- Sudden deafness
- Sensorineural hearing loss
- Viral infection
A number of theories have been proposed to explain the etiopathogenesis of idiopathic sudden sensorineural hearing loss (ISSHL), including viral infection, vascular occlusion, breaks of labyrinthine membranes, immune-mediated mechanisms and abnormal cellular stress responses within the cochlea. In the present paper, we provide a critical review of the viral hypothesis of ISSHL. The evidence reviewed includes published reports of epidemiological and serological studies, clinical observations and results of antiviral therapy, morphological and histopathological studies, as well as results of animal experiments. The published evidence does not satisfy the majority of the Henle-Koch postulates for viral causation of an infectious disease. Possible explanations as to why these postulates remain unfulfilled are reviewed, and future studies that may provide more insight are described. We also discuss other mechanisms that have been postulated to explain ISSHL. Our review indicates that vascular occlusion, labyrinthine membrane breaks and immune-mediated mechanisms are unlikely to be common causes of ISSHL. Finally, we review our recently proposed theory that abnormal cellular stress responses within the cochlea may be responsible for ISSHL.
Copyright © 2008 S. Karger AG, Basel
- De Kleyn A: Sudden complete or partial loss of function of the octavus-system in apparently normal persons. Acta Otolaryngol (Stockh) 1944;32:407–429.
- Rasmussen H: Sudden deafness. Acta Otolaryngol 1949;37:65–70.
- van Dishoeck H, Bierman T: Sudden perceptive deafness and viral infection (report of the first one hundred patients). Ann Otol Rhinol Laryngol 1957;66:963–980.
- Simmons FB: Theory of membrane breaks in sudden hearing loss. Arch Otolaryngol 1968;88:41–48.
- Veldman JE: Cochlear and retrocochlear immune-mediated inner ear disorders. Pathogenetic mechanisms and diagnostic tools. Ann Otol Rhinol Laryngol 1986;95:535–540.
- Merchant SN, Adams JC, Nadol JB: Pathology and pathophysiology of idiopathic sudden sensorineural hearing loss. Otol Neurotol 2005;26:151–160.
- Schuknecht HF, Kimura RS, Naufal PM: The pathology of sudden deafness. Acta Otolaryngol (Stockh) 1973;76:75–97.
- Schuknecht HF, Donovan ED: The pathology of idiopathic sudden sensorineural hearing loss. Arch Otorhinolaryngol 1986;243:1–15.
- Wilson WR: The relationship of the herpesvirus family to sudden hearing loss: a prospective clinical study and literature review. Laryngoscope 1986;96:870–877.
- Rivers TM: Viruses and Koch’s postulates. J Bacteriol 1937;33:1.
- Evans AS: Causation and disease: the Henle-Koch postulates revisited. Yale J Biol Med 1976;49:175–195.
- Vuori M, Lahikainen EA, Peltonen T: Perceptive deafness in connection with mumps. A study of 298 servicemen suffering from mumps. Acta Otolaryngol 1962;55:231–236.
- Veltri RW, Wilson WR, Sprinkle PM, Rodman SM, Kavesh DA: The implication of viruses in idiopathic sudden hearing loss: primary infection or reactivation of latent viruses? Otolaryngol Head Neck Surg 1981;89:137–141.
- Yanagita N, Murahashi K: A comparative study of mumps deafness and idiopathic profound sudden deafness. Arch Otorhinolaryngol 1986;243:197–199.
- Nomura Y, Harada T, Sakata H, Sugiura A: Sudden deafness and asymptomatic mumps. Acta Otolaryngol Suppl 1988;456:9–11.
- Nomura Y, Harada T, Hara M: Viral infection and the inner ear. ORL J Otorhinolaryngol Relat Spec 1988;50:201–211.
- Okamoto M, Shitara T, Nakayama M, Takamiya H, Nishiyama K, Ono Y, Sano H: Sudden deafness accompanied by asymptomatic mumps. Acta Otolaryngol Suppl 1994;514:45–48.
- Kobayashi H, Suzuki A, Nomura Y: Unilateral hearing loss following rubella infection in an adult. Acta Otolaryngol Suppl 1994;514:49–51.
- Pitkäranta A, Vasama JP, Julkunen I: Sudden deafness and viral infections. Otorhinolaryngol Nova 1999;9:190–197.
- Koide J, Yanagita N, Hondo R, Kurata T: Serological and clinical study of herpes simplex virus infection in patients with sudden deafness. Acta Otolaryngol Suppl 1988;456:21–26.
- Fukuda S, Furuta Y, Takasu T, Suzuki S, Inuyama Y, Nagashima K: The significance of herpes viral latency in the spiral ganglia. Acta Otolaryngol Suppl 1994;514:108–110.
