Susac syndrome

Susac syndrome is a rare autoimmune disorder characterized by the clinical triad of encephalopathy, sensorineural hearing loss, and visual disturbance resulting from branch retinal artery occlusion (BRAO) ¹. The encephalopathy is manifested by headache, motor deficiencies, sensor deficiencies, aphasia, cognitive impairment, and urinary insufficiency ². The hearing loss is usually bilateral, and it can be associated with tinnitus and vertigo. The branch retinal artery occlusion may be extensive or subtle and unilateral or bilateral. The specific cause of Susac syndrome is unknown, however it is believed to be an autoimmune-mediated condition that causes micro infarcts due to endothelium-induced occlusion of the microvessels in the central nerve system (CNS), inner ear, and retina ³. Although its prevalence is rare, Susac syndrome is an important differential diagnosis for several neurologic, psychiatric, ear, nose, and throat, and ophthalmologic conditions ⁴. Susac syndrome diagnosis is difficult to establish since the full clinical triad rarely exists on the first presentation ⁵.

Susac syndrome has a slight female-to-male preponderance of 3:1 and predilection in those of Caucasian ancestry ⁶. Most reports of Susac syndrome are derived from the North American and European continents, with the first clinical ramifications of Susac syndrome noted between 16-40 years, with an extended age range of 7-72 years ⁷. As Susac syndrome remains both underdiagnosed and misdiagnosed, this results in an unknown true incidence and prevalence. Currently, there are a total of 304 documented cases of Susac syndrome worldwide, with a higher reported incidence during the spring and summer months ⁸.

Figure 1. Susac syndrome MRI

Footnote: Sagittal T1-weighted magnetic resonance imaging scan shows small round microinfarctions of the corpus callosum (arrows), consistent with the diagnosis of Susac syndrome.

[Source ⁹ ]

Susac syndrome causes

Although the exact cause of Susac syndrome remains elusive, histopathological findings support an autoimmune endotheliopathy of cerebral, retinal and cochlear microvasculature ¹⁰. Visualized changes include an affinity for small (< 100 mm) precapillary arterioles with endothelial cell necrosis, basement membrane thickening, inflammatory cell infiltration and complement deposition (C4d and C3d). Following this injury, diffuse microvascular changes ultimately result in microischemia and infarction leading to the observed clinical manifestations of encephalopathy, visual changes, and sensorineural hearing loss ¹¹. Nevertheless, Susac syndrome is a considerable challenge to diagnose as it is very uncommon for patients to initially present with all features of the classically described triad ¹². There are two broad categories of Susac syndrome; the first is a primarily encephalopathic presentation with either concurrent or eventual manifestation of visual disturbances and sensorineural hearing loss and the second is a recurrent course of branched retinal artery occlusion and hearing loss, which may be accompanied with encephalopathy months to years later ¹³.

Susac syndrome symptoms

Clinical presentation in Susac syndrome:

• Brain (corpus callosum) 88%
• Cochlea 52%
• Retina 46%
• All three structures 20%

Nervous system

Encephalopathic features typically follow a subacute or acute course and are often preceded by or concurrent with a migrainous headache, likely secondary to leptomeningeal involvement ⁸. Encephalopathic signs may be the initial presentation of Susac syndrome or secondary to retinal or vestibulocochlear pathology. Encephalopathy often manifests with the abrupt onset of multifocal neurologic deficits and/or neuropsychiatric disturbances. Symptoms may be dominated by confusion, memory and cognitive disturbances or by acute and profound changes in mood and personality. Focal findings such as seizures, pyramidal signs, dysarthria and hyperreflexia may also be present ¹⁴. While generally reversible, some initial deficits may be permanent depending on the location and extent of the involved cerebral vasculopathy. In the original descriptions by Susac and colleagues ¹⁵, multifocal microinfarctions of the cerebral grey and white matter were noted with associated necrosis and gliosis. Subsequent developments via brain biopsy highlighted characteristic findings of an autoimmune vasculopathy primarily affecting the precapillary arteriolar endothelium in both the cortex and leptomeninges. Visualized changes also include subacute microinfarctions, perivascular oedema, chronic inflammation and gliosis/reactive astrocytosis ¹⁶. The absence of fibrinoid necrosis, necrotising vasculitis, or demyelination assists in the pathologic distinction of Susac syndrome from other systemic vasculidities or autoimmune demyelinating conditions ¹⁷.

