Catharina M Legierse; Marijke R Canninga-Van Dijk; Carla AFM Bruijnzeel-Koomen; Veronica CM Kuck-Koot

doi:10.1684/ejd.2008.0397

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Sneddon syndrome and the diagnostic value of skin biopsies – Three young patients with intracerebral lesions and livedo racemos

European Journal of Dermatology. Volume 18, Numéro 3, 322-8, May-June 2008, Clinical report

DOI : 10.1684/ejd.2008.0397

Summary

Auteur(s) : Catharina M Legierse, Marijke R Canninga-Van Dijk, Carla AFM Bruijnzeel-Koomen, Veronica CM Kuck-Koot , Department of Dermatology, Academic Medical Center, Department of Dermatology P.O. Box 22700, 1100 DE Amsterdam, The Netherlands, Department of Pathology, University Medical Center, Utrecht, The Netherlands, Department of Dermatology, University Medical Center, Utrecht, The Netherlands.

Illustrations

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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