RIVISTA TRIMESTRALE DI OTORINOLARINGOLOGIA, AUDIOLOGIA FONIATRIA, CHIRURGIA CERVICO-FACCIALE MAXILLO-FACCIALE PLASTICA RICOSTRUTTIVA OTONEUROCHIRURGIA VOL.60 No.

3 SETTEMBRE 2010

Intratympanic therapies for inner ear disorders

Guest Editors: A. De Stefano, F. Dispenza

OTORINOLARINGOLOGIA
Rivista trimestrale di otorinolaringologia, audiologia, foniatria chirurgia cervico-facciale, maxillo-facciale, plastica-ricostruttiva, otoneurochirurgia. Continuazione di: Minerva Otorinolaringologica, Nuovo Archivio Italiano di Otologia, Rinologia e Laringologia, Bollettino delle malattie dellorecchio, della gola, del naso, LOtorinolaringologia Italiana
Direttori A. OTTAVIANI - O. PIGNATARO Consulenti e Revisori

Otorinolaringologia e chirurgia cervico-facciale

A. ANTONELLI A. BOSATRA M. BUSSI C. CENACCHI G. CERVELLERA A. CIMINO V. COLLETTI S. CONTICELLO G. CORTESINA I. DE VINCENTIIS C. GIORDANO A. DI GIROLAMO P. FERRARA P. FILIPPI G. GALETTI B. GALIOTO C. GALLETTI G. MAFFEI T. MARULLO M. MAURIZI

P. MIANI E. MIRA G. MOTTA F. PIRAGINE E. PIRODDA P. PUXEDDU G. RALLI V. RICCI O. SALA A. SARTORIS G. SULSENTI C. ZINI

Chirurgia maxillo-facciale
R. BRUSATI C. CURIONI

Chirurgia plastica-ricostruttiva
A. AZZOLINI L. DONATI G. ZAOLI

Anatomia patologica
H. E. KAISER (USA)

Otoneurochirurgia
A. MAZZONI R. VILLANI

Audiologia
G. GRISANTI

Otoneurologia
A. DE STEFANO F. DISPENZA E. MIRA

Foniatria
L. CROATTO M. IENGO O. SCHINDLER Direttore Responsabile A. OLIARO

Rinologia
D. PASSALI

This journal is PEER REVIEWED and is quoted in: EMBASE/ Excerpta Medica Redazione - Edizioni Minerva Medica - Via Lamarmora 3 - 20122 Milano - Tel. (02) 55.18.43.79 - 59.90.00.41 - Fax (02) 55.18.09.54 Direzione, ufficio grafico, ufficio pubblicit, fotocomposizione, amministrazione - Edizioni Minerva Medica - Corso Bramante 83-85 - 10126 Torino -

Tel. (011) 67.82.82 - Fax (011) 67.45.02 - E-mail: minervamedica@minervamedica.it Web Site: www.minervamedica.it Stampa - Edizioni Minerva Medica - Tipografia di Saluzzo - Corso IV Novembre 29-31 - 12037 Saluzzo (CN) - Tel. (0175) 249405 - Fax (0175) 249407 Abbonamento annuo: Italia - Individuale: Cartaceo 85,00, Cartaceo+Online 90,00; Istituzionale: Cartaceo 120,00, Online (Small 230,00, Medium 260,00, Large 300,00, Extra Large 315,00), Cartaceo+Online (Small 240,00, Medium 275,00, Large 315,00, Extra Large 330,00); il fascicolo 35,00. Unione Europea - Individuale: Cartaceo 145,00, Cartaceo+Online 155,00; Istituzionale: Cartaceo 225,00, Online (Small 230,00, Medium 260,00, Large 300,00, Extra Large 315,00), Cartaceo+Online (Small 240,00, Medium 275,00, Large 315,00, Extra Large 330,00); il fascicolo 60,00. Paesi extraeuropei - Individuale: Cartaceo 160,00, Cartaceo+Online 170,00; Istituzionale: Cartaceo 250,00, Online (Small 255,00, Medium 285,00, Large 330,00, Extra Large 345,00), Cartaceo+Online (Small 265,00, Medium 300,00, Large 345,00, Extra Large 360,00); il fascicolo 70,00. Gli abbonati possono utilizzare le seguenti forme di pagamento: a) assegno bancario; b) bonifico bancario a: Edizioni Minerva Medica, INTESA SANPAOLO Agenzia n. 18 Torino. IBAN: IT45 K030 6909 2191 0000 0002 917 c) conto corrente postale 00279109 intestato a Edizioni Minerva Medica, Corso Bramante 83-85, 10126 Torino; d) carte di credito Diners Club International, Master Card, VISA, American Express I cambi di indirizzo di spedizione, e-mail o di qualsiasi altro dato di abbonamento vanno segnalati tempestivamente inviando i nuovi e vecchi dati per posta, fax, e-mail o direttamente sul sito www.minervamedica.it alla sezione I tuoi abbonamenti - Contatta ufficio abbonamenti. I reclami per i fascicoli mancanti devono pervenire entro 6 mesi dalla data di pubblicazione del fascicolo. I prezzi dei fascicoli e delle annate arretrati sono disponibili su richiesta. Edizioni Minerva Medica - Torino 2010 Tutti i diritti sono riservati. Nessuna parte di questa pubblicazione pu essere riprodotta, trasmessa e memorizzata in qualsiasi forma e con qualsiasi mezzo Pubblicazione trimestrale. Autorizzazione del Tribunale di Torino n. 553 del 19-5-1981. Iscrizione nel registro nazionale della stampa di cui alla legge 5-81981 n. 416 art. 11 con il numero 00 148 vol. 2 foglio 377 in data 18-8-1982. Pubblicazione periodica trimestrale poste italiane spedizione in a.p. 45% art. 2 comma 20/b legge 662/96 aut. 605/dc/dci/cn

