Vascular involvement in the pathophysiology of idiopathic sudden sensorineural hearing loss (iSSNHL) has been previously proposed. The objective of this study was to perform a systematic review of the current literature and conduct meta-analyses to evaluate associations between cardiovascular risk factors, cerebral small vessel disease, and subsequent stroke after presentation with iSSNHL. Three systematic literature reviews and meta-analyses were conducted using PubMed, Embase, and CINAHL. All studies investigating associations between iSSNHL and the cardiovascular risk factors: body mass index (BMI), diabetes mellitus, hyperlipidemia, hypertension, medical history of myocardial infarction (MI), smoking, the degree of white matter hyperintensities, and incidence of stroke were included. Adhering to the PRISMA guidelines, two independent reviewers reviewed the articles and assessed risk of bias. The cardiovascular risk factors of abnormal BMI, diabetes, hypertension, total cholesterol, low-density lipoprotein cholesterol, and a medical history of MI were significantly associated with iSSNHL. The adjusted hazard ratio of a higher degree of white matter hyperintensities was 0.70 (95% CI 0.44, 1.12). Patients with iSSNHL showed a higher risk of stroke compared to controls, with hazard ratios ranging from 1.22 up to 4.08. Several cardiovascular risk factors are more frequently present in patients with iSSNHL than in the general population. The degree of white matter hyperintensities does not appear to be increased in patients with iSSNHL, while the risk of stroke following ISSNHL is increased. Prospective studies with larger study populations are needed to confirm the associations between generalized cardiovascular disease and iSSNHL and to assess whether these patients benefit from cardiovascular risk management to prevent future cardiovascular and cerebrovascular disease.

Sudden hearing loss is an otologic emergency that is defined by acute hearing loss of at least 30 dB over 3 contiguous frequencies occurring within 72 h [Chandrasekhar et al., 2019]. The incidence of sudden deafness is described to be 11 up to 77 per 100,000 subjects [Chandrasekhar et al., 2019]. Various theories on the underlying pathophysiology of sudden deafness have been suggested, including infectious, auto-immune, or metabolic involvement, though the exact cause of sudden deafness remains unknown in the majority of cases [Chau et al., 2010]. Recently, a vascular hypothesis of origin has gained considerable attention. Since hearing loss is the sole manifestation in 0.6 up to 3% of patients with a posterior circulation cerebral infarction and in 8 up to 31% hearing loss is prodromal to neurological symptoms [Kim and Lee 2017], idiopathic sudden sensorineural hearing loss (iSSNHL) might be an indicator of future stroke and thus may warrant adequate cardiovascular risk management.

Literature in recent years has focused on correlations between iSSNHL and general cardiovascular disease. Lin et al. summarized articles investigating several risk factors for developing iSSNHL in 2011 [Lin et al., 2012]. Several other case-controlled studies followed that either supported or contradicted their results [Huang et al., 1993; Chang et al., 2013; Ciorba et al., 2015; Chou et al., 2018; Kim et al., 2018; Lammers et al., 2020].

Cardiovascular risk factors are known to cause arteriosclerosis, which could result in cerebral small vessel disease, visible on magnetic resonance imaging (MRI) as white matter hyperintensities (WMH). The presence of white matter hyperintensities alone increases the risk of future stroke [Wardlaw et al., 2015]. With this systematic review and corresponding meta-analyses, we provide a comprehensive overview of the scientific evidence regarding the association between iSSNHL and generalized cardiovascular disease. We investigated cardiovascular risk factors for developing iSSNHL, the presence of white matter hyperintensities in patients with iSSNHL, and the subsequent risk of stroke after experiencing iSSNHL.

These systematic reviews and meta-analyses were performed and reported according to the Preferred Reporting Item for Systematic Reviews and Meta-analyses (PRISMA) guideline.

Literature Search

A literature search was performed using the medical databases Embase, Pubmed, and CINAHL, from inception up to May 18, 2022, to identify studies that address the following research questions. (1) Do the cardiovascular risk factors of increased body mass index (BMI), diabetes, hyperlipidemia, hypertension, and a medical history of myocardial infarction (MI) raise the risk of developing iSSNHL? (2) Is there more cerebral small vessel disease visible on MRI in patients with iSSNHL compared to controls? (3) Do patients with iSSNHL have an increased risk to develop a stroke compared to controls? The search was repeated on November 08, 2022, just before completion of the article in order to update the search results.

Article selection was performed using the online research tool Rayyan (Rayyan Systems Inc., Cambridge, MA, USA). After detection and deletion of duplicates, all articles were screened for eligibility based on title and abstract by two authors independently from each other, either F.O. and T.B. or F.O. and R.L. We included only clinical research papers that were published in English or Dutch. Case reports with less than 5 included cases and literature reviews were excluded.

Research Question 1: Risk Factors of iSSNHL

The search terms “risk factor” and “sudden sensorineural hearing loss,” including their synonyms, were adapted according to the syntax of each specific database. Details of the search strategies used and their results are displayed in online supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000530686).

Articles that did not investigate the presence of any of the cardiovascular risk factors of BMI, diabetes mellitus (DM), hyperlipidemia, hypertension, medical history of MI, or smoking were excluded. The remaining articles were then evaluated by full text. Articles that did not compare the prevalence of these risk factors with a control cohort or nationwide prevalence estimates were excluded (shown in Fig. 1a).

Fig. 1.

The inclusion process for the systematic reviews following the PRISMA 2020 updated guideline for reporting systematic reviews. a Flow diagram of the inclusion process or articles investigating the cardiovascular risk factors for SSNHL. b Flow diagram of the inclusion process of articles investigating the degree of white matter hyperintensities in patients with SSNHL. c Flow diagram of the inclusion process of articles investigating the risk of stroke following SSNHL. n, number; SSNHL, sudden sensorineural hearing loss. * Literature search through 3 separate databases. ** Articles were excluded based on title and abstract using the publicly available research tool Rayyan.ai.

Fig. 1.

The inclusion process for the systematic reviews following the PRISMA 2020 updated guideline for reporting systematic reviews. a Flow diagram of the inclusion process or articles investigating the cardiovascular risk factors for SSNHL. b Flow diagram of the inclusion process of articles investigating the degree of white matter hyperintensities in patients with SSNHL. c Flow diagram of the inclusion process of articles investigating the risk of stroke following SSNHL. n, number; SSNHL, sudden sensorineural hearing loss. * Literature search through 3 separate databases. ** Articles were excluded based on title and abstract using the publicly available research tool Rayyan.ai.

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Research Question 2: Cerebral Small Vessel Disease in iSSNHL

The terms “white matter hyperintensities,” “silent brain infarctions,” and “idiopathic sudden sensorineural hearing loss,” including their synonyms, were adapted according to the syntax of each database. Online supplementary Table 1 shows the search strategy used for identification of articles in the three databases. Articles that did not study cerebral small vessel disease and sudden deafness were excluded based on title and abstract. The remaining articles were evaluated by full-text reading. Articles that included non-idiopathic cases of sudden sensorineural hearing loss and articles describing a pediatric population were excluded.

Research Question 3: Risk of Stroke after iSSNHL

The search terms “sudden sensorineural hearing loss” and “cerebrovascular disease,” including their synonyms, were adapted according to the syntax of each of the three databases used (see online suppl. Table 1). Articles that did not investigate the association between hearing loss and stroke were excluded. The remaining articles were then evaluated by full-text reading. Articles that investigated the risk of iSSNHL after experiencing stroke were excluded. Also, articles that investigated age-related hearing loss, as opposed to sudden sensorineural hearing loss, were excluded. The inclusion process is described in a PRISMA flow diagram (shown in Fig. 1c).

Risk of Bias Assessment

Risk of bias assessment was performed using the Joanna Briggs Institute risk of bias assessment tool for either case-control studies or cohort studies, whichever was appropriate [Joanna Briggs Institute 2020]. The risk of bias was assessed by evaluation of the equality of the study population and identification of cases, the confounding factors and handling thereof, the outcomes, the duration of follow-up, and the statistical analysis used. Two authors independently assessed the risk of bias; discrepancies were discussed until consensus was reached.

Statistical Analysis

Meta-analyses were performed for each of the identified cardiovascular risk factors and the degree of WMH present on MRI using Review Manager version 5.4 (The Cochrane Collaboration, London, UK). Odds ratios for dichotomous values and the mean difference for continuous values including their confidence intervals were calculated using a fixed effects model. Proportional odds ratios for the ordinal outcome, the Fazekas score, were analyzed using a dichotomous model since establishing the clinical meaning of the summary statistic of an ordinal model would be challenging. We used a cut-off value in the dichotomous model of 3, since normal Fazekas scores would range from zero to 2 with increasing age [Leeuw et al., 2001; Zhuang et al., 2018].

Heterogeneity is defined as a proportion of observed variance that reflects real differences in effect size. The common metric for measuring the magnitude of the between-study heterogeneity is I2. In case of heterogenetic data, a sequential algorithm sensitivity analysis was performed, described in detail by Patsopoulos [Patsopoulos et al., 2008]. We accepted an analysis to be reliable in terms of heterogeneity when I2 <50%. Statistical significance was defined as a two-tailed p value <0.05.

Research Question 1: Risk Factors of iSSNHL

Of the total of 6,641 articles, full text was assessed for 62. Repetition of the search strategy just before completion of the article resulted in another eligible study [Park et al., 2022]. A total of 33 articles met the inclusion criteria; 21 of these investigated total cholesterol values, 18 investigated HDL-cholesterol, 19 investigated low-density lipoprotein (LDL)-cholesterol, 13 investigated hypertension, 12 investigated DM, 14 investigated smoking, 5 investigated history of MI, and 9 investigated BMI. An overview of the characteristics and results of each included study can be found in Table 1.

Table 1.

