This article includes discussion of ulnar neuropathies, Guyon canal neuropathy, ulnar neuropathy at the wrist, and flexor carpi ulnaris exit compression.
Jun. 07, 2021
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Susac syndrome presents with a triad of retinal arterial occlusion, deafness, and encephalopathy. Since its recognition in 1973, over 393 cases have been reported in the literature. In this article, the author describes the clinical features, pathology, and diagnosis of this syndrome as well as atypical presentations. The pathological findings include microinfarcts in the territories of end arterioles of the brain, retina, and inner ear. MRI plays an important role in demonstrating the CNS lesions. Management of Susac syndrome is also discussed.
• Susac syndrome is typically a triad of encephalopathy, retinopathy, and hearing loss, but may have an atypical presentation.
• Over 400 cases have been reported in the literature, mostly in women.
• Special diagnostic procedures are audiography, retinal angiography, and brain MRI.
• Important treatments include corticosteroids and immunotherapy.
• The syndrome is self-limiting and may go on for years, with fluctuations in its course.
Since 1973 there have been reports of patients (mostly young women) presenting with a combination of retinal arterial occlusion, deafness, and encephalopathy (85). This syndrome was delineated in 1979 as a noninflammatory vasculopathy causing small infarcts in the cochlea, the retina, and the brain (104). It has been called “retinopathy,” “encephalopathy,” and “deafness associated microangiopathy,” or “RED-M syndrome” (69). Another proposal was to call it “SICRET syndrome” after the first letters of “small infarctions of cochlear, retinal, and encephalic tissue” (100). It is still referred to as SICRET syndrome in the French literature (66). The triad of microangiopathy of the brain and retina with hearing loss was finally dubbed “Susac syndrome” (102). Further cases of this syndrome were reported in subsequent years (08; 14; 99). It has been reviewed under the name of Susac syndrome (77; 80). Other authors have preferred the term “retinocochleocerebral vasculopathy” (83). In partial forms of this syndrome, only 2 of 3 components of the syndrome are clinically manifest; the third is silent. Examples of this are reports of subacute bilateral sensorineural hearing loss with bilateral retinal artery occlusion, but without obvious central nervous system signs (113; 21). MRI findings may be abnormal in these patients in the absence of symptoms specifically referable to the brain (115). Cerebral and retinal involvement may occur without hearing loss (38). These are also included as variants of Susac syndrome. A branch retinal artery occlusion subset of this syndrome has been recognized (92).
The triad of clinical features is encephalopathy, retinopathy, and hearing loss. Most of the patients do not have the clinical triad at the onset of symptoms, but rather recurrences of one or more of the components of the triad. The number of attacks in the reported cases has varied between 1 and 8 with an interval of 1 to 34 months between episodes. The mean duration of the illness was 46.7 months. In a series of 10 cases reported from Israel, only 2 patients presented with the full triad of Susac syndrome, and 7 patients developed the full triad during a mean follow-up period of 35 months (111). The authors suggested classifying the disease course into suspected, incomplete, and complete Susac syndrome to facilitate early diagnosis.
Encephalopathy. Headache is the prodromal symptom that may precede the development of any manifestations of encephalopathy; it may be accompanied by a visual aura. Headache is migraine-like but presentations could be different in relation to the onset of the syndrome (76). 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 (102). Neurologic signs are diffuse, multifocal, and progress during 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. This is characterized by impaired vision due to multiple bilateral branch retinal occlusions. These can be detected by fundoscopic examination, which may show occlusion of the branches of the central retinal artery with a cherry-red appearance of the macula (18). 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. Multiple peripheral arterial occlusions in both the eyes found on fundus examination were confirmed with fundus fluorescein angiography in a 19-year-old female who presented with blurred vision, intermittent hearing loss, headache, ataxia, vertigo, and confusion (53). Diagnosis of Susac syndrome was made with other findings of hyperintense lesions in white matter on MRI and raised protein as well as lymphocytes in CSF. Clinical improvement on treatment with steroids, azathioprine, and intravenous immunoglobulins was associated with improvement in retinal circulation on repeat fluorescein angiography. In a 23-year-old woman who presented with vision loss and vertigo, fluorescein angiography showed branch retinal artery occlusion, audiometry revealed bilateral hearing loss, and diagnosis of Susac syndrome was confirmed by the presence of lesions in the central corpus callosum on MRI (87). Long-term management with prednisone led to stabilization of the disease with no new symptoms or lesions.
