Brief Communication

obstructive pulmonary disease:

long-term trends. Int Med J 2007; 37:
87-94.
15 Dolan S, Varkey B. Prognostic factors
in chronic obstructive pulmonary
disease. Curr Opin Pulm Med 2005; 11:
149-52.
16 Steer J, Gibson G, Bourke S. Predicting
outcomes following hospitalization for
acute exacerbations of COPD. QJM 2010;
103: 817-23.
17 Ranieri P, Bianchetti A, Margiotta A,
Virgilio A, Clini E, Trabucchi M.
Predictors of 6-month mortaiity in

elderly patients with mild chronic

obstructive puimonday disease
discharged from a medicai ward
after acute nonacidotic exacerbation.
J Am Geriatr Soc 2008; 56: 909-13.
18 Terzano C, Conti V, Di Stefano F,
Petroianni A, Ceccarelli D, Graziani E
et al. Comorbidity, hospitalization, and
mortality in COPD: results from a
longitudinai study. Lung 2010; 188:
321-9.
19 Curtis J. Palliative and end of life care
for patients with severe CQPD. Eur
Respir J 2008; 32: 796-803.

20 Elkington H, White P, Addington-Hall J.

The healthcare needs of chronic
obstructive puimonary disease patients
in the last year of life. Pallit Med 2005;
19: 483-91.
21 Solano J, Gomes B, Higginson 1. A
comparison of symptom prevalence in
far advanced cancer, AIDS, heart
disease, chronic obstruaive pulmonary
disease and renal disease. J Pain Symptom
Manage 2006; 31: 58-69.

Mesiotemporal changes on magnetic resonance imaging

in neurosyphiils
R. B. Saunderson and R. C. Chan
Department of Microbiology, Royal Prince Aifred Hospitai, Sydney, New Soutin Waies, Austraiia

Key words

Abstract

syphiiis, herpes encephaiitis, magnetic

resonance imaging, mesiotemporal.
Correspondence
Raymond Cinristopiner Cinan, Royai Prince
Aifred iHospitai, Camperdown, NSW 2050,
Australia.
Emaii; raymond.chan@sswains,nsw.gov.au

We report a case of neurosyphilis with magnetic resonance imaging (MRI) hrain scan
findings compatible with a diagnosis of herpes simplex encephalitis with negative testing
for herpes simplex virus in the cerebral spinal fluid. An extensive review of the literature
has been undertaken revealing 24 cases worldwide where there are mesiotemporal
changes on MRI concurrent with a diagnosis of neurosyphilis. Therefore, it is now well
established that neurosyphilis, 'the great imitator', should be considered in the differential diagnosis in all patients demonstrating mesiotemporal changes on MRI, changes
usually seen in herpes simplex encephalitis.

Received 23 June 2011 ; accepted 24 August

2011.
doi:10.1111/j.1445-5994.2012.02829.x

Syphifis is a sexually transmitted disease caused by the

spirochaete Treponema pallidum. It is characterised by
four stages; primary syphifis, characterised by an ulcer
(chancre) and regional lymphadenopathy; secondary
syphilis manifested by a macular rash, condylomata lata,
mucocutaneous lesions and generafised lymphadenopathy; latent syphilis, occurring after the secondary stage,
which is asymptomatic and detected serologically only.

Funding; None.
Conflict of interest; None.
2012 The Authors
internai Medicine Journai 2012 Royai Austraiasian Coiiege of Physicians

and finally, tertiary syphilis, which has widespread and

complex manifestations, which may include disease of
the neurological and cardiac systems.''^ Despite the introduction of antibiotics, syphilis has not been eradicated,
and in many parts of the world, there has been a resurgence of this disease and the incidence continues to rise.
This is thought to be a result of increased travel, the sex
industry, sexual promiscuity, human immunodeficiency
syndrome (HTV) and the misconception of the curability
of sexually transmitted infections.'"'
Given the variability of clinical presentation, clinicians
need to have a high index of suspicion for syphilis, 'the
1057

