Clinical manifestations

Presentation and course

The triad of clinical features in Susac syndrome is encephalopathy, retinopathy, and hearing loss. Most affected individuals do not have the clinical triad at the onset of symptoms but, rather, recurrences of one or more of the triad components. In a series of 10 cases reported from Israel, only two patients presented with the full triad of Susac syndrome, and seven patients developed the full triad during a mean follow-up period of 35 months (120); the authors suggested classifying the disease course into suspected, incomplete, and complete Susac syndrome to facilitate early diagnosis. In a series of 19 cases of Susac syndrome reported from Turkey, only three presented with the complete clinical triad (129). In a retrospective review of 32 adult patients with Susac syndrome from an Australasian cohort, 19% presented with brain-eye-ear involvement, 44% with brain-ear involvement, 19% with brain-eye involvement, and 19% with just brain involvement (116).

Few cases with the complete triad have been reported in children, adolescents, or young adults (48; 32; 97; 53).

The number of attacks in reported cases has varied between one and eight, with an interval of 1 to 34 months between episodes. The mean duration of the illness is about 4 years.

Encephalopathy. Headache is a prodromal symptom that may precede the development of encephalopathy. Headache is often migraine-like and may be accompanied by a visual aura (78). Cognitive disturbance, characterized by short-term memory loss and disorientation, is present in about 75% of the cases. Psychiatric disturbances are frequent and include bizarre behavior. In 25% of patients, the first attack is preceded by slowly progressive personality and mental changes (109). Neurologic signs are diffuse or multifocal and progress over the course of the disease. Corticospinal tract symptoms and signs, including weakness and hyperreflexia, usually occur bilaterally. Rarely, sphincter disturbances and seizures have been described.

Retinopathy. Retinopathy manifests by impaired vision due to multiple bilateral branch retinal artery occlusions without intraocular inflammation. These can be detected by fundoscopic examination (56), which may show occlusion of the branches of the central retinal artery with a cherry-red appearance of the macula (22). Yellow to yellow-white, nonrefractile, or refractile retinal arterial wall plaques (Gass plaques) found at midarteriolar segments are common findings in Susac syndrome (103).

Usually, segmental loss of vision occurs. Hemianopsia has not been reported in any of the cases. If the occlusions are confined to the peripheral branches of the retinal artery, there may be no visual symptoms, and the fundoscopic examination may be negative.

In exceptional cases, unilateral occlusion or staged bilateral occlusions of the central retinal artery may develop rather than branch retinal artery occlusions (06). Recurrent branch retinal artery occlusion without the classic triad may be the only presenting symptom of Susac syndrome (05).

Audiovestibular dysfunction. Neuro-otological symptoms in Susac syndrome are almost universal, and an increasing low- to high-frequency sensorineural hearing loss should prompt consideration of Susac syndrome (52). Hearing loss is often the presenting feature and may be acute, unilateral, or bilateral and may be accompanied by vertigo, tinnitus, nausea, and vomiting. It may also be asymptomatic and evident only on audiometry. Vestibular dysfunction, sensorineural hearing loss, and severe tinnitus in the early phase of Susac syndrome may lead to misdiagnosis as Meniere disease. Additional symptoms include ataxic gait and nystagmus, which may be due to infarction within the membranous labyrinth.

Low- and middle-frequency sensorineural hearing loss is due to microinfarctions of the apical cochlea in the setting of the endotheliopathy rather than due to localized damage to the vestibulocochlear nerve, whereas vestibular dysfunction may indicate lesions in the vestibular apparatus itself or may be the result of central microinfarctions within the cerebellum or brainstem (85).

Dermatological manifestations. A dermatological examination may reveal skin lesions compatible with livedo reticularis or livedo racemosa on the extremities and a diffuse faint pink micropapular (ie, tiny or pinpoint papules) eruption with a “sandpaper” quality on the chest and abdomen (117; 26; 41).

There have been at least 14 reported cases in whom dermatological manifestations were associated with Susac syndrome, most of which were livedo reticularis, and many of which occurred as a prodrome to the onset of classical symptoms and signs (117; 26; 41).

Livedo reticularis results from an impaired blood flow in the dermal arteries, which variously is due to spasm, inflammation, or vascular obstruction (41). The appearance of livedo reticularis at Susac syndrome onset and resolution with immunosuppressant treatment suggests that the underlying etiological processes responsible for Susac syndrome also contributed to the development of livedo reticularis (41).

Livedo reticularis and the micropapular rash may resolve within 2 weeks after initiation of treatment for Susac syndrome (41).

Livedo racemosa (ie, a reddish-blue mottling of the skin in an irregular, reticular pattern) has also been reported as a prodrome of the onset of Susac syndrome (117). A 24-year-old man had the onset of Susac syndrome with the full clinical triad 2 weeks after the onset of a livedo racemosa of the flanks and feet (117); skin biopsies revealed a thrombus in several dermal arterioles, endothelial cell swelling, and a mild perivascular lymphocytic infiltrate. Livedo racemosa differs from the more common livedo reticularis by its shape and response to warming (115). Livedo racemosa consists of broken circular segments in a larger pattern than the fine, regular, complete network of livedo reticularis (115). Livedo racemosa results from impaired peripheral blood flow and, unlike livedo reticularis, persists on warming (115).

