Neurol Sci
DOI 10.1007/s10072-013-1531-5
BRIEF COMMUNICATION
Neurosyphilis manifesting with rapidly progressive dementia:
report of three cases
A. Stefani • M. Riello • F. Rossini • S. Mariotto •
F. Fenzi • G. Gambina • G. Zanusso • S. Monaco
Received: 5 May 2013 / Accepted: 28 August 2013
Ó Springer-Verlag Italia 2013
Abstract Neurosyphilis is rather an unusual cause of
dementia characterized by a rapidly progressive course and
psychiatric symptoms. Diagnosis of neurosyphilis should
be suspected in the presence of a global cognitive impair-
ment consisting in disorientation, amnesia and severe
impairment of speech and judgement and psychiatric
symptoms such as depression, mania and psychosis, with a
subacute onset. More commonly, clinical manifestations of
neurosyphilis include general PARESIS (involvement of
Personality, Affect, Reflexes, Eye, Sensorium, Intellect and
Speech). Upon clinical suspicion, diagnosis of neurosyph-
ilis is confirmed by a reactive cerebrospinal fluid (CSF)-
Venereal Disease Research Laboratory. Here we report
three Human Immunodeficiency Virus (HIV)-negative
male patients presenting with psychiatric symptoms and a
rapidly evolving dementia. Although magnetic resonance
imaging did not address to diagnosis, CSF examination was
mandatory in neurosyphilis diagnosis. Other diagnostic
tools such as neuropsychology and single-photon emission
computed tomography resulted supportive in the diagnosis.
We showed that a prompt antibiotic treatment might stop
disease progression. Therefore, neurosyphilis should be
always considered even in HIV-negative patients in the
presence of unexpected psychiatric symptoms accompa-
nied by a rapidly evolving cognitive decline.
A. Stefani (&)
M. Riello
F. Rossini
S. Mariotto
F. Fenzi

G. Zanusso
S. Monaco
Department of Neurological, Neuropsychological,
Morphological and Motor Sciences, University of Verona,
Verona, Italy
e-mail: ambra.stefani@gmail.com
G. Gambina
Neurology Unit, Azienda Ospedaliera Universitaria Integrata,
Verona, Italy
Keywords Neurosyphilis
Rapidly progressive
dementia
General paresis
Introduction
A recent increase in syphilis cases is described in the USA
and in Western European nations, characterized by low-
level endemicity. This rise is in part driven by an increase
in cases among homosexual males, often associated with
Human Immunodeficiency Virus (HIV) coinfection, albeit
more recent increases among heterosexual people have also
been reported [1].
Neurosyphilis results from the infection of the central
nervous system (CNS) by Treponema pallidum subspe-
cies pallidum. The spirochete disseminate to the CNS
within days after exposure in many if not most patients.
Clinical manifestations of neurosyphilis can occur during
any stage of the infection and include early (asymptom-
atic and acute meningeal syphilis) and late (meningo-
vascular, paretic and tabetic neurosyphilis) forms of
presentation [2].
Paretic neurosyphilis or general paresis usually develops
15–20 years after infection. PARESIS is an acronym for
Personality, Affect, Reflexes, Eye, Sensorium, Intellect and
Speech which are the main aspects of this disease, whose
manifestations (e.g. cognitive impairment, behavioural
changes, psychiatric features besides neurological signs
such as dysarthria, myoclonus, intention tremors, seizures,
hyperreflexia and Argyll Robertson pupils [3]) are indeed
protean.
We present three cases of neurosyphilis in HIV-negative
male patients, all clinically characterized by cognitive
impairment and psychiatric symptoms.
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Case presentation
Case 1
A 62-year-old man presented with memory impairment,
emotional lability and behavioural changes evolving over
the preceding 2 years. Neurological examination was unre-
markable, whereas neuropsychological evaluation revealed
a multi-domain cognitive impairment with a Mini Mental
Status Examination (MMSE) score of 14/30. EEG showed
diffuse slow activity prominent in left frontotemporal
regions. A neurodegenerative dementia was suspected and,
therefore, laboratory and imaging diagnostic workup was
performed. Magnetic resonance imaging (MRI) revealed
mild cortical atrophy more marked in mesial temporal lobes
(Fig. 1a) and cerebral single-photon emission computed
tomography (SPECT) disclosed a diffuse reduction of per-
fusion in frontal and left parieto-temporal lobes (Fig. 1b).
