Original Paper

Dermatology 2013;226:148–156 Received: August 30, 2012

Accepted after revision: December 30, 2012
DOI: 10.1159/000347109
Published online: April 19, 2013

Clinical Spectrum of Neurosyphilis

among HIV-Negative Patients in the
Modern Era
Hui-Lin Zhang a Li-Rong Lin a, b Gui-Li Liu a Yan-Li Zeng a Jing-Yi Wu c
Wei-Hong Zheng c Man-Li Tong a Jie Dong b Yuan-Hui Su b Li-Li Liu a, b
Tian-Ci Yang a, b
a
Center of Clinical Laboratory, Zhongshan Hospital, Medical College of Xiamen University, b Xiamen Zhongshan
Hospital, Fujian Medical University, and c Department of Neurology, Zhongshan Hospital, Medical College of Xiamen
University, Xiamen, China

Key Words ous clinical manifestations, laboratory findings and magnet-

Syphilis · Neurosyphilis · Clinical spectrum · Cerebrospinal
fluid · Treponema pallidum · Syphilitic serologic tests
Abstract
Background: The clinical spectrum of neurosyphilis (NS) has
changed over time. Objective: To describe the clinical spec-
trum and characteristics of NS in HIV-negative patients.
Methods: A retrospective chart review was performed for
149 in patients with NS. Result: All patients were >25 years
old, including 16.8% asymptomatic for NS, 15.4% with syph-
ilitic meningitis, 24.2% with meningovascular NS, 38.9% with
general paresis, 4.0% with tabes dorsalis and 0.7% with gum-
matous NS. The original misdiagnosis rate was 84.6%. All 149
patients had positive serum Treponema pallidum particle ag-
glutination (TPPA) and rapid plasma reagin (RPR). The overall
positive rates of cerebrospinal fluid RPR (CSF-RPR) and CSF-
TPPA were 57.0 and 89.9%, respectively. CSF pleocytosis and
elevated CSF protein were found in 40.3% of patients. Non-
specific abnormal brain magnetic resonance imaging and
electroencephalography findings were present in 60.4 and
54.8% of NS patients, respectively. Conclusions: NS has vari-
ic resonance imaging and electroencephalography findings,
but all studies lack specificity. Every patient with neurologi-
cal or psychiatric symptoms that are without unambiguous
causes should have blood tests for syphilis. When serology
proves positive, patients should undergo CSF examination.
Copyright © 2013 S. Karger AG, Basel
Introduction
Long known as ‘the great mimicker’, syphilitic infec-
tion can be difficult to recognize clinically, and this par-
ticularly holds true for neurological manifestations of
the disease [1]. Neurosyphilis (NS) is defined as an infec-
tion of the central nervous system during any stage of the
disease, and it is caused by Treponema pallidum. Up to
4–10% of patients with untreated syphilis may develop
NS [2]. The availability of antibiotics has led to a precip-
Hui-Lin Zhang, Li-Rong Lin and Gui-Li Liu contributed equally to this
work.
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© 2013 S. Karger AG, Basel Tian-Ci Yang or Li-Li Liu

