Clinical manifestations

Presentation and course

The characteristic dermatologic lesion of livedo reticularis is a fixed, patchy, netlike, violaceous skin discoloration, appearing typically on the trunk and extremities and sparing the face.

Livedo may develop concurrent with or precede the cerebrovascular symptoms by as many as 30 years, with an approximate average of 5 years. The dermatopathy occasionally develops after the neurologic manifestations.

Ischemic stroke, particularly in the territory of the middle cerebral artery, is the neurologic hallmark of Sneddon syndrome and has been documented to occur first between the ages of 10 and 64 years, with an average age of 42 years (88). Only a few pediatric cases have been described (102; 38; 41). Stroke may be preceded by episodes of dizziness and headache or transient ischemic attacks (103). Migraines may precede stroke, and migraineurs with livedo reticularis may be at increased risk of stroke (95). Headache frequency is not significantly higher in those with positive antiphospholipid antibodies, however (94). In rare exceptions, headache may be the only manifestation (14). Seizures occasionally occur, although usually late in the course of disease (87; 74; 81; 77; 32) and probably result from an ischemic or infarcted focus. One case described tremor as the initial neurologic manifestation of Sneddon syndrome (17). Cognitive impairment is likely related to recurrent stroke leading to vascular dementia (77; 76; 91), although some authors have reported that cognitive decline may occur in the absence of antecedent stroke (18; 79; 100; 01). A case report highlights that Sneddon syndrome may also become clinically manifest as cognitive impairment without typical stroke signs (61; 27). Both monocular and binocular ischemic events, presumably related to ophthalmic or retinal artery occlusion, have been documented in Sneddon syndrome (45; 72; 78). Isolated third cranial nerve palsy has been reported (44). Central retinal vein occlusion has been described as an initial manifestation (02). Peripheral retinal capillary occlusions with neovascularization have also been reported (37).

Labile hypertension was noted in 5 of the 6 patients originally described by Sneddon and has been reported in the majority of subsequently recognized cases. The basis for the blood pressure elevation in this syndrome is not well understood, as most of the hypertensive subjects have had no evidence of renal disease. Cardiac manifestations of Sneddon syndrome include ischemic heart disease and valvular abnormalities, particularly mitral valve thickening (74; 48; 29). Degeneration of the cardiac valves may also occur (21). The presence of left-sided cardiac disease raises the possibility that some of the ischemic strokes in Sneddon syndrome are cardioembolic in origin (22).

Other systemic vascular manifestations include mesenteric ischemia (51) and renal involvement (90; 71; 59).

Prognosis and complications

The natural history of Sneddon syndrome is not well characterized. Many persons, including those described by Sneddon, have suffered recurrent ischemic infarcts without significant clinical disability. A prospective longitudinal study of 13 cases of Sneddon syndrome described a relative benign course (10). Over a 6-year period, most individuals did not experience further neurologic events, although MRI findings suggested the development of additional subcortical lesions (10). In other instances, this progressive disorder is severely crippling and may lead to severe vascular dementia (89; 80; 13; 30). Although sensorimotor deficits may considerably improve, neuropsychological sequelae can be severely disabling, including suicidal behavior (98; 43). Limited data suggest that several factors influence prognosis. A single cerebrovascular event, the absence of angiographic evidence of intracranial occlusive disease (76), and the absence of antiphospholipid antibodies (48) may portend a better prognosis (88). Pregnancy or use of oral contraceptives may promote clinical deterioration in women (103). The mortality rate in 1 population was estimated at 9.5% within an average observation time of 6.2 years (103). Few studies have been published on long-term sequelae, yet some relate the chronic nature of the condition (33).

Clinical vignette

A 43-year-old woman presented with acute onset of right upper extremity weakness and numbness. She dropped a bottle from her hand and noted that she was unable to grasp objects. Her symptoms progressed to involve her face with consequent dysarthria, although she did not suffer any lower extremity involvement. On review of systems, she reported several prior episodes of visual blurring and other transient neurologic symptoms. Past medical history included hypertension. Livedo reticularis was apparent on her torso and upper extremities. Laboratory testing failed to identify the presence of antiphospholipid antibodies, but revealed homozygosity for Factor V Leiden mutation. Transesophageal echocardiography revealed thickening of the mitral valve with prolapse. MRI demonstrated an ischemic stroke in the left frontoparietal cortices within middle cerebral artery distribution. Empiric anticoagulation with adjusted-dose warfarin was initiated. At 6 months she had regained her prior deficits and continued symptom-free. Subsequent assays detected the presence of antiphospholipid antibodies.