Study characteristics of the articles in the cardiovascular risk factor analysis

AuthorYearPopulationAge (mean±SD)Risk factorDefinitionResultsOR (p value)
Aimoni 2010 SSNHL: 141Controls: 271 SSNHL: 54.6±15.8Controls: 55.0±15.8 TC Absolute serum total cholesterol value SSNHL 227.2 mg/dL (SD 40.0)Controls 214.4 mg/dL (SD 40.8) 2.17 (0.006) 
 Diabetes 1. History of physician-diagnosed DM2. Taking antidiabetic medicationFasting blood glucose >126 mg/dL SSNHL: 15.6%Controls: 8.5% 2.07 (0.039) 
Hypertension 1. History of physician-diagnosed HTNTaking antihypertensive drugs SSNHL: 33.3%Controls: 33.2% 1.02 (0.945) 
Smoking Former or current cigarette smoking SSNHL: 55.8% (26 former, 46 current)Controls: 52.0% (former 67, current 77) 1.10 (0.709) 
Ballesteros 2009 SSNHL: 99Controls: 150 SSNHL: 51.7±16.4Controls: 49.9±13.6 BMI Weight/height2 = kg/m2 SSNHL: 26.2 (SD 4.02)Controls: n.d. n.d. 
 TC Absolute serum total cholesterol value SSNHL: 208.73 mg/dL (SD 48.92)Controls: n.d. n.d. 
HDL-C Serum HDL-cholesterol SSNHL: 57.24 mg/dL (SD 19.06)Controls: n.d. n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 131.29 mg/dL (SD 34.23)Controls: n.d. n.d. 
Diabetes n.d. SSNHL: 7%Controls: 3% n.d. 
Hypertension n.d. SSNHL: 21.1%Controls: 12.% n.d. 
MI MI and other acute coronary syndromes SSNHL: 8.8%Controls: 2.5% n.d. 
Smoking n.d. SSNHL: 30.5%Controls: 22% n.d. 
Cadoni 2007 SSNHL: 30Controls: 34 SSNHL: 45.6 (range 23–72)Controls: 49.3 (range 23–77) TC Absolute serum total cholesterolHypercholesterolemia: total cholesterol >200 mg/dL SSNHL: 200 mg/dL (SD38.95)Controls: 175 mg/dL (SD 26.51) 6.88 (0.0007) 
 LDL-C Serum LDL-cholesterol Hypercholesterolemia: LDL-cholesterol >130 mg/dL SSNHL: 128 mg/dL (SD 35.89)Controls: 110.7 mg/dL (SD 31.34) 3.25 (0.0298) 
Cadoni 2010 SSNHL: 43Controls: 43 SSNHL: 50±14Controls: 43±11 TC Absolute serum total cholesterolHypercholesterolemia: total cholesterol >200 mg/dL SSNHL: 213 mg/dL (SD 44)Controls: 175 mg/dL (SD21.4) 5.17 (p < 0.001) 
 LDL-C Serum LDL-cholesterol LDL-cholesterol >130 mg/dL SSNHL: 131 mg/dL (SD 32.30)Controls: 110 mg/dL (SD 22.66) 5.20 (0.024) 
Capaccio 2007 SSNHL: 100Controls: 200 SSNHL: 48.1±14.6Controls: n.d. TC Absolute serum total cholesterol value SSNHL: 224 mg/dL (SD 32.6)Controls: 185.8 mg/dL (SD 18.5) 1.06 (p = n.d.) 
Chang 2014 SSNHL + Hch: 73,957SSNHL – Hch: 73,957 n.d. TC HCh: ICD-9 code 272.0–272.1 (pure hypercholesterolemia, pure hypertriglycerimia) SSNHL in + HCh cohort: 503SSNHL in – HCh cohort: 308 1.62 (p < 0.01)* 
Chien 2015 SSNHL: 181Controls: 181 SSNHL: 48.7±14.1Controls: 46.4±11.0 HDL-C Serum HDL-cholesterol SSNHL: 49 mg/dL (84–136)Controls: 53 mg/dL (46–63) n.d. 
 Diabetes Taking antidiabetic medication SSNHL: 20 (11.0%)Controls: 13 (7.2%) n.d. 
Hypertension Taking antihypertensive drugs SSNHL: 71 (39.2%)#Controls: 43 (23.8%) n.d. 
Smoking n.d. SSNHL: 28 (15.5%)Controls: 26 (14.4%) n.d. 
Ciccone 2012 SSNHL: 29Controls: 29 SSNHL: 54±15Controls: 46±16 BMI Weight/height2 = kg/m2 SSNHL:.28 (SD 5)Controls: 26 (SD 6) n.d. 
 TC Absolute serum total cholesterol SSNHL: 188 mg/dL (SD 33)Controls: 171 mg/dL (SD 29) 0.977 (0.317) 
HDL-C Serum HDL-cholesterol SSNHL: 48 mg/dL (SD10)Controls: 49 mg/dL (SD 10) 1.013 (0.759) 
LDL-C Serum LDL-cholesterol SSNHL: 118 mg/dL (SD 27)Controls: 101 mg/dL (SD 28) 1.046 (0.098) 
Diabetes Fasting blood glucose level >126 mg/dL or taking antidiabetic medication SSNHL: 3 (10%)Controls: 5 (17%) n.d. 
Hypertension Systolic blood pressure>140 mm Hg and/or diastolic pressure >90 mm Hg or taking antihypertensive drugs SSNHL: 17 (58%)Controls: 12 (41%) n.d. 
Smoking Regularly smoked at least 5 cigarettes/day during the previous 3 months or had stopped smoking less than 1 year before start study SSNHL: 7 (24)Controls: 4 (14) n.d. 
Elden 2012 SSNHL: 52Controls: 50 SSNHL: 50.0±23.50Controls: 42.50±16.25 BMI Weight/height2 = kg/m2 SSNHL: 26.48±4.71Controls: 27.46±4.31 n.d. 
 TC n.d. SSNHL: 187 mg/dL (51)Controls: 192.50 (29.50) n.d. 
HDL-C n.d. SSNHL: 43.56 mg/dL (SD 6.59)#Controls: 46.58 mg/dL (SD 4.63) n.d. 
LDL-C n.d. SSNHL: 123.17 mg/dL (SD 29.40)Controls: 129 mg/dL (SD 27.49) n.d. 
Hypertension Systolic and diastolic blood pressure in mm Hg SystSSNHL: 127.60 mm Hg (SD 18.46)#Controls: 111.6 mm Hg (SD 15.95)DiastSSNHL: 78.46 mm Hg (SD 12.30)Controls: 72 mm Hg (SD 12.45) n.d. 
Smoking n.d. SSNHL: 19 (36.5%)Controls: 18 (36%) n.d. 
Fasano 2017 SSNHL: 131Controls: 77 SSNHL: 54Controls: 52.5 TC Absolute serum total cholesterol SSNHL: 186.9 mg/dL (SD43.2)Controls: 194.4 mg/dL (SD 28.9) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 55.7 mg/dL (SD1.27)Controls: 58.4 mg/dL (SD 12.0) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 112.5 mg/dL (SD 36.3)#Controls: 123.2 mg/dL (SD 27.8) n.d. 
Jalali 2020 SSNHL:81Controls: 243 SSNHL: 45.2±14.6Controls: 44.9±14.3 TC Absolute serum total cholesterol SSNHL: 176 mg/dL (SD 33)Controls: 178.4 mg/dL (SD26.4) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 43.0 mg/dL (SD 7.7)#Controls: 46.5 mg/dL (SD 8.0) 2.99 (<0.001) 
LDL-C Serum LDL-cholesterol SSNHL: 99.0 mg/dL (SD 24.7)Controls: 103.3 mg/dL (SD 22.0) n.d. 
Diabetes 1. History of physician-diagnosed DM2. Taking antidiabetic medicationFasting blood glucose >126 mg/dL SSNHL: 9 (11.1%)Controls: 13 (5.3%) n.d. 
Hypertension 1. History of physician-diagnosed HTN2. Taking antihypertensive drugs SSNHL: 12 (14.8%)#Controls: 17 (7.0%) 2.64 (0.029) 
Smoking n.d. SSNHL: 13 (16.0%)Controls: 40 (16.5%) 0.96 (0.917) 
Kaneva 2019 SSNHL: 27Controls: 24 SSNHL: 37.7 (27–51)Controls: 32.3 (25–47) TC Absolute serum total cholesterol SSNHL: 4.26 mmol/L (3.84, 5.00)Controls: 4.09 mmol/L (3.61, 4.63) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 1.36 mmol/L (0.93, 1.51)Controls: 1.39 mmol/L (91.12, 1.80) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 2.55 mmol/L (1.87, 3.18) Controls: 1.92 mmol/L (1.34, 2.91) n.d. 
Lee 2015 SSNHL: 324Control: 972 SSNHL: 49.6±16.5Controls: 48.8±14.7 BMI Weight/height2 = kg/m2BMI >27.5 kg/m2 SSNHL: 23.91 kg/m2 (SD 3.29)Controls: 23.30 kg/m2 (SD 3.21) n.d. 
 TC Absolute serum total cholesterol SSNHL: 192.92 mg/dL (SD 37.9)Controls: 183.46 mg/dL (SD 34.89) n.d. 
HDL-C Serum HDL-cholesterol SSNHL: 57.62 mg/dL (SD 15.3)#Controls: 54.34 mg/dL (SD 13.05) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 110.64 mg/dL (SD 35.61)Controls: 107.21 mg/dL (SD 31.25) n.d. 
Li 2021 SSNHL: 2288Controls: 2288 SSNHL: 49.7±15.3Controls: 51.0±13.4 TC Absolute serum total cholesterol SSNHL: 5.24 mmol/L (SD 1.16)Controls: 5.29 mmol/L (SD1.04)# 0.96 (0.107) 
 HDL-C Serum HDL-cholesterol SSNHL: 1.35 mmol/L (SD 0.34)Controls: 1.40 mmol/L (SD 0.35)# 0.67 (<0.001) 
LDL- Serum LDL-cholesterol SSHNL: 2.96 mmol/L (SD 0.93)Controls: 2.90 mmol/L (SD 0.81) 1.10 (0.006) 
Lin 2012 Diabetes: 26,556No diabetes: 26,556 n.d. Diabetes ICD-9 code 250.xx and A-181 Diabetes: 245 SSNHL (0.92%)No diabetes: 153 SSNHL (0.58%) 1.54 (<0.0001)* 
Marcucci 2005 SSNHL: 155Controls: 155 SSNHL: 55 (range 19–79)Controls: 54 (range 19–78) TC Total cholesterol >200 mg/dL SSNHL: 52 (33.5%)Controls: 11 (7.0%) 19 (<0.0001) 
 Hypertension Systolic blood pressure >140 mm Hg and/or diastolic pressure >90 mm Hg SSNHL: 25 (16.1%)Controls: 18 (11.6%) 0.7 
Smoking n.d. SSNHL: 21 (13.5%)Controls: 23 (14.8%) 0.9 
Mohammed 2014 SSNHL: 22Controls: 55 SSNHL: 44.7±11.3Controls: 41.7±11.1 TC Absolute serum total cholesterol SSNHL: 190.5 mg/dL (SD 43.2)#Controls: 145.1 mg/dL (SD 31.5) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 48.3 mg/dL (SD 8.75)Controls: 49.7 mg/dL (SD 8.77) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 118.6 mg/dL (SD 36.0)#Controls: 81.8 mg/dL (SD 34.2) n.d. 
Mosnier 2011 SSNHL: 96Controls: 179 SSNHL: 50.0Controls: n.d BMI Weight/height2 = kg/m2 SSNHL: 25.2 kg/m2 (SD 2.6)Controls: 24.7 kg/m2 (SD 0.4) n.d. 
 Hypertension Systolic and diastolic blood pressure in mm Hg SystSSNHL: 130 mm Hg (SD 1.7)#Controls: 124 mm Hg (SD 1.1)DiastSSNHL: 74 mm Hg (SD 1.2)Controls: 76 mm Hg (SD 0.9) Syst. 1.04Diast. n.d. 
MI Coronary artery insufficiency OR Myocardial infarction OR Stroke OR TIA OR intermittent claudication SSNHL 10.8%#Controls: 3.4% 3.94 
Nakamura 2001 SSNHL: 154Controls: 16,043 SSNHL: 49.7±14.1Controls: 52.5±10.1 Smoking Current cigarette smoking SSNHL: 49 (31.8)Controls: 5,261 (32.8) n.d. 
Nakashima 1997 SSNHL: 109Controls: 109 SSNHL: 44.2±16.2Controls: 43.8±15.9 Diabetes n.d. SSNHL: 6 (5.5%)Controls: 5 (4.6%) 1.25 
 Hypertension n.d. SSNHL: 23 (21.1)Controls: 13 (11.9) 2.00 (0.07) 
Smoking Current cigarette smoking SSNHL: 29 (26.9%)Controls: 31 (29.0) 1.12 
Oiticica 2010 SSNHL: 166Controls: Brazilian population n.d SSNHL: 46.5±16.2Controls: 44.7±15.7 TC Total cholesterol >200 mg/dL SSNHL: 79 (50.3%)Controls: 40% n.d. 
 LDL-C LDL-cholesterol >160 mg/dL SSNHL: 32 (20.5)Controls: 30 (20.3) n.d. 
Oreskovic 2010 SSNHL: 54Controls: 55 SSNHL: 55±14Controls: 40±15 TC Absolute serum total cholesterol SSNHL: 5.9 mmol/L (SD 1.1)#Controls: 5 mmol/L (SD 1.0) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 1.3 mmol/L (0.6–3.5)Controls: 1.3 mmol/L (0.8–2.4) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 3.7 mmol/L (SD 0.9)#Controls: 2.9 mmol/L (SD 0.8) n.d. 
Park 2022 SSNHL: 239Controls: 239 SSNHL: 52.3±16.3Controls: 54.5±15.0 Diabetes ≥100 mg/dL high blood sugar-fasting glucose SSNHL: 42 (17.6%)#Controls: 27 (11.3) n.d. 