Studio grafico della copertina: Eleonora Garosci

NORME PER GLI AUTORI

La rivista Otorinolaringologia pubblica articoli scientifici su argomenti di otorinolaringologia, chirurgia capo-collo, chirurgia plastica ricostruttiva, otoneurochirurgia. I contributi possono essere redatti come editoriali, articoli originali, review, casi clinici, note di terapia, articoli speciali, lettere alla direzione. I manoscritti devono essere preparati seguendo rigorosamente le norme per gli Autori, che sono conformi agli Uniform Requirements for Manuscripts Submitted to Biomedical Editors editi a cura dellInternational Committee of Medical Journal Editors (www.icmje.org). Non saranno presi in considerazione gli articoli che non si uniformano agli standard internazionali. I lavori redatti in lingua italiana o inglese o duplice versione inglese e italiana devono essere inviati alla redazione online raggiungibile dal sito delle Edizioni Minerva Medica: www.minervamedica.it Linvio del manoscritto sottintende che il lavoro originale e non ancora stato pubblicato n totalmente n in parte e che, se accettato, non verr pubblicato altrove n integralmente n in parte. Tutto il materiale iconografico deve essere originale. Liconografia tratta da altre pubblicazioni deve essere corredata da permesso dellEditore. Gli Autori accettano di trasferire la propriet dei diritti di autore alla rivista Otorinolaringologia nelleventualit che il lavoro sia pubblicato. La rivista recepisce i principi presentati nella Dichiarazione di Helsinki e ribadisce che tutte le ricerche che coinvolgano esseri umani siano condotte in conformit ad essi. La rivista recepisce altres gli International Guiding Principles for Biomedical Research Involving Animals raccomandati dalla WHO e richiede che tutte le ricerche su animali siano condotte in conformit ad essi. Gli Autori, se necessario, devono indicare che lo studio stato approvato dal comitato etico e che i pazienti hanno dato il loro consenso informato. Gli Autori devono inoltre indicare se hanno un accordo finanziario con organizzazioni coinvolte nella ricerca compilando il relativo modulo. Il lavoro deve essere accompagnato dalla seguente dichiarazione relativa ai diritti dautore, aspetti etici e conflitti di interesse, firmata da tutti gli Autori: I sottoscritti Autori trasferiscono la propriet dei diritti di autore alla rivista Otorinolaringologia, nella eventualit che il loro lavoro sia pubblicato sulla stessa rivista. Essi dichiarano che larticolo originale, non stato inviato per la pubblicazione ad altra rivista e non stato gi pubblicato n integralmente n in parte. Essi dichiarano di essere responsabili della ricerca, che hanno progettato e condotto, e di aver partecipato alla stesura e alla revisione del manoscritto presentato, di cui approvano i contenuti. Nel caso di studi condotti sugli esseri umani gli Autori riferiscono che lo studio stato approvato dal comitato etico e che i pazienti hanno sottoscritto il consenso informato. Dichiarano inoltre che la ricerca riportata nel loro lavoro stata eseguita nel rispetto della Dichiarazione di Helsinki e dei Principi internazionali che regolano la ricerca sugli animali. Si impegnano, infine, a segnalare alle Edizioni Minerva Medica eventuali conflitti di interesse, in particolare accordi finanziari con ditte farmaceutiche o biomedicali i cui prodotti siano pertinenti allargomento trattato nel manoscritto. Gli Autori accettano implicitamente che il lavoro venga sottoposto a peer-review. Tutti i lavori saranno esaminati dal Comitato di Lettura che si riserva il diritto di rifiutare il lavoro senza sottoporlo a revisione nel caso che largomento, il formato o gli aspetti etici siano inadeguati. Tutti i manoscritti accettati saranno sottoposti a revisione editoriale. In caso di richiesta di modifiche, la nuova versione corretta deve essere risottoposta alla redazione online sottolineando ed evidenziando le parti modificate. La nuova versione deve essere accompagnata da una lettera con le risposte punto per punto ai commenti dei revisori. La correzione delle bozze di stampa dovr essere limitata alla semplice revisione tipografica; eventuali modifiche del testo saranno addebitate agli Autori. Le bozze corrette dovranno essere restituite entro 3 giorni lavorativi alla redazione online di Otorinolaringologia. In caso di ritardo, la redazione della rivista potr correggere dufficio le bozze sulla base del manoscritto originale. I moduli per la richiesta di estratti vengono inviati insieme alle bozze. Per ulteriori informazioni sulle condizioni di pubblicazione contattare la redazione di Otorinolaringologia, Edizioni Minerva Medica, Corso Bramante 83-85, 10126 Torino - Tel. 011 678282 - Fax 011 674502 E-mail journals.dept@minervamedica.it TIPI DI ARTICOLI SCIENTIFICI Istruzioni per i pi frequenti tipi di lavori inviati alla rivista. Editoriale. Su invito (del Redattore Capo, del Direttore Responsabile), deve riguardare un argomento di grande rilevanza in cui lAutore esprime la sua opinione personale. Sono ammesse non pi di 1000 parole (3 pagine dattiloscritte con spaziatura doppia) e fino a 15 citazioni bibliografiche. Articolo originale. Deve portare un contributo originale allargomento trattato. Il testo deve essere di 3000-5500 parole (8-16 pagine dattiloscritte con spaziatura doppia) escluse bibliografia, tabelle e figure. Sono ammesse fino a 50 citazioni bibliografiche. Larticolo deve essere suddiviso nelle sezioni: introduzione, materiali e metodi, risultati, discussione, conclusioni. Nellintroduzione sintetizzare chiaramente lo scopo dello studio. Nella sezione dei materiali e metodi descrivere in sequenza logica come stato impostato e portato avanti lo studio, come sono stati analizzati i dati (quale ipotesi stata testata, tipo di indagine condotta, come stata fatta la randomizzazione, come sono stati reclutati e scelti i soggetti, fornire dettagli accurati sulle caratteristiche essenziali del trattamento, sui materiali utilizzati, sui dosaggi di farmaci, sulle apparecchiature non comuni, sul metodo statistico ...). Nella sezione dei risultati dare le risposte alle domande poste nellintroduzione. I risultati devono essere presentati in modo completo, chiaro, conciso eventualmente correlati di figure, grafici e tabelle. Nella sezione discussione riassumere i risultati principali, analizzare criticamente i metodi utilizzati, confrontare i risultati ottenuti con gli altri dati della letteratura, discutere le implicazioni dei risultati. Nelle conclusioni riassumere brevemente il significato dello studio e le sue implicazioni future. Review. Preferibilmente su invito (del Redattore Capo, del Direttore Responsabile), deve trattare un argomento di attualit ed interesse, presentare lo stato delle conoscenze sullargomento, analizzare le differenti opinioni sul problema trattato, essere aggiornata con gli ultimi dati della letteratura. Il testo deve essere di 6000-12000 parole (17-34 pagine dattiloscritte con spaziatura doppia) escluse bibliografia, tabelle e figure. Sono ammesse fino a 100 citazioni bibliografiche. Caso clinico. Descrizione di casi clinici di particolare interesse. Il testo deve essere di 2000-3000 parole (6-8 pagine dattiloscritte con spaziatura doppia) escluse bibliografia, tabelle e figure. Sono ammesse fino a 30 citazioni bibliografiche. Larticolo deve essere suddiviso nelle sezioni: introduzione, caso clinico o casistica clinica, discussione, conclusioni. Nota di terapia. Presentazione e valutazione di nuovi farmaci e trattamenti chirurgici. Il testo deve essere di 3000-5500 parole (8-16 pagine dattiloscritte con spaziatura doppia) escluse bibliografia, tabelle e figure. Sono ammesse fino a 30 citazioni bibliografiche. Larticolo deve essere suddiviso nelle sezioni: introduzione, materiali e metodi, risultati, discussione, conclusioni. Articolo speciale. Larticolo deve trattare argomenti di storia della medicina, organizzazione sanitaria, etica, politiche economiche e legislative riguardanti lotorinolaringologia. Il testo deve essere di 3000-7000 parole (8-20 pagine dattiloscritte con spaziatura doppia) escluse bibliografia, tabelle e figure. Sono ammesse fino a 50 citazioni bibliografiche. Lettera alla direzione. Pu far riferimento ad articoli precedentemente pubblicati sulla rivista o ad osservazioni e dati scientifici che gli autori intendano portare allattenzione dei lettori in forma sintetica. Il testo deve essere di 500-1000 parole (1-3 pagine dattiloscritte con spaziatura doppia) escluse bibliografia, tabelle e figure. Sono ammesse fino a 5 citazioni bibliografiche. Linee guida. Documenti redatti da comitati speciali o da fonti autorevoli. Il numero delle figure e delle tabelle deve essere adeguato al tipo e alla lunghezza del lavoro. PREPARAZIONE DEL MANOSCRITTO File del testo Per la preparazione del manoscritto si prega di utilizzare il modello predisposto per il tipo di lavoro prescelto (editoriale, articolo originale, review, caso clinico, , nota di terapia, articolo speciale, lettera alla direzione).

Larticolo dovr essere dattiloscritto con spaziatura doppia e con margini di almeno 2,5 cm su cartelle del formato 212297 mm (ISOA4). I formati accettati sono Word e RTF. Il file del manoscritto deve contenere il titolo, i dati autori, le note, il riassunto, le parole chiave, il testo, la bibliografia, le didascalie delle tabelle e delle figure. Tabelle e figure devono essere inviate in file separati. Titolo e dati autori Titolo (in inglese e in italiano) conciso, senza abbreviazioni. Nome e Cognome degli Autori. Affiliazione (sezione, dipartimento e istituzione) di ciascun autore. Note Dati di eventuali Congressi ai quali il lavoro sia gi stato presentato. Menzione di eventuali finanziamenti o contratti di ricerca o conflitti di interesse. Ringraziamenti. Nome, cognome, indirizzo, e-mail dellautore di contatto. Riassunto e parole chiave Il riassunto (in inglese e in italiano) non deve superare n essere inferiore alle 200-250 parole e, in caso di articolo originale e nota di terapia, deve essere strutturato nelle sezioni: obiettivo (scopo dello studio), metodi (disegno sperimentale, pazienti e interventi), risultati (cosa stato trovato), conclusioni (significato dello studio). Per le parole chiave (in inglese e in italiano) usare i termini del Medical Subjects Heading (MeSH) di MEDLINE/PubMed. Gli editoriali e le lettere alla direzione non necessitano di riassunto. Testo Per i lavori presentati in duplice versione, il testo in lingua inglese deve essere speculare al testo in lingua italiana. Identificare metodologie, apparecchiature (nome e indirizzo del costruttore tra parentesi) e procedure con dettaglio sufficiente a permettere ad altri studiosi di riprodurre i risultati. Menzionare le metodologie gi definite, incluse quelle statistiche; menzionare e fornire brevi descrizioni circa metodologie che sono state pubblicate ma non sono ben conosciute; descrivere metodologie nuove o modificate in modo sostanziale; giustificare il loro utilizzo e valutarne i limiti. Di tutti i farmaci si deve citare nome generico, dosaggio e vie di somministrazione. I nomi commerciali dei farmaci vanno citati tra parentesi. Unit di misura, simboli, abbreviazioni devono essere conformi agli standard internazionali. Le misure di lunghezza, altezza, peso e volume dovrebbero essere riportate in unit del sistema metrico (metro, chilogrammo, litro) o in loro multipli decimali. Le temperature dovrebbero essere espresse in gradi Celsius. Le pressioni arteriose in millimetri di mercurio. Tutte le misurazioni di chimica clinica dovrebbero essere espresse in unit del sistema metrico nei termini dellInternational System of Units (SI). Si scoraggia luso di simboli e sigle poco comuni. Essi vanno comunque spiegati alla prima apparizione nel testo. Bibliografia sottointeso che gli articoli citati in bibliografia siano stati letti dagli autori. La bibliografia, che deve comprendere i soli Autori citati nel testo, va numerata con numeri arabi in ordine consecutivo di prima citazione nel testo. Il richiamo delle voci bibliografiche nel testo deve essere fatto con numeri arabi in apice. La bibliografia deve essere citata nello stile standardizzato approvato dallInternational Committee of Medical Journals Editors (www.icmje.org). RIVISTE Per ogni voce si devono riportare il cognome e liniziale del nome degli Autori (elencare tutti gli Autori fino a sei, se sette o pi elencare solo i primi sei nomi seguiti da: et al.), il titolo originale dellarticolo, il titolo della rivista (attenendosi alle abbreviazioni usate di MEDLINE/ PubMed), lanno di pubblicazione, il numero del volume, il numero di pagina iniziale e finale. Nelle citazioni bibliografiche seguire attentamente la punteggiatura standard internazionale. Esempi: Articolo standard. Sutherland DE, Simmons RL, Howard RJ. Intracapsular technique of transplant nephrectomy. Surg Gynecol Obstet 1978; 146:951-2. Articolo a nome di una commissione. International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. Ann Int Med 1988;108:258-65.