1018–8665/13/2262–0148$38.00/0 Center of Clinical Laboratory, Zhongshan Hospital
Medical College of Xiamen University
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E-Mail karger@karger.com
Xiamen 361004 (China)
www.karger.com/drm
E-Mail yangtianci @ xmu.edu.cn or liulili @ xmu.edu.cn
itous decline in the incidence of NS [3, 4]. However,
some researchers have hypothesized that the widespread
use of antibiotics for a variety of infections unrelated to
syphilis may result in the incomplete treatment of pa-
tients with undiagnosed underlying syphilis, which could
potentially cause changes in the clinical manifestations
of NS [5, 6].
NS itself has classically been separated into early and
late forms. Early NS may present with meningitis, head-
ache, blurry vision or, as in most cases, be asymptomatic.
It occurs within the first year after the initial infection
and resolves regardless of treatment [7]. The late form of
NS can be considered a tertiary manifestation of the dis-
ease, but it is important to note that the appearance of
neuropsychiatric signs and symptoms in NS may present
at any time after the infection [1]. Late NS can further be
subdivided into overlapping meningovascular and pa-
renchymal forms. However, all clinical manifestations of
NS represent a spectrum of the same pathophysiological
process, and there can be a significant overlap of signs
and symptoms in individual cases. In the pre-antibiotic
era, general paresis and tabes dorsalis were the most
commonly recognized forms of NS [7]. During recent
decades, some authors have reported changes in the clin-
ical patterns of this disease [8–11], and these changes
have generally been attributed to the expanded use of
antibiotics and the growing number of patients who are
coinfected with HIV. In recent years, there has been a
remarkable increase in the incidence of NS in China [4].
Because of the recurrence of syphilis in mainland China
in the 1990s, NS is expected to peak soon. Our study ret-
rospectively reviewed 149 cases of NS in Zhongshan
Hospital, Medical College of Xiamen, from June 2005 to
April 2012, and analyzed the clinical spectrum and labo-
ratory indices of NS among HIV-negative patients in the
modern era.
Subjects and Methods
Study Design and Patients
A retrospective review of patient records at Zhongshan Hospi-
tal, Medical College of Xiamen University, was performed. From
June 2005 to April 2012, a total of 323 patients were clinically di-
agnosed with NS based on the interpretation of clinical and labora-
tory findings as recommended by the guidelines of the Centers for
Disease Control (CDC) in the US [12]. Patients were excluded if
their records had no documentation of an HIV test, if they had an
HIV-positive test, were already being treated using antibiotics, had
any other diseases, had no complement information or did not
agree to participate in the study. This left 149 hospitalized patients
(109 males and 40 females) with an average age of 52.0 years who
Clinical Spectrum of Neurosyphilis
were enrolled in our study. The study protocol followed the ethical
guidelines of the 1975 Declaration of Helsinki as reflected in the
approval by the ethics committees at the Medical College of Xia-
men University. Informed consent was obtained from all of the
subjects. The possibility of HIV infection was excluded in all pa-
tients with ELISA using HIV 1+2 antigens/antibodies (Beijing
Wantai Biological Pharmacy Enterprise Co. Ltd., China).
Diagnostic Criteria
The diagnosis of syphilis was established using standard tech-
niques, including reactive serum non-treponemal tests (rapid plas-
ma reagin [RPR] or venereal disease research laboratory [VDRL]
tests) and treponemal tests (T. pallidum particle agglutination
[TPPA] or fluorescent treponemal antibody absorption (FTA-
Abs]) [13, 14]. Patients identified with syphilis were further evalu-
ated for neurological findings [12]. The diagnostic criteria for NS
complied with the guidelines of the CDC in the US, with estab-
lished surveillance definitions used epidemiologically [12]. The
two categories include ‘confirmed’ and ‘presumptive’ NS. ‘Con-
firmed’ is defined as any stage of syphilis with reactive cerebrospi-
nal fluid (CSF) VDRL. ‘Presumptive’ is defined as (1) any stage
of syphilis with (2) a nonreactive CSF VDRL, (3) CSF pleocytosis
(>10 × 106 cells/l) or elevated protein (>500 mg/l), and (4) clinical
signs or symptoms consistent with syphilis without an alternate
diagnosis to account for these manifestations. Based on the related
literature [4, 15], a positive CSF TPPA can also be used for diag-
nosing NS.
Syphilitic Serologic Tests
The syphilitic serologic tests for each sample were performed
using RPR (InTec, Xiamen, China) and TPPA tests (Fujirebio, To-
kyo, Japan) according to the manufacturer’s instructions and the
related literature [13, 14, 16].
Biochemical Examination
Approximately 2-ml CSF samples were collected in plain sterile
tubes and analyzed within 1 h to determine the proteins using a
Roche-Hitachi Modular P800 GMMI clinical chemistry analyzer
(Roche Diagnostics, F. Hoffmann-La Roche Ltd., Basel, Switzer-
land) and the CSF white blood cells (WBCs) using an automatic
blood cell XE5000 analyzer (Sysmex International Reagents Co.,
Ltd., Japan).
Statistical Analysis
All statistical analyses were conducted using SPSS for Windows
version 13. Fisher’s exact test was employed to determine the sig-
nificant differences between males and females in different groups.
Results
Proportion of Patients with Different Clinical Phases
of NS
A total of 149 patients from Zhongshan Hospital,
Medical College of Xiamen University, hospitalized from
June 2005 to April 2012, were included in the current
study. The study included 25 cases (16.8%) of asymptom-
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Dermatology 2013;226:148–156 149
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 Table 1. Proportion of different clinical phases among 149 NS patients