Visual system

Visual disturbances related to branched retinal artery occlusion are heterogeneous in nature and depend on the location and extent of diseased vessels within the retina. Those with small, peripheral arteriolar occlusions may be asymptomatic or have subtle visual changes, with a normal funduscopic exam ¹⁸. Conversely, those who suffer from more extensive lesions of the retina and macula may experience profound or complete vison loss. Patients may also present with additional ocular complaints of blurred vision, scintillating scotoma, or photopsia ¹⁹. Fluorescein angiography assists in visualizing the extent of the occlusive retinal microangiopathy and illustrates characteristic ocular findings such as arteriolar narrowing, arteriolar wall hyperfluorescence, and segmental non-perfusion ²⁰. Additionally, yellow-white arterial wall plaques (Gass plaques) located at the midarteriolar segments may be seen, proposed to be the result of arteriolar wall damage and subsequent extravasation of blood and lipids forming atheromatous plaques ²¹. Their location at the midarteriolar segments is indicative of endothelial integrity loss, rather than an end-artery embolic pathology. These plaques may be transient throughout the clinical progression of this condition; however, their presence is confirmatory of Susac syndrome ²².

Auditory and vestibular systems

Sensorineural hearing loss is a prominent feature of Susac syndrome with highly variable characteristics ²³. Hearing loss is often precipitous in onset and typically rapidly progressive, sometimes resulting in complete deafness in either one or both ears. In some instances, hearing loss may abruptly occur in one ear, followed by loss in the contralateral ear days to weeks later, resulting in the so-called “bang-bang” type of hearing loss ²⁴. Due to the commonly detected pattern of low and middle-frequency sensorineural hearing loss, microinfarctions of end arterioles and damage to the apical cochlea are thought to be responsible in the setting of the observed endotheliopathy ²⁰. This pattern of damage is further supported by the clinical observation of sensorineural hearing loss with maintained acoustic reflexes, rather than localised damage to the vestibulocochlear nerve, which suggests cochlear disease as the underlying cause ²⁵. Simultaneous vestibular dysfunction is also common in the early phase of Susac syndrome; patients can present with severe tinnitus accompanying their abrupt sensorineural hearing loss, which often leads to the misdiagnosis of Ménière’s disease ²⁶. The presence of vestibular dysfunction may indicate lesions in the vestibular apparatus itself or may be the result of central microinfarctions within the cerebellum or brainstem ¹². This is in stark contrast to other autoimmune inner ear diseases such as Cogan syndrome, where the pattern of damage demonstrates extensive endolymphatic hydrops, saccular collapse following intense dilation, fibrotic changes in the perilymphatic space of the posterior semicircular canal, and absorption of enchondral bone with no pathological changes within the inner ear vasculature ²⁷. Additional symptoms which may be present in Susac syndrome include gait ataxia, aural pressure, and prominent jerky nystagmus, which is hypothesised to be due to infarction within the membranous labyrinth ⁷. In Susac syndrome patients with prominent encephalopathic features, it may be difficult to assess the presence or extent of vestibulocochlear dysfunction, in which case brainstem auditory evoked potential testing may be necessary ¹⁹.

Integumentary and musculoskeletal systems

Historically, patients have described both myalgias as well as skin changes during the early phase of Susac syndrome ¹⁷. Turc and colleagues ²⁸ noted skin lesions consistent with livedo reticularis in a patient with Susac syndrome; skin biopsies performed demonstrated similar pathologic findings in other affected systems with evidence of microvascular thrombi in dermal arterioles, minimal perivascular lymphocytic infiltration and endothelial cell swelling. Similarly, Petty and colleagues reported subclinical microangiopathy involving muscular arterioles in 5 biopsy specimens with Susac syndrome, further supporting the notion of a systemic endotheliopathy, unifying features of this condition ¹².

Susac syndrome diagnosis

Timely diagnosis of Susac syndrome is extremely important to ensure appropriate treatment before irreversible harm to the brain, retina and inner ear occurs. Few clinicians are highly experienced with Susac syndrome. The care and diagnosis of patients with Susac syndrome requires a team of experts familiar not only with this condition but also with its mimics to ensure an accurate diagnosis and workup.

