The clinical triad of encephalopathy, branch retinal artery occlusions
and hearing loss
John O. Susac, M.D.
In 1975, I saw a young woman with a previously unreported clinical triad of encephalopathy, branch retinal artery occlusions, and deafness. This patient was presented to me at a conference in Albany, NY. Shortly thereafter, Dr. John Selhorst referred to me a 40-year-old woman with an identical set of clinical findings. With Dr. John Hardimann, Armed Forces Institute of Pathology neuropathologist, who interpreted the brain biopsy findings in the Selhorst case, we reported these cases in 1979 as microangiopathy of the brain and retina. Since then there have been 70 additional patients reported, and I have personally cared for ten additional patients in my practice. In addition, I have been consulted several times from patients, doctors and lawyers. The Internet has been a lightning rod for these cases.
In 1986, I presented a 26-year-old woman with this syndrome to Dr. William F. Hoyt at the San Francisco Neuro-ophthalmological Symposium held in his honor. When Dr. Hoyt saw the branch retinal artery occlusions, he announced the diagnosis as "Susac's syndrome". Because the syndrome is almost invariably misdiagnosed as acute disseminated encephalomyelitis or multiple sclerosis, Dr. Robert Daroff, then Editor-in-Chief of Neurology, asked me to write a brief review for neurologists (1994). Modesty would have prevented me from using this eponymic title, but Dr. Daroff insisted that I refer to the disorder as "Susac's syndrome", and of course, I complied.
The syndrome usually affects young women between the ages of 20 and 40 and the first 20 patients I saw were all women. Since that time, however, men have been reported and currently there is a 3:1 ratio of women to men. The age range now extends from 16 to 58. It will be easily recognized if one pays particular attention to the MRI and the ophthalmoscopic examination of the retina.
The encephalopathy usually evolves subacutely and is frequently associated with psychiatric features. These patients are often encountered on the psychiatric floor with personality change and bizarre and paranoid behavior. Invariably, they have bilateral extensor plantar responses and pseudobulbar speech. The encephalopathy may progress to a stage where the patient is totally unable to communicate. Seizures and myoclonus may occur. In other cases, patients may present with brainstem/cerebellar signs and symptoms that may overshadow the encephalopathy. Transient paresthesias and hemiparesis may presage the encephalopathy and may be interpreted as being due to transient ischemic attacks.
Hearing loss is usually bilateral, is often associated with tinnitus and vertigo and may be the presenting feature of the illness. The cochlear hearing loss is usually greatest for low to moderate frequency tones and may be due to microinfarction of the apical turn of the cochlea. In the markedly encephalopathic patient, however, the hearing loss may be difficult to identify. Prominent jerk nystagmus may be present and is probably related to microinfarction of the semicircular canals. The hearing loss may be sudden (overnight) or may be subacute in onset. The degree of hearing loss may range from very mild to very severe. In severe cases, cochlear implants have been successfully used in several instances, and I personally know of at least ten patients who have benefitted.
Headache is almost always present in those patients who present with encephalopathy. It is unrelenting, generalized and intense. Migraine headaches are also frequently seen in these patients and especially in those who present with branch retinal artery occlusions and hearing loss. I have two patients who presented to headache clinics with migraine headaches and branch retinal artery occlusions and were misdiagnosed as "complicated migraine". The migraine headaches respond to triptans and Topamax. The generalized headaches that are seen with the encephalopathy respond to high doses of intravenous methylprednisolone.
The MRI is the diagnostic procedure of choice. We have recently submitted to Neurology a series of 27 patients and their MRI findings. The white matter, especially the corpus callosum, is always involved. There is a preferential involvement of the central portion of the corpus callosum with relative preservation of the peripheral portion. [This is in contrast to the involvement seen with multiple sclerosis where the inferior surface (callosal septal interface) is primarily affected.] In addition to the white matter, the gray matter is frequently affected (three-quarters of the cases) and gadolinium enhancement is also seen in approximately three-fourths of these patients. Leptomeningeal enhancement is less frequently seen, but is an important diagnostic finding. If the encephalopathy is severe, atrophy will ensue in the chronic phase and is commonly a residual finding. Spinal fluid examination has invariably shown an elevated protein in the range of 100 mg to 3 grams. A minimal pleocytosis (5 to 30 lymphocytes) is seen occasionally. Because the affected vessels are less than 100 um, cerebral angiography is almost always normal. Likewise, laboratory testing for collagen vascular disease, coagulopathy, infectious disease, including syphilis and Lyme disease, is unrevealing. The sed-rate may be elevated in a minority of cases. The EEG will be diffusely slow in the encephalopathic phase.
The clinical course is self-limited, ranging from one to four years, but usually lasts from two to four years in most cases. During this fluctuating clinical course, the patient may have had one or more episodes of the triad but there is a definite remission noted at four years. There are exceptions, however, including Bogousslavsky's patient who had a progressive course over five years. There is a definite tendency towards spontaneous improvement in this disorder. Blindness is rare, but hearing loss may be significantly impaired. The severe hearing loss can be successfully treated with cochlear implants. Approximately one-half of these patients are able to return to an essentially normal lifestyle, but the other half do not fare as well because of mild to moderate dementia. A spastic gait is also a frequent residual in the severely affected patients.
Although the pathogenesis of this syndrome is unknown, an autoimmune basis is felt to be likely. Recent brain biopsies have shown perivascular inflammation of small vessels and microinfarctions of the brain. Necrosis is not found in the vessel walls and therefore it is a vasculopathy (microangiopathy) rather than a vasculitis.
We now recommend treatment with intravenous methylprednisolone, followed by oral steroids in conjunction with the use of intravenous immunoglobulin (IVIG). In some instances, we have added cyclophosphamide (Cytoxan) to these two agents at the very onset. We would reserve plasmapheresis for any breakthrough symptomatology or if the patient is not improving with the above.
Imuran (AZT) does not appear to be effective. Cytoxan seems to be preferable and can be given in monthly intravenous pulses or orally. We prefer the monthly intravenous pulses.
For patients who have had only the recurrent branch retinal artery occlusions with or without hearing loss, we would recommend oral steroids plus IVIG pulsed monthly for several months. If this would not arrest the process, we would then recommend Cytoxan. For the seriously ill encephalopathic patient, steroids, IVIG, and Cytoxan can all be used at the very onset and then the steroids tapered. Plasmapheresis could be employed as well.
Neither anticoagulation with Coumadin nor antiplatelet therapy has any effect on this disorder.
Pfaffenbach and Hollenhorst described two young women with BRAO and neurologic changes but no hearing loss. Weidauer and Tenner reported a young woman with bilateral neurosensory hearing loss and bilateral BRAO but without encephalopathy. Likewise, Gass and Johnson have described idiopathic BRAO in young patients. Some of them have had tinnitus, vertigo and hearing loss but no neurological involvement. Some of them have had abnormal MRIs. I have also seen five patients who have had BRAO and hearing loss but who have not yet developed encephalopathy. Interestingly, most of these have had abnormal MRIs with corpus callosal involvement. Thus, in these patients it is important to obtain an MRI with thin sections through the corpus callosum using sagittal T1 and sagittal T2/FLAIR/proton density weighted images.