Sneddon''s syndrome: clinical and immunohistochemical findings

Results of immunological studies on skin biopsies of 5 patients with Sneddon's syndrome are reported. Also studied were coagulation factors and autoantibodies believed to play a role in this syndrome. Hemostasis was normal except for a mild increase of fibrinogen in one subject; lupus anticoagulant (LAC) and anticardiolipin antibodies were negative in all. The skin biopsies ruled out systemic vasculitis and vasculitis in association with connective tissue diseases. Sneddon's syndrome is a peculiar clinico-pathological condition, probably with several etiologies, but is distinct from primary antiphospholipid syndrome.     

Sneddon's syndrome (livedo reticularis and cerebrovascular lesions) with antiphospholipid antibodies and severe dementia in a young man: a case report

We present the case of 37-year-old man with Sneddon's syndrome and antiphospholipid antibodies. His chief neurological manifestation was rapidly progressive dementia, which developed 6 years after the appearance of livedo reticularis.     

Neuropsychological deficits in patients with Sneddon's syndrome

The results of a neurological, neuropsychological and MRI study of the brain in 21 patients (aged 18–59 years) with Sneddon's syndrome are reported. The predominant findings were marked neuropsychological deficits in two-thirds of the patients. While sensorimptor deficits after stroke in these patients had a good prognosis, neuropsychological deficits persisted. Of the 21 patients, 14 were incapable of gainful employment, 10 because of severe cognitive dysfunction.     

Sneddon's syndrome: clinical course and outcome

Summary Fifteen patients with Sneddon's syndrome presenting since 1979 were re-examined. After a neurological examination, an orienting test of mental ability as well as an electroencephalogram were performed in all patients. In 10 of the 15 patients computed tomography of the brain was performed, too. Preceding reports and the results of the present study have been used to discuss the characteristics and prognosis of Sneddon's syndrome.     

Lupus anticoagulant and Sneddon's syndrome

We present the coagulation and serological studies of four patients with Sneddon's syndrome, in which antiphospholipid antibodies (anticardiolipin antibodies and lupus anticoagulant) were determined using cardiolipin and a mixture of phospholipid from rabbit brain as antigen for detection of lupus anticoagulant by ELISA. Our results support a relation between Sneddon's syndrome and lupus anticoagulant (IgG subtype) in all cases. The anticardiolipin antibody test was positive only in two cases (one in low level). All patients could be diagnosed as having primary antiphospholipid antibody syndrome. Antiaggregant treatment was not effective in preventing thrombosis in two cases. Three of four patients received long-term oral anticoagulation therapy, with no recurrence of thrombosis observed for a period of at least 3 years.     

Cerebrovascular lesions and livedo reticularis (Sneddon's syndrome) — a progressive cerebrovascular disorder?

Summary Four cases are described in which livedo reticularis was associated with repeated cerebrovascular accidents, which eventually resulted in severe disability in two cases. Patients with severe disability had a history of many years, whereas two patients with little or moderate residual disability had a follow-up of 3 years each. CT scan revealed multifocal cerebral infarctions and cortical atrophy in all cases. Repeated cerebral angiograms, done in three cases, showed no signs of a vascular disease. There were no parameters that pointed to active immunological or inflammatory disorder. Neither clinical evidence of heart or large vessel disease was found. Observations suggest that a so-far unknown progressive cerebral vessel disease associated with livedo is the cause of a steady increase in multiple small cerebral infarctions. Because of the progressive character of the disease the search for effective therapy is needed.     

Clinical and neuroradiological aspects of Sneddon's syndrome and primary antiphospholipid antibody syndrome. A follow-up study

We performed a study to investigate differences and similarities between patients with Sneddon's syndrome and those with primary antiphospolipid syndrome (PAS), by clinical follow-up, magnetic resonance imaging (MRI) and angiography. Nine patients with Sneddon's syndrome and 11 patients with PAS were assessed at diagnosis and followed for a mean fo 6 years. The clinical and MRI findings indicated that Sneddon's syndrome and PAS are distinct entities. Patients with Sneddon's syndrome had a progressive clinical course with increasing disability and cognitive deterioration; patients with PAS had a more benign course. Infarcts in territories of the main cerebral arteries were frequent in PAS, while leukoaraiosis and smaller lacunar infacts were more comon in Sneddon's syndrome. In 3 of 7 women initially diagnosed with PAS, the diagnosis was changed to systemic lupus erythematosus during follow-up. Differential diagnosis of Sneddon's syndrome and PAS is important, as early therapy is effective for the latter, more benign, condition. Received: 9 December 1999 / Accepted in revised form: 16 May 2000     