Involvement of auditory and vestibular system. Hearing loss is often the presenting feature and may be acute, unilateral, or bilateral, and accompanied by vertigo, tinnitus, nausea, and vomiting. It may also be asymptomatic and discoverable only on an audiogram. Simultaneous vestibular dysfunction is also common in the early phase of Susac syndrome and patients can present with severe tinnitus, which may lead to the misdiagnosis of Ménière’s disease. Additional symptoms include ataxic gait and nystagmus, which may be due to infarction within the membranous labyrinth.
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 (25). Several cases of Susac syndrome present with unusual features as follows:
• A 14-year-old girl presented with headache, left hemiparesis, sphincter deficit, and cognitive deficits and retinal occlusions as well as encephalopathy on further investigations (96).
• Another unusual presentation was that of a 30-year-old woman with migraine headaches and unilateral hearing loss along with multifocal subcortical white matter lesions shown on MRI and a left retinal cotton wool spot (114). She had a brain biopsy. The common pathological feature of various lesions was a microangiopathy, and her condition was stabilized with oral steroid therapy.
• A 50-year-old man presented with multiple branch retinal arteriolar occlusions and encephalopathy 10 days following smallpox vaccination (58).
• A 38-year-old woman suffering from hepatitis C developed the characteristic triad of Susac syndrome; a brain MRI showed signal abnormalities in the basal ganglia and corpus callosum (15).
• In a case report of Susac syndrome, a 30-year-old female presented with change in her personality and history of migraine and recurrent bilateral loss of vision as well as hearing, and investigations revealed occlusions of the multiple branches of retinal arteries, multiple lesions on brain MRI, and markedly elevated protein content of the cerebrospinal fluid (71).
• An atypical finding in a 25-year-old woman with typical triad of Susac syndrome was interrupted vessels and microaneurysms accumulation in the peripheral retina of both eyes as observed on funduscopy (07).
• Susac syndrome has been diagnosed in a 9-year-old girl on the basis of characteristic MRI lesions, even though the complete triad of symptoms was absent (30).
• Four male patients with Susac syndrome have been reported; 3 had the typical triad, but in one, the diagnosis was made only by typical appearance of retinal arteries and brain MRI findings (101).
• In a series of 5 patients reported with Susac syndrome (4 female and 1 male), only 2 presented with the typical triad, and the predominant involvement in 3 cases was: (1) ophthalmologic; (2) otolaryngologic; and (3) neurologic manifested as encephalopathy, headache, and transient ischemic attacks (65). Brain MRI showed typical corpus callosum lesions, and all patients improved with immunosuppressant therapy.
• In a 25-year-old male, the evolution of the full triad of Susac syndrome took one year (110).
• Unilateral occlusion of the central retinal artery rather than that of a branch was the sole presenting sign of Susac syndrome in a young man (05). The blood column of several arterioles was partially or totally substituted by long segments of fibrin-like white material. Later, there was involvement of the contralateral retinal artery, and lesions were demonstrated in corpus callosum as well. Recurrent branch retinal artery occlusion without the classic triad was the only presenting symptom in a 23-year-old man, and optical coherence tomography angiography as well as subtle MRI findings aided in the early diagnosis of Susac syndrome and start of therapy with improvement (04).
• Atypical presentation may lead to mistaken diagnosis of multiple sclerosis. A 66-year-old man who presented with recurrent episodes of encephalopathy and hearing loss was started on natalizumab under the presumptive diagnosis of multiple sclerosis, but deterioration of neurologic deficits led to discontinuation of natalizumab and consideration of the diagnosis of Susac syndrome even though he had only 2 of the 3 classical features, ie, characteristic lesions in the corpus callosum on MRI and hearing loss, with the additional finding of microangiopathy on brain biopsy (121). He was treated with intravenous immune globulin and had no recurrences during 14 months of follow-up.
• Delay in the diagnosis of Susac syndrome was reported in a 35-year-old man who initially presented with encephalopathy and sensorineural hearing loss of 75 dB in the left ear (46). Diagnosis was established later after extensive investigations, including MRI that showed typical ovoid lesions of the corpus callosum. Although the patient did not present with ophthalmologic symptoms, fluorescence angiography of the eyes showed typical occlusions of retinal artery branches in both eyes, which were located peripherally and did not impair visual acuity and visual fields. Treatment with a combination of methylprednisolone, acetylsalicylic acid, and intravenous immune globulin led to considerable improvement.
