Accepted Article Received date: 03-Jun-2014 Accepted date: 12-Dec-2014 Article type: Review Title Page Controversies in the management of sudden sensorineural hearing loss (SSNHL): an evidence based review. Author for correspondence: Miss Rachael Lawrence Sheffield Children’s Hospital Western Bank Sheffield S10 2TH [email protected] 07980 27 37 97 Other Author: Mr Ravi Thevasagayam Sheffield Children’s Hospital Western Bank Sheffield S10 2TH This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/coa.12363 This article is protected by copyright. All rights reserved. Accepted Article Controversies in the management of sudden sensorineural hearing loss (SSNHL): an evidence based review. Background: Sudden Sensorineural Hearing Loss (SSNHL) is considered an otological emergency. It may present as an isolated condition or be the presenting feature of a systemic disease process. Idiopathic sudden sensorineural hearing loss (ISSNHL) is diagnosed when an underlying cause or condition cannot be identified. Objective of review: To review the current literature on SSNHL and propose a treatment algorithm based on the highest quality evidence. Search strategy and type of review: An evidence based literature review using Medline (search terms ‘sudden sensorineural hearing loss’ and ‘acute sensorineural hearing loss’). Results: (i) Baseline Investigations: All patients should be assessed with a thorough history and examination. This should include a Pure Tone Audiogram (PTA) where possible. Baseline and targeted laboratory tests should be carried out to diagnose specific conditions. (ii) Imaging: MRI should be carried out in all cases of ISSNHL. If MRI imaging is contraindicated either CT or Auditory Brainstem Response (ABR) testing should be performed. (iii) Medical Management: If a specific cause for a SSNHL is found, the patient should be managed accordingly. If idiopathic in nature, patients may be offered a course of oral steroid. If systemic steroids are contraindicated and/or there is no improvement with initial oral therapy, intratympanic steroids (IT) as either primary or salvage therapy may be considered. (iv) Further Management: There is no evidence to support the routine use of antiviral therapy. The cost, limited availability and lack of strong evidence for Hyperbaric Oxygen Therapy (HBOT) make it impractical at present. Due to the variability in the vasodilator and vasoactive agents used, there is insufficient evidence to support the routine use of these agents. This article is protected by copyright. All rights reserved. Accepted Article Consideration should be given to both temporary and permanent hearing amplification when required. Conclusions: SSNHL is an important condition that can have a significant impact on quality of life. Some patients respond spontaneously without intervention, however evidence tells us that certain interventions such as corticosteroid treatment may improve outcomes. Further high quality research is required. Meanwhile, an interim indicative treatment algorithm for SSNHL based on the current best evidence available is outlined. Sudden sensorineural hearing loss (SSNHL) has an estimated incidence in adulthood of between 5 and 30 cases per 100,000 per year . Population studies have shown a wide age distribution, with an average of 50 to 60 years and no sex preference . It is unilateral in the vast majority of cases with bilateral involvement occurring in less than 5 per cent of cases . It may present as an isolated condition or be the presenting feature of a systemic disease process. If an underlying condition cannot be identified on history and physical examination then SSNHL is said to be idiopathic in nature. In terms of severity, the hearing loss is divided almost equally into mild, moderate, severe and profound . There is no strict clinical definition of SSNHL although the one most commonly used is a hearing loss of at least 30 decibels (dB) in 3 consecutive frequencies in the standard pure tone audiogram (PTA) over 72 hours or less [1,2,3,4]. Premorbid audiometry is often unavailable therefore hearing loss is usually defined in relation to the opposite ear’s thresholds. The purpose of this paper is to establish current practice and discuss the areas of controversy and their related evidence. This article is protected by copyright. All rights reserved. Accepted Article Method A literature review was conducted in January 2014 using Medline and the search terms ‘sudden sensorineural hearing loss’ and ‘acute sensorineural hearing loss’ and was limited to English language. Further papers were identified on reading the results of the initial search. Discussion In this section we discuss an evidence-based approach to investigating and managing patients presenting with SSNHL and subdivide into (i) Baseline Investigations, (ii) Imaging, (iii) Medical Management and (iv) Further Management. We propose a management algorithm for SSNHL based on current evidence and this is presented in Figure 