ARTICLE
Auteur(s) : Cornelia
Erfurt1, Matthias Lueftl1, Miklos Simon
Jr1, Gerold Schuler1, Erwin S
Schultz1,2
1Department of Dermatology, University Hospital
Erlangen, Hartmannstrasse 14, 91052 Erlangen, GermanyFax:
(+49)-9131-85 34098
2Department of Dermatology and Allergology, University
Hospital Giessen and Marburg, Deutschhausstr. 9, 35033 Marburg,
Germany
accepté le 1 Mars 2006
The most recent epidemic of syphilis was noted in 1990 in the
United States, with reported rates for primary and secondary
syphilis at 20 per 100,000 persons, a 59% increase since 1985. In
1991, there was a reversal of the increasing trend in the United
States and Western Europe and the incidence declined until the late
1990s [1]. However, current epidemiologic investigations show a
renewed trend of increasing rates since the initial decline of
syphilis, especially among homosexual men [2, 3]. In Eastern Europe
and the former Soviet Union, an increase in large-scale syphilis
epidemics was already seen in the early 1990s [4]. Early syphilis
is most frequently diagnosed, while only a few cases of late
(tertiary) syphilis are detected, either as a result of ineadequate
treatment of early syphilis or because of occasional antibiotic
therapies for other infections. However, former investigators
observed late manifestations in about 20% of untreated cases - with
exclusive cutaneous involvement such as nodules or gummas in 16%
[5]. So, while some cases of late syphilis are still being
reported, they require special attention to achieve a correct
diagnosis [1].
Case report
A 54-year-old-man was referred to our department for evaluation of
a nonpruritic papulous eruption present on his right forehead and
left side of the neck for about one month. Initial skin biopsy
specimens from the forehead showed lymphocytic infiltrates with
numerous plasma cells, which did not allow an exact diagnosis, but
can be observed due to treponemal infections. There were no
systemic complaints and he had been treated previously with topical
corticosteroids without any effect. His medical history was
significant for hypertension and his only current medication was
bisoprolole.
On admission to our department – one week after the first biopsy
had been taken –, physical examination revealed infiltrated,
erythematous plaques on the right side of his forehead ( (figure 1A) ) with
increasing tendency of growth. Another single lesion with advancing
borders in annular configuration was found at the left side of the
neck. In addition, on the sole of the left foot a serpiginous scaly
plaque was seen( (figure
1B) ). No mucosal lesions, genital ulcers, alopecia or
affection of palms was found. There was no enlargement of lymph
nodes or affection of internal organs. Neurologic and
ophthalmologic investigations revealed normal findings. There was
no previous history of sexually transmitted diseases or complaints
of genital ulcera.
Another biopsy specimen was obtained from the cervical lesion
and showed a rich perivascular, but also follicular lymphocytic
infiltrate. Again, numerous plasma cells were found ( (figures 2A and 2B) ).
Initial laboratory studies (table 1( Table
1 )) revealed a normal white blood cell and slightly
lowered erythrocyte counts (4.13 × 106/μL), hemoglobine
(12.8 g/dL) and haematocrit value (37.8%). Differential blood cell
count showed lowered lymphocyte counts (16%), stab cells (2%) and
increased number of neutrophils (79%). Increased serum uric acid
(8.0 mg/dL), gamma-glutamyl-transferase (56 U/L) and C-reactive
protein (96 mg/L) were found. Human immunodeficiency virus and
Borrelia burgdorferi serology were both negative. Also in the
biopsy specimen a PCR testing for borrelia burgdorferi was unable
to reveal specific sequencies.
Rapid plasma reagin titres were positive (1:160) and treponema
pallidum haemagglutination (TPHA) was reactive with a titer of
1:81920. Treponema specific IgM-antibodies showed a very low titer
of 1:20. Cerebrospinal fluid (CSF) studies were performed to
exclude an involvement of the CNS and revealed two white blood
cells/mm3 and slightly increased levels for
immunoglobuline G and A in liquor. TPHA was very low with a titer
of 1:20 in the liquor. The ratio of immunoglobulines in serum and
liquor was normal with a value of 0.1 and an involvement of the CNS
could not be detected.
