NORD gratefully acknowledges Peter Berlit, MD, FAAN, FANA, FAAEM, Professor of Neurology, Secretary General of the German Neurological Society, Berlin Germany for assistance in the preparation of this report.
Sneddon syndrome is a rare progressive disorder affecting small- and medium-sized blood vessels. The disorder is characterized by the association of a skin condition and neurological abnormalities. Characteristic findings include multiple episodes of reduced blood flow to the brain (cerebral ischemia) causing mini-strokes or stroke and bluish net-like patterns of discoloration on the skin surrounding normal-appearing skin (livedo reticularis). Additional symptoms may include headache, dizziness, abnormally high blood pressure (hypertension), and heart disease. Lesions may develop within the central nervous system as a result of reduced blood flow to the brain, which can cause reduced intellectual ability, memory loss, personality changes, and/or other neurological symptoms. The combination of stroke symptoms and livedo reticularis differentiates this syndrome from other disorders. The exact cause of Sneddon syndrome is not fully understood.
Sneddon syndrome was first described a separate clinical entity in the medical literature by Dr. Sneddon and colleagues in 1965. Since that time, significant debate has existed as to whether Sneddon syndrome is a distinct disorder, part of a spectrum of disorders, or a subtype of antiphospholipid syndrome. Some researchers believe that Sneddon syndrome should be separated into primary and secondary cases. Primary Sneddon syndrome would denote cases where there was no known cause (idiopathic); secondary Sneddon syndrome would denote cases that are believed to occur secondary to another disorder or thrombophilic state. Some researchers believe that Sneddon syndrome should be differentiated by whether antiphospholipid antibodies are present (aPL-positive) or absent (aPL-negative), others discuss autoimmune/inflammatory etiopathogenesis versus thrombophilia.
Sneddon syndrome is a slowly progressive disorder of small- and medium-sized arteries, which are the blood vessels that carry blood away from the heart. The disorder is characterized by blockages (occlusions) of the arteries that cause a reduction of blood flow to the brain and to the skin. Associated symptoms vary from one person to another based, in part, upon the specific arteries that are affected. An irregular, net-like pattern of bluish skin discoloration surrounding areas of normal-appearing skin (livedo reticularis) is characteristic of this disorder. The arms and legs are most often affected as well as the trunk, buttocks, and hands and feet. Livedo reticularis is worsened by cold and pregnancy. (In the European medical literature, the term livedo reticularis is used to describe the skin changes of the extremities only that disappear when the skin is warmed. Livedo racemosa is used to describe skin changes that involve also the buttocks and the trunk and do not disappear with warm temperatures. These two dermatologic conditions are separated because livedo reticularis is much more frequent, but the association with strokes exists for livedo racemosa only).
Generally, livedo reticularis develops before the neurological symptoms by as much as 10 years, although sometimes the onset of skin symptoms may occur at approximately the same time. Only rarely, do the skin symptoms occur after the neurological symptoms. Painfully cold fingers and toes caused by dilation or constriction of small vessels in response to cold (Raynaud’s phenomenon) may also occur. Blues discoloration of the hands and feet due to the lack of blood flow (acrocyanosis) has also been reported.
Recurrent episodes of mini-strokes (transient ischemic attacks) or strokes (cerebrovascular accidents) are a common finding of Sneddon syndrome. Less frequently, microbleeds and intracerebral hemorrhages also occur in Sneddon syndrome. The associated neurological symptoms vary depending upon the location of arterial blockages or bleedings. These symptoms may include difficulty concentrating, memory loss, confusion, personality changes, impaired vision, and weakness of one side of the body (hemiparesis). Sneddon syndrome may cause progressive reduction of mental and cognitive function, potentially resulting in dementia. Aphasia, which is defined as a communication disorder that impairs the ability to process language including impairing the ability to speak or understand others, is also common. Less often, seizures, muscle pain and stiffness, and abnormal movements caused by repetitive, jerky muscle contractions (chorea) may also occur.
Generalized symptoms (e.g., headaches and migraines and/or dizziness or vertigo) may be present for several years before neurological symptoms and/or visible skin discoloration appears. High blood pressure (hypertension) is also common.
Heart murmurs, heart disease resulting from reduced blood flow to heart tissue (ischemic heart disease), or thickening of the valves between the chambers of the heart (valvular stenosis) have also been diagnosed in people with Sneddon syndrome and may be associated with rheumatic heart disease or endocarditis. In rare cases, impairment of the kidneys may occur.
The exact cause of Sneddon syndrome is unknown. Most cases occur randomly for no apparent reason (sporadically). Possible immunological, environmental, genetic, and/or other factors are under investigation as potential causes of the disorder.