1. Areas of controversy within the pathway are discussed in detail where appropriate throughout the article. (i) Baseline Investigations History and examination. All patients with SSNHL should be assessed with a thorough history, general physical and neurologic examination [1,3]. This assessment should include a drug history as SSNHL has been previously attributed to a number of therapeutic agents. Trauma may also account for a SSNHL and causes include barotrauma, noise trauma, ear surgery and temporal bone fracture. Pertinent clues will be established from the history. Temporal bone fractures causing SSNHL are usually transverse and if there is otic capsule involvement there may be a complete unilateral loss. If there is no otic capsule involvement, labyrinthine concussion manifesting as a high-frequency loss may still occur and is thought to be due to shearing forces of the cochlear membranes or hair cell stereocilia. Patients subjected to noise trauma may experience a temporary threshold shift in hearing possibly due to the negative effect of the trauma on inner ear structures, however this temporary SSNHL resolves as structures recover. Examination must include tympanic membrane visualisation, which may require removal of cerumen. It is imperative to differentiate between a This article is protected by copyright. All rights reserved. Accepted Article conductive and sensorineural hearing loss as they have very different management strategies and in the first instance this should involve the use of tuning forks. A delay in treatment of a SSNHL may result if it is assumed a patient has conductive rather than a sensorineural hearing loss. This delay may affect prognosis in terms of hearing outcomes following any commenced treatment for a SSNHL. Despite the limitations of tuning forks, they are an important step in suggesting a SSNHL, which some clinicians argue should be treated as a medical emergency. The next step is confirmation with Pure Tone Audiometry (PTA). This may not be available out of hours and in this situation treatment should proceed on the basis of the history, examination and tuning fork testing. The presence of bilateral sudden hearing loss, recurrent episodes of sudden hearing loss or focal neurologic findings should be established to assess for underlying disease . Among such causes are systemic disorders, autoimmune disorders, metabolic disorders, bilateral Ménière’s disease and certain neurological disorders. If any of these systemic disorders are identified, the patient should be investigated and managed in accordance with the suspected diagnosis. Table 1 shows conditions that may be associated with bilateral SSNHL and Table 2 demonstrates features often associated with specific disorders underlying hearing loss. INSERT TABLES 1 & 2 Regarding the cases of SSNHL without an apparent cause, the rapid nature of onset of this condition has led to the belief that a vascular event may occur although viral infection, autoimmune disease and inner ear membrane rupture have also been postulated. These theories have driven the development of various treatment modalities. The vascular theory is supported by the fact that cardiovascular disease, hypertension and cigarette smoking are risk factors for SSNHL . Some studies have demonstrated hypercoagulability states in SSNHL  although the clinical and histopathological evidence for the vascular theory remains contradictory . The viral infection theory is supported by the fact that This article is protected by copyright. All rights reserved. Accepted Article higher rates of seroconversion have been demonstrated for influenza B, enterovirus, herpes simplex virus (HSV), mumps, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) [1,5]. However, these findings have not been consistent and have been contradicted in other studies. HSV, CMV and rubella are well-documented causes of congenital sensorineural hearing loss and varicella zoster virus (VSV) infection in Ramsay Hunt syndrome is also associated with SSNHL. Despite this, direct causal evidence for a viral aetiology in ISSNHL is still lacking. Other infective causes include bacterial meningitis that is associated with SSNHL in about a third of survivors. SSNHL is also described as a presenting feature of otosyphilis and HIV . Lyme disease should be considered in endemic areas. A systematic review of the evidence for the aetiology of SSNHL suggested that just over two thirds of all cases of SSHNL were idiopathic . Blood tests. There is little evidence that a routine battery of blood tests will alter the diagnosis, treatment or prognosis of the SSNHL . However, laboratory tests that are designed to alert clinicians to the possibility of an underlying cause for the SSNHL may be helpful . Full blood count (FBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), antinuclear antibodies (ANA), anticardiolipin antibodies, lupus anticoagulant, antineutrophil cytoplasmic antibodies (ANCA), clotting factors, and syphilis