Supplemento ad un fascicolo Payne DK, Sullivan MD, Massie MJ. Womens psychological reactions to breast cancer. Semin Oncol 1996;23(1 Suppl 2):89-97. LIBRI E MONOGRAFIE Per pubblicazioni non periodiche dovranno essere indicati i nomi degli Autori, il titolo, ledizione, il luogo di pubblicazione, leditore e lanno di pubblicazione. Esempi: Libro di uno o pi Autori. Rossi G. Manuale di otorinolaringologia. Torino: Edizioni Minerva Medica; 1987. Capitolo di un libro. De Meester TR. Gastroesophageal reflux disease. In: Moody FG, Carey LC, Scott Jones R, Kelly KA, Nahrwold DL, Skinner DB, editors. Surgical treatment of digestive diseases. Chicago: Year Book Medical Publishers; 1986. p. 132-58. Atti congressuali. Kimura J, Shibasaki H, editors. Recent advances in clinical neurophysiology. Proceedings of the 10th International Congress of EMG and Clinical Neurophysiology; 1995 Oct 15-19; Kyoto, Japan. Amsterdam: Elsevier; 1996. MATERIALE ELETTRONICO Articolo standard di rivista su Internet Kaul S, Diamond GA. Good enough: a primer on the analysis and interpretation of noninferiority trials. Ann Intern Med [Internet]. 2006 Jul 4 [cited 2007 Jan 4];145(1):62-9. Available from: http://www.annals.org/cgi/reprint/145/1/62.pdf Citazione standard di un libro su CD-ROM o DVD Kacmarek RM. Advanced respiratory care [CD-ROM]. Version 3.0. Philadelphia: Lippincott Williams & Wilkins; 2000. 1 CD-ROM: sound, color, 4 3/4 in. Citazione standard di una homepage AMA: helping doctors help patients [Internet]. Chicago: American Medical Association; 1995-2007 [cited 2007 Feb 22]. Available from: htpp://www.ama-assn.org/. Per la redazione della bibliografia non utilizzare le note a pie di pagina e le note di chiusura di Word. Le voci bibliografiche citate per la prima volta in una tabella o nella didascalia di una figura devono essere numerate in sequenza con le voci bibliografiche citate nel testo tenendo conto del punto in cui la tabella o la figura richiamata per la prima volta. Di conseguenza tali voci bibliografiche non devono essere elencate in fondo alla bibliografia ma secondo lordine di citazione nel testo. Didascalie delle tabelle e delle figure Per i lavori presentati in duplice versione le didascalie delle tabelle e delle figure devono essere redatte in lingua inglese. Le didascalie di tabelle e figure devono essere inserite sia nel file di testo sia nel file delle tabelle e delle figure. File delle tabelle Le tabelle devono essere inviate come file separati. I formati accettati sono Word e RTF. Ogni tabella deve essere correttamente dattiloscritta, preparata graficamente secondo lo schema di impaginazione della rivista, numerata in cifre romane, corredata dal rispettivo titolo. Eventuali annotazioni devono essere inserite al piede della tabella e non nel titolo. Le tabelle devono essere richiamate nel testo in ordine consecutivo. Per i lavori presentati in duplice versione, le tabelle e le didascalie delle tabelle devono essere redatte in lingua inglese. File delle figure Le figure devono essere inviate come file separati. Formati accettati: preferibilmente JPEG con risoluzione di 300 dpi; altri formati accettati sono TIFF, PNG, PDF (alta qualit) e Word (per i grafici). Le figure devono essere numerate in cifre arabe e corredate dalla rispettiva didascalia. Le figure devono essere richiamate nel testo in ordine consecutivo. Per i lavori presentati in duplice versione, le didascalie delle figure devono essere redatte in lingua inglese. La riproduzione deve essere limitata alla parte essenziale ai fini del lavoro. Le foto istologiche devono sempre essere accompagnate dal rapporto di ingrandimento e dal metodo di colorazione. Per le figure a colori specificare sempre se si desidera la riproduzione a colori o in bianco e nero. Il costo della riproduzione delle figure a colori sar addebitato agli Autori. Le dimensioni ottimali per la riproduzione sulla rivista sono: cm 8,6 (base) cm 4,8 (altezza) cm 8,6 (base) cm 9 (altezza) cm 17,6 (base) cm 9 (altezza) cm 17,6 (base) cm 18,5 (altezza): 1 pagina.

NOTICE TO AUTHORS
The journal Otorinolaringologia publishes scientific papers on otolaryngology, head and neck surgery, plastic and reconstructive surgery, otoneurosurgery. Manuscripts may be submitted in the form of editorials, original articles, review articles, case reports, therapeutical notes, special articles and letters to the Editor. Manuscripts are expected to comply with the instructions to authors which conform to the Uniform Requirements for Manuscripts Submitted to Biomedical Editors by the International Committee of Medical Journal Editors (www.icmje.org). Articles not conforming to international standards will not be considered for acceptance. Papers should be submitted directly to the online Editorial Office at the Edizioni Minerva Medica website: www.minervamedica.it Submission of the manuscript means that the paper is original and has not yet been totally or partially published and, if accepted, will not be published elsewhere either wholly or in part. All illustrations should be original. Illustrations taken from other publications must be accompanied by the publishers permission. The Authors agree to transfer the ownership of copyright to Otorinolaringologia in the event the manuscript is published. The journal adheres to the principles set forth in the Helsinki Declaration and states that all reported research concerning human beings should be conducted in accordance with such principles. The journal also adheres to the International Guiding Principles for Biomedical Research Involving Animals recommended by the WHO and requires that all research on animals be conducted in accordance with these principles. The Authors, if necessary, must indicate that the study has been approved by the ethics committee and that patients have given their informed consent. Authors must also indicate whether they have any financial agreement with any organization that were involved in the research by filling the relevant form. Papers must be accompanied by the following authors statement relative to copyright, ethics and conflicts of interest, signed by all authors: The undersigned authors transfer the ownership of copyright to Otorinolaringologia should their work be published in this journal. They state that the article is original, has not been submitted for publication in other journals and has not yet been published either wholly or in part. They state that they are responsible for the research that they have designed and carried out; that they have participated in drafting and revising the manuscript submitted, whose contents they approve. In the case of studies carried out on human beings, the authors confirm that the study was approved by the ethics committee and that the patients gave their informed consent. They also state that the research reported in the paper was undertaken in compliance with the Helsinki Declaration and the International Principles governing research on animals. They agree to inform Edizioni Minerva Medica of any conflict of interest that might arise, particularly any financial agreements they may have with pharmaceutical or biomedical firms whose products are pertinent to the subject matter dealt with in the manuscript. The authors implicitly agree to their paper being peer-reviewed. All manuscripts will be reviewed by Editorial Board members who reserve the right to reject the manuscript without entering the review process in the case that the topic, the format or ethical aspects are inappropriate. Once accepted, all manuscripts are subjected to copy editing. If modifications to the manuscript are requested, the corrected version should be sent to the online Editorial Office with the modified parts underlined and highlighted. The revised version should be accompanied by a letter with point-by-point responses to the reviewers comments. Correction of proofs should be limited to a simple check of the printing; any changes to the text will be charged to the authors. Corrected proofs must be sent back within 3 working days to the online Editorial Office of Otorinolaringologia. In case of delay, the editorial staff of the journal may correct the proofs on the basis of the original manuscript. Forms for ordering reprints are sent together with the proofs. For further information about publication terms please contact the Editorial Office of Otorinolaringologia, Edizioni Minerva Medica, Corso Bramante 83-85, 10126 Torino, Italy Phone +39-011678282 Fax +39-011-674502 E-mail journals.dept@minervamedica.it. ARTICLE TYPES Instructions for the most frequent types of articles submitted to the journal. Editorials. Commissioned by the Editor in Chief or the Managing Editor, editorials deal with a subject of topical interest about which the author expresses his/her personal opinion. No more than 1000 words (3 typed, double-spaced pages) and up to 15 references will be accepted. Original articles. These should be original contributions to the subject. The text should be 3000-5500 words (8 to 16 typed, doublespaced pages) not including references, tables, figures. No more than 50 references will be accepted. The article must be subdivided into the following sections: introduction, materials and methods, results, discussion, conclusions. In the introduction the aim of the study should be clearly summed up. The materials and methods section should describe in a logical sequence how the study was designed and carried out, how the data were analyzed (what hypothesis was tested, what type of study was carried out, how randomization was done, how the subjects were recruited and chosen, provide accurate details of the main features of treatment, of the materials used, of drug dosages, of unusual equipments, of the statistical method ...). In the results section the answers to the questions posed in the introduction should be given. The results should be reported fully, clearly and concisely supported, if necessary, by figures, graphs and tables. The discussion section should sum up the main results, critically analyze the methods used, compare the results obtained with other published data and discuss the implications of the results. The conclusions should briefly sum up the significance of the study and its future implications. Review articles. Generally commissioned by the Editor in Chief or the Managing Editor, review articles should discuss a topic of current interest, outline current knowledge of the subject, analyze different opinions regarding the problem discussed, be up-to-date on the latest data in the literature. The text should be 6000-12000 words (17 to 34 typed, double-spaced pages) not including references, tables, figures. No more than 100 references will be accepted. Case reports. These give a description of particularly interesting cases. The text should be 2000-3000 words (6 to 8 typed, doublespaced pages) not including references, tables, figures. No more than 30 references will be accepted. The article must be subdivided into the following sections: introduction, case report or clinical series, discussion, conclusions. Therapeutical notes. These are intended for the presentation and assessment of new medical and surgical treatments. The text should be 3000-5500 words (8 to 16 typed, double-spaced pages) not including references, tables, figures. No more than 30 references will be accepted. The article must be subdivided into the following sections: introduction, materials and methods, results, discussion, conclusions. Special articles. These are articles on the history of medicine, health care delivery, ethics, economic policy and law concerning otolaryngology. The text should be 3000-7000 words (8 to 20 typed, doublespaced pages) not including references, tables, figures. No more than 50 references will be accepted. Letters to the Editor. These may refer to articles already published in the journal or to a subject of topical interest that the authors wish to present to readers in a concise form. The text should be 500-1000 words (1 to 3 typed, double-spaced pages) not including references, tables, figures. No more than 5 references will be accepted. Guidelines. These are documents drawn up by special committees or authoritative sources. The number of figures and tables should be appropriate for the type and length of the paper. Preparation of manuscripts Text file Manuscripts must be drafted according to the template for each type of paper (editorial, original article, review, case report, therapeutical note, special article, letter to the Editor).

