Otologic manifestations of Susac syndrome
Susac syndrome, a rare autoimmune disorder first described as a classic triad (encephalopathy, branch retinal artery occlusion, and sensorineural
hearing loss) in 1979 by renowned physician John O. Susac, has been an advancing area of clinical interest and scientific research
over the last several decades. This comprehensive review aims to succinctly highlight the breadth and detail of this enigmatic disease, with
a primary focus on otologic manifestations. Topics discussed include epidemiology, pathophysiology, clinical manifestations, differential
diagnoses, classification schema, laboratory investigations, characteristic audiometric findings, high-yield radiographic imaging, temporal
bone histopathology, treatment strategies and overall prognosis.
Susac Syndrome (SS) is a unique clinical condition first described in 1979 by Dr. Susac, who identified two young women with the clinical triad of subacute multifocal encephalopathy, visual changes and hearing loss secondary to systemic microangiopathy of the cerebrum, retina and cochlea 1. While the underlying aetiology of this disease remains unknown, it is widely believed the observed clinical manifestations are the result of an autoimmune endotheliopathy of the cerebral, retinal and cochlear microvasculature 2 3. This hypothesis has been further purported by both ex vivo histopathologic specimens of the cerebrum and temporal bone as well as in vivo findings of the retina via fluorescein angiography 4-9. Despite significant advances in the understanding of this disorder, the presentation of SS remains highly variable with respect to disease onset, course, duration and prognosis. Similarly, data enumeration on patterns and ramifications of SS are also limited given the small number of cases presently available in the published literature worldwide 10. The heterogeneity of presenting symptomology associated with this condition, along with its similarities to other more ubiquitous disease states indeed makes SS a challenging undertaking to astutely diagnose. This is particularly true of the otologic manifestations of SS, where the observed sensorineural hearing loss is often irreversible and progressive in nature, despite early and aggressive therapies. This comprehensive review aims to concisely highlight the current understanding of this enigmatic condition with a distinct emphasis on otologic features pertinent to the field of otolaryngology. To briefly summarise, this study was designed and performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Protocol. Independent searches of the PubMed MEDLINE database were performed on February 12, 2018, by the first and second authors to identify studies which specifically described the otologic manifestations of SS using the Boolean method and relevant search term combinations. English and full-length original articles were employed as inclusion criteria to assess for data extraction eligibility. Exclusion criteria include absent full-text articles and non-English articles, resulting in the omission of 33 and 14 articles, respectively. The search strategy is summarised as follows: 250 articles retrieved, 203 full-length titles and abstracts screened, and 13 studies included in final study data synthesis (i.e. 12 case reports and 1 original article). The abstracted clinical information was supplemented with targeted searches to address specific needs identified in writing this comprehensive review.
SS is a rare autoimmune disorder with a slight female-to-male preponderance of 3:1 and predilection in those of Caucasian ancestry 11. Most reports of SS are derived from the North American and European continents, with the first clinical ramifications of SS noted between 16-40 years, with an extended age range of 7-72 years 12. As SS remains both underdiagnosed and misdiagnosed, this results in an unknown true incidence and prevalence. Currently, there are a total of 304 documented cases of SS worldwide, with a higher reported incidence during the spring and summer months 10 13.
Pathophysiology and clinical manifestations
Although the exact aetiology of SS remains elusive, histopathological findings support an autoimmune endotheliopathy of cerebral, retinal and cochlear microvasculature (Fig. 1). Visualised 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 microischaemia and infarction leading to the observed clinical manifestations of encephalopathy, visual changes, and sensorineural hearing loss 14. Nevertheless, SS is a considerable challenge to diagnose as it is very uncommon for patients to initially present with all features of the classically described triad (Table I) 7. There are two broad categories of SS; 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 15.
a. 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 10. Encephalopathic signs may be the initial presentation of SS 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 16. 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, multifocal microinfarctions of the cerebral grey and white matter were noted with associated necrosis and gliosis 1. Subsequent developments via brain biopsy highlighted characteristic findings of an autoimmune vasculopathy primarily affecting the precapillary arteriolar endothelium in both the cortex and leptomeninges. Visualised changes also include subacute microinfarctions, perivascular oedema, chronic inflammation and gliosis/reactive astrocytosis 4 5. The absence of fibrinoid necrosis, necrotising vasculitis, or demyelination assists in the pathologic distinction of SS from other systemic vasculidities or autoimmune demyelinating conditions 6 7.
