Opinion
EDITORIAL
Syphilis Screening in Neurology
Christina M. Marra, MD
The US Preventive Services Task Force recommendation state-
ment on syphilis screening in nonpregnant adults and
adolescents1 recommends screening asymptomatic patients
who are at increased risk for
syphilis, in particular men
Related articles at jama.com, who have sex with men as
jamadermatology.com, well as men and women liv-
jamapediatrics.com ing with human immunode-
ficiency virus, the groups in
whom the incidence of syphilis in the United States is high-
est. The statement is less directive regarding the best method
for and frequency of syphilis screening. The increased risk of
false-positive results using the reverse sequence screening
algorithm is noted, as is the potential benefit of screening ev-
ery 3 months compared with annually in those at high risk for
disease. While neurologists are unlikely to screen primary care
patients for syphilis, the recommendation statement raises
issues of relevance to us, which I frame as 3 questions.
First, why should the recommendation statement be of
interest to neurologists? The number of reported cases of pri-
mary and secondary syphilis in the United States has steadily
increased since 2000. Between 2013 and 2014, the rate of pri-
mary and secondary syphilis in the United States increased
15%.2 Asymptomatic and symptomatic neurosyphilis can
occur at any stage of syphilis. Clinical presentations most
commonly include symptomatic meningitis, cranial nerve ab-
normalities (including hearing loss), stroke, and cognitive im-
pairment. Imaging abnormalities may mimic those seen
in herpes simplex encephalitis3 or, in the case of cerebral gum-
mas, meningiomas or other brain tumors.4 The Centers for Dis-
ease Control and Prevention recently released an ocular syphi-
lis advisory, identifying more than 200 cases of ocular syphilis,
a complication of syphilis that can cause permanent blind-
ness, in 20 states during the last 2 years.5 Neurosyphilis is not
often reported in the United States, so the number of yearly
cases is not known. A recent population-based study of indi-
viduals with syphilis in SeattleKing County, Washington, how-
ever, documented confirmed neurosyphilis (based on cere-
brospinal fluid abnormalities) or ocular syphilis in 3.5%
(95% CI, 2.2%-5.4%).6
Second, when it comes to syphilis screening, are there is-
sues of particular relevance to neurologists? Traditionally, pa-
tients have been screened for syphilis first with a serum non-
treponemal test such as the rapid plasma reagin test or the
Venereal Disease Research Laboratory test. Reactive serum
nontreponemal test results are confirmed with a serum
treponemal test such as the fluorescent treponemal antibody
absorption test or the Treponema pallidum particle agglutina-
tion test. In recent years, some large laboratories have imple-
jamaneurology.com
Copyright 2016 American Medical Association. All rights reserved.
Downloaded From: http://archneur.jamanetwork.com/ by a University College London User on 06/07/2016
Figure. Example of a Reverse Sequence Algorithm for Syphilis Screening
Automated treponemal test
Reactive Nonreactive
Quantitative RPR test No syphilis
Reactive Nonreactive
Consistent with Different
past or current treponemal test
syphilis (different platform
and target antigens)
Reactive Nonreactive
Possible syphilis; Unlikely to be
requires historical syphilis, but could be
and clinical very early disease;
evaluation if patient is at high
risk, retest in 1 mo
Automated serum treponemal tests include enzyme-linked and
chemiluminescence immunoassays that measure IgG and IgM antibodies to
recombinant Treponema pallidum subsp pallidum proteins. Alternative serum
treponemal tests available in the United States include the fluorescent
treponemal antibody absorption test and the T pallidum particle agglutination
test, which measure IgG and IgM antibodies to antigens derived from whole
T pallidum subsp pallidum organisms. RPR indicates rapid plasma reagin.
mented reverse sequence testing, which starts with a serum
treponemal test, typically an automated enzyme-linked im-
munoassay (EIA) or a chemiluminescence immunoassay (CIA).
Serum treponemal test results typically become reactive be-
fore serum nontreponemal tests, but unlike nontreponemal
tests, treponemal test results generally remain reactive for life
in a patient who has ever had syphilis, even after successful
treatment. There are many problems with reverse sequence
testing. Although they have a low rate of false-negative re-
sults, the automated treponemal tests are frequently falsely
positive and cannot distinguish between treated and un-
treated syphilis. Thus, the rate of reactive results in low-
prevalence populations is higher than with rapid plasma re-
agin screening, as noted in the US Preventive Services Task
Force recommendation statement. In the setting of a reactive
EIA or CIA result but nonreactive nontreponemal test result,
a second treponemal test, ideally using a different testing plat-
form and different antigens, should be performed for confir-
mation (Figure). While these limitations and procedures might
(Reprinted) JAMA Neurology Published online June 7, 2016 E1
 Opinion Editorial