Unusual presentations. The triad of encephalopathy, branch retinal artery occlusions, and hearing deficits is seen at some point during the evolution of Susac syndrome in 85% of cases, but only 13% of patients manifest all these symptoms on presentation (26).

Some cases of Susac syndrome present with unusual features (114; 62; 107; 08; 19; 32; 74; 101; 123; 68; 119; 130; 41; 47; 13; 03; 17).

An atypical presentation may lead to a mistaken diagnosis of multiple sclerosis (130; 03) or cerebral infarction (80).

Prognosis and complications

The disease is usually self-limiting after initial fluctuations that may last from months to years. Some reported cases improved during periods when they were not receiving any treatment. About half of the cases recover enough to lead a normal life. One patient, who was treated with cyclophosphamide and methylprednisolone, recovered from encephalopathy, and the retinal arteries became free of obstruction, but deafness remained unchanged at follow-up over 14 months (21). Neurologic deficits remained unchanged in a case that was followed for 13 years (106). Occasionally, a patient may continue to deteriorate with dementia, blindness, and deafness as late sequelae.

After improvement is stabilized, the syndrome usually does not recur. An exceptional case of recurrence after 18 years of remission was reported in a 51-year-old woman with symptoms, signs, and brain MRI findings consistent with Susac syndrome (87).

A French study of nine cases followed for a mean duration of 6.4 years found that most patients had returned to work, and none had severe impairment, but some cases experienced episodic clinical flares (07). The long-term risk of future relapses of Susac syndrome is not yet clear, but it may be prudent to continue maintenance treatment for at least 2 additional years after achieving clinical remission (121).

Susac syndrome is usually not fatal, but exceptional cases, even with appropriate treatment, may develop severe neurologic complications leading to death (104).

Biological basis

Etiology and pathogenesis

The cause of Susac syndrome is unknown.

The pathological findings are microinfarcts in the territories of end arterioles of the brain, retina, and inner ear. Brain biopsies show wedge-shaped microinfarcts surrounded by microglia (51). Microscopic examination shows areas of necrosis measuring up to 500 µ in diameter in the cerebral cortex and white matter with loss of neurons, axons, and myelin. The microinfarcts are caused by a microangiopathic process with arteriolar wall proliferation, lymphocytic infiltration, and basal lamina thickening (45).

Selective distribution of the infarcts in the brain, eyes, and ears may be due to the common embryologic origin of these tissues. Both the retina and the inner ear have barriers analogous to the blood-brain barrier.

One case with a patent foramen ovale improved after anticoagulation, leading the authors to postulate that the syndrome was due to microembolism (44). However, typical ophthalmologic findings point to thrombosis, rather than embolism, as the mechanism of arterial occlusion. In a series of four cases, retinal arterial wall plaques were seen, and the authors cautioned that these should not be misinterpreted as emboli (30); these plaques resolved over time. Retinal arterio-arterial collaterals have also been reported (89).

In six reported patients, virologic studies suggested recent viral infection, suggesting an immune-mediated mechanism triggered by an infectious antigenic agent (86). No infectious agent, however, has been identified in the CSF. Biopsies of various tissues, including the brain, have provided few etiologic clues. Brain biopsy specimens usually demonstrate small infarcts and minimal perivascular inflammatory changes. There is no evidence of a vasculitis. In a few cases, subclinical microangiopathy in muscles suggested that the vasculopathy in Susac syndrome is a systemic disease with a preponderance of retinal, cochlear, and cerebral manifestations (86).

The exact mechanism of arteriolar occlusion in Susac syndrome is unknown but is presumed to be mediated by an autoimmune response to an unknown antigen. Susac himself proposed that the syndrome is an autoimmune endotheliopathy, and pathological studies have shown endothelial changes typical for an antiendothelial cell injury syndrome (110). Cases rarely have demonstrable thrombophilia or overt coagulopathy, such as factor V Leiden mutation (11).

Some cases have other concurrent pathological processes. One patient suffered from both Susac syndrome and a lupus-like systemic disease and had abnormal CSF as well as disseminated white matter hyperintensities on brain MRI (76). One patient was on fenfluramine for weight reduction before the onset of the disease (106); because fenfluramine is neurotoxic and may also cause vasculitis, its potential etiologic role remains suspect but unproven.

Various hypotheses attribute aspects of the etiopathogenesis of Susac syndrome to an autoimmune process (110), an inflammatory process (01; 126), in situ clot formation with microembolization (11), and vasospasm (37). None of these have been proven. An inflammatory process is suggested by the common clinical fluctuations in the course, but histologically no evidence of vasculitis has been demonstrated, and cases have developed severe adverse outcomes while on aggressive immunosuppressive treatment (01; 126). A vasospastic disorder in one case report was suggested by a history of cold hands, a prolonged flow arrest time after cooling in nailfold capillary microscopy, and an increased plasma level of endothelin-1, a potent vasoconstrictor peptide produced by vascular endothelial cells (37).

