Susac syndrome: challenges in the diagnosis and treatment

Abstract

Abstract Susac syndrome (SuS) is a disorder thought to be mediated by an autoimmune response towards endothelial cells (ECs), leading to a characteristic clinical triad of encephalopathy, visual disturbances due to branch arterial occlusions (BRAO), and sensorineural hearing impairment (SNHL). Although it is a rare disease, three reasons make it important. First, given its variable presentation, Susac syndrome is underdiagnosed. Second, it is considered an important differential diagnosis in different neurological, psychiatric, ophthalmological and hearing disorders, and consequently is frequently misdiagnosed. Third, in many cases, SuS is diagnosed and treated late, with significant irreversible sequelae including dementia, blindness and hearing loss. Neuropathology findings derived from both SuS patient tissue, and novel transgenic mouse models indicate cytotoxic CD8+ T cells adhere to microvessels, inducing endothelial cell (EC) swelling, vascular narrowing and occlusion, causing microinfarcts. Anti-endothelial cell antibodies are present in serum, in 25% of SuS patients, but it is unclear whether they are etiologically related to the disease, or an epiphenomenon. The clinical triad comprising encephalopathy, BRAOs, and SNHL is considered pathognomonic, although great variability is found in presentation, and natural course of disease. At first evaluation, only 13-30% of patients exhibit the full clinical triad, making diagnosis difficult. Retinal fluorescein angiography, optic coherence tomography, MRI, and tonal audiometry are helpful methods for diagnosing and monitoring disease activity during treatment. By contrast, there are no reliable, objective immune markers to monitor disease activity. Immunosuppression is the current treatment, with high-dose corticosteroid therapy as the mainstay, but additional therapies such as intravenous immunoglobulins, cyclophosphamide, rituximab, and mycophenolate mofetil are often necessary, since the disease can be devastating, causing irreversible organ damage. Unfortunately, low rates of disease, variability in presentation, and paucity of objective biomarkers, make prospective, controlled clinical trials for SuS treatment difficult. Current immunosuppressive treatments are therefore based on empirical evidence, mainly from retrospective case series and expert opinion. In this Review, we draw attention to the need to take SuS considered in the differential diagnosis of different neurological, psychiatric, ophthalmological, and hearing disorders. Furthermore, we summarize our current knowledge of this syndrome, in reference to its pathophysiology, diagnosis, and management, emphasizing the need for prospective and controlled studies that allow a better therapeutic approach.