Serum Venereal Disease Research Laboratory (VDRL) test
Fig. 1 a Patient 1 MRI. T2-weighted image showing mild cortical
atrophy more marked in both mesial temporal lobes. b Patient 1
SPECT showing diffuse cortical reduction of perfusion in frontal
regions and in left parietotemporal cortex. c Patient 2 MRI. T2-
weighted image, negative. d Patient 2 SPECT showing hypoperfusion
of cerebral grey matter at both middle frontal regions and, to a lesser
extent, in posterior parietal regions bilaterally; mild hypoperfusion in
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Neurol Sci
was reactive 1:256 and Treponema Pallidum Particle
Agglutination (TPPA) positive 1:20,480; HIV tests were
negative. CSF analysis showed hyperproteinorrachia
(1.21 g/L), mild pleocytosis (20 leukocytes/mm3, mainly
lymphocytes) and positive OB. Tau protein levels were
492 pg/mL and 14-3-3 protein was positive. CSF yielded
positive for VDRL 1:4. Thereafter, a diagnosis of neuro-
syphilis was made and the patient was treated with intrave-
nous Ceftriaxone 2 g/day for 2 weeks.
A year later, the patient presented language distur-
bances, wandering and paranoia. Neurological examination
showed disorientation in time and space and to person,
poor speech, brisk deep tendon reflexes and lower limb
hypopallesthesia. EEG was normal and MRI unmodified.
Neuropsychological examination showed a worsening of
short- and long-term memory skills, while executive
functions (tests: attentional matrix and phonologic/seman-
tic verbal fluency) improved. MMSE was 19/30. CSF
analysis was normal and VDRL resulted negative.
right temporal region and at the head of the left caudate nucleus.
e Patient 3 MRI. FLAIR-weighted image showing marked hyperin-
tensity in frontal periventricular white matter bilaterally. f Patient 3
SPECT showing diffuse cortical hypoperfusion except for visual area,
basal ganglia and subtentorial cortex; hypoperfusion is worse in
anterior regions and in left cortical regions
Neurol Sci
Case 2
A 67-years-old man presented with memory impairment,
disorientation, physical and mental slowing and personality
changes over the past months. Neurological examination
was unremarkable except for disorientation in time and
space. Neuropsychological evaluation revealed depressed
mood and global cognitive impairment, particularly of
verbal and visual memory and conceptual reasoning. He
exhibited also mild deficits in tests exploring attention,
visual–spatial exploration, verbal fluency and language
skills. MMSE resulted 16/30. EEG showed slightly irreg-
ular background activity. Although brain MRI was nega-
tive (Fig. 1c), brain SPECT revealed hypoperfusion in
middle-frontal regions and, to a lesser extent, in posterior
parietal lobes, in right temporal region and in the head of
the left caudate nucleus (Fig. 1d).
Since the patient had high-sexual promiscuity, he was
investigated for syphilis. Serum VDRL test was reactive
1:4 and Treponema Pallidum Hemagglutination Test
(TPHA) 1:1,280. HIV tests were negative. CSF analysis
revealed mild hyperproteinorrachia (0.56 g/L) and positive
OB. CSF VDRL was positive 1:1. A diagnosis of neuro-
syphilis was made and the patient was treated with Ceph-
alexin for 3 days (1 g first day, 2 g second day and 3 g
third day) followed by a treatment with Penicillin G
sodium for 14 days (2,000,000 IU first day, 4,000,000 IU
second day, 6,000,000 IU third day, 8,000,000 IU fourth
day and 10,000,000 IU for the following 10 days).
One year later, neurological examination revealed upper
limb tremor, more pronounced on left arm. The patient
appeared more confused manifesting severe memory
impairment and reduction of spontaneous speech and ver-
bal comprehension. MMSE was 14/30. CSF routine ana-
lysis was normal and VDRL was reactive 1:4. A second
cycle of Penicillin G treatment was made.
On control evaluation 1 year later, the patient appeared
confused, disoriented and developed urinary incontinence.
Neuropsychological examination disclosed multi-domain
cognitive impairment including dressing apraxia as well as
psychiatric symptoms such as agitation and persecutory
hallucinations. EEG showed slow waves on left hemi-
sphere and brain CT diffuse cortical atrophy. CSF analysis
was normal and VDRL positive 1:1.
