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Long-Term Outcome in Susac Syndrome

Aubart-Cohen, Fleur MD; Klein, Isabelle MD, PhD; Alexandra, Jean-François MD; Bodaghi, Bahram MD, PhD; Doan, Serge MD; Fardeau, Christine MD; Lavallée, Philippa MD; Piette, Jean-Charles MD; Hoang, Phuc Le MD, PhD; Papo, Thomas MD

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doi: 10.1097/MD.0b013e3180404c99
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Abstract

INTRODUCTION

Susac syndrome is a microangiopathy causing small infarcts in the brain, cochlea, and retina. It is characterized by the clinical triad of acute or subacute encephalopathy, sensorineural hearing loss, and branch retinal artery occlusions, mostly in young women. The pathogenesis of such vasculopathy remains unknown. Since the first report by Susac et al in 197928, almost 100 cases have been reported. Although clinical features and magnetic resonance imaging (MRI) findings are now well described, little is known about long-term outcome. The disease is thought to have a fluctuating self-limited course, with residual cognitive, visual, and/or hearing disability26,27. To our knowledge, the course and long-term outcome of Susac syndrome have not been specifically addressed. We report a series of 9 patients who had defined Susac syndrome, with special emphasis on clinical outcome including pregnancy and long-term sequelae.

METHODS

Nine patients had been referred to Bichat Hospital or Pitié-Salpétrière Hospital, Paris (tertiary care centers of internal medicine and ophthalmology) between May 1993 and June 2003. Patients were eligible if they had the clinical triad of encephalopathy, hearing loss or vertigo, and impaired vision or scotoma. Brain MRI features and cerebrospinal fluid (CSF) analysis were consistent with Susac syndrome in all cases (see below).

Differential diagnosis included mostly multiple sclerosis, ADEM (acute disseminated encephalomyelitis), viral and bacterial infections, primary or secondary vasculopathies including systemic vasculitis, systemic autoimmune disorders, embolic causes, neoplasms and primary central nervous system lymphoma, atherosclerosis, migraine, MELAS (syndrome of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), and CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy)5,22. Demographic data were collected. Brain, eye, and ear involvement at the first visit or admission were described, as well as the time elapsing from the first manifestation to the complete triad. All patients had MRI, ophthalmoscopy, retinal fluorescein angiography, and audiogram. Eight of the 9 patients had lumbar puncture. Electroencephalogram; auditory, visual, and sensitive evoked responses; and formal neuropsychologic testing were also analyzed when available.

Patients were seen on an outpatient basis and regularly assessed, at time intervals ranging from 3 to 12 months depending on their clinical status. Brain MRI, lumbar puncture, retinal angiography, and audiogram were closely monitored during the active phase. They were repeated at least yearly until lasting remission. Brain MRI images were reviewed by 2 of the authors, who were blinded to the patient's medical history. All patients had MRI when encephalopathy occurred. Localization, type, gadolinium enhancement, size, and number of lesions were analyzed. Brain, corpus callosum, and cerebellum atrophy was also evaluated.

Treatment options and modifications were carefully collected, as well as side effects. Four pregnancies occurred during follow-up. The clinical manifestations of Susac syndrome during pregnancy and postpartum were recorded, and pregnancy outcome. Data analysis ended in December 2005.

RESULTS

Nine patients (7 unpublished) were eligible for the study: 7 women and 2 men. Mean age at onset was 30.4 years (range, 19-43 yr). Eight of 9 patients were white, 1 was African. All were healthy at the time of diagnosis. Two were current smokers and 2 were former smokers. None was receiving any treatment at the time of the first symptom, except for oral contraceptives in 2 patients, analgesics and treatments for migraine in 2 patients. One patient had a history of eating disorder and 1 had a history of depression. Migraine was noted in 3 patients. One had migraine since the age of 18 years. Two patients had migraine that started 2 and 3 years, respectively, before the first symptom of Susac syndrome. Mean follow-up was 6.4 years (range, 18 mo to 13 yr).

Onset of Susac Syndrome

In 7 of 9 patients, the first symptom occurred between April and September. It is noteworthy that the clinical triad was incomplete in most of the patients (8 of 9) at the onset (Figure 1). The first clinical manifestation was an ocular symptom in 2 patients, isolated hearing loss in 1, neurologic and visual involvement in 5, and neurologic, visual, and inner ear involvement in 1. None had isolated encephalopathy at the onset. Mean delay from the first symptom to the complete triad was 13 months (range, 0-3 yr) (Table 1).

