The n e w e ng l a n d j o u r na l of m e dic i n e

Review Article

Dan L. Longo, M.D., Editor

Neurosyphilis
Allan H. Ropper, M.D.​​

N
eurosyphilis, the clinical result of infection of the nervous
system by Treponema pallidum, preoccupied the fields of neurology and psy-
chiatry for two centuries. The disease was ubiquitous, and practitioners
recognized it from the slightest clinical manifestations. There has been a resurgence
of syphilis in low- and middle-income countries and in certain populations in devel-
oped countries, but the diagnosis of neurosyphilis tends to be overlooked because
of its rarity.1 Ocular and auditory forms of syphilis are aligned with neurosyphilis,
but they are not discussed here.

This article was updated on October 3,
2019, at NEJM.org.
N Engl J Med 2019;381:1358-63.
DOI: 10.1056/NEJMra1906228
Copyright © 2019 Massachusetts Medical Society.
Epidemiol o gy
Cases of primary and secondary syphilis have increased in the United States every
year since 2000, with 9.5 cases per 100,000 persons in 2017.2 In China, there were
22 cases per 100,000 persons in 2008.3 Neurosyphilis is uncommon now, as com-
pared with the era before the introduction of penicillin, but 3.5% of patients with
clinical or ophthalmologic features of syphilis in a contemporary series had neuro-
syphilis on the basis of cerebrospinal fluid (CSF) findings.4 Rates of neurosyphilis
in various series have been estimated at 0.47 to 2.1 cases per 100,000 population.5,6
In the United States, in 10 states with regular case reporting, the prevalence of
neurosyphilis was 1.8% among persons with early syphilis.7 In some series, half
of patients with early syphilis have been coinfected with the human immunodefi-
ciency virus (HIV),3 and neurosyphilis is estimated to occur in twice as many per-
sons with coinfection as persons without HIV infection.7

Cl inic a l Fe at ur e s of Neuros y phil is

The syndromes produced by neurosyphilis and their temporal connection to primary,
secondary, and tertiary stages of syphilis are abstractions8 (Fig. 1). The treponeme
invades the nervous system within days after primary infection, and subsequent
neurosyphilis can be categorized as asymptomatic or symptomatic and as early (1 to
2 years after primary infection) or late. The late form includes general paresis and
tabes dorsalis; these conditions are detailed below.
Most information about neurosyphilis comes from eras before the introduction
of penicillin, but clinical descriptions from 1970 to 1984 are not substantially dif-
ferent from those in the period from 1930 to 1940.11,12 However, patients with HIV
coinfection may have earlier development of neurologic features than people with-
out HIV infection, as well as incomplete responses to treatment.13-18
Early neurosyphilis is usually characterized by asymptomatic meningitis, evi-
denced only by a cellular reaction in the CSF, but it can be symptomatic with head-
ache, meningismus, cranial-nerve palsies, and blindness or deafness (Table 1). In

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 Neurosyphilis

100 Serum FTA-ABS

90
CSF FTA-ABS
Percentage of Patients with Positive Tests

80

70

60
Serum VDRL or RPR
50

40 CSF VDRL

30

20

10

Tabes dorsalis

General paresis

Meningovascular syphilis
Asymptomatic meningeal reaction

0 2 4 6 8 10 12 2 10 20
Wk Wk Wk Wk Wk Wk Yr Yr Yr
Time since Primary Infection

Figure 1. Serologic and Clinical Features of Early and Late Established Neurosyphilis.
On the curve for the cerebrospinal fluid (CSF) fluorescent treponemal-antibody absorption (FTA-ABS) test, the
dashed line indicates uncertain test results in late neurosyphilis. The percentage of patients whose serum non-
treponemal test results stay reactive is lower if the patients have been treated for syphilis (and would not be likely
to acquire neurosyphilis) than if the patients are untreated. In the lower panel, the thickness of the colored areas
represents the prevalence of each form of neurosyphilis. RPR denotes rapid plasma reagin, and VDRL Venereal
Disease Research Laboratory. Adapted from Peeling and Ye9 and from Hook and Marra.10