Sneddon syndrome has been reported in more than one family member (e.g., siblings) in a few cases, supporting the possibility of genetic susceptibility as a factor in some cases. A person who is genetically predisposed to a disorder carries a gene (or genes) for the disease, but it may not be expressed unless it is triggered or “activated” under certain circumstances.
Symptoms of Sneddon syndrome are caused by a progressive increase in the number of cells in the walls of affected arteries (endothelial proliferation). The cell proliferation leads to a build-up of material, narrowing the arteries and decreasing blood flow. Arteries may become blocked (occluded) and prevent blood from reaching areas of tissue (thrombosis). Clumps of cells may break loose and circulate in the blood stream. The clumps may lodge in an artery and block blood flow (embolism). Tissue loss or damage may occur in areas deprived of blood flow.
Some affected individuals have high levels of antiphospholipid antibodies in the blood. Antibodies are part of the body’s immune system and act against invading or foreign microorganisms (e.g., bacteria or viruses). Antiphospholipid antibodies mistakenly recognize phospholipids (part of a cell’s membrane) as foreign and act against them. The significance of antiphospholipid antibodies in approximately 40 to 50 % of patients with Sneddon syndrome is unknown. Some researchers believe that, in familial cases of Sneddon syndrome, affected individuals may have a genetic predisposition to the production of these antibodies. The presence of antiphospholipid antibodies in some cases suggests a possible association with an autoimmune disorder called antiphospholipid syndrome. However, the specific relationship between these two disorders is unknown.
Antiphospholipid syndrome is an autoimmune disorder, a disorder that occurs when the body’s immune system mistakenly targets healthy tissue. Less often, Sneddon syndrome can be associated with other autoimmune disorders such as systemic lupus erythematosus (SLE), Behcet’s disease, or mixed connective tissue disease. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
It is unknown whether individuals with Sneddon syndrome with antiphospholipid antibodies have a different disorder from individuals with Sneddon syndrome without antiphospholipid antibodies. In 2003, researchers determined several members of one family who had Sneddon syndrome without antiphospholipid antibodies had an alteration (mutation) in the CERC1 gene.
Sneddon syndrome has been reported more often in females than in males. Almost 80% of the patients are women with a median age of diagnosis at 40 years. Symptoms usually begin in early to middle adulthood, but can occur at any age including childhood. The incidence and prevalence are unknown. One estimate places the incidence at approximately one out of 250,000 individuals in the general population.
The diagnosis of Sneddon syndrome is usually suggested by the combination the pattern of skin discoloration called livedo reticularis and neurological symptoms, particularly unexplained stroke in young individuals. Diagnosis of cerebrovascular damage is confirmed when imaging techniques such as magnetic resonance imaging (MRI) or computed tomography (CT) reveal lesions (infarcts) in the brain.
Surgical removal and microscopic study of tissue samples (skin biopsy) may confirm the progressive arterial disease (arteriopathy) characteristic of Sneddon syndrome demonstrating occlusion of the vessel lumina with no vasculitis. Blood tests may reveal the presence of antiphospholipid antibodies in some affected individuals.
There is no specific treatment for Sneddon syndrome. Treatment is symptomatic and supportive, but there are no standardized treatment protocols or guidelines. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of patients. Various treatments have been reported in the medical literature as part of single case reports or small series of patients. Treatment trials would be very helpful to determine the long-term safety and effectiveness of specific medications and treatments for individuals with Sneddon syndrome.
Anti-aggregants such as aspirin or direct oral anticoagulants (DOAC) or vitamin K-antagonsists such as warfarin may be given to thin the blood and to prevent the formation of blood clots. Some physicians recommend that individuals with Sneddon syndrome without antiphospholipid antibodies should be treated in a less aggressive manner through antiplatelet therapy with aspirin and patients with antiphospholipid antibodies should receive DOAC or warfarin with an international normalize ratio (INR) target of 2 to 3. But even with heart valve involvement, antiplatelet therapy was not inferior in comparison to anticoagulation. And always the risk of microbleeds and intracerebral hemorrhage must be taken into account.
The use of anti-inflammatory or immunosuppressive therapies is discussed controversial, but may be considered in patients with biopsy or laboratory findings indicative of an inflammation. Always the association with an autoimmune disorder like lupus must be excluded.
Drugs that widen (dilate) the blood vessels known as vasodilators such as nifedipine may be prescribed to reduce blood pressure and/or reduce the risk of blockage although these drugs have primarily shown benefit only with skin symptoms. Immunosuppressive drugs may be used to offset high levels of antiphospholipid antibodies in the blood of some people with Sneddon syndrome.
Angiotensin-converting enzyme (ACE) inhibitors have been used to try to reduce the growth and spread of epithelial cells (endothelial proliferation) and a fatty-like compound known as prostaglandin has been tried to improve the flow of blood through small blood vessels (microvascular perfusion).
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