• A 67-year-old man with a history of bilateral presbycusis presented with acute onset of delirium and multifocal neurologic deficits, and MRI demonstrated supratentorial as well as infratentorial subcortical and periventricular T2-hyperintense lesions and multiple central lesions of the corpus callosum leading to the diagnosis of Susac syndrome (10). The patient improved with intravenous methylprednisolone, but a relapse occurred during corticosteroid tapering. Prednisone was resumed with improvement and combined with mycophenolate and intravenous rituximab. The improvement was maintained along with partial regression of brain lesions during long-term follow-up. Delirium and lack of visual symptoms are unusual features of this case.
• A 22-year-old young man is one of the few cases of Susac syndrome in a young man with the complete diagnostic triad reported in the literature (50).
The disease is usually self-limiting after initial fluctuations that may last from months to years. Some of the reported cases improved during periods that they were not receiving any treatment. About half of the patients recovered enough to lead a normal life. One patient, who was treated with cyclophosphamide and methylprednisolone recovered from encephalopathy, and retinal arteries became free of obstruction, but deafness remained unchanged at follow-up for 14 months (17). Neurologic deficits remained unchanged in a case that was followed for 13 years (100). Occasionally, a patient may continue to deteriorate; dementia, blindness, and deafness are late sequelae. After improvement is stabilized, the syndrome usually does not recur. The first case of recurrence after 18 years of remission has been reported in a 51-year-old woman with symptoms, signs, and brain MRI findings consistent with diagnosis of Susac syndrome (84).
A report from France describes the clinical outcome, including pregnancy and long-term sequelae, during follow-up for a mean duration of 6.4 years on a series of 9 patients with Susac syndrome, 7 female and 2 male (06). At the end of follow-up, most patients had returned to work and none had severe impairment, but the course of Susac syndrome was found to be not self-limited as there were some clinical flares. Susac syndrome is usually non-lethal but one case has been reported because of its severe neurologic evolution, leading to death despite treatment (98).
The real long-term risk of future relapses of Susac syndrome has not been determined, but once the disease goes into remission, it may be prudent to continue maintenance treatment for at least 2 additional years (112).
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 several wedge-shaped microinfarcts surrounded by microglia (49). 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 (43).
Typical ophthalmologic findings point to thrombosis, rather than embolism, as the mechanism of arterial occlusion. One patient with this syndrome had a patent foramen ovale that improved after anticoagulation, leading the authors to postulate that the syndrome was due to microembolism (42).
In a series of 4 cases of Susac syndrome, retinal arterial wall plaques were seen, and the authors cautioned that these should not be misinterpreted as emboli (28). These plaques resolved over time. Retinal arterio-arterial collaterals have also been reported (86).
In 6 of the reported patients, virologic studies suggested recent viral infection, pointing to an immune-mediated mechanism triggered by an infectious antigenic agent (83). No infectious agent, however, has been identified in the cerebrospinal fluid. Biopsy of various tissues, including the brain, provides few clues as to the cause of the disease. Brain biopsy specimens usually demonstrate small infarcts and minimal perivascular inflammatory changes. There is no evidence of a vasculitis. Susac syndrome is an autoimmune endotheliopathy, and pathological studies have shown endothelial changes that are typical for an antiendothelial cell injury syndrome (103). Pathology of the other organs has not been described except in a few cases where subclinical microangiopathy in muscles suggested that vasculopathy in Susac syndrome is a systemic disease with a preponderance of retinal, cochlear, and cerebral manifestations (83).
Some cases of the syndrome have been reported in patients with other pathological processes. One patient suffered from both Susac syndrome and a lupus-like systemic disease and had abnormal cerebrospinal fluid as well as disseminated white matter hyperintensities on brain MRI (74). Other organs were involved in this patient, and neurologic deficits were still persisting 6 years after onset. One patient was on fenfluramine for weight reduction prior to the onset of the disease (100). Because fenfluramine is neurotoxic and may also cause vasculitis, the role in the causation of this syndrome remains suspect but unproven.
