Review Article

Neurosyphilis
Address correspondence to
Dr Christina M. Marra,
University of Washington,
Harborview Medical Center,
325 9th Avenue, Department Christina M. Marra, MD, FAAN
of Neurology, Box 359775,
Seattle, WA 98104,
cmarra@uw.edu.
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.
Unlabeled Use of
has steadily increased since 2000. The highest rates are among men who have sex
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
unlabeled/investigational use of
can develop at any time in the course of syphilis. Two neuroimaging patterns should
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):17141728.

INTRODUCTION lems in the first half of the 1900s. With

Neurosyphilis can develop at any time
in the course of syphilis. Because no
single highly sensitive and specific diag-
nostic test exists, the diagnosis relies
on consideration of clinical findings
and CSF abnormalities as well as clinical
judgment. While diagnosis is relatively
straightforward when patients present
with symptomatic meningitis or stroke
in the setting of known untreated syph-
ilis or strongly reactive syphilis serologic
tests, deciding whether patients with non-
specific cognitive complaints, reactive
treponemal but nonreactive nontrep-
onemal tests, and nonspecific CSF ab-
normalities have neurosyphilis can be a
challenge. This article reviews the clinical
manifestations, diagnosis, and treatment
of neurosyphilis, with a focus on issues
of particular relevance to neurologists.
EPIDEMIOLOGY
In the United States, syphilis and neuro-
syphilis were major public health prob-
1714 www.ContinuumJournal.com
the advent of penicillin, the incidence
of syphilis and the prevalence of neu-
rosyphilis declined.1 However, at the
beginning of the acquired immunodefi-
ciency syndrome (AIDS) epidemic, cases
of neurosyphilis were noted in patients
infected with human immunodeficiency
virus (HIV) who had been adequately
treated for early syphilis,2 drawing at-
tention to the possibility of increased
risk of neurosyphilis in this population,
but also reminding clinicians of a pre-
viously underrecognized disease.
Syphilis is a reportable disease in the
United States. The number of cases of
primary and secondary syphilis in the
United States has steadily increased
since 2000; in 2013, the number of cases
was the most recorded since 1995. Rates
were highest among men, and 75% of
patients were men who have sex with
men; approximately half of these in-
dividuals were HIV infected.3 World-
wide, the incidence of syphilis is high.
December 2015

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.


