ARTICLE
Auteur(s) : Rosanna
Satta1, Antonello Pala2, Giulio
Rosati2, Francesca Cottoni1
1Institute of Dermatology, University of Sassari,
Italy
2Institute of Clinical Neurology, University of Sassari,
Italy
accepté le 6 Avril 2005
Prion diseases are transmissible spongiform encephalopathies in
humans and animals characterized by the accumulation of a modified
proteinase-resistant isoform (PrPres) of the cellular prion-related
protein (PrPc), within the central nervous system.
PrPc is a normal cell surface glycoprotein,
predominantly expressed within the central nervous system. Prion
proteins do not self-replicate but are thought to trigger the
conversion of PrPc to the pathologic PrPres. The
accumulation of the modified PrPres in the central nervous system
may not be sufficient to explain Creutzfeldt-Jakob’s disease (CJD),
but it may constitute a critical step in cellular dysfunction [1].
Sporadic (“classical”) CJD is the most common of the human prion
diseases, affects elderly individuals and remains of unknown cause.
Among other forms of CJD, new variant CJD is caused by the
transmission of bovine spongiform encephalopathy to humans and
cases of secondary iatrogenic transmission via blood transfusion
have been reported.So far as the literature regarding dermatology
is concerned, reports on prion pathologies are rare and consist
mostly in experimental observations and few case reports. In vitro
studies have shown PrPc expression in squamous epithelia
of normal and diseased human skin. This normal cellular
glycoprotein, in vitro, can transform into the pathological isoform
by means of a propagation mechanism that includes physical contact
among molecules [2]. These laboratory observations show the skin as
a possible peripheric target for prion infections. The practical
consequences of this observation are manifold, and concern in
particular the potential for transmission via the skin. In
dermatology, a possible source of percutaneous infection is the use
of bovine-derived substances, in particular collagen, administered
via injection [3]. In addition, the possibility of transmission of
prion material has been hypothesized both for injectable
preparations containing human serum albumin, such as commercially
available botulinum neurotoxin products, and for skin grafts
derived from human cell cultures [4]. Still, from the point of view
of dermatological interest, there are recent studies concerning the
level of percutaneous transmission via insect bite in prion
diseases [5]. As to clinical case-reports, the literature carries
only two cases of prion pathologies in association with
dermatological diseases [6, 7].We present here a case of unusual
skin vasculitis in the course of CJD.
Case report
A 72-year-old housewife, with negative family history for
neurological pathologies, had suffered from emotional
deterioration, starting from December 2001, with mood swings and
dysphoric signs, ideative and dysperceptive disorders with
appearance of mnesic disturbance, spatial-temporal disorientation,
and difficulties in walking, mostly of an ataxic nature. On account
of these symptoms, the patient was admitted in January 2002 to the
Institute of Neurology at the University of Sassari where her
condition progressively deteriorated with the appearance of
oppositional hypertone in the four limbs and increased motor
incapacity, along with disturbances at the level of verbal
articulation and swallowing. Three days after admission and over a
period of 12 hours, a single large (18 × 15 cm) purplish
irregular erythemato-edematous area with bullous detachment
appeared on the patient’s antero-medial right thigh (( figure 1 )). The lesion
rapidly evolved into an ulcer covered by a blackish necrotic
eschar. Histological examination showed an essentially intact
epidermis but with a high degree of necrotizing vasculitis in the
vessels of the underlying middle and deep dermis with
leukocytoclasia and fibrinoid necrosis (( figure 2 )). Direct
immunofluorescence showed intense vascular IgM and C3 deposits
around the vessel walls of the middle and deep dermis. Treatment
was started with prednisone 25 mg/die, and three weeks later the
ulcerative lesion appeared significantly improved. Complete healing
with residual scarring occurred within one further month.
Routine laboratory tests were effected. Haemochrome and white
blood count were normal. Alanine aminotransferase was at 49 U/L
(normal values, n.v. 10-45), aspartate aminotrasferase at 51 U/L
(n.v. 10-55), γ-GT at 81 U/L (n.v. 8-78). Urea and electrolytes,
coagulative functions, C and S proteins as well as neoplastic
markers were within the norm. Autoantibodies ANA, ASMA, C-ANCA,
anti-ENA and antiphospholipids were absent. Serum antibodies to
neurotropic viruses and Treponema pallidum were absent. Serum
protein electrophoresis and immunodiffusion were within the norm.