The exact mechanism of arteriolar occlusion in Susac syndrome is not known but is presumed to be mediated by an autoimmune response to an unknown antigen. Various hypotheses are:
• An inflammatory process is suggested by the fluctuations in the clinical course, but histologically no evidence of vasculitis has been demonstrated. Development of acute macular neuroretinopathy of the left eye in a 49-year-old man with Susac syndrome (involvement of retinal branch in the right eye), despite aggressive immunosuppressive treatment for 4 months, supports retinal ischemia as the precipitating factor and inflammation as a potential cause of acute macular neuroretinopathy (116). A 24-year-old woman with classic findings of Susac syndrome lapsed into a coma and died despite intensive immunosuppressive therapy. Neuropathological examination revealed perivascular inflammation as well as vasculitis involving small vessels, associated with vascular narrowing and occlusion, and numerous microinfarcts distributed diffusely throughout the brain (01). The findings establish Susac syndrome as a neuroinflammatory condition that can include vasculitis.
• In situ clot formation with microembolization has also been postulated, but no evidence of a coagulopathy exists. Only one of the 60 reported cases had factor V Leiden mutation; this mutation is associated with a thrombotic tendency (08).
• Vasospasm has been considered as a cause. Evidence supporting Susac syndrome as a manifestation of a vasospastic disorder in one case report included a history of cold hands, prolonged flow arrest time after cooling in nailfold capillary microscopy, and an increased plasma level of endothelin-1 (35).
• Selection distribution of the infarcts in brain, eye, and ear may be due to common embryologic origin of these tissues. Both the retina and the inner ear have barriers analogous to the blood-brain barrier. Abnormalities of the structure, function, and antigenic properties of this common endothelium may lead to arteriolar occlusion in Susac syndrome.
• Immunopathogenesis in a 16-year-old girl who presented with Susac syndrome was considered to have much in common with that of juvenile dermatomyositis, an autoimmune endotheliopathy that causes ischemic injury in a different triad of tissues (muscle, skin, and gastrointestinal tract) (94). This was the basis of immunosuppressive treatment of this patient.
Susac syndrome is still considered rare. However, the frequency is underestimated, as all the cases are not correctly diagnosed and reported. With better awareness of Susac syndrome, cases are being reported all over the world. There have been over 400 cases reported as of August 2020, including case reports and case series, some of which include cases reported individually. Among the reported cases, 86% had arterial occlusions, and these 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 (103).
A 35-year-old man was reported with acute encephalopathy, neurosensory hearing loss, and occlusion of retinal artery branches (90). A case of a 41-year-old man who presented with migraine-like headaches, transient visual loss, and dizziness was reported from Brazil; diagnosis was made on the basis of MRI findings of scattered hyperintense white matter lesions bilaterally and retinal vasculitis on fluorescein angiography, as well as raised protein and lymphocytes in CSF (37). This patient improved with immunoglobulin and methylprednisone treatment. Susac syndrome is extremely rare in Asia, but 2 cases were reported from China (118). The first case of Susac syndrome reported from Korea was a 23-year-old female patient with all the typical features that resolved following immunosuppressive therapy with oral steroid and azathioprine, but there was a relapse of vasculitis (52). Another Korean patient, an 18-year-old female, had triad of ocular, cochlear, and neurologic involvement (16). This patient was treated with high doses of systemic corticosteroids, and no neuropsychological sequelae were observed. A 30-year-old man from Croatia with Susac syndrome was followed over several years and progressed from unilateral hearing loss to bilateral hearing loss and bilateral retinal occlusions (107). An unusual feature in this case was occurrence of seizures. In a series of 19 cases of Susac syndrome reported from Turkey, only 3 presented with the complete clinical triad (120).
Another case with review of the previous literature was published in 2003 (73). Four cases of this syndrome diagnosed by MRI, retinal fluorescein angiography, and audiography findings were published with remarks that early therapy may reduce sequelae and improve recovery (24). A retrospective case study was conducted at a tertiary otolaryngology referral center, and another case was reported (44). A 2013 review is based on all the published cases up to that year (25). The Susac Syndrome International Collaborative Study is ongoing with the aim to collect clinical information about all aspects of this syndrome on at least 50 current, 50 past, and 50 future patients with Susac Syndrome from around the world. The data can be accessed at http://my.clevelandclinic.org/disorders/susac-syndrome/susac-syndrome.aspx.
No relevant information is available that pertains to the prevention of Susac syndrome.
Differential diagnosis of Susac syndrome includes any condition that can cause multifocal neurologic symptoms, visual loss, hearing loss, or any combination of these. Several conditions are considered in the differential diagnosis of Susac syndrome, as shown in Table 1. Exclusion of neurologic manifestation of systemic disease is an important criterion for diagnosis of Susac syndrome.