Skin involvement in Susac syndrome is pathologically plausible because serum antibodies have been identified that bind directly to the CNS and generic endothelium cells (117). High titers of circulating antibodies directly binding to generic endothelium cells have been observed in the serum of 30 patients with Susac syndrome (110; 117). In addition, antibodies belonging to the complement activating IgG1 subclass and binding to endothelial cells of the CNS and the inner ear have been demonstrated in the serum of a patient with Susac syndrome (54).

Epidemiology

Susac syndrome is rare. However, the frequency is underestimated because some cases are not correctly diagnosed and reported. With better awareness of Susac syndrome, cases are being reported worldwide. Compared to the annual incidence of Susac syndrome in Austria of 0.024/100,000, a single-center retrospective study in Israel found a 7-fold greater annual incidence and, based on serological findings, suggested a postinfectious mechanism to explain the significantly higher incidence (125).

There have been over 400 cases reported, including case reports and case series. Among reported cases, 86% had arterial occlusions, which were bilateral in 47%; 75% reported hearing loss; and 68% had some form of encephalopathy. Women are more commonly affected than men by a ratio of 3:1; the age of onset ranges from 9 to 72 years, but young women between the ages of 20 and 40 are most vulnerable (110).

Susac syndrome is rarely diagnosed in Asia, but two cases were reported from China (128), and two cases were reported from Korea (55; 20).

Prevention

No means of primary prevention is available for Susac syndrome.

Differential diagnosis

Confusing conditions

The differential diagnosis of Susac syndrome includes any condition that can cause multifocal neurologic symptoms, visual loss, hearing loss, or any combination of these. Exclusion of neurologic manifestations of systemic disease is an important criterion for diagnosing Susac syndrome.

Susac syndrome is frequently misdiagnosed at initial presentation despite many symptoms or radiological features that are red flags for the diagnosis (116). The varied presentations of Susac syndrome and clinician failure to consider or recognize Susac syndrome are the main factors leading to misdiagnosis (116). Unfortunately, misdiagnosis or delayed diagnosis can lead to unnecessary patient morbidity.

In a retrospective review of the medical records of 32 adult patients from an Australasian cohort of patients with Susac syndrome, 30 (94%) were initially misdiagnosed, with seven (22%) receiving two or more incorrect diagnoses (116). The median time to diagnosis of Susac syndrome was 3 months (range 0.5 to 100 months). The commonest misdiagnoses were migraine (31%), cerebral vasculitis (19%), multiple sclerosis (16%), and stroke (16%). Approximately two thirds (69%) were treated for alternative diagnoses, and about one third (31%) had further clinical manifestations before diagnosis of Susac syndrome. At presentation, 22% met criteria for definite Susac syndrome, 59% for probable Susac syndrome, and 19% for possible Susac syndrome. Diagnostic delay varied with presentation; for example, among patients with the complete triad of symptoms, the median delay to diagnosis was 3 months (range 1 to 9 months) compared to 5.25 months (range 0.5 to 100 months) for patients presenting with encephalopathy and ocular symptoms.

Migraine. Cerebral as well as retinal ischemia may occur in migraine. Because headache is an early symptom of Susac syndrome, it may be confused with migraine, particularly when there are visual scotomata. Infarctions from migraine usually involve larger cerebral vessels and can be distinguished from those in Susac syndrome clinically and by MRI.

Vasculopathies.

Primary angiitis of the CNS. Primary angiitis of the CNS may cause multifocal neurologic deficits with an MRI appearance like that seen in Susac syndrome, but it rarely involves the retinal vessels. Brain biopsy shows a necrotizing vasculitis, something not seen in patients with Susac syndrome.

Temporal arteritis. Temporal arteritis is a disease of the elderly and may cause cerebral and retinal infarctions. Ocular manifestations are due to occlusion of the posterior ciliary arteries rather than the small arteriolar occlusions seen in Susac syndrome. Erythrocyte sedimentation rate is elevated in temporal arteritis, and the diagnosis can be confirmed by biopsy of the temporal artery.

Drug-induced cerebral vasculitis. Drug-induced cerebral vasculitis may occur as an adverse reaction to several therapeutic drugs (or drug abuse) and can result in strokes with multifocal neurologic signs. History of drug intake is often helpful in the evaluation of cases, but a history of drug abuse may also be misleading. For example, a young male drug user who presented with psychosis was initially suspected of having drug-induced CNS vasculitis but was finally diagnosed with Susac syndrome (12). On angiography, cerebral vasculitis characteristically shows intracranial arterial beading (ie, alternating areas of constriction in the intracranial arteries give the appearance of beads strung together).

Takayasu arteritis. Takayasu arteritis tends to afflict younger women; stroke with retinal ischemia may occur but involves medium-sized and larger arteries.