Chorea and high antiphospholipid antibodies: probable primary antiphospholipid syndrome

A young man presented with generalized chorea as the first manifestation of probable primary antiphospholipid syndrome. He was well till 3 months before admission when he started to have involuntary, choreiform movements involving all extremities, the head and the bulbar muscles. Apart from these movements his physical examination was otherwise unremarkable. Laboratory investigations revealed mild thrombocytopenia, high partial thromboplastin time (PTT) only partially corrected by the addition of normal plasma, false positive syphilis serology, weakly positive antinuclear antibody and a high level of IgG anticardiolipin antibodies. Brain magnetic resonance imaging (MRI) showed multiple scattered small areas of high signal intensity on T2 weighted image in the area of centrum semiovale bilaterally. The patient was started on aspirin and prednisone with rapid symptomatic improvement. Despite the difficulty in proving the association between chorea and the high antiphospholipid antibodies, chorea appears in this case to be the initial symptom of primary antiphospholipid syndrome and we suggest screening for antiphospholipid antibodies in unexplained cases of chorea.     

Peripheral vascular disease in antiphospholipid syndrome

Atherosclerosis has been considered an inflammatory disease based on the finding that atherosclerotic lesion contains activated T lymphocytes reacting with oxidized low-density lipoproteins (oxLDL) and heat shock proteins (HSP); it also contains autoantigens like β₂GPI, a target of antibodies occurring in an immune-mediated thrombophilia called antiphospholipid syndrome (APS). Further support to this hypothesis comes from the cross-reactivity, which occurs between antiphospholipid antibodies (aPL) and antibodies to oxLDL. Animal experiments have shown that aPL are associated with atheroma. In addition, accelerated atherosclerosis has been detected in patients with a prototype systemic autoimmune disease, such as systemic lupus erythematosus (SLE). However, the association of APS or aPL with atherosclerosis is a matter of debate due to the small numbers of patients studied, and the fact that traditional risk factors for atherosclerosis coexist. The prevalence of APS ranges from 1.7% to 6%, and that of aPL reaches to 14% among patients with peripheral vascular disease defined on the basis of clinical outcomes. On the other hand, the prevalence of asymptomatic atherosclerosis, defined in terms of plaques in ultrasonography, reaches to 15% of patients with APS compared to 9% of SLE patients and 3% of normal controls. Among SLE patients with aPL, the prevalence of plaques ranges from 6% in premenopausal women to 31% in unselected patients. Less than 10% of APS patients express premature atherosclerosis in the absence of other risk factors. Which APS patient will develop atherosclerosis is unpredictable.     

Recurrent transient global amnesia in a case with cerebrovascular lesions and livedo reticularis (sneddon syndrome)

Summary Eight attacks of transient global amnesia were observed in a female patient who suffered from livedo reticularis and a series of other neurological symptoms, which were transient in most stances. The neurological deficits include focal epileptic attacks, unilateral loss of vision, paresis of left arm and/or leg and dysarthria. The first amnestic attack was seen at the age of 19. The episodes lasted from a few to 3 days. The intervals between the amnestic episodes varied between a few days and 11 years. The livedo reticularis became more obvious during each neurological episode and was less pronounced during the time of remission. A benign type of essential hypertension and paraproteinemia (gamma-M) was found. The investigations failed to show any evidence of essential thrombocythemia, polyarteriitis nodosa, lupus erythematodes and other immune complex diseases. The underlaying disease remained unclear.

