Risk factors for severe hearing loss in Susac syndrome: A national cohort study

Abstract Background Nonreversible hearing loss (HL) is the main sequelae of Susac syndrome (SuS). We aimed to identify risk factors for HL in SuS. Methods The CARESS study is a prospective national cohort study that started in December 2011, including all consecutive patients with SuS referred to the French reference center. The CARESS study was designed with a follow‐up including fundoscopy, audiometry, and brain magnetic resonance imaging at 1, 3, 6, and 12 months after diagnosis and then annually for 5 years. The primary outcome was the occurrence at last follow‐up of severe HL defined as the loss of 70 dB in at least one ear on audiometry or the need for hearing aids. Results Thirty‐six patients (female 66.7%, median age 37.5 [range 24.5–42.5] years) included in the clinical study were analyzed for the primary outcome. Thirty‐three patients (91.7%) had cochleovestibular involvement at SuS diagnosis including HL >20 dB in at least one ear in 25 cases. At diagnosis, 32 (88.9%), 11 (30.6%), and 7 (19.4%) patients had received steroids, intravenous immunoglobulin, and/or immunosuppressive (IS) drugs, respectively. After a median follow‐up of 51.8 [range 29.2–77.6] months, 19 patients (52.8%) experienced severe HL that occurred a median of 13 [range 1.5–29.5] months after diagnosis. Multivariable analysis showed that the odds of severe HL were lower in patients who received IS drugs at diagnosis (OR 0.15, 95% CI 0.01–1.07, p = 0.058). Conclusions Severe HL in SuS is associated with the absence of IS drugs given at diagnosis. Our findings support the systematic use of IS drugs in SuS.


INTRODUC TI ON
Susac syndrome (SuS) is a rare disease affecting mainly young women and characterized by an occlusive microvessel disease limited to the brain, retina, and inner ear [1][2][3], although spinal cord and skin involvement have been reported [4].The pathophysiology is not fully elucidated [5] but recent advances support the hypothesis that SuS is an autoimmune endotheliopathy affecting the cerebral, retinal, and cochlear small vessels [6].SuS is recognized in the presence of the pathognomonic triad associating: (i) subacute encephalopathy with corpus callosum lesions on brain magnetic resonance imaging (MRI); (ii) eye involvement with occlusions of the branches of the central artery of the retina; and (iii) cochleovestibular damage with hearing loss (HL) predominating at low frequencies on audiometry [7].Nonreversible HL is the main long-term damage of SuS found in about 50% of patients [8,9] and might require hearing aids [10,11].There are no known predictive factors for poor outcomes.
We herein leverage the prospective national cohort study (CARESS study) to identify risk factors for severe HL in SuS.

Primary outcome
The primary outcome was the occurrence of severe HL at last follow-up.Severe HL was defined as the loss of 70 dB in at least one ear on audiometry or the need for hearing aids.

Standard protocol approvals, registrations, and patient consents
The CARESS study has been approved by the Committee for the Protection of Persons (CPP, Ile de France 1, Paris, France; IRB00008522).All patients signed informed consent.Detailed inclusion and exclusion criteria for the CARESS study are available on the Clini calTr ials.gov portal (Identifier: NCT01481662).

Statistical analysis
Continuous variables are expressed as median [1st quartile (Q1)-3rd quartile (Q3)].Categorical variables are expressed as frequencies and percentages.Data were compared using chi-square test (or Fisher test) for dichotomous variables and Mann-Whitney test for continuous variables.To determine which characteristics were associated with the primary outcome, we performed univariate and multivariable logistic regression procedures calculating odds ratios (ORs) and their 95% confidence intervals (95% CIs) using the Firth's penalized method for small samples [12].Clinically relevant variables associated with the primary outcome in univariate analysis with a p-value < 0.05 were considered for the multivariable analysis.Statistical analysis was performed using R® software (Version 1.0.153).A p-value < 0.05 was considered statistically significant.

Characteristics of patients
Fifty-seven patients from 20 different centers in France with SuS were included in the CARESS (Clini calTr ials.gov Identifier NCT01481662) study.Among them, 21 patients were excluded from the analysis because of missing audiometry (n = 20) or cophosis prior to SuS (n = 1).Overall, 36 SuS patients were analyzed for the primary outcome (Figure S1, flowchart).Twenty-four patients (66.7%) were women and the median age at diagnosis was 37.5 [range 24.5-42.5]years.The triad was complete in 31 (86.1%)patients at disease onset, and 3 (8.3%)additional patients completed the triad during disease course.At diagnosis, all but 4 patients (88.9%) received steroids including high-dose intravenous pulses in 93.8% (n = 30/32) of cases.Steroids were associated with intravenous immunoglobulin (IVIG) therapy (n = 11) and/or immunosuppressive (IS) drugs (cyclophosphamide n = 5, azathioprine n = 1, or methotrexate n = 1).Antiplatelet therapy was given in all but two patients (94.4%).

Risk factors associated with severe hearing loss
The primary outcome was evaluated after a median follow-up of    2).

DISCUSS ION
In Severe HL defined as the loss of 70 dB in at least one ear on audiometry or the need for hearing aids at last follow-up.
b Multivariable analysis.
c On first MRI available (n = 24) performed during the 3 months following the onset of symptoms in all but one patient.
All patients participated in the national multicenter CARESS (Phenotypic and Etiological Characterization of Susac Syndrome -National Clinical Research Hospital Program) study.The CARESS study is an ongoing cohort study that started in December 2011 and included all consecutive case of patients with SuS referred to the French reference center (Department of Internal Medicine, Bichat Claude Bernard Hospital, Paris).Inclusion criteria were a minimal age of 18 years and SuS defined either by (i) the triad of encephalopathy with typical brain MRI abnormalities, cochleovestibular damage including unilateral or bilateral sensorineural HL on the audiometry and multiple occlusions of retinal central artery branches, and/or retinal vasculitis on retinal fluorescein angiography or (ii) at least two of the three aforementioned criteria without any alternative diagnosis, as required by current diagnostic criteria [7].

51. 8 [
range 29.2-77.6]months while SuS was in remission for more than 12 months in all but one patient with no later relapse.Although HL slightly improved in 11 patients (median increase of 22.5 [range TA B L E 1 Characteristics of Susac syndrome patients (N = 36).
Abbreviations: dB, decibel; DWI-HL, hyperintense lesions on diffusion-weighted imaging; IS, immunosuppressive; IVIG, intravenous immunoglobulin; MRI, magnetic resonance imaging.a On first MRI available (n = 24) performed during the 3 months following the onset of symptoms in all but one patient.
2011, a national clinical-based cohort (CARESS study) was set up in order to better characterize the epidemiological, clinical, and etiological features of SuS.In the current study, all CARESS patients for TA B L E 2 Risk factors associated with severe hearing loss in Susac syndrome patients.Quantitative variables are expressed as median [1st quartile-3rd quartile].Qualitative variables are expressed as number (percentage)