The paper should be type written double spaced with margins of at least 2.5 cm on 212297 mm format sheets (ISOA4). The formats accepted are Word and RTF. The text file must contain title, authors details, notes, abstract, key words, text, references and titles of tables and figures. Tables and figures should be submitted as separate files. Title and authors details Short title, with no abbreviations. First name and surname of the authors. Affiliation (section, department and institution) of each author.

Issue with supplement Payne DK, Sullivan MD, Massie MJ. Womens psychological reactions to breast cancer. Semin Oncol 1996;23(1 Suppl 2):89-97. BOOKS AND MONOGRAPHS For occasional publications, the names of authors, title, edition, place, publisher and year of publication must be given. Examples: Books by one or more authors Rossi G. Manual of Otorhinolaryngology. Turin: Edizioni Minerva Medica; 1987. Chapter from book De Meester TR. Gastroesophageal reflux disease. In: Moody FG, Carey LC, Scott Jones R, Ketly KA, Nahrwold DL, Skinner DB, editors. Surgical treatment of digestive diseases. Chicago: Year Book Medical Publishers; 1986. p. 132-58. Congress proceedings Kimura J, Shibasaki H, editors. Recent advances in clinical neurophysiology. Proceedings of the 10th International Congress of EMG and Clinical Neurophysiology; 1995 Oct 15-19; Kyoto, Japan. Amsterdam: Elsevier; 1996. ELECTRONIC MATERIAL Standard journal article on the Internet Kaul S, Diamond GA. Good enough: a primer on the analysis and interpretation of noninferiority trials. Ann Intern Med [Internet]. 2006 Jul 4 [cited 2007 Jan 4];145(1):62-9. Available from: http://www.annals.org/cgi/reprint/145/1/62.pdf Standard citation to a book on CD-ROM or DVD Kacmarek RM. Advanced respiratory care [CD-ROM]. Version 3.0. Philadelphia: Lippincott Williams & Wilkins; 2000. 1 CD-ROM: sound, color, 4 3/4 in. Standard citation to a homepage AMA: helping doctors help patients [Internet]. Chicago: American Medical Association; 1995-2007 [cited 2007 Feb 22]. Available from: http://www.ama-assn.org/. Footnotes and endnotes of Word must not be used in the preparation of references. References first cited in a table or figure legend should be numbered so that they will be in sequence with references cited in the text taking into consideration the point where the table or figure is first mentioned. Therefore, those references should not be listed at the end of the reference section but consecutively as they are cited. Titles of tables and figures Titles of tables and figures should be included both in the text file and in the file of tables and figures. File of tables Each table should be submitted as a separate file. Formats accepted are Word and RTF. Each table must be typed correctly and prepared graphically in keeping with the page layout of the journal, numbered in Roman numerals and accompanied by the relevant title. Notes should be inserted at the foot of the table and not in the title. Tables should be referenced in the text sequentially. File of figures Each figure should be submitted as a separate file. Formats accepted: JPEG set at 300 dpi resolution preferred; other formats accepted are TIFF, PNG, PDF (high quality) and Word (for graphs). Figures should be numbered in Arabic numerals and accompanied by the relevant title. Figures should be referenced in the text sequentially. Reproductions should be limited to the part that is essential to the paper. Histological photographs should always be accompanied by the magnification ratio and the staining method. If figures are in color, it should always be specified whether color or black and white reproduction is required. The cost of color figures will be charged to the Authors. Optimal dimensions for publication of figures in the journal are: 8.6 cm (base) 4.8 cm (height) 8.6 cm (base) 9 cm (height) 17.6 cm (base) 9 cm (height) 17.6 cm (base) 18.5 cm (height): 1 page.

Notes Dates of any congress where the paper has already been presented. Mention of any funding or research contracts or conflict of interest. Acknowledgements. Name, address, e-mail of the corresponding author.

Abstract and key words Articles should include an abstract of between 200 and 250 words. For original articles and therapeutical notes, the abstract should be structured as follows: aim (aim of the study), methods (experimental design, patients and interventions), results (what was found), conclusion (meaning of the study). Key words should refer to the terms from Medical Subject Headings (MeSH) of MEDLINE/PubMed. No abstracts are required for editorials or letters to the Editor. Text Identify methodologies, equipment (give name and address of manufacturer in brackets) and procedures in sufficient detail to allow other researchers to reproduce results. Specify well-known methods including statistical procedures; mention and provide a brief description of published methods which are not yet well known; describe new or modified methods at length; justify their use and evaluate their limits. For each drug generic name, dosage and administration routes should be given. Brand names for drugs should be given in brackets. Units of measurement, symbols and abbreviations must conform to international standards. Measurements of length, height, weight and volume should be given in metric units (meter, kilogram, liter) or their decimal multiples. Temperatures must be expressed in degrees Celsius. Blood pressure must be expressed in millimeters of mercury. All clinical chemistry measurements should be expressed in metric units using the International System of Units (SI). The use of unusual symbols or abbreviations is strongly discouraged. The first time an abbreviation appears in the text, it should be preceded by the words for which it stands. References It is expected that all cited references will have been read by the authors. The references must contain only the authors cited in the text, be numbered in Arabic numerals and consecutively as they are cited. Bibliographical entries in the text should be quoted using superscripted Arabic numerals. References must be set out in the standard format approved by the International Committee of Medical Journal Editors (www.icmje.org). JOURNALS Each entry must specify the authors surname and initials (list all authors when there are six or fewer; when there are seven or more, list only the first six and then et al.), the articles original title, the name of the Journal (according to the abbreviations used by MEDLINE/PubMed), the year of publication, the volume number and the number of the first and last pages. When citing references, please follow the rules for international standard punctuation carefully. Examples: Standard article. Sutherland DE, Simmons RL, Howard RJ. Intracapsular technique of transplant nephrectomy. Surg Gynecol Obstet 1978;146:951-2. Organization as author International Committee of Medical Journal Editors. Uniform requirements for manuscripts submitted to biomedical journals. Ann Int Med 1988;108:258-65.

OTORINOLARINGOLOGIA
Vol. 60 Settembre 2010 Numero 3

INDICE
TERAPIE INTRATIMPANICHE PER I DISORDINI DELLORECCHIO INTERNO
Guest Editors: A. De Stefano e F. Dispenza

Pag. XII

Congressi

145
Steroidi intratimpanici per la perdita di udito neurosensoriale improvvisa: una revisione
Jeremic G., Parnes L. S.

125
Presentazione
De Benedetto M.

155
Trattamento intratimpanico della patologia autoimmune dellorecchio interno
De Stefano A., Kulamarva G., Dispenza F.

127

Introduzione
Serra A.

165 129
Storia dei trattamenti intratimpanici dei disordini dellorecchio interno
Mankekar G., Kirtane M. V., Chavan K., Pachauri S.

Somministrazione intratimpanica di gadolinio per la valutazione delle dimensioni dello spazio endolinfatico e il movimento dei farmaci nellorecchio interno
Nakashima T., Naganawa S., Sone M., Teranishi M.

171 135
Anatomia della coclea e della finestra rotonda
David S., Bucchieri F., Cappello F., Zummo G.

Gentamicina intratimpanica per la malattia di Menire monolaterale

Slattery III W. H., Teufert K. B.

141
Farmacocinetica dei farmaci dopo somministrazione transtimpanica
Dispenza F., Kulamarva G., De Stefano A.

183
La gentamicina intratimpanica: suo effetto sulludito e strategie per minimizzare il danno allorecchio interno
Citraro L., De Stefano A., Kulamarva G., Dispenza F., Croce A.