Brief Communication

great imitator'. We report a case of neurosyphilis in a

man presenting with psychiatric illness.
A 53-year-old right-handed heterosexual male was
apprehended at Sydney International Airport when he
was found to be agitated, aggressive and combative. Since
he appeared to be acutely psychotic, he was referred to
the local emergency department.
On assessment the patient was acutely disorganised,
with elevated mood, agitation, pressured speech, tangential thought patterns and grandiose ideas. His past
medical history included an episode of urethral gonorrhoea in 1992, which was treated with antibiotics. Of
note, the patient had no previous psychiatric history.
He had no allergies and did not take any regular
medications and had no notable family history. He previously worked for the United States Air Force as a cinematographer and had tertiary level qualifications,
including a Masters and Doctor of Philosophy in Media
Studies and Culture. He was a non-smoker and consumed two standard drinks daily and denied recreational drug use.
On examination, the patient was afebrile and vitally
intact although the patient was noted to be hypertensive
with a blood pressure of 160/85. His chest was clear
to auscultation, heart sounds were dual without auscultation of murmurs, and his abdomen was soft and
non-tender without organomegaly. He had an unremarkable neurological examination. He scored 24/30 on
mini-mental state examination, showing disorientation
and recalling 2/3 objects after distraction. He showed
significant dysgraphia. A urinalysis was negative for blood,
protein and leukocytes.
An organic screen was performed, with investigations
including computerised tomography of the brain with
contrast, full blood count, electrolytes including calcium,
magnesium and phosphate, renal function, thyroid function, coagulation studies and liver function tests. These
were entirely normal. C-reactive protein was marginally
elevated at 12.2 mg/L.
A collateral history from his partner indicated the
patient had a subacute decfine; in the 9 months prior
to presentation, he had behavioural and mood changes,
poor attention, disorganised behaviour, irritable mood
and poor memory. This had precipitated a marital breakdown after 7 years of marriage, and both the patient and
his wife had separated and were returning to the United
States to lead separate lives; he was apprehended at the
airport prior to taking his fiight back to the United States.
In the 2 weeks prior to presentation, she reported he was
grandiose, irritable and demonstrated insomnia.
The patient was admitted to the psychiatric unit with
a provisional diagnosis of an acute manic episode
secondary to bipolar disorder. He was commenced on
1058

anti-psychotic medications, lithium 500 mg twice daily

and olanzapine 10 mg nocte.
Serological tests for syphilis showed a rapid plasma
reagin test titre of 128, a positive result by chemiluminescent microparticle immunoassay (ARCHITECT
Syphilis TP) and a reactive result by T. pallidum particle
agglutination assay (TPPA). Cerebrospinal fluid showed
elevated protein at 0.115 g/L, and tested positive by
venereal disease research laboratory (VDRL) assay, TPPA
and fluorescent treponemal antibody (absorbed) assay.
The patient was promptly commenced on treatment
with intravenous benzylpenicillin 1.8 grams fourth
hourly for a 14-day period to treat for neurological
disease.
Further history from the patient was unyielding as
to where he acquired syphilis. His only identified risk
factor was his previous episode of urethral gonorrhoea.
He denied infidelity during the 7 years of marriage to his
wife, and his wife tested negative for syphilis, providing
further support of the diagnosis of late syphilis.
The patient underwent further investigation with
a full sexually transmitted infection screen, including
hepatitis B and C screen, HIV, Neisseria gonorrhoea and
Chlamydia trachomatis, and this was negative. Echocardiography, formal neuropsychiatrie testing and magnetic
resonance imaging (MRI) of brain were also undertaken.
The patient had a normal echocardiography, without
evidence of a dilated aortic root. Formal neuropsychiatrie
testing demonstrated widespread cognitive dysfunction,
with attention, working memory and processing speed
most affected.
Magnetic resonance imaging was performed with Tl,
T2, coronal FLAIR and gradient echo sequences obtained.
This demonstrated a small number of focal signal hyperintensities in the subcortical white matter of both hemispheres and linear enhancement in the left frontal lobe
superiorly. Changes were most marked in the temporal
lobe, with signal hyperintensity on T2-weighted images,
a finding usually described in herpes simplex encephalitis
(Fig. 1). Herpes simplex polymerase chain reaction (PCR)
was performed on the patient's cerebrospinal fluid (CSF),
and was negative. Following treatment, the patient was
discharged into the care of his family and returned to the
United States. Therefore, limited progress and follow-up
are available.
There are limited case reports in the literature of
mesiotemporal changes in neurosyphflis mimicking
herpes simplex encephalitis, the implication being that
neurosyphilis should be considered in the differential
diagnosis when mesiotemporal changes are discovered
on imaging. A full review of the literature has been
undertaken. The results are summarised in Table 1 and
discussed below.
2012 The Authors
Internai Medicine Journal 2012 Royai Austraiasian Coiiege of Physicians