• Cerebral infarction
• Multiple sclerosis
• Temporal arteritis
Cerebral infarction. These are usually discrete infarcts in larger arterial territories in the brain and are usually associated with thromboembolism. These do not resemble the MRI abnormalities seen in Susac syndrome; however, MRI appearance of lacunar stroke can resemble that in Susac syndrome, but this tends to occur in older patients with risk factors for stroke, such as atherosclerosis and hypertension.
Leukoencephalopathy with sensorineural hearing loss. There is report of a patient with fluctuating sensorineural hearing loss, episodic headache, and white matter stroke due to platelet hypercoagulability (75). 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.
Acute disseminated encephalomyelitis. This was the initial diagnosis of the first Japanese case of Susac syndrome reported in a 34-year-old man (72). There was no evidence of systemic disease during the first episode. Remission occurred one year after symptom onset, and the patient demonstrated all the clinical features associated with Susac syndrome.
CNS infections. Several central nervous system infections can cause multifocal neurologic signs, including loss of hearing. The infections may be associated with meningitis, so cerebrospinal fluid examination can help in the detection of microorganisms. Angiography may show abnormalities of arteries at the base of the brain, whereas this examination is usually normal in patients with Susac syndrome.
Cogan syndrome. This is characterized by cochleovestibular symptoms and loss of vision due to interstitial keratitis. There is uveitis, but rarely is there retinal vasculitis. Central nervous system involvement is rare, and these findings help to distinguish this syndrome from Susac syndrome.
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 due to migraine usually involve larger cerebral vessels and can be distinguished from those in Susac syndrome clinically and by MRI.
Mitochondrial disorders. Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes 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.
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.
Multiple sclerosis. Some of the patients with Susac syndrome had the initial diagnosis of multiple sclerosis, but hearing loss and retinal arteriolar occlusive disease is unlikely in multiple sclerosis. 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 (106).
Primary CNS lymphoma. This may manifest with multifocal neurologic manifestations with multiple MRI lesions and visual loss. These patients usually have uveitis, a condition that does not occur in Susac syndrome.
Systemic lupus erythematosus. This can cause cerebral infarction and retinal ischemia. Ophthalmologic findings are different 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; both signs are not found in Susac syndrome. Antiphospholipid antibodies are a more common cause of central nervous system disorder in systemic lupus erythematosus.
Vasculopathies involving the CNS. Primary angiitis of the central nervous system may cause multifocal neurologic deficits with 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. Features of Sneddon syndrome include characteristic livedo reticularis and ischemic cerebrovascular disease.
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.
Takayasu arteritis. Takayasu arteritis tends to afflict younger women; stroke with retinal ischemic may occur but involves medium-size and larger arteries.
Drug-induced cerebral vasculitis. This may occur as an adverse reaction to several therapeutic drugs (or drug abuse) and can result in stroke with multifocal neurologic signs. History of drug intake helps in the evaluation of cases. Angiographic appearances of cerebral vasculitis with beaded appearance of the arteries are typical. History of drug abuse may also be misleading. A young male drug user who presented with psychosis was initially suspected to have drug-induced CNS vasculitis, but was finally diagnosed with Susac syndrome (09).
Wegener granulomatosis. This is a necrotizing systemic vasculitis that affects various organs. It may cause stroke due to cerebral vessel involvement, visual loss due to optic nerve involvement, and hearing loss due to involvement of the eighth cranial nerve.
Transient inverted vision. This is reported in patients with vertebrobasilar transient ischemic attacks and demyelinating diseases. This was the presenting symptom in a 41-year-old woman who was eventually diagnosed with Susac syndrome (119). Although a rare presenting symptom, Susac syndrome should be included in the differential diagnosis of transient inverted vision.
The following diagnostic procedures are recommended in a young patient with encephalopathy, hearing loss, and visual impairment. Most of the patients do not initially present with the complete triad of symptoms. However, if the clinical presentation is suggestive of Susac syndrome, a search should be made for absent components of the triad. A list of diagnostic procedures is shown below, of which the important items are MRI, fluorescein angiography, and audiometry.
• Complete blood count with coagulation studies
• Several studies have attempted to identify biomarkers of Susac syndrome, but none have been validated yet. Anti-endothelial cell antibodies have been reported in Susac syndrome, but it is not certain if these antibodies are unique to the syndrome and of value as a diagnostic or if they represent a nonspecific epiphenomenon (51). Measurement of titer of antiendothelial cell antibodies in the serum, however, may be used to gauge the severity of illness as well as response to therapy (103). The antiendothelial cell antibodies, which can be detected in serum samples from patients by use of indirect immunofluorescence and Western blot studies, seems specific in many cases and may be a biomarker of Susac syndrome (64).