Granulomatosis with polyangiitis (formerly called Wegener granulomatosis). Granulomatosis with polyangiitis is a rare, necrotizing, small-vessel vasculitis that affects various organs. Hallmark features include necrotizing granulomas and pauci-immune vasculitis (ie, associated with minimal evidence of hypersensitivity on immunofluorescent staining for IgG) that most commonly affects the upper respiratory tract, lungs, and kidneys. It may cause stroke, visual loss, and hearing loss due to involvement of the eighth cranial nerve.

Sneddon syndrome. Sneddon syndrome is a rare progressive disorder affecting small- and medium-sized blood vessels, especially of the skin and nervous system. Characteristic findings include episodes of cerebral ischemia and livedo reticularis (ie, a bluish net-like pattern of discoloration surrounding normal-appearing skin). Clinical features may include headache, dizziness, cognitive impairment, memory loss, personality changes, hypertension, and heart disease. The exact cause of Sneddon syndrome is not fully understood.

Systemic lupus erythematosus. Systemic lupus erythematosus can cause cerebral infarction and retinal ischemia. Ophthalmologic findings differ from those in Susac syndrome and consist of ischemic optic neuropathy, central retinal artery occlusion, and central retinal vein occlusion. Two common findings in lupus retinopathy are cotton wool exudates and retinal hemorrhages, neither of which is found in Susac syndrome. Antiphospholipid antibodies are a more common cause of CNS disorder in systemic lupus erythematosus.

CADASIL. CADASIL may have retinal involvement. The pathological feature of the disease is a noninflammatory vasculopathy of the penetrating arteries of the brain with thickening of the arterial wall and deposition of eosinophilic material in the media. CADASIL can be distinguished by its hereditary nature and demonstration of juxtafoveal telangiectasis on fundus examination.

Mitochondrial disorders. MELAS can occur in young women but can be distinguished from Susac syndrome by clinical, radiological, and pathological features. Retinal arteriolar occlusions are absent in MELAS. Patients with Susac syndrome do not show ragged red fibers on muscle biopsy.

Cerebral infarction. Compared to Susac syndrome, cerebral infarction usually involves discrete thromboembolic infarcts in larger arterial territories in the brain. These do not resemble the MRI abnormalities seen in Susac syndrome; however, the MRI appearance of lacunar stroke can resemble that in Susac syndrome, but this tends to occur in older patients with vascular risk factors, such as atherosclerosis and hypertension.

Leukoencephalopathies.

Multiple sclerosis. Some cases of Susac syndrome had the initial diagnosis of multiple sclerosis (130; 03; 99), but hearing loss and retinal arteriolar occlusive disease are not features of multiple sclerosis (99; 38; 116). Susac syndrome is characterized by a neuroimaging triad of white matter lesions, grey matter lesions, and leptomeningeal enhancement on MRI, whereas multiple sclerosis shows only white matter lesions (100). Moreover, MRI lesions in Susac syndrome are usually more numerous and smaller than in multiple sclerosis and occur in deep gray matter, an unlikely location for lesions in multiple sclerosis. Unlike multiple sclerosis, Susac syndrome progresses over a 1- to 2-year period and then goes into remission. Besides the clinical symptoms, Susac syndrome is differentiated from multiple sclerosis by typical radiological features on MRI and branch retinal artery occlusions, which are best evaluated using fluorescein angiography (113).

An atypical presentation may lead to cerebral infarction (80).

Acute disseminated encephalomyelitis. Acute disseminated encephalomyelitis was the initial diagnosis of the first Japanese case of Susac syndrome reported in a 34-year-old man (75). There was no evidence of systemic disease during the first episode. Remission occurred 1 year after symptom onset, and the patient demonstrated all the clinical features associated with Susac syndrome.

Leukoencephalopathy with sensorineural hearing loss. There is a report of a patient with fluctuating sensorineural hearing loss, episodic headache, and white matter stroke due to platelet hypercoagulability (77). No visual symptoms or abnormalities on funduscopic examination were reported in this case. Such cases should be followed up with detailed retinal examination to rule out the possibility of developing Susac syndrome.

Other.

CNS infections. Cogan syndrome is an autoimmune disease characterized by inflammation of the inner ears and the eyes, cochleovestibular symptoms, and loss of vision due to interstitial keratitis. There is rarely retinal vasculitis or CNS involvement, helping to distinguish this syndrome from Susac syndrome.

Primary CNS lymphoma. Primary CNS lymphoma may manifest with multifocal neurologic manifestations and visual loss with multiple MRI lesions. These patients usually have uveitis, a condition that does not occur in Susac syndrome.

Diagnostic workup

Key tests and procedures

Because many patients do not have the complete triad of encephalopathy, retinal arterial occlusion, and hearing loss at symptom onset and diagnostic delays depend heavily on the presenting manifestations, Susac syndrome is likely underdiagnosed (93). Audiometry, fluorescein angiography, and brain MRI should be performed regardless of the mode of presentation to avoid missing components of the triad and to provide a baseline to assess progression and response to treatment (84); these three tests should be repeated during the first year and periodically for long-term follow-up.