 Hypertension Systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85mmhg SSNHL: 64 (26.9%)Controls: 47 (19.7%) n.d 
HDL-C Serum HDL-cholesterol SSNHL: 52.2 (SD 11.5)Controls: 50.4 (SD 12.1) n.d. 
Passamonti 2015 SSNHL: 118Controls: 415 SSNHL: 48 (range 34–57)Controls 41 (32–52) Diabetes Fasting plasma glucose levels >126 mg/dL SSNHL: 2 (2%)Controls: 4 (1%) n.d. 
 Hypertension Systolic blood pressure >140 mm Hg or diastolic blood pressure >90mmhg SSNHL: 29 (24%)Controls: 42 (10%) n.d. 
Smoking Current cigarette smoking SSNHL: 37 (31%)Controls: 91 (22%) n.d. 
Quaranta 2008 SSNHL: 37Controls: 47 SSNHL: 46.3 (range 13–79)Controls: 44.8 (range 16–70) TC Absolute serum total cholesterol SSNHL: 183.94 mg/dL (SD 50.22)Controls: 186.8 mg/dL (SD 42.06) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 52.37 mg/dL (SD 17.61)Controls: 43.73 mg/dL (SD 548.19) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 119.06 mg/dL (SD 39.74)Controls: 112.46 mg/dL (SD 36.32) n.d. 
Rajati 2016 SSNHL: 30Controls: 30 SSNHL: 45±12.7Controls: 45±11.8 BMI n.d. SSNHL: 25.32 (SD 4.4)Controls: 26.49 (SD 4.9) n.d. 
 TC Absolute serum total cholesterol SSNHL: 207.8 mg/dL (SD 50.8)Controls: 196.6 mg/dL (SD 46.7) n.d. 
HDL-C Serum HDL-cholesterol SSNHL: 51.9 mg/dL (SD 9.6)Controls: 47.5 mg/dL (SD 13.5) n.d. 
3LDL-C Serum LDL-cholesterol SSNHL: 135.4 mg/dL (SD 37.3)Controls: 124.6 mg/dL (SD 38.6) n.d. 
Rinaldi 2020 SSNHL: 39Controls: 44 SSNHL: 53.70±13.73Controls: 48.43±11.13 BMI Weight/height2 = kg/m2 SSNHL:26.80 kg/m2 (SD 3.44)#Controls: 25.23 kg/m2 (SD 3.52) n.d. 
 TC Absolute serum total cholesterol SSNHL: 193.69 mg/dL (SD 37.27)Controls: 188.89 mg/dL (SD 38.44) n.d. 
HDL-C Serum HDL-cholesterol SSNHL: 56.08 mg/dL (13.19)Controls: 54.61 mg/dL (SD 13.33) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 118 mg/dL (SD 33.80)Controls: 113.87 mg/dL (SD 32.28) n.d. 
Smoking Regularly smoked at least 5 cigarettes/day during the previous 3 months or had stopped smoking less than 1 year before start study SSNHL: 11 (18.21%)Controls: 17 (38.64%) n.d. 
Rudack 2006 SSNHL: 142Controls: 84 SSNHL: 51.2±17.2Controls: 49.8±13.6 TC Absolute serum total cholesterol SSNHL: 215 mg/dL (SD 32)Controls: 227 mg/dL (SD 38) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 61 mg/dL (SD 16)Controls: 54 mg/dL (SD 14) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 114 mg/dL (SD 29)Controls: 124 mg/dL (SD 29) n.d. 
Diabetes History of physician-diagnosed DM SSNHL: 8 (5.6%)Controls: 2 (2.4%) n.d. 
Hypertension Systolic blood pressure >140 mm Hg or diastolic blood pressure >90mmhg at blood withdrawal SSNHL: 20 (14.1%)Controls: 20 (23.8%) n.d. 
MI History of physician-diagnosed MI SSNHL: 5 (3.5%)Controls: 2 (2.4%) n.d. 
Smoking Current cigarette smoking at blood withdrawal SSNHL: 80 (56.3%)#Controls: 16 (19.0%) n.d. 
Schulz 2014 SSNHL: 23Controls: 10 SSNHL: 64 (30–78)Controls: 58.5 (19–75) BMI Weight/height2 = kg/m2 SSNHL: 27.1 (21.3, 34.6)∞Controls: 26.1 (22.8, 37.6) n.d. 
 Diabetes Taking antidiabetic medication OR fasting blood glucose >126 mg/dL SSNHL 2 (8.7%)Controls: 3 (30%) n.d. 
Smoking n.d. SSNHL: zero (0%)Controls: 2 (20% n.d. 
Suckfull 2002 SSNHL: 53Controls: 53 SSNHL: 53.7±17.9Controls: 53.5±17.7 TC Absolute serum total cholesterol SSNHL: 217 mg/dL (SD 52)Controls: 214 mg/dL (SD 33) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 56 mg/dL (SD 16)Controls: 57 mg/dL (SD 33) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 139 mg/dL (SD 40)Controls: 132 mg/dL (SD 30) n.d. 
Umesawa 2017 SSNHL: 3,073Controls: 7,641 SSNHL men: 55.9±15.1SSSNHL women: 55.7±15.3 BMI Weight/height2 = kg/m2BMI >25 kg/m2 SSNHL men: 23.9 kg/m2Control men: n.dSSNHL women: 23.0 kg/m2Control women: n.d n.d. 
 Diabetes 1. History of physician-diagnosed DM2. Taking antidiabetic medication SSNHL men: 21.9%Control men: n.dSSNHL women: 13.0%Control women: n.d n.d. 
MI History of heart disease assessed by questionnaire SSNHL men: 15.1%Control men: n.d.SSNHL women: 8.8%Control women: n.d. n.d. 
Smoking Consuming cigarettes daily SSNHL men: 38.0%Control men: n.d.SSNHL women: 12.2%Control women: n.d. n.d. 
Wang 2020 SSNHL: 324Controls: 972 SSNHL: 49.6±16.5Controls: 48.8±14.7 Hypertension n.d. SSNHL: 71 (21.91%)Controls: 175 (18%) 1.28 (0.1208) 
 MI History of coronary heart disease (n.f.s.) SSNHL: 6 (1.85%)Controls: 17 (1.75%) 1.06 (0.9033) 
Weng 2013 SSNHL: 250Controls: 250 SSNHL: 56.4 (range 15–84)Controls: n.d. TC Absolute serum total cholesterol SSNHL: 4.738 mmol/L (SD 1.021)Controls: 4.378 mmol/L (SD 0.937) 1.459 (<0.01) 
 HDL-C Serum HDL-cholesterol SSNHL: 1.432 mmol/L (SD 0.401)Controls: 1.459 mmol/L (SD 0.420) 0.849 (0.448) 
LDL-C Serum LDL-cholesterol SSNHL: 2.679 mmol/L (SD 0.856)Controls: 2.380 mmol/L (SD 0.723) 1.628 (<0.01) 
AuthorYearPopulationAge (mean±SD)Risk factorDefinitionResultsOR (p value)
Aimoni 2010 SSNHL: 141Controls: 271 SSNHL: 54.6±15.8Controls: 55.0±15.8 TC Absolute serum total cholesterol value SSNHL 227.2 mg/dL (SD 40.0)Controls 214.4 mg/dL (SD 40.8) 2.17 (0.006) 
 Diabetes 1. History of physician-diagnosed DM2. Taking antidiabetic medicationFasting blood glucose >126 mg/dL SSNHL: 15.6%Controls: 8.5% 2.07 (0.039) 
Hypertension 1. History of physician-diagnosed HTNTaking antihypertensive drugs SSNHL: 33.3%Controls: 33.2% 1.02 (0.945) 
Smoking Former or current cigarette smoking SSNHL: 55.8% (26 former, 46 current)Controls: 52.0% (former 67, current 77) 1.10 (0.709) 
Ballesteros 2009 SSNHL: 99Controls: 150 SSNHL: 51.7±16.4Controls: 49.9±13.6 BMI Weight/height2 = kg/m2 SSNHL: 26.2 (SD 4.02)Controls: n.d. n.d. 
 TC Absolute serum total cholesterol value SSNHL: 208.73 mg/dL (SD 48.92)Controls: n.d. n.d. 
HDL-C Serum HDL-cholesterol SSNHL: 57.24 mg/dL (SD 19.06)Controls: n.d. n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 131.29 mg/dL (SD 34.23)Controls: n.d. n.d. 
Diabetes n.d. SSNHL: 7%Controls: 3% n.d. 
Hypertension n.d. SSNHL: 21.1%Controls: 12.% n.d. 
MI MI and other acute coronary syndromes SSNHL: 8.8%Controls: 2.5% n.d. 
Smoking n.d. SSNHL: 30.5%Controls: 22% n.d. 
Cadoni 2007 SSNHL: 30Controls: 34 SSNHL: 45.6 (range 23–72)Controls: 49.3 (range 23–77) TC Absolute serum total cholesterolHypercholesterolemia: total cholesterol >200 mg/dL SSNHL: 200 mg/dL (SD38.95)Controls: 175 mg/dL (SD 26.51) 6.88 (0.0007) 
 LDL-C Serum LDL-cholesterol Hypercholesterolemia: LDL-cholesterol >130 mg/dL SSNHL: 128 mg/dL (SD 35.89)Controls: 110.7 mg/dL (SD 31.34) 3.25 (0.0298) 
Cadoni 2010 SSNHL: 43Controls: 43 SSNHL: 50±14Controls: 43±11 TC Absolute serum total cholesterolHypercholesterolemia: total cholesterol >200 mg/dL SSNHL: 213 mg/dL (SD 44)Controls: 175 mg/dL (SD21.4) 5.17 (p < 0.001) 
 LDL-C Serum LDL-cholesterol LDL-cholesterol >130 mg/dL SSNHL: 131 mg/dL (SD 32.30)Controls: 110 mg/dL (SD 22.66) 5.20 (0.024) 
Capaccio 2007 SSNHL: 100Controls: 200 SSNHL: 48.1±14.6Controls: n.d. TC Absolute serum total cholesterol value SSNHL: 224 mg/dL (SD 32.6)Controls: 185.8 mg/dL (SD 18.5) 1.06 (p = n.d.) 
Chang 2014 SSNHL + Hch: 73,957SSNHL – Hch: 73,957 n.d. TC HCh: ICD-9 code 272.0–272.1 (pure hypercholesterolemia, pure hypertriglycerimia) SSNHL in + HCh cohort: 503SSNHL in – HCh cohort: 308 1.62 (p < 0.01)* 
Chien 2015 SSNHL: 181Controls: 181 SSNHL: 48.7±14.1Controls: 46.4±11.0 HDL-C Serum HDL-cholesterol SSNHL: 49 mg/dL (84–136)Controls: 53 mg/dL (46–63) n.d. 
 Diabetes Taking antidiabetic medication SSNHL: 20 (11.0%)Controls: 13 (7.2%) n.d. 
Hypertension Taking antihypertensive drugs SSNHL: 71 (39.2%)#Controls: 43 (23.8%) n.d. 
Smoking n.d. SSNHL: 28 (15.5%)Controls: 26 (14.4%) n.d. 
Ciccone 2012 SSNHL: 29Controls: 29 SSNHL: 54±15Controls: 46±16 BMI Weight/height2 = kg/m2 SSNHL:.28 (SD 5)Controls: 26 (SD 6) n.d. 
 TC Absolute serum total cholesterol SSNHL: 188 mg/dL (SD 33)Controls: 171 mg/dL (SD 29) 0.977 (0.317) 
HDL-C Serum HDL-cholesterol SSNHL: 48 mg/dL (SD10)Controls: 49 mg/dL (SD 10) 1.013 (0.759) 
LDL-C Serum LDL-cholesterol SSNHL: 118 mg/dL (SD 27)Controls: 101 mg/dL (SD 28) 1.046 (0.098) 
Diabetes Fasting blood glucose level >126 mg/dL or taking antidiabetic medication SSNHL: 3 (10%)Controls: 5 (17%) n.d. 
Hypertension Systolic blood pressure>140 mm Hg and/or diastolic pressure >90 mm Hg or taking antihypertensive drugs SSNHL: 17 (58%)Controls: 12 (41%) n.d. 
Smoking Regularly smoked at least 5 cigarettes/day during the previous 3 months or had stopped smoking less than 1 year before start study SSNHL: 7 (24)Controls: 4 (14) n.d. 
Elden 2012 SSNHL: 52Controls: 50 SSNHL: 50.0±23.50Controls: 42.50±16.25 BMI Weight/height2 = kg/m2 SSNHL: 26.48±4.71Controls: 27.46±4.31 n.d. 
 TC n.d. SSNHL: 187 mg/dL (51)Controls: 192.50 (29.50) n.d. 
HDL-C n.d. SSNHL: 43.56 mg/dL (SD 6.59)#Controls: 46.58 mg/dL (SD 4.63) n.d. 
LDL-C n.d. SSNHL: 123.17 mg/dL (SD 29.40)Controls: 129 mg/dL (SD 27.49) n.d. 
Hypertension Systolic and diastolic blood pressure in mm Hg SystSSNHL: 127.60 mm Hg (SD 18.46)#Controls: 111.6 mm Hg (SD 15.95)DiastSSNHL: 78.46 mm Hg (SD 12.30)Controls: 72 mm Hg (SD 12.45) n.d. 
Smoking n.d. SSNHL: 19 (36.5%)Controls: 18 (36%) n.d. 
Fasano 2017 SSNHL: 131Controls: 77 SSNHL: 54Controls: 52.5 TC Absolute serum total cholesterol SSNHL: 186.9 mg/dL (SD43.2)Controls: 194.4 mg/dL (SD 28.9) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 55.7 mg/dL (SD1.27)Controls: 58.4 mg/dL (SD 12.0) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 112.5 mg/dL (SD 36.3)#Controls: 123.2 mg/dL (SD 27.8) n.d. 