The World Health Organization (WHO)
estimates that there were 10.6 million
incident cases of syphilis in 2008, of
which 60% were from Africa and South-
east Asia.4
In contrast to syphilis, neurosyphilis
is not a reportable disease in the United
States or elsewhere. A retrospective study
conducted in Los Angeles, California, be-
tween 2001 and 2004 showed that the
rate of neurosyphilis in patients with
early syphilis was 2.1% in individuals
who were HIV infected and 0.6% in
those not infected with HIV.5 A retro-
spective study from the Netherlands
found that between 1999 and 2010, the
mean annual incidence of neurosyphilis
was 0.7 per 100,000 in men and 0.2 per
100,000 in women, with median ages of
47 and 54 years, respectively.6 The re-
sults of both of these studies should be
interpreted carefully given the retrospec-
tive design and limited information re-
garding diagnostic criteria. Nonetheless,
they point out features that can help
identify those at greatest risk for neu-
rosyphilis: male gender, younger age,
men who have sex with men, and those
who are infected with HIV.
ETIOLOGY
Syphilis is caused by the bacterium Trep-
onema pallidum subspecies pallidum,
a pathogenic treponeme that cannot be
cultured in vitro. In the prepenicillin era,
CSF was commonly analyzed in all pa-
tients with syphilis, demonstrating that
T. pallidum invaded the CSF early in the
course of disease. This finding has been
confirmed in the modern era: 25% to 40%
of untreated neurologically asymptomatic
patients with primary, secondary, or early
latent syphilis have CSF pleocytosis and
20% to 30% have a reactive CSFYVenereal
Disease Research Laboratory (CSF-VDRL)
test.7,8 In our ongoing study of CSF abnor-
malities in patients with syphilis, T. pallidum
was identified by reverse transcriptase
polymerase chain reaction (RT-PCR) in CSF
Continuum (Minneap Minn) 2015;21(6):17141728
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KEY POINTS
from 21% of 134 neurologically asymp- h In the United States, the
tomatic patients with untreated early incidence of syphilis has
syphilis (unpublished data). steadily increased since
Studies from the prepenicillin era 2000. In 2013, rates of
also demonstrated that the proportion syphilis were highest
of patients with neuroinvasion (based among men, in particular
on CSF analysis) exceeded the number men who have sex with
that developed symptomatic neurosyph- men. Approximately half
ilis, leading to the hypothesis that of these individuals were
T. pallidum is cleared from the CSF human immunodeficiency
virusYinfected.
and, by analogy, the central nervous
system in some individuals. Those in h In the developed world,
whom clearance failed were deemed to male gender, younger
have asymptomatic neurosyphilis and age, men who have sex
with men, and human
were at risk for progression to symptom-
immunodeficiency
atic neurosyphilis, with those with the
virus infection are
most abnormal CSF at greatest risk. Then features associated
and now, patients with asymptomatic neu- with neurosyphilis.
rosyphilis are treated with a neurosyphilis
h Neurosyphilis can occur
regimen to prevent this progression.
at any time in the
Today, the value of identifying CSF course of infection and
abnormalities in neurologically asymp- should not be considered
tomatic patients with syphilis remains to be solely a tertiary
debated.9 The likelihood of CSF abnor- manifestation of syphilis.
malities decreases after treatment for
uncomplicated syphilis,10 and currently,
no means exist of identifying those indi-
viduals who are destined to clear CSF
abnormalities versus those who will
not. Persons who are HIV infected may
be the exception, with well-documented
instances of development of early neu-
rosyphilis after recommended antibiotic
treatment of uncomplicated syphilis,2,11
a phenomenon that is not described in
individuals not infected with HIV. Other
factors increase risk of CSF abnormali-
ties in patients with syphilis, including
bacterial strain type12 and host genetic
polymorphisms that influence the im-
mune response,8 but their clinical rele-
vance remains to be determined.
CLINICAL MANIFESTATIONS
Neurosyphilis can occur at any time in
the course of infection, thus, it should
not be considered to be solely a ter-
tiary manifestation of syphilis. The early
forms of neurosyphilis occur within
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 Neurosyphilis

KEY POINTS
h The early forms of months to the first few years after pri- to restrict my comments to studies for
neurosyphilis occur mary infection and affect the meninges which individual patient diagnoses meet
within months to the and blood vessels, while the late forms the criteria described below.
first few years after occur years to decades after primary
infection and affect the infection and also affect the brain and Early Neurosyphilis:
meninges and blood spinal cord parenchyma (Figure 10-1). Asymptomatic Syphilitic
vessels, while the late Because syphilis and neurosyphilis Meningitis, Symptomatic
forms occur years to were so common in the first half of the Syphilitic Meningitis, and
decades after infection 1900s, much of what is known about Meningovascular Neurosyphilis
and also affect the clinical manifestations of neurosyph- Patients with asymptomatic neuro-
the 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.
findings as well as clinical judgment. 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.
pleocytosis, elevated rosyphilis does not make it so. In re- In a large prepenicillin series,13 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.

