Sneddon's Syndrome Is a Thrombotic Vasculopathy

Sneddon's syndrome is the association of cerebral vascular disease and livedo reticularis (racemosa) ^[1-5]. Its prevalence and its etiology are unknown ^[3]. The average time to diagnosis of Sneddon's syndrome is 10 years from the onset of symptoms, and it is likely an underdiagnosed condition ^[3]. Although some studies have reported that up to 35% of patients with this syndrome test positive for antiphospholipid antibodies, ^[4] most test negative ^[2,3,5,6]. Reports of dermatologic pathology have been conflicting; while some have revealed vasculitic features including small-vessel endothelitis and inflammatory obstruction, ^[2,6] others describe a noninflammatory vasculopathy restricted to small and medium-sized arteries ^[3,5]. The brain pathology has been inferred from MRI and CT studies; no brain biopsies and only one limited autopsy specimen have been reported ^[3,7]. In addition, only a few reports ^[2-6,8] have included angiographic or single-photon emission computerized tomographic (SPECT) studies.

We report the unusual case of a young woman with a progressive vascular dementia due to Sneddon's syndrome and discuss the results of her clinical and laboratory evaluation, including cerebral angiography, in the context of the histopathologic findings in her brain biopsy.

Case report. A 47-year-old right-handed woman presented with a progressive 8-year decline in cognitive function. She exhibited loss of judgment, increasing word-finding difficulties, and a change in personality. Two years earlier she had lost her ability to manage her finances, and in the last 10 months she stopped cooking because she could not follow instructions. She gradually evolved from a sometimes petulant and aggressive person into an easygoing, passive individual with an increased libido. She complained of intermittent headaches, which varied in laterality and position over frontal, temporal, and occipital regions, as well as episodic dizziness.

Her medical history was significant for an episode of transient left leg weakness 10 years earlier and focal seizures at age 20, as well as mild hypertension, Raynaud's phenomenon for 10 years, and presumed autoimmune hypothyroidism (antimicrosomal antibody, 1/25,000). Her medications included nifedipine and levothyroxine. She had a 25-pack-year history of smoking. Her mother had had frequent acrocyanosis and a livedolike rash and had committed suicide in her early 50s after two strokes that had occurred in her mid-40s. Her younger sister had acrocyanosis, peripartum deep venous thrombosis, and pulmonary embolus, and a paternal aunt had suffered from chronic headaches, paroxysmal dizziness, and a livedolike rash before dying in her early 50s after multiple strokes.

On examination, the patient had a blood pressure of 130/96 mm Hg. Her Mini-Mental State Examination ^[9] score was 17 of 30. Her attention was poor, and she exhibited frontal lobe dysfunction, poor recall with preserved recognition, poor constructions, and micrographia. Her speech was explosive and she had pseudobulbar palsy. Motor examination revealed mildly increased tone in both upper extremities with decreased fine motor movements throughout. Her muscle stretch reflexes were brisk and symmetric, and plantar responses were flexor.

MRI showed confluent increased signal on T₂-weighted and proton-density images in the periventricular regions and deep white matter, and right frontal and parietal encephalomalacia (figure 1). SPECT studies revealed decreased cerebral blood flow in the left frontal, temporal, and parietal and right frontal and parietal cortices consistent with multifocal cerebral infarctions. Cerebral angiography demonstrated multiple branch occlusions of small middle cerebral artery branches bilaterally. Transesophageal echocardiography revealed a thickened bicuspid aortic valve but did not show cardiac thrombus, valvular vegetations, or aortic plaque or calcification. Extensive laboratory studies uncovered no evidence of vasculitis, hypercoagulable state, or toxic-metabolic disturbances. The following tests were all normal: serum complement, ANA, SS-DNA, DS-DNA, anti-streptolysin O, anti-neutrophil cytoplasmic antibody, lupus anticoagulant (four negative tests in 1 year using the dilute Russell viper venom and rabbit brain neutralization procedure), anti-cardiolipin (four negative tests using ELISA over a 1-year period), IgG <15 IU (0 to 15 negative, 15 to 30 indeterminate), IgM and IgA <10 IU (0 to 10 negative, 10 to 20 indeterminate), anti-phosphatidylserine, protein C, protein S, antithrombin III, VDRL, FTA, HIV, thyroid and liver function studies, serum protein and immunoelectrophoresis, serum immunoglobulins, cryoglobulins, arylsulfatase A, and urine heavy metals. Lumbar puncture was unremarkable. An MRI-guided stereotactic brain biopsy of the right frontal lobe revealed moderate astrocytic gliosis without evidence of vasculitis or vascular inflammation in cortical, meningeal, or dural vessels (figure 2). No neurofibrillary tangles, neuritic plaques, diffuse plaques, or Lewy bodies were seen.