seem like a nightmare for the primary care provider who is try-
ing to identify incident syphilis, the ability of treponemal tests
to identify ever syphilis is helpful to the neurologist.
Patients cannot have neurosyphilis if they have never had
syphilis. Thus, reactivity of serum treponemal tests identi-
fies patients who are at risk for neurosyphilis; conversely, a non-
reactive treponemal test result effectively removes neuro-
syphilis from the differential diagnosis. Screening with the
serum fluorescent treponemal antibody absorption test or the
T pallidum particle agglutination test, both of which are sen-
sitive and specific for current or past syphilis,7 will avoid false-
positive results. If patients are screened with an EIA or CIA, a
reactive result must be confirmed (Figure).
Third, which patients with dementia should be screened
for syphilis? In the early 1900s, syphilis was a common cause
of dementia, and even those of us who were trained much later
were taught that testing for syphilis was an obligatory part of
a dementia workup. As noted earlier, patients in whom neu-
rosyphilis is included in the differential diagnosis should be
screened for syphilis using a treponemal test, ideally the se-
rum fluorescent treponemal antibody absorption test or
T pallidum particle agglutination test. Although it is rare, pa-
tients with late neurosyphilis (dementia and tabes dorsalis) can
have nonreactive serum nontreponemal test results8; screen-
ing first with nontreponemal tests will miss these individu-
als. That said, routine screening for syphilis in patients with
dementia is currently not recommended9 and should be re-
served for those who, based on history or epidemiological
factors, are at greatest risk for syphilis. The diagnosis of symp-
tomatic neurosyphilis is based on clinical findings and cere-
brospinal fluid examination for abnormalities that support the
diagnosis, including pleocytosis, elevated protein concentra-
tion, and reactive cerebrospinal fluidVenereal Disease
Research Laboratory test results. One approach is to ask, Is
my clinical suspicion for syphilitic dementia sufficiently high
that I will perform a lumbar puncture if the treponemal serol-
ogy is reactive? If the answer is no, as it should likely be in
elderly individuals or those with a prolonged dementia course,
screening should not be undertaken.
The US Preventive Services Task Force recommendation
on screening for syphilis is relevant to us as neurologists for
several reasons. The number of individuals diagnosed as
having syphilis in the United States is increasing dramati-
cally. Neurosyphilis and ocular syphilis can occur at any stage
of disease, cause significant morbidity, and are seen in a siz-
able minority of patients. Large laboratories have switched
from the traditional screening procedure to a reverse se-
quence algorithm that, while problematic for the primary care
provider, can be effective for the neurologist, provided that a
reactive EIA or CIA result is confirmed. Nonetheless, screen-
ing for syphilis should not be routine in patients with demen-
tia but should be reserved for those in whom historical, epi-
demiological, and clinical data indicate a high degree of
suspicion for neurosyphilis.

ARTICLE INFORMATION
Author Affiliations: Department of Neurology,
University of Washington, Seattle; Division of
Infectious Diseases, Department of Medicine,
University of Washington, Seattle.
Corresponding Author: Christina M. Marra, MD,
Departments of Neurology and Medicine,
University of Washington, Harborview Medical
Center, 325 Ninth Ave, Box 359775, Seattle, WA
98104 (cmarra@uw.edu).
Published Online: June 7, 2016.
doi:10.1001/jamaneurol.2016.1955.
Conflict of Interest Disclosures: None reported.
Additional Contributions: I thank Sheila A.
Lukehart, PhD, University of Washington, Seattle,
for insightful comments on a draft of the
manuscript; she received no compensation.
REFERENCES
1. US Preventive Services Task Force (USPSTF).
Screening for syphilis infection in nonpregnant
adults and adolescents: US Preventive Services
Task Force recommendation statement [published
online June 7, 2016]. JAMA. doi:10.1001/jama
.2016.5824.
2. Centers for Disease Control and Prevention.
Sexually Transmitted Disease Surveillance 2014.
Atlanta, Georgia: US Dept of Health & Human
Services; 2015.
3. Saunderson RB, Chan RC. Mesiotemporal
changes on magnetic resonance imaging in
neurosyphilis. Intern Med J. 2012;42(9):1057-1063.
4. Fargen KM, Alvernia JE, Lin CS, Melgar M.
Cerebral syphilitic gummata: a case presentation
and analysis of 156 reported cases. Neurosurgery.
2009;64(3):568-575, 575-576.
5. Centers for Disease Control and Prevention.
Clinical advisory: ocular syphilis in the United
States. http://www.cdc.gov/std/syphilis
/clinicaladvisoryos2015.htm. Accessed April 25,
2016.
6. Dombrowski JC, Pedersen R, Marra CM, Kerani
RP, Golden MR. Prevalence estimates of
complicated syphilis. Sex Transm Dis. 2015;42(12):
702-704.
7. Larsen SA, Steiner BM, Rudolph AH. Laboratory
diagnosis and interpretation of tests for syphilis.
Clin Microbiol Rev. 1995;8(1):1-21.
8. Merritt HH, Adams RD, Solomon HC.
Neurosyphilis. New York, NY: Oxford University Press;
1946.
9. Knopman DS, DeKosky ST, Cummings JL, et al.
Practice parameter: diagnosis of dementia (an
evidence-based review): report of the Quality
Standards Subcommittee of the American Academy
of Neurology. Neurology. 2001;56(9):1143-1153.

E2 JAMA Neurology Published online June 7, 2016 (Reprinted) jamaneurology.com

Copyright 2016 American Medical Association. All rights reserved.

Downloaded From: http://archneur.jamanetwork.com/ by a University College London User on 06/07/2016