Susac's syndrome: 1975–2005 microangiopathy/autoimmune endotheliopathy

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Abstract

Susac's syndrome (SS) consists of the clinical triad of encephalopathy, branch retinal artery occlusions (BRAO) and hearing loss. It is due to a microangiopathy affecting the precapillary arterioles of the brain, retina, and inner ear (cochlea and semicircular canals). Women are more commonly affected than men (3:1); the age of onset ranges from 9 to 58 years; but young women between the ages of 20 and 40 are most vulnerable. The encephalopathy is almost always accompanied by headache which may be the presenting feature. Multifocal neurological signs and symptoms, psychiatric disturbances, cognitive changes, memory loss, and confusion may rapidly progress to dementia. The MRI shows a distinctive white matter disturbance that always affects the corpus callosum. The central callosal fibers are particularly vulnerable and central callosal holes develop as the active lesions resolve. Linear defects (spokes) and rather large round lesions (snowballs) sometime dominate the MRI findings, which include cortical, deep gray (70%) and leptomeningeal involvement (33%). Frequently, the lesions enhance and may be evident on diffusion weighted imaging (DWI). The BRAO are best evaluated with fluorescein angiography, which may show the pathognomonic multifocal fluorescence. Gass plaques are frequently present and reflect endothelial damage. Brain biopsy shows microinfarction to be the basic pathology, but more recent pathological studies have shown endothelial changes that are typical for an antiendothelial cell injury syndrome. Elevated levels of Factor VIII and von Willebrand Factor Antigen reflect the endothelial perturbation. Despite extensive evaluations, a procoagulant state has never been demonstrated. SS is an autoimmune endotheliopathy that requires treatment with immunosuppressants: steroids, cyclophosphamide, and intravenous immunoglobulin, usually in combination. Aspirin is a useful adjunct.

Introduction

Since first reported in 1979 [1], there have been over a hundred cases of SS reported [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26]. This syndrome has protean manifestations and is often misdiagnosed [5]. Misinterpretation of the MRI leads to diagnoses of multiple sclerosis or acute disseminated encephalomyelitis (ADEM). Herpes simplex encephalitis is frequently considered when the patients present with a rather profound encephalopathy that has evolved over a short period of time. The rapid onset of dementia, sometimes associated with myoclonus and seizures, suggests Creutzfeldt–Jakob disease. Headaches are almost always associated with the encephalopathy and may be quite severe and migrainous in nature; when associated with sensory symptoms, a diagnosis of complicated migraine may be made. Occasionally a diagnosis of metastatic cancer is considered because of the headache with the MRI showing enhancement of the leptomeninges and enhancing lesions in the brain. Although the onset is usually subacute, the presentation may be so acute, as to suggest stroke.

Section snippets

MRI findings

Careful interpretation of the MRI with particular attention to the corpus callosum will yield the answer in almost all patients. The corpus callosum is always involved. Although any part of the corpus callosum may be affected, the central portion is preferentially involved [3], [5], [7] with microinfarcts that are typically small but may be large and assume a “snowball” appearance [3]. Occasionally, linear defects (spokes) may extend from the callosal septal surface to the superior margin of

Branch retinal artery occlusions

These corpus callosum lesions should alert the clinician to examine the retina for BRAO. This requires dilation of the pupil, and perhaps sedation; neuro-ophthalmological and retinal consultation is desirable. Fluorescein angiography is useful in evaluating these BRAO, which may be subtle, and may show the distinctive multifocal fluorescence that may be pathognomonic. Gass plaques, which are yellow–white deposits seen at the mid segments of the arteriole, are a helpful finding in making the

Hearing loss

Like the BRAO, the hearing loss may be difficult to evaluate in the encephalopathic patient. Brainstem auditory evoked response may show loss of wave I (cochlear response). A prominent jerk nystagmus with vertigo should alert the clinician to infarction of the membranous labyrinth. Should the patient be cooperative, audiometry shows that the lower tones are first affected; this reflects the vulnerability of the cochlear apex to microinfarction. Occasionally, the hearing loss is acute and may

Laboratory investigations

Despite extensive laboratory investigation, no consistent abnormalities have been found. The erythrocyte sedimentation rate and C-reactive protein may be elevated. Minor elevations of the antinuclear antibody and antiphospholipid antibody are infrequent. A procoagulant state has never been demonstrated. Cerebrospinal fluid examination may show a lymphocytic pleocytosis (less than 20), and the protein is invariably elevated during the encephalopathy. The presence of oligoclonal bands and

Pathology

Cynthia Magro [27] eloquently showed endothelial damages in the precapillary arterioles in a patient at the Susac's Syndrome Symposium held at Ohio State University, April 2005. These changes ranged from mummification to frank necrosis of the endothelial cells. C4d deposition, the hallmark of autoimmune antiendothelial cell antibody syndromes, was present in the endothelium. The pathological findings included pauci inflammatory, perivascular cuffing of the microvasculature with

Treatment

The treatment of SS requires immunosuppression. Steroid therapy is the mainstay of treatment, and is most effective in severe cases, when used in conjunction with IVIG and cyclophosphamide. While there is a natural tendency for the disease to spontaneously improve, there are devastating cases that progress dramatically to severe dementia in a relatively short period of time. In the accompanying paper, we propose a protocol for treating both the encephalopathic presentation, and the BRAO/hearing

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