- Takasaki T, Higashikawa M, Motoyama S, Sugita K, Kurane I: Serum antibodies to human herpesvirus 7, human herpesvirus 6 and cytomegalovirus in patients with idiopathic facial nerve palsy or sudden deafness. J Laryngol Otol 1998;112:617–621.
- Straus SE: Introduction to Herpesviridae; in Mandell GL, Bennett JE, Dolin R (eds): Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, ed 6. Philadelphia, Elsevier Churchill Livingstone, 2005, pp 1756–1761.
- Pitkäranta A, Julkunen I: Sudden deafness: lack of evidence for systemic viral infection. Otolaryngol Head Neck Surg 1998;118:397–399.
- Mattox DE, Simmons FB: Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86:463–480.
- Stokroos RJ, Albers FW, Tenvergert EM: Antiviral treatment of idiopathic sudden sensorineural hearing loss: a prospective, randomized, double-blind clinical trial. Acta Otolaryngol 1998;118:488–495.
- Tucci DL, Farmer JC Jr, Kitch RD, Witsell DL: Treatment of sudden sensorineural hearing loss with systemic steroids and valacyclovir. Otol Neurotol 2002;23:301–308.
- Westerlaken BO, Stokroos RJ, Wit HP, Dhooge IJM, Albers FWJ: Treatment of idiopathic sudden sensorineural hearing loss with antiviral therapy: a prospective, randomized, double-blind clinical trial. Ann Otol Rhinol Laryngol 2003;112:993–1000.
- Uri N, Doweck I, Cohen-Kerem R, Greenberg E: Acyclovir in the treatment of idiopathic sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2003;128:544–549.
- Nadol JB Jr: Hearing loss as a sequela of meningitis. Laryngoscope 1978;88:739–755.
- Modlin JF: Coxsackieviruses, echoviruses, and newer enteroviruses; in Mandell GL, Bennett JE, Dolin R (eds): Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, ed 6. Philadelphia, Elsevier Churchill Livingstone, 2005, pp 2148–2161.
- Azimi PH, Cramblett HG, Haynes RE: Mumps meningoencephalitis in children. JAMA 1969;207:509–512.
- Westmore GA, Pickard BH, Stern H: Isolation of mumps virus from the inner ear after sudden deafness. BMJ 1979;1:14–15.
- Schuknecht HF, Benitez J, Beekhuis J, Igarashi M, Singleton G, Ruedi L: The pathology of sudden deafness. Laryngoscope 1962;72:1142–1157.
- Beal DD, Hemenway WG, Lindsay JR: Inner ear pathology of sudden deafness. Arch Otolaryngol 1967;85:591–598.
- Gussen R: Sudden deafness of vascular origin: a human temporal bone study. Ann Otol Rhinol Laryngol 1976;85:94–100.
- Nomura Y, Hiraide F: Sudden deafness: a histopathological study. J Laryngol Otol 1976;90:1121–1142.
- Ishii T, Toriyama M: Sudden deafness with severe loss of cochlear neurons. Ann Otol Rhinol Laryngol 1977;86:541–548.
- Sando I, Harada T, Loehr A, Sobel JH: Sudden deafness: histopathologic correlation in temporal bone. Ann Otol Rhinol Laryngol 1977;86:269–279.
- Gussen R: Sudden hearing loss associated with cochlear membrane rupture. Arch Otolaryngol 1981;107:598–600.
- Gussen R: Sudden deafness associated with bilateral Reissner’s membrane ruptures. Am J Otolaryngol 1983;4:27–32.
- Schuknecht HF: Pathology of the Ear, ed 2. Philadelphia, Lea and Febiger, 1993, p 672.
- Yoon TH, Paparella MM, Schachern PA, Alleva M: Histopathology of sudden hearing loss. Laryngoscope 1990;100:707–715.
- Vasama JP, Linthicum FH Jr: Idiopathic sudden sensorineural hearing loss: temporal bone histopathologic study. Ann Otol Rhinol Laryngol 2000;109:527–532.
- Khetarpal U, Nadol JB Jr, Glynn RJ: Idiopathic sudden sensorineural hearing loss and postnatal viral labyrinthitis: a statistical comparison of temporal bone findings. Ann Otol Rhinol Laryngol 1990;99:969–976.
- Woolf NK, Harris JP, Ryan AF, Butler DM, Richman DD: Hearing loss in experimental cytomegalovirus infection of the guinea pig inner ear: prevention by systemic immunity. Ann Otol Rhinol Laryngol 1985;94:350–356.