Neuron specific enolase in the cerebrospinal fluid was within the
norm. The search for 14-3-3 protein in spinal liquor proved
positive and homozygosity for valine at polymorphic codon 129 of
the PRNP gene was found. An electroencephalogram showed generalized
non-specific slow-wave activity of variable degree without
lateralization. Cerebral nuclear magnetic resonance showed
hyperintensity at lenticular nucleus and caudate nuclear head. On
the basis of these data and of the clinical picture, a diagnosis of
sporadic CJD was made. The patient experienced a rapid progressive
decline and died of respiratory insufficiency in May 2002.
Post-mortem analysis of the patient’s brain tissue was performed at
the Laboratory of Virology, “Istituto Superiore di Sanità”, Rome.
Immunoblotting of frozen tissue extracts showed the presence of
PrPres protein glycotype 2A, confirming the diagnosis of CJD. The
same technique was also employed to examine protein extracts
obtained from the lesional skin biopsy used for immunofluorescence
studies, but no PrPres protein could be detected.
Discussion
This case of sporadic CJD was characterized by the appearance
during the course of the disease of a vasculitic skin
manifestation. The literature refers only two other cases of CJD
with associated skin manifestations [6, 7]. The first case,
reported in 1976, describes the appearance of CJD in a patient
under steroid treatment for pemphigus vulgaris. This being a work
hailing from a pre-prion era, a role for immunosuppression in the
induction of the mysterious neurological pathology was hypothesized
[6]. In 1981, a classic CJD case associated with vasculitic skin
manifestations was described. This patient presented multiple
vasculitic lesions on limbs and trunk with an ulcerative evolution.
The authors stated that the pathologic findings were unique and may
have reflected an unusual host response to the etiologic agent
causing CJD, which at that time, was hypothesized as being a virus
[7].
Our case, twenty years after this latter report, constitutes the
second description of skin vasculitis in the presence of CJD. It
was characterized by the sudden and rapid appearance during CJD of
a vast isolated necrotic area with eschar on the anterior right
thigh. The lesion presented a histological picture of extensive
necrotizing vasculitis with leukocytoclasia and fibrinoid
degeneration of the dermal vessels and direct immunofluorescence
showed vascular IgM and C3 deposits around vessels walls.
Considering the various factors present in the case, a possible
connection between the underlying neurological pathology and skin
vasculitis was taken into account.
Numerous studies have in the past demonstrated that the prion
protein, a proteinase resistant isoform of the PrPc, is
poorly immunogenic because the immune system should be tolerant to
such a self-protein. This would therefore have made unlikely an
immunological role for the prion protein in the appearance of
vasculitic skin lesions, as was our case, during CJD [2, 8, 9]. On
the other hand, more recently, the theory that the immune system is
prion-tolerant has been thoroughly re-examined and various cells
with important immunological functions are considered as playing
key roles in the pathogenesis of prion pathologies. In particular,
the Langerhans cells would seem to be involved in prion
accumulation and diffusion [10, 11]. Indeed, even in the course of
CJD, extraneural pathological PrPres expression has been
demonstrated [12]. Therefore, we looked for the possible presence
of PrPres in lesional skin extracts by immunoblotting analysis.
This analysis, carried out in the same laboratory where the brain
had been studied, gave negative results. In order to confirm, or
indeed deny, any causal nexus between CJD and skin manifestations,
the analysis should have been repeated on protein extracts from
both lesional and normal patient’s skin and the search for
PrPc protein should have been performed in parallel. In
our case, post-mortem skin specimens could not be obtained, due to
national regulations.
To conclude, it is not as yet possible to establish a causal
nexus between the observed vasculitis and CJD. At present,
therefore, the significance of our observation of a localized skin
vasculitis in a patient affected with CJD remains uncertain and the
association is possibly coincidental. However, considering the
increasing interest in pathologies caused by prions, it is our view
that a watching brief should be held for all dermatological
manifestations in the course of prion diseases.
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