum RPR or VDRL Serum treponemal testing

b
Primary 62-78% Primary
FTA-ABS + TPPA 78-100%
Very limited data; Immunoassays 82-100%c
false positives can
Secondary 97-100% occur in 1-2% of Secondary
92-100%d; see
the population and FTA-ABS 93-100% FIGURE 9-4 for
are usually low titer potential causes
(<1:8); see FIGURE 9-4 TPPA + immunoassays 100%
of false-positive
for potential causes results
Early latent 82-100% Early latent 94-100%
of false-positive
Late latent or 61-64% results Late latent or unknown 85-100%
unknown duration duration

Tertiary 47-64% All stages combined

Immunoassays 95-100%

CSF VDRL 74-100%; false CSF treponemal testing 55-100%; false

e positives can f positives can
Neurosyphilis 49-88% Neurosyphilis 76-100%
occur with CNS occur with blood
Ocular syphilis ≤50% malignancy or blood contamination;
contamination higher TPPA titer
cutoff can improve
specificity

CSF = cerebrospinal fluid; FTA-ABS = fluorescent treponemal antibody absorption; RPR = rapid plasma reagin; TPPA = Treponema pallidum
particle agglutination; VDRL = Venereal Disease Research Laboratory.
a
Data from Tuddenham S, et al, Clin Infect Dis54; Park IU, et al, Clin Infect Dis55; and Harding AS, Sex Transm Dis.56
b
The sensitivity of nontreponemal testing for primary syphilis has been shown to be 50% and 93% in two outlier studies.54
c
The sensitivity of a treponemal immunoassay for primary syphilis in one study was 54%.57
d
Specificities as low as 83% to 87% have been reported.55
e
The sensitivity of CSF VDRL for neurosyphilis may be as low as 30%.58
f
The performance characteristics of treponemal and nontreponemal testing in the CSF are highly dependent on the criteria used to define
neurosyphilis and the non-neurosyphilis comparative population. The sensitivity of CSF treponemal testing for neurosyphilis is generally higher
when a reactive CSF VDRL is used to define neurosyphilis.

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NEUROSYPHILIS

FIGURE 9-4
Interpretation of possible permutations of syphilis serologic test results.
FTA-ABS = fluorescent treponemal antibody absorption; HIV = human immunodeficiency virus; RPR =
rapid plasma reagin; TPPA = Treponema pallidum particle agglutination.
a
For reverse-sequence algorithm testing, assume both initial treponemal and second confirmatory tests
are reactive.

syphilis71-73 and an even higher proportion of individuals with otologic

syphilis74 may have a normal CSF examination. However, although reports of
“burned out” tabes dorsalis with normal CSF have been described,75 as has
normal CSF in a relatively high proportion of patients with general paresis in
modern case series,38 this clinical scenario should still be viewed as atypical
for neurosyphilis.

Serologic Testing From CSF

The performance characteristics of treponemal and nontreponemal testing in the
CSF depend on the non-neurosyphilis population included for comparison and
the criteria used to define neurosyphilis. Furthermore, studies investigating the
utility of syphilis testing to diagnose neurosyphilis can suffer from incorporation
bias, in which the laboratory test being evaluated is actually used in the gold
standard definition of neurosyphilis. Two 2020 systematic reviews on syphilis
laboratory diagnostics provide discerning assessments of the methods
used in studies evaluating syphilis test performance characteristics
(summarized in TABLE 9-1).54,55
The CSF VDRL is regarded as a mainstay of diagnostic testing for
neurosyphilis. A reactive CSF VDRL is highly specific and considered diagnostic
for neurosyphilis. False positives have been described infrequently in the context
of CNS malignancy or of CSF with visible blood contamination if the serum