The European Susac Consortium has integrated clinical presentation and paraclinical findings into formal criteria to facilitate the diagnosis of Susac syndrome (59); for a definite diagnosis of Susac syndrome, all subcriteria under the main criteria of involvement of the brain, retina, and vestibulocochlear system must be fulfilled, whereas probable and possible cases fulfill these criteria partially (Table 1).

Table 1. Summary of European Susac Consortium Diagnostic Criteria

The most important diagnostic procedures for suspected Susac syndrome are neuroimaging with brain MRI, fluorescein angiography, and audiometry.

Neuroimaging. Clinical diagnosis of Susac syndrome is supported by the neuroimaging triad of (1) white matter lesions, (2) gray matter lesions, and (3) leptomeningeal enhancement (29).

On T2-weighted brain MRI, small, multifocal white matter hyperintensities are characteristic (04).

The distribution of lesions in the corpus callosum is disease-specific in Susac syndrome and only a few other entities, such as Marchiafava-Bignami disease (35). MRI shows a distinctive pattern of supratentorial white matter lesions that always involve the corpus callosum, often having the appearance of "snowballs" on mid-sagittal T2/FLAIR sequences, and "black holes" on T1-weighted images (112; 125).

Early in the disease, callosal lesions are usually best seen on thin-section sagittal FLAIR and sagittal T1 images with contrast (97).

Acutely, lesions may enhance with gadollinium (33).

Central callosal lesions on MRI are specific for Susac syndrome and are considered "diagnostic" of the syndrome (29).

Rapid cystic transformation of callosal lesions can be considered pathognomonic of this condition. Callosal atrophy is a common late manifestation of the callosal lesions.

Serial diffusion-weighted MRI and apparent diffusion coefficient maps may be useful in differentiating Susac syndrome from demyelinating diseases (41; 04).

The type and severity of encephalopathy in Susac syndrome are much better demonstrated by the impairment of fiber integrity in prefrontal white matter detected by diffusion tensor imaging than by the mostly sparse white matter abnormalities seen on conventional MRI (58).

Cerebral angiography should be considered if vasculitis is suspected.

Ophthalmological examinations. On funduscopy, branch retinal artery occlusions may be evident (33).

Small punctuate yellow Gass plaques are almost unique to this disorder, and their characteristic location and color should assist in confirming the diagnosis (31). Funduscopy may also show fluffy white patches corresponding to areas of dye leakage on fluorescein angiography (41).

Ultra-widefield fundus imaging has been used for both diagnosis and follow-up (102). Widefield and ultra-widefield fundus imaging provides high-resolution details of the central and peripheral damage in Susac syndrome (42; 09).

Abnormalities in fluorescein angiography serve as a valuable biomarker of Susac syndrome, and serial examinations may be useful for monitoring the effect of the treatment and for detection of complications, such as capillary nonperfusion and new vessel formation (56; 90; 125; 09).

Wide field fluorescein angiography may demonstrate peripheral branch retinal artery occlusions and focal arterial leakage.

In the absence of the full clinical triad, arteriolar wall hyperfluorescence on fluorescein angiography in retinal arterioles remote from areas of retinal ischemia is highly specific for and, therefore, strongly supportive of a diagnosis of Susac syndrome (29). Important ophthalmologic features on retinal angiography include (1) absence of intraocular inflammation, (2) focal, labile, nonperfused retinal arterioles, and (3) integrity of the choroidal circulation (71).

Paracentral acute middle maculopathy on optical coherence tomography is reported in Susac syndrome (49); patients who present with multifocal retinal ischemia and are found to have paracentral acute middle maculopathy should be checked for characteristic MRI lesions and hearing loss.

High-definition optical coherence tomography angiography may show decreased vascular perfusion corresponding to ischemic areas observed on fluorescein angiography as well as an increased foveal avascular zone area in both superficial and deep vascular plexuses (09).

Multifocal electroretinography may be useful for assessing subclinical retinal dysfunction after recovery of subjective symptoms of branch retinal artery occlusion in Susac syndrome (118).

Audiovestibular function testing. In a case series of 30 patients with Susac syndrome, a rising configuration of low-frequency worse than high-frequency sensorineural hearing loss was the most characteristic finding on audiological testing (present in 37% of reviewed audiograms), although this pattern can also be seen, for example, in Meniere syndrome (52; 125). Disproportionately poor speech discrimination was identified in 20% of cases, and one case demonstrated a retrocochlear pattern on electrophysiological testing. Hearing loss in Susac syndrome may not recover (108).

Cervical vestibular evoked myogenic potentials may be absent acutely, with gradual recovery later over a period of months (81; 108).

Video head impulse test results may be abnormal in a minority of patients with Susac syndrome and vertigo (81).

Other studies. Other studies may selectively include the following as well as others appropriate to particular presenting complications:

Management

Because of the limited number of patients treated with a wide variety of agents and regimens, it is difficult to recommend a definitive plan of action. There are no controlled clinical trials, and anecdotal reports of diverse treatment regimens abound.