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convulsions, confusion, and focal and
cranial nerve abnormalities, particularly
involving cranial nerves II, VII, and VIII.
Syphilitic meningitis most commonly
occurred within a year of infection, and
7.5% of patients had concomitant sec-
ondary syphilis.
Localized syphilitic meningitis can re-
sult in focal mass lesions called gummas,
which most commonly arise from the pia
mater over the convexities14 and may be
mistaken for tumors. Syphilitic menin-
gitis may uncommonly affect the spinal
cord, causing meningomyelitis. Syphilitic
meningitis may be accompanied by
ocular or otologic abnormalities; vision
or hearing loss due to syphilis can also
be seen in isolation. A full discussion of
these forms of syphilis is beyond the
scope of this article; the reader is re-
ferred to two recent review articles.15,16
Syphilitic meningitis may cause arter-
itis and stroke affecting vessels of the
brain or, less commonly, the spinal cord.
Accordingly, this form of neurosyphilis
is termed meningovascular. Merritt and
colleagues17 described 42 patients with
brain meningovascular syphilis. Most
were 30 to 50 years of age and devel-
oped meningovascular syphilis within
months to years after infection, with
an average of 7 years.17 Stroke in the
distribution of the middle cerebral ar-
tery was the most common clinical find-
ing, with hemiparesis, hemiplegia, or
aphasia. Prodromal symptoms, such as
headache, dizziness, and personality
changes for days or weeks before the
onset of stroke were common. Modern
studies18 conform to the clinical descrip-
tions Merritt and colleagues provided
and also show the utility of advanced
neuroimaging techniques in identifying
syphilitic vasculitis (Case 10-1).21
Late Neurosyphilis: Dementia
and Tabes Dorsalis
Syphilitic dementia is also called general
paresis, general paralysis of the insane,
Continuum (Minneap Minn) 2015;21(6):17141728
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KEY POINTS
or dementia paralytica. In the prepen- h Patients with symptomatic
icillin era, it was most commonly seen syphilitic meningitis
in individuals 35 to 50 years of age and present with typical
occurred from 5 to 25 years after pri- findings of aseptic
mary infection.17 Merritt stated, The meningitis, including
clinical manifestations of paretic neu- headache, stiff neck,
rosyphilis are protean. Exact replicas of nausea, and vomiting.
every type of mental disorderI are en- There may be
countered. In other words, the clinical concomitant cranial
picture may duplicate any psychiatric nerve involvement,
particularly of cranial
syndrome or disease.17 Early in the
nerves II, VII, and VIII.
course, patients are forgetful and have
personality changes. With time, they may h Focal areas of syphilitic
develop psychiatric symptoms, such as meningitis may result in
a gumma, a mass lesion
mania, depression, or psychosis. How-
that usually arises from
ever, most patients simply experience
the pia mater and can
worsening of deficits in memory and mimic a tumor.
judgment, progressing to frank demen-
tia. In its latest stages, patients become h Syphilitic meningitis may
cause arteritis and
immobile and incontinent and may have
stroke affecting vessels
seizures. The most frequent neurologic of the brain or, less
examination findings are pupillary ab- commonly, the spinal
normalities; facial and limb hypotonia; cord. This form of
intention tremors of the face, tongue, neurosyphilis is termed
and hands; and reflex abnormalities. Early meningovascular.
in the course of disease, other than h Early in the course of
cognition, the neurologic examination syphilitic dementia,
can be normal. patients are forgetful
Cases of syphilitic dementia con- and have personality
tinue to be reported in the modern era, changes. With time,
characterized by rapidly progressive they may develop
cognitive decline with or without psy- psychiatric symptoms,
chiatric features. Zheng and colleagues22 such as mania,
reported a retrospective series of depression, or psychosis.
However, most patients
116 patients with syphilitic dementia.
simply experience
All had reactive serum treponemal and
worsening of deficits in
nontreponemal tests, 56 had CSF pleo- memory and judgment
cytosis (the cutoff was not defined), and progressing to
100 had reactive CSF nontreponemal frank dementia.
tests. Ages ranged from 30 to 76 years.
Dementia, personality change, abnor-
mal behavior, and emotional prob-
lems were the most common findings.
Thirty-nine percent of patients had de-
lusions and 16% had seizures. Of note,
neurosyphilis was not suspected ini-
tially in 36% of patients, with a delay in
diagnosis between 1 and 24 months
(Case 10-2).22
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 Neurosyphilis