a study of aseptic meningitis involving 60 patients festations are general paresis (also called “gen-
in South Africa, 3.3% of cases were due to syphi- eral paresis of the insane”) and tabes dorsalis.
lis.19 Meningovascular syphilis is a form of men- Both have been considered to be the result of a
ingitis involving vasculitis of small and medium- chronic meningeal reaction to spirochetal invasion
size arteries in the central nervous system; it and destruction of adjacent neural tissue, some-
causes strokes and many types of myelopathy. times coupled with cerebral infarction due to me-
Meningovascular syphilis is usually interposed ningovascular disease (Table 1).
temporally between early and later forms of neu- General paresis altered the concept of mad-
rosyphilis,8 typically occurring 1 to 10 years af- ness with the discovery that it was a structural
ter the primary infection. brain disorder that simulated many forms of men-
Late symptomatic neurosyphilis, which devel- tal disease. It is a frontotemporal dementia that
ops decades after the primary infection, has been was associated with colorful manifestations of
reported in 10 to 20% of cases, according to data grandiose delusions such as being emperor, own-
obtained before the introduction of penicillin7,20; ing all of Africa,21 or being so wealthy that dia-
the rates may be lower now. The archetypal mani- monds flowed out with one’s urine.22 Unusual

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 The n e w e ng l a n d j o u r na l of m e dic i n e

Table 1. Stages of Neurosyphilis According to Clinical Features and Associated Laboratory Test Results.

Stage Clinical Features Laboratory Testing*

Early
Asymptomatic early Asymptomatic, with pleocytosis developing
neurosyphilis weeks after infection
Syphilitic meningitis Headache, meningismus, photophobia, cranial-
nerve palsies (including optic or auditory
neuropathies [blindness, vertigo, deafness]),
confusion, lethargy, seizures; symptoms oc-
cur weeks or months after infection‡
Early or late
Meningovascular syphilis Stroke, cranial-nerve palsies, meningismus, me-
ningomyelitis with progressive myelopathy,
including sphincter dysfunction
Late
General paresis Progressive dementia, psychiatric syndromes,
personality change, manic delusions, tremor,
dysarthria (characterized by halting and syl-
labic repetition), Argyll Robertson pupils in
fewer than half of patients
Tabes dorsalis Ataxic gait, prominent Romberg’s sign, lightning
pains in legs and trunk, greatly impaired deep
and proprioceptive sensation, Charcot joints,
Argyll Robertson pupils in most patients,
paraparesis with leg areflexia, sphincter dys-
function§
Reactive serum and CSF VDRL test
results†
Reactive serum and CSF VDRL test
results, reactive CSF FTA-ABS
test result; CSF white-cell count,
10–400/mm3†
Reactive serum and CSF VDRL test
results; CSF white-cell count,
5–100/mm3†
Reactive serum VDRL test result in
at least half of cases, reactive
CSF VDRL test result, usually re-
active CSF FTA-ABS test result;
mild, chronic pleocytosis
Possibly nonreactive serum VDRL
test result, reactive CSF VDRL
test result, usually reactive CSF
FTA-ABS test result; mild, chron-
ic pleocytosis

* The fluorescent treponemal-antibody absorption (FTA-ABS) test is not specific. CSF denotes cerebrospinal fluid, and
VDRL Venereal Disease Research Laboratory.
† The serum VDRL test may not become reactive in the early, primary stage of syphilis.
‡ Vision may also be impaired from syphilitic chorioretinitis or retinitis (ocular syphilis).
§ Loss of deep sensation indicates the absence of a response to pressure on visceral structures such as muscles, tendons,
testicles (Pitres’s sign), or eyeballs. Charcot joints are also known as neuropathic arthropathy.

halting and repetitive speech patterns were, and
still are, a feature. Untreated, the disorder pro-
gressed to a state of mental and physical dissolu-
tion, often with seizures. Currently, general pare-
sis is characterized by psychosis, depression,
personality change, or nondescript progressive
dementia, sometimes with — as in the past —
flamboyant delusions. Among 149 HIV-negative
Chinese patients with neurosyphilis, 46 of 58 with
general paresis had psychiatric presentations.23
Neurosyphilis accounted for 3.6% of cases of
dementia in a Moroccan series and was more fre-
quent in that population than Creutzfeldt–Jakob
disease, herpes encephalitis, and HIV-related de-
mentia combined.24
Tabes is characterized by gait ataxia with
Romberg’s sign (falling or stepping to one side
when standing with feet together and eyes closed)
and in most cases by Argyll Robertson pupils (con-
striction of the pupils when the eyes are focused
on a nearby object but not when the pupil is illu-
minated). The gait was identifiable by its “stamp
and stick” sound, with the patient landing force-
fully and flat-footed on a wide base in order to
detect the position of the feet and then striking
a cane on the floor for stability. The sound and
cadence of the tabetic gait are still characteristic
but are now more commonly caused by other
forms of sensory ataxia such as diabetic neuropa-
thy or spinal multiple sclerosis. Charcot joints
(neuropathic arthropathy) were most fully apparent
when caused by tabes but are currently caused by
the same disorders of afferent innervation that
produce tabetic gait. Lancinating pains in the
abdomen and limbs from tabes can mimic dis-
orders requiring emergency surgery.25 Tabes has
become more rare than general paresis for un-
known reasons.26 In a series of 161 patients with
neurosyphilis in South Africa, only 2 had tabes
and 13 had other forms of myelopathy.12