Given the asymmetry and morphology of the cutaneous lesions, the
personal history of the patient who denied any sexual contact for
the last three years and the serological as well as the
histological findings, the diagnosis of late (tertiary) syphilis
was established. The patient was initially treated with intravenous
penicilline (6 million units, 5 times a day) for 7 days and
subsequently – after exclusion of neurosyphilis – with 3 doses of
intramuscular benzathine penicillin (2.4 million units per week).
The eruption cleared rapidly.
Table 1 Blood test results. Test was performed on day
of admission. Only abnormal results are listed
|
Patient value
|
Normal range
|
|
Erythrocytes
|
4.13 × 106/μL
|
4.2-5.9 × 106/μL
|
|
Hemoglobine
|
12.8 g/dL
|
13-17 g/dL
|
|
Haematocrit
|
37.8%
|
42-52%
|
|
Differential blood cell count
|
|
Lymphocytes
|
16%
|
25-50%
|
|
Neutrophils
|
79%
|
50-70%
|
|
Stab cells
|
2%
|
3-5%
|
|
Serum analysis
|
|
Uric acid
|
8.0 mg/dL
|
3.4-7.0 mg/dL
|
|
Gamma-glutamyl-transferase
|
56 U/L
|
< 55 U/L
|
|
C-reactive protein
|
96 mg/L
|
< 5 mg/L
|
Discussion
Secondary syphilis has traditionally been considered to be the
“great imitator” in view of its clinical and histological
presentations [5]. But skin lesions of late syphilis are also
challenging to diagnose. Manifestations of late syphilis can occur
after a latency of up to 10 years after the primary infection. It
has to be assumed that about 75% of untreated secondary syphilis
lesions heal spontaneously, but 25% develop a late syphilis [1].
Characteristically, late syphilis presents on the skin with
syphilitic lesions, either the cutaneous tubercular or the
subcutaneous gummatous ones [7]. The tubercular lesion appears as
nodular circinated lesions with peripheral extension. In some
cases, a scaly component can lead to misdiagnosis of psoriasis or
Bowen’s disease. Further clinical differential diagnoses of the
tubercular syphilitic lesions are granuloma annulare, lupus
vulgaris, sarcoidosis, lupus erythematosus or (pseudo)lymphoma.
Tubercular lesions favor the arms, back and face. Involvement of
internal organs such as the cardiovascular or neuronal system
usually appear 10-30 years after infection and were not found in
our patient. He showed, however, an erythematous plaque on his
right forehead and left neck. Moreover, a typical circinate lesion
with elevated borders was found on the sole of his left foot.
The characteristic histological features of tubercular late
syphilis include perivascular infiltration of lymphocytes and
plasma cells as we found in the case presented here. This is
accompanied by intimal proliferation in arteries and veins,
eventually followed by ischemia and ulceration. Papular skin
lesions of late syphilis also often show endothelial swelling in
dermal vessels [6] which was not found in our patient.
Cases of late syphilis bearing a striking resemblance of
lymphoreticular malignancies have been described only rarely [8].
One patient presented with scaly plaques with atrophic scarring on
his leg. Histologically, lymphocytic infiltrates and epithelioid
cells were found in the dermis and subcutaneous tissue. Rare counts
of plasma cells complicated the diagnosis [9]. Another case
described a patient with annular plaques on his arms diagnosed as
granuloma annulare according to clinical and histopathological
findings. Exacerbation of the lesions under topical treatment led
to further causative studies and revealed the diagnosis of tertiary
(late) syphilis. Retrospectively, plasma cells and granulomas with
lymphocytic infiltrates were consistent with the syphilis diagnosis
[10]. Two other patients from Portugal were reported recently with
clinical manifestations of annular plaques and psoriasiform
scaling. Skin biopsies showed plasmocytic infiltrates without
granulomas. Interestingly VDRL tests were negative in both cases
and the diagnosis could not be confirmed until specific treponemic
tests were positive [11].
In our patient, the erythematous plaque on the forehead was
clinically primarily suggestive for a pseudolymphoma. The frequent
occurrence of plasma cells pointed to the possibility of a
Borrelia-associated pseudolymphoma. Indeed, taking into
consideration the clinical presentation, medical history, histology
and serological findings, the diagnosis of late syphilis could be
achieved.