• Funduscopy. Small punctuate yellow Gass plaques are almost unique to this disorder, and their characteristic location and color should assist in confirming the diagnosis (29). Ultra-widefield fundus imaging has been used for the diagnosis and follow-up of a case of Susac syndrome who initially presented with retinal detachment and required surgical reattachment (97). Ultra-widefield fluorescein angiography confirmed the avascularity of two thirds of the retina and findings of severe neurosensory hearing loss, and postoperative clinical depression led to the diagnosis of Susac syndrome. Widefield and ultra-widefield imaging provides high-resolution details of the central and peripheral damage in Susac syndrome (40).
• Cerebrospinal fluid examinationrituxi
• Retinal fluorescein angiography, which shows arteriolar wall hyperfluorescence. Abnormalities in fluorescein angiography serve as a valuable biomarker, 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. In the absence of classical triad, arteriolar wall hyperfluorescence on fluorescein angiography in retinal arterioles remote from retinal ischemia combined with central callosal lesions on MRI are diagnostic of Susac syndrome because they have never been described in any other condition (27).
• Visual field measurement
• Electroencephalography. Frontal intermittent rhythmic delta activity has been observed in Susac syndrome.
• Multifocal electroretinography may be useful for assessing subclinical retinal dysfunction after recovery of subjective symptoms of branch retinal artery occlusion in Susac syndrome (109).
• Brain MRI with T2-weighted images. Small, multifocal white matter hyperintensities are characteristic. The distribution of lesions in the corpus callosum, the largest white matter tract in the brain, is disease-specific in only a few entities such as Susac syndrome and Marchiafava-Bignami disease (33).
• Cerebral angiography if vasculitis is suspected
• Muscle biopsy if systemic involvement is suspected
• Brain biopsy if the diagnosis remains in doubt and the patient does not improve
Based on examination of 7 cases, diagnostic ophthalmologic features on retinal angiography were absence of intraocular inflammation and focal, labile, nonperfused retinal arterioles with integrity of choroidal circulation (68). Paracentral acute middle maculopathy has been reported in association with a case of Susac syndrome (47). Patients who present with paracentral acute middle maculopathy should be checked for characteristic magnetic resonance imaging lesions of Susac syndrome.
Clinical diagnostic of Susac syndrome can be confirmed by the neuroimaging triad of white matter lesions, deep gray matter lesions, and leptomeningeal disease. In the absence of this triad, arteriolar wall hyperfluorescence on fluorescein angiography in retinal arterioles remote from retinal ischemia and central callosal lesions on MRI remote from retinal vascular injury and central callosal lesions are confirmatory of the diagnosis because they have never been described in any other condition (27). MRI shows a distinctive pattern of supratentorial white matter lesions that always involve the corpus callosum and should support the diagnosis of Susac syndrome in patients with at least 2 of the 3 features of the clinical triad (105). The presence of characteristic MRI-imaging findings of callosal involvement, along with clinical presentation of left hemiparesis, hearing loss on the left, and visual impairment on the left, were useful in confirming the diagnosis of Susac syndrome in a young woman (22). In another case of a young woman, characteristic MRI lesions plus retinal artery occlusion enabled early diagnosis of Susac syndrome (60). Rapid cystic transformation of callosal lesions can be considered pathognomonic of this condition. Diffusion tensor imaging demonstrates fiber impairment in Susac syndrome. Serial diffusion-weighted MRI and apparent diffusion coefficient maps may be useful in differentiating Susac syndrome from demyelinating diseases. MRI is the best imaging modality for Susac syndrome, and in a young male patient with sensorineural hearing loss, a unique MRI finding of eighth cranial nerve enhancement was reported (03). 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 (54). A 35-year-old male presented with unilateral visual loss progressing to bilateral loss, hemiparesis, behavioral changes, and hearing loss, leading to the diagnosis of Susac syndrome (31). Ophthalmic examinations revealed multiple branch retinal artery occlusions in both eyes, and MRI showed multiple "punched-out" lesions in the corpus callosum, which confirmed the diagnosis. His condition deteriorated despite intravenous corticosteroid therapy. Perhaps early diagnosis and treatment might have saved this patient.