Biological basis

Etiology and pathogenesis

The cause for the predilection for dermal and intracranial cerebral vessels is uncertain but may relate to a common antigenic stimulus or gene expression common to the 2 vascular beds whose tissues both arise from ectoderm. Although hypertension and cigarette smoking are commonly present, the young age of stroke onset and pathological data suggest that factors other than atherosclerosis are important in the pathogenesis of the syndrome. The predilection for women in their childbearing years suggests an etiologic role for estrogen (103). Antiphospholipid antibodies have been associated with a significant number of cases of Sneddon syndrome although absence (25) or fluctuating titers may also occur (88).

The pathogenesis of Sneddon syndrome is unknown. Although in many instances skin biopsies have been normal or nonspecific (87; 77; 80), it is generally agreed that this is an arteriopathy of small and medium sized vessels (75; 77; 91). The sensitivity of skin biopsy may be augmented by employing multiple deep punch biopsies in different areas of the livedo (99; 54). Endarteritis obliterans, referring to a noninflammatory obstruction of muscular arteries from an intimal endothelial proliferation within a fibromucinous matrix, has been described (16; 75) and may represent a primary vasculopathy. Thrombi in the artery lumen and perivascular lymphocytic infiltration have also been reported (49). Some authors have described a distinct histopathological time course with early inflammatory reactions ("endotheliitis") followed by subendothelial proliferation of smooth muscle cells and a late fibrotic stage associated with luminal stenosis (91; 84), suggesting that the syndrome results from systemic vasculitis. Although vasculopathic luminal compromise and consequent hypoperfusion is typically invoked as the cause of ischemia, distal thromboembolism may also occur (86). Evidence of a mild, chronic perivascular inflammatory reaction in the absence of vasculitis has been noted on skin biopsy (89). Digital artery biopsies in 7 subjects in whom skin biopsies had been normal (77) demonstrated intimal hyperplasia with luminal narrowing, focal zones of absent or reduplicated internal elastic lamina, and adventitial fibrosis. There was no evidence of inflammation, and immunofluorescent studies were all negative.

A paucity of detailed pathologic data from the brain and cerebral vessels in Sneddon syndrome has greatly hampered our understanding of the pathogenesis of stroke in this syndrome. Infrequent histopathologic observations have revealed a diffuse cerebral vasculopathy with musculoelastic hyperplasia (74; 11; 36; 32; 42). These findings are similar to the changes seen in dermal and digital arteries described above. Leptomeningeal biopsy in a single case revealed granulomatous infiltration, supporting the concept of an inflammatory etiology (11), although other specimens have been devoid of an inflammatory component (74; 36; 03). Temporal artery biopsies from patients with Sneddon syndrome have been normal (80; 72) or have shown various degrees of intimal hyperplasia and medial fibrosis (49).

Histological examination of a patient with Sneddon syndrome dying of noncardiac causes showed moderate coronary arteriosclerosis but no significant small artery pathology (80). An autopsied heart in a patient who had myocardial infarction showed multiple platelet thrombi of various ages in the small intramyocardial arterioles as well as a thickened aortic valve with an organizing platelet thrombus at the free margin of the noncoronary cusp (70). Another heart from a patient with Sneddon syndrome and myocardial infarction had multiple thrombi within myocardial arteries and intimal hyperplasia of the small and medium coronary arteries, in addition to mitral valve endocarditis (74). None of the patients had evidence of coronary vasculitis.