b. 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 17. 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 18. Fluorescein angiography assists in visualising the extent of the occlusive retinal microangiopathy and illustrates characteristic ocular findings such as arteriolar narrowing, arteriolar wall hyperfluorescence, and segmental non-perfusion 19. 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 20. 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 SS 9.
c. Auditory and vestibular systems
Sensorineural hearing loss is a prominent feature of SS with highly variable characteristics 4 7 21-24. 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 15 25. 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 6 19 26. 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 aetiology 24. Simultaneous vestibular dysfunction is also common in the early phase of SS; patients can present with severe tinnitus accompanying their abrupt sensorineural hearing loss, which often leads to the misdiagnosis of Ménière’s disease 27. 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 7. 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 28. Additional symptoms which may be present in SS include gait ataxia, aural pressure, and prominent jerky nystagmus, which is hypothesised to be due to infarction within the membranous labyrinth 12. In SS 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 18.
d. Integumentary and musculoskeletal systems
Historically, patients have described both myalgias as well as skin changes during the early phase of SS 6 7. Turc and colleagues noted skin lesions consistent with livedo reticularis in a patient with SS; 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 29. Similarly, Petty and colleagues reported subclinical microangiopathy involving muscular arterioles in 5 biopsy specimens with SS, further supporting the notion of a systemic endotheliopathy, unifying features of this condition 7.
Differential diagnoses and classification schema
SS is an orphan disease which must be considered in the differential diagnosis of a broad variety of medical disorders 30. Given the potential for diversely presenting symptomatology, SS remains a pertinent diagnosis chiefly in the realm of neurologic, ophthalmologic, rheumatologic and otolaryngologic practitioners. A concise yet non-exhaustive list which outlines conditions that present with similar clinical characteristics is outlined in Table II. A classification system described by Vishnevskia-Dai and colleagues can also be applied to assist clinicians in the early diagnosis of this enigmatic condition. This schema was designed in part using a combination of clinical information derived from the medical literature (case reports, reviews and meta-analysis) as well as the author’s case series of 10 patients, with a focus on clinical presentation and diagnostic imaging findings (Table III) 31. Although novel in applicability, studies have suggested that early diagnosis may lead to better prognosis in young patients, prompting a high level of suspicion and early intervention in patients with SS 30.
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 SS. While audiometric data on SS 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 4 7 22-24 27. To date, Roeser and colleagues have provided the most comprehensive description of audiometric findings in SS 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 (Fig. 2). 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 24.
b. Vestibular-evoked myogenic potentials
Vestibular-evoked myogenic potentials can be applied in the workup of a patient with suspected SS, particularly if there is evidence of acute vestibular dysfunction upon clinical presentation. In a study by Magliulo and colleagues, they were able to successfully characterise a vestibular-evoked myogenic potential deficit, with both delayed latency and reduced amplitude in a patient with SS (Fig. 3). It is reasonable to extrapolate that the initial otologic damage in SS may involve a restricted portion of the vestibular apparatus 32. Further investigation is necessary to explore such mechanistic details.
c. Laboratory investigations
Due to variability in presenting features of SS, 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 (Table II).
d. Radiographic imaging
Subclinical pathology occurs in many patients with suspected SS without overt clinical manifestations, prompting emphasis on an appropriate diagnostic workup with dedicated imaging to confirm the diagnosis of SS. To date, SS patients with documented evidence of sensorineural hearing loss lack visualised radiographic aberrations within the external, middle and inner ear 24.
e. Temporal bone histopathology
The first description of otopathologic findings in SS was described by Francis and colleagues in 2011 who harvested two post-mortem temporal bones from a 51-year-old female with SS and audiometrically confirmed bilateral severe sensorineural hearing loss without concomitant vestibular symptomology 8. Pertinent histopathologic findings in SS are outlined in detail below with generalised atrophy and degeneration involving the apical half of the cochlear duct with preservation of cochlear neurons (Fig. 5).
Given the small number of SS 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 SS 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 SS 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 SS; however, current literature supports a different approach for patients with the recurrent branch retinal artery occlusion and hearing loss subset of SS 34. This has prompted in parallel a significant interest in the exploration of otologic surgical interventions for SS patients 5 25. 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.
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 SS relapses 15. 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.
b. 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 SS patients with severe or relapsing patterns of disease who have not responded to conventional medical therapies 38.
Immunomodulatory drugs should be initiated early in the treatment of SS 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 BID 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.