Jalali 2020 SSNHL:81Controls: 243 SSNHL: 45.2±14.6Controls: 44.9±14.3 TC Absolute serum total cholesterol SSNHL: 176 mg/dL (SD 33)Controls: 178.4 mg/dL (SD26.4) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 43.0 mg/dL (SD 7.7)#Controls: 46.5 mg/dL (SD 8.0) 2.99 (<0.001) 
LDL-C Serum LDL-cholesterol SSNHL: 99.0 mg/dL (SD 24.7)Controls: 103.3 mg/dL (SD 22.0) n.d. 
Diabetes 1. History of physician-diagnosed DM2. Taking antidiabetic medicationFasting blood glucose >126 mg/dL SSNHL: 9 (11.1%)Controls: 13 (5.3%) n.d. 
Hypertension 1. History of physician-diagnosed HTN2. Taking antihypertensive drugs SSNHL: 12 (14.8%)#Controls: 17 (7.0%) 2.64 (0.029) 
Smoking n.d. SSNHL: 13 (16.0%)Controls: 40 (16.5%) 0.96 (0.917) 
Kaneva 2019 SSNHL: 27Controls: 24 SSNHL: 37.7 (27–51)Controls: 32.3 (25–47) TC Absolute serum total cholesterol SSNHL: 4.26 mmol/L (3.84, 5.00)Controls: 4.09 mmol/L (3.61, 4.63) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 1.36 mmol/L (0.93, 1.51)Controls: 1.39 mmol/L (91.12, 1.80) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 2.55 mmol/L (1.87, 3.18) Controls: 1.92 mmol/L (1.34, 2.91) n.d. 
Lee 2015 SSNHL: 324Control: 972 SSNHL: 49.6±16.5Controls: 48.8±14.7 BMI Weight/height2 = kg/m2BMI >27.5 kg/m2 SSNHL: 23.91 kg/m2 (SD 3.29)Controls: 23.30 kg/m2 (SD 3.21) n.d. 
 TC Absolute serum total cholesterol SSNHL: 192.92 mg/dL (SD 37.9)Controls: 183.46 mg/dL (SD 34.89) n.d. 
HDL-C Serum HDL-cholesterol SSNHL: 57.62 mg/dL (SD 15.3)#Controls: 54.34 mg/dL (SD 13.05) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 110.64 mg/dL (SD 35.61)Controls: 107.21 mg/dL (SD 31.25) n.d. 
Li 2021 SSNHL: 2288Controls: 2288 SSNHL: 49.7±15.3Controls: 51.0±13.4 TC Absolute serum total cholesterol SSNHL: 5.24 mmol/L (SD 1.16)Controls: 5.29 mmol/L (SD1.04)# 0.96 (0.107) 
 HDL-C Serum HDL-cholesterol SSNHL: 1.35 mmol/L (SD 0.34)Controls: 1.40 mmol/L (SD 0.35)# 0.67 (<0.001) 
LDL- Serum LDL-cholesterol SSHNL: 2.96 mmol/L (SD 0.93)Controls: 2.90 mmol/L (SD 0.81) 1.10 (0.006) 
Lin 2012 Diabetes: 26,556No diabetes: 26,556 n.d. Diabetes ICD-9 code 250.xx and A-181 Diabetes: 245 SSNHL (0.92%)No diabetes: 153 SSNHL (0.58%) 1.54 (<0.0001)* 
Marcucci 2005 SSNHL: 155Controls: 155 SSNHL: 55 (range 19–79)Controls: 54 (range 19–78) TC Total cholesterol >200 mg/dL SSNHL: 52 (33.5%)Controls: 11 (7.0%) 19 (<0.0001) 
 Hypertension Systolic blood pressure >140 mm Hg and/or diastolic pressure >90 mm Hg SSNHL: 25 (16.1%)Controls: 18 (11.6%) 0.7 
Smoking n.d. SSNHL: 21 (13.5%)Controls: 23 (14.8%) 0.9 
Mohammed 2014 SSNHL: 22Controls: 55 SSNHL: 44.7±11.3Controls: 41.7±11.1 TC Absolute serum total cholesterol SSNHL: 190.5 mg/dL (SD 43.2)#Controls: 145.1 mg/dL (SD 31.5) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 48.3 mg/dL (SD 8.75)Controls: 49.7 mg/dL (SD 8.77) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 118.6 mg/dL (SD 36.0)#Controls: 81.8 mg/dL (SD 34.2) n.d. 
Mosnier 2011 SSNHL: 96Controls: 179 SSNHL: 50.0Controls: n.d BMI Weight/height2 = kg/m2 SSNHL: 25.2 kg/m2 (SD 2.6)Controls: 24.7 kg/m2 (SD 0.4) n.d. 
 Hypertension Systolic and diastolic blood pressure in mm Hg SystSSNHL: 130 mm Hg (SD 1.7)#Controls: 124 mm Hg (SD 1.1)DiastSSNHL: 74 mm Hg (SD 1.2)Controls: 76 mm Hg (SD 0.9) Syst. 1.04Diast. n.d. 
MI Coronary artery insufficiency OR Myocardial infarction OR Stroke OR TIA OR intermittent claudication SSNHL 10.8%#Controls: 3.4% 3.94 
Nakamura 2001 SSNHL: 154Controls: 16,043 SSNHL: 49.7±14.1Controls: 52.5±10.1 Smoking Current cigarette smoking SSNHL: 49 (31.8)Controls: 5,261 (32.8) n.d. 
Nakashima 1997 SSNHL: 109Controls: 109 SSNHL: 44.2±16.2Controls: 43.8±15.9 Diabetes n.d. SSNHL: 6 (5.5%)Controls: 5 (4.6%) 1.25 
 Hypertension n.d. SSNHL: 23 (21.1)Controls: 13 (11.9) 2.00 (0.07) 
Smoking Current cigarette smoking SSNHL: 29 (26.9%)Controls: 31 (29.0) 1.12 
Oiticica 2010 SSNHL: 166Controls: Brazilian population n.d SSNHL: 46.5±16.2Controls: 44.7±15.7 TC Total cholesterol >200 mg/dL SSNHL: 79 (50.3%)Controls: 40% n.d. 
 LDL-C LDL-cholesterol >160 mg/dL SSNHL: 32 (20.5)Controls: 30 (20.3) n.d. 
Oreskovic 2010 SSNHL: 54Controls: 55 SSNHL: 55±14Controls: 40±15 TC Absolute serum total cholesterol SSNHL: 5.9 mmol/L (SD 1.1)#Controls: 5 mmol/L (SD 1.0) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 1.3 mmol/L (0.6–3.5)Controls: 1.3 mmol/L (0.8–2.4) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 3.7 mmol/L (SD 0.9)#Controls: 2.9 mmol/L (SD 0.8) n.d. 
Park 2022 SSNHL: 239Controls: 239 SSNHL: 52.3±16.3Controls: 54.5±15.0 Diabetes ≥100 mg/dL high blood sugar-fasting glucose SSNHL: 42 (17.6%)#Controls: 27 (11.3) n.d. 
 Hypertension Systolic blood pressure ≥130 mm Hg or diastolic blood pressure ≥85mmhg SSNHL: 64 (26.9%)Controls: 47 (19.7%) n.d 
HDL-C Serum HDL-cholesterol SSNHL: 52.2 (SD 11.5)Controls: 50.4 (SD 12.1) n.d. 
Passamonti 2015 SSNHL: 118Controls: 415 SSNHL: 48 (range 34–57)Controls 41 (32–52) Diabetes Fasting plasma glucose levels >126 mg/dL SSNHL: 2 (2%)Controls: 4 (1%) n.d. 
 Hypertension Systolic blood pressure >140 mm Hg or diastolic blood pressure >90mmhg SSNHL: 29 (24%)Controls: 42 (10%) n.d. 
Smoking Current cigarette smoking SSNHL: 37 (31%)Controls: 91 (22%) n.d. 
Quaranta 2008 SSNHL: 37Controls: 47 SSNHL: 46.3 (range 13–79)Controls: 44.8 (range 16–70) TC Absolute serum total cholesterol SSNHL: 183.94 mg/dL (SD 50.22)Controls: 186.8 mg/dL (SD 42.06) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 52.37 mg/dL (SD 17.61)Controls: 43.73 mg/dL (SD 548.19) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 119.06 mg/dL (SD 39.74)Controls: 112.46 mg/dL (SD 36.32) n.d. 
Rajati 2016 SSNHL: 30Controls: 30 SSNHL: 45±12.7Controls: 45±11.8 BMI n.d. SSNHL: 25.32 (SD 4.4)Controls: 26.49 (SD 4.9) n.d. 
 TC Absolute serum total cholesterol SSNHL: 207.8 mg/dL (SD 50.8)Controls: 196.6 mg/dL (SD 46.7) n.d. 
HDL-C Serum HDL-cholesterol SSNHL: 51.9 mg/dL (SD 9.6)Controls: 47.5 mg/dL (SD 13.5) n.d. 
3LDL-C Serum LDL-cholesterol SSNHL: 135.4 mg/dL (SD 37.3)Controls: 124.6 mg/dL (SD 38.6) n.d. 
Rinaldi 2020 SSNHL: 39Controls: 44 SSNHL: 53.70±13.73Controls: 48.43±11.13 BMI Weight/height2 = kg/m2 SSNHL:26.80 kg/m2 (SD 3.44)#Controls: 25.23 kg/m2 (SD 3.52) n.d. 
 TC Absolute serum total cholesterol SSNHL: 193.69 mg/dL (SD 37.27)Controls: 188.89 mg/dL (SD 38.44) n.d. 
HDL-C Serum HDL-cholesterol SSNHL: 56.08 mg/dL (13.19)Controls: 54.61 mg/dL (SD 13.33) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 118 mg/dL (SD 33.80)Controls: 113.87 mg/dL (SD 32.28) n.d. 
Smoking Regularly smoked at least 5 cigarettes/day during the previous 3 months or had stopped smoking less than 1 year before start study SSNHL: 11 (18.21%)Controls: 17 (38.64%) n.d. 
Rudack 2006 SSNHL: 142Controls: 84 SSNHL: 51.2±17.2Controls: 49.8±13.6 TC Absolute serum total cholesterol SSNHL: 215 mg/dL (SD 32)Controls: 227 mg/dL (SD 38) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 61 mg/dL (SD 16)Controls: 54 mg/dL (SD 14) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 114 mg/dL (SD 29)Controls: 124 mg/dL (SD 29) n.d. 
Diabetes History of physician-diagnosed DM SSNHL: 8 (5.6%)Controls: 2 (2.4%) n.d. 
Hypertension Systolic blood pressure >140 mm Hg or diastolic blood pressure >90mmhg at blood withdrawal SSNHL: 20 (14.1%)Controls: 20 (23.8%) n.d. 
MI History of physician-diagnosed MI SSNHL: 5 (3.5%)Controls: 2 (2.4%) n.d. 
Smoking Current cigarette smoking at blood withdrawal SSNHL: 80 (56.3%)#Controls: 16 (19.0%) n.d. 
Schulz 2014 SSNHL: 23Controls: 10 SSNHL: 64 (30–78)Controls: 58.5 (19–75) BMI Weight/height2 = kg/m2 SSNHL: 27.1 (21.3, 34.6)∞Controls: 26.1 (22.8, 37.6) n.d. 
 Diabetes Taking antidiabetic medication OR fasting blood glucose >126 mg/dL SSNHL 2 (8.7%)Controls: 3 (30%) n.d. 
Smoking n.d. SSNHL: zero (0%)Controls: 2 (20% n.d. 
Suckfull 2002 SSNHL: 53Controls: 53 SSNHL: 53.7±17.9Controls: 53.5±17.7 TC Absolute serum total cholesterol SSNHL: 217 mg/dL (SD 52)Controls: 214 mg/dL (SD 33) n.d. 
 HDL-C Serum HDL-cholesterol SSNHL: 56 mg/dL (SD 16)Controls: 57 mg/dL (SD 33) n.d. 
LDL-C Serum LDL-cholesterol SSNHL: 139 mg/dL (SD 40)Controls: 132 mg/dL (SD 30) n.d. 
Umesawa 2017 SSNHL: 3,073Controls: 7,641 SSNHL men: 55.9±15.1SSSNHL women: 55.7±15.3 BMI Weight/height2 = kg/m2BMI >25 kg/m2 SSNHL men: 23.9 kg/m2Control men: n.dSSNHL women: 23.0 kg/m2Control women: n.d n.d. 
 Diabetes 1. History of physician-diagnosed DM2. Taking antidiabetic medication SSNHL men: 21.9%Control men: n.dSSNHL women: 13.0%Control women: n.d n.d. 
MI History of heart disease assessed by questionnaire SSNHL men: 15.1%Control men: n.d.SSNHL women: 8.8%Control women: n.d. n.d. 
Smoking Consuming cigarettes daily SSNHL men: 38.0%Control men: n.d.SSNHL women: 12.2%Control women: n.d. n.d. 
Wang 2020 SSNHL: 324Controls: 972 SSNHL: 49.6±16.5Controls: 48.8±14.7 Hypertension n.d. SSNHL: 71 (21.91%)Controls: 175 (18%) 1.28 (0.1208) 
 MI History of coronary heart disease (n.f.s.) SSNHL: 6 (1.85%)Controls: 17 (1.75%) 1.06 (0.9033) 
Weng 2013 SSNHL: 250Controls: 250 SSNHL: 56.4 (range 15–84)Controls: n.d. TC Absolute serum total cholesterol SSNHL: 4.738 mmol/L (SD 1.021)Controls: 4.378 mmol/L (SD 0.937) 1.459 (<0.01) 
 HDL-C Serum HDL-cholesterol SSNHL: 1.432 mmol/L (SD 0.401)Controls: 1.459 mmol/L (SD 0.420) 0.849 (0.448) 
LDL-C Serum LDL-cholesterol SSNHL: 2.679 mmol/L (SD 0.856)Controls: 2.380 mmol/L (SD 0.723) 1.628 (<0.01) 