Observations from around the world that antiphospholipid antibodies, including anticardiolipin antibodies and lupus anticoagulant, are present in some subjects with Sneddon syndrome raises consideration that the antibodies play a role in the development of the syndrome (45; 55; 67; 97; 49; 62; 68; 60; 73). The mechanisms by which antiphospholipid antibodies theoretically contribute to ischemic brain and skin disease include inhibition of phospholipid-dependent endogenous anticoagulants (ie, antithrombin III, protein C, protein S, thrombomodulin), direct vascular endothelial damage (ie, antiendothelial cell antibodies), and antibody-mediated platelet activation, all of which may promote thrombosis. Autoimmune thrombocytopenia may also occur (66). The mechanism by which antiphospholipid antibodies might promote the characteristic vascular pathology is uncertain. Of the patients with Sneddon syndrome who have been screened for antiphospholipid antibodies, the percentage of positivity ranges from 0% to 86%, with a mean of 59% (40 of 68) (97; 50; 91). The reasons for the discrepancy are unclear but may include the known variability over time of antiphospholipid antibody titers in individuals, as well as a lack of a standard battery of tests for antiphospholipid antibodies, the lack of standardization of laboratory methods, and various definitions for positive and negative values. A large review of antiphospholipid antibody syndrome cited livedo reticularis in 20.4% and stroke in 13.1% of cases (15). A comparison of the clinical profiles of antiphospholipid antibody-positive subjects with Sneddon syndrome to their antibody-negative counterparts (Table 1) does not support considering these as 2 separate entities, acknowledging that only those with the antibodies meet clinical and immunological criteria for the primary antiphospholipid antibody syndrome. Concomitant coagulopathies may also be present in the absence of frank antiphospholipid antibody demonstration. An analysis of protein Z, a vitamin K-dependent glycoprotein coagulation inhibitor, in cases of Sneddon syndrome suggests that this factor may also play a role in the underlying pathophysiology (04). Antimitochondrial type M5 antibodies may also be observed, likely representing another manifestation of the associated autoimmune derangements (83). Sneddon syndrome has also been described in association with protein S deficiency (82).

Table 1. Sneddon Syndrome: Comparison of aPL+ and aPL- Patients

Analysis of the clinical manifestations in 46 consecutive cases confirmed similarities with or without the presence of antiphospholipid antibodies, although seizures, echocardiographic evidence of mitral regurgitation, and thrombocytopenia were more frequent in patients with antiphospholipid antibodies (35). An evolving list of serologic markers associated with Sneddon syndrome has been reported, including antiprothrombin antibodies (47) and antiendothelial cell antibodies (34). Anti-beta 2-glycoprotein 1 antibodies have also been detected in Sneddon syndrome, although the etiologic role of these factors has yet to be established (39).

Genetic factors appear to play a role in several of the reported cases of Sneddon syndrome, with first-degree relatives having either livedo reticularis (77; 97; 62; 57) or the full syndrome (77; 76; 73; 78; 93). The presence of antiphospholipid antibodies in family members of persons with Sneddon syndrome lends further credence to the theory that these antibodies play an important role in the development of the syndrome (97; 58; 73). Familial deficiency of antithrombin-III has been reported in association with Sneddon syndrome (23). A high prevalence of heterozygous factor V mutation has also been described in Sneddon syndrome (08), as has a single case of familial dysfibrinogenemia (52). Familial Sneddon syndrome has also been associated with a mutation in NOTCH3 (40).

Epidemiology

The true incidence of Sneddon syndrome in the general population is unknown, but has been estimated to be 4 cases per million (103). We estimate, based on our experience, that the idiopathic form of Sneddon syndrome occurs approximately once in every 2100 stroke patients seen, whereas the pairing of livedo reticularis and stroke from any cause is several times more common. In Spain, Sneddon syndrome accounted for only 0.26% of total cases of cerebrovascular diseases seen in 1 hospital (77). It is likely that the syndrome is frequently unrecognized, as even Sneddon acknowledged that the significance of livedo may be easily overlooked in patients presenting with neurologic problems.

The majority of the reported cases of persons with Sneddon syndrome are female and hypertensive, often without evidence of significant renal involvement (77; 13; 49).

Prevention

Although labile hypertension and cigarette smoking are commonly associated with Sneddon syndrome, there are no large epidemiological studies to suggest their role as risk factors. Use of oral contraceptives and pregnancy may promote Sneddon syndrome in women (103).

Differential diagnosis

Recognizing the limitations in the diagnostic evaluation of Sneddon’s original patients, Sneddon syndrome generally refers to the association of livedo reticularis and ischemic cerebrovascular disease in the absence of a recognized connective tissue disease, inflammatory condition, or infection. Diagnosis of livedo reticularis should prompt a systematic search for an underlying specific cause or condition (Table 2). With virtually all of these conditions, ischemic cerebrovascular disease has also been reported in some subjects. It is uncertain whether patients with these conditions have established and genotypically different conditions, whether they truly have Sneddon syndrome, or whether they simply have a disease that is phenotypically identical to Sneddon syndrome.