Because there are barely controlled studies for the variety of
therapy-influencing factors, the regimens for the therapy of
syphilis are mostly based on experience. There are concurrently
several international guidelines about the treatment of late
syphilis with different therapy drafts. Differences still remain
around many details, but there is consensus that penicillin is
still the treatment of first choice, since no resistance of
treponema against penicillin has developed within the last 60 years
of treatment. The efficacy of therapy for syphilis is determined by
slow replication time of T. pallidum and therefore a prolonged
course of treatment is necessary, especially for late-phase
syphilis where the treponemes are supposed to divide even more
slowly. Therefore the length of treatment should last 3-4 weeks.
Parenteral administration is preferable to an oral one to reach a
sufficient level of penicillin in the serum. Unless the diagnosis
of neurosyphilis is completely excluded, the infection has to be
treated according to the neurosyphilis schedule. All patients who
have syphilis should be tested for HIV, because HIV-positive
patients have an increased risk for neurologic complications and
higher rates of treatment failure. Prior to HIV infections the
treatment of late latent syphilis revealed only a few cases of
progressions to neurosyphilis [12]. There is no treatment for
HIV-positive patients that proved to be more efficient than the
common regimen for HIV-negative individuals.
A variety of preparations and regimens are actually used for the
therapy of late syphilis, but only a few studies have been
performed recently. table 2( Table 2 )
shows the actual guidelines by the German STD Society (DSTDG), the
European Guidelines and the US Guidelines by the Center of Disease
Control concerning the therapy regimen for tertiary (late) syphilis
and neurosyphilis [13-15]. Treatment failure can occur with any
regimen. Patients should be re-examined clinically and
serologically, but limited information is available concerning the
clinical response of patients with late syphilis. In the case of
neurosyphilis, CSF should be reassessed not earlier than 1-2 years
after treatment.
However, before an adequate therapy can be initiated, the
clinician has to be able to make an appropriate diagnosis. Syphilis
is notorious for having many different clinical presentations and
histological findings, and it is likely that this is the reason why
a case such as the one presented here has only infrequently been
described. In conclusion, we emphasize the necessity of keeping
syphilis in mind in the differential diagnoses of papulo-nodular
lesions to ensure the early diagnosis and treatment.
Table 2 Therapy regimen for late and neuro-syphilis
according to the DSTDG-Guidelines, European Guidelines and
CDC-Guidelines (adjusted from 13-15)
|
Tertiary Syphilis
|
Neurosyphilis
|
|
Standard
|
Alternative
|
Standard
|
Alternative
|
|
DSTDG-Guidelines[13]
|
- BBP 2.4 M i.m. day 1, day 8 and day 15
- PBP 1.2 M i.m. for 21 days
|
- Doxicycline 2 × 100 mg/d p.o. for 28 days
- Erythromycin 2g/d i.v. for 21 days
- Off-label use of ceftriaxone 1-2g/d i.v. or i.m. for 14d
|
BP 6 × 3-4 Mio or 3 × 10 M or 5 × 5 M i.v. for at least 14
days
|
- Doxicycline 4 × 200 mg/d for 28 days
- Ceftriaxone 1 × 2g i.v. for 10-14 days
|
|
European Guidelines[14]
|
- BBP 2.4. M i.m. day 1, 8 and 15
- PBP 0.6-1.2 M i.m. for 21 days
- BP 1M daily i.m. for 21 days
|
- Doxicycline 2 × 100 mg/d p.o. for 28 days
- Tetracycline 4 × 500 mg p.o. for 28 days
- Erythromycin 4 × 500 mg p.o. for 28 days
|
- BP 6 × 2-4 M i.v. for 10-21 days or 0.15 M/kg/d in 6 doses
for 10-14 days
- PBP 1.2 – 2.4 M i.m. plus Probenecid 4 × 500mg for
10-21 days
|
Doxicycline 2 × 200 mg/d p.o. for 28 days
|
|
CDC-Guidelines[15]
|
BBP 2.4 M i.m. day 1, day 8 and day 15
|
- Doxicyclin 2 × 100 mg/d p.o. for 28 days
- Tetracycline 4 × 500 mg p.o. for 28 days
|
BP 6 × 3-4 Mio i.v. for at least 10-14 days
|
PBP 2.4 M i.m. plus Probenecid 4 × 500mg for 10-21 days
|
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