Susac's syndrome
This patient presented with a history of subacute progression of encephalopathy, together with recent onset of hearing loss and tinnitus. Although he did not complain of visual disturbance, retinal abnormalities were clearly evident on physical examination. On MR imaging, white matter lesions were scattered throughout the brain, with a remarkable amount of involvement of the corpus callosum. Several lesions also appeared to be quite distally located. Given the evidence for multifocal, subacute CNS lesions, diagnostic possibilities included multiple infarctions secondary to a hypercoagulable state, primary CNS vasculitis or infection, neurological complications of systemic collagen vascular disease, acute disseminated encephalomyelitis (ADEM), a primary mitochondrial disorder, multiple sclerosis, and Susac's syndrome. The triad of encephalopathy with callosal involvement, hearing loss, and retinal infarctions suggested a diagnosis of Susac's syndrome.
He had received an extensive evaluation at an outside hospital prior to admission to the Methodist Hospital in Houston, Texas. At the Methodist Hospital, MRI, lumbar puncture, EEG and blood tests were repeated. The EEG documented diffuse alteration of brain function, but did not suggest seizure activity or other diagnostically helpful patterns to explain the patient's state. None of the laboratory findings suggested a systemic collagen vascular disease, lactate elevation suggestive of mitochondrial dysfunction, or a hypercoagulable state. CSF findings did not strongly support an infectious process. Cerebral angiography, performed at the outside hospital, did not show evidence to suggest vasculitis of large or medium sized vessels. However, fluorescein retinal angiography revealed multiple retinal artery branch occlusions. Given the sensorineural hearing loss confirmed by an audiogram, the presence of retinal artery occlusions and encephalopathy, the patient was diagnosed with Susac's syndrome.
He received high dose intravenous methylprednisolone and cyclophosphamide, with improvement. By the time of transfer to another facility near his home, he demonstrated decreased encephalopathy with some improvement in his gait and short term memory.
Susac's syndrome, a microangiopathy characterized by the triad of encephalopathy, retinal artery occlusion, and hearing loss, was well described by Susac, Hardman and Selhorst in two encephalopathic women without evidence to support the diagnosis of other known vasculitides. Other authors had described a similar triad years earlier, but had attributed it to systemic lupus erythematosus or another undiagnosed form of vasculitis. Susac's syndrome is also referred to in medical literature as microangiopathy of the brain and retina, retinocochlear vasculopathy, RED-M (retinopathy, encephalopathy, deafness associated microangiopathy), and SICRET (small infarctions of cochlear, retinal and encephalic tissue).
Since the original description of this clinical triad in the 1970s, numerous cases have been reported. Originally thought to be a disorder of women only, several cases affecting men have also been reported. However, the disease most frequently occurs in young women, with an age range from 8 to 59 years, mean age of 28 years and median age of 29 years.
In a recent analysis (Susac et al., 2003), MRI images from 27 patients fulfilling the diagnostic criteria of Susac's syndrome were reviewed. Multifocal supratentorial lesions were present in all patients. Most lesions were small (3 to 7 mm), though some were larger than 7 mm. All 27 patients had corpus callosum lesions. These all had a punched-out appearance on follow up MRI. Though most commonly involving white matter, many patients also had lesions in deep grey matter structures (19 of 27), as well as leptomeningeal enhancement (9 of 27). Multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM) can mimic the MRI changes seen in patients with Susac's syndrome. However, the callosal lesions in Susac's syndrome are centrally located. In comparison, patients with MS and ADEM typically have lesions involving the undersurface of the corpus callosum. Deep gray matter involvement commonly occurs in ADEM but is very rare in MS. Leptomemingeal involvement is not typical of either MS or ADEM.
In the March 1979 report in Neurology, Drs. Susac, Hardman and Selhorst reported two patients with the triad of encephalopathy, hearing loss and microangiopathy of the retina. The first patient underwent brain biopsy, which revealed sclerosis of the media and adventitia of small pial and cortical vessels, suggestive of a healed angiitis. Both patients underwent fluorescein retinal angiography that demonstrated multifocal retinal artery occlusions without evidence of embolic disease.
Though the exact pathogenesis of this disorder is unknown, the findings of retinal microangiopathy and brain biopsies suggest a small vessel vasculitis leading to arteriolar occlusion and microinfarction of cerebral, retinal and cochlear tissue. Demyelination is not a typical feature of Susac's syndrome. Muscle biopsies from such patients are usually normal, but some have also shown nonspecific signs of inflammation such as dense hyaline material surrounding endomysial capillaries. This suggests a possible systemic component of this disease, despite the predominance of central nervous system features.
Proposed causes include autoimmune vasculitis, hypercoagulable state and viral infection. Evidence for viral infection includes a prodromal illness in some patients. Development of symptoms during pregnancy and oral contraceptive use suggest a possible contribution of coagulation abnormalities in such patients. However, the relatively infrequent recognition of this syndrome has provided few cases for systematic study of possible causative factors.
For most patients, the disease appears to be self-limited. In most reported cases, the duration of the disease is two months to two years. Some patients may experience several episodes or exacerbations of the triad of Susac's syndrome, but most patients experience stabilization or remission after two years. However, there have been reported cases of patients with a more progressive course over several years, and one reported case of recurrence after remission for 18 years. Of note, all the patients reported in these series received immunomodulatory treatments such as prednisone, methylprednisolone, cyclophosphamide, or intravenous immunoglobulin.
There appears to be a decrease in permanent morbidity in patients who are diagnosed early and receive immunosuppressive therapy. However, given the rarity and variable clinical course of Susac's syndrome, counseling patients as to expected outcomes is difficult. Furthermore, the treatments patients receive for incorrectly diagnosed diseases (e.g. multiple sclerosis) are similar to the treatments employed in cases of Susac's syndrome, which could further complicate prognostication. However, the specter of permanent sequelae, which may include mild to severe cognitive deficits, hearing and visual impairment, spastic quadriparesis, hemisensory loss, personality change, and depression, warrant strong consideration of empiric immunosuppressant treatment once the diagnosis has been established. Most patients exhibit some degree of cognitive deficit, particularly short term memory loss, any of which can be disabling.
Often treatment involves escalating therapy, first with oral or IV corticosteroids, and then add-on therapy with cyclophosphamide if corticosteroids fail to produce a rapid and sustained response. Intravenous immunoglobulin is also believed to be of value in empiric treatment. In general, authors of case reports note that rapid improvement occurs following administration of these agents. Mixed results have occurred with the use of anticoagulation and antiplatelet agents and generally they are not used in the treatment of Susac's syndrome. The optimal duration of therapy, protocols for escalation of therapy and dosages of immunosuppression have not been formally established in prospective studies. Most authors advocate a slow taper of oral corticosteroids after initial intravenous therapy.
This patient's excellent case presentation by Dr. Schadendorf highlights the importance of clinical suspicion, meticulous history taking and physical examination in patients with undiagnosed white matter disorders. Early recognition of the clinical features of Susac's syndrome may help to avoid more invasive procedures such as brain biopsy, and lead to earlier intervention with empiric immunosuppressive therapies.
We thank Dr. J.O. Susac for helpful comments on this patient's case.
-- Dennis R. Mosier, M.D., Ph.D.
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