Clinical phase Cases Males Females Average age Median age,

range, years years

Asymptomatic NS 25 (16.8%) 16 9 49.0 46.0

Syphilitic meningitis 23 (15.4%) 14 9 48.0 52.0
Meningovascular NS 36 (24.2%) 25 11 59.0 56.0
General paresis 58 (38.9%) 47 11 53.0 50.0
Tabes dorsalis 6 (4.0%) 6 0 38.0 35.5
Gummatous NS 1 (0.7%) 1 0 51.0 51.0
Total 149 (100%) 109 40 52.0 50.0

There was no significant difference in the presentation between males and females in different clinical phases
of NS using Fisher’s exact test (χ2 = 7.489, p = 0.187).

atic NS and 124 cases (83.2%) of symptomatic NS. Among

symptomatic NS patients, 23 (15.4%) had syphilitic men- 50
ingitis, 36 (24.2%) meningovascular NS, 64 (42.9%) pa- 45
renchymal syphilis (including general paresis [58, 38.9%] 40
35
and tabes dorsalis [6, 4.0%]), and 1 (0.7%) had gumma-
Patients (%)

30
tous NS. There was no significant difference in the pre- 25
sentation between males and females among the different 20
clinical phases of NS when the data were analyzed using 15
Fisher’s exact test (χ2 = 7.489, p = 0.187) (table 1). 10
5
0
Age Distribution of NS 0–25 26–45 46–60 ≥61
There were no patients between the ages of 0 and 25 Age (years)

years. The number of NS patients aged 26–45 years, 46–

60 years and ≥61 years was 48 (32.2%), 65 (43.6%) and 36
Fig. 1. Age distribution of 184 NS patients.
(24.2%), respectively (fig. 1).

Primary Signs and Symptoms of NS

Among the 124 symptomatic NS patients, the most
common presenting symptoms were weakness of the
limbs (47, 37.9%). Other symptoms included dizziness
(31, 25.0%) and headache (25, 20.2%). Less common
(<15%) symptoms included gatism, seizure and hypopsia.
There was no significant difference in the presentation
between males and females in different primary signs
when the data were analyzed with Fisher’s exact test (χ2 =
10.802, p = 0.055). The clinical signs of our patients in-
cluded cognitive decline, aphasia, sensory disturbances,
psychological and behavior disorders, affective disorder,
dysarthria, ataxia, oculomotor paralysis and Argyll-Rob-
ertson pupil. Among these findings, cognitive decline
(47.6%), aphasia (37.9%) and sensory disturbances
(36.3%) were most common, with an overall incidence of
35%. Only 5 patients demonstrated Argyll-Robertson pu-
pils (pupils that are small, asymmetric, irregular and
poorly responsive to direct light with maintained appro-
priate constriction on accommodation), a characteristic
clinical sign of NS. There was no significant difference in
the presentation between males and females in different
primary symptoms when assessed by Fisher’s exact test
(χ2 = 4.438, p = 0.816) (table 2). Our symptomatic NS pa-
tients with one, two, three and four symptoms represent-
ed 50, 27, 11 and 2 cases, respectively. Our symptomatic
NS patients with one, two, three, four and five signs men-
tioned above represented 27, 39, 33, 16 and 3 cases, re-
spectively.
46 patients presented with psychiatric manifestations,
all occurring in general paresis patients. The most com-
mon presenting symptoms were amnesia, personality
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150 Dermatology 2013;226:148–156 Zhang /Lin /Liu /Zeng /Wu /Zheng /Tong /
             