A description of all 32 included studies is provided including the definition used for the identification of cardiovascular risk factors, the main results, and the odds ratio.

BMI, body mass index; HDL-C, high-density lipoprotein cholesterol; HTN, hypertension; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; n.d.; not determined; n.f.s., not further specified; OR, odds ratio; SD, standard deviation; SSNHL, sudden sensorineural hearing loss; TIA, transient ischemic attack; TC, total cholesterol.

# Significant difference at p < 0.005.

Median and interquartile ranges are displayed due to non-normally distributed data.

Risk of Bias Assessment

The risk of bias assessment of each article is shown in online supplementary Table 2. Two cohort studies evaluated the incidence of sudden deafness in a cohort either with or without the cardiovascular risk factor hypercholesterolemia or diabetes [Lin et al., 2013; Chang et al., 2014]. Both studies were of good quality. In both articles, the cohorts were matched for age and gender. Also, other cardiovascular risk factors (CVRFs) were identified and corrected for in a Cox proportional hazard model. The identification of cases was based on the national health insurance databases of Taiwan and Korea using the ICD-9 classification which might have resulted in some wrongful inclusion of patients who did not meet the standardized criteria for iSSNHL [Chandrasekhar etal., 2019].

The quality of the remaining case-control studies ranged from poor (3/31 articles) to good (12/31 articles). In most studies, controls were matched for age and gender, and in some also for CVRFs like DM, renal insufficiency, or coronary artery disease. However, in 9 articles, no matching was performed [Ballesteros et al., 2009; Cadoni et al., 2010; Oiticica and Bittar, 2010; Oreskovic et al., 2011; Ciccone et al., 2012; Passamonti et al., 2015; Umesawa et al., 2017; Kaneva et al., 2019; Genç Elden et al., 2022]. Two of these studies did not recruit a control cohort but instead compared the CVRF incidence in their study cohort to the reported prevalence estimates nationwide [Oiticica and Bittar, 2010; Umesawa et al., 2017].

Eleven articles presented unadjusted results [Suckfüll et al., 2002; Quaranta et al., 2008; Ballesteros et al., 2009; Oiticica and Bittar, 2010; Oreskovic et al., 2011; Mohammed, 2014; Fasano et al., 2017; Umesawa et al., 2017; Rinaldi et al., 2020; Genç Elden et al., 2022; Park et al., 2022]. Two studies adjusted for several CVRFs together, without a separate analysis per risk factor [Passamonti et al., 2015; Chien et al., 2016]. Another two studies did perform a regression analysis with multiple outcomes but did not include possible confounders in these analyses [Cadoni et al., 2007; Schulz et al., 2014]. All studies with adjusted results used a logistic regression model.

Two studies presented data from a secondary analysis by Lee et al. [Weng et al., 2013; Wang et al., 2020]. These articles did differ in terms of CVRFs analyzed and were therefore selectively included in the meta-analyses. Two other studies used the same database and had overlapping inclusion periods, but the studied CVRFs differed between the studies [Chang et al., 2014; Lin et al., 2016].

Study Outcomes

Body Mass Index

Nine articles measured the BMI in patients with iSSNHL. One article did not describe the BMI in controls and was therefore excluded [Ballesteros et al., 2009; Ciccone et al., 2012]. Another study compared the BMI between women and men with iSSNHL and could therefore not be included in the analysis [Umesawa et al., 2017].

The remaining six articles found a 0.55 kg/m2 higher mean BMI in patients with iSSNHL (95% CI 0.24–0.86)[Mosnier et al., 2011; Lee et al., 2015; Rajati et al., 2016; Rinaldi et al., 2020; Genç Elden et al., 2022] (shown in Fig. 2). No sensitivity analysis was required.

Fig. 2.

Results of the meta-analysis including 570 patients with SSNHL from 6 articles that investigate the average BMI of patients with SSNHL compared to controls. A fixed effects model was used. CI, confidence interval.

Fig. 2.

Results of the meta-analysis including 570 patients with SSNHL from 6 articles that investigate the average BMI of patients with SSNHL compared to controls. A fixed effects model was used. CI, confidence interval.

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Total Cholesterol

Total cholesterol was assessed in 21 articles [Suckfüll et al., 2002; Rudack et al., 2006; Cadoni et al., 2007; Capaccio et al., 2007; Quaranta et al., 2008; Aimoni et al., 2010; Cadoni et al., 2010; Oreskovic et al., 2011; Ciccone et al., 2012; Weng et al., 2013; Mohammed, 2014; Lee et al., 2015; Rajati et al., 2016; Fasano et al., 2017; Jalali and Azgomi, 2020; Rinaldi et al., 2020]. Of these articles, 3 articles did not provide absolute values of cholesterol but only described the number of patients with elevated total cholesterol and another article did not provide control data [Marcucci et al., 2005; Ballesteros et al., 2009; Chang et al., 2014]. These articles were therefore not included in the meta-analysis. The mean total cholesterol was higher in patients with SSNHL; the difference was 4.89 mg/dL (95% CI 3.11–6.68) (shown in Fig. 3a). A sensitivity analysis was performed where we excluded 7 articles until the I2 dropped below 50%, indicating modest heterogeneity. In this analysis, patients with iSSNHL had on average 8.44 mg/dL higher mean total cholesterol values than controls (95% CI 5.21–11.68, p < 0.00001) (shown in Fig. 3b).