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INDICE

189
Trattamento della malattia di Menire con steroidi intratimpanici
Pistorio V., Achilli V.

207
Trattamento intratimpanico dellototossicit correlata a chemioterapia
Parham K.

195
Trattamento intratimpanico degli acufeni: illusioni e speranze
Oliveira C. A., Arajo M. F. S., Sampaio A. L. L.

213
Tecniche di somministrazione transtimpanica
Marchese D., Riggio F., Gallina S., Speciale R.

OTORINOLARINGOLOGIA

September 2010

OTORINOLARINGOLOGIA
Vol. 60 September 2010 No. 3

CONTENTS
INTRATYMPANIC THERAPIES FOR INNER EAR DISORDERS
Guest Editors: A. De Stefano and F. Dispenza
Pp.XII

Congresses

145
Intratympanic steroids for sudden sensorineural hearing loss. A review
Jeremic G., Parnes L. S.

125
Preface
De Benedetto M.

155
Intratympanic management for autoimmune inner ear disease
De Stefano A., Kulamarva G., Dispenza F.

127

Foreword
Serra A.

165 129
History of intratympanic managements for inner ear disorders
Mankekar G., Kirtane M. V., Chavan K., Pachauri S.

Intratympanic gadolinium administration for evaluation of endolymphatic space size and drug movement into the inner ear
Nakashima T., Naganawa S., Sone M., Teranishi M.

135
Anatomy of cochlea and round window
David S., Bucchieri F., Cappello F., Zummo G.

171
Intratympanic gentamicin for unilateral Menires disease
Slattery III W. H., Teufert K. B.

141
Pharmacokinetics of drugs in transtympanic administration
Dispenza F., Kulamarva G., De Stefano A.

183
Intratympanic gentamicin: its effect on hearing and strategies to minimize inner ear damage
Citraro L., De Stefano A., Kulamarva G., Dispenza F., Croce A.

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189
Management of Menires disease with intratympanic steroids
Pistorio V., Achilli V.

207
Intratympanic treatment for chemotherapy-related ototoxicity
Parham K.

195
Intratympanic management of tinnitus: illusions and hopes
Oliveira C. A., Arajo M. F. S., Sampaio A. L. L.

213
Techniques of intratympanic administration
Marchese D., Riggio F., Gallina S., Speciale R.

XII

OTORINOLARINGOLOGIA

September 2010

CONGRESSES

February 28-March 2, 2011 Wurzburg (Germany) 23rd Course on Microsurgery

May 12-15, 2011 Athens (Greece) 10th European

September 11-14, 2011 San Francisco (CA, USA)

of the Middle Ear

Contact: Website: www.hno.uni-wuerzburg.de

Symposium on Pediatric Cochlear Implantation

Contact: Website: www.espci2011.com

Annual Meeting of the American Academy of Otolaryngology Head and Neck surgery
Contact: Website: www.entnet.org

March 1-4, 2011 Auckland (New Zealand) 12th Asia-Oceania

May 25-28, 2011 Brussels (Belgium)

ORL Congress
Contact: Website: www.asia-oceania2011.org

International Mastercourse on Endoscopic Sinus Surgery (IMESS)

Contact: Website: www.everyoneweb.com/imess

October 21-22, 2011 Naples (Italy) 6th International

Symposium on Childhood Deafness

March 25-29, 2011 Milano (Italy) 6th Biennal International

Milano Masterclass
Contact: Website: www.milanomasterclass.it

June 5-9, 2011 New Orleans (LA, USA) 10th International Symposium

Contact: Website: www.chdeaf.org

on Recent Advances in Otitis Media

Contact: Website: www.om2011.com

June 3-7, 2012 Nagasaki (Japan)

April 28-29, 2011 Utrecht (The Netherlands)

Intercontinental Rhinoplasty Course Higlights of functional and esthetic rhinoplastic surgery

Contact: Website: www.intercontinental-rhinoplasty.com

July 2-6, 2011 Barcelona (Spain) 1st Congress of the

Confederation of the European ORL-HNS (CE-ORL-HNS)

Contact: Website: www.ceorlhnsbarcelona2011.org

Cholesteatoma Conference 2012 9th International Conference on Cholesteatoma and Ear Surgery
Contact: Website: www.chole2012.jp

April 28-May 1, 2011 Chicago (IL, USA)

COSM Combined Otolaryngological Spring Meeting

Contact: Website: www.cosm.md

of the International Academy of Oral Oncology IAOO

Contact: Website: www.eastman.ucl.ac.uk/iaoo

July 14-17, 2011 Singapore 3rd World Congress

June 17-21, 2012 Toulouse (France) 24th Congress

of the European Rhinologic Society

Contact: Website: www.ers-isian2012.com
[to be continued at page XXI]

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September 2010

INTRATYMPANIC THERAPIES FOR INNER EAR DISORDERS

Guest Editors: A. De Stefano and F. Dispenza
OTORINOLARINGOL 2010;60:125

Preface - Presentazione
M. DE BENEDETTO

ver the past 10 years several improvements have been recorded in the field of medical therapy of inner ear diseases, due to the increasing use of medications applied directly into middle ear cleft. Initially, the aim of such treatment was to induce, by transtympanic administration of drugs, an irreversible damage of inner ear neural epithelium in order to obtain a comparable result as well as what surgically achieved, but in a much more conservative way. Subsequently, the transtympanic route has progressed together with clinical indications, changing the goal of treatment: obtaining not only the damage of inner ear cells, but also a curative action. However, they remain specific therapeutic approaches for selected diseases and that is why the progresses reached in this field are doubtfully part of the common knowledge of the otolaryngologist, and the reported data are acquired with an average retard of about five years from the beginning of clinical use. The great value of De Stefano and Dispenzas work was the systematization of all topics about intratympanic treatments in a single issue, giving to all physicians, and ENT specialists in particular, a complete view of all therapeutic options for the various diseases manageable with intratympanic treatment. We have now the opportunity to read, in a single work, contributes of several authors who treated the intratympanic therapy worldwide. It is certainly a good and useful possibility to know the results obtained and the adverse events that may occur. Finally, my personal acknowledgments to the young researchers De Stefano and Dispenza for the invitation and I wish them to continue making research with the same enthusiasm. Thanks to all colleagues who will decide to read the present work.
Prof. Michele De Benedetto President of Societas ORL Latina Chief of Otolaryngology Department Vito Fazzi Hospital, Lecce, Italy

farmaci allinterno dellorecchio medio. Allinizio lobiettivo era quello di provocare, attraverso la somministrazione di principi attivi per via transtimpanica, un danno irreversibile del neuroepitelio per ottenere un risultato sovrapponibile a quanto si poteva ottenere per via chirurgica, ma in modo molto pi conservativo. Successivamente, tale via di somministrazione si sempre pi ampliata, di pari passo con le indicazioni cliniche, per cui cambiato lobiettivo del trattamento: non ottenere pi solo un danno irreversibile del neuroepitelio ma cercare di ottenere unazione curativa. Trattandosi pur sempre di approcci terapeutici di nicchia e per patologie ben selezionate, i progressi raggiunti rientrano difficilmente nelle conoscenze medie dello specialista otorinolaringoiatra se non con un ritardo che, mediamente, stato stimato in almeno 5 anni rispetto allinizio dellutilizzo clinico. Il grande merito dei colleghi De Stefano e Dispenza stato quello di aver sistematizzato tutto ci che attualmente viene effettuato ricorrendo alla terapia topica intratimpanica, dando la possibilit a tutti gli specialisti di avere un quadro completo delle possibilit terapeutiche per le numerose patologie che stato dimostrato si avvantaggiano di tali terapie. Poter leggere in un unico lavoro i contributi dei numerosi autori che in tutto il mondo si sono interessati a tale problema, prendendo conoscenza dei risultati ottenuti e delle possibili complicanze, certamente unopportunit di grande utilit. Ai giovani ricercatori De Stefano e Dispenza, infine, va il mio personale ringraziamento per avermi voluto coinvolgere nel loro lavoro ed il mio augurio a voler continuare a fare ricerca con lentusiasmo che li caratterizza. A tutti coloro che avranno deciso di leggere questo lavoro, un grazie per la fiducia, sicuramente meritata, riposta negli autori.
Prof. Michele De Benedetto Presidente Societas ORL Latina Direttore U. O. Otorinolaringoiatria Ospedale Vito Fazzi, Lecce, Italia

N ologia dellorecchio interno,ricorso a somministrazione di notevoli novit si sono registrate grazie al sempre maggiore
egli ultimi 10 anni, nellambito delle terapie mediche per pat

Corresponding author. Prof. M. De Benedetto, Unit of Otolaryngology, Vito Fazzi Hospital, Lecce, Italy. E-mail: orl.lecce@clio.it