serology would be appropriate in most cases . Targeted investigations based on suspicions elicited during initial assessment are likely to be the most fruitful. INSERT ‘KEY POINTS ON BASELINE INVESTIGATIONS’ BOX (ii) Imaging Ten to 20% of patients with a vestibular schwannoma will report a sudden decrease in their hearing at some point  therefore all patients with SSNHL need to be screened for such pathology. This article is protected by copyright. All rights reserved. Accepted Article MRI scanning. There is an established consensus that MRI is the imaging modality of choice in cases of SSNHL [1, 3, 4, 5]. The sensitivity and specificity of MRI with gadolinium for diagnosing a vestibular schwannoma larger than 3 mm approaches nearly 100% . Contrast enhanced MRI can identify an abnormality in approximately 10 to 57% of patients with SSNHL such as a cerebellopontine angle (CPA) tumor, labyrinthine hemorrhage, cerebrovascular accident or any demyelinating process . If a patient is unsuitable for MRI scanning (severe claustrophobia, intra ocular metallic foreign body, non “MRI safe” medical implant) then CT scanning and Auditory Brainstem Response (ABR) testing may be considered. However, neither test has the sensitivity of MRI imaging. INSERT ‘KEY POINTS ON IMAGING’ BOX (iii) Medical Management Patient management should be targeted towards any identified systemic or local cause for the hearing loss. If no cause is identified then the SSNHL is said to be idiopathic (ISSNHL) in nature. Treatment regimens for ISSNHL are discussed and a recommendation provided according to current evidence. A flowchart for the suggested management pathway is shown in Figure 1. INSERT FIGURE 1 The heterogeneity of the treatment regimes within the literature slightly complicates the process of drawing conclusions and making recommendations. A lack of consensus about what constitutes a successful hearing result following an intervention is also problematic. Another factor to consider is the high rate of spontaneous recovery varying from 30 to 68% , which in combination with low patient numbers signifies that high quality RCTs are generally lacking. Most interventions are assessed in uncontrolled retrospective case series that This article is protected by copyright. All rights reserved. Accepted Article support the intervention but these studies must be viewed in the context of the high spontaneous resolution rate and the low patient numbers. Where possible RCTs and meta-analyses have been used in our evidence base, but in view of the aforementioned facts even these must be viewed with caution. Oral steroids. The rationale behind the use of steroid therapy is a potential decrease in any associated pathogenic inflammation and oedema. The use of oral corticosteroids is probably the most widely used therapeutic intervention in ISSNHL. A commonly suggested regimen for oral prednisolone use is 1mg/kg/day (to maximum 60mg) for 7-14 days then taper over similar time period. Multiple studies have proposed some benefit although robust evidence is still lacking. A Cochrane review updated in 2013 identified only 3 suitable trials involving 267 patients and even these trials had significant methodological concerns . One trial involving 47 patients showed that twice as many patients experienced significant benefit from therapy versus placebo. However, there were only 18 patients in the steroid group and 56 patients in the control group . The other 2 trials failed to demonstrate an effect . Two other meta-analyses of the data suggested an improvement with therapy that failed to reach statistical significance [6,9]. Evidence remains contradictory although there have been studies showing effect and in view of the potentially devastating disability of SSNHL and the relatively low morbidity of treatment it seems sensible to offer patients therapy whilst advising them that the evidence is unclear. It appears reasonable that when steroids are a relative contraindication such as diabetes and hypertension, the risks of systemic steroid treatment may not be justified, however patient preference should be paramount. This article is protected by copyright. All rights reserved. Accepted Article Primary Intratympanic (IT) steroids. The rationale for use is the same as the oral route however is potentially associated with a lower risk of systemic effects and a higher perilymph concentration. No consensus for IT therapy currently exists. Dexamethasone 4mg/ml, 5mg/ml, 10mg/ml or Methylprednisolone 40mg/ml, 30mg/ml with 0.4ml to 0.8ml every 3 - 7 days for 3 - 4 sessions are among suggested therapeutic regimens. IT steroids can be directly injected through the tympanic membrane but administration via a tympanostomy tube or round window microcatheter has also been described [3,9]. Risks of therapy in addition to the oral route consist of pain, transient caloric vertigo, otitis media, vasovagal episode and tympanic membrane perforation. There have been multiple observational