After presentation of 2 new cases of this syndrome and review of the previously reported cases, it was concluded that a high percentage of patients do not have the triad of retinal arterial occlusion, hearing loss, and encephalopathy at the time of onset of symptoms and, therefore, this disease may be underdiagnosed (91). Thus, patients with unexplained encephalopathy should be examined by an ophthalmologist and have an audiogram performed. Audiogram, retinal angiography, and brain MRI should be performed regardless of the mode of presentation in order not to miss one (or 2) features of the triad of Susac syndrome (81). These 3 tests should be repeated during the first year and for long-term follow-up.
In a case of Susac syndrome in a young woman that was diagnosed by MRI and retinal angiography, brain positron emission tomography showed abnormalities that were comparable with other types of central nervous system vasculitis and distinct from those found in multiple sclerosis (23). The European Susac Consortium has integrated clinical presentation and paraclinical findings and published formal criteria to facilitate the diagnosis of Susac syndrome (55). For a definite diagnosis of Susac syndrome, each of the subcriteria under the main criteria of involvement of the brain, retina, and vestibulocochlear system has to be fulfilled, whereas probable and possible cases fulfil these criteria partially.
Because of the limited number of patients that have been treated with a variety of methods, it is difficult to recommend a definitive plan of action. There are no controlled clinical trials. Comments on various methods of treatment are described below.
Anticoagulants. Of the 5 patients treated with these agents, only 1 improved, 2 developed new symptoms while under treatment, and the condition of 2 patients remained unchanged. 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.
Corticosteroids and immunosuppressants. Susac syndrome is an immune-mediated endotheliopathy; it responds well to immunosuppressive therapies when treatment is prompt, aggressive, and sustained. Corticosteroids are the most frequently used drugs in Susac syndrome. Additional therapies such as intravenous immunoglobulin, mycophenolate mofetil, and cyclophosphamide are often necessary; rituximab, a monoclonal antibody used in the treatment of autoimmune diseases, should be considered (93). About 90% of the reported cases appear to have improved during such therapies at some time during the course of the disease. Tapering of the corticosteroid dose has led to the development of new signs and symptoms in some cases. Corticosteroids given orally or intravenously are recommended as the first-line therapy. The first Japanese patient reported in the literature responded to high-dose intravenous methylprednisolone therapy during the exacerbated phase of the disease, and a definite remission occurred within 2 years of onset (108).
Immunosuppressants such as cyclophosphamide, azathioprine, and intravenous immunoglobulin have been added to corticosteroids. In one case, immunotherapy was sequentially escalated because repeated attempts at steroid reduction following initial response led to clinical worsening; finally, high-dose cyclophosphamide every 4 weeks enabled adequate control of disease activity (56). In another case, combined treatment with cyclophosphamide and intravenous immunoglobulin resulted in dramatic improvement of the clinical status of the patient over the following months of observation (79). A young woman with typical Susac syndrome was maintained with partial recovery on long-term immunosuppressive treatment with azathioprine and prednisolone, as well as inhibition of thrombocyte function with acetylsalicylic acid (26). In a series of 8 patients from a center, all but one patient received a treatment combining high doses of methylprednisolone and cyclophosphamide intravenously (62). Of these, 5 patients who had early diagnosis and prompt aggressive treatment improved and were able to go back to work, whereas 3 patients who had delayed diagnosis as well as cognitive sequelae were unable to resume work.
Oral prednisolone has been reported to be ineffective in several patients who deteriorated while on this therapy (63; 102). Two patients with Susac syndrome improved following acute treatment with intravenous immune globulin and intravenous methylprednisolone with no further relapses (36).
In a young woman with classical Susac syndrome, serial fluorescein angiograms enabled monitoring of therapeutic response to immune suppression with tacrolimus, but not steroids alone, and provided evidence of a lack of efficacy of nimodipine and aspirin (67).
Intraocular injection of triamcinolone, a long-acting synthetic corticosteroid. A 23-year-old woman who presented with sudden visual loss in the left eye along with other features of Susac syndrome and multiple bilateral occlusions of retinal artery branches shown on fluorescein angiography received a single intravitreal injection of triamcinolone in the left eye with resolution of visual loss before the start of systemic corticosteroids (117).
Nimodipine. Nimodipine has been recommended as an adjuvant therapy on the presumption that it will have an antivasospastic and neuroprotective effect. No significant efficacy has been shown in reported cases in which it was tried.