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Figure 1. Proton-density MRI reveals multifocal, often confluent, increased signal throughout the cortical white matter. There are areas of increased signal in a gyriform pattern bilaterally, consistent with multifocal infarction

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Figure 2. Right frontal cortex demonstrates mild to moderate astrogliosis. Two microvessels exhibit no evidence of inflammation or vasculitis (hematoxylin and eosin-stained 6-microns sections; x 540 before 52% reduction). None of the other cortical, meningeal, or dural vessels sampled showed evidence of inflammation or vasculitis

Six months later, she was admitted with acute-onset right hemiparesis. Her blood pressure was 146/90 mm Hg. She was nearly mute with sparse, hypophonic speech but relatively intact comprehension, naming, and reading. A right-sided Babinski sign was present. CT revealed a new left-sided parietotemporal infarction. Nifedipine (30 mg three times a day) was withheld to avoid hypotension in the acute peri-stroke period. The next afternoon she had new widespread livedo reticularis and severe, painless acrocyanosis, neither of which diminished on warming. Nifedipine treatment was resumed and the Raynaud's syndrome and livedo reticularis receded. Further questioning at this time uncovered a 20-year history of intermittent livedo reticularis confined largely to the lower back, elbows, and knees. The diagnosis of Sneddon's syndrome was established, and anticoagulation with warfarin and a trial of high-dose pulse steroids were initiated. Anticoagulation was achieved to an international normalized ratio (INR) of 3, and she received 3 days of IV methylprednisolone (1 g/d). Improvement in her right-sided weakness and hypophonia was noted coincident with the initiation of anticoagulation. She has had no further deterioration while undergoing chronic warfarin therapy (INR, 3.0 to 4.0) after 8 months.

Discussion. This patient demonstrates many clinical features associated with Sneddon's syndrome in addition to the cardinal features of livedo reticularis and stroke. These features include a history of transient focal neurologic deficits during young adulthood, episodic dizziness and headaches, cardiac valve anomalies, acrocyanosis, and hypertension ^[2-6]. Cognitive deficits are often uncovered in patients with Sneddon's syndrome. This patient's presentation with overt dementia emphasizes that Sneddon's syndrome should be considered in the differential diagnosis of vascular dementia in a young person.

The family history in this patient suggests a significant genetic contribution to her illness. Although most investigators have not emphasized genetic factors, ^[3,6] a few have documented family histories consistent with autosomal dominant inheritance and variable penetrance, ^[3,5] including one recent report of two brothers with Sneddon's syndrome, one with moderately elevated titer anticardiolipin antibody and the other with lupus anticoagulant ^[8]. Our patient has been tested for anticardiolipin and lupus anticoagulant antibodies four times in 1 year and none have been detected, suggesting that in our patient, inheritance of lupus anticoagulant or anticardiolipin antibodies did not occur and was not essential to her Sneddon's syndrome. Most patients reported in large series are also seronegative for antiphospholipid antibodies ^[2,3,6].

The cause of Sneddon's syndrome and the nature of the cerebrovascular pathology remain a source of controversy. Previous reports of cardiac pathology and dermatopathology in Sneddon's syndrome are conflicting. Some hypothesize that vasculitis is not a feature of this syndrome, ^[3,5] while others have reported a series of patients with skin biopsy results consistent with vasculitis ^[2,6]. In the only other report of CNS pathology in a patient with Sneddon's syndrome, Pinol-Aguade et al ^[7] demonstrated a thrombosed meningeal vessel with recanalization and no evidence of vasculitis. Brain biopsy in our patient revealed astrocytic gliosis with no evidence of vasculitis in multiple dural, meningeal, cortical, and subcortical vessels. Astrocytic gliosis is a nonspecific finding, consistent with the MRI and angiographic findings of multifocal cortical and subcortical infarction. The presence of endocarditis, valvular abnormalities, and other cardiac pathology in many cases suggests that in addition to in situ cerebrovascular thrombosis, cardiac embolism may be an important source of stroke in patients with Sneddon's syndrome ^[4,7,8].

The lack of vasculitic features in the biopsy specimen may reflect sampling error; however, it was MRI-guided, it was studied by serial section, and an additional sample was taken directly from the burr hole. Furthermore, the results of the biopsy are consistent with those of cerebral angiography, which demonstrated multiple small branch artery occlusions signifying multifocal thrombosis or embolism. There was no evidence of vasculitis on the cerebral angiogram.

Antiplatelet agents and various immunotherapies, including steroids and azathioprine, have not been fully effective in treating either antiphospholipid syndromes or Sneddon's syndrome ^[2-4,6,10]. Although nifedipine did reduce our patient's livedo reticularis and acrocyanosis, it is unlikely to play a significant role in treating the cerebrovascular complications. The success of warfarin in the treatment of antiphospholipid syndromes ^[10] and the frequent presence of cardiac valvular abnormalities, ^[4,7] coupled with the failure of other therapies, suggest that anticoagulation may be the most appropriate intervention in Sneddon's syndrome. The absence of antiphospholipid antibodies in patients with Sneddon's syndrome should not preclude warfarin anticoagulation, especially in patients with progressive or threatened neurologic deterioration. Sneddon's syndrome or another seronegative vasculopathy should be considered in young patients with stroke, TIA, or possible vascular dementia whose rheumatologic work-up is negative.

Acknowledgments

The authors gratefully acknowledge Dr. Michael Rosove for helpful discussions and hematologic consultation, as well as the dermatologic and rheumatologic services at UCLA for suggestions in managing this case.