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Table 2. Primary signs and symptoms of 124 symptomatic NS Misdiagnosis Rate for NS Patients
patients Of the 149 NS patients, 23 were diagnosed with NS by
another hospital and transferred to our hospital before
Primary signs and symptoms Cases Males Females
using antibiotics, or were diagnosed with syphilis in our
Symptoms outpatient department that was then confirmed by lum-
Weakness of limbs 47 (37.9%) 38 9 bar puncture while they were inpatients. The remaining
Dizziness 31 (25.0%) 27 4 126 patients were treated for the first time in the neurol-
Headache 25 (20.2%) 17 8 ogy department. None of these patients were initially sus-
Gatism 17 (13.7%) 14 3
Seizure 14 (11.3%) 7 7 pected of having NS; they were all diagnosed during their
Hypopsia 11 (8.9%) 10 1 follow-up treatment. The original misdiagnosis rate was
84.6% (126/149). The misdiagnosis rate of syphilitic men-
Signs
Cognitive decline 59 (47.6%) 50 9 ingitis was the highest (95.7%) (except for gummatous
Aphasia 47 (37.9%) 39 8 NS, with only 1 patient), followed by meningovascular
Sensory disturbances 45 (36.3%) 38 7 NS, asymptomatic NS, general paresis and tabes dorsalis,
Psychological and behavior disorders 36 (29.0%) 26 10 with misdiagnosis rates of 91.7, 84.0, 77.6 and 66.7%, re-
Affective disorder 32 (25.8%) 26 6 spectively (table 3).
Dysarthria 31 (25.0%) 25 6
Ataxia 15 (12.1%) 13 2
Oculomotor paralysis 13 (10.5%) 10 3 Analysis of Laboratory Findings in NS Patients
Argyll-Robertson pupil 5 (4.0%) 5 0 All patients had positive serum RPR (80 sero-RPR ti-
ters ≤1:16 and 69 sero-RPR titers ≥1:32). 64 CSF samples
Symptoms: There was no significant difference in the presenta- (43.0%, 64/149) were RPR-negative and 85 CSF samples
tion between males and females in different primary signs using
Fisher’s exact test (χ2 = 10.802, p = 0.055). (57.0%, 85/149) were RPR-reactive, with titers ≤1: 16
Signs: There was no significant difference in the presentation (fig. 2). All 149 NS patients had positive serum TPPA. 15
between males and females in different primary symptoms using CSF samples were TPPA-negative and 134 CSF samples
Fisher’s exact test (χ2 = 4.438, p = 0.816). (89.9%, 134/149) were TPPA-reactive (fig. 3).
88 patients (59.1%) had CSF pleocytosis, and 84
(56.4%) had elevated CSF protein levels. 60 patients
(40.3%) had both CSF pleocytosis and elevated CSF pro-
Table 3. Misdiagnosis rate for NS patients with different clinical
phases
tein levels, while 37 (24.8%) had normal CSF WBC and
protein levels (fig. 4).
Clinical phase Patients Misdiagnosis rate
newly diagnosed
Magnetic Resonance Imaging of the Brain
%
NS cases A total of 111 patients underwent brain magnetic res-
onance imaging (MRI). 67 (60.4%) patients had abnor-
Asymptomatic NS 25 21 84.0 mal findings, including cerebral infarction ischemic
Syphilitic meningitis 23 22 95.7
stroke (38 patients, 34.2%), cerebral atrophy (15 patients,
Meningovascular NS 36 33 91.7
General paresis 58 45 77.6 13.5%), demyelination (6 patients, 5.4%), hydrocephalus
Tabes dorsalis 6 4 66.7 (3 patients, 2.7%), encephalitis or meningitis (2 patients,
Gummatous NS 1 1 100.0 1.8%), hippocampal sclerosis (2 patients, 1.8%) and cere-
Total 149 126 84.6 bral hemorrhage (1 patient, 0.9%) (table 4).