Case 3
A 57-year-old man presented with hypophonic and dys-
arthric speech since a month. Brain MRI disclosed small
vascular lesions and a widened left lateral ventricle. A few
months later, the patient showed behavioural changes and
underwent psychiatric evaluation which did not detect
pathological changes.
One year later, the patient showed acute confusional state
and falls. Neurological examination revealed global disori-
entation, poor speech with apparent preservation of compre-
hension, ideomotor apraxia, agnosia, visual–spatial deficit and
severe memory deficit. Patient was bradykinetic, with cam-
ptocormic posture, festinating gait, hand rest tremor and
rigidity (prevalent on the left side); saccadic eye movements
were fragmented and sphincterial control compromised.
Owing to his psychiatric features neuropsychological evalu-
ation was impossible. EEG was diffusely slow. Brain MRI
revealed marked hyperintensity of frontal periventricular
white matter on T2 and fluid attenuated inversion recovery
(FLAIR) weighted images (Fig. 1e). Serum VDRL was
positive 1:64 and serum TPPA [1:20,480. HIV tests were
negative. CSF examination revealed mild hyperproteinorra-
chia (0.94 g/L), endogenous synthesis index of 5.45, elevated
immunoglobulins, positive OB and VDRL positive 1:8. Tau
protein was 257 pg/mL and 14-3-3 protein positive. CSF
cytology disclosed pleocytosis (lymphocytes 85 %, mono-
cytes 14.9 % and granulocytes 0.1 %). A diagnosis of neu-
rosyphilis was made and the patient was treated with sodium
Penicillin G 24 million units intravenously per day as a con-
tinuous infusion for 14 days.
One month after treatment, neurological examination
revealed confabulation and partial recover of orientation.
Neuropsychological evaluation showed verbal and numerical
span tasks within normal range, attention deficits and easy
distractibility. The patient showed impairment in encoding,
consolidation and recall of verbal material semantically
related and in Clock Drawing Test. Behavioural assessment
still showed verbal disinhibition and confused speech. MMSE
was 17/30. CSF examination revealed a decrease in protein
content (0.56 g/L) and an increase in leukocytes (42/lL);
VDRL resulted positive 1:1. EEG showed theta–delta slowing
prevailing on frontal regions. MRI was unmodified. SPECT
disclosed diffuse cortical hypoperfusion (worse in anterior
and left cortical regions) except for visual area, basal ganglia
and subtentorial cortex (Fig. 1f).
Discussion
Rapidly progressive dementia (RPD) associated with neu-
ropsychiatric symptoms is the most common form of pre-
sentation of general paresis and includes a series of
disturbances such as personality changes, amnesia, delu-
sions, hallucinations and delirium. Less frequent clinical
manifestations include stroke, cranial nerve and brain stem
dysfunction, seizures with or without encephalopathy.
All our patients showed psychiatric symptoms and
dementia at onset, without a clinical history for psychiatric
disease. Neuropsychiatric symptoms embrace a spectrum
of neurological disorders spanning different etiologies such
123

as neurodegenerative, inflammatory, infectious, autoim-
mune, vascular, neoplastic/paraneoplastic, toxic-metabolic
and iatrogenic (e.g. lithium encephalopathy [4]) conditions.
In all patients, neuropsychological evaluation at onset
showed behavioural changes and multi-domain cognitive
impairment. These symptoms overlap those reported in
previous studies in HIV-negative patients with neuro-
syphilis [5, 6]. Conversely Argyll Robertson pupil, which
is considered a typical sign, was not observed.
Magnetic resonance imaging is helpful to exclude other
diagnoses which clinically mimic neurosyphilis, such as
sporadic Creutzfeldt–Jakob disease (sCJD), inflammatory/
autoimmune, malignancy-related or toxic-metabolic condi-
tions rather than addressing neurosyphilis diagnosis, while
there is no specific MRI pattern. Focal or diffuse atrophy as
well as infarcts and white matter changes are described [7].
According to literature, our patients showed different
radiological findings, including periventricular hyperinten-
sity. This pattern could be due to inflammation usually
observed in initial stage of neurosyphilis, whereas brain
cortical atrophy reflects a longer disease course.
In neurosyphilis, CSF analysis shows lymphocytic and
monocytic pleocytosis and hyperproteinorrachia [2] and
such a pattern was observed in all our patients, while in
neurodegenerative dementia CSF standard is usually nor-
mal. In addition, 14-3-3 protein was positive, but Tau
protein levels showed only slight increase, indicating that
the degree of neuronal damage occurred at a low rate.