Fig. 3.

a Results from the meta-analysis including 3,544 patients with SSNHL from 16 articles investigating the total cholesterol value of patients with SSNHL versus controls. b Results from the sensitivity analysis after exclusion of 7 articles due to large heterogeneity in data. CI, confidence interval; SSNHL, sudden sensorineural hearing loss.

Fig. 3.

a Results from the meta-analysis including 3,544 patients with SSNHL from 16 articles investigating the total cholesterol value of patients with SSNHL versus controls. b Results from the sensitivity analysis after exclusion of 7 articles due to large heterogeneity in data. CI, confidence interval; SSNHL, sudden sensorineural hearing loss.

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HDL-Cholesterol

HDL-cholesterol values were assessed in 18 articles [Suckfüll et al., 2002; Rudack et al., 2006; Quaranta et al., 2008; Ballesteros et al., 2009; Oreskovic et al., 2011; Ciccone et al., 2012; Weng et al., 2013; Mohammed, 2014; Lee et al., 2015; Chien et al., 2016; Rajati et al., 2016; Fasano et al., 2017; Kaneva et al., 2019; Jalali and Azgomi, 2020; Rinaldi et al., 2020; Li et al., 2021; Genç Elden et al., 2022; Park et al., 2022]. However, one article did not describe the absolute value of HDL in the control cohort and could therefore not be included in the meta-analysis [Ballesteros et al., 2009]. Two other studies only reported the median and interquartile ranges of the HDL values and were excluded from the analysis [Chien et al., 2016; Kaneva et al., 2019]. The article by Weng et al. used previously published data by Lee et al. and was therefore excluded [Weng et al., 2013]. On average, HDL-cholesterol was 0.06 mg/dL (95% CI −0.11–0.01, p = 0.01) lower in patients with iSSNHL compared to controls (shown in Fig. 4a). After subsequent sensitivity analysis including 10 articles, the mean HDL value was 0.16 mg/dL lower in patients with iSSNHL compared to controls (95% CI −0.21 to −0.11, p < 0.00001) (shown in Fig. 4b).

Fig. 4.

a Results from the meta-analysis including 3,421 patients with SSNHL from 14 articles investigating the HDL-cholesterol value of patients with SSNHL versus controls. b Results from the sensitivity analysis after exclusion of 4 articles due to large heterogeneity in data. CI, confidence interval; HDL, high-density lipoprotein; SSNHL, sudden sensorineural hearing loss.

Fig. 4.

a Results from the meta-analysis including 3,421 patients with SSNHL from 14 articles investigating the HDL-cholesterol value of patients with SSNHL versus controls. b Results from the sensitivity analysis after exclusion of 4 articles due to large heterogeneity in data. CI, confidence interval; HDL, high-density lipoprotein; SSNHL, sudden sensorineural hearing loss.

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LDL-Cholesterol

Nineteen articles investigated LDL-cholesterol values in patients with iSSNHL [Suckfüll et al., 2002; Rudack et al., 2006; Cadoni et al., 2007; Quaranta et al., 2008; Ballesteros et al., 2009; Cadoni et al., 2010; Oreskovic et al., 2011; Ciccone et al., 2012; Weng et al., 2013; Lee et al., 2015; Rajati et al., 2016; Fasano et al., 2017; Kaneva et al., 2019; Jalali and Azgomi, 2020; Rinaldi et al., 2020; Li et al., 2021; Genç Elden et al., 2022]. Of these, one article did not report the values in control patients, and another did not provide absolute LDL-cholesterol values [Ballesteros et al., 2009; Kaneva et al., 2019].

In the remaining articles, LDL-cholesterol was on average 0.08 mg/dL higher in patients with iSSNHL than in controls (95% CI −0.04–0.13) (shown in Fig. 5a). After sensitivity analysis with 10 articles, this mean difference decreased to 0.08 mg/dL (95% CI 0.03–0.13, p = 0.002) (shown in Fig. 5b).

Fig. 5.

a Results from the meta-analysis including 3,355 patients with SSNHL from 15 articles investigating the LDL-cholesterol value of patients with SSNHL versus controls. b Results from the sensitivity analysis after exclusion of 5 articles based on large heterogeneity. CI, confidence interval; LDL, low-density lipoprotein; SSNHL, sudden sensorineural hearing loss.

Fig. 5.

a Results from the meta-analysis including 3,355 patients with SSNHL from 15 articles investigating the LDL-cholesterol value of patients with SSNHL versus controls. b Results from the sensitivity analysis after exclusion of 5 articles based on large heterogeneity. CI, confidence interval; LDL, low-density lipoprotein; SSNHL, sudden sensorineural hearing loss.

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Diabetes

Twelve articles described the correlation between DM and iSSNHL [Nakashima et al., 1997; Rudack et al., 2006; Ballesteros et al., 2009; Aimoni et al., 2010; Ciccone et al., 2012; Schulz et al., 2014; Passamonti et al., 2015; Lin et al., 2016; Xianli et al., 2016; Umesawa et al., 2017; Jalali and Azgomi, 2020; Park et al., 2022]. One article compared the incidence of iSSNHL in patients with and without DM [Lin et al., 2016]. Another article compared the incidence of diabetes between women and men with iSSNHL [Umesawa et al., 2017]. Both articles were excluded from the meta-analysis. On average, patients with iSSNHL had an odds ratio of 1.64 of having diabetes compared to controls (95% CI 1.24–2.19, p = 0.0006) (shown in Fig. 6). The in-between-study heterogeneity was 0%, so no sensitivity analysis was applied.

Fig. 6.

Results from the meta-analysis including 1,162 patients with SSNHL from 10 articles investigating the prevalence of diabetes among patients with SSNHL versus controls. CI, confidence interval; SSNHL, sudden sensorineural hearing loss.

Fig. 6.

Results from the meta-analysis including 1,162 patients with SSNHL from 10 articles investigating the prevalence of diabetes among patients with SSNHL versus controls. CI, confidence interval; SSNHL, sudden sensorineural hearing loss.

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Hypertension

Thirteen articles were included in the systematic review [Nakashima et al., 1997; Marcucci et al., 2005; Rudack et al., 2006; Ballesteros et al., 2009; Aimoni et al., 2010; Mosnier et al., 2011; Ciccone et al., 2012; Passamonti et al., 2015; Chien et al., 2016; Jalali and Azgomi, 2020; Wang et al., 2020; Genç Elden et al., 2022; Park et al., 2022]. Two articles did not describe the incidence of hypertension but measured the average systolic and diastolic blood pressure and compared this to a control cohort; these studies were therefore excluded from further analysis [Mosnier et al., 2011; Genç Elden et al., 2022].

Patients with iSSNHL had an odds ratio of 1.46 of having hypertension compared to controls (95% CI 1.25–1.71, p < 0.00001) (shown in Fig. 7a). After sensitivity analysis including 10 articles, the odds ratio of having hypertension was 1.55 (95% CI 1.32–1.82, p < 0.00001) for patients with iSSNHL (shown in Fig. 7b).

Fig. 7.

a Results from the meta-analysis including 1,618 patients with SSNHL from 11 articles investigating the prevalence of hypertension among patients with SSNHL versus controls. b Results of the sensitivity analysis after exclusion of one article due to the large heterogeneity in the data. CI, confidence interval; SSNHL, sudden sensorineural hearing loss.

Fig. 7.

a Results from the meta-analysis including 1,618 patients with SSNHL from 11 articles investigating the prevalence of hypertension among patients with SSNHL versus controls. b Results of the sensitivity analysis after exclusion of one article due to the large heterogeneity in the data. CI, confidence interval; SSNHL, sudden sensorineural hearing loss.

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Smoking

Fourteen articles investigated the incidence of smoking among patients with iSSNHL [Nakashima et al., 1997; Nakamura et al., 2001; Marcucci et al., 2005; Rudack et al., 2006; Ballesteros et al., 2009; Aimoni et al., 2010; Ciccone et al., 2012; Schulz et al., 2014; Passamonti et al., 2015; Chien et al., 2016; Umesawa et al., 2017; Jalali and Azgomi, 2020; Rinaldi et al., 2020; Genç Elden et al., 2022]. Of these, one article was excluded from the analysis since it did not describe the incidence of smoking in the total control cohort but subdivided the control cohort into men and women [Umesawa et al., 2017].

The odds ratio of smoking was 1.24 in patients with iSSNHL (95% CI 1.06–1.45) (shown in Fig. 8a). After sensitivity analysis including 12 articles, the odds ratio for smoking was non-significantly higher in patients with iSSNHL, OR 1.10 (95% CI 0.93–1.30, p = 0.28) (shown in Fig. 8b).

Fig. 8.

a Results from the meta-analysis including 1,322 patients with SSNHL from 13 articles investigating the prevalence of smoking among patients with SSNHL versus controls. b Results from the sensitivity analysis after exclusion of one article due to the large heterogeneity in data. CI, confidence interval; SSNHL, sudden sensorineural hearing loss.

Fig. 8.

a Results from the meta-analysis including 1,322 patients with SSNHL from 13 articles investigating the prevalence of smoking among patients with SSNHL versus controls. b Results from the sensitivity analysis after exclusion of one article due to the large heterogeneity in data. CI, confidence interval; SSNHL, sudden sensorineural hearing loss.

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Cardiac Disease

Five articles reported the prevalence of a medical history of cardiac disease in patients with iSSNHL [Rudack et al., 2006; Ballesteros et al., 2009; Mosnier et al., 2011; Umesawa et al., 2017; Wang et al., 2020]. In one article, the difference was calculated in women and men seperately and did not include the primary data [Umesawa et al., 2017]. This article was therefore not included in the analysis. The remaining four articles resulted in a mean odds ratio of 2.05 for having a medical history of cardiac disease in patients with iSSNHL (95% CI 1.19–3.52, p = 0.010) (shown in Fig. 9).

Fig. 9.

Results from the meta-analysis including 661 patients with SSNHL from 4 articles investigating the prevalence of cardiac disease among patients with SSNHL versus controls.

Fig. 9.

Results from the meta-analysis including 661 patients with SSNHL from 4 articles investigating the prevalence of cardiac disease among patients with SSNHL versus controls.

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Research Question 2: Cerebral Small Vessel Disease and iSSNHL

A total of 413 original articles were identified. Only five articles reported the presence of cerebral small vessel disease, in particular white matter hyperintensities, in patients with iSSNHL [Ciorba et al., 2019; Dicuonzo et al., 2019; Fusconi et al., 2019; Shin et al., 2022]. One of these articles was a cohort study that compared the prognosis of hearing loss between iSSNHL patients with and without white matter hyperintensities. This article reported the prevalence of each Fazekas score in the studied cohort and was therefore included in the systematic review but excluded from the meta-analysis [Shin et al., 2022].

All 4 case-control articles compared the presence of white matter hyperintensities in patients with and without iSSNHL [Ciorba et al., 2019; Dicuonzo et al., 2019; Fusconi et al., 2019]. Table 2 displays the study characteristics of the included studies.

Table 2.