FIGURE 1
FIGURE 1:
Occurrence of brain, retina, and inner ear involvement in 9 patients with Susac syndrome.
TABLE 1
TABLE 1:
Clinical Features, Follow-Up, and Treatment in Patients With Susac Syndrome, Present and Previously Reported Cases

On the basis of the initial diagnostic procedure, brain involvement was demonstrated at the onset in 6 patients. It occurred during follow-up in 3 other patients, with a mean delay of 10 months (range, 3-24 mo). Inner ear involvement was present at the onset in 2 patients. It occurred in all other patients, with a mean delay of 11 months (range, 1-36 mo). Eye involvement was elicited at the onset in all but 1 patient, in whom it occurred 3 years after the onset.

Brain Involvement

Clinical findings were as follows: headache (n = 7), cognitive or personality changes (n = 6), confusion (n = 4), paresthesia (n = 4). Physical examination was normal in 6 of 9 patients. In others, it revealed bilateral corticospinal tract syndrome (n = 3), Babinski sign (n = 3), ataxia (n = 2), frontal lobe syndrome (n = 1), hypoesthesia in 1 upper limb (n = 1). All but 1 patient had some degree of encephalopathy. In 7 of 8 patients, encephalopathy was preceded by neurologic symptoms: paresthesia (n = 4) and headache (n = 3). Six of 8 patients were receiving no treatment when encephalopathy occurred. One was treated with anticoagulation. One was receiving low-dose aspirin. The ninth patient was given anticoagulation when arterial retinal occlusions and paresthesia occurred and did not suffer from further clinical encephalopathy.

Lumbar puncture was performed in 8 patients when encephalopathy occurred. The last patient, who did not experience encephalopathy, had lumbar puncture at the onset because of unexplained cheiro-oral paresthesia. CSF was normal in 3 patients (33%). In the 5 other cases, CSF analysis revealed lymphocytic pleocytosis (mean, 24.6; range, 6-85 cells) and elevated protein content (mean, 210, range, 113-365 mg/dL). CSF electrophoresis never showed oligoclonal bands.

Electroencephalogram was performed in 4 patients. It showed diffuse slowing (n = 4), seizure activity (n = 1), and delta activity (n = 1). Formal psychometric tests were performed in 4 patients at the time of encephalopathy. All patients had impaired attention and executive function. Additionally, 1 patient had impaired memory, and 1 other had subcortical frontal disturbances. Brain MRI was abnormal in all patients. All patients had, at least once, 5 mm axial T2, proton density, and/or fluid-attenuated inversion recovery (FLAIR), axial and sagittal T1. Seven patients had additional coronal T2-weighted images. Seven patients had T1-weighted images with gadolinium. Four patients had diffusion-weighting imaging.

Four patients underwent MRI before encephalopathy had occurred; these 4 patients had retinal arteriolar occlusions and paresthesia or headache at the time of MRI. One had additional hearing loss. MRI was initially normal in 3 of these 4 patients. It is noteworthy that in 1 patient, MRI revealed 1 punctuate supratentorial deep white matter lesion, which was hyperintense on diffusion-weighted imaging. MRI became abnormal in all patients.

Eight patients underwent MRI when encephalopathy occurred (the ninth patient had no clinical encephalopathy) (Table 2). All 8 patients had multifocal supratentorial white matter lesions, more numerous on T2-weighted images than on FLAIR images. Patients had a mean number of 36 lesions (range, 20-60 lesions), usually ranging in size from 1 to 3 mm. Five patients had 1 greater lesion (between 5 and 10 mm). Lesions were predominant in deep white matter, although also present in the subcortical and periventricular areas. Six patients had confluent periventricular anterior and posterior lesions. Seven of 8 patients had involvement of corpus callosum, more frequently in corpus and splenium. Lesions of corpus callosum were better depicted in coronal and sagittal planes. Three patients had linear lesions of the corpus callosum. Two patients had gray matter lesions: 1 patient had lesions of the basal ganglia, and 1 had lesions of the cerebral cortex. Four patients had infratentorial white matter lesions. These were mostly seen in middle cerebellar peduncles (n = 4) and cerebellum (n = 3). One had brainstem lesions. T1-weighted images were abnormal in 4 patients. Two patients during encephalopathy had T1-weighted images with gadolinium. No gadolinium enhancement was observed. One patient had diffusion-weighting imaging during encephalopathy, which was normal.