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

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 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 partners 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-
sponse to painful stimuli), optic atrophy,
lancinating pains, sensory changes, pro-
gressive ataxia, and bowel and bladder
dysfunction.17 Early sensory changes
included paresthesia or hyperesthesia in
radicular distributions. Later, pain, vi-
bration, and tactile sensation became
impaired, and reflexes were lost. Sen-
sory ataxia, usually involving the lower
more than the upper extremities, was a
feature in 42%.17 Bladder dysfunction
occurred early, with urinary retention
and overflow incontinence. As noted
above, tabes is now an uncommon form
of neurosyphilis, but cases continue to
be described.18,23
DIAGNOSIS
The diagnosis of neurosyphilis is based
on clinical findings and on the results
of serologic tests and CSF examination.
Neuroimaging may also be useful.
Serologic Tests Used
on Blood
Two types of serologic tests exist for
syphilis. Nontreponemal tests include
the rapid plasma reagin (RPR) test, the
VDRL test, and the toluidine red un-
heated serum test (TRUST). These as-
says measure IgG and IgM antibodies
to a cardiolipin-lecithin-cholesterol an-
tigen. Results are generally expressed
as a titer, with higher titers reflecting
greater disease activity. Success of ther-
apy is, in part, determined by decline in
titer, and a fourfold drop or reversion to
nonreactive is evidence of treatment suc-
cess. However, even without treatment,
nontreponemal titers will decline over
time, and the proportion of patients with

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 Neurosyphilis

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

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 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- even after treatment.
RPR titers, and rarely otherwise (Case 10-4).
cator of previous infection. Patients Thus, a reactive CSF-VDRL establishes h CSF white blood cell
with reactive treponemal tests but concentration in
the diagnosis of neurosyphilis, but a non-
nonreactive nontreponemal tests have neurosyphilis is generally
reactive test does not exclude it. greater than 10/2L
either very early syphilis (generally the Because the CSF-VDRL test is not with a lymphocytic
treponemal tests become reactive be- available worldwide, the use of alter- predominance.
fore the nontreponemal tests), treated native nontreponemal tests on CSF has
syphilis, or late untreated syphilis. h The CSFYVenereal
been investigated. We showed that the Disease Research
CSF-RPR was significantly more spe- Laboratory (CSF-VDRL)
Cerebrospinal Fluid 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
Merritts17 series is shown in Table 10-126. but that the CSF-RPR was negative in for neurosyphilis
CSF white blood cell (WBC) concentra- 36% of CSF-VDRLYreactive samples.27 diagnosis. However, the
tion in neurosyphilis is generally greater A large study from China found that CSF-VDRL may be
than 10/2L with a lymphocytic predom- 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 CSF-VDRL
reactive samples were CSF-TRUST non-
establishes the diagnosis
occurring form of neurosyphilis, may some- reactive.28 Thus, the problem of low
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.
for diagnosis of neurosyphilis. However, h In contrast to the
In contrast to the CSF-VDRL, CSF tre-
CSFYVenereal Disease
depending upon the diagnostic criteria ponemal tests are generally sensitive,
Research Laboratory
chosen, the CSF-VDRL may be reactive in but not specific, for the diagnosis of test, CSF treponemal
tests are generally
sensitive, but not
TABLE 10-1 Cerebrospinal Fluid Profiles in the Different Forms of
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):17141728 www.ContinuumJournal.com 1721

Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Neurosyphilis

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 patients 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.