Diagnostic workup

Audiometry

Audiological evaluation in the form of pure tone audiometry remains essential to confirm the presence of sensorineural hearing loss in patients presenting with concern for Susac syndrome. While audiometric data on Susac syndrome patients is limited, the observed sensorineural hearing loss appears to affect the low and middle frequencies, with an occasional loss appreciated at the high frequencies ²⁶. To date, Roeser and colleagues ²⁹ have provided the most comprehensive description of audiometric findings in Susac syndrome patients. In their cases series of 23 patients, representing a total of 34 affected ears, most frequencies were found to be affected, with losses noted at 500 and 1,000 Hz and an overall “upsloping” pattern of sensorineural hearing loss. Tympanometry for all 23 patients was found to be type A, indicating a normal middle ear system. The pure-tone average of the 34 affected ears was 41.5 dB, with a mean percent binaural hearing loss of 26.4%. The American Academy of Otolaryngology-Head and Neck Surgery hearing classification of this cohort demonstrated primarily type A (47%) hearing, with losses also noted in categories type B (23.5%), type C (6.0%), and type D (23.5%). Finally, word recognition scores were poor in this study group, with only 26.5% of affected ears exhibiting 100%-word recognition ²⁹.

Vestibular-evoked myogenic potentials

Vestibular-evoked myogenic potentials can be applied in the workup of a patient with suspected Susac syndrome, particularly if there is evidence of acute vestibular dysfunction upon clinical presentation. In a study by Magliulo and colleagues ³⁰, they were able to successfully characterise a vestibular-evoked myogenic potential deficit, with both delayed latency and reduced amplitude in a patient with Susac syndrome. It is reasonable to extrapolate that the initial otologic damage in Susac syndrome may involve a restricted portion of the vestibular apparatus ³⁰. Further investigation is necessary to explore such mechanistic details.

Laboratory investigations

Due to variability in presenting features of Susac syndrome, individuals are often subjected to a myriad of diagnostic laboratory tests, often with few abnormal findings. Focused serologic testing is recommended, with expansion as indicated to evaluate for related differential diagnoses.

• Antibody markers. Mild elevation of antinuclear, antiphospholipid, anti-thyroid microsomal, anti-thyroid peroxidase, perinuclear anti-neutrophil cytoplasmic, and rheumatoid factor autoantibodies have all been reported in Susac syndrome patients. In a case series by Jarius and colleagues of 25 Susac syndrome patients, 3 patients (13.0%) were reported to have anti-nuclear antibody positivity, 1 patient (4.0%) was reported to have perinuclear anti-neutrophil cytoplasmic antibody positivity, 1 patient was reported to have anti-thyroid microsomal antibody positivity, and 1 patient (4.0%) was reported to have anti-thyroid peroxidase antibody positivity ³¹. Anti-endothelial cell antibodies, a heterogeneous family of antibodies which bind to various endothelial cell antigens, have also been detected in the serum of Susac syndrome patients; it has been postulated to serve as a biomarker of disease activity ³². In the case series by Jarius and colleagues ³¹, 7 patients (28%) were found to have anti-endothelial cell antibody positivity. However, it remains uncertain whether these antibodies are unique to Susac syndrome or represent a non-specific epiphenomenon. At this time, it remains a non-specific assay as it has been reported in other vasculitic and autoimmune processes including systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome and sarcoidosis. There are several methods to detect anti-endothelial cell antibodies but sensitivity and specificity of these antibodies as biomarkers for Susac syndrome have yet to be established.
• Hematologic panel. A complete blood count with differential may be performed, which occasionally reveals monocytosis and eosinophilia ³³. Similarly, mild elevation in acute phase reactants including erythrocyte sedimentation rate and C-reactive protein has been reported in Susac syndrome patients. Elevated levels of factor VIII and von Willebrand factor antigen have also been documented in Susac syndrome, likely due to endothelial perturbation, as the close association of these factors with endothelium would be consistent with the observed endotheliopathy ²².
• Cerebrospinal fluid analysis. Cerebrospinal fluid examination reveals lymphocytic pleocytosis (5-30 cells/mm³), elevated protein levels (range: 100-3000 mg/dl), usually during the encephalopathic phase, and occasionally elevated myelin basic protein ³⁴. In a case series by Mateen and colleagues ³⁵ of 29 patients with Susac syndrome, the mean cerebrospinal fluid protein level was found to be 130 mg/dl (median: 129, range: 35-268, normal range: 15-45 mg/dl), with a mean cell count of 14 cells/ml (median: 5, range: 0-86, normal range: 0-5 cells/ml). Analysis for oligoclonal bands is often performed due to overlapping clinical features of Susac syndrome with multiple sclerosis as Susac syndrome patients have no evidence of oligoclonal bands or an elevated Immunoglobulin G index.