TABLE 2
TABLE 2:
Brain MRI Images in 9 Patients With Susac Syndrome

In the patient who did not have encephalopathy, MRI revealed multiple punctuate supratentorial white matter lesions, without lesions of basal ganglia, cerebral cortex, brainstem, or cerebellum. He also had confluent periventricular lesions.

In all patients, the neurologic condition initially improved. Encephalopathy relapsed in 3 patients. In 2 patients a relapse occurred when the steroid dosage was diminished, 5 and 10 months after initial encephalopathy, respectively. These 2 patients quickly improved following reinstitution of high-dose steroids. Of note, in these 2 patients, oral anticoagulation was added at the time of relapse. The last patient had transient headache with visual signs 4 years after the onset. At this time, CSF analysis and funduscopic examination were normal, and MRI showed no new lesions. A fourth patient experienced aphasia with no other sign of encephalopathy 3 years after the onset, accompanying new retinal occlusions. CSF analysis was unremarkable. MRI showed no new lesions. Anticoagulation was started because of new retinal occlusions, and the patient improved.

At the end of follow-up, 5 patients had neurologic sequelae. Three patients suffered from cognitive or psychiatric sequelae: personality disturbances (n = 2), mild cognitive dysfunction (n = 1), fluctuating depression (n = 1). Two patients complained of other neurologic sequelae: difficulty walking because of pyramidal spasticity (n = 1) and recurrent headache (n = 1). Physical examination normalized in all but 2 patients in whom hyperreflexia and Babinski sign were persistent. Formal neuropsychologic testing normalized in all but 1 patient, who showed slight personality disturbances. None was severely impaired, and all patients returned to work except for 1 patient who suffered from a mood disorder. Severity of initial encephalopathy did not correlate with presence or severity of sequelae.

Lumbar puncture was performed in 2 patients when neurologic symptoms had improved (2 and 7 months after encephalopathy, respectively). CSF analysis revealed 1 and 8 cells, respectively, and protein content was 56 and 70 mg/dL.

On MRI, the number of white matter lesions diminished over time in all patients, although none of the patients had normal MRI images at the end of follow-up. In 7 patients, atrophy was seen in subcortical (n = 7), corpus callosum (n = 4), and cortical (n = 2) areas. In 2 patients, atrophy appeared shortly (2 months) after encephalopathy onset. Clinical and MRI evolution were not parallel. Some patients had new white matter lesions without clinical signs. Conversely, in patients with relapsing encephalopathy (n = 3), MRI was unchanged, or ameliorated with less numerous lesions.

Inner Ear Involvement

Inner ear involvement was present at the onset in only 2 patients and occurred in all others with a mean delay of 11 months (range, 2-24 mo). In 1 patient, isolated hearing loss occurred 2 years before neurologic symptoms and 3 years before retinal arteriolar occlusions.

Clinical findings were hearing loss (n = 8), tinnitus (n = 5), and vertigo (n = 4). Hearing loss was always bilateral, although initially unilateral in 3 patients. Audiogram showed a mean loss of 49 dB (range, 15-80 dB). In 7 of 9 patizents, hearing loss involved low and medium frequencies. One patient had hearing loss only in high frequencies (3000 Hz), which was asymptomatic. One had hearing loss in all frequencies.

Five of 9 patients were already treated when hearing loss or vertigo occurred. Treatment included corticosteroids and anticoagulation (n = 2); anticoagulation alone (n = 1); aspirin (n = 1); and corticosteroids, anticoagulation, and aspirin (n = 1). Four patients had no treatment. Hearing loss never improved significantly, either spontaneously or under treatment. Vertigo and ataxia improved with rehabilitation, except for 2 patients. At the end of follow-up, 8 of 9 patients suffered from bilateral hearing loss. The mean hearing loss was 34 dB (range, 15-70 dB). Three patients suffered from tinnitus (n = 1), vertigo (n = 1), or ataxia (n = 1).

Eye Involvement

The eye was involved at the onset in 8 patients. In 1 patient, visual signs occurred 3 years after hearing loss. Visual signs were associated with neurologic symptoms in 7 of 9 patients, especially headache (n = 6). They heralded Susac syndrome in 2 patients. Eight of 9 patients complained of ocular symptoms: scotoma (n = 6) and visual loss (n = 5). The last patient had asymptomatic eye involvement.

Funduscopic examination revealed retinal branch occlusions in all patients. Foveola was ischemic in 2 patients. Retinal fluorescein angiography showed artery branch occlusions and late dye leakage with hyperfluorescence of the arterial wall in the 9 patients. Retinal veins were never involved. These findings were initially bilateral in 4 patients. Retinal artery branch disease relapsed in the 9 patients and became bilateral in all.

