Susac’s Syndrome

John O. Susac

Susac’s syndrome consists of the clinical triad of encephalopathy, branch retinal artery occlusions, and hearing loss. In 1975, I saw two patients with this syndrome within a matter of 3 weeks while serving in the United States Army at Walter Reed Army Hospital. The first patient was presented to me at a conference in Albany, New York, and the second was referred to me by Dr. John Selhorst. I reported these two cases at the 1977 annual meeting of the American Academy of Neurology and subsequently described these findings as microangiopathy of the brain and retina (1). None of my previous mentors at Letterman Army Hospital (Robert Daroff, Darell Buchanan, and Carl Gunderson), at the University of California (William Hoyt, Robert Fishman), or at the University of Miami (J. Lawton Smith, Joel Glaser, Daroff) had recognized this symptom complex. While at Walter Reed, I had Frank Walsh and David Cogan as consultants and neither of these senior giants in the neuro-ophthalmological field had ever encountered such patients.

Initially, I strongly considered this syndrome as a form of granulomatous angiitis (now designated “primary CNS vasculitis”), but branch retinal artery occlusions and hearing loss are not described in that disorder. I called it a “microangiopathy,” since only the precapillary arterioles (<100 μm) were affected, and I presumed it to be immunologically mediated.

While in private practice in Winter Haven, Florida, I encountered two additional young women with this syndrome, and in 1986 presented one of them to Dr. William F. Hoyt at a Neuroophthalmological Symposium held in his honor. This young woman had an enigmatic encephalopathy for 6 months before she developed branch retinal artery occlusions and hearing loss. When Dr. Hoyt saw the branch retina artery occlusions, he announced the diagnosis as “Susac’s syndrome.” Dr. Robert B. Daroff, then Editor-in-Chief of Neurology, asked me to write a review in 1994 and insisted that I refer to the disorder as “Susac’ s syndrome” (2). Modesty would have prevented me from by using this eponymic title, but Dr. Daroff was most persuasive and prevailed.

At that time, 1994, it seemed that Susac syndrome exclusively affected young women between the ages of 2l and 41 years: the first 20 patients reported had been women. Men were later reported, but there is a female predominance of 3 to 1, and the age range extends from 16 years to 58 years.

Headache, often severe and sometimes migrainous in character, is an almost constant complaint and may be the major presenting feature of the encephalopathy, which can manifest with cognitive changes, confusion, and memory and psychiatric disturbances. The accompanying multifocal neurologic signs usually distinguish this from a true psychiatric illness.

In 1994 at the Walsh Society meeting in Chicago, a case from the University of Michigan entitled, “The Eyes Have It,” was presented. It was of a young woman admitted to a psychiatric ward with the history of being found in her bathroom “flushing the evil demons down the drain.” An MR image showed multifocal white matter changes, including those in the corpus callosum. Following this, the presenter said, “A diagnostic maneuver was performed.” Dr. Hoyt jumped up and said, “I guess you’re going to show the branch retinal artery occlusions that Susac described.” He pointed to me in the back of the room and actually spelled out my name, “S-U-S-A-C.” The neuroradiologist on the panel disagreed with this violently and stated that the young woman must have multiple sclerosis and an unrelated process that was affecting her retinal arteries. The presenters from Michigan also rejected the Susac syndrome diagnosis. Hoyt almost had to be restrained.

MR findings in Susac syndrome always show corpus callosum involvement. We recently described this in 27 previously unreported patients in whom there was a predilection for the white mailer of both the supratentorial and infratentorial compartments (3). The lesions are typically small, multifocal, and frequently enhance during the acute stage (70%). Leptomeningeal enhancement was present in 33% and deep gray matter involvement (basal ganglia and thalamus) in 70%.

Although any part of the corpus callosum may be involved in Susac syndrome, the callosal lesions typically involve the central fibers with relative sparing of the periphery. Central callosal holes ensue as the active lesions resolve (3). In contrast to Susac syndrome, the callosal involvement in both multiple sclerosis and acute disseminated encephalomyelitis is on the undersurface of the corpus callosum at the septal interface. As encephalopathy abates, white matter lesions typically disappear, but atrophy becomes evident.

No strict clinical correlation exists between the degree of encephalopathy and the number of lesions evident on the MR image. There may be only a few white matter lesions in a patient who is profoundly encephalopathic. A prime example of this was in a 58-year-old man whose hemispheric white matter lesions could have easily been misinterpreted as age related, except for the characteristic callosal lesions of Susac syndrome.