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OTORINOLARINGOL2010;60:1-2

Foreword - Prefazione
A.SERRA

rancisBacon,EnglishphilosopherofXVIIcentury,inhis reflection on the sense and the meaning of scientific innovations, said: He that will not apply new remedies must expect new evils; for time is the greatest innovator. It is this phrase that comes to my mind as Im going to present this work on intratympanic therapy of inner ear diseases:theevolutionofknowledgeandthedevelopmentofthe techniques,infact,allowedtodelivermedicinalsubstancesin sitesbelievedinaccessibleastheinnerear. Changesandimprovementsinintratympanictherapeuticapproachhavebeennumerousifcomparedwithfirstapplications: atypicalexampleisSchuknechtsattempttoobtainthechemical labyrinthectomy in patients affected by Menires disease byintratympanicadministrationofstreptomycinin1957. Theseinitialintuitionshaveopeneddoorstonewtherapeuticfrontiersnowrepresentingactualclinicalevidences(even ifSchuknechtstreatmentunfortunatelyresultedinsomeinconveniencesforpatients,suchasaseverehearingloss). It is possible to assert that the treatment of inner ear diseaseshasfoundavalidscientificandpracticalsupportinthe intratympanic therapy, especially in Menires disease, sudden hearing loss, presbiacusis and tinnitus, characterized by notalwayswell-definedevolutionandprognosis. TheworkoftheAuthors,comingfromdifferentcountries and cultural backgrounds, is entirely fitted on current scientificstandardanditalsohasallmultidisciplinarycharactersof bothmodernscientificthoughtandclinicalresearch. ItthereforegivesmegreatpleasuretocongratulatetheAuthorsand,applaudingthisinitiativeandwishingallthesuccessitdeserves,Ihopethiseffortwillopenthedoortofurther possibilitiesforscientificresearchandwiderclinicalapplications.
Prof. Agostino Serra AUORL President Chief of Otolaryngology Department University of Catania, Italy

rancis Bacon, filosofo inglese del XVII secolo, in una sua riflessione sul senso ed il significato delle innovazioni scientifiche ebbe a dire. Chi non applica nuovi rimedi deve essere pronto a nuovi mali; perch il tempo il pi grande degli innovatori. proprio tale frase che mi si presenta alla mente mentre mi accingo a presentare questo testo sulla terapia intratimpanica delle patologie dellorecchio interno: la evoluzione di conoscenze ed il perfezionamento delle tecniche, infatti, hanno consentito di giungere alla introduzione di sostanze medicamentose in siti prima ritenuti inaccessibili quali ad esempio lorecchio interno. Numerosi certamente sono state le variazioni ed i perfezionamenti che tale tipo di approccio terapeutico ha subito rispetto alle prime prove applicative: esempio emblematico rimane il tentativo di Schuknecht nel 1957 di ottenere lablazione chimica del sistema vestibolare in pazienti menierici, mediante somministrazione intratimpanica di streptomicina. Sono stati proprio tali intuizioni iniziali (anche se il trattamento adottato da Schuknecht oltre allablazione vestibolare determin purtroppo anche alcuni inconvenienti nei pazienti trattati, quale ad esempio la compromissione del sistema uditivo) che hanno aperto le porte verso nuove frontiere terapeutiche, la cui utilit ed efficacia rappresentano oggi delle vere e proprie evidenze cliniche. E possibile affermare, infatti, che il trattamento di patologie dellorecchio interno, ad andamento evolutivo e prognostico non sempre ben definibile, quali la malattia di Meniere, lipoacusia improvvisa, le ipoacusie progressive e gli acufeni abbia trovato nella terapia intratimpanica un valido supporto scientifico oltre che pratico. Il lavoro intrapreso dagli Autori, di diversa provenienza ed estrazione culturale, appare alla luce delle considerazioni effettuate non solo pienamente corrispondente ai canoni scientifici attuali, ma anche dotato dei caratteri di modernit e di interdisciplinariet di cui si avvale la evoluzione del pensiero scientifico e della ricerca clinica. con vivo piacere, quindi, che mi complimento per il lavoro svolto dagli Autori e nel plaudire alliniziativa e nellaugurare tutto il successo che merita, spero che questo sforzo compiuto possa aprire le porte ad ulteriori possibilit di ricerca scientifica e a consentire pi ampie applicazioni cliniche. Prof.AgostinoSerra PresidenteAUORL DirettoreU.O.diOtorinolaringoiatria, UniversitdegliStudidiCatania,Catania,Italia

Correspondingauthor.Prof.A.Serra,DepartmentofOtolaryngology,AziendaOspedaliero-UniversitariaPoliclinicoVittorioEmaluele, UniversityofCatania,Catania,Italy.E-mail:aserra@unict.it

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REVIEWS
OTORINOLARINGOL 2010;60:129-33

History of intratympanic managements for inner ear disorders

G. MANKEKAR 1, M. V. KIRTANE
1, 3 ,

K. CHAVAN 1, S. PACHAURI

Treatment of ear diseases has ranged from crushed garlic cloves and oil to oxens bile over the centuries. But the classic intratympanic treatment started only about half a century ago after the development of the microscope and our visualisation of the tympanic membrane. In addition there was improvement in diagnostic technology like pure tone audiometry and availability of various drug formulations. This historical review article describes the various intratympanic treatment modalities for inner ear disorders like Menires disease, tinnitus and sudden sensorineural hearing loss over the past half a century. Key words: Intratympanic Gentamicin Steroids Lidocaine - Menires disease - Sensorineural hearing loss Tinnitus.

Hinduja Hospital, Mahim, Mumbai, India GS Medical College and KEM Hospital Mumbai, India 3PD Hinduja Hospital, Saifee Hospital, Breach Candy Hospital and Cumballa Hospital, Mumbai, India
2Seth

1PD

ccording to Dictionary.com intratympanic means situated or occurring within the middle ear. Although intratympanic therapy was first described in the 1950s, publications on intratympanic therapy began appearing more frequently only in the 1990s. A MEDLINE search reveals 394 articles for the search intratympanic therapy; 119 articles of these 21 review articles for the search intratympanic steroids and 167 articles of these 18 review articles for the search intratympanic gentamycin, intratympanic + gentamicin showed up 216 articles with 34 review articles. Intratympanic therapy has several advantages over systemic or intravenous medications: being focused, it can achieve higher local therapeutic concentration of the drugs with the use of much
Corresponding author: Dr. G. Mankekar, MS, PhD, ENT Consultant, PD Hinduja Hospital, Mahim, Mumbai, 400016, India. E-mail: dr_gmankekar@hindujahospital.com

smaller quantity of medication besides avoiding the systemic side-effects of the medications. Intratympanic drug therapy has been described for the treatment of Menires disease;1, 2 sudden sensorineural hearing loss,3 tinnitus 4 and even facial palsy.5 A variety of drugs have been used intratympanically from steroids, aminoglycosides to lignocaine. According to Lustig and Carey,6 the treatment potential of intratympanic drug delivery will be fully realized once the developmental sequence of the Organ of Corti has been established. In the near future intratympanic therapy may expand to include the use of antoxidants, medications to protect the ear during parenteral ototoxic treatment (e. g. chemotherapy or antibiotics), neurogenic proteins, gene therapy and growth factors to correct genetic or acquired and metabolic defects.6 Intratympanic therapy in Menires disease Harold Schuknecht should be the first to be credited for the modern attempt at transtympanic treatment of Menires disease by injecting streptomycin as an alternative to unilateral surgical ablation of the affected labyrinth.1 According to Schuknecht the

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idea of using streptomycin intra-tympanically came as a sequel to their practice of using 10% formalin intra-tympanically after death to arrest post-mortem degeneration until such time as the ears could be removed at autopsy. The efficiency of this method for preserving the inner ear was further proven by a controlled experiment in animals. Thus it seemed possible that because formalin passed readily into the inner ear streptomycin might also do so, although at a slower rate. Schuknecht also suggested injecting streptomycin through a small plastic tubing which was introduced in to the middle ear through a small knife wound in the annulus tympanicus. He hoped that by varying the frequency of injection and the concentration of the streptomycin solution a method could be developed whereby vestibular function could be destroyed and hearing saved.1 He used large daily doses (150-600 mg/day i.e. 0.1 cc; 0.5 g/cc concentration) of streptomycin every 4 hours until one day after the appearance of disequilibrium and the loss of caloric responses. This developed approximately in four to five days. The vertigo was controlled in five of eight patients treated but the five patients experienced profound sensorineural hearing loss. In another article,2 Schuknecht published studies in cats showing loss of hair cells in the cristae, maculae and the organ of Corti following intratympanic streptomycin application. As a result of this cochleotoxicity, the use of intratympanic therapy fell into relative disrepute for almost two decades. In the late 1970s, Lange 7, 8 revived intratympanic aminoglycoside therapy for 52 patients of Menires disease in Germany. He used an indwelling catheter to inject 0.1 mL of streptomycin sulfate, 0.33 g/mL, every 5 hours, day and night, for 2 days. Although complete vertigo relief occurred in 96% patients over an eight year follow-up, 24% patients suffered form varying degrees of hearing loss in the treated ear. As result, Lange suggested the use of intratympanic gentamicin due to its lower cochleotoxicity instead of streptomycin. Other German colleagues, Beck and Schmidt 9 not only used gentamicin but also reduced the frequency of intratympanic dosing to reduce the risk of hearing loss. Katzke 10 injected 16 mg of intratympanic gentamicin daily to an average total dose of 90 mg to achieve total vertigo control in 66% patients and hearing loss in 34% patients. Blessing and Schlenter 11 reported 33% deterioration in speech discrimination in 82 patients with vertigo control in 89% patients. Other colleagues 12, 13 who