with a high degree of certainty, but a
negative result is less able to exclude
symptomatic neurosyphilis. Specificity
may be improved by excluding sam-
ples with blood contamination.30 Two
studies have shown that using a titer
cutoff of greater than 1:320 improves
the diagnostic specificity of the CSFY
Treponema pallidum hemagglutina-
tion (CSF-TPHA) test, a treponemal test
that is not available in the United States,
for clinical and laboratory diagnoses
of neurosyphilis.31,32
In the United States, syphilis is most
common in men who have sex with
men, many of whom are HIV infected.
In addition, HIV infection may in-
crease the risk of neurosyphilis. No
data suggest that CSF nontreponemal
or treponemal tests perform differ-
ently in individuals who are HIV
infected compared to those who are
not HIV infected. However, mild CSF
pleocytosis is common in individuals
who are HIV infected but do not have
syphilis, particularly in those who are
relatively immunocompetent. For ex-
ample, Marshall and colleagues 33
showed that 16% of CSF samples from
649 individuals who were HIV infected
had greater than 10 WBC/2L, with pro-
gressive decline in CSF WBC concen-
tration with more advanced stages of
disease. We showed that CSF pleocy-
tosis 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-
ings have been described in neuro-
syphilis, two patterns should alert the
neurologist to a diagnosis of neuro-
syphilis. First, cerebral gummas are cir-
cumscribed pial-based mass lesions that
are low intensity on T1-weighted MRI
Continuum (Minneap Minn) 2015;21(6):17141728
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
KEY POINT
sequences and isointense or high in- h Two neuroimaging
tensity on T2-weighted MRI sequences; patterns should alert
enhance homogenously, sometimes the neurologist to a
with a nodular component and often diagnosis of neurosyphilis:
with a dural tail; and have associated (1) cerebral gummas,
edema (Figure 10-3).14 Second, MRI may pial-based lesions that
mimic herpes encephalitis, with high can mimic meningiomas;
signal intensity on T2-weighted or and (2) high signal
diffusion-weighted images in one or both intensity on T2-weighted
or diffusion-weighted
medial temporal lobes (Figure 10-4).35
MRI in one or both
medial temporal lobes
Synthesizing the Diagnosis
that can mimic
Establishing a diagnosis of neurosyphilis, herpes encephalitis.
especially the diagnosis of syphilitic dem-
entia, can be a frustrating experience
for neurologists. As noted above, the
diagnosis is based on clinical findings,
CSF abnormalities, and clinical judg-
ment. The greatest experience comes
from the prepenicillin era, to which many
of us turn for guidance. However, the
accuracy of some of these data has been
disputed, mostly based on results of se-
rum and CSF serologic tests. For exam-
ple, Simon suggested that erroneous
Axial fluid-attenuated
FIGURE 10-4
inversion recovery (FLAIR)
MRI showing increased
in the medial left temporal lobe in a
patient with syphilitic dementia.
Reprinted with permission from Lee JW, et al,
35
Neurology. www.neurology.org/content/65/11/1838.
short. B 2005 American Academy of Neurology.
www.ContinuumJournal.com 1723
 Neurosyphilis

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. positive serum or CSF serologic tests,
Similarly, Patterson and colleagues1
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
Merritts 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 95/2L or 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.
HIV RNA and on antiretroviral therapy: CSF WBCs 95/2L
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 neu-
rosyphilis 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 reac-
tivity, 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.
a
may cause CSF pleocytosis, particularly
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