- Nomura Y, Kurata T, Saito K: Cochlear changes after herpes simplex virus infection. Acta Otolaryngol 1985;99:419–427.
- Tanaka K, Fukuda S, Suenaga T, Terayama Y: Experimental mumps virus-induced labyrinthitis: immunohistochemical and ultrastructural studies. Acta Otolaryngol Suppl (Stockh) 1988;456:98–105.
- Harris JP, Fan JT, Keithley EM: Immunologic responses in experimental cytomegalovirus labyrinthitis. Am J Otolaryngol 1990;11:304–308.
- Tamura M, Ogino S, Matsunaga T, Asada H, Kondo K, Kurata T, Yamanishi K: Experimental labyrinthitis in guinea pigs caused by a hantavirus. ORL J Otorhinolaryngol Relat Spec 1991;53:1–5.
- Stokroos RJ, Albers FWJ, Schirm J: The etiology of idiopathic sudden sensorineural hearing loss: experimental herpes simplex virus infection of the inner ear. Am J Otol 1998;19:447–452.
- Karmody CS: Viral labyrinthitis. An experimental study. Ann Otol Rhinol Laryngol 1975;84:179–181.
- Davis LE, Johnson RT: Experimental viral infections of the inner ear. I. Acute infections of the newborn hamster labyrinth. Lab Invest 1976;34:349–356.
- Davis GL: In vitro models of viral-induced congenital deafness. Am J Otol 1981;3:156–160.
- Tanaka K, Hirai T, Suenaga T, Terayama Y, Fukuda S, Matsumiya H: Experimental Sendai virus-induced labyrinthitis in guinea pigs: an ultrastructural study of cochlear lesions. Ann Otol Rhinol Laryngol 1984;93:240–246.
- McKenna MJ, Kristiansen AG, Tropitzsch A, Tranebjærg L, Merchant SN: Deoxyribonucleic acid contamination in archival human temporal bones – a potentially significant problem. Otol Neurotol 2002;23:789–792.
- Noonan JP, Coop G, Kudaravalli S, Smith D, Krause J, Alessi J, Chen F, Platt D, Paabo S, Pritchard JK, Rubin EM: Sequencing and analysis of Neanderthal genomic DNA. Science 2006;314:1113–1118.
- Green RE, Krause J, Ptak SE, Briggs AW, Ronan MT, Simons JF, Du L, Egholm M, Rothberg JM, Paunovic M, Paabo S: Analysis of one million base pairs of Neanderthal DNA. Nature 2006;444:330–336.
- Perlman HB, Kimura RS, Fernandez C: Experiments on temporary occlusion of the internal auditory artery. Laryngoscope 1959;69:591–613.
- Perlman HB, Kimura R: Experimental obstruction of the venous drainage and arterial supply of the inner ear. Ann Otol Rhinol Laryngol 1957;66:537–546.
- Belal A: The effects of vascular occlusion on the human inner ear. J Laryngol Otol 1979;93:955–968.
- Goodhill V: Labyrinthine membrane ruptures in sudden sensorineural hearing loss. Proc R Soc Med 1976;69:565–572.
- Simmons FB: The double membrane break syndrome in sudden hearing loss. Laryngoscope 1979;89:59–66.
- Veldman JE, Hanada T, Meeuwsen F: Diagnostic and therapeutic dilemmas in rapidly progressive sensorineural hearing loss and sudden deafness. Acta Otolaryngol (Stockh) 1993;113:303–306.
- García Berrocal JR, Ramírez-Camacho R: Sudden sensorineural hearing loss: supporting the immunologic theory. Ann Otol Rhinol Laryngol 2002;111:989–997.
- Yoo TJ, Tomoda K, Hernandez AD: Type II collagen-induced autoimmune inner ear lesions in guinea pigs. Ann Otol Rhinol Laryngol Suppl 1984;113:3–5.
- Boulassel MR, Tomasi JP, Deggouj N, Gersdorff M: Identification of beta-actin as a candidate autoantigen in autoimmune inner ear disease. Clin Otolaryngol Allied Sci 2000;25: 535–541.
- Boulassel MR, Deggouj N, Tomasi JP, Gersdorff M: Inner ear autoantibodies and their targets in patients with autoimmune inner ear diseases. Acta Otolaryngol 2001;121:28–34.
- Solares CA, Edling AE, Johnson JM, Baek MJ, Hirose K, Hughes GB, Tuohy VK: Murine autoimmune hearing loss mediated by CD4+ T cells specific for inner ear peptides. J Clin Invest 2004;113:1210–1217.