Therapy is considered inadequate if there are new or enhancing lesions on MRI or new visual field defects and fluorescein angiography shows arterial wall hyperfluorescence remote from branch retinal artery occlusions (29). Therapy is considered adequate and should be maintained if there are no new or enhancing lesions on MRI and no new visual field defects, even if fluorescein angiography shows arterial wall hyperfluorescence remote from branch retinal artery occlusion (29). Therapy can be stopped or reduced if there are no new or enhancing lesions on MRI and no new visual field defects and if fluorescein angiography shows no arterial wall hyperfluorescence (29).

Corticosteroids and other immunosuppressants. From available case reports and case series, Susac syndrome generally responds well to immunosuppressive therapy when treatment is prompt, aggressive, and sustained. Corticosteroids are the most frequently used drugs in Susac syndrome and, given orally or intravenously, are recommended as the first-line therapy. However, oral prednisolone was considered ineffective in several patients who deteriorated while on this therapy (66; 109). Thus, corticosteroids are often combined with other immunosuppressants, even at the initiation of treatment.

Immunosuppressants, such as intravenous immunoglobulin (IVIg), mycophenolate mofetil, cyclophosphamide, azathioprine, methotrexate, and rituximab, have been given alone or in combination or have been added to corticosteroids to achieve adequate control of disease activity (82; 39; 96; 97; 27; 60; 70; 41; 65). For example, a 16-year-old girl who presented with Susac syndrome was successfully treated with a complicated multi-immunosuppressant regimen (pulsed prednisone, IVIG, cyclophosphamide, mycophenolate mofetil, and methotrexate) modeled after the treatment of juvenile dermatomyositis, an autoimmune endotheliopathy that causes ischemic injury in a different triad of tissues (ie, muscle, skin, and gastrointestinal tract) (97).

One recommended treatment approach for initial treatment of Susac syndrome includes corticosteroids plus IVIg monthly for 6 months (29). For breakthrough disease, add mycophenolate mofetil and/or rituximab (29). For breakthrough disease after adding mycophenolate mofetil and rituximab, add cyclophosphamide (29).

About 90% of reported cases improve with immunosuppressive therapies, although tapering the corticosteroid dose may result in the development of new signs and symptoms.

Some examples will give an idea of the management of this disorder:

Case 1 (16). A 21-year-old female college student developed paresthesias in her fingers, mouth, and lips, followed by fatigue and forgetfulness and was subsequently "giddy and giggly" before developing headache, vomiting, and incoherence. On day 12 of illness, she was admitted with headaches, vomiting, decreased mental alertness, slow thought processing, confusion and disorientation, short-term memory impairment, odd behaviors, impaired insight, decreased executive function (disorganized, not able to take care of her affairs or make good decisions), personality change, emotional lability, apraxia, paresthesias, imbalance, bladder dysfunction, and vertigo but no hearing loss, tinnitus, or convincing visual symptoms. Brain MRI on admission revealed several “snowball” lesions in her corpus callosum, as well as several scattered smaller lesions elsewhere in her white matter.

Case 2 (16). A 14-year-old girl developed headache followed by “slowed thinking,” difficulty verbalizing her thoughts, urinary incontinence, ataxia, fatigue, somnolence, emotional lability, occasional vomiting, right-hand numbness, and left jaw or lateral neck region pain. Admission MRI on day 12 revealed multifocal T1 hypointensity and T2 hyperintensity lesions in the periventricular and supraventricular cerebral white matter and of the corpus callosum. CSF protein was elevated, with a CSF white blood cell count of 5/mm3. Erythrocyte sedimentation rate was normal. On day 13, ophthalmological evaluation revealed a branch retinal artery occlusion in the left eye. On day 15, she was started on aggressive immunosuppression.

After initiation of immunosuppression, she initially improved but then developed an acute and intense relapse at 5 weeks: ataxia and urinary incontinence returned and were accompanied by inability to stand, extremity weakness, muteness, emotional lability, and moderate-severe binaural hearing loss (from which she never recovered). Repeat MRI revealed multiple new diffusely scattered lesions, with restricted diffusion and enhancement, and new diffuse leptomeningeal enhancement. Additional lesions were noted throughout the basal ganglia, thalami, putamen, and anterior limb of the internal capsule. This acute relapse prompted an escalation of immunosuppressive treatment. Her neurologic status slowly but steadily improved during weeks 6 to 21 but then did not significantly improve thereafter. After week 21, she continued to have neurologic deficits, apparently due to damage sustained during the first 5 to 6 weeks of illness. She experienced no further flare-ups of disease activity in the brain, retina, or inner ear but suffered considerable neurologic and cochlear residua.

In summary, she experienced a severe encephalopathy during the first 2 to 3 months of her disease, which was difficult to control despite prompt and aggressive immunosuppression. After 3 months of sustained, aggressive immunosuppression, her active disease subsided, but by this point, she had sustained significant damage despite aggressive treatment during her initial severe and unrelenting encephalopathy.