Treatment at time of relapse consisted of anticoagulation (n = 6), corticosteroids (n = 5), aspirin (n = 4), and cyclophosphamide (n = 1). Two patients relapsed when anticoagulation was discontinued. In the first patient, anticoagulation reinstitution was followed by angiography normalization 6 months later, without relapse. In the second patient, angiography revealed new retinal occlusions 3 months after anticoagulation reinstitution, but normalized at 6 months without relapse.

Fluorescein angiography normalized in 3 patients with a mean delay of 36 months. In 6 other patients, angiography was still abnormal at the end of follow-up, showing either occlusions or leakage at 1.5, 2, 4, and 10 years. Retinal occlusions and leakage seen on fluorescein angiography were mostly asymptomatic, unilateral, and peripheral. Leakage was more frequent than new occlusions. These late angiographic findings resumed spontaneously and remitted in other retinal arterial sites. When follow-up angiography disclosed new retinal occlusion or leakage, audiogram and brain MRI (and sometimes lumbar puncture) were repeated. When artery branch disease was isolated and asymptomatic, treatment was not modified.

Most of the patients (6 of 9) had a residual visual field deficit, which was asymptomatic except for 1 patient. None had impaired visual acuity at the end of follow-up.

Pregnancy

Three patients underwent 4 pregnancies after the onset of Susac syndrome (Table 3). No patients had a spontaneous miscarriage during the course of the disease. One patient had 2 miscarriages several years before the first symptoms of Susac syndrome. One patient had undergone voluntary abortion 4 years before the first symptoms of Susac syndrome. Of note, in early postabortum, she had presented unilateral transient hearing loss of unknown significance.

TABLE 3
TABLE 3:
Pregnancy in Susac Syndrome

Two patients underwent induced abortion before 10 weeks of gestation. The first patient was receiving monthly intravenous cyclophosphamide when pregnancy was discovered (11 months after the onset of Susac syndrome). The second patient became pregnant 3 months after the onset of the disease, while new retinal occlusions appeared. Therapeutic abortion was proposed because of behavioral disturbances and uncontrolled disease activity. In these 2 patients, no additional symptom occurred during the short course of pregnancy or postabortum.

One patient had pregnancy 3 years after the first symptoms (retinal occlusions and headache). One year before pregnancy, she had experienced recurrent retinal occlusion. She was receiving only aspirin at the time of pregnancy. She reported no additional symptoms while she was pregnant. The newborn was healthy. In the early postpartum, confusion, vertigo, and hearing loss developed.

The patient who had had therapeutic abortion because of encephalopathy had another pregnancy 4 years after the onset of the disease. At the time, she was treated with antiplatelet agents. There was no relapse when she was pregnant, nor in postpartum.

Treatment

Initial Therapy

At onset, treatment was mostly delivered in a primary or secondary care center and was highly heterogeneous, depending on the type of first clinical manifestation of Susac syndrome. Mean delay from the first symptom to treatment was 9 months. Initial treatment was corticosteroids and anticoagulation (n = 3); anticoagulation alone (n = 2); corticosteroids, anticoagulation, and aspirin (n = 1); corticosteroids, aspirin, and nimodipine (n = 1); corticosteroids, anticoagulation, aspirin, and nimodipine (n = 1); and aspirin alone (n = 1). Hence, first treatment consisted of anticoagulation (n = 7), antiplatelet agents (n = 4), corticosteroids (n = 6), and nimodipine (n = 2).

Corticosteroids and Immunosuppressive Drugs

Six of 9 patients were given corticosteroids for more than 1 month. All had neurologic and visual involvement when steroids were started. Four patients received corticosteroids at the onset. Two patients received corticosteroids 5 months and 3 years, respectively, after the first symptom. Four patients were given intravenous methylprednisolone pulses: 1 initially, 1 because of worsening course, and 2 both initially and during follow-up because of relapse. Additionally, 1 patient had a short oral course of prednisone for initial retinal occlusion. The mean duration of steroid therapy was 3 years.

Two patients were treated with immunosuppressive drugs (cyclophosphamide, 6 and 9 monthly infusions, respectively). These patients were receiving anticoagulation and high-dose corticosteroids (>0.5 mg/kg per d) when disease worsened. In the first patient, intravenous cyclophosphamide was started because of new bilateral retinal occlusions, tinnitus, and hearing loss. Hearing loss did not improve and she had new retinal occlusions 1 year after cyclophosphamide was started. In the second patient, encephalopathy occurred under treatment which had been given for retinal occlusions. She received both intravenous methylprednisolone pulses and intravenous cyclophosphamide, and her neurologic condition improved.