change and incoherent speech, with an overall incidence
of 50%. Other symptoms included hostility, dysarthria,
confusion and hyposomnia, with an overall incidence of
15–20%. Less common (<10%) psychiatric manifesta-
tions included dysphoria, paranoia, hallucinations, ex-
pansive mood and mania.
Electroencephalography
A total of 42 patients underwent electroencephalogra-
phy (EEG). Of these, 19 cases (45.2%) were normal and
23 cases (54.8%) were abnormal. Among the 23 abnormal
cases, 15 were minimally abnormal, 5 were moderately
abnormal and 3 were severely abnormal. Abnormal EEG
findings included background activity abnormality (11
cases), diffuse abnormality (5 cases), local abnormality
(4 cases) and attack wave abnormality (3 cases) (table 5).
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 80

60

Cases (n)
40

20
CSF-RPR
0 Sero-RPR
Neg. 1:1 1:2 1:4 1:8 1:16 1:32 1:64 ≥128
Fig. 2. RPR reactivity among 149 NS pa-
tients.

35

30

25

20
Cases (n)

15

10

0
g.
Ne 1:8
0
60
1:1 20 40
1:3 1:6 0 CSF-TPPA
,28 0
1:1 ,56 20 Sero-TPPA
1:2 1:5
,1 40
0,2 
1:1 –

Fig. 3. TPPA reactivity among 149 NS pa-
tients.

70
60
50
Patients (%)