Radiographic imaging

Subclinical pathology occurs in many patients with suspected Susac syndrome without overt clinical manifestations, prompting emphasis on an appropriate diagnostic workup with dedicated imaging to confirm the diagnosis of Susac syndrome. To date, Susac syndrome patients with documented evidence of sensorineural hearing loss lack visualised radiographic aberrations within the external, middle and inner ear ²⁵.

• Computed tomography. Computed tomography of the brain is typically normal in the initial stages of Susac syndrome, however with disease progression, this could progress to radiographically evident cortical atrophy ³⁶. In parallel, single-photon emission computed tomography of the brain can also be utilised which reveals multifocal involvement corresponding to areas of cerebral hypoperfusion, confirming the presence of microangiopathy seen in Susac syndrome ³⁷.
• Magnetic resonance imaging. Magnetic resonance imaging is the neuroimaging study of choice to evaluate for Susac syndrome. Typical findings include central corpus callosum involvement and brain infarctions. The cerebellum, cerebellar peduncles, brain stem and thalamus are less frequently involved. The deep gray matter is involved in approximately 70% of Susac syndrome cases and the leptomeninges is affected in about 33% of Susac syndrome cases ³⁸. T2-weighted sequences typically reveal multifocal, small, hyperintense foci which mainly involve the central aspect of the corpus callosum with peripheral sparing. Fluid-attenuated inversion recovery sequences may also show lesions in the corpus callosum centrally located in the periventricular and subcortical white matter. T1-weighted sequences reveal hypointense areas during the subacute or late phase of Susac syndrome ³⁹. During periods of encephalopathy, the corpus callosum is universally affected and reveals a characteristic pattern of small-to-large round white matter lesions (“snowballs”) best visualised on sagittal T2-weighted fluid-attenuated inversion recovery sequences and linear defects (“spokes”) found in the central fibers of the corpus callosum. As acute changes resolve over time, central callosal lesions develop (“holes”) and are best visualised on sagittal T1-weighted sequences ⁴⁰. Diffusion tensor imaging can also be used to evaluate for Susac syndrome as it is specifically sensitive to structural impairment of axonal integrity based on normal values for fractional anisotropy, a measure which reflects spatial directionality of water diffusion ⁴¹. The mean fractional anisotropy reduction in the genu of the corpus callosum and prefrontal white matter, as well as widespread impairment of white matter fibre integrity and fiber disruption involving the genu of the corpus callosum, appears to be typical for Susac syndrome, revealing microstructural degeneration of cerebral fibres and extensive microstructural dysfunction ⁴².

Temporal bone histopathology

The first description of otopathologic findings in Susac syndrome was described by Francis and colleagues ⁴³ in 2011 who harvested two post-mortem temporal bones from a 51-year-old female with Susac syndrome and audiometrically confirmed bilateral severe sensorineural hearing loss without concomitant vestibular symptomology. Pertinent histopathologic findings in Susac syndrome are outlined in detail below with generalised atrophy and degeneration involving the apical half of the cochlear duct with preservation of cochlear neurons.