Brief Communication

Figure 1 A T2-welghted coronal image showing signal hyperintensity

bilaterally in the temporal lobes, more marked on the left (arrow).

The United States National Library of Medicine database, PubMed, was searched using the terms 'syphilis',
'herpes encephalitis' and 'MRI'. This returned only 11
results, and so the search was broadened using the terms
'syphilis' and 'MRI'. This returned 262 results. Studies
reporting MRI changes in the mesiotemporal region were
selected for inclusion. Articles published in English and
German were included. Twenty-two publications met
criteria. A further two publications were found through
references cited in case reports found using the above
search, and were also included. A search was also
conducted using Medline, combining terms 'syphilis' and
'MRI' but did not return any additional literature than
that already found using PubMed.
Twenty-four patients (21 males, one female, two
unknown gender) were reported to have signal hyperintensities in the mesial temporal regions. The average age
was 46 11 years. Clinical presentations were variable,
with cognitive changes, seizures and personality changes
being the most commonly cited.
In 16 out of 24 cases, the CSF was tested for herpes
simplex virus using PCR, and in each of these cases,
the test was negative. One out of 24 tested for HSV
using serum antibodies, and this was also negative. The
remaining cases were not tested. CSF protein levels were
available for 18 of 24 patients, and in all instances, were
elevated. CSF cell count was available in 22 of 24 cases,
and the count was raised in 18 of these cases (leukocyte
range 5-114). The predominant finding was an elevation
in lymphocytes, but monocytes and polymorphonuclear
cells were often present. The CSF glucose was tested in 12
cases, and was normal in all but two cases where the level
was low. Twenty of 24 patients were tested for HIV, and
had a negative result.
2012 The Authors
Internal Medicine Journal 2012 Royai Australasian College of Physicians

Treatment outcomes were available in 16 cases; and

in all reported cases; improvement of neurological function was reported in the immediate period following
treatment with penicillin. However, those patients who
underwent longer term follow-up demonstrated persistent neurological deficiency of varying severity.
In all cases, testing of the CSF to confirm a diagnosis
of neurosyphilis (using Treponema pallidum haemagglutination. Venereal Diseases Research Laboratory (VDRL) or
fiuorescent treponemal antibody (absorbed) (FTA-ABS))
was performed. Where available, the titres have been
provided. The number of patients, presenting symptoms,
age, sex, MRI findings, investigations and treatment outcomes has been included in a tabulated form below.
We report a case of neurosyphilis in a patient with
a psychiatric presentation, with MRI demonstrating
signal hyperintensity in the mesial temporal lobes; a
finding described as pathognomonic of herpes simplex
encephalitis.
There are various case reports in the literature describing mesiotemporal changes on MRI in patients with
neurosyphilis; however, to date, this is the first comprehensive literature review describing all cases of neurosyphilis with MRI fitidings similar to those seen in herpes
simplex encephalitis. This literature suggests that the MRI
changes seen in herpes simplex encephalitis and neurosyphilis are indistinguishable.
This is especially pertinent, since other presenting
features, such as cognitive changes, memory impairment,
seizures and fevers can be present in both herpes simplex encephalitis and neurosyphilis. Furthermore, CSF
findings in both conditions are also non-specific, with
common findings including a lymphocytosis, elevated
protein and normal glucose. Unfortunately from the
information available, we cannot conclude if neurosyphilis presents with a more subacute presentation compared
with herpes simplex encephalitis; however, our patient
reported had a subacute decline spanning over 9 months.
These findings are important as it is now established
that neurosyphilis should always be considered in the
differential diagnosis of patients with mesiotemporal
abnormalities on MRI.
The patient in our case study had a high rapid plasma
reagin test (RPR) titre (1:128) raising the possibility of an
earlier stage of infection than late syphilis. Given the
patient's subacute decline over the preceding 9 months
and the absence of infection in his wife (after a marriage
of 7 years), we felt that the clinical presentation was most
consistent with neurological disease occurring in late
syphilis. Some of the cases reported in the literature also
have high serum titres of non-treponemal tests. Anecdotally, at least, it seems that even in late disease, nontreponemal titres can remain high.