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Zusammenfassung Acht Episoden einer transitorischen globalen Amnesie wurden bei einer Patientin beobachtet, bei der eine Livedo reticularis auch mit einer Reihe anderer, meist reversibler neurologischer Ausfälle verbunden war. Diese setzten sich aus fokalen epileptischen Anfällen, einseitigem Visusverlust, Paresen der linken oberen und/oder unteren Extremität und dysarthrischen Störungen zusammen. Die erste amnestische Episode trat im Alter von 19 Jahren auf. Die Episoden hielten meist nur wenige Stunden, einmal aber auch drei Tage an. Die Zeitabstände zwischen den einzelnen Attacken lagen zwischen wenigen Tagen und 11 Jahren. Die Ausprägung der Livedo reticularis verstärkte sich in den Perioden mit neurologischen Ausfällen und nahm in den Rückbildungsphasen ab. Die Laboruntersuchungen ergaben eine benigne Form einer essentiallen Hypertonie und Paraproteinämie (Gamma-M). Hinweise für eine essentielle Thrombozytämie, eine Polyarteriitis nodosa, einen Lupus erythematodes oder für andere Immunkomplex-Erkrankungen waren nicht zu erheben. Die Ursache der Symptomenkombination blieb ungeklärt.

     

Sneddon syndrome presenting with hemicranic attacks: a case report

The case of a young woman suffering from a rare cerebrovascular disease associated with livedo reticularis (Sneddon syndrome) is reported. Hemicranic attacks were the first symptom detected. The patient had a progressive clinical course of neurologic symptoms. Cerebral CT scan, NMR and cerebral arteriography revealed a progressive cerebral multifarctual feature involving middle-size arteries.     

Management of the neurological manifestations of APS--what do the trials tell us?

Purpose: To systematically review evidence from clinical trials about the management of neurological manifestations of Antiphospholipid Syndrome (APS). Methods: Articles reporting case-control, cohort and prospective studies and treatment trials of primary or secondary stroke prevention in patients with aPL were identified in an OVID literature search from 1966 to 2004, using the keywords: APS, aPL and cerebrovascular disease. Articles were evaluated according to the standard system for assessing medical evidence to answer the following questions: (1) What is the role of aPL and recurrent stroke risk in both primary and secondary APS populations? (2) What is the evidence to support specific treatment strategies for secondary prevention of aPL-associated stroke? (3) What is the evidence to support specific treatment strategies for primary prevention of aPL-associated stroke? Conclusions: (1) aPL are a risk factor for incident stroke (Grade A, established as useful for the given condition in the specified population). (2) The evidence to support the role of aPL in recurrent stroke is conflicting and, therefore, inconclusive. (3) Warfarin at moderate-intensity doses is equally effective in preventing a recurrent thrombotic event as warfarin at high-intensity doses in patients with APS (Grade A evidence, established as useful for the given condition in the specified population). (4) Warfarin, at moderate-intensity doses is as effective as aspirin (at a dose of 325 mg/day) in preventing recurrent thrombotic events in patients who are aPL-positive at the time of an initial stroke (Grade B evidence, probably useful for the given condition in the given population). (5) Currently there are no data to support the use of any prophylactic therapy in patients with aPL and no clinical manifestations for the purposes of preventing an incident stroke.     

The interface of multiple sclerosis and antiphospholipid antibodies

The interface between multiple sclerosis (MS) and the antiphospholipid syndrome (APS) is of great clinical relevance and may also shed some light on their pathogenesis. Although formal diagnostic criteria of these two immune syndromes are ostensibly mutually exclusive, many patients with subcortical white matter brain lesions share features of both MS and APS. The main diagnostic feature of APS, the antiphospholipid antibodies (aPLAb), is relatively common in multiple sclerosis and increased fibrin deposition is a feature of both APS lesions and MS plaques. A closer examination of the clinical and laboratory data reveals, however, fundamental differences between the syndromes: MS is a diffuse disease of white matter compared to a much more patchy disease in APS as demonstrated by recent studies in imaging and electrophysiology. Furthermore, a closer examination of the specific aPLAb profile reveals significant differences: we have found that although aPLAb were common in MS patients (32%), these antibodies did not depend on the presence of serum factors for binding to phospholipids and none of the MS patients had antibodies to β2-glycoprotein-I (β2-GPI), the major autoantigen in APS. Animal models of the two syndromes are induced by very different antigens and may serve to assess overlapping pathogenic mechanisms. The most common treatment used in MS are β-interferons which theoretically may exacerbate APS, while anticoagulation, the mainstay of APS treatment, is of unknown value in MS. The relationship of MS to APS remains to be clarified by focused large collaborative studies.     