Positive OB also suggested CNS inflammation. Therefore,
CSF signs of blood–brain barrier damage and immune
reaction suggested an infectious disease and further
investigation with VDRL assay addressed the diagnosis.
Brain perfusion SPECT is described in few patients with
general paresis and has been reported to show a bilateral
reduction in cerebral blood flow in frontal and temporal
lobes [8]. In patient 2 it resulted more sensitive than MRI
to identify damaged brain areas. However, in neurosyphilis
SPECT imaging might overlap those observed in neuro-
degenerative disease [9].
Patients with neurosyphilis may have different outcome.
Despite prompt and proper antibiotic treatment recovery is
often incomplete, especially if tissue damage has occurred
[10]. Case 1 showed an improvement after treatment but not
a full recovery; we assume that brain damage already
occurred. Patient 2 presented a general worsening even after
two cycles of treatment likely related to a not appropriate
therapeutic regimen (he was treated before current CDC
guidelines were formulated). Patient 3 showed a rapid
improvement in clinical conditions after therapy, with per-
sistence of psychiatric symptoms and partial disorientation
in time and space. This patient showed the best response to
therapy in our series, probably because he received proper
therapy in an acute phase of infection. Hence early diagnosis
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Neurol Sci
is crucial since it allows early treatment, during inflamma-
tory phase, before irreversible tissue damage occurs.
Conclusions
Neurosyphilis CSF analysis should be part of the diagnostic
workout of patients showing cognitive impairment and
psychiatric disturbances. Dementia as a symptom of gen-
eral paresis could improve with prompt treatment or, if
neuronal loss already occurred, the course of the disease
can be stopped. This is why early diagnosis and early
beginning of therapy are critical.
As a matter of fact, neuropsychological and MRI data
might lead to a diagnosis of neurodegenerative dementia
due to the overlap of clinical signs. A rigorous evaluation
of the cognitive functioning might play a role in the dif-
ferential diagnosis.
Especially, diagnosis of neurosyphilis should not be
overlooked and it ought to be considered even in HIV-
negative heterosexual patients when a RPD or atypical
dementia occurs.
Conflict of interest The authors declare that they have no conflict
of interest.
References
1. Fenton KA, Breban R, Vardavas R, Okano JT, Martin T, Aral S,
Blower S et al (2008) Infectious syphilis in high-income settings
in the 21st century. Lancet Infect Dis 8:244–253
2. Ghanem KG (2010) Neurosyphilis: a historical perspective and
review. CNS Neurosci Ther 16:e157–e168
3. Bradley WG, Daroff RB, Fenichel GM, Jankovic J (2004) Neu-
rology in clinical practice. Butterworth Heinemann, Philadelphia
4. Mignarri A, Chini E, Rufa A, Rocchi R, Federico A, Dotti MT
et al (2013) Lithium neurotoxicity mimicking rapidly progressive
dementia. J Neurol 260(4):1152–1154
5. Jantzen SU, Ferrea S, Langebner T, Gaebel W, Griese M, Arendt
G, Dihné M (2011) Late-stage neurosyphilis presenting with
severe neuropsychiatric deficits: diagnosis, therapy, and course of
three patients. J Neurol 259(4):720
6. Zheng D, Zhou D, Zhao Z, Liu Z, Xiao S, Xing Y, Suo WZ, Liu J
et al (2011) The clinical presentation and imaging manifestation of
psychosis and dementia in general paresis: a retrospective study of
116 cases. J Neuropsychiatry Clin Neurosci 23(3):300–307
7. Nagappa M, Sinha S, Taly AB, Rao SL, Nagarathna S, Bindu PS,
Bharath RD, Murthy P et al (2013) Neurosyphilis: MRI features
and their phenotypic correlation in a cohort of 35 patients from a
tertiary care university hospital. J Neuroradiol 55(4):379–388
8. Kawai N, Baba A, Mizukami K, Sakai T, Shiraishi H, Koizumi J
et al (1994) CT, MR, and SPECT findings in general paresis.
Comput Med Imaging Graph 18(6):461–465
9. Borghesani PR, DeMers SM, Manchanda V, Pruthi S, Lewis DH,
Borson S et al (2010) Neuroimaging in the clinical diagnosis of
dementia: observations from a memory disorders clinic. J Am
Geriatr Soc 58(8):1453–1458
10. Marra CM (2009) Update on neurosyphilis. Curr Infect Dis Rep
11:127–134