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plasma HIV RNA or in patients who are
not taking antiretroviral medications, these
factors influence CSF diagnostic crite-
ria for asymptomatic neurosyphilis. CSF
protein concentration is also increased
in patients who are HIV infected, but
the association with clinical or labora-
tory features of HIV is less clearly defined.
In the setting of clear symptoms and
signs of neurosyphilis, the influence of
HIV on CSF abnormalities is not as
rigorously considered.
The exceptions related to intracra-
nial gumma and tabes dorsalis should
be noted here. While serum treponemal
tests will be reactive in both these forms
of neurosyphilis, the CSF profile may
uncommonly be normal. In the case of
gumma, neuroimaging is integral to es-
tablishing the diagnosis. In the case of
tabes, diagnosis may need to be based
solely on highly characteristic clinical
findings, keeping in mind that normal
CSF is the exception, not the rule.
TREATMENT
The Centers for Disease Control and
Prevention (CDC) recommends high-
dose IV penicillin G as the first-line ther-
apy for neurosyphilis; IM procaine
KEY POINTS
penicillin G with oral probenecid is an h Penicillin G is the
alternative (Table 10-3).9 For patients recommended treatment
who are allergic to penicillin and can- for neurosyphilis.
not undergo desensitization or who Ceftriaxone may be an
cannot take penicillin for other reasons, acceptable alternative.
ceftriaxone, 2 g/d IV, may be an accept- h The success of
able alternative to penicillin based on neurosyphilis treatment
small studies.37,38 However, ceftriaxone is determined by
is not recommended by the CDC for resolution or stabilization
neurosyphilis treatment. The 2008 of clinical abnormalities
European39 and 2008 United Kingdom40 and by normalization of
syphilis guidelines recommend doxycy- CSF abnormalities.
cline 200 mg orally 2 times a day for Clinical abnormalities
are more likely to resolve
28 days as an alternative neurosyphilis
in early than in
treatment regimen in selected instances;
late neurosyphilis.
this regimen is not recommended in
the 2014 European guidelines41 and is
not recommended by the CDC.
The success of neurosyphilis treat-
ment is determined by resolution or
stabilization of clinical abnormalities and
by normalization of CSF abnormalities.
Clinical abnormalities are more likely to
resolve in early than in late neurosyph-
ilis. Patients with syphilitic meningitis
and intracranial gummas completely
recover. In contrast, in patients with
meningovascular syphilis, meningeal
symptoms and signs will resolve, but
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.

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Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

 Neurosyphilis
and signs. Similarly, treatment of pa-
tients with dementia or tabes may arrest
disease progression but is unlikely to
reverse dementia or sensory ataxia.18
The CDC guidelines state that CSF
WBC count should decline at 6 months
and all CSF abnormalities should resolve
by 2 years after treatment.9 My approach
differs, with the first follow-up lumbar
puncture performed 3 months after
therapy because the median time for
normalization of CSF WBC, CSF-VDRL,
and serum RPR was approximately
4 months in our prospective study.42 Ce-
rebrospinal protein concentration is slow
to normalize and may remain elevated
even after normalization of other CSF
and clinical abnormalities,42,43 thus, the
decision to re-treat should not be based
solely on failure of CSF protein con-
centration to normalize. If CSF abnor-
malities persist at 3 months (excluding
elevated protein concentration), CSF
should be reexamined at 6 months
after therapy and at 12 months if ple-
ocytosis and CSF-VDRL reactivity persist
at 6 months. Failure of the CSF WBC
count to decrease 6 months after ther-
apy or failure of CSF-VDRL to decline
fourfold (or to nonreactive if the initial
titer is less than 1:2) 1 year after therapy
are indications for retreatment. Serum
nontreponemal tests should be ob-
tained at 3, 6, and 12 months after ther-
apy. Failure of the serum RPR or VDRL
to decline fourfold (or to nonreactive if
the initial titer is less than 1:2) at 1 year
after therapy is an additional indica-
tion for retreatment. Keep in mind that
RPR and VDRL titers are usually not
equivalent in the same serum sample
(the RPR titer is usually 2 to 4 times
higher than the VDRL titer). Thus, titers
should be compared within RPRs or
within VDRLs, not RPR to VDRL or vice
versa. Normalization of serum RPR after
neurosyphilis therapy (as defined above)
predicts normalization of CSF WBCs and
1726 www.ContinuumJournal.com
Copyright American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
CSF-VDRL reactivity with a high degree
of certainty, except in patients infected
with HIV who are not taking antiretro-
viral agents.
CONCLUSION
Neurosyphilis can develop at any time
in the course of syphilis. Diagnosis re-
lies on consideration of clinical find-
ings and CSF abnormalities as well as
clinical judgment, which is based on a
sound understanding of the spectrum
of disease and the strengths and lim-
itations of diagnostic tests. Penicillin G
remains the first-line treatment for neu-
rosyphilis, but ceftriaxone may be an ac-
ceptable alternative. Success of treatment
is judged by resolution or stabilization
of clinical abnormalities and by normal-
ization of CSF abnormalities. Clinical
abnormalities are more likely to resolve
in early than in late neurosyphilis.
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