Study characteristics of articles in the cerebral small vessel disease analysis

AuthorYearStudy designPopulationAgeOutcomeResults
Ciorba 2019 Retrospective case-control SSNHL: 64Controls: 32SSNHL <55 year: 23 SSNHL: 58.25±14.91Controls: 40.28±13.64 WMLFazekas scaleWahlund scale SSNHLControls: n.d 
Dicuonzo 2019 Prospective case-control SSNHL: 36Controls: 36 SSNHL: 54.4±15.6Controls: 53.0±12.5 WMLFazekas scale  
Fusconi 2019 Retrospective case-control SSNHL: 113Controls: 107 SSNHL: 44.54Controls: 44.75 WMLFazekas scale  
Oussoren 2022 Retrospective case-control SSNHLControls SSNHL: 65.9±9.3Controls: 65.1±9.0 WMLFazekas scale  
Shin 2022 Retrospective cohort SSNHL: 107 SSNHL: 54.6±13.4 Hearing outcomes compared between the Fazekas scores SSNHL0: 781: 172: 12Significant hearing difference between Fazekas score 1 and 2 (p = 0.009) 
AuthorYearStudy designPopulationAgeOutcomeResults
Ciorba 2019 Retrospective case-control SSNHL: 64Controls: 32SSNHL <55 year: 23 SSNHL: 58.25±14.91Controls: 40.28±13.64 WMLFazekas scaleWahlund scale SSNHLControls: n.d 
Dicuonzo 2019 Prospective case-control SSNHL: 36Controls: 36 SSNHL: 54.4±15.6Controls: 53.0±12.5 WMLFazekas scale  
Fusconi 2019 Retrospective case-control SSNHL: 113Controls: 107 SSNHL: 44.54Controls: 44.75 WMLFazekas scale  
Oussoren 2022 Retrospective case-control SSNHLControls SSNHL: 65.9±9.3Controls: 65.1±9.0 WMLFazekas scale  
Shin 2022 Retrospective cohort SSNHL: 107 SSNHL: 54.6±13.4 Hearing outcomes compared between the Fazekas scores SSNHL0: 781: 172: 12Significant hearing difference between Fazekas score 1 and 2 (p = 0.009) 

A description of all 5 included articles is provided including the study design, the mean age of the subjects, the effect size of the outcome, and the main results.

F, Fazekas scale; n.d., not determined; SSNHL, sudden sensorineural hearing loss; W, Wahlund scale; WML, white matter leukoaraiosis.

Risk of Bias Assessment

The quality of the four case-control studies ranged from poor to good. Three studies had a retrospective study design, and one study included patients with sudden deafness prospectively [Dicuonzo et al., 2019]. In three studies, the control cohort was matched for sociodemographic characteristics, such as age and gender [Ciorba et al., 2019; Dicuonzo et al., 2019], though Fusconi et al. did not further specify the matching characteristics [Fusconi et al., 2019]. In the study by Ciorba et al., the control cohort was significantly younger than the study cohort [Ciorba et al., 2019].

In only one study, both cohorts underwent pure-tone audiometry (PTA) assessment [Ciorba et al., 2019]. MRI assessment was performed using T2-weighted or FLAIR sequences in all studies. The number of raters was only described in two articles, and the reliability of the MRI assessments was only tested in one study.

All four articles used the Fazekas score as measurement for the degree of white matter hyperintensities. Ciorba et al. additionally reported the Wahlund scale for white matter hyperintensities [Ciorba et al., 2019]. Oussoren et al. also identified silent brain infarctions, though the incidence thereof was low in both cohorts [Oussoren et al., 2023]. Three articles provided the total Fazekas scores, the sum of the white matter hyperintensities both periventricular and in the deep white matter, while Dicuonzo et al. compared the incidence of hyperintensities in the periventricular white matter (PVWM) and deep white matter (DWM) separately [Dicuonzo et al., 2019]. Three studies used a (ordinal) logistic regression model to adjust for potential confounders like age, gender, and MRI sequence [Dicuonzo et al., 2019; Fusconi et al., 2019; Oussoren et al., 2023].

The only cohort study was of fair quality but did not compare the Fazekas scores in patients with and without iSSNHL [Shin et al., 2022]. The data were retrospectively retrieved from hospital records; however, missing data were not reported. Non-idiopathic cases of SSNHL were excluded. The authors clearly described the radiological assessment and PTA tests. Binary logistic regression was performed to adjust the average hearing thresholds for age and other possible confounders [Shin et al., 2022].

Outcomes

Since the cohort study did not describe a control cohort without iSSNHL, we could not include their results in the meta-analysis. The article by Dicuonzo et al. did not provide the total Fazekas scores and was consequently excluded from the meta-analysis. Data on the total Fazekas score of each included patient could not be distilled from the article by Ciorba et al., and therefore, it was also excluded from the meta-analysis. We included two articles with a total study population of 456 patients, of whom 231 were diagnosed with iSSNHL [Dicuonzo et al., 2019; Oussoren et al., 2023].

Forty-five patients with iSSNHL had a Fazekas score higher than three, compared to 57 patients in the control cohort. Patients with iSSNHL did not have a higher odds of a higher Fazekas (OR 0.70, 95% CI 0.44–1.12, p = 0.14) score (shown in Fig. 10).

Fig. 10.

Results from the meta-analysis including 231 patients with SSNHL from 2 articles investigating the degree of white matter hyperintensities among patients with SSNHL versus controls. Events display the number of patients who had a Fazekas score of 3 or higher on MRI. CI, confidence interval, SSNHL, sudden sensorineural hearing loss.

Fig. 10.

Results from the meta-analysis including 231 patients with SSNHL from 2 articles investigating the degree of white matter hyperintensities among patients with SSNHL versus controls. Events display the number of patients who had a Fazekas score of 3 or higher on MRI. CI, confidence interval, SSNHL, sudden sensorineural hearing loss.

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Research Question 3: Risk of Stroke after iSSNHL

Of the 3,583 articles screened for eligibility, 7 articles met the inclusion criteria. Table 3 displays the study characteristics and outcomes.

Table 3.

Study characteristics of articles included in the risk of stroke analysis

Author, yearStudy designDatabaseStudy populationInclusion periodDefinition SSNHLDefinition StrokeEffect sizeFollow-up, yearsResults
Lin et al., 2008 Retrospective case control TNHIRD SSNHL: 1,423Appendectomy: 5,692 1998–2003 ICD-9-CM code 388.2 ICD-9-CM code 430 up to 438 Hazard rates 10 HR stroke in SSNHL 1.64 (1.31–2.07) 
Chang et al., 2013 Retrospective cohort Hospital records SSNHL: 349 2000–2004 SSNHL: Hearing loss 30 dB over 3 contiguous frequencies within 72 h Acute neurological deficits and/or infarction or hemorrhage on imaging Incidence rates 6.8 IR stroke in SSNHL cohort: 4.6%IR in population: 0.3–0.6% 
Ciorba et al., 2015 Retrospective cohort Hospital discharge data and regional statistics office SSNHL: 484 and 8,188Stroke: 9,985 and 103,004 2001–2012 SSNHL: ICD-9-CM 388.2 ICD-9-CM 43301, 43311, 43321, 43331, 43381, 43391, 43401, 43411, 436 Annual crude incidence ratesExpected versus observed number of strokes IR stroke in SSNHL: 1.9%Expected: 6Observed: 9 
Chang, T.P. et al., 2017 Retrospective cohort TNHIRD SSNHL alone: 1,998 SSNHL with vertigo: 678Vertigo alone: 215,980 2002–2009 SSNHL alone: ICD-9-CM code 388.2SSNHL with vertigoICD-9-CM code 388.2 and 386.x or 780.4 (within 30 days)Vertigo alone: ICD-9-CM code 386.x or 780.4 ICD-9-CM codes 430 upto 438 Hazard rates 7* HR stroke in SSNHL with vertigo 1.75 versus SSNHL aloneHR SSNHL with vertigo 1.23 versus vertigo alone (latter non-sig) 
Kim, J.Y. et al., 2018 Retrospective case-control KNHIS SSNHL: 154Control: 616 2002–2005 SSNHL: ICD-10-CM codes H9120, H9121, H9129, H810. Received a PTA and steroid treatment ICD-10-CM codes I60 up to I63 Hazard rates 11* Stroke in SSNHL: Adjusted HR 2.02 95% CI (1.16–3.51) 
Kim, S.Y. et al., 2018 Retrospective case-control KNHIS SSNHL: 4,944Control: 19,776 2002–2013 SSNHL: ICD-10-CM code 91.2Received a PTA and steroid treatment ICD-10-CM codes I60 up to I63 Hazard rates 5* HR stroke in SSNHL: 1.22 95% CI (1.05–1.43) 
Chou et al., 2018 Retrospective case-control TNHIRD SSNHL with HD: 288HD alone: 1,728 1997–2008 ICD-9-CM code 388.2 and ICD-9-CM code 585, 3 months of HD or PD. ICD-9-CM codes 430 up to 438 Hazard rates 11* HR 2.34, 95% CI 1.45–3.78 
Author, yearStudy designDatabaseStudy populationInclusion periodDefinition SSNHLDefinition StrokeEffect sizeFollow-up, yearsResults
Lin et al., 2008 Retrospective case control TNHIRD SSNHL: 1,423Appendectomy: 5,692 1998–2003 ICD-9-CM code 388.2 ICD-9-CM code 430 up to 438 Hazard rates 10 HR stroke in SSNHL 1.64 (1.31–2.07) 
Chang et al., 2013 Retrospective cohort Hospital records SSNHL: 349 2000–2004 SSNHL: Hearing loss 30 dB over 3 contiguous frequencies within 72 h Acute neurological deficits and/or infarction or hemorrhage on imaging Incidence rates 6.8 IR stroke in SSNHL cohort: 4.6%IR in population: 0.3–0.6% 
Ciorba et al., 2015 Retrospective cohort Hospital discharge data and regional statistics office SSNHL: 484 and 8,188Stroke: 9,985 and 103,004 2001–2012 SSNHL: ICD-9-CM 388.2 ICD-9-CM 43301, 43311, 43321, 43331, 43381, 43391, 43401, 43411, 436 Annual crude incidence ratesExpected versus observed number of strokes IR stroke in SSNHL: 1.9%Expected: 6Observed: 9 
Chang, T.P. et al., 2017 Retrospective cohort TNHIRD SSNHL alone: 1,998 SSNHL with vertigo: 678Vertigo alone: 215,980 2002–2009 SSNHL alone: ICD-9-CM code 388.2SSNHL with vertigoICD-9-CM code 388.2 and 386.x or 780.4 (within 30 days)Vertigo alone: ICD-9-CM code 386.x or 780.4 ICD-9-CM codes 430 upto 438 Hazard rates 7* HR stroke in SSNHL with vertigo 1.75 versus SSNHL aloneHR SSNHL with vertigo 1.23 versus vertigo alone (latter non-sig) 
Kim, J.Y. et al., 2018 Retrospective case-control KNHIS SSNHL: 154Control: 616 2002–2005 SSNHL: ICD-10-CM codes H9120, H9121, H9129, H810. Received a PTA and steroid treatment ICD-10-CM codes I60 up to I63 Hazard rates 11* Stroke in SSNHL: Adjusted HR 2.02 95% CI (1.16–3.51) 
Kim, S.Y. et al., 2018 Retrospective case-control KNHIS SSNHL: 4,944Control: 19,776 2002–2013 SSNHL: ICD-10-CM code 91.2Received a PTA and steroid treatment ICD-10-CM codes I60 up to I63 Hazard rates 5* HR stroke in SSNHL: 1.22 95% CI (1.05–1.43) 
Chou et al., 2018 Retrospective case-control TNHIRD SSNHL with HD: 288HD alone: 1,728 1997–2008 ICD-9-CM code 388.2 and ICD-9-CM code 585, 3 months of HD or PD. ICD-9-CM codes 430 up to 438 Hazard rates 11* HR 2.34, 95% CI 1.45–3.78 

A description of the seven included studies in the systematic review including the study design, definition used for iSSNHL, the effect sizes, and the main results.