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nontreponemal titer is high.54,76,77 However, the variable sensitivity of the CSF KEY POINTS
VDRL, which may be as low as 30%,58 is a major drawback of its use. A 2020
● Although reports of
review of the performance characteristics of nontreponemal testing in the “burned out” tabes dorsalis
diagnosis of neurosyphilis found that the sensitivity of CSF VDRL ranged with normal CSF have been
from 49% to 88%.54 The high specificity but variable sensitivity of the described, as has normal
CSF VDRL (TABLE 9-1) makes it a clinically informative test when CSF in a relatively high
proportion of patients with
reactive, whereas a nonreactive test does not exclude the diagnosis of
general paresis in modern
neurosyphilis. case series, this clinical
In addition to the limitations of the CSF VDRL as a gold standard test for scenario should be viewed
neurosyphilis, it is also logistically challenging to perform because of specific as atypical for neurosyphilis.
resource requirements and, thus, may not be readily available in resource-limited
● The high specificity but
regions of the world.78 Data comparing the performance of the CSF VDRL with variable sensitivity of the
other nontreponemal tests that are often more accessible outside the CSF Venereal Disease
United States (eg, RPR, toluidine red unheated serum test [TRUST]) are limited. Research Laboratory (VDRL)
The CSF RPR and CSF TRUST may be more specific but less sensitive than the makes it a clinically
informative test when
already flawed sensitivity of the CSF VDRL.79,80 Point-of-care syphilis tests, reactive, whereas a
which require minimal training and no special equipment or refrigeration, may nonreactive test does not
overcome some of the challenges of neurosyphilis diagnosis in resource-limited exclude the diagnosis of
settings. One study found the sensitivity and specificity of a point-of-care test neurosyphilis.
from the CSF to diagnose neurosyphilis was comparable to the CSF VDRL.78
● CSF treponemal tests are
These point-of-care tests, most of which are treponemal tests, may have a role in less specific than the VDRL
neurosyphilis diagnosis in low- and middle-income countries where CSF VDRL is and do not distinguish
inaccessible, although further evaluation is needed. between previously treated
neurosyphilis and active
Compared with the CSF VDRL, CSF treponemal tests are more sensitive but
infection.
less specific for neurosyphilis (TABLE 9-1). If the CSF VDRL is nonreactive in a
patient for whom the clinical suspicion for neurosyphilis is high, obtaining a CSF ● If the CSF VDRL is
treponemal assay is a reasonable next step (FIGURE 9-3). A nonreactive CSF nonreactive in a patient for
treponemal test is highly reassuring against neurosyphilis, although it may not whom the clinical suspicion
for neurosyphilis is high,
always rule out symptomatic neurosyphilis if the pretest probability is high.55,56 obtaining a CSF treponemal
Similar to the CSF VDRL, the specificity of treponemal testing is reduced in CSF assay is a reasonable next
contaminated by blood.81 As with serum testing, a reactive CSF treponemal test step.
often remains reactive even after appropriate treatment, although seroreversion
to nonreactive may occur in a proportion of patients treated early in infection.
Thus, a reactive CSF treponemal test does not differentiate between previously
treated and untreated neurosyphilis.
One explanation of the lower specificity of treponemal assays for
neurosyphilis is passive diffusion of treponemal antibodies from blood into the
CSF. Using a higher cutoff in the CSF to establish a positive treponemal test,
which would presumably capture intrathecal production and not just passive
diffusion of antibodies, may circumvent this issue and improve specificity. A
2017 study found that using a CSF TPPA titer cutoff greater than 1:320 enhanced
specificity for neurosyphilis.82 In a validation data set of 380 participants, the
specificity of a CSF TPPA 1:640 or greater was more than 90% (97%, 93.8%, and
93.3%) for three different definitions used for neurosyphilis and did not differ by
HIV status. Ten CSF samples that were nonreactive by VDRL were reactive using
TPPA 1:640 or greater. These findings argue for the utility of a higher treponemal
titer cutoff value in the CSF to establish the diagnosis of neurosyphilis. The
enhanced specificity of a higher cutoff coupled with the superior sensitivity of
treponemal testing could result in a single test that outperforms the CSF VDRL,
at least for patients with a first-time diagnosis of neurosyphilis. At the least, a

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NEUROSYPHILIS

CSF TPPA could be obtained if the CSF VDRL is negative in a patient for
whom the clinical suspicion for neurosyphilis is high. Although additional
confirmatory studies are needed, the United Kingdom’s British Association
for Sexual Health and HIV national guidelines already include a CSF TPPA
titer greater than 1:320 as a supporting criterion for the diagnosis of
neurosyphilis.83
In summary, the diagnosis of neurosyphilis requires neurologists to interpret
serologic testing from both serum and CSF in the appropriate clinical and
epidemiologic context. This includes judicious consideration of the pretest
probability and prevalence of syphilis both before ordering testing and on return
of the results, along with appraisal of presenting neurologic signs and
symptoms and the associated CSF profile. A suggested diagnostic approach to
symptomatic neurosyphilis is outlined in FIGURE 9-3.