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 Neurosyphilis

Table 2. Sensitivity and Specificity of Laboratory Tests for Neurosyphilis.*

Test Sensitivity Specificity

Early Late, Symptomatic Late, Symptomatic
Neurosyphilis Neurosyphilis Neurosyphilis
percent
Serologic tests
Serum VDRL and RPR† 100‡ 50–75 90
CSF VDRL 75§ 30–70 100
(if not contaminated with blood)
Serum FTA-ABS, TPHA 100‡ Approximately 96 Approximately 60
CSF FTA-ABS 100 Approximately 99 Approximately 50–70
CSF content
White-cell count >5–10/mm3¶ 100 95 Approximately 97
Protein >45 mg/dl‖ 90 95 <50

* Data are from case series that show variable results, depending on the base rate of syphilis and whether control sam-
ples were from patients with or without syphilis.28 Data on specificity are from patient populations without syphilis sur-
veyed by the Centers for Disease Control and Prevention. Specificity can be lower for some tests when uncomplicated
primary syphilis has been adequately treated with penicillin. The Treponema pallidum hemagglutination assay (TPHA) is
not available in the United States.
† The prozone phenomenon (high titers giving false negative results) is infrequent but has been reported, mainly in cases
of secondary syphilis. The percentage for reactive test results in early neurosyphilis is inferred from results in primary
and secondary syphilis. The rapid plasma reagin (RPR) test may be less sensitive than the VDRL test and is not used as
frequently for the diagnosis of neurosyphilis.30
‡ The tests may be negative in the early, primary stage of syphilis but are positive in most cases of asymptomatic and
symptomatic neurosyphilis.
§ The test is almost always positive in cases of symptomatic meningitis.
¶ The specificity is lower for patients with human immunodeficiency virus (HIV) infection because of the possibility of
HIV-related meningitis. A CSF white-cell count of more than 10 per cubic millimeter is often used as a diagnostic crite-
rion for neurosyphilis in patients with HIV infection.
‖ In patients with general paresis, the protein electrophoretic pattern (formerly called the paretic pattern) is characterized
by a ratio of IgG to total protein that exceeds 0.7.

L a bor at or y Di agnosis tein levels. Because of HIV-related meningitis,

of Neuros y phil is
The laboratory diagnosis of neurosyphilis is based
on abnormal results of serum and CSF serologic
tests and on elevations in the CSF white-cell count
and protein level, but these tests are imperfect and
have no benchmarks. Blood and CSF serologic
tests for neurosyphilis are classified as nontrepo-
nemal (tests using Venereal Disease Research
Laboratory [VDRL] or rapid plasma reagin [RPR]
techniques) or treponemal (tests using fluorescent
treponemal-antibody absorption [FTA-ABS] and
related techniques). Estimates of serologic sensi-
tivity and specificity depend on the choice of con-
trols, the prevalence and stage of syphilis, and
the accuracy of laboratory and clinical diagnoses
used as a reference. Neurosyphilis is usually ac-
companied by CSF pleocytosis, which declines
over decades (Table 1),8 and mildly elevated pro-
pleocytosis is less specific in patients with HIV
infection than in those without HIV infection;
this is especially true in HIV-infected patients
who are not receiving HIV treatment and in
those with high peripheral-blood CD4+ T-cell
counts.27
Serum nontreponemal tests are reactive in al-
most all cases of neurosyphilis during and after
the secondary stage of syphilis but can become
negative in late neurosyphilis because of waning
titers over time, especially after treatment (Fig. 1).28
The CSF VDRL test is specific for neurosyphilis
(barring blood contamination) but is only 30 to
70% sensitive29; the false negative rate for the
CSF RPR test may be higher.30 If the CSF VDRL
test is negative in a patient with a syndrome that
is consistent with neurosyphilis, CSF treponemal
tests are advised.31 The sensitivity and specificity
of serologic and other tests are shown in Table 2.

