Introduction

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.

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Branch Retinal Artery Occlusions (BRAO)

Figure 1. Right fundus photograph demonstrating retinal artery occlusions. The superior temporal artery occlusion is more extensive and involves the paramacular region. At 12 o'clock, there is an arteriole partially occluded by segments of fibrin-like material.

The key to the diagnosis is the detection of branch retinal artery occlusions (figure 1), which may be quite extensive and spectacular or may be very subtle. If the infarctions involve the posterior pole, the patient will complain of impaired vision. If the occlusions occur in the more peripheral portion of the retina or if the patient is encephalopathic, the patient may not describe visual symptoms. The branch retinal artery occlusions are usually bilateral and may be the presenting symptom of the illness or occur later in the clinical course. An example of the latter was in a 26-year-old woman who initially presented with an encephalopathy without any other diagnostic features. Several months later branch retinal artery occlusions occurred (figure 1) and hearing loss ensued. Fluorescein angiography is a very helpful tool in evaluating the branch retinal artery occlusions.

A distinctive staining of the vessels, that is pathognomonic for this disorder (Gass), occurs in some cases. When the branch retinal artery occlusions resolve, the funduscopic appearance of silver streaks may replace the occluded arterioles as illustrated in our 1979 article. Subsequently, we have found Gass plaques (retinal arterial wall plaques) that are frequently encountered at the mid segments of the retinal arterioles (Egan). These Gass plaques may be confused with Hollenhorst plaques and the patients may undergo a fruitless cardioembolic workup.

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Encephalopathy

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.

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Hearing Loss

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.

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Headache

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.

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Clinical Investigations (MRI)

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.

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Clinical Course

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.

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Pathogenesis and Treatment as of September 2003

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.

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Forme Fruste Cases

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.

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References

1. Susac JO. Susac syndrome: the triad of microangiopathy of the brain and retina with hearing loss in women. Neurology 1994; 44:59 1-593.
2. Susac JO, Hardimann JM, Selhorst JB. Microangiopathy of the brain and retina. Neurology 1979; 29:313-3 16.
3. O'Halloran HS, Pearson PA, Lee WB, Susac JO, and Berger JR. Microangiopathy of the brain, retina, and cochlea (Susac syndrome): a report of five cases and a review of the literature. Ophthalmology 1998; 105:1038-1044.
4. McKusick VA. On the naming of clinical disorders, with particular reference to eponyms. Medicine 1998; 77: 1-2.
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6. Petty GW, Engel AG, Younge BR, Duffy J, Yanagihara T, Lucchinetti CF, Barleson JD, Parisi JE, Kasperbauer JL, Rodriguez M. Retinocochleocerebral vasculopathy. Medicine 1998; 77: 12-40.
7. Liu GT, Volpe NJ, Galetta SL: Neuro-Ophthalmology Diagnosis and Management. W.B. Saunders Co., Philadelphia, PA, 2001.
8. Monteiro ML, Swanson RA, Coppeto JR, Cuneo RA, DeArmond SJ, Prusiner SB. A microangiopathic syndrome of encephalopathy, hearing loss, and retinal arteriolar occlusions. Neurology 1985; 35: 1113-21.
9. Vila N, Graus F, Blesa R, Santamaria J, Ribalta T, Tolosa E. Microangiopathy of the brain and retina (Susac's syndrome): Two patients with atypical features. Neurology 1995; 45: 1225-26.
10. Fialho D, Holmes P, Riordan-Eva P, Silber B. A blinding headache falling on deaf ears (Susac's Syndrome). Practical Neurology 2002 (2): 358-361.
11. Notis CM, Kitei RA, Cafferty MS, Odel JG, and Mitchell JP. Microangiopathy of brain, retina, and inner ear. J Neuroophthalmol 1995; 15:1-8.
12. Gordon DL, Hayreh SS, Adams HP Jr. Microangiopathy of the brain, retina, and ear: Improvement without immunosuppressive therapy. Stroke 1991; 22: 933-37.
13. Turner BW, Digre KB, Shelton C. Susac syndrome. Otolaryngol Head Neck Surg 1998; 118: 866-7.
14. Ayache D, Plouin-Gaudon I, Bakouche P, Elbaz, P, Gout 0. Microangiopathy of the inner ear, retina and brain (Susac syndrome). Arch Otolaryngol Head Neck Surg 2000;126: 82-84.
15. Petty GW, Matteson EL, Younge BR, McDonald TJ. Recurrence of Susac syndrome (retinocochleocerebral vasculopathy. Mayo Clin Proc 2001,76:958-960.
16. Barker RA, Anderson JR, Meyer P, Dick DJ, Scolding NJ. Microangiopathy of the brain and retina with hearing loss in a 50 year old woman: extending the spectrum of Susac's syndrome. J Neurol Neurosurg Psychiatry 1999; 66:641-643.
17. Tashima K, Uyama E, Hashimoto Y, Yonehara T, Uchino M: Susac's Syndrome: Beneficial effects of corticosteroid therapy in a Japanese case. Internal Medicine (Tokyo) 2001; 40, #2: 135-139.
18. Saw VPJ, Canti PA, Green CM, Briggs RJ, Cremer PV, Harrisberg B, McCluskey P, Oday J, Paine M, Wakefield D, Watson JDG. Susac syndrome: microangiopathy of the retina, cochlea and brain. Chin, and Experimental Ophthal 2000; 28:373-381.
19. Weinshenker BG, Lucchinetti CF: Acute leukoencephalopathies: Differential diagnosis and investigation. The Neurologist 1998; 4:156-161.
20. Ballard E, Butzer JF, Donders J: Susac's syndrome: neuropsychological characteristics in a young man. Neurology 1996; 47:266-268.adiol 2002; 23:803-808.
21. Gass JDM, Tiedeman J, Thomas MA. Idiopathic recurrent branch retinal artery occlusion. Ophthalmology 1986; 93: 1148-1157.
22. Johnson MW, Flynn HW, Gass JDM. Idiopathic recurrent branch retinal artery occlusion. Arch Ophthalmol 1989; 107:757.
23. Gass JDM. Stereoscopic atlas of macular disease: diagnosis and treatment, ed. 4. St. Louis: Mosby, 1997: 446-448,456-462.
24. Egan RA, Nguyen TH, Gass DM, Rizzo JF, Tivnan J, Susac JO: Retinal Arterial Wall Plaques in Susac Syndrome. Am J Ophthalmol 2003; 483-486.

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Articles

As of August, 2009, a total of 123 articles have been published on what is now recognized to be Susac's Syndrome. Most of these articles have consisted of case reports in which only one patient (76 articles) or two patients (13 articles) are reported. Only 7 of the articles discuss a group of more than 4 patients.

These 123 articles have been authored by physicians from a total of 23 countries: United States, Canada, France, Germany, United Kingdom, Spain, Israel, Italy, Belgium, Denmark, Portugal, Finland, Switzerland, Hungary, Slovakia, Turkey, Tunisia, Kuwait, China, Japan, Singapore, and Brazil. In addition, there have been reports of Susac's Syndrome occurring in patients from African and Indian (east India) descent. The 123 articles have documented the occurrence of Susac's Syndrome in a total of 208 patients from around the world. Most of the reported patients have been women, but children and men with Susac's Syndrome have also been identified Most patients have been between the ages of 20-40, but many patients in their 40s and 50s have been reported. The oldest reported patient was 59 at the time of disease onset. Susac's Syndrome has been reported in 6 children under age 17, including an 8 year old and a 9 year old. In addition, Susac's Syndrome has been reported in 6 young adults (age 17, 18, 19). More than half of the articles have been published since January, 2004---most likely a reflection of ever-increasing awareness of Susac's Syndrome.    Click here to see the current list (pdf format) of Susac's Syndrome Articles. Click here to see the complete list (pdf format) of Susac's Syndrome Articles and additional Article details.

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