• Cochlea. The organs of Corti were found to be absent or represented by a mound of supporting cells and devoid of hair cells. The tectorial membranes revealed marked pathologic changes, which were more extensive in the left ear and characterised by cellular encapsulation and detachment from the spiral limbus. The lateral cochlear walls revealed near-total atrophy of the stria vascularis and severe degeneration of spiral ligament fibrocytes with replacement via connective tissue cells. The stria vascularis revealed patchy atrophy in the 3-7 mm region on the right and 0-3 mm region in the left. Some capillaries within the stria vascularis revealed likely occlusion of the vessel lumen by an acellular substance or thickening of the vessel wall. The number of capillaries appeared to be reduced in the lateral cochlear wall of the middle and apical turns. The scala media in the middle and apical turns demonstrated scattered cellular debris, likely secondary to sloughing cells degenerating within the stria vascularis and organ of Corti. Finally, dendrites leading up to the organ of Corti similarly revealed atrophy in the middle and apical turns ⁴³.
• Saccule. The saccular macula in the left ear reveals diminution of type I hair cells; the saccular lumen in both ears contains free-floating cells, arranged in strands and folded strips. The origin of these cells is unclear, but they could represent detached cells which formerly lined the saccular duct ⁴³.
• Leptomeninges. The leptomeninges within the internal auditory canals revealed numerous psammoma bodies. Several small arterioles within the leptomeninges also revealed thickening of the vessel lumen to the point of occlusion. In some instances, there was cellular proliferation within or around the vessel wall causing occlusion, whereas other areas revealed a dense basophilic material occluding the vessel lumen ⁴³.

Susac syndrome treatment

Given the small number of Susac syndrome cases reported worldwide as well as an incomplete understanding of disease pathogenesis, determination of an optimal treatment strategy remains difficult. As the observed clinical fractures are postulated to be vasculitic in nature, management of Susac syndrome is primarily focused on anti-inflammatory and disease-modifying therapies. Although recommendations for treatment protocols do exist, it is important to note most therapies are based on limited cohorts of Susac syndrome patients. As such, response to proposed medical regimens may be highly variable based upon individual disease characteristics. Initial treatment protocols were first designed for patients presenting with primarily encephalopathic forms of Susac syndrome; however, current literature supports a different approach for patients with the recurrent branch retinal artery occlusion and hearing loss subset of Susac syndrome ⁴⁴. This has prompted in parallel a significant interest in the exploration of otologic surgical interventions for Susac syndrome patients ¹⁶. Regardless of disease subtype, it is increasingly evident as well as imperative that early, aggressive treatment should be initiated whenever possible 15,34,45,46.

Corticosteroids

In the acute phase, intravenous steroids are employed in an aggressive fashion as the initial treatment modality. Treatment begins with intravenous methylprednisone 1,000 mg/day over 3 days, followed by high dose oral prednisone 60-80 mg/day for a period of 2-4 weeks. This is followed by a slow taper with a daily dose reduction of 10% every 2 weeks, with a maintenance dose of 5-10 mg every other day ⁴⁵. An alternative to a prolonged course of oral prednisone, given long-term ramifications of corticosteroid use, is to utilize frequent pulses of intravenous methylprednisone, which may be beneficial particularly for Susac syndrome relapses ¹³.. When inner ear disease accompanies central disease pathology, treatment of encephalopathic features using methylprednisone will simultaneously address any existing inner ear disease. Should otologic symptoms (acute sensorineural hearing loss, tinnitus and vertigo) predominate, it would be appropriate to promptly administer both intravenous methylprednisolone and intravenous immunoglobulin, with at least a moderate course of prednisone ⁴⁶.

Intravenous immunoglobulin and plasmapheresis

Along with corticosteroids, concomitant intravenous immunoglobulin should be initiated in the first week of definitive treatment. The most commonly reported regimen consists of 2 g/kg the first week, followed by 2 g/kg every 2-4 weeks over a treatment period of 6 months ⁴⁵. Plasmapheresis may also have a role for Susac syndrome patients with severe or relapsing patterns of disease who have not responded to conventional medical therapies ³⁵.