What frustrates me is that with current MR imaging, the small cortical microinfarctions are not seen. They are almost certainly there, because every time a brain biopsy is done, microinfarctions are seen in the cortex as well as in the white matter and leptomeninges. There are occasional enhancing lesions within the cortex, but only rarely are the cortical microinfarctions evident on FLAIR, proton density–weighted, or T2-weighted images.

The cranial nerves are not involved in Susac syndrome. The hearing loss is due to cochlear involvement and the vertigo, if present, is due to semicircular canal involvement. We have been unsuccessful in detecting microinfarcts in either of these structures with gadolinium-enhanced T1-weighted imaging.

I asked Dr. Hoyt why this syndrome was not more frequently recognized and his response was, “The branch retinal artery occlusions were always hard to find.” Thus, we recommend that in any unexplained encephalopathy predominantly involving the white matter, but also the gray matter and leptomeninges, a neuro-ophthalmologist or retinal specialist should evaluate the patient with a dilated funduscopic examination. If the branch retinal artery occlusions are not seen at the very onset, the examination should be repeated at frequent intervals, because occlusions may develop later in the course. These specialists are well attuned to the characteristic fundus picture of the branch retinal artery occlusions that are often associated with Gass plaques (4) and the multifocal fluorescence that Dr. Gass believes is pathognomonic for Susac syndrome.

Another reason Susac syndrome is under-diagnosed is that radiologists and neuroradiologists are not familiar with it. Frequently, the MR image is interpreted as “typical” for MS or acute disseminated encephalomyelitis. Other diagnoses that are entertained include meningeal carcinomatosis, aseptic meningitis, Lyme disease, cardioembolic disorder, complicated migraine, chronic encephalitis, and even Creutzfeldt-Jakob disease.

Extensive diagnostic laboratory studies will not show any evidence of connective tissue disorder, pro-coagulant state, or infectious disease. EEG findings are diffusely slow during encephalopathy. Lumbar puncture usually reveals a high spinal fluid protein and occasionally mild pleocytosis, usually lymphocytic. On occasion, an elevated IGG Index or synthesis rate and oligoclonal bands will be evident, leading to a mistaken diagnosis of multiple sclerorosis. Cerebral arteriography findings are almost always normal, because the involved precapillary arterioles (<100 μm) are beyond the resolution of arteriography. Fluorescein angiography, however, is extremely useful and will often show the branch retinal artery occlusions as well as the pathognomonic multifocal fluorescence of the branch arterioles.

The clinical course of Susac syndrome is usually self-limited, fluctuating, and monophasic. It lasts from 2–4 years but may be as short as 6 months or as long as 5 years in duration. Although some patients recover with little or no residual disease, others are profoundly impaired with cognitive deficits, gait disturbance, and hearing loss. Usually, vision is not seriously impaired.

The pathogenesis of this syndrome is unknown. Since these patients tend to improve spontaneously, it is difficult to evaluate the results of treatment, but treatment with intravenous methylprednisolone followed by oral steroids, in conjunction with cyclophosphamide or immunoglobulin, seems helpful. Some patients seem to respond to monotherapy with steroids, cyclophosphamide, or immunoglobulin. Anticoagulation has no role in the treatment of this disorder.

There is a form fruste of the disease in which recurrent branch retinal artery occlusions and hearing loss occur in the absence of encephalopathy. Even in these cases, MR imaging may show white matter changes, especially in the corpus callosum.

Finally, I would like to stress to neuroradiologists that lesions of the corpus callosum are not pathognomonic of multiple sclerosis and when they involve the central fibers, sparing the periphery, think Susac syndrome.

References

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Susac JO, Hardimann JM, Selhorst lB. Microangiopathy of the brain and retina. Neurology 1979;29:313–316
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Susac JO. Susac’ s syndrome: the triad of microangiopathy of the brain and retina with hearing loss in young women. Neurology 1994;44:591–593
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Susac JO, Murtagh FR, Egan RA, et al. MRI findings in Susac’s syndrome. Neurology 2003;61:1783–1787
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Egan RA, Nguyen TH, Gass DM, Rizzo JF, Tivnan J, Susac JO. Retinal arterial wall plaques in Susac syndrome. Am J Ophthalmology 2003;483–486