Sneddon Syndrome

Sneddon's syndrome (SS) is a rare non-inflammatory thrombotic vasculopathy characterized by the combination of cerebrovascular disease with livedo racemosa.

Epidemiology

SS has an estimated annual incidence of approximately 1/250,000. The disease predominantly affects women in young adulthood.

Clinical description

The mean age of onset of neurological symptoms is 39 years, though the livedo is generally observed up to 10 years earlier and sometimes since childhood. Livedo racemosa is a persistent net-like violaceous-cyanotic, mottled discoloration of the skin affecting primarily the legs and arms, but also involving the buttocks and the trunk, and that is exacerbated by cold or pregnancy. Livedo reticularis, that is limited to the extremities and is visible only in the cold, has also been observed in some cases. Neurological manifestations include recurrent transient ischemic attacks (TIAs) and infarcts, often of the middle cerebral artery territory resulting in contralateral hemiparesis, aphasia, and/or visual field defects. Rarely, spinal strokes or intracranial or subarachnoid hemorrhages occur. Headache and vertigo may precede the onset of livedo racemosa and cerebrovascular manifestations by several years. In the course of the disease, memory disturbances, personality changes, and cognitive decline leading to dementia occur frequently. Rare neurologic symptoms include seizures, chorea, or myelopathies. Secondary hypertension is common, as are valvular heart disease, ocular and kidney involvement.

Etiology

While about 50% of cases are idiopathic, SS can be associated with autoimmune diseases like systemic lupus erythematosus, antiphospholipid syndrome, Behçet disease, and mixed connective tissue disease (see these terms). The manifestations of SS are caused by a progressive, non-inflammatory arteriopathy, usually of the small to medium arteries, leading to occlusion of these arteries by excessive endothelial proliferation with impaired blood flow and clotting. Genetic factors may play a role in the pathogenesis of SS. Loss-of-function mutations in cat eye syndrome chromosome region candidate 1 CECR1 (22q11.2) encoding adenosine deaminase 2 have been found.

Diagnostic methods

SS is suspected on the basis of the clinical picture. It has to be considered in cases of unexplained stroke at a young age, cognitive decline without stroke, and assumed autoimmune-related vasculitis in which immunosuppressive therapy has proven ineffective. Skin biopsy may confirm the diagnosis, revealing occlusion of arterioles by intimal proliferation. MRI typically reveals white matter changes, infarcts, microbleeds or atrophy, and is more sensitive than CT. Laboratory testing for antiphospholipid antibodies may be positive in about 60% of cases.

Differential diagnosis

Differential diagnoses include reversible cerebral vasoconstriction syndrome, MELAS syndrome, cerebrovascular dementia (see these terms), migraine, the autoimmune diseases with which SS can be associated, and cerebral angiitis.

Genetic counseling

Most cases are sporadic but some familial cases with an autosomal dominant inheritance have been reported. In these cases, a genetic susceptibility is likely.

Management and treatment

The most widely accepted treatment is anticoagulation with warfarin. Some suggest that aPL-negative patients should follow a less aggressive approach consisting of antiplatelet therapy with aspirin, while others recommend warfarin with a higher international normalized ratio (coagulation index) target. Angiotensin-converting enzyme (ACE) inhibitors have been suggested to reduce endothelial proliferation, and prostaglandin to improve microvascular perfusion. Successful intravenous systemic fibrinolysis with tissue plasminogen activator (tpA) has been reported in acute ischemic stroke. While the use of immunosuppressive therapy (azathioprine, cyclophosphamide) doesn't seem effective, there are data indicating that rituximab may be effective in aPL-positive patients.

Prognosis

SS is a chronic, intermittent or progressive disease leading to major morbidity. Dementia occurs in 50% of patients resulting in early retirement.