40
30
20
10
0
Pleocytosis Elevated Both Normal
protein pleocytosis CSF WBC
and elevated and protein
Fig. 4. CSF abnormalities of 149 NS pa- protein
tients.
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Table 4. Brain MRI findings among 111 NS patients neurological complaints [23, 24]. A study from South Af-
rica [25] reported that the majority of patients with NS
Brain MRI finding n % Males Females
presented with subtle clinical signs and suggested that
Normal 44 39.6 38 6 atypical NS may be common. In this study, we examined
Abnormal 67 60.4 55 12 149 NS inpatients (age >25 years) from Zhongshan Hos-
Infarct ischemic stroke 38 34.2 31 7 pital, Medical College of Xiamen University, from June
Cerebral atrophy 15 13.5 14 1 2005 to April 2012. These included 16.8% asymptomatic
Demyelination 6 5.4 5 1
Hydrocephalus 3 2.7 1 2
for NS, 42.9% with parenchymal syphilis, including gen-
Encephalitis or meningitis 2 1.8 1 1 eral paresis and tabes dorsalis, 24.2% with meningovas-
Hippocampal sclerosis 2 1.8 2 0 cular NS, 15.4% with syphilitic meningitis and 0.7% with
Cerebral hemorrhage 1 0.9 1 0 gummatous NS. Our results show that the NS clinical
Total 111 100 93 18 spectrum appears to be changing over time, with a trend
to less frequent late forms, mainly a decline in tabes dor-
salis.
T. pallidum disseminates systemically hours to days
after inoculation, and neurological manifestations of
Table 5. EEG findings of 42 NS patients
syphilis can and do occur during any stage of the infec-
EEG finding n % tion [26]. NS may be asymptomatic, or it may be associ-
ated with cranial nerve palsies (especially involvement of
Normal 19 45.2 nerves VII and VIII), papilledema, neuropsychiatric fea-
Abnormal 23 54.8 tures, headaches, hearing loss, spastic quadriparesis (sec-
Abnormality degree of EEG ondary to syphilitic meningomyelitis), medullary syn-
Minimal 15 65.2
Moderate 5 21.7 dromes, acute and subacute strokes, gait disturbances,
Severe 3 13.1 optic atrophy and papillary changes [27]. A study from
Manifestation of EEG South Africa [28] by Timmermans and Carr reported
Background activity abnormality 11 47.8 that the classical presentation of NS had not changed in
Diffuse abnormality 5 21.7 161 NS patients from 1990 to 1999, although tabes dor-
Local abnormality 4 17.4
Attack wave abnormality 3 13.1 salis had become rare. Their patients had clinical syn-
dromes that were identical to those described in the
pre-antibiotic era, i.e. neuropsychiatric presentations,
strokes, cranial nerve and brain stem dysfunctions, sei-
zures with or without encephalopathy and spinal cord
Discussion disease, both acute and indolent. In the present study,
the primary symptoms of 149 NS patients included
In recent decades, the focus on syphilis has been on focal stroke-like neurological deficits (e.g. weakness of
changes in the clinical manifestations of NS [6, 17, 18]. In the limbs, sensory disturbances, dysarthria and aphasia),
the pre-penicillin era, tabes dorsalis was the most com- dizziness, cognitive decline, headache, ataxia, psycholog-
mon manifestation of NS [19, 20]. Meningovascular ical and behavior disorders, seizures, Argyll-Robertson
syphilis, uncommon in the pre-antibiotic era, has been pupil, hypopsia, oculomotor paralysis, affective disorder
observed more often [4], and parenchymatous NS has de- and gatism.
creased in incidence [4, 17, 19, 21]. These changes are Currently, mental disorders and cognitive impairment
thought to be related to prior exposure of patients with are the most common expressions of NS [29]. NS can
syphilis to penicillin for treatment of non-syphilitic ill- mimic many other neuropsychiatric disorders, including
nesses [2, 17]. The spectrum of NS was reported to have personality disorder, psychosis and dementia [30]. Oth-
changed, as suggested by a study by Hooshmand et al. er presenting psychiatric symptoms include personal-
[22], in which 241 new cases of NS were reported. How- ity change, cognitive impairment, dysphoria or elevated
ever, the majority of these were asymptomatic, and the mood, hallucinations, mania and delirium [30, 31]. Al-
remainder had atypical syndromes. Several other investi- though it may present as virtually any psychiatric disor-
gators have reported a change in the clinical spectrum of der, a significant number of patients with NS present with
NS, with more patients presenting with vague, ill-defined an insidious process of dementia that leads to a progres-
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sive global deterioration in intellectual functioning. It is
recognized that NS infection often manifests with psychi-
atric symptoms such as fury and/or psychosis, hallucina-