studies purporting to show evidence that IT steroid therapy improves outcomes. A randomized trial involving 250 patients showed no difference in outcomes between oral and IT steroid therapy . Two high quality RCTs showed no improvement over systemic steroids although two lower quality RCTs showed superior results . The evidence suggests that IT steroid therapy is at least as effective as systemic steroids. IT therapy may be appropriate if relative contraindications to systemic therapy exist. There is insufficient robust evidence to support the use of preferential IT steroids as initial therapy. A Cochrane review is underway to assess this further. IT steroid therapy for salvage. The same aforementioned regimen for primary IT steroid therapy may be appropriate after failure of initial treatment and should ideally be administered within 1 - 4 weeks of SSNHL onset although some studies show benefit irrespective of onsetto-treatment interval . Although there is still no definitive evidence that primary IT steroid therapy is more effective than systemic therapy, there is some evidence that it may provide additional benefit where there has been no response This article is protected by copyright. All rights reserved. Accepted Article to primary therapy . A limited meta-analysis showed a mean difference of improvement of 13.3 dB that was statistically significant . Salvage IT therapy may be considered where primary therapy has failed, especially when the disability is severe and is the preference of a well informed patient. The risk profile, discomfort and the labour intensive nature of the intervention must be taken into account. Hyperbaric Oxygen Therapy (HBOT) for ISSNHL. It is postulated that HBOT delivers an increased partial pressure of oxygen to inner ear structures, which may be beneficial as vascular compromise and cochlear ischaemia are suggested to contribute to ISSNHL. Risks of therapy consist of middle ear, sinus and pulmonary barotrauma. Some patients may not be suitable for this treatment modality due to confinement anxiety. A Cochrane review reported an improvement in hearing with HBOT in the included studies, although it warned that methodological inadequacies meant results had to be interpreted with caution. The analysis suggested that we would need to treat 5 patients with HBOT in order to improve the hearing of one person by 25%  Currently the cost and limited availability of HBOT in addition to the lack of high quality evidence make it impractical for most patients may be an area of research interest for the future. Anitviral therapy for ISSNHL. Viral infection is thought to be a potential cause for SSNHL. The most commonly used regimen in the literature was IV acyclovir 10mg/kg TDS. A 2012 Cochrane review identified 4 RCTs involving 257 patients. All involved an antiviral therapy versus placebo in addition to systemic corticosteroid therapy. No significant improvement was demonstrated in any of the trials . Therefore, there is no evidence to support the routine use of antiviral therapy in ISSNHL. This article is protected by copyright. All rights reserved. Accepted Article Vasodilators and vasoactive substances for ISSNHL. An interruption of vascular flow to the cochlea is a theoretical cause of SSNHL. Carbogen (5% carbon dioxide and 95% oxygen) has been shown to increase mean perilymph oxygen tension  and hence its use in SSHNL has been evaluated. Prostoglandin E1 is a known vasodilator and Dextran is thought to improve microcirculation through an antithrombotic effect. A Cochrane review from 2010 identified only 3 RCTs that examined Carbogen, Prostoglandin E1 and naftidrofuryl with Dextran . Prostoglandin E1 showed no benefit in mean hearing although there was benefit in high frequency hearing gain and an improvement in tinnitus. Of the patients receiving Carbogen 76.9% showed an improvement versus 50% in the control group. Patients receiving naftidrofuryl with dextran showed marked improvement in the low audiometric frequencies in 70% of cases versus 40% receiving dextran alone. This group of agents is particularly difficult to assess due to the heterogeneity of the agents and regimens used. There is currently insufficient evidence to support the routine use of these agents. INSERT ‘KEYPOINTS ON MEDICAL MANAGEMENT’ BOX (iv) Further Management Patients must be managed on an individual basis. If there is a severe bilateral loss consideration must be given to hospital admission, especially if there are fears that they will not cope at home with the new level of hearing disability. If the ability to communicate is affected then temporary amplification should be provided for the patient. More permanent amplification via hearing aids, bone anchored hearing aids and cochlear implantation should be considered if there is no satisfactory resolution of hearing levels after a period of observation. This article is protected by copyright. All rights reserved. Accepted Article Patients must be treated with empathy