- Nair TS, Kozma KE, Hoefling NL, Kommareddi PK, Ueda Y, Gong TW, Lomax MI, Lansford CD, Telian SA, Satar B, Arts HA, El-Kashlan HK, Berryhill WE, Raphael Y, Carey TE: Identification and characterization of choline transporter-like protein 2, an inner ear glycoprotein of 68 and 72 kDa that is the target of antibody-induced hearing loss. J Neurosci 2004;24:1772–1779.
- Disher MJ, Ramakrishnan A, Nair TS, Miller JM, Telian SA, Arts HA, Sataloff RT, Altschuler RA, Raphael Y, Carey TE: Human autoantibodies and monoclonal antibody KHRI-3 bind to a phylogenetically conserved inner-ear-supporting cell antigen. Ann NY Acad Sci 1997;830:253–265.
- Nair TS, Raphael Y, Dolan DF, Parrett TJ, Perlman LS, Brahmbhatt VR, Wang Y, Hou X, Ganjei G, Nuttall AL, Altschuler RA, Carey TE: Monoclonal antibody induced hearing loss. Hear Res 1995;83:101–113.
- Nair TS, Prieskorn DM, Miller JM, Mori A, Gray J, Carey TE: In vivo binding and hearing loss after intracochlear infusion of KHRI-3 antibody. Hear Res 1997;107:93–101.
- Adams JC: Clinical implications of inflammatory cytokines in the cochlea: a technical note. Otol Neurotol 2002;23:316–322.
- Kikuchi T, Kimura RS, Paul DL, Adams JC: Gap junctions in the rat cochlea: immunohistochemical and ultrastructural analysis. Anat Embryol (Berl) 1995;191:101–118.
- Kikuchi T, Kimura RS, Paul DL, Takasaka T, Adams JC: Gap junction systems in the mammalian cochlea. Brain Res Brain Res Rev 2000;32:163–166.
J.R. García-Berrocal: The critical review presented by the authors states the lack of evidence for any etiology for SSHL, including the viral infection. Although viral and vascular etiologies were classically suggested, inner ear membrane breaks and more recently immune-mediated mechanisms have been added. Efforts to assign either etiology may be conceptually wrong based on current knowledge since the implication of diverse etiopathogenetic factors in suddenly presenting cochleovestibular damage has been proven. Thus, an immune reaction could be triggered by a virus, leading to vasculitis and lymphocyte recruitment to the inner ear. However, until advances in technology allow us to identify viruses in vivo in inner ear fluids without causing irreparable damage, as well as to confirm the direct cytopathic effects of viral infection in the cochlea, the application of immunological and serological studies will continue to provide a presumptive diagnosis in some patients with sensorineural hearing loss. Otherwise, authors consider an attractive hypothesis that states that idiopathic sudden deafness (SD) may be induced by activation of cellular stress inside the cochlea. Triggering events such as a systemic viral illness, a systemic inflammatory disorder and physical, mental or metabolic stress have been previously involved as predisposing risk factors in the development of SD. Stressors modulate immune function; after initiation of a psychological or physical stressor, a transient increase in the number of CD8 and natural killer lymphocytes is observed . Chronic stress decreases CD8 T cells, contributing to the increase in viral infectious diseases (increased susceptibility to infection or to activation of latent infection) because the CD8 population is a critical defense against viral infections . During an immune response, the nervous and the immune system interact and this interaction is essential for maintaining homeostasis, even under stressful stimulation/challenge. Hence, stress has a significant impact upon the activity of the immune response. Cortisol, the end product of the hypothalamic-pituitary-adrenal (HPA) axis, is produced and secreted in stress and is capable of decreasing proinflammatory activities by inhibiting type 1 immunological pathways (thereby favoring type 2 activities). Further, under stimulation the catecholamine norepinephrine, an effector of the sympathetic nervous system (SNS), is released from the sympathetic nerve terminals in lymphoid organs and the target immune cells express adrenoreceptors. Through stimulation of these receptors, norepinephrine affects lymphocyte traffic, circulation and proliferation, and it modulates cytokine production and the functional activity of different lymphoid cells. Catecholamines also inhibit the production of type 1 proinflammatory cytokines, where they stimulate the production of type 2 – mainly anti-inflammatory cytokines – and various types of antibodies . Therefore, the activation of stress response components – mainly the SNS – during an immune response may have proinflammatory consequences as well. Stress/stressors (bacterial and viral infections, free radicals, oxidative stress) and basic stress response functions (HPA axis and SNS activity) involve the stimulation of stress-sensitive heat shock protein production/gene expression and NFκB activation. The nuclear transcription factor NFκB triggers the activation of a large number of genes in response to inflammation, viral and bacterial infections and other stressful situations. Proinflammation involves complex pathways