Case 3 (97). Over a 2-week period, a 16-year-old girl developed incapacitating headaches, recurrent vomiting, visual disturbance ("round, dark black spots"), hearing loss, "roaring" tinnitus, dysarthria, unsteady gait, mild neck stiffness, confusion, emotional lability, personality change, and somnolence. When seen 2 weeks into the course of her illness, her visual acuity was 20/20 in both eyes, but dilated ophthalmologic examination revealed a subtle "cotton wool" spot in her right eye. She had difficulty performing rapid alternating movements, her gait was unsteady, and she had bilateral long tract signs. In addition, formal neuropsychological evaluation revealed a Full Scale IQ of 104 with an estimated pre-morbid IQ of 121. She had poor verbal fluency, mild aphasia, short-term memory impairment, slow processing speed, and executive dysfunction.

Brain MRI showed widespread small hyperintense white matter lesions on T2 and FLAIR in the supratentorial and infratentorial compartments. Several lesions enhanced, and there was marked leptomeningeal enhancement surrounding the cerebral and cerebellar hemispheres. The central corpus callosum was extensively involved.

Similar lesions were present in the basal ganglia. Diffusion-weighted images showed restriction in many of these lesions. The MRI findings were initially misinterpreted as atypical acute disseminated encephalomyelitis or atypical multiple sclerosis.

CSF examination revealed an elevated protein (166 mg/dl), mild lymphocytic pleocytosis (11 WBC/mm3, all lymphocytes), and an elevated myelin basic protein (28.5 ng/ml, with the upper limit of the reference range 4.1 ng/ml). The CSF IgG index was normal, and there were no oligoclonal bands.

Fluorescein retinal angiography showed a resolved branch retinal artery occlusion in the right eye and multifocal arteriolar disease in the retinal periphery. Audiograms showed bilateral, low-frequency sensorineural hearing loss sloping to normal above 2 KHz. Speech discrimination was impaired.

The ophthalmological and audiological findings led to a reinterpretation of the MRI findings, and when coupled with the central location of the corpus callosal lesions, the involvement of the basal ganglia, and the presence of leptomeningeal enhancement, a correct diagnosis of Susac syndrome was made.

She was aggressively treated with a complicated immunosuppressant regimen initially involving high-dose oral prednisone, frequent pulses of methylprednisolone, monthly IVIg, and monthly pulses of intravenous cyclophosphamide.

Within 2 days after treatment initiation, her headache and vomiting resolved, and her encephalopathy began to improve. After receiving six monthly pulses of cyclophosphamide, she was placed on mycophenolate mofetil maintenance therapy; however, she was unable to tolerate mycophenolate mofetil due to malaise and nausea, so pulse cyclophosphamide therapy was resumed.

A repeat neuropsychological evaluation at week 41 revealed a Full Scale IQ of 122, consistent with her expected baseline. Her branch retinal artery occlusion quickly resolved without further visual complaints and without recurrence. Her vision at 41 weeks was 20/20 in both eyes, with only a tiny asymptomatic field defect in the right eye. Her audiogram improved modestly during the first 2 weeks of treatment but did not change afterward. Her tinnitus was initially very distressing during the first 2 months but has since been tolerable. One year after treatment onset, she scored in the 98th percentile on her college entrance examination. A repeat MRI at 60 weeks revealed marked resolution of the previously noted white matter lesions, but her corpus callosum was thinned and showed the typical residual callosal "holes" of Susac syndrome.

Her immunosuppressant medications were tapered and ultimately discontinued after 2 years of therapy. At her last follow-up at 36 months, she had stable residual hearing loss and mild tinnitus, subtle short-term memory impairment, and mild executive dysfunction. Although much improved from a neurologic perspective, she was struggling emotionally to cope with her impairments.

Intraocular injection of triamcinolone, a long-acting synthetic corticosteroid. A 23-year-old woman presented with sudden visual loss in the left eye along with multiple bilateral occlusions of retinal artery branches shown on fluorescein angiography and other features of Susac syndrome; she received a single intravitreal injection of triamcinolone in the left eye with resolution of visual loss before the start of systemic corticosteroids (127).

Anticoagulants. Anecdotal experience with anticoagulants in Susac syndrome has not been encouraging (with clinical improvement less common than either clinical stabilization or improvement), so anticoagulants are not recommended unless there is evidence of a procoagulant state.

Aspirin. Low doses of aspirin carry little risk of hemorrhagic complications and may be beneficial.

Nimodipine. Nimodipine has been recommended as adjuvant therapy on the presumption that it will have an antivasospastic and neuroprotective effect. However, no significant efficacy has been shown in reported cases in which it was tried.

Tumor necrosis factor inhibitor therapy. A patient with Susac syndrome was reported to improve immediately after treatment with the monoclonal antibody infliximab, which inhibits tumor necrosis factor (50); histological examination of brain lesions in this case as well as two other cases suggested a T cell-mediated inflammatory contribution to lesion pathogenesis and provided a rationale for using infliximab (51). A patient with Susac syndrome who was refractory to a conventionally prescribed combination of immunosuppressive agents (including high-dose corticosteroids, intravenous cyclophosphamide, methotrexate, plasma exchange, rituximab, and mycophenolate) was stabilized with infliximab in combination with a tapering course of low-dose prednisone (34).

