Microangiopathy of brain, retina, and cochlea (i.e., Susac syndrome (SS)) is a rare condition characterized by the clinical triad of encephalopathy, branch retinal artery occlusion (BRAO), and sensorineural hearing loss. However, all three features may not be present concurrently upon initial presentation. This condition may also be referred as small infarctions of cochlear, retinal, and encephalic tissue (SICRET), microangiopathy with retinopathy, encephalopathy, and deafness (RED-M), and retinocochleocerebral vasculopathy.
Etiology & pathophysiology
SS is a presumed autoimmune endotheliopathy causing microinfarcts in the precapillary arterioles of the brain, retina, and inner ear (cochlea and semicircular canals). The exact mechanism is unclear, but pathogenesis does resemble the microinfarction of muscle and skin seen in dermatomyositis. New studies have suggested that anti-endothelial cell antibodies (AECAs) may be involved since biopsy findings in SS revealed endothelial cell necrosis, which are associated with AECAs. AECAs have been hypothesized to mediate thrombotic depositions in the vessels, though preference for the brain, retina, and inner ear arterioles are unclear. SS can be categorized into three clinical courses: monocyclic, polycyclic, and chronic continuous. Monocyclic courses are acute and self-limiting within two years without recurrence. The polycyclic course requires remission followed by relapses occurring beyond two years, and chronic continuous never has a clear remission.
SS has a slight female predominance and typically affects those aged 16-40 years. Of reported cases, most patients are white individuals from North America and Europe. There has also been a small number of cases diagnosed during pregnancy and post-partum period.
Signs & symptoms
On initial presentation, the clinical triad of SS is often not complete. Symptoms of CNS dysfunction are the most likely manifestation, followed by visual then vestibulocochlear symptoms. Migraine-like headaches are also common (80% of reported cases) and may precede presenting symptoms by several months. It may take an average of 5 months from initial onset until all three features of the triad may present. Complete triad on initial presentation only occurred in 13% of 304 reported cases and was more common in monocyclic cases. Though CNS dysfunction symptoms will vary, symptoms of encephalopathy will predominate. These include cognitive impairment, confusion, emotional disturbance, behavioral or personality changes, apathy, psychosis, and reduction of vigilance. Other symptoms of CNS dysfunction include ataxia, vertigo, gait abnormality, sensory disturbance, upper motor neuron signs, paresis, nausea and vomiting, dysarthria, oculomotor dysfunction, urinary dysfunction, and diplopia.
Vestibulocochlear manifestations typically involves bilateral sensorineural hearing loss, though unilateral hearing loss may also occur. Patients may also complain of tinnitus and vertigo with severe hearing loss.
Physical exam should include a full neurological and eye exam and may reveal findings as listed above. Visual field defects may be detected, and a fundus exam may range from normal findings to subtle arteriolar wall hyperfluorescence (AWH) to obvious BRAO.
The differential diagnosis for SS includes, but is not limited to, multiple sclerosis and acute disseminated encephalomyelitis (ADEM) as these are common misdiagnoses. However, lack of oligoclonal bands could help to differentiate from multiple sclerosis.
Workup for SS includes magnetic resonance imaging (MRI), retinal fluorescein angiography (FA), and audiogram. Spectral domain-optical coherence tomography (SD-OCT) has also shown to assist diagnosis in the later stage of SS.
In the acute phase of SS, T2-weighted MRI will reveal supratentorial white matter lesions, particularly in the central corpus callosum. A “snowball lesion” in the corpus callosum is a characteristic sign of the microinfarcts. As the disease progresses, T1 MRI may reveal brain atrophy and callosal holes, icicle and spokes configuration, and thinning. MRI may also reveal microinfarcts of the corpus callosum in a string-of-pearls configuration if long-tract symptoms are present. Leptomeningeal enhancement and deep grey matter and cortical involvement may also be present and can distinguish this disease from MS or ADEM.
When SS is suspected, FA and audiograms could assist in diagnosis to further characterize a BRAO and sensorineural hearing loss, respectively, even if patients appear asymptomatic. Audiograms will typically reveal bilateral low to middle frequency hearing loss. During the acute phase of SS, FA may reveal BRAO and/or multifocal AWH.2,3 Gass plaques, or yellow retinal arterial wall plaques, between arteriole bifurcation may also be detected. SD-OCT has also been proposed as a complementary method to detect the long-term sequelae effects. Patchy thinning from the retinal nerve fiber layer to the outer plexiform layer, particularly in the temporal quadrants, with sparing of the outer nuclear and photoreceptor layers will be present. These findings are consistent with layers affected by the retinal and not choroidal arteries.
Cerebral spinal fluid analysis in SS may reveal elevated protein and lymphocytic pleocytosis. While presence of oligoclonal bands does not affect diagnosis of SS, lack of this can help to differentiate from multiple sclerosis. EEG can be done. Other tests, such as autoantibodies and clotting abnormalities screening, cerebral catheter angiography, and leptomeningeal biopsy have shown to provide little use in diagnosis.
As there is a lack of research on this rare disease, management is based on expert recommendations. Therapy of SS closely resembles that of dermatomyositis due to their similar pathogenesis. Early and aggressive immunosuppressive treatment has been shown to be important in preventing future relapses, and treatment is not necessarily delayed awaiting presence of complete clinical triad. Treatment in the acute period may include high-dose glucocorticosteroids in addition to a fast-onset immunosuppressive drug, such as cyclophosphamide or rituximab. IVIG and plasmapheresis may also be a beneficial adjunct. Maintenance therapy is then initiated for around 2 years following clinical improvement and involves a slow tapering of corticosteroids at 2-4 week intervals and transition to immunosuppressive drugs with lower risk long-term side effects, including mycophenolate mofetil, methotrexate, and azathioprine. Monitoring with brain MRI and FA for relapse during remission is crucial prior to stopping treatment. Those with recurrent BRAO are often self-limiting and only close monitoring is recommended. Hearing aids and cochlear implants can be offered to improve quality of life for those with hearing loss. There has also been discussion about the use antiplatelets and nimodipine, but these have not been shown to be beneficial.
- Dörr J, Krautwald S, Wildemann B, et al. Characteristics of Susac syndrome: a review of all reported cases. Nat Rev Neurol. 2013;9(6):307-316. doi:10.1038/nrneurol.2013.82
- Greco A, De Virgilio A, Gallo A, et al. Susac’s syndrome — Pathogenesis, clinical variants and treatment approaches. Autoimmun Rev. 2014;13(8):814-821. doi:10.1016/j.autrev.2014.04.004
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