1059

Brief Communication

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2012 The Authors

Internal iVledicine Journai 2012 Royai Austraiasian Coiiege of Physicians

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2012 The Authors
Internal Medicine Journal 2012 Royal Australasian College of Physicians

1061

Brief Comnnunication

The average age of patients was 46 years with a standard deviation of 11 years, with the commonest presentations being cognitive changes, seizures and personality
changes. Across the world, in developed and developing
countries, the overall rates of syphilis have begun to rise,
and many clinicians are not experienced with the varied
presentations of syphifis.'"'
Therefore, this review also emphasises the need to
consider syphilis in middle-aged patients presenting
with any of the above symptoms or with an unexplained
elevation in CSF protein.
Of interest, all but one of the 22 cases were males (in
two cases, the gender was not known). While it is established that rates of syphilis are higher in men than
women, a partial result of the high rates of syphilis in
men who have sex with men, and also due to screening
of women during pregnancy with opportunity for intervention, this ratio appears to he exaggerated, bringing
into question whether men are more susceptible to neurosyphilis affecting the mesiotemporal regions. Further
studies are required to confirm this observation.
Outcomes were reported in 16 patients, with variable
follow-up periods. In all cases, there was neurological
improvement with standard treatment. This further
emphasises the need to accurately diagnose neurosyphilis, since treatment significantly reduces morbidity.
Overall, this review of the literature has highlighted
that it is now well established that neurosyphilis should
be included in the differential diagnosis when mesiotemporal changes are seen on MRI.
The diagnosis of syphilis is made through the use of
non-treponemal (VDRL, RPR) and treponemal tests (FTAABS, TPPA, enzyme immunoassay and chemilumines-

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1062

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LETTERS TO THE EDITOR

Clinical-scientific notes
Pancytopenia due to severe
folate deficiency
In the Western world, folate deficiency is an uncommon
cause of anaemia and a rare cause of pancytopenia.
Prompt identification of severe haematinic deficiencies is
essential, as they may be mistaken for marrow infiltration by malignancy and lead to unnecessary investigation
and therapy. We also emphasise that the mean corpuscular volume (MCV) may not always refiect the severity
of deficiency and should not be used alone to initiate
testing.
We report the case of a 27-year-old PhD student who
presented to the emergency department with a 6-week
history of lethargy, weight loss, increasing breathlessness
and severely reduced exercise tolerance. His past medical
history was of cleft palate repair in childhood. His alcohol
consumption was minimal. On examination, he was pale,
anicteric, and with no palpable lymphadenopathy or
hepatosplenomegaly. He was pyrexial at 38.2C, hypotensive, tachycardie and tachypnoeic with preserved oxygnation as assessed by pulse oximetry. His blood results were
haemoglobin (Hb) 4.4 g/dL, MCV 86.3 fL, red cell distribution width (RDW) 14.2, white blood cell (WBC) 2.2 x
1O''/L, neutrophils 1.8 x lO'/L, lymphocytes 0.3 x 10*/L,
2012 Tile Authors
internai Medicine Journai 2012 Royai Austraiasian Coiiege of Physicians

Figure 1 Peripheral blood film showing anisopojkilocytosis.

platelets 45 x lO'/L, Iactate dehydrogenase 5250 iu/L, and

C-reactive protein 27 with normal electrolytes, liver
function and coagulation profile. A blood film confirmed
pancytopenia with anisopoikilocytosis and no blasts or
schistiocytes (Fig. 1). There were only occasional oval
macrocytes and hypersegmented neutrophils. Chest X-ray
was normal and an electrocardiogram showed sinus
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