that include stress response, heat shock protein, NFκB, iNOS and free radical activation/induction and may represent an underlying concept that contributes to the onset and progression of various disease processes . Thereby, the stress response theory could represent a common etiopathogenetic pathway for the main etiologies suggested for SD. Likewise, this hypothesis provides a main role to type II fibrocytes and supporting cells of the organ of Corti. In this respect, we fully agree with the authors since these cells should be a critical target of any treatment for inner ear disorders . However, further research must be performed in order to clarify clinical situations in which patients with a stress-induced SD do not improve their hearing after corticosteroid therapy and situations in which the hearing loss is not reversed after such a treatment in patients with an autoinflammatory disease [unpubl., pers. obs.].References1Herbert TB, Cohen S, Marsland AL, Bachen EA, Rabin BS, Muldoon MF, Manuck SB: Cardiovascular reactivity and the course of immune response to an acute psychological stressor. Psychosom Med 1994;56:337–344.2Rabin BS: Effect of stress on immune function, allergy and health. Curr Opin Otolaryngol Head Neck Surg 2000;8:234–238.3Esch T, Stefano GB: Proinflammation: a common denominator or initiator of different pathophysiological disease processes. Med Sci Monit 2002;8:HY1–HY9.4Ramírez-Camacho R, García-Berrocal JR, Trinidad A, González-García JA, Verdaguer JM, Ibáñez A, Rodríguez A, Sanz R: Central role of supporting cells in cochlear homeostasis and pathology. Med Hypotheses 2006;67:550–555.
T. Linder: Saumil Merchant and his colleagues very elegantly listed the pros and cons of a viral etiopathogenesis for sudden sensorineural hearing loss (SNHL). Except for mumps virus, there are few other viral pathogens known which could consistently induce a unilateral SNHL [see the article by Oliveira et al., this issue, pp. 42–51]. Their arguments clearly illustrate the fact, that viral inflammation of the inner ear or cochlear nerve is very unlikely in SNHL. Even 1.5- and 3-tesla MRI scans performed within days of the acute onset could not verify signs of inflammation, ischemia or bleeding as a possible incident. Therefore, it is mandatory to look for other etiologies and they have come up with an interesting theory of ‘stress’-induced activation of NFκB within the cochlea. However, in their membrane-rupture section they state that ‘Indeed, many patients report experiencing deafness upon awakening or while being sedentary’ with no consistent relation to known stress factors within the body. Also the unilaterality of SNHL needs to be further addressed in their theory. In summary, there is great need for new ideas on a possible etiopathogenesis of SNHL and the NFκB theory is tempting to follow.
R. Maire: The authors made an excellent and exhaustive critical review of the different hypotheses proposed to explain the etiology and pathogenesis of idiopathic SSHL. Especially, they focused on the viral hypothesis which is severely questioned. As a new postulate, they proposed and discussed the pathophysiological concept of abnormal cellular stress response, which may be a promising alternative to explain SD.
C.A. Oliveira: This is a very thorough review of the current knowledge about the etiology of SSHL. At least two etiologies seem to be the cause of some but not all SSHL cases: viral and vascular etiologies. Other possible etiologies have less reliable evidence to support them. It seems to me that at least one statement could have been made from this review: SSHL seems to have multiple causes. Two are reasonably acceptable at least in some cases: viral and vascular causes.
I. Pyykkö: The paper describes an interesting mechanism producing apoptosis in the inner ear by activating the NFκB pathway, but the actual mechanism was not explained. No evidence for activation of this mechanism was demonstrated either. Therefore, no argument for or against it can be presented. An argument against viral infection presented in this paper was that Pitkäranta and Julkunen did not find cytokine activation that commonly occurs in general viral infection. Therefore, the ‘viral theory’ would be unlikely. The clinical evidence shows that it is very unlikely that in a local activation of viral replication the body cytokine responses would be significantly affected.
Saumil N. Merchant, MD
Massachusetts Eye and Ear Infirmary
243 Charles Street
Boston, MA 02114 (USA)
Tel. +1 617 573 3503, Fax +1 617 573 3939, E-Mail firstname.lastname@example.org
Published online: February 1, 2008
Number of Print Pages : 11
Number of Figures : 0, Number of Tables : 0, Number of References : 80
ORL (Journal for Oto-Rhino-Laryngology, Head and Neck Surgery)
Vol. 70, No. 1, Year 2008 (Cover Date: February 2008)
Journal Editor: O'Malley Jr., B.W.
ISSN: 0301–1569 (Print), eISSN: 1423–0275 (Online)
For additional information: http://www.karger.com/ORL
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.