Immunomodulators

Immunomodulatory drugs should be initiated early in the treatment of Susac syndrome patients suffering from severe disease. This consists of intravenous cyclophosphamide 10-15 mg/kg spaced 2 weeks apart, followed by additional doses if no change in symptomatology is seen. If notable improvement in symptoms does occur, patients should be switched to mycophenolate mofetil 1000-1500 mg twice daily for maintenance therapy. Alternatives to this regimen include a combination of mycophenolate mofetil and tacrolimus. This should be administered as mycophenolate mofetil 500 mg twice daily + tacrolimus 2 mg twice daily via intravenous formulation as maintenance therapy. For patients with extremely severe disease who fail to respond to previously described therapies, rituximab may be of benefit. This should be administered with an initial dose of 1,000 mg, followed by the same dose 2 weeks later and subsequent doses at intervals of 4-6 months and 6-12 months. In rare instances, new additive ischaemic ‘‘hits’’ to the cochlea may occur, even during active treatment with corticosteroids, intravenous immunoglobulin, mycophenolate mofetil and rituximab. As the window of opportunity to protect the inner ear is short, replacement of mycophenolate mofetil, with cyclophosphamide and mycophenolate mofetil plus tacrolimus, may be indicated. Intravenous cyclophosphamide should be administered at a dose of 10-15 mg/kg every 2 weeks for a total of 2 doses. If improvement is unsatisfactory, one additional dose may be administered in 2 weeks, with future doses every 3 weeks for a total of 3 doses followed with a final round every 4 weeks with a total of 1-3 doses ⁴⁶.

Anticoagulants

Owing to the microischemic and prothrombotic state associated with Susac syndrome, some authors advocate to administer aspirin 81 mg on a daily basis as part of a maintenance medical therapy ⁴⁷. Observations of improvement in sensorineural hearing loss with a combination of aspirin and nimodipine have also been reported, likely secondary to an improved microvascular blood supply within the cochlea ¹⁶. Other anticoagulants, such as clopidogrel, dipyridamole and fondaparinux, have been tested, although their efficacy in the management of Susac syndrome has yet to be established ³¹.

Transtympanic dexamethasone

Transtympanic dexamethasone injections can be utilized in patients with Susac syndrome and concomitant findings of sensorineural hearing loss confirmed via audiometry ²⁵. Advantages of intratympanic perfusion include a higher concentration of medication delivered locally to the inner ear, ease of administration, the diseased ear is preferentially treated without adversely affecting the contralateral ear, and potential avoidance of systemic side effects ⁴⁸. Transtympanic injection of dexamethasone in the acute phase of sensorineural hearing loss in the setting of Susac syndrome may provide transient benefit with respect to halting progressive hearing loss and justify more aggressive systemic immunotherapy on grounds of potential reversibility.

Cochlear implantation

Should conservative medical therapies and transtympanic dexamethasone injections fail to result in notable clinical improvement, cochlear implantation is recommended for Susac syndrome patients with irreversible otologic disease. Currently, cochlear implantation has been successfully employed in 5 patients who met surgical candidacy within the otolaryngology literature. Postoperatively, there was evidence of functional hearing restoration and notable improvement in communication abilities for all implanted Susac syndrome patients ⁴⁹.

Susac syndrome prognosis

Early diagnosis and treatment of Susac syndrome is hallmark to avoid devastating neurological, visual, and auditory complications ¹⁰. Overall, the prognosis can be significantly improved following prompt, aggressive, and sustained therapies, although poor outcomes often result from delayed, suboptimal management with premature, rapid tapering of treatment schedules ¹⁹. Three major clinical courses have been described in Susac syndrome: monocyclic, polycyclic and chronic continuous. In the monocyclic course, the disease remits spontaneously after 1-2 years without evidence of recurrence. The polycyclic course includes variable periods of remission which may persist for years. Susac syndrome patients with branch retinal artery occlusion and sensorineural hearing loss are at increased risk for following a prolonged polycyclic course. The chronic continuous course demonstrates variations in severity of symptoms. Remission may occur in this group but there is no clear evidence of complete disease diminution. It remains difficult on initial presentation to identify which patients may regress spontaneously or progress with more fulminant symptomology ⁵⁰. In addition, relapses after decades of quiescence have also been described, further muddling long-term outcomes ⁵¹. Accordingly, this disease entity requires lifetime monitoring in conjunction with an ophthalmologist, otolaryngologist, neurologist and rheumatologist. Risk factors for relapse include pregnancy, as Susac syndrome patients will often be tapered off treatment regimens to minimise risk of foetal toxicity ⁵⁰. Unlike other features of this condition, sensorineural hearing loss associated with Susac syndrome is often irreversible and sometimes progressive in nature, despite early and aggressive treatment ⁵². Surgical interventions, chiefly transtympanic dexamethasone as well as cochlear implantation, are viable options to halt progression of otologic disease and augment serviceable hearing for those who meet surgical candidacy, respectively.

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