tions, mood disorders, delirium, aggression and depres-
sion [29]. Kararizou et al. [29] described a case that ini-
tially presented as persistent headache and untreatable
psychosis. The patient had had a persistent headache for
the previous 5 years, developed paranoid ideation (delu-
sions of persecution), acoustic hallucinations of threaten-
ing content, social withdrawal, loss of body weight and
blunted affect. The clinical features of patients in our
study included amnesia, personality change, incoher-
ent speech, hostility, dysarthria, confusion, hyposomnia,
dysphoria, paranoia, hallucinations, expansive mood and
mania.
Syphilis is commonly known as ‘the great imitator’ or
‘the great impostor’ because of its wide range of clinical
symptoms [1, 32]. Several case series have described these
symptoms as atypical or ‘formes frustes’ [22, 25, 33]. Es-
tablishing the diagnosis is often difficult because most
patients are asymptomatic or present with nonspecific
symptoms [34]. Thus, the rate of misdiagnosis is quite
high, preventing patients from receiving the most appro-
priate treatment, resulting in more severe neurological
damage. Based on the analysis of the clinical misdiagnosis
rate in our study, 126 of the 149 cases were treated for the
first time in the hospital’s neurology department, and
none of them were initially suspected of having NS. They
were all diagnosed during their follow-up treatment. The
misdiagnosis rate was 84.6%.
The diagnostic criteria for NS are currently based on a
combination of clinical symptoms, CSF pleocytosis, CSF
protein level and positive CSF syphilis serology (reactive
RPR or VDRL, or TPPA, FTA-Abs or enzyme immuno-
assay). The interpretation of syphilis serology is difficult.
Although a patient with neurological symptoms and a
positive CSF VDRL test clearly has NS, the CSF VDRL is
highly specific but has a sensitivity as low as 30% [35] and
may be negative in NS [36]. Because of the low sensitivity
of the CSF VDRL, treponemal tests (CSF FTA-Abs and
CSF TPPA) have been used to exclude a diagnosis of NS.
We and some other investigators have used positive CSF
TPPA and/or CSF FTA-Abs for diagnosing NS [4, 15, 37].
In the present study, 85 of the 149 NS patients had a reac-
tive CSF RPR (used in place of the unavailable VDRL
test), and 134 had reactive CSF TPPA tests. Marra et al.
[38] even used a reactive CSF VDRL test result or CSF
WBC count >20 cells/ml as the laboratory definition for
NS in HIV-infected patients. Other investigators recom-
mended that the criteria for diagnosis of NS be a CSF
154 Dermatology 2013;226:148–156
DOI: 10.1159/000347109
WBC count ≥20/μl, a reactive CSF VDRL and/or a posi-
tive intrathecal T. pallidum antibody index [39]. These
views are echoed in the CDC’s 2010 sexually transmitted
diseases treatment guidelines [37]. Thus, it is understand-
able that 15 patients had a negative CSF TPPA in our co-
hort. However, according to the guidelines of the Euro-
pean CDC [36], NS patients with serologically negative
RPR or negative CSF TPPA may be extremely rare or may
not exist. In our study of 149 NS patients, CSF examina-
tion showed pleocytosis in 59.1% of patients and eleva-
tion of protein in 56.4% of patients, and both in 40.3% of
patients. Thus, the diagnosis of NS cannot be excluded
even when cell counts and biochemistry of the CSF are
normal.
Although NS could be diagnosed by clinical symptoms
and laboratory findings in some patients, new techniques,
such as polymerase chain reaction, CSF tau protein and
CSF CXCL13, should also be considered when the diag-
nosis of syphilis cannot be confirmed [40–43]. The lead-
ing edge diagnostic techniques for syphilis include the de-
velopment of a multiplex polymerase chain reaction for
the etiological evaluation of genital ulcer diseases. Other
new technologies for diagnosing syphilis are currently
under evaluation or in the early implementation stage.
Several new treponemal tests have shown excellent per-
formance by using preparations of recombinant T. palli-
dum antigens [13, 14]. Paraskevas et al. [41] indicated that
increased total tau protein in the CSF may be useful in the
discrimination of NS from syphilis without nervous sys-
tem involvement.
A serum RPR ≥1:32 has been considered to be a useful
cut-off for performing a lumbar puncture in HIV-posi-
tive patients [36, 38, 39]. Marra et al. [38] performed lum-
bar punctures on 326 patients with syphilis, and of these
patients, 65 had NS. In multivariate analyses, serum RPR
titers ≥1:32 increased the odds of NS 10.85-fold in HIV-
negative subjects and 5.98-fold in HIV-positive subjects
[38]. Libois et al. [39] reviewed 112 cases of HIV-positive
patients with syphilis who underwent lumbar punctures,