reduced the injections to once per day found that the patients were relieved of vertigo but the incidence of hearing loss was in the range of 30-40%. Laitakari 14 found that in addition to hearing loss daily intratympanic gentamicin also caused postablative disequilibrium and vertigo recurrences. Nedzelski et al.1517 buffered the drug to a lower concentration (26.7 mg/mL) although they gave the dose thrice daily for 4 days or less or fewer if unsteadiness, nystagmus or hearing loss developed. Magnusson et al.18 found that clinical unsteadiness did not appear for 2-3 days after intratympanic gentamicin. Toth and Parnes 19 introduced the term titration protocol in which injections were given only once per week until symptoms of ototoxicity appeared. They compared 21 patients treated with shot gun therapy of three injections of buffered gentamicin (26 mg/mL) per day for 4 days to a group of 16 treated with titration protocol of injections given once per week. The weekly injections continued for 4 weeks or until there was inner ear damage. They found that 80% of the patients had control of vertigo irrespective of the protocol used. Although treatment of medically refractory Menires disease with intratympanic gentamicin has become standard therapy there are still conflicting reports to the contrary. In 1999, Nguyen et al.20 reported that out of 78 patients, 75 (96%) achieved sufficient vertigo control with IT gentamicin to avoid ablative surgery. On the other hand, Derebery et al., in 2010,21 based on published data and retrospective review, reported that higher percentage of patients undergoing ablative shunt surgery attained complete vertigo control/hearing preservation relative to intratympanic gentamicin. They conclude that there is significant variability in gentamicin outcomes suggesting that the technique requires further refinement before consistently producing good outcomes. Intratympanic therapy in tinnitus Tinnitus is often associated with hearing loss and increases with the severity level of the hearing loss.22 Accepted treatment modalities for tinnitus are hearing aid amplification, tinnitus retraining therapy, some oral medications and intratympanic therapy. Kroath in 1960 23 first reported in German literature the use of intratympanic lidocaine for Menires disease and its associated symptoms. But it was not until

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the late 1970s that Sakata et al.4 used intratympanic steroids, initially along with lidocaine and then alone to treat tinnitus and other symptoms of Menires disease. Lidocaines ability to inhibit tinnitus was first noted during its intravenous administration for other conditions and through its anesthetic properties, it is thought to silence the hyperfunctional neuronal pathways responsible for generation of noise, similar to its action on pain pathways within the body.24 Sakata et al.25 reported relief of severity in 48 of 52 patients with tinnitus using intratympanic lidocaine thereby avoiding systemic toxicity. Subsequently they reported that tinnitus was abolished in 34% patients, considerably ameliorated in 50% and unchanged in 16% when intratympanic lidocaine was given in 168 patients. In another follow-up study, Itoh and Sakata in 1991 26 reported that lidocaine perfusion generally resulted in nausea and vertigo and was usually performed in an inpatient setting whereas IT steroid could be performed as an outpatient procedure. Silverstein et al.27 while studying the effects of IT dexamethasone and methylprednisolone on various causes of inner ear disease and tinnitus in 46 patients found improvement in tinnitus in 47% patients; of these 60% were patients with Menires disease. Shea and Ge 28 reported that 82% patients with Menires disease experienced reduction in tinnitus following IT dexamethasone along with oral dexamathasone. However in the only prospective randomized double blind cross-over trial for IT perfusion, Silverstein et al.29 could not show any significant changes in hearing, tinnitus, caloric vestibular responses or in patients responses over a 6 week study period. Hicks 30 reported complete improvement of tinnitus in 3 patients with Menires disease who received IT perfusion of 40 mg/mL gentamicin one week apart with a gelfoam placed in the round window niche. Subsequently in another three patients, in the same study, Hicks placed round window microcatheter under general anesthesia to deliver gentamicin more precisely over a period of time. All three patients experienced total relief from tinnitus. In another study, Silverstein et al.31 applied 26.7 mg/ mL gentamicin to the round window membrane after otoendoscopy, laser assisted tympanostomy and placement of gelfoam in the round window niche. Tinnitus improved in three of six patients after single gentamicin injection, five of eight patients after two injections and in three of nine patients after repeated injections. In 2002. Jackson and Silverstein 32

reported on 92 patients with Menires disease who underwent Silverstein MicroWick placement in the round window niche and gentamicin perfusion. 57% patients reported improvement or relief of tinnitus in a subsequent questionnaire. Dodson and Sismanis 33 reported mixed results of IT steroids in Menires patients with about 50% patients experiencing control of their vertigo, some experiencing improvement in hearing and decrease in tinnitus within 72 hours following perfusion. They suggest that patients with Menires disease with a low frequency, fluctuating hearing loss respond better than those with a flat and non-fluctuant hearing loss. Intratympanic therapy(IT) in sudden sensorineural hearing loss Sudden sensorineural hearing loss (SSNHL) is one of the commonest otologic emergencies and was first reported by DeKleyn in 1944.34 It has been speculated by Simmons 35 that the incidence of SSNHL is underestimated because many who recover quickly never seek medical attention. In addition, unilateral hearing loss often goes unnoticed even by the patients themselves. SSNHL is an otologic emergency because the window of oportunity for treatment is narrow and studies have shown that early administration of high dose prednisone is more useful than watchful waiting.36 Mattox and Simmons 37 found that 65% recover completely spontaneously and independent of any type of medical treatment with majority doing so within 14 days and many within the first few days. Despite this a MEDLINE search shows 1387 articles for the term sudden hearing loss and treatment with various treatment modalities having been suggested from oral (36), intravenous and intratympanic steroids 27 to vasodilators 39, 40 to hyperbaric oxygen therapy and stellate ganglion blocks.41, 42 In 1999, Parnes et al.43 used a guinea pig model to compare the concentrations of different steroid formulations in plasma, endolymph, perilymph and cerebrospinal fluid when given orally, intravenously and via intratympanic routes. They found that intravenous administration caused higher levels in plasma than in the other compartments while intratympanic injection yielded highest levels in inner ear with equal concentration in endolymph and perilymph. Of the three steroid formulations they used, meth-

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yprednisolone produced the highest concetrations in inner ear fluid for the longest time and so they concluded that it had the greatest potential for clinical application. They gave 13 patients of SSNHL IT methyprednisolone, of these only one had received any prior therapy. All presented within 6 weeks of SSNHL onset. 3 of 12 had full recovery, 3 of 12 had partial recovery while 6 of 12 had no response. This was equivalent to the results with oral steroids. Thus the observation that intratympanic therapy could achieve equivalent or better hearing recovery than oral steroids while avoiding the risks of systemic adminstration made IT steroid therapy more appealing. The finding of the high concentration and duration of methylprednisolone in the inner ear after IT adminstration suggested that it might be more effective in cases refractory to oral steroids or in cases which present 2-4 weeks after onset.i.e as salvage therapy. Kopke et al.44 administered IT methylprednisolone through an implanted middle ear microcatheter and continuous infusion pump for 14 days to six patients who presented within 6 weeks of onset and did not respond to a 2 week course of oral prednisolone. Of these, 2 patients had full recovery while 2 patients had partial recovery. Lefebvre and Staecker 45 used a 10 L/h continuous infusion pump to administer IT 62.5 mg/mL methylprednisone solution for 10 days to six patients who had failed to recover after a 6 day shotgun therapy of oral and intravenous steroids, carbogen inhalation, oral naftidrofryl (vasodilator), diazepam and heparin. All 6 patients showed a 16.25-25 dB improvement in hearing as well as dramatic improvement in speech discrimination scores. According to Suckfuell 46 no clinical trial of the highest evidence level has yet been published to document the efficacy of any type of treatment for sudden, idiopathic sensorineural hearing loss. However, there is evidence from trials with lower levels of evidence, post-hoc analyses, and assessments of secondary endpoints of clinical trials indicating that plasma-expander therapy, the systemic and local (intratympanic) administration of cortisone, and the reduction of acutely elevated plasma fibrinogen levels may be beneficial.46 Currently the consensus seems to be to use intratympanic steroids as salvage therapy in refractory cases of SSNHL which have not improved with conventional systemic steroids.47, 48

Conclusions Intratympanic administration of medications for inner ear disorders has gained popularity over the past few decades as it avoids the systemic side-effects of the drugs, can achieve higher local therapeutic concentration of the drugs with the use of much smaller quantity of medication. According to Hu and Parnes, there are no good studies on IT steroids which meet the criteria of comparability, internal validity and external validity. It is difficult to compare studies due to the heterogeneous nature of the data. More rigorously designed studies are required to determine the efficacy of this treatment, the optimal steroid to use, and the best treatment regimen.49 Besides the usage of intratympanic gentamicin for Menires disease and intratympanic steroids for SSNHL, newer technologies like hydrogels and nanoparticles are being explored. Intracochlear devices that use recent advances in microsystems technology are being developed to apply medications directly in to the inner ear. Such devices could be used to deliver neurotrophic factor and steroid delivery with cochlear implantation, RNA interference technologies and stem cell therapy.50 Riassunto
Storia dei trattamenti intratimpanici dei disordini dellorecchio interno Il trattamento delle patologie dellorecchio variato nei secoli dagli spicchi di aglio schiacciati allolio fino alla bile dei buoi. Tuttavia, il classico trattamento intratimpanico si diffuso soltanto circa mezzo secolo fa, dopo lo sviluppo del microscopio e la visualizzazione della membrana timpanica. Inoltre, vi stato un miglioramento nella tecnologia diagnostica, con laudiometria tonale pura, e nella disponibilit di diverse formulazioni farmacologiche. Questa revisione storica descrive le diverse modalit di trattamento intratimpanico per le patologie dellorecchio interno come la malattia di Menire, il tinnito e la sordit improvvisa, nellultima met secolo. Parole chiave: Intratimpanico - Gentamicina - Steroidi - Lidocaina - Malattia di Menire - Sordit neurosensoriale Acufene.