Table 2. Differential Diagnosis of Livedo Reticularis

Diagnostic workup

Table 3 offers a diagnostic approach to patients with livedo reticularis and cerebrovascular disease, with the emphasis on identification of specific disease processes that might present with a phenotype identical to Sneddon syndrome.

Table 3. Diagnostic Evaluation

Radiologic findings. In Sneddon syndrome, brain computed tomography and magnetic resonance imaging usually show single or multiple, small- to moderate-sized cerebral infarcts, with MRI being the more sensitive of the 2 imaging modalities (46). In a preliminary report of 39 subjects with Sneddon syndrome, all but 1 patient had ischemic lesions less than 3 cm in diameter (28), with the majority of lesions located in the superficial cortex. Another series described small, multifocal infarcts but with a predominance in the periventricular deep white matter (91). One comparison study of Sneddon syndrome with primary antiphospholipid antibody syndrome suggested a periventricular predominance of infarcts in Sneddon syndrome with leukoaraiosis and small lacunar lesions (30). The majority of patients with Sneddon syndrome have some degree of cortical atrophy (77; 80; 09; 48; 91). Intracerebral hemorrhage has been described in patients with Sneddon syndrome, more frequently occurring in the later stages of the disease (20; 19; 96; 24; 69; 03; 85; 101). One report describes hemorrhage as the presenting feature (53). Although the mechanism of hemorrhage is unfounded, hemorrhagic sequelae may result from the combination of hypertension and a chronic vasculopathy (24). Intraventricular hemorrhage may also occur (05). Cerebral microbleeds may be evident on susceptibility-weighted MRI sequences (56). Transcranial Doppler ultrasonography may reveal silent cerebral microembolism (86). Cerebral angiography, when abnormal, shows multiple occlusions of the distal branches of the cerebral arteries (87; 75; 77; 49). Moyamoya syndrome has also been described in the setting of Sneddon syndrome (31). Involvement of extracranial vessels is distinctly unusual. Cases of collateral circulation of the brain via anastomoses between intracranial vessels, across the dura and through the deep perforating vessels, have also been documented (77; 03). The angiographic findings should be distinguished from the angiomatoses of Divry-van Bogaert syndrome (07). Cerebral blood flow studies, such as HMPAO-SPECT (64; 65), may reveal perfusion deficits in the absence of structural brain lesions. Perfusion techniques may elucidate findings of cortical atrophy and the clinical observation of progressive cognitive decline in a subset of patients. Angiography of the digital arteries, similar to those in the brain, reveals multiple arterial occlusions, as well as segmental narrowing and dilatation (77).

Management

The treatment of this rare stroke syndrome is empiric. Antihypertensive drugs are commonly prescribed, although the role of hypertension in the development of this syndrome is unclear. Warfarin and antiplatelet agents are frequently used to prevent recurrent arterial thromboses, with warfarin the preferred agent in those who also have venous thromboses or who have a presumed cardiac source of emboli. The presence of associated antiphospholipid antibodies may warrant anticoagulation. Absence of such antibodies, however, may be unrelated to the nature of the ischemic strokes, yet a more moderate course has been suggested (12). Some authors have cited the risk of intracranial hemorrhage as a reason to pursue angiography prior to consideration of anticoagulation (03). Combination of antiplatelet therapies has also been advocated (32), with only limited experience. Immunosuppressive agents have been used but in an uncontrolled trial did not prevent recurrent cerebrovascular events (76). Prednisone, plasmapheresis, and intravenous gamma-globulin may play a role in patients with antiphospholipid antibodies. Intravenous thrombolysis has also been pursued in acute presentation of Sneddon syndrome (92).

Special considerations

Pregnancy

As the syndrome appears to be more common in women than in men, with first symptoms generally appearing during the childbearing years, it has been postulated that female hormones may play a role in the clinical manifestations. Several women have had exacerbations during pregnancy (103).

Anesthesia

Perioperative anesthesiologic recommendations for patients with Sneddon syndrome include attention to cardiac manifestations, arterial hypertension, renal involvement, and adequate seizure prophylaxis (41; 06). Enflurane should be used with caution, as this agent may impair renal function and precipitate seizures (41).