HD, hemodialysis; SSNHL, sudden sensorineural hearing loss; HR, hazard rate; ICD-CM, International Classification of Diseases-Clinical Modification; IR, incidence rates; KNHIS, Korean National Health Insurance system; PTA, pure tone audiometry; TNHIRD, Taiwanese National Health Insurance and Research Database.

*The follow-up duration of all subjects combined. There is no mention of the mean follow-up duration.

Risk of Bias Assessment

The risk of bias assessment is shown in online supplementary Table 2. Two cohort studies described the incidence of stroke in a iSSNHL cohort and compared this to the general population of Taiwan and of Emilia Romagna region, respectively, but the studies did not include a control cohort [Ciorba et al., 2015; Chang et al., 2013]. Another article compared the incidence of stroke between patients with iSSNHL alone, iSSNHL with vertigo, and vertigo alone, but no healthy control cohort was compiled [Chang et al., 2017]. In the remaining articles with a control cohort, this cohort was matched for age and gender and, in most cases, also for cardiovascular comorbidities like diabetes and hypertension. One of the case-control studies described the incidence of stroke after iSSNHL in a cohort of hemodialysis patients [Chou et al., 2018].

Two studies used hospital discharge data [Lin et al. 2008; Ciorba et al., 2015], the other studies were performed using data gathered from the national health insurance databases of Korea and Taiwan, respectively [Lin et al., 2008; Chang et al., 2017; Kim and Lee 2017; Chou et al., 2018; Kim et al., 2018]. Health insurance claims of almost all inhabitants in these countries can be retrieved from these databases, enabling large-scale cohort or case-controlled studies. The diagnosis codes used for inclusion were broad; hence, patients might not have met the standardized criteria for iSSNHL, which could have resulted in inclusion bias. The different codes used from the international classification system are summarized in online supplementary Table 3.

The total inclusion period ranged from 1998 until 2015. The inclusion periods of the two Taiwanese studies overlapped in inclusion period, as did two Korean studies. This might have resulted in inclusion of identical cases. All studies had a retrospective study design, although the follow-up duration varied. The Italian cohort study did not control for potential confounders [Ciorba et al., 2015]. All remaining studies used a Cox proportional hazard model to adjust for potential confounders. Overall, the case-controlled studies were performed accurately with limited chance of bias, while the cohort studies were performed without a control group and consequently their results are more difficult to interpret and extrapolate to the general population. No data on prophylactic therapy for stroke or other cardiovascular disease, after sudden sensorineural hearing loss had occurred, could be retrieved.

Study Outcomes

All four case-control studies described higher incidences of stroke in the iSSNHL cohort compared to controls, with hazard ratios ranging from 1.22 up to 4.08. The upper limit of the hazard ratio is based on a study that compared hemodialysis patients with and without iSSNHL.

In a European cohort study, Ciorba et al. compared the incidence of stroke after iSSNHL with the general population. They found a stroke incidence of 1.9%. Nine cases of stroke were found, while according to the annual incidence of stroke in the Italian region, one would have expected to find 6 cases of stroke [Ciorba et al., 2015]. This difference was, however, not statistically significant. In another study, patients with iSSNHL were divided into two cohorts; patients who experienced stroke and patients who did not experience stroke. The incidence of stroke after iSSNHL was compared to the overall incidence of stroke in the Taiwanese population. The incidence rate in the study cohort was 0.6% versus an incidence of 0.3–0.6% in the entire population [Chang et al., 2013]. In the cohort study by Chang et al., incidence rates of stroke were compared between three study groups; iSSNHL with vertigo, iSSNHL without vertigo, and vertigo alone [Chang et al., 2017]. The hazard ratio of stroke in patients with iSSNHL with vertigo was 1.75 and 1.23 compared to iSSNHL without vertigo and vertigo alone, respectively.

With this systematic review and meta-analyses, we systematically assessed the association between sudden deafness and systemic cardiovascular disease. We compared the presence of cardiovascular risk factors, the degree of white matter hyperintensities, and the risk of subsequent stroke after experiencing idiopathic sudden deafness. Patients with iSSNHL had on average a higher BMI, a higher total and LDL-cholesterol, and higher odds of having diabetes, hypertension and a medical history with cardiac disease compared to healthy controls. HDL-cholesterol was significantly lower in the iSSNHL cohorts, while smoking was non-significantly higher in patients with iSSNHL. In contrast, patients with iSSNHL did not have a higher degree of white matter hyperintensities measured with the Fazekas scale compared to healthy controls. Patients with iSSNHL did have a higher odds of developing stroke in the years following their sudden deafness.

The acute onset of hearing loss resembles the presentation of acute cardiovascular disease. With limited collateral blood supply to the cochlea and vestibule, the organ is vulnerable to ischemia and a vascular origin of sudden deafness seems therefore plausible. The hypothesized mechanism of vascular involvement in the etiology of iSSNHL is that atherosclerosis causes hypoperfusion of the cochlea, resulting in a reduction of the number of inner and outer hair cells and stiffening of the basilar membrane. This, in conjunction with increased plasma viscosity, leads to degeneration of the stria vascularis, without complete artery occlusion [Ohlemiller and Gagnon 2004]. Identification of thrombotic events and localized damage is difficult due to the microscopical size, complex anatomy, and location of the cochlea in the temporal bone. Therefore, assessment of the vascular involvement in the pathophysiology of iSSNHL is primarily based on associations with generalized cardiovascular disease.

The association between iSSNHL and cardiovascular risk factors has been investigated intensively over the last decade, but this has resulted in conflicting results from heterogeneous study populations. While Lin et al. identified smoking as a risk factor of iSSNHL in a meta-analysis from 2012 [Lin et al., 2012], more recent case-control studies could not confirm this association [Jalali and Azgomi 2020; Rinaldi et al., 2020; Schulz et al., 2014]. Not surprisingly, the odds for smoking favored patients with iSSNHL compared to controls, though non-significantly. A more recent meta-analysis by Simões et al. identified hypertriglyceridemia and hypercholesterolemia as independent risk factors for iSSNHL, while no increased risk was found for diabetes and hypertension, which are known risk factors for stroke [Simões et al. 2023]. Simões et al., however, excluded many articles from their meta-analysis based on heterogeneous outcomes. While Simões and colleagues only included dichotomous outcomes for all CVRFs, we compared the average total cholesterol, HDL-cholesterol, and LDL-cholesterol in order to increase the number of included articles. We additionally analyzed other cardiovascular risk factors (i.e., BMI, smoking, and medical history of MI) to complete the CVRF panel. In doing so, we included a total of 33 articles. Since we included articles that described mean cholesterol values, we also included some articles of which the mean cholesterol value was below the threshold to define hypercholesterolemia. After exclusion of these articles, we still found a significantly higher mean cholesterol value in patients with iSSNHL compared to controls. We performed an additional analysis where we removed articles with skewed weight. We defined skewed weight to be articles that contributed over 50% of the total included number of subjects since their result would strongly influence the outcome of the meta-analysis. Exclusion of the articles responsible for skewed weight did not alter the outcome, though the heterogeneity between the included articles remained high.

The main limitations of the included studies are the small study populations. Eleven studies included less than 60 cases of iSSNHL, compared to only three articles with over 150 cases. Most studies did not perform a power analysis, so type I and II errors remain possible. The reliability of a regression analysis declines significantly with small study populations, especially in non-stratified cohorts, while in some articles the mean age differed significantly between the iSSNHL and control cohorts. Additionally, three studies used national health insurance databases to compile their cohorts. Without hospital data to verify the diagnosis, this could result in wrongful inclusion of subjects who did not meet the generally accepted criteria for sudden deafness [Chandrasekhar et al., 2019].

To our knowledge, we are the first to review articles investigating the degree of white matter hyperintensities in patients with iSSNHL. If cardiovascular risk factors are more frequently present in patients with iSSNHL, these are likely to result in cerebral small vessel disease (CSVD) such as WMH since the presence thereof is associated with CVRFs like hypertension and increased age. Contrary to this hypothesis, we did not find an increased degree of white matter hyperintensities in patients with iSSNHL when compared with controls. This result is, however, based on only two articles. Several articles that also investigated the association between WMH and iSSNHL were excluded since their primary data could not be retrieved from the article or otherwise. The main limitation of the included studies is the retrospective study design and absence of proper power analyses. The chances of a type II error are small, however, due to the adequate matching for age and gender and regression analysis for possible confounders. The mean age of both articles did differ. While Fusconi et al. did not apply age restrictions, Oussoren et al. only included patients aged 50 or older. Fusconi et al. found a positive association between iSSNHL and Fazekas score in patients aged 48 up to 60 but Oussoren et al. could not confirm this association.

The final association between cardiovascular disease and iSSNHL is the risk of subsequent stroke. In 2008, Lin et al. were the first to report an increased risk of stroke following sudden deafness. In the past years, multiple retrospective cohort studies have analyzed the same association. A recent meta-analysis by Lammers et al. summarized these articles and found an overall increased adjusted risk of stroke of 1.21–1.63 following iSSNHL, compared to controls. However, their overall result was based on only 3 articles, all from Asian populations with solely positive outcomes. The articles describing negative associations were not included due to their heterogeneous outcomes. To provide a thorough review of all available literature, we decided to include all articles in our systematic review without quantitative analysis. While Lammers et al. found an adjusted risk of stroke of 1.21–1.63 in an all-Asian population, the only European article by Ciorba et al. did not find a higher risk of stroke than in the general Italian population. Yet, in terms of numbers, this article included only a fraction of the study population size used in the Asian studies. Nonetheless, it does bring to mind the possibility of ethnical differences in the risk of stroke. It is known that stroke is more common in Asian populations than in the non-Hispanic white population [Feigin et al., 2014]; therefore, it might be possible that the risk of stroke after sudden deafness is also higher among Asians. As mentioned before, the most significant limitation of the Korean and Taiwanese studies included is the lack of hospital data.

Hypertension, diabetes, a medical history with MI, elevated total cholesterol and LDL-cholesterol appear to be independent risk factors for iSSNHL. Also, patients with iSSNHL have a higher risk of stroke compared to controls. These outcomes are in favor of vascular involvement in the pathogenesis of iSSNHL. In contrast, patients with iSSNHL do not show more CSVD on MRI. These conclusions should be interpreted with care due to the significant risk of bias and large heterogeneity in study data and study outcomes. Prospective cohort studies with hospital-derived clinical data are needed to establish the accuracy of the investigated associations and whether or not cardiovascular risk management in case of sudden hearing loss is appropriate.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors have no conflicts of interest to declare.

These authors have not received any grant or other type of funding for this research.

Fieke K. Oussoren is responsible for the primary search strategies, the selection process of eligible articles, the risk of bias assessment in all three study questions, the execution of the meta-analysis, interpretation of the results, and drafting of the article. Tjard. R. Schermer supervised the statistical analysis and interpretation of the results, contributed in drafting the article, and corrected the final manuscript. Roeland B. van Leeuwen contributed to the study design, the selection process of eligible articles, and risk of bias assessment of research questions 1 and 2; supervised the writing process; and corrected the final manuscript. Tjasse D. Bruintjes contributed to the study design, the selection process of eligible articles, and risk of bias assessment of research question 3; supervised the writing process; and corrected the final manuscript.

All data used for this systematic review and meta-analyses are available in the published articles. Upon reasonable request, the authors are willing to share the database used in the meta-analyses.

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