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 The n e w e ng l a n d j o u r na l
Table 3. Treatment Recommendations for Early and Late Neurosyphilis.*
Geographic Region Treatment Guidelines
United States (CDC) 31
Aqueous crystalline penicillin G, 3–4 million units IV
every 4 hr or 18–24 million units every 24 hr as a
continuous infusion, for 10–14 days; or, if adher-
ence is ensured, penicillin G procaine, 2.4 mil-
lion units IM daily, plus probenecid, 500 mg
orally four times a day, for 10–14 days
United Kingdom39 Penicillin G procaine, 1.8–2.4 million units IM every
24 hr, plus probenecid, 500 mg orally every 6 hr,
or benzylpenicillin, 1.8–2.4 g IV every 4 hr, for
14 days; also suggested, prednisolone, 40–60 mg
daily for 3 days, starting 24 hr before first peni­
cillin dose
Europe40 Benzylpenicillin, 3–4 million units IV every 4 hr for
10–14 days (alternatively, there is weak evidence
for ceftriaxone, 1–2 g IV daily for 10–14 days); or
penicillin G procaine, 1.2–2.4 million units IM
every 24 hr, plus probenecid, 500 mg orally four
times a day, for 10–14 days
* CDC denotes Centers for Disease Control and Prevention, IM intramuscularly,
and IV intravenously.
Serum and CSF treponemal tests usually re-
main positive for the lifetime of an untreated
person, but the CSF test becomes negative years
after the treatment of uncomplicated syphilis in
up to 15% of patients.32 A false positive result of
a CSF FTA-ABS test due to blood contamination
probably requires more than 1000 red cells per
cubic millimeter.33
From a practical standpoint, a diagnosis of
symptomatic neurosyphilis is unlikely unless a
serum FTA-ABS test is reactive (reflecting pre-
vious syphilis) and a CSF VDRL test is reactive
(indicating neurosyphilis). A nonreactive CSF
treponemal test essentially rules out asymp-
tomatic neurosyphilis and makes symptomatic
disease unlikely, but it is not specific, particu-
larly in the context of a clinical syndrome that
is consistent with neurosyphilis.34,35 In the
United States, testing for HIV infection is rec-
ommended for persons with syphilis, including
neurosyphilis.31
Lumb a r Punc t ur e
Examination of the CSF has been recommended
if there is serologic evidence of syphilis in the
serum and a clinical syndrome that is consistent
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of m e dic i n e
with neurosyphilis.31 Serial reexamination of the
CSF white-cell count has been used to determine
the adequacy of treatment, and retreatment has
been suggested if pleocytosis has not abated in
6 months or has not been eliminated 2 years after
treatment.31 It has been suggested on the basis of
one study that CSF retesting may not be necessary
if the serum RPR titer decreases by a factor of 4
or becomes nonreactive,36 but my colleagues and
I continue to check the CSF until the cell count
abates. The value of repeated CSF examination
after adequate treatment for neurosyphilis is also
uncertain in neurologically asymptomatic pa-
tients with HIV infection.31 Routine CSF testing
for syphilis in persons with dementia has not been
recommended but may be appropriate if there is
a risk of syphilis — for example, because of HIV
infection.37
T r e atmen t of Neuros y phil is
Declining rates of general paresis during the past
half-century suggest that treatment of early syph-
ilis has prevented the subsequent development of
neurosyphilis.38 Parenteral penicillin treats all
forms of neurosyphilis. Treatment guidelines in
the United States,31 the United Kingdom,39 and
Europe40 differ slightly (Table 3). On the basis of
historical experience, penicillin probably does not
improve late neurosyphilitic syndromes but usu-
ally halts their progression.41
For patients with penicillin allergy, skin test-
ing and desensitization are recommended.31 Lim-
ited evidence suggests that ceftriaxone, tetracy-
cline,42 or doxycycline is effective in the treatment
of neurosyphilis, but penicillin is strongly pre-
ferred.31
C onclusions
Neurosyphilis persists, has varied presentations,
and can be detected by laboratory tests. Diagnosis
and treatment, as in previous eras, depend on
clinical recognition.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the author are available with the
full text of this article at NEJM.org.
I thank Dr. Christina Marra for invaluable advice during the
preparation of the review.