Owing to the microischaemic and prothrombotic state associated with SS, some authors advocate to administer aspirin 81 mg on a daily basis as part of a maintenance medical therapy 2. 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 5 47. Other anticoagulants, such as clopidogrel, dipyridamole and fondaparinux, have been tested, although their efficacy in the management of SS has yet to be established 33.
e. Transtympanic dexamethasone
Transtympanic dexamethasone injections can be utilised in patients with SS and concomitant findings of sensorineural hearing loss confirmed via audiometry 24. 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 SS may provide transient benefit with respect to halting progressive hearing loss and justify more aggressive systemic immunotherapy on grounds of potential reversibility.
f. Cochlear implantation
Should conservative medical therapies and transtympanic dexamethasone injections fail to result in notable clinical improvement, cochlear implantation is recommended for SS 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 SS patients 21 24 49-51.
Early diagnosis and treatment of SS is hallmark to avoid devastating neurological, visual, and auditory sequelae. 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 18. Three major clinical courses have been described in SS: 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. SS 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 52. In addition, relapses after decades of quiescence have also been described, further muddling long-term outcomes 53 54. Accordingly, this disease entity requires lifetime monitoring in conjunction with an ophthalmologist, otolaryngologist, neurologist and rheumatologist. Risk factors for relapse include pregnancy, as SS patients will often be tapered off treatment regimens to minimise risk of foetal toxicity 52. Unlike other features of this condition, sensorineural hearing loss associated with SS is often irreversible and sometimes progressive in nature, despite early and aggressive treatment 19 55. 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.
Although modern advances have significantly extended our scope of knowledge regarding SS, this enigmatic disorder remains incompletely understood. As insights into the pathophysiology of SS continue to evolve, research endeavours remain broadly focused within several disciplines, which may provide evidence-based standardised diagnostic and treatment protocols for disease sufferers in the future. The current body of available evidence suggests SS is likely due to a selective endotheliopathy of the systemic microvasculature, which appears to vasculitic in origin. This distinction is critical, as the inner ear is not an immunologically privileged site; cochlear injury typically occurs via a robust response to foreign and self-antigens through both humoral and cell-mediated mechanisms. Thus, not only should SS be routinely considered as part of the differential diagnosis in patients presenting with multi-system disease and hearing loss, but also it should be considered as a unique vasculitic otologic entity-akin, yet pathologically dissimilar to traditional autoimmune otologic disease. Important otologic manifestations of SS include fluctuating sensorineural hearing loss, tinnitus and vertigo. Audiometric evaluation typically reveals an upsloping pattern of sensorineural hearing loss in the low to middle frequencies. Given the observed sensorineural hearing loss is often irreversible and progressive, surgical interventions including transtympanic cexamethasone and cochlear implantation are viable options to halt disease progression and augment serviceable hearing for those who meet device candidacy, respectively. Multicentre prospective studies are needed to expand our experience with SS and plan future consensus-based recommendations. This comprehensive review has been designed to serve as a centralised and up-to-date resource for clinicians and should be updated whenever novel and high-level clinical evidence becomes available.
Figures and tables
|Brain (corpus callosum)||88% (100%)|
|All three structures||20%|
|Inflammatory demyelinating CNS * disease||Acute disseminated encephalomyelitis Multiple sclerosis Neuromyelitis optica (Devic’s disease)|
|Cerebrovascular disease||Cerebral autosomal dominant Arteriopathy with subcortical infarcts and Leukoencephalopathy (CADASIL) Stroke Transient ischaemic attack|
|Vasculitic, connective tissue, and autoimmune disease||Antiphospholipid antibody syndrome Behçet disease Churg-Strauss syndrome Dermatomyositis Eales disease Limbic encephalitis Polyarteritis nodosa Primary CNS * vasculitis Sarcoidosis Sjögren syndrome Systemic lupus erythematosus Takayasu Disease Vogt-Koyanagi-Harada syndrome Wegener granulomatosis|
|Infectious CNS * disease||Creutzfeldt-Jakob disease Lyme disease Progressive multifocal leukoencephalopathy Syphilis Toxoplasmosis Tuberculosis Viral encephalitis|
|Malignancy||CNS * metastases Primary CNS * lymphoma Paraneoplastic syndrome|
|Otologic disease||Cogan syndrome Ménière’s disease Sudden sensorineural hearing loss|
|Other||Cryoglobulinemia Lactate acidosis and stroke-like Episodes (MELAS) Marchiafava-Bignami disease Migraines Psychotic disorders|
|Suspected||One triad manifestation † One risk factor * Female 20-40 Years Within 1 year of pregnancy Characteristic MRI findings Corpus callosum lesions Periventricular lesions|
|Incomplete||Two triad manifestations †|
|Complete||Three triad manifestations †|