A small multicenter retrospective cohort study of five patients diagnosed with Susac syndrome evaluated patient disease activity before and after the introduction of anti-TNF therapy and its value as a steroid-sparing agent (15). All were initially treated with a combination of corticosteroids and classical immunosuppressive drugs. Infliximab was started in three patients and adalimumab in two patients. Anti-TNF treatment reduced relapses of ocular symptoms and enabled the reduction of corticosteroid dosage with complete discontinuation in four patients. Both drugs were well tolerated, and no serious adverse events were reported. Anti-TNF therapy may be a valuable option for treating ocular Susac syndrome and may be considered in those patients unresponsive to conventional immunosuppressive treatment.

Hyperbaric oxygen therapy. In the first report of hyperbaric oxygen therapy for Susac syndrome, there was dramatic posttreatment improvement in visual fields and visual acuity (64). HBOT reduced the visual sequelae in a patient in whom single photon emission computed tomography showed a microangiopathic disorder of the brain (73). In another reported case, HBOT minimized ischemic lesions (23).

Cochlear implantation for hearing loss. Patients with Susac syndrome and significant hearing impairment may benefit from cochlear implantation, either unilaterally or bilaterally (98; 14; 46; 63). Bilateral simultaneous cochlear implantation successfully restored significant hearing in a patient with Susac syndrome (98). A patient with unilateral hearing loss due to Susac syndrome achieved 100% open-set sentence recognition in noise conditions and 92% monosyllable and 68% medial consonant recognition in quiet conditions after 6 months of cochlear implant use (14). In a Susac syndrome patient with unilateral hearing loss, a left cochlear implant was placed, although there was possible involvement of retrocochlear pathways (46). Unilateral cochlear implantation gave good results in a patient with Susac syndrome who presented with the classical triad, including bilateral sensory neural nearing loss, and failed to respond to initial treatment using immunoglobulin and plasmapheresis (63). Within 6 months, he could talk on the telephone and showed satisfying speech recognition without lip reading; within a year, audiometry revealed a pure-tone average threshold of 33 dB and a speech recognition threshold of 100% in open field.

Management of sequelae of Susac syndrome and rehabilitation. Patients with persisting neurologic deficits and psychiatric disturbances require appropriate rehabilitation services (91). Vestibular rehabilitation and hearing aids may be required for patients with persisting cochleovestibular disturbances.

Ocular neovascularization with vitreous hemorrhage can be a late manifestation of occlusive arteriopathy in Susac syndrome and may require panretinal photocoagulation (61).

Special considerations

Pregnancy

Susac syndrome has been reported during pregnancy in several patients, although it is still rare. The course of the disease and outcome of pregnancy depend on coexisting pathology and treatment and vary from normal course to complications. No definitive score or clinical feature can predict the outcome of the disease. Guidelines for treating Susac syndrome in pregnant women are not well established (92).

Examples of good response to therapy during pregnancy. A 35-year-old pregnant patient who presented at 31 weeks with acute bilateral visual loss due to retinal arteritis, as well as acute unilateral hearing loss in combination with cerebral changes detectable by MRI, was diagnosed with Susac syndrome and treated with steroids, resulting in improvement and normal course of the pregnancy (36). A pregnant woman with a 1-month history of behavioral changes and MRI changes diagnostic of Susac syndrome showed a marked and prompt clinical and radiological improvement after treatment with intravenous immunoglobulins (43). Another case of Susac syndrome was successfully managed using intravenous methylprednisolone followed by oral prednisone and intravenous immunoglobulin up to 36 weeks of gestation with minimal disease burden to both the mother and newborn (02).

Induction of premature delivery due to potential toxicity of therapy on the fetus. A 25-year-old woman who presented in the 20th week of pregnancy with Susac syndrome initially received corticosteroids and intravenous immunoglobulin with improvement, but recurrent disease was treated with cyclophosphamide and rituximab after induction of premature delivery at 35 weeks' gestation "to spare the fetus possible toxicity" (24).

Deterioration may occur after delivery. Clinical exacerbation of Susac syndrome occurred immediately following the delivery of a stillborn anencephalic child (22). Another patient deteriorated after delivery of a normal baby and improved after treatment with corticosteroids (66). In a series examining Susac syndrome, three patients had four pregnancies; two needed induced abortions, one was uneventful, and one was complicated with disease flare in the early postpartum period (07).

Anesthesia

A patient with Susac syndrome developed papilledema due to raised intracranial pressure and required anesthesia for brain biopsy (57). The authors administered propofol and instituted mild hyperventilation to reduce intracranial pressure but cautioned that this technique may not be advisable as it can worsen cerebral-retinal-cochlear perfusion in an already existing microangiopathic state. Volatile anesthetics with normocapnia would be desirable in the absence of raised intracranial pressure.