Antiplatelet Agents

Eight patients were treated with antiplatelet agents. Aspirin was given at the onset in association with anticoagulation (n = 2) or alone (n = 2). Aspirin was always associated with corticosteroids except for 1 patient who was initially treated with aspirin alone. One patient who had aspirin without anticoagulation at the onset was given anticoagulation 1 year after because of neurologic relapse. The other patient who was treated only with aspirin at the onset was given anticoagulation when encephalopathy and hearing loss occurred. Aspirin was prescribed in 3 patients after anticoagulation was stopped.

Anticoagulation

All patients were treated with anticoagulant agents at some point during follow-up. Seven received anticoagulation as initial therapy. Two patients did not receive anticoagulation at the onset but were given aspirin. In 1 patient, aspirin was administered at the onset with corticosteroids and nimodipine. Confusion and personality disturbances recurred 10 months later, and new retinal occlusions occurred. Aspirin was switched for anticoagulation as a single therapeutic modification. The patient's condition improved with no neurologic relapse. He had no new retinal occlusion, although retinal fluorescein angiography 20 months later revealed dye leakage. In the second patient, aspirin alone was prescribed when headache and retinal arterial occlusions had occurred. Three years after the onset, encephalopathy and hearing loss developed, and aspirin was switched for anticoagulation. Encephalopathy improved and the patient did not suffer new retinal occlusions.

Mean duration of anticoagulation was 3.5 years. One patient continued low-dose anticoagulation for 10 years, because she was unwilling to stop. One patient stopped anticoagulation after 17 months because of fluindione-related hepatitis. Two patients developed new retinal occlusions after anticoagulation was discontinued, which necessitated its resumption.

Treatment at the End of Follow-Up

At the end of the study, all patients were still being treated. Three patients were receiving anticoagulation, 3 aspirin, and 3 anticoagulation and aspirin. Additionally, 4 patients were still receiving low-dose prednisone: with anticoagulation (n = 2), or with anticoagulation and aspirin (n = 2).

DISCUSSION

Susac syndrome is a rare microangiopathy involving the brain, cochlea, and retina. To our knowledge 92 cases have been reported so far, and clinical features and MRI findings are now well described. Susac syndrome is thought to be self-limited, without relapses after 2-4 years. Several new lines of data can be drawn from our observation of 9 patients with defined Susac syndrome, followed in the same institution with a mean follow-up of 6.4 years.

Demographic Data

Susac syndrome affects women more than men (sex ratio 3:1) and the age of onset is usually between 20 and 40 years, with a median age of 32 years22,23 (see Table 1). A woman was reported to suffer the first symptoms of Susac syndrome at the age of 55 years8. However, postmenopausal onset of the disease remains atypical. In our series, mean age at the onset was 30.4 years. Susac syndrome has been reported in North America and Europe but also in Asian patients18,30,33.

Prodromal-like symptoms suggestive of an infection have been reported at the onset of the disease in some patients19,21. It is noteworthy that in our series, a higher incidence of Susac syndrome onset was noted in spring and summer: in 7 of 9 patients, the first symptom occurred between April and September. In the 29 cases previously reported with available information on month of occurrence, we found 19 cases in whom the first symptom started between April and September. Hence, Susac syndrome started in Spring or Summer in 68% of all cases. Of note, some viruses such as West Nile virus or Nipah virus33 have a seasonal peak incidence in late summer and may cause retinal occlusions2 and encephalopathy.

Clinical Features at Onset

The complete triad (encephalopathy, inner ear involvement, retinal arteriolar occlusions) was rarely clinically obvious at the onset27 (see Figure 1). Only 1 of our patients presented with brain, inner ear, and eye involvement at onset. The triad was completed several years (from 0 to 3 yr) after the first symptom. Isolated headache, always with migrainous features, was present in our series before all other symptoms in 33% of patients. In our study, the first manifestation was more frequently visual or neurologic than hearing loss. Eye involvement was present at the onset in 89% of patients. Brain involvement was present at the onset in 67% of patients. Conversely, hearing loss or vertigo occurred at onset in only 22% of patients.