26 of whom had NS. Neurological manifestations and se-
rum RPR were significantly associated with NS (p = 0.036
and p = 0.018, respectively). Using a receiver operating
curve analysis, a serum RPR titer of 1:32 seemed to be the
best cut-off point for performing a lumbar puncture (sen-
sitivity 100%, specificity 40%) [39]. However, of our 149
NS patients, 89 had a serum RPR ≤1:16, and only 60 cas-
es had a serum RPR ≥1:32. Our study showed that a se-
rum RPR ≥1:32 is not a useful cut-off for performing a
lumbar puncture in HIV-negative patients.
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 The imaging features of NS are variable because the
infection involves different sites in different pathologi-
cal stages. The existing literature indicates that brain
MRI scans of most NS patients are normal or have non-
specific changes [44, 45]. There are no pathognomonic
radiographic findings that suggest a diagnosis of NS.
Marano et al. [46] suggested that brain MRI might not
be helpful for the diagnosis of NS but may be beneficial
for follow-up treatment. Other reports have suggested
that brain MRI findings of cerebral atrophy or vasculi-
tis-related infarcts may support the diagnosis of NS [47,
48]. In our study, 67 of 111 NS patients (60.4%) had an
abnormal brain MRI. MRI findings included cerebral
ischemic stroke, cerebral atrophy, demyelination, hy-
drocephalus, encephalitis or meningitis, hippocampal
sclerosis and cerebral hemorrhage. Sinha et al. [49]
found that patients with NS generally had abnormal
EEGs, including epileptiform discharges, periodic later-
alized epileptiform discharges and slowing of back-
ground activity. In contrast to the conclusion by Sinha
et al., 42 out of 149 NS patients in our study included
23 cases (51.0%) with abnormal EEGs. Abnormal EEG
findings included background activity, diffuse abnor-
mality, local abnormality and attack wave abnormality.
Therefore, some scholars have suggested that EEG and
MRI findings are valuable in the diagnosis of general
paresis of NS [50].
Interestingly, our study found that only 23 of the 149
NS patients were diagnosed as dominant syphilis before
their hospitalization and had symptoms and processes of
the disease. The remaining 126 cases were all diagnosed
as syphilis for the first time and did not have any mani-
festations of primary syphilis or secondary syphilis. In-
vestigators believed that the course of events after neuro-
invasion was, at least in part, determined by the host re-
sponse to infection. For example, several investigators
noted a correlation between the severity of the secondary
syphilis skin rash and identification of CSF abnormalities
in early syphilis [51]. Merritt et al. [19] noted that symp-
tomatic NS was rarely seen in individuals who had expe-
rienced severe skin manifestations. Patients with fewer
skin lesions may have a lower concentration of organisms
in their blood. Exposure to lower concentrations of or-
ganisms could attenuate the host immune response, lead-
ing to impaired ability to clear those organisms that man-
aged to invade the central nervous system and result in a
greater likelihood of developing subsequent symptomat-
ic NS. Tantalo et al. [51] support the association between
NS and poor skin lesion development observed in hu-
mans in a rabbit model.
Clinical Spectrum of Neurosyphilis
Conclusion
NS has various clinical manifestations, laboratory
findings, MRI and EEG findings, but all studies lack spec-
ificity. The importance of a rapid diagnosis of NS is em-
phasized because early and effective treatment may not
only prevent further disease progression, but may also al-
low for a complete recovery [22]. Therefore, it is recom-
mended that every patient with neurological or psychiat-
ric symptoms without unambiguous causes should have
a blood test for syphilis. When serology proves positive,
patients should undergo CSF examination. Our study
also showed that a serum RPR ≥1:32 is not a useful cut-
off for performing a lumbar puncture in HIV-negative
patients.
Acknowledgments
The current study was supported by the National Natural Sci-
ence Foundation’s Major Research Planning (grant No. 91029729),
the National Natural Science Foundation (grants No. 81171625,
81201360, 81101324 and 81271335), the Technology Foundation’s
Major Project of Social Development in Fujian Province (grant
No. 2011Y4009) and the Natural Science Foundation of Fujian
Province (grant No. 2012D039).
Disclosure Statement
The authors confirm that there is no potential conflict of inter-
est as described in the instruction for authors. All authors have
read and approved the manuscript.
1 Shah BB, Lang AE: Acquired neurosyphilis
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