TREATMENT AND FOLLOW-UP

High-dose IV penicillin G administered for 10 to 14 days is the treatment of
choice for neurosyphilis. IM procaine penicillin G with oral probenecid 4 times a
day for 10 to 14 days is considered a potential alternative first-line regimen in the
CDC guidelines.12 Because no treatments are established as alternatives to
penicillin for the treatment of neurosyphilis, skin testing and desensitization
are recommended in patients with a penicillin allergy, followed by treatment
with a first-line regimen. IV ceftriaxone 2 grams daily may be an acceptable
alternative for the treatment of neurosyphilis based on limited data.12,84 The
CDC guidelines include ceftriaxone as a treatment option for patients with a
penicillin allergy, whereas the most recent European and UK guidelines
consider ceftriaxone to be an acceptable alternative regimen for any patient
with neurosyphilis.83,85 Other discrepancies between the CDC and UK
guidelines include the use of doxycycline and steroids. No stand-alone oral
antibiotic regimen is recommended by the CDC for neurosyphilis, whereas oral
doxycycline is included as an alternative regimen in the UK guidelines. In
addition, steroids are not routinely recommended in the approach to the
treatment of neurosyphilis in the United States, whereas they are part of the
UK guidelines.83
After appropriate treatment, patients with neurosyphilis should experience
improvement in symptoms and, at the least, clinical stabilization. In general,
patients with early neurosyphilis are more likely to respond to treatment, both in
terms of clinical recovery and resolution of CSF abnormalities. In contrast, in late
neurosyphilis, clinical manifestations due to long-standing parenchymal injury
may be irreversible. In a single-center retrospective study investigating the
clinical course of 29 patients with neurosyphilis without HIV who were seen in
follow-up between 6 months and more than 2 years after initial diagnosis, 42%
with early neurosyphilis recovered completely compared with none of the
patients with late neurosyphilis. One-third of patients with late neurosyphilis
experienced no improvement in their clinical status.36
Syphilis cure is defined as a fourfold decline from a serum nontreponemal titer
documented at the time of treatment. However, even with appropriate treatment,
nontreponemal titers may not serorevert to nonreactive; this clinical scenario,
known as a serofast state, may occur in more than one-third of patients treated for
syphilis.86 The CDC guidelines suggest that the expected serologic response of a
fourfold decline in titer should occur by 12 months after treatment for primary,

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secondary, or early latent syphilis, and by 24 months for late latent syphilis or KEY POINTS
syphilis of unknown duration.12 After appropriate therapy for neurosyphilis,
● High-dose IV penicillin G
repeat serum nontreponemal tests are typically performed at 3 months, 6 months, for 10 to 14 days is the
12 months, and 24 months. Although a fourfold decrease in the serum treatment of choice for
nontreponemal titer has been shown to be an accurate predictor of concomitant neurosyphilis. IV ceftriaxone
normalization of CSF pleocytosis and VDRL in patients with neurosyphilis (with 2 grams daily may be an
acceptable alternative
the exception of people with untreated HIV),87 the CDC guidelines recommend
therapy, especially for those
serial CSF examinations every 6 months until normalization of the pleocytosis and with a penicillin allergy.
reduction in the CSF VDRL by a factor of four (or seroreversion of a VDRL of 1:2
or less to nonreactive).12 A decline in the CSF white blood cell count is expected at ● Patients with early
6 months, with normalization in all CSF parameters by 2 years. One caveat to this neurosyphilis are more likely
to respond to treatment
is the CSF protein concentration, which can remain elevated after treatment and than those with late
does not necessarily signal treatment failure.16 neurosyphilis, both in terms
Treatment failure and retreatment should be considered in patients who are of clinical recovery and
noted to have a persistent CSF pleocytosis or failure of the serum RPR or CSF resolution of CSF
abnormalities.
VDRL to decline fourfold within 12 to 24 months of therapy. However, in clinical
practice, the serologic response to therapy, including time to cure,88 can vary
from patient to patient. Early syphilis and higher serum nontreponemal titers
have been associated with a greater likelihood of both serologic response and
seroreversion to nonreactive.88-90 The biological and clinical relevance of
serologic treatment failure (ie, failure to achieve a fourfold decline in serum
nontreponemal titers) is unclear, and retreatment does not necessarily lead to
higher rates of cure.90

CONCLUSION
Symptomatic neurosyphilis can occur at any stage of infection. Although serum
and CSF laboratory testing provides valuable information, neurologists should be
aware of the limitations of serologic testing in the diagnosis of neurosyphilis and
exercise clinical judgment to determine the likelihood of the diagnosis. To avoid
missing the diagnosis of this treatable infection, a high index of suspicion should
be maintained based on an understanding of the protean manifestations of
neurosyphilis. With appropriate and timely treatment with high-dose IV
penicillin, patients with early neurosyphilis typically have a complete clinical
recovery unless ischemic injury has occurred in the setting of meningovascular
disease, and in those with late neurosyphilis, further disease progression
may be prevented.

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