Rituximab. A 22-year-old man with Susac syndrome presented with prominent skin findings, including livedo reticularis and a micropapular eruption, which responded promptly to rituximab, a monoclonal antibody used for treatment of hematological cancers and autoimmune diseases (39). In refractory cases of Susac syndrome, rituximab may be combined with intravenous immunoglobulin and corticosteroids.
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 (48). Histological examination of brain lesions in this case as well as 2 other cases shows T cell-mediated inflammatory contribution to lesion pathogenesis providing a rationale for use of infliximab (49). A patient with Susac syndrome who was refractory to the conventionally prescribed combination of immunosuppressive treatments, including high-dose potent corticosteroids, intravenous cyclophosphamide, methotrexate, plasma exchange, rituximab, and mycophenolate, was stabilized with infliximab in combination with a tapering course of low-dose prednisone (32).
A multicenter retrospective cohort study of 5 patients diagnosed with Susac syndrome evaluated patient disease activity before and after introduction of anti-TNF therapy, and its value as a steroid-sparing agent (12). All were initially treated with a combination of corticosteroids and classical immunosuppressive drugs. Infliximab was started in 3 patients, and adalimumab in 2 patients. Anti-TNF treatment reduced relapses of ocular symptoms and enabled reduction of corticosteroid dosage with complete discontinuation in 4 out of 5 patients. Both drugs were well tolerated, and no serious adverse events were reported. Anti-TNF therapy may be a valuable option for the treatment of 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 treatment for Susac syndrome, there was dramatic posttreatment improvement in visual field and visual acuity (61). Treatment with hyperbaric oxygen reduced the visual sequelae in a patient in whom single photon emission computed tomography showed a microangiopathic disorder of the brain (70). In another reported case, hyperbaric oxygen therapy minimized ischemic lesions (19).
Revascularization of retina. In a patient who presented with retinal detachment initially and later diagnosed with Susac syndrome, a significant portion of the retina was found to be avascular bilaterally. Surgery for retinal reattachment was performed successfully with scleral buckle and neovascularization of retina was observed at 8-month follow-up (97).
Cochlear implantation for hearing loss. Bilateral simultaneous cochlear implantation was successful in restoring significant hearing in a patient with Susac syndrome (95). 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 six months of cochlear implant use (11). In a Susac syndrome patient with unilateral hearing loss, a left cochlear implant was placed, although there was possible involvement of retrocochlear pathways (45). Unilateral cochlear implantation gave good results in a patient with Susac syndrome who presented with classical triad including bilateral sensory neural nearing loss and failed to respond to initial treatment using immunoglobulin and plasmapheresis (59). In less than a year following implant, audiometry revealed a threshold of 30 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. Vestibular rehabilitation and hearing aids may be required for patients with persisting cochleovestibular disturbances. A 43-year-old man who was initially diagnosed as a case of acute disseminated encephalomyelitis improved with steroids and immunoglobulin and had a recurrence of symptoms; further investigations led to the diagnosis of Susac syndrome (88). Cyclophosphamide, an immunosuppressant anticancer drug, was added to his therapy, and he was sent for rehabilitation resulting in faster and full functional recovery.
Ocular neovascularization with vitreous hemorrhage can be a late manifestation of occlusive arteriopathy in Susac syndrome. A 37-year-old male with a history of suffering from Susac syndrome a decade previously presented with painless blurring of vision in the right eye due to vitreous hemorrhage and neovascularization in both eyes, which was managed with panretinal photocoagulation (57).
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 as well as treatment and vary from normal course to complications. No definitive score or clinical feature can predict the outcome of the disease. Guidelines for the treatment of Susac syndrome in pregnant women are not well established (89).
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 (34). A pregnant woman with a 1-month history of behavioral changes and MRI changes diagnostic of Susac syndrome showed a marked and prompt clinical as well as radiological improvement after treatment with intravenous immunoglobulins (41).
Deterioration may occur after delivery. Clinical exacerbation of Susac syndrome occurred immediately following the delivery of a stillborn anencephalic child (18). Another patient deteriorated after delivery of a normal baby and improved after treatment with corticosteroids (63). In a series examining Susac syndrome 3 patients had 4 pregnancies; 2 needed induced abortions, one was uneventful, and one was complicated with disease flare in the early postpartum period (06).
Termination of pregnancy due to potential toxicity of therapy on the fetus. A 25-year-old woman who presented at 20 weeks' 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 avoid possible toxic effects on the fetus (20).
K K Jain MD
Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.See Profile
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