Brain Involvement

Brain involvement in Susac syndrome usually presents as encephalopathy, from mild memory loss or personality changes to confusion21-23. In our series, all but 1 patient had abnormalities in memory, behavior, personality, or cognition. Five had neuropsychiatric manifestations. Physical examination was abnormal in only 3 patients, showing corticospinal tract syndrome, ataxia, or hemiparesia. None had clinical seizures or sphincter disturbances. We did not observe amenorrhea, as previously reported, which had been ascribed to a speculative hypothalamic or pituitary involvement23.

In all of our patients, neurologic condition initially improved. In 3 patients (33%), encephalopathy relapsed. At the end of protracted follow-up (mean, 6.4 yr), 5 patients (56%) had sequelae, but none was severely impaired. Initial severity of encephalopathy did not correlate with the severity of sequelae. We found 36 other cases in which brain sequelae were described. Seven (20%) were demented or aphasic or could not walk. Eighteen (50%) had mild sequelae, such as behavioral or personality changes, memory, concentration or slight cognitive disturbances, ataxia, and hemiparesia. Eleven (30%) had no brain sequelae. Our report argues against the notion that brain involvement is frequently debilitating3,21,26 (see Table 1).

CSF analysis usually shows a mild inflammatory response, including increased protein content and mild pleocytosis, usually no greater than 20 cells/mL. In the current series, it was normal in 33% of patients. Of note, in 1 patient CSF contained 85 cells/mL. As far as we know, such a high cell count has never been described in Susac syndrome, which was otherwise well defined in this patient.

Electroencephalography usually demonstrates diffuse slowing, which underscores the multifocal brain microangiopathy. In the current series, electroencephalography was abnormal in all patients. One had seizure activity. Nevertheless, electroencephalography is not helpful for diagnosis.

Brain CT scan is normal in Susac syndrome, except for atrophy, which may develop during follow-up. Brain MRI in Susac syndrome typically shows bilateral gray and white matter lesions29,32. These lesions are predominantly supratentorial, but may also involve infratentorial compartment. Lesions are numerous and often small (3-7 mm). White matter lesions present as hypointensities in T1-weighted images and small T2 and FLAIR hyperintensities29,32. There is frequent involvement of the cerebellum, the cerebellar peduncles, brainstem, deep gray basal ganglia, and thalamus. Deep basal ganglia and thalamus are involved in 70% of cases. Lesions of corpus callosum involve the central fibers with relative sparing of the periphery29. One-third of patients have leptomeningeal enhancement. Gadolinium enhancement of gray and white matter lesions is found in up to 70% of patients29. In the current series, gray matter and infratentorial involvement were less frequent than previously reported (see Table 2). White matter lesions size was 1 mm rather than 3-7 mm. Hypointensities in T1-weighted images were not frequent. However, we found that confluent periventricular lesions were frequently observed in Susac syndrome, as well as linear lesions of corpus callosum, which seem rather specific to the disease. T2-weighted images were more sensitive than FLAIR images to detect white matter lesions because of the highest resolution obtained with T2 imaging. Coronal and sagittal planes are essential to avoid missing lesions of corpus callosum. We cannot conclude about gadolinium enhancement because not all of our patients had gadolinium injection.

Diffusion-weighted imaging and apparent diffusion coefficient have been proved to be sensitive to the histologic and physiologic changes associated with brain infarction. During the acute phase, infarcted cerebral tissue is hyperintense on diffusion-weighted MRI and has reduced apparent diffusion coefficient13. In Susac syndrome, hyperintense lesions have been reported, with reduced apparent diffusion coefficient33. In our experience, diffusion-weighted imaging was not sensitive enough to elicit the small lesions observed in Susac syndrome.

MRI and clinical evolution were not always parallel, since some patients improved or relapsed despite unchanged MRI. Moreover, we could not find any association between the number of lesions on MRI and the severity of encephalopathy, nor relapses or sequelae. Such paradoxical observation may be explained by the fact that encephalopathy is caused by diffuse microinfarcts of the cerebral cortex, which are revealed by microscopic brain analysis but too small to be visible on brain MRI. When encephalopathy recovered, white and deep gray lesions became less numerous, but the MRI remained abnormal in all cases.

MRI findings of Susac syndrome may be attributed to demyelination as in multiple sclerosis or acute disseminated encephalomyelitis. However, gray matter involvement can help in differential diagnosis. In multiple sclerosis, in contrast with Susac syndrome, high signal lesions are mostly observed in cerebral white matter, their diameter is greater than 6 mm, and the lesion axis is usually perpendicular to ventricles. Some authors report that serial diffusion-weighted MRI is helpful in differentiating Susac syndrome from multiple sclerosis7,33. However, the low sensitivity of diffusion-weighted imaging in Susac syndrome due to the small size of the lesions is clearly a limitation.