References
1. Schuknecht H. Ablation therapy for the relief of Menires disease. Laryngoscope 1956;66:859-70.

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2. Schuknecht H. Ablation therapy in the management of Menires disease. Acta Otolaryngol ( Stockh) 1957;S132:3-42. 3. Mattox DE, Simmons FB. Natural histpry of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86:389-98. 4. Sakata E, Umeda Y, Takahashi K,Ohtsu K. Treatment of the cochlear tinnitus blocking therapy with 4% lidocaine. Nippon Jibiinkoka Gakkai Kaiho 1976;79:741-6. 5. Bryant FL. Intratympanic injection of steroid for treatment of facial paralysis. Laryngoscope 1973;83:700-6. 6. Lustig LR, Carey J. Intratympanic treatment of inner ear disease. Otolaryngol Clin N Am 2004;37: ix-x. 7. Lange G. Ototoxische Antibiotika in der Behandlung des Morbus Menire. Therapie Woche Wochenschrift Fur Praktische Medizin 1976;26:1-6. 8. Lange G. The intratympanic treatment of Menires disease with ototoxic antibiotics. A follow up study of 55 cases. Laryngol Rhinol Otol (Stuttg) 1977;56:409-14. 9. Beck C, Schmidt CL. 10 years of experience with intratympanically applied streptomycin (gentamicin) in the therapy of Morbus Menire. Arch of Otolaryngol 1978;221:149-52. 10. Katzke D. treatment of Menires disease with intratympanically applied gentamicin sulphate. Laryngol Rhinol Otol (Stuttg) 1982;61:4-8. 11. Blessing RE, Schlenter WW. Long term results of gentamicin therapy of Menires disease. Laryngorhinootologie 1989;68:65760. 12. Moller C, Odkvist LM, Thell J et al. Vestibular and audiologic functions in gentamicin treated Menires disease. Am. J Otol 1988;9:383-91. 13. Odkvist LM. Middle ear ototoxic treatment for inner ear disease. Acta Otolaryngol Suppl 1989;457:83-6. 14. Laitakari K. Intratympanic gentamicin in severe Menires disease. Clin Otolaryngol 1990;15:545-8. 15. Nedzelski JM, Schessel DA, Bryce GE et al. Chemical labyrinthectomy:local application of gentamicin for the treatment of unilateral Menires disease. Am J Otol 1992;13:18-22. 16. Nedzelski JM, Bryce GM, Pfleiderer AG. Treatment of Menires disease with topical gentamicin:a preliminary report. J Otolaryngol 1992;21:95-101. 17. Nedzelski JM, Chiong CM, Fradet G et al. Intratympanic gentamicin instillation as treatment of unilateral Menires disease:update of an ongoing study. Am J Otol 1993;14:278-82. 18. Magnusson M, Padoan S. delayed onset of ototoxic effects of gentamicin in treatment of Menires disease. Rationale for extremely low dose therapy. Acta otolaryngol 1991;111:671-6. 19. Toth AA, Parnes LS. Intratympanic gentamicin for Menires disease:preliminary comparison of two regimes. J Otolaryngol 1995;24:340-4. 20. Nguyen KD, Minor LB, Santina CC, Carey JP. Time course of repeated intratympanic gentamicin for Menires disease. Laryngoscope 2009;119:792-8. 21. Derebery MJ, Fisher LM, Berliner K, Chung J, Green K. Outcomes of endolymphatic shunt surgery for Menires disease: comparison with intratympanic gentamicin on vertigo control and hearing loss. Otol Neurotol 2010;31:649-55. 22. Chung DY, Gannon RP, Mason K. Factors affecting the prevalence of tinnitus. Audiology 1984;23:441-52. 23. Kroath F. Transtympanic injection in the therapy of Menires syndrome. Z. Laryngol Rhinol Otol 1960;39:190-5. 24. Shulman A. Neuroprotective drug therapy:a medical and pharmacological treatment for tinnitus control. Int Tinnitus J 1997;3:77-93. 25. Sakata E, Nakazawa H, Iwashita N. Therapy of tinnitus. Tymapnic cavity infusion of lidocaine and steroid solution. Auris Nasus Larynx 1984;11:11-8. 26. Itoh, Sakata E. Treatment of vestibula disorders. Acta Otolaryngol Suppl 1991;481:617-23. 27. Silverstein H, Choo D, Rosenberg SI, Kuhn J, Seidman M, Stein

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I. Intratympanic steroid treatment of inner ear disease and tinnitus (prelim report). Ear Nose and Throat J 1996;75:468-71;474-476. Shea JJ Jr, Ge X. Dexamethasone perfusion of the labyrinth plus intravenous dexamethasone for Menires disease. Otolaryngol Clin North Am 1996;29:353-8. Silverstein H, Isaacson JE, Olds MJ, Rowan PT, Rosenberg S. Dexamethasone inner ear perfusion for the treatment of Menires disease:a prospective randomized double blind cross over trial. Am J Otol 1998;122:143-8. Hicks GW. Intratympanic and round window drug therapy: effect on cochlear tinnitus. Int Tinnitus J 1198;4:144-7. Silverstein H, Arruda J, Rosenberg SI, Deems D, Hester TO. Direct round window membrane application of gentamicin in the treatment of Menires disease. Otolaryngol Head Neck Surg 1999;120:649-55. Jackson LE, Silverstein H. Chemical perfusion of the inner ear. Otolaryngol Clin North Am 2002;35:639-53. Dodson K, Woodson E, Sismanis A. Intratympanic perfusion for Menires disease. Presented at the meeting of the American Neurotology society, Nashville (TN), May 3, 2003. DeKleyn A. Sudden complete or partial loss of function of the octavus-system in apparently normal persons. Acta Otolaryngol 1944;32:407-29. Simmons FB. Sudden idiopathic sensorineural hearing loss:some observations. Laryngoscope 1973;83:1221-7. Chen CY, Halpin C, Rauch SD. Oral steroid treatment of sudden sensorineural hearing loss:a ten year retrospective analysis. Otol Neurotol 2003;24:728-33. Mattox DE, Simmons FB. Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86(4 Pt 1):463-80. Rauch SD. Intratympanic steroids for sensorineural hearing loss. Otolaryngol Clin N Am 2004;37:1061-74. Sekula J, Wlodyka J. 20% Mannitol in the treatment of sudden hearing loss. Otolaryngol Pol 1975;29:129-36. Martin G, Jacobs P. Clinical comparison of dextran 40 and xantinol nicotinate in the treatment of sudden deafness caused by shock waves (authors transl) Laryngol Otolog Rhinlog (Stuttg) 1977;56:860-3. Haug O, Draper WL, Haug SA. Stellate ganglion blocks for idiopathic sensorineural hearing loss. Arch Otolaryngol 1976;102:58. Goto F, Fujita T, Kitani Y, Kanno M, Kamei T, Ishii H. Hyperbaric Oxygen and stellate ganglion blocks for idiopathic hearing loss. Arch Otolaryngol 1979;88:335-42. Parnes LS, Sun AH, Freeman DJ.Corticosteroid pharmacokinetics in the inner ear fluids:an animal study followed by clinical application. Laryngoscope 1999;109 (7 Pt 2):1-17. Kopke R, Hoffer M, Wester D et al. Targeted topical steroid therapy in suden sensorineural hearing loss. Otol Neurotol 2001;22:475-9. Lefebvre PP, Staecker H:Steroid perfusion of the inner ear for sudden sensorineural hearing loss after failure of conventional therapy:a pilot study. Acta Otolaryngol 2002;12:698-702. Suckfuell M. Perspectives on the pathophysiology and treatment of sudden idiopathic sensorineural hearing loss. Dtsch Arztebl Int 2009;106:669-75; quiz 676. She W, Dai Y, Du X, Yu C, Chen F, Wang J, Qin X. Hearing evaluation of intratympanic methylprednisolone perfusion for refractory sudden sensorineural hearing loss 48. Otolaryngol Head Neck Surg 2010;142:266-71. Dallan I, De Vito A, Fattori B, Casani AP, Panicucci E, Berrettini S et al. Intratympanic methylprednisolone in refractory sudden hearing loss:a 27-patient case series with univariate and multivariate analysis. Otol Neurotol 2010;31:25-30. Hu A, Parnes LS. Intratympanic steroids for inner ear disorders-a review. Audiol Neurotol 2009;14:373-82. McCall AA, Swan EE, Borenstein JT, Sewell WF, Kujawa SG, McKenna MJ. Drug delivery for treatment of inner ear disease:current state of knowledge. Ear Hear 2010;31:156-65