References
1. Yanhua W, Haishan S, Le H, et al.
Clinical and neuropsychological charac-
teristics of general paresis misdiagnosed
as primary psychiatric disease. BMC Psy-
chiatry 2016;​16:​230-6.
2. Sexually transmitted disease surveil-
lance 2017: syphilis. Atlanta: Centers for
Disease Control and Prevention (https://
www​.cdc​.gov/​std/​stats17/​Syphilis​.htm).
3. Tucker JD, Chen X-S, Peeling RW.
Syphilis and social upheaval in China.
N Engl J Med 2010;​362:​1658-61.
4. Dombrowski JC, Pedersen R, Marra
CM, Kerani RP, Golden MR. Prevalence es-
timates of complicated syphilis. Sex Transm
Dis 2015;​42:​702-4.
5. Daey Ouwens IM, Koedijk FDH, Fiolet
ATL, et al. Neurosyphilis in the mixed
urban-rural community of the Netherlands.
Acta Neuropsychiatr 2014;​26:​186-92.
6. Conde-Sendín MA, Amela-Peris R,
Aladro-Benito Y, Maroto AA. Current clini-
cal spectrum of neurosyphilis in immuno-
competent patients. Eur Neurol 2004;​52:​
29-35.
7. de Voux A, Kidd S, Torrone EA. Re-
ported cases of neurosyphilis among early
syphilis cases–United States, 2009 to 2015.
Sex Transm Dis 2018;​4539-41.
8. Merritt HH, Adams RD, Solomon HC.
Neurosyphilis. New York:​Oxford Univer-
sity Press, 1948.
9. Peeling RW, Ye H. Diagnostic tools for
preventing and managing maternal and
congenital syphilis: an overview. Bull
World Health Organ 2004;​82:​439-46.
10. Hook EW III, Marra CM. Acquired
syphilis in adults. N Engl J Med 1992;​326:​
1060-9.
11. Wolters EC. Neurosyphilis: a chang-
ing diagnostic problem? Eur Neurol 1987;​
26:​23-8.
12. Timmermans M, Carr J. Neurosyphi-
lis in the modern era. J Neurol Neurosurg
Psychiatry 2004;​75:​1727-30.
13. Johns DR, Tierney M, Felsenstein D.
Alteration in the natural history of neuro-
syphilis by concurrent infection with the
human immunodeficiency virus. N Engl J
Med 1987;​316:​1569-72.
14. Symptomatic early neurosyphilis
among HIV-positive men who have sex
with men — four cities, United States,
January 2002–June 2004. MMWR Morb
Mortal Wkly Rep 2007;​56:​625-8.
15. Hook EW III. Syphilis and HIV infec-
tion. J Infect Dis 1989;​160:​530-4.
16. Gordon SM, Eaton ME, George R, et
n engl j med 381;14 nejm.org  October 3, 2019
The New England Journal of Medicine
Downloaded from nejm.org at Northwestern University Galter Health Sciences Library on October 5, 2019. For personal use only. No other uses without permission.
Copyright © 2019 Massachusetts Medical Society. All rights reserved.
Neurosyphilis
al. The response of symptomatic neuro-
syphilis to high-dose intravenous penicil-
lin G in patients with human immunode-
ficiency virus infection. N Engl J Med
1994;​331:​1469-73
17. Hutchinson CM, Hook EW III, Shep-
herd M, Verley J, Rompalo AM. Altered
clinical presentation of early syphilis in
patients with human immunodeficiency
virus infection. Ann Intern Med 1994;​121:​
94-100.
18. Rolfs RT, Joesoef MR, Hendershot EF,
et al. A randomized trial of enhanced
therapy for early syphilis in patients with
and without human immunodeficiency
virus infection. N Engl J Med 1997;​337:​
307-14.
19. Silber E, Sonnenberg P, Ho KC, et al.
Meningitis in a community with a high
prevalence of tuberculosis and HIV infec-
tion. J Neurol Sci 1999;​162:​20-6.
20. Gjestland T. The Oslo study of un-
treated syphilis: an epidemiologic investi-
gation of the natural course of the syphi-