Histologic analysis of brain biopsy specimen in patients with Susac syndrome has been reported in 10 patients. There is no autopsy case. Histologic examination reveals foci of necrosis of about 500 μm in diameter in cerebral cortex and white matter. Small vessels of 40-60 μm in diameter with features of precapillary arterioles have been found within the infarcts. The arterioles may be surrounded by lymphocytes, although there is no evidence of vasculitis or thrombosis.

Inner Ear Involvement

The hearing loss seen in Susac syndrome is bilateral most of the time and involves low and medium frequencies, which is caused by apical cochlear damage ascribed to occlusion of the cochlear end arterioles17. In the current series, hearing loss did not improve over time, and all but 1 patient had some degree of permanent hearing impairment. Conversely, tinnitus and vertigo resolved with rehabilitation in 4 of 5 patients. Inner ear sequelae were described in 30 previously reported cases of Susac syndrome. Only 3 patients (10%) had no hearing loss at the end of follow-up. One was deaf. Twenty-six patients had uni- or bilateral hearing loss. Thus, inner ear involvement in Susac syndrome leads to frequent and debilitating sequelae (see Table 1).

Eye Involvement

In the current series, initial eye involvement was asymptomatic in only 1 patient. In the other cases, patients complained of scotoma or visual acuity loss. Visual field was always abnormal. All patients retained good visual acuity despite visual field defects.

Funduscopic examination in Susac syndrome reveals retinal ischemic whitening, cotton-wool patches, periarterial whitening, box-car segmentation, and cherry red spot9,23. Optic disk pallor may occur in the later stages. Retinal arterial wall plaques have sometimes been described in Susac syndrome9. They are yellow and usually located away from arterial bifurcations, which helps to distinguish them from visible emboli. In the current series, funduscopic examination showed artery branch occlusions and ischemic retina in all patients. During follow-up, all patients had several arterial occlusions, most of the time asymptomatic. Nevertheless, funduscopy was less sensitive than fluorescein angiography for detecting new occlusions.

Retinal arteriolar branch occlusions and arterial wall hyperfluorescence are typical features of Susac syndrome on fluorescein angiography. Although the most frequent cause of retinal occlusions is clearly embolic (cardiac disease or carotid stenosis), arterial wall hyperfluorescence is not a usual finding in embolic occlusions25. Bilaterality, occurrence in young persons, or relapses after several months are also unusual features in branch retinal artery occlusions and should evoke Susac syndrome21. Arterioles multifocal fluorescence is especially evocative for Susac syndrome. Branch retinal artery occlusions and arterial wall hyperfluorescence are not parallel: they are not always detected in the same site nor at the same time. Arterial wall hyperfluorescence zones may represent preocclusive lesions, and may be taken as an indicator of active disease26. They are asymptomatic most of the time. Retinal arterial occlusions have a wax and wane course in Susac syndrome. Isolated new hyperfluorescence zones may appear several years after the onset of disease. In the current series, all patients experienced several new retinal branch artery occlusions. Fluorescein angiography normalized in only 33% of our patients at the end of follow-up.

At the end of follow-up, no patient had visual loss, although 1 patient had symptomatic residual visual field deficit. Retinal sequelae were described in 31 previously reported cases of Susac syndrome. Ten patients (32%) had visual sequelae. Only 1 was blind. One had bilateral atrophy of the optic nerves. Three (10%) suffered from severe visual loss. Three (10%) had bilateral mild visual loss, and 2 (6%) had unilateral mild visual loss. Two patients had retinal neovascularization treated by laser photocoagulation11,16. Although the retina is a frequent site of relapse in Susac syndrome, it does not usually lead to debilitating sequelae (see Table 1).

Pregnancy

During the 4 pregnancies of our patients (2 interrupted before week 10), no symptom or sign of Susac syndrome was reported. Nevertheless, in 1 patient, encephalopathy developed during the early postpartum period.

Gordon et al10 reported the case of a 28-year-old patient who presented with hearing loss, visual signs, and encephalopathy in her 28th week of pregnancy. After delivery, the patient's mental status improved and her neurologic examination normalized 6 weeks later, with persistent visual field deficits and hearing loss. Coppeto et al6 described a patient whose initial condition subsided when she became pregnant but recurred after she delivered a stillborn anencephalic child. MacFadyen et al15 and Petty and colleagues24 reported the case of a woman who developed arteriolar retinal occlusions, hearing loss, and mild encephalopathy during pregnancy. She improved without treatment. She delivered a normal baby but encephalopathy relapsed early postpartum. She was treated with corticosteroids and her condition improved. This patient relapsed 18 years later, 1 year after having begun estrogen replacement therapy.