as the illness may have a devastating impact on their quality of life. Conclusion SSNHL is an important condition that can have a significant impact on quality of life. Initial assessment is directed at establishing a potential cause that should be treated accordingly. All patients should have a retrocochlear lesion excluded, an MRI scan with contrast being the investigation of choice. Although there is contradictory evidence regarding the efficacy of oral steroid therapy, the potential severity of the disability and relatively low morbidity of treatment suggests that steroid therapy should be offered to patients. If systemic steroids are a relative contraindication then consideration may be given to IT therapy. Furthermore, when there has been a failure to respond to oral steroid therapy then consideration may be given to salvage IT steroids. In each of these scenarios the patient should be counselled regarding the paucity of current evidence and the potential side effects of therapy. Further high quality, well-designed clinical trials using homogenous treatment regimens are very eagerly awaited. 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JAMA. 305, (20), 2071-2079.  Spear S.A. & Schwartz S.R. (2011) lntratympanic steroids for sudden sensorineural hearing loss: a systematic review. Otolaryngol Head Neck Surg. 145, (4), 534-43.  Bennett M.H., Kertesz T., Perleth M. et al. (2012) Hyperbaric oxygen for idiopathic sudden sensorineural hearing loss and tinnitus. Cochrane Database Syst Rev. D004739.  Awad Z., Huins C., Pothier DD. (2012) Antivirals for idiopathic sudden sensorineural hearing loss. Cochrane Database Syst Rev. CD006987.  Agarwal L., Pothier D.D. (2009) Vasodilators and vasoactive substances for idiopathic sudden sensorineural hearing loss. Cochrane Database Syst Rev. CD00342 This article is protected by copyright. All rights reserved. Accepted Article Table 1. Selected Conditions That May Be Associated with Bilateral Sudden Hearing Loss. Taken from . This article is protected by copyright. All rights reserved. Accepted Article Table 2. Features Often Associated with Specific Disorders Underlying Hearing Loss. Taken from . Sudden onset of bilateral hearing loss. Antecedent fluctuating hearing loss on one or both sides. Isolated low-frequency hearing trough suggesting Meniere disease. Concurrent onset of severe bilateral vestibular loss with oscillopsia. Accompanying focal weakness, dysarthria, hemiataxia, encephalopathy, severe headaches, diplopia. Downbeating or gaze-evoked nystagmus. Brain imaging indicating stroke or structural lesion likely to explain the hearing loss. Severe head trauma coincident with the hearing loss on one or both sides. Recent acoustic trauma. A history of concurrent or recent eye pain, redness, lacrimation, and photophobia. Key points On Medical Management • • • • If a specific cause for SSNHL is found, the patient should be managed according to the diagnosis. If idiopathic in nature, patients may be offered a course of oral steroids. If systemic steroids are contraindicated and/or there is no improvement with initial oral therapy, IT steroids as either primary or salvage therapy may be considered. The use of antiviral, HBOT, vasodilator and vasoactive agents are not currently supported by the literature. Key points On Imaging • • All patients with SSNHL should undergo MRI scanning unless contraindicated. If MRI is contraindicated, CT imaging and ABR testing should be considered. This article is protected by copyright. All rights reserved. Accepted Article Key points On Baseline Investigations • • • All patients with SSNHL should be assessed with a thorough history and examination to identify any specific systemic cause. A PTA should be performed in all patients. Targeted laboratory investigations should be formed after initial patient This article is protected by copyright. All rights reserved. Accepted Article Patient identified with SSNHL Assessment by ENT History & Examination (Including Drug History) No systemic cause found or suspected. ISSNHL PTA Baseline Investigations: FBC, ESR, CRP, Antinuclear antibodies, Anticardiolipin antibodies, Lupus anticoagulant, Antineutrophil cytoplasmic antibodies, clotting factors & syphilis serology. Imaging: MRI scanning should be performed in all patients. If MRI is contraindicated then CT or ABR testing should be performed. Contraindication to systemic steroid therapy. Management with Oral Steroid Therapy: Discuss the evidence for steroid therapy with the patient. Offer patient oral prednisolone 1mg/kg/day for 7 to 10 days followed by tapering dose. Consider Intratympanic (IT) Steroid Therapy. Systemic cause found. Initiate management for identified cause. CP angle lesion identified. Refer for Neuro-otology assessment. No improvement or IT therapy declined by patient. Refer for auditory amplification if appropriate. Review in 10-14 days with PTA. No improvement. Improved This article is protected by copyright. All rights reserved.