litic infection based upon a re-study of the
Boeck-Bruusgaard material. Acta Derm
Venereol Suppl (Stockh) 1955;​35:​Suppl 34:​
3-368.
21. Conrad J. Heart of Darkness. Edin-
burgh:​William Blackwood, 1902.
22. Lerner MG. Maupassant. New York:​
George Braziller, 1975.
23. Zhang HL, Lin LR, Liu GL, et al. Clin-
ical spectrum of neurosyphilis among
HIV-negative patients in the modern era.
Dermatology 2013;​226:​148-56.
24. Benabdeljlil M, Essahli N, Rahmani
M, Aidi S, Aloui Faris E. Infectious de-
mentias: experience of the Memory Cen-
tre of Rabat. Eur J Neurol 2016;​23:​Suppl 2:​
113.
25. Lees R. Surgical aspects of tabes dor-
salis. Br J Vener Dis 1953;​29:​198-202.
26. Drago F, Merlo G, Ciccarese G, et al.
Changes in neurosyphilis presentation: a
survey on 286 patients. J Eur Acad Derma-
tol Venereol 2016;​30:​1886-900.
27. Marra CM, Maxwell CL, Collier AC, et
al. Interpreting cerebrospinal fluid pleo-
cytosis in HIV in the era of potent antiret-
roviral therapy. BMC Infect Dis 2007;​7:​37.
28. Sparling PF. Diagnosis and treatment
of syphilis. N Engl J Med 1971;​284:​642-
53.
29. Davis LE, Schmitt JW. Clinical signifi-
cance of cerebrospinal fluid tests for neu-
rosyphilis. Ann Neurol 1989;​25:​50-5.
30. Marra CM, Tantalo LC, Maxwell CL,
Ho EL, Sahi SK, Jones T. The rapid plasma
reagin test cannot replace the venereal
disease research laboratory test for neu-
rosyphilis diagnosis. Sex Transm Dis
2012;​39:​453-7.
31. Workowski KA, Bolan GA. Sexually
transmitted diseases treatment guidelines,
2015. MMWR Recomm Rep 2015;​ 64
(RR-3):​1-137.
32. Romanowski B, Sutherland R, Fick
GH, Mooney D, Love EJ. Serologic re-
sponse to treatment of infectious syphi-
lis. Ann Intern Med 1991;​114:​1005-9.
33. Jaffe HW, Larsen SA, Peters M, Jove
DF, Lopez B, Schroeter AL. Tests for
treponemal antibody in CSF. Arch Intern
Med 1978;​138:​252-5.
34. Harding AS, Ghanem KG. The perfor-
mance of cerebrospinal fluid treponemal-
specific antibody tests in neurosyphilis:
a systematic review. Sex Transm Dis 2012;​
39:​291-7.
35. Marra CM. Syphilis screening in neu-
rology. JAMA Neurol 2016;​73:​926-7.
36. Marra CM, Maxwell CL, Tantalo LC,
Sahi SK, Lukehart SA. Normalization of
serum rapid plasma reagin titer predicts
normalization of cerebrospinal fluid and
clinical abnormalities after treatment of
neurosyphilis. Clin Infect Dis 2008;​ 47:​
893-9.
37. Knopman DS, DeKosky ST, Cum-
mings JL, et al. Practice parameter: diag-
nosis of dementia (an evidence-based
review): report of the Quality Standards
Subcommittee of the American Academy
of Neurology. Neurology 2001:​56:​1143-
53.
38. Isdoe O, Guthe T, Willcox RR. Peni-
cillin in the treatment of syphilis: the ex-
perience of three decades. Bull World
Health Organ 1972;​47:​Suppl:​1-68.
39. Kingston M, French P, Higgins S, et
al. UK national guidelines on the man-
agement of syphilis 2015. Int J STD AIDS
2016;​27:​421-46.
40. Janier M, Hegyi V, Dupin N, et al. 2014
European guideline on the management
of syphilis. J Eur Acad Dermatol Venereol
2014;​28:​1581-93.
41. Moore JE, Hopkins HH. Asymptom-
atic neurosyphilis: VI. The prognosis of
early and late asymptomatic neurosyphi-
lis. JAMA 1930;​95:​1637-41.
42. Shann S, Wilson J. Treatment of neu-
rosyphilis with ceftriaxone. Sex Transm
Infect 2003;​79:​415-6.
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