Immunologic manipulation for the threatened fetus

Management of the pregnant woman with the antiphospholipid syndrome (APLS) has improved over the last 10 years. The recurrent pregnancy loss that is associated with this disease is managed with prophylactic low dose aspirin and heparin therapy. This therapy leads to a 40% absolute risk reduction in pregnancy loss. However, many women still fail to deliver a live infant despite this therapy so immunologic manipulation of the mother's disease in this group needs to be considered. Intravenous immunoglobulin and plasma exchange may have a role. New immunosuppressive drugs such as tacrolimus have yet to be tried. Monoclonal antibodies to B cells, B-cell growth factors, complement proteins and integrin molecules, all of which appear to play a role in the disease process, may also offer patients some hope. Similarly, biologics such as C1 esterase inhibitor protein, cell surface complement regulator proteins or interleukin-3 need to be tried given their efficacy in models of antibody-induced cell injury.     

Anticoagulant therapy for the thrombotic complications of the antiphospholipid antibody syndrome

Patients with antiphospholipid antibodies (APLA) are at risk of arterial thromboembolism (ATE) or venous thromboembolism (VTE). The true strength of the association between APLA and first TE is unknown as there are no prospective studies of a large, well-characterized inception cohort of matched patients with and without APLA. Thus, evidence-based treatment recommendations for primary prophylaxis of TE in such patients cannot be made. Optimal therapy of patients with recent TE and APLA remains controversial; although there is no doubt that some such patients have a malignant hypercoagulable state characterized by resistance to “usual intensity” anticoagulation; recent evidence suggests that most such patients are adequately treated with “usual therapy”. After warfarin discontinuation, such patients appear to be at increased risk of recurrent TE, as demonstrated in a series of studies of discontinuation of secondary TE prophylaxis in patients with APLA and venous TE (VTE). Because of this increased risk of recurrent TE, after anticoagulants are discontinued, most “experts” recommend extended duration therapeutic dose warfarin for such patients. This paper will briefly review this evidence.     

Antiphospholipid antibodies and thrombosis

Antiphospholipid syndrome is an autoimmune disease which combines vascular thrombosis and/or pregnancy complications with the presence of antiphospholipid antibodies. It could be a devastating and sometimes life-threatening condition. As vascular thrombosis presents as typical venous or arterial thromboembolism diagnosis is based on laboratory data. Therefore proper performance and interpretation of laboratory tests is crucial. Broader knowledge about clinical and laboratory aspects of the syndrome and their associations are essential for proper evaluation and management of the patients.     

Risk factors for arterial thrombosis in antiphospholipid syndrome

Introduction

Antiphospholipid syndrome (APS) is associated with the risk of both arterial and venous thrombosis. However, it is not known which factors might determine the location of thrombosis.

Materials and Methods

To retrospectively characterize factors associated with the risk of arterial thrombosis in a cohort of APS patients. Analysis included laboratory and clinical criteria of APS, together with classical cardiovascular risk factors and the possible role of platelet integrin α₂β₁ (807 C/T) and α_IIbβ₃ (PI A1/2) genetic polymorphisms. We enrolled 163 APS patients (123 women and 40 men aged 21-75; mean age 43 years); 78 suffered from arterial thrombosis.

Results

There were no significant differences in the frequency or titers of different antiphospholipid antibodies with the exception of slightly increased frequency of IgG anticardiolipin antibodies (ACL) in the arterial thrombosis group. Livedo reticularis was observed significantly more often in the arterial thrombosis group, particularly in stroke patients.In univariate analysis arterial thrombosis was associated with male gender (OR-2,201; p = 0,033), arterial hypertension (OR-2,81; p = 0,002) and hypercholesterolemia (OR-3,69; p = 0,001). On multivariate analysis arterial hypertension (OR = 1,78; p = 0,008) and hypercholesterolemia (OR = 2,001; p = 0,002) remained as independent risk factors for arterial thrombosis. Platelet glycoprotein polymorphisms studied did not show any significant associations with arterial thrombosis in APS patients.

Conclusions

Among APS patients those with ACL IgG antibodies, having livedo reticularis, and suffering from hypertension an hypercholesterolemia are at the increased risk of arterial thrombosis.