Hence, the clinical course of Susac syndrome appears to worsen postpartum (see Table 3).

Outcome and Treatment

Although Susac syndrome is thought to be self-limited, we showed that late relapses may occur, especially in the retina with asymptomatic new arterial occlusions. To our knowledge, no death related to Susac syndrome has been reported.

Corticosteroids, antiplatelets, anticoagulation, and oral or intravenous cyclophosphamide have been frequently used to treat Susac syndrome (see Table 1). Azathioprine, hyperbaric oxygen14, plasma exchanges, and intravenous immunoglobulins have had anecdotal success1,31,34. Nimodipine has been used because of the possibility of vasospasm. All these results should be tempered because of the fluctuant course of the disease, which may mimic therapeutic success.

In our patients, corticosteroids appeared to be efficient to treat encephalopathy. Interestingly, encephalopathy relapsed in some patients when corticosteroid dosage was diminished and improved when it was increased again. Among 49 patients previously described, all but 4 received oral or intravenous corticosteroids. In most of the cases, corticosteroids appeared beneficial to treat encephalopathy. As in our series, when corticosteroids dosage was tapered, relapses often occurred11,20,27,28,33. Most patients improved when high-dose steroids were reinstituted. However, encephalopathy worsened in some patients despite corticosteroids8,17,21,33,34.

Susac26 previously stated that anticoagulation has no role in the treatment of Susac syndrome. Among 48 patients previously described, 12 received aspirin or clopidogrel and 9 were given oral or intravenous anticoagulation, most of the time associated with other treatments. One patient received only aspirin and had no sequelae 4 months later12. One patient received only heparin then warfarin, and had no sequelae10. In all our patients, disease improved under antiplatelet agents and/or anticoagulation therapy. In some, disease recurred when oral anticoagulation was stopped, and remitted when it was reinstituted. In others, disease exacerbated under antiplatelet agent treatment and improved when it was switched to oral anticoagulation. In our experience, anticoagulation efficacy was clear, especially on visual manifestations.

Two patients in the current series received immunosuppressive drugs (cyclophosphamide), which led to quick improvement of encephalopathy, as previously reported1,16,31. Estrogen use was proscribed in all women because of the drug-related thrombotic risk. Of note, Susac syndrome may also improve without treatment4,10.

During follow-up of our patients, when an asymptomatic new retinal lesion was disclosed on angiography, physical examination, brain MRI, and audiogram were performed systematically. No change in therapy was prescribed when retinal occlusions occurred as an isolated manifestation. Only a closer clinical follow-up was applied. Late isolated retinal findings were mostly related to hyperfluorescence of the arterial wall rather than true luminal occlusions on angiography. Such new asymptomatic arteriolar retinal findings did not herald disease flare and always resolved spontaneously.

Conclusion

Based on the current long-term protracted study, the former perspective on Susac syndrome may be altered in several respects:

  1. Disease onset: the triad of Susac syndrome is not clinically obvious at the onset and may be complete only after several years. To be recognized, systematic and repeated funduscopic examination must be performed ahead of unexplained encephalopathy, especially when associated with hearing loss. The first manifestation of Susac syndrome appears to occur more often between April and September.
  2. Pregnancy may affect Susac syndrome course, with encephalopathy relapses postpartum.
  3. Treatment: corticosteroids are efficient to treat encephalopathy, and relapses may occur when their dosage is tapered. However, corticosteroids do not treat hearing loss or prevent new retinal arteriolar occlusions. Anticoagulation has a role in treating encephalopathy and retinal arteriolar occlusions.
  4. Sequelae: in the current series, patients did not suffer from severe cognitive sequelae. All but 1 patient returned to work. Vision was usually not seriously impaired. Most of the patients had bilateral hearing loss, with limited disability.
  5. Late manifestations and unlimited course: Susac syndrome has a fluctuant course. Our main finding was that the course of Susac syndrome is not self-limited as previously thought, since isolated retinal arteriolar involvement-vascular leakage more than occlusion-may occur as a very late asymptomatic manifestation. Such late arteriolar retinal manifestations do not require treatment modification if they are isolated and asymptomatic, but a closer follow-up is then warranted.

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