ARTICLE
Auteur(s) : Catharina M
Legierse1, Marijke R Canninga-Van Dijk2,
Carla AFM Bruijnzeel-Koomen3, Veronica CM
Kuck-Koot3
1Department of Dermatology, Academic Medical Center,
Department of Dermatology P.O. Box 22700, 1100 DE Amsterdam, The
Netherlands
2Department of Pathology, University Medical Center,
Utrecht, The Netherlands
3Department of Dermatology, University Medical Center,
Utrecht, The Netherlands
accepté le 4 Février 2008
Sneddon syndrome (SS) was first described by Champion and Rook
in 1960 [1]. The disease is a rare disorder characterised by
generalised livedo racemosa of the skin and cerebrovascular
lesions. In 1965 it was named after the British dermatologist
Sneddon, who described six patients with these characteristics [2].
Sneddon made no statements about etiology, but thought it might be
a type of endarteritis obliterans. In the years that followed, the
existence of the syndrome was confirmed [3-5], and researchers
tried to unravel the pathogenetic mechanism and determine the
diagnostic criteria of SS [6-10]. The value of biopsies in the
diagnosis of SS has been investigated. Some investigators’ results
did not show specific changes in the biopsies [8], while others
concluded the positive value of skin biopsies [4, 7, 9, 11-13].
Histological findings, a non-inflammatory thickening of the vessel
wall with eventual occlusion of the lumen, were found to be
characteristic, though not specific [4]. Research has also
investigated the involvement of antiphospholipid antibodies (aPL)
in the pathogenesis of SS, which has been suggested by some [5,
14-16], while not supported by others [17].
A gold standard for diagnosing SS is still lacking. No consensus
exists about how to diagnose SS, based on clinical features, on
histological findings, or both, as well as about the additive value
of laboratory parameters. In this paper we illustrate this
still-existing difficulty of defining the diagnostic criteria of
SS, and discuss the additive value of a relatively highly specific
skin biopsy in this process.
Case 1
A 23-year-old male presented with severe neurological symptoms of
hemianopsia and sensory loss (table 1).
Magnetic resonance imaging (MRI) scans of the brain confirmed
ischemic lesions in the occipital lobe, but the cause of his
symptoms remained unclear. Dissection was ruled out by angiography,
cardiac embolisms were not plausible and infection and blood
clotting parameters were normal. One year later he developed livedo
racemosa of the lower extremities. The cause of his skin colouring
was not found in this period. Routine blood chemistry tests
revealed normal values.
Two years later, neurological problems occurred again. He
experienced transient motor and sensory loss in one leg. Magnetic
resonance angiography (MRA) revealed a lacunar infarct and the
known occipital infarcts. In the meantime he had become disabled
for work. Seven years after his first neurological problems, he had
symptoms of cerebral infarcts again. Histological results of skin
biopsies, two 4 mm biopsies and four 2 mm biopsies of the
arm and trunk, showed an intima proliferation of cells around the
cutaneous small arteries and arterioles, according to the
intermediate phase, or stage III, described by Zelger et al. [12]
(figures 1A and
B) and (figure
2). The proliferated cells appeared positive in alpha
SMA-colouring, meaning it concerned a proliferation of smooth
muscle cells or myo-fibroblastic cells. This, together with the
clinical picture, confirmed the diagnosis of SS. Coagulation tests,
like the detection of proteins C, Z and S, fibrinogen and
prothrombin, as well as immunological test results, including
rheumatoid factor, antinuclear antibodies (ANA) lupus
anticoagulans, anticardiolipin antibodies (aCL) and antineutrophil
cytoplastmatic antibodies (ANCA), were repeatedly tested and always
found normal.
The patient then evolved hyperhomocysteinemia
(40-60 μmol/L) and hypertension, which later appeared to be
due to renal dysfunction. He was treated with platelet aggregation
inhibitors, folic acid and antihypertensive drugs.
Table 1 Findings in three patients with clinical
features of Sneddon
|
Case 1
|
Case 2
|
Case 3
|
|
Sex
|
Male
|
Male
|
Female
|
|
Age of onset (years)
|
23
|
21
|
28
|
|
Risk factors for vascular disease
|
Cigarette smoking, positive family history for vascular disease,
obesity, hypertension, hyperhomocysteinemia,
hypercholesterolemia
|
Cigarette smoking, positive family history for vascular disease,
hypertension, hyperhomocysteinemia
|
Cigarette smoking, obesity, positive family history for vascular
disease, oral contraception
|
|
Livedo racemosa
|
Lower extremities, trunk
|
Extremities, trunk
|
Lower extremities, trunk
|
|
Onset of livedo (age)
|
24
|
27
|
30
|
|
Skin biopsy
|
Abnormal small, deep dermal vessels, arteriolar endothelial
proliferation
|
Vascular occlusion, arteriolar endothelial proliferation
|
Normal
|
|
Antiphospholipid antibodies
|
Negative
|
Negative
|
Negative
|
|
Blood pressure
|
170/90 mmHg
|
180/90 mmHg
|
130/90 mmHg
|
|
ARRAY(0x230ab0)
|
|
Neurological disorder
|
Unilateral loss of sensory function, hemianopsia, short lasting
total blindness
|
Transient hemiplegia, dysarthria, left facialis paresis, partial
paresis left arm and hand
|
Variable hemiparesis, hemihypesthesia, dysarthria, headache
|
|
Cerebral MRA
|
Lacunar and occipital ischemic lesions
|
Hypoplastic vertrebral artery in the left hemisphere
|
Normal
|
|
Cerebral MRI
|
Ischemic lesions
|
Ischemic lesions
|
Small ischemic lesion right hemisphere
|
Case 2
A 21-year-old, sporty male experienced sudden right hemiplegia,
which spontaneously cleared up in a few days. Two years later he
had the same transient symptoms on the left side of his body.
Computer tomography (CT) scan, showing multiple hypodensity in both
hemisperes, revealed intracerebral ischemic lesions, which were
explained as the cause of his neurological problems (figures 3A and 3B).
MRI showed multiple old and recent intracerebral ischemic lesions.
The small vessels had proliferated and were tortuous (figures 4A and 4B).
MRA demonstrated no changes in the big extracranial and
intracranial arteries. A biopsy of the cerebral cortex was
performed in order to specify the aspect of these small vessels. It
showed signs of ischemic lesions in arteries and arterioles. No
signs of vasculitis were found.
Six years later the patient had new cerebral infarcts. In the
meantime he had developed livedo racemosa. This skin pattern and
the history of multiple cerebral infarcts brought up the diagnosis
SS. Three 2 mm skin biopsies of both arms, showing signs of
stage III, as described by Zelger et al. (1992) [12], as well as
stage IV, namely small arteries with a thickened wall in the deeper
dermis and occluded arterioles with newly formed capillar vessels.
No signs of vasculitis were revealed. Alpha-SMA colouring showed
smooth muscle cells in the vessel walls, with a widened
endothelium. These results supported the diagnosis of SS. All
immunological tests, repeatedly performed, including rheumatoid
factor, lupus anticoagulants, aCL, ANA ANCA, showed no
abnormalities. Hypertension and hyperhomocysteinemia (20 μmol/L),
most likely due to renal dysfunction, were found a few weeks later.
A biopsy of the kidney showed ischemic damage of the glomeruli and
tubuli, most likely resulting from the thickened vessel walls
described in SS. Treatment consisted of platelet aggregation
inhibitors, folic acid and antihypertensive drugs.
Case 3
A 29-year-old, obese woman had suffered from unexplained symptoms
of fatigue, headache, periods of fever and leucocyturia for years
when she presented at the emergency room with transient periods of
paresis and anaesthesia of the left side of her body and face,
accompanied by dysarthria. Analysis for the cause of her sudden
illness with MRI and MRA showed a small intracerebral lesion. Its
origin remained unknown.
One year later she developed livedo racemosa on her legs and
trunk (figures 5A-C). One
2 mm skin biopsy was taken from the left upper leg. Apart from
a few slightly dilated small vessels in the dermis, the skin biopsy
was normal. All immunological test results were normal on several
occasions.
Her neurological complaints got worse, with recurrent symptoms
of transient ischemic attacks. Further analysis (MRI, MRA,
electro-encephalogram, duplex and liquor punctures) did not reveal
any cause. Therefore, no treatment was started at this point. The
patient will be seen again and a new biopsy will be taken in the
near future.
Discussion
We present three patients with livedo racemosa and neurological
symptoms, as described by Sneddon in 1965 [2], though skin biopsies
could only confirm the diagnosis of SS in two of the patients.
Manifestations
SS is characterised by cerebrovascular ischemic attacks and livedo
racemosa. Other symptoms, like involvement of the heart or kidney,
arterial hypertension and complicated obstetric or gynaecological
history in women, have been described [15, 16, 18].
Cutaneous manifestation
Livedo racemosa is defined as an erythematous, irregular netlike
pattern, which is typically distributed over the trunk and
extremities [3, 19]. It is located on the limbs (100%), trunk
(84-89%), buttocks (68-74%), face (15-16%) or hands or feet
(53-59%) [12]. The pattern of livedo racemosa is difficult to
distinguish from the pattern of livedo reticularis. Livedo racemosa
is the result of a reduced peripheral blood flow through occluded
small cutaneous arteries [3, 12, 20], whereas livedo reticularis is
a result of a generalised reduction of blood flow [12, 21].
Furthermore, livedo racemosa is more generalised and has an
irregular shape with broken circular segments [11]. In contrast to
livedo racemosa, no histological vascular alterations can be found
in biopsies of livedo reticularis [21].
Livedo racemosa has been associated with numerous conditions,
including collagen vascluar diseases, adverse effects of drugs,
vasculitis, infection, metabolic disorders, neoplasms, hematologic
diseases, neurologic disorders, pancreatitis and emboli. About half
the cases are idiopathic [4].
Extracutaneous manifestations
Central nervous system manifestations include headache (85%),
transient ischemic attacks, hemiplegia, hemihypestesia,
hemianopsia, dysarthria, central facial palsy, epileptic attacks,
chorea, tremor, myelopathy and acute encephalopathy [2, 8, 20-23].
Epileptic seizures are most often described in SS patients with
positive aPL [24]. The presence of several other manifestatios such
as cardiac and kidney lesions suggests that it is a systemic
syndrome. Secondary symptoms can include arterial hypertension,
cardiac abnormalities such as valvulopathy (61%) and ischemic heart
disease, ocular (50-70%), gastrointestinal, renal involvements
(50-70%) and venous occlusions [16, 21, 25, 26]. Mild to moderate
hypertension has been found in 60%-80% of patients with SS [3, 27].
No direct relationship has been described between
hyperhomocysteinemia and SS. Increased homocysteine can be
considered a risk factor for vascular disease [28, 29]. Central
retinal artery occlusion has often been described. Renal function
is an important determinant of circulating homocysteine
concentrations, and high levels of homocysteine are found in
patients with renal failure [30, 31]. In the course of the disease,
nearly all SS patients show signs of cognitive dysfunction [21].
Epidemiology
SS has been regarded a rare disorder, with an incidence of four per
million per year. Although two of the patients presented here are
male, SS mainly affects women (50-80% of cases) in early adult life
(25-42 years) [3, 19-21]. In about 50% of the cases recorded,
livedo racemosa precedes cerebrovascular events [8, 17]. It has
been estimated that SS occurs in about one in every two thousand
stroke patients [32, 33].
Pathophysiology
The pathophysiological background of SS is still unknown. The
pathogenesis seems to involve a focal thrombotic or embolic process
in the arterial or arteriolar vascular system in the skin and the
central nervous system [34]. Autoimmune phenomena orientated
towards the endothelial cells have been observed, particularly in
combination with the antiphospholipid antibody syndrome (APLS). A
division has been suggested, into primary SS, if no etiological
factor can be detected, or secondary SS, which occurs as part of an
autoimmune disorder or in a thrombophilic state [35]. Francès et
al. (1999) proposed that SS should be classified as idiopathic SS
with neither aPL nor SLE, primary APLS-related SS and SLE-related
SS with or without aPL [22]. Sneddon considered the syndrome to be
a type of endarteritis obliterans [2]. Others regarded SS as a
systemic vasculitis of small to medium sized arteries [36]. Though
some familial cases have been described and genetic predisposition
in an autosomal dominant or recessive pattern has been proposed, so
far no gene chromosome localisation has been found [17, 37-40].
Because of the increased risk of a thrombotic or embolic process,
smoking and oral contraception have been described as risk factors
for developing SS [19].
Antiphospholipid antibodies (aPL)
aPL are antibodies against phospholipids, that are associated with
venous and/or arterial thrombosis, thrombocytopenia and
miscarriage. In all three patients reported, no aPL were detected.
However, the association of SS with aPL has been frequently
described. Some researchers could confirm the relationship [5, 6,
8, 14-16], while others could not [17]. In about 50% of SS patients
aPL can be detected and according to many authors these cases
should be classified as primary APLS [40]. Other researchers
concluded the prevalence of aPL in SS highly variable, ranging from
0% to 85% [16, 22, 41]. The presence of aPL can explain the
thrombotic process of the endarteritis obliterans proposed by
Sneddon [2].
Differential diagnosis
Kraemer et al. (2005) described a spectrum of differential
diagnoses in neurological patients with livedo racemosa. The most
important diagnoses besides SS are primary APLS (5%-10%), systemic
lupus erythematodes (SLE) with or without APLS, essential
thrombocythaemia, polycythaemia vera, rheumatic disorders, Morbus
Cadasil, Divry Van Bogaert’s syndrome and Susac syndrome [17, 21,
42].
APLS is an acquired multisystem disorder of hypercoagulation,
occuring either secondary to an autoimmune disease or as a primary
disease [17, 43]. Serological markers are lupus anticoagulant and
anticardiolipin antibodies. APLS has been classified into primary
and secondary syndromes. Primary APLS occurs in the absence of
other underlying or associated diseases and is more common than
secondary APLS. Secondary APLS is associated with a large spectrum
of diseases including SS, SLE, other autoimmune diseases,
malignancy, and infections [13]. Clinical features include
recurrent thrombotic events, repeated fetal loss and
thrombocytopenia. Cutaneous manifestations may occur and include
among others livedo racemosa, as in SS, necrotising vasculitis,
livedoid vasculitis, purpura and erythematous macules [13]. The
fishnet of the livedo was described as clearly larger in
aPL-negative SS patients [16]. Seizures and clinically audible
mitral regurgitation were more frequently observed in aPL-positive
SS patients [16]. The most important histopathological difference
is the non-inflammatory vascular thrombosis in APLS, whereas
endothelitis and endarteritis obliterans are more characteristic in
SS [12, 13].
SLE is a multi-systemic autoimmune disease characterised by
circulating autoantibodies. The incidence is 7.3 per 100,000 [21].
In SLE and SS, the presence of similar features such as
cerebrovascular disturbances, livedo racemosa, fetal loss,
thrombocytopenia, and antibodies to phospholipids that can be
found, are all related to APLS. To differentiate between SS and SLE
one should pay attention to the skin lesions and other
differentiating symptoms. In SS, there are no skin lesions typical
for SLE such as ‘butterfly’, discoid lupus and
photosensibilisation, as well as mucous oral cavity sores and
polyarthritis. As SS emerges with livedo, cerebrovascular
disturbances and systemic APLS appearances, SLE in 75% of cases
begins with its classical symptoms and in 25% with systemic APLS
appearances, but never with livedo racemosa or cerebrovascular
disturbances [44]. It seems that the similarity between SLE and SS
is due to the development of secondary APLS.
Divry Van Bogaert’s syndrome is characterised by recurrent
strokes in young patients, mainly males, preceded by livedo
racemosa, mainly on the face and distal extremities. It is a very
serious disease leading to a bedridden state and dementia. The
prognosis for the patients seems very poor [21]. Skin biopsies show
no vasculitis, but an increased number of dermal vessels with
smooth muscle fibers around them [17, 45]. Historically the
distinguishing features between Divry Van Bogaert’s syndrome and SS
have been the presence of cerebromeningeal angiomatosis and the
familiar presentation of the first, although an autosomal and
recessive inheritance in SS has been reported [10, 21].
Susac syndrome consists of the clinical triad of encephalopathy,
hearing loss, and retinal artery branch occlusions, and mainly
affecting young women [42, 46].
Morbus Cadasil, cerebral autosomal dominant arteriopathy with
subcortical infarcts and leukoencephalopathy, is a small vessel
disease of the brain characterised by lesions of smooth muscle
cells. It is a disorder that mainly affects, but is not restricted
to the small brain arteries [16]. Its clinical manifestations begin
during mid-adulthood and include recurrent ischemic subcortical
events, attacks of migraine with aura, severe mood disorders,
subcortical dementia and, on MRI, widespread
leukencephalopathy.
Diagnostic tests
In diagnosing SS, though no gold standard is available, laboratory
parameters, skin biopsies and CT scan or MRI/MRA of the brain are
recommended. Doppler and duplex sonography of extra- and
intracerebral arteries, electroencephalography, ECG en and 24-hour
blood pressure monitoring could also be done, as well as a cortical
brain biopsy.
Laboratory tests
Though no specific laboratory parameters for SS have been found,
laboratory research is necessary to distinguish SS from other
diseases, such as APLS, coagulation disorders, SLE and infections
[11]. Recommended tests are annual routine laboratory tests such as
a full blood and platelet count, sedimentation rate, fasting lipid
profile, and creatinine clearance. Coagulation tests include
detection of antithrombin III, protein C, Z and S, fibrinogen,
prothrombin, and definition of prothrombin time. Immunological
testing includes C reactive protein, serum immunelectrophoresis,
complement, rheumatoid factor, ANA, ANCA, lupus anticoagulant, aCL,
anti smooth muscle and Sjögren A and B [21, 47]. These
immunological tests should at least be performed twice, with a six
week interval.
Skin biopsy
Histological proof of endothelitis of small arteries, followed by
occlusion of these arterioles by intimal proliferation, makes skin
biopsy (stage I to IV as described by Zelger et al. and Sepp et
al.) the only diagnostic criterium with a relatively high
specificity [7, 9, 12, 21].
An initial phase (stage I), characterised by attachment of
lymphohistiocytic cells to, and detachment of endothelial cells, is
followed by an early phase (stage II), in which the lumen is
partially or completely occluded by a plug of lymphohistiocytic
cells and fibrin. In the following stage, in the intermediate phase
(stage III), the occluding plug is replaced by proliferating
subendothelial cells, and in the final phase (stage IV) this is
followed by fibrosis and shrinkage. Arteries are either completely
occluded or recanalised [9, 12]. Ultrastructural and
immunohistochemical investigations have shown that the
subendothelially accumulating cells are migrating cells of the
tunica media containing smooth muscle actin (smooth muscle cells or
myofibroblastic cells), a phenomenon also seen in essential
thrombocythaemia or polycythaemia vera, or sometimes in livedo
reticularis [7, 9, 10].
Despite the relatively high specificity of skin biopsies, cases
of SS have been described with divergent skin biopsies. Some
researchers describe cases of SS with normal skin biopsies [8, 16,
20, 45], others describe the presence of endothelial cells,
characterised by Weibel-Palade bodies among the smooth muscle cells
in the occluded vessel lumen, in skin biopsies of an SS patient.
According to them, this may be comparable with the initial stage
described by Zelger et al. [48]. Also, false negative biopsies may
occur. Therefore, a negative biopsy does not exclude underlying
disease [22]. As skin biopsy can only show the characteristic
features of SS or another pathology, it is important to interpret
the results in connection with clinical and laboratory findings
[27].
Several researchers emphasise the importance of the right biopsy
technique. It has been suggested to take more than one deep punch
biopsy (4 mm) from the white areas of the livedo [10, 27].
Since the discoloration of the skin is provoked by a reactive
dilatation of venules, the red areas often show no abnormalities
[4, 7]. Sensitivity increases from 27% with one biopsy, 53% with
two biopsies to 80% with three biopsies [11]. In our third patient,
as well as in above mentioned normal biopsies in SS patients, one
could discuss the biopsy technique employed.
Radiology
In diagnosing SS, CT or MRI easily detects cortical or subcortical
abnormalities suggestive of arterial ischemic infarcts. In this
process MRI is more suitable as it has better sensitivity in the
diagnosis of subtle cerebral vascular lesions [27]. Periventricular
white matter changes can also be found in SS. Some authors
recommend angiography [19], though it carries some risks because SS
affects mainly small intracerebral arteries. Therefore others
suggest the combination of MRA and duplex sonography as a strategy
for the exclusion of large-vessel obstruction [27].
Treatment
Evaluation of treatment of SS is complicated by the intermittent
nature of the disease. Treatment with corticosteroids, platelet
aggregation inhibitors, and beta-adrenergic-blocking agents has
been investigated, but most of the patients did not experience
apparent benefit. Corticosteroids reportedly reduced transient
ischemic attacks and strokes in some patients with APLS but not in
SS. This may be due to the fact that corticosteroids have no effect
on the metabolism of platelets, which are likely to play a role in
SS [12]. The use of platelet inhibiting agents may have a modest
effect [3, 4]. Smoking, obesity and oestrogen-containing oral
contraceptives should be avoided [3, 21].
Course and prognosis
SS is a chronic, relapsing and mostly progressive disease. There
does not seem to be a correlation between the extent of the
cutaneous involvement and the severity of the central nervous
system manifestations, but prognosis is better for patients with
livedo racemosa and one cerebrovascular event compared to patients
with multiple lesions on CT of the head [3]. No correlation was
found between the duration of the disease and the histopathological
stage of the vascular lesions [12]. In SS patients, antibodies to
prothrombin (aPT), one of the cofactor proteins responsible for
binding aPL to phospholipids, seem to be a marker of comparatively
low risk of thrombosis and less severe course of the disease [49].
Fetoni et al. found a more benign course of disease in patients
with APLS compared to SS [50]. Hypertensive patients show more
worsening of neurological symptoms [45]. As a result of chronic or
recurrent stroke attacks, vascular dementia can develop in SS
patients [20]. Compared to young patients with cerebral infarction,
the prognosis of SS patients is poor [21]. Long term follow-up (6.2
years) of SS patients showed a mortality rate of 9.5% [12]. In a
six year prospective follow-up study, Boesch et al. observed a low
incidence of territorial stroke, but a progressive
leucencephelopathy in 17 SS patients [47].
Conclusion
Our three patients show the characteristic clinical features of SS.
However, only two of them have the histology that is pathognomic
for the syndrome. None of them had positive serology for aPL. This
paper stresses the still-existing difficulty in diagnosing SS as,
so far, no ‘gold standard’ has been found. We think that the added
value of skin biopsies has been determined and should play a
dominant role in the process of diagnosing SS, provided that it is
always employed using the right biopsy technique and is evaluated
in connection with clinical and laboratory findings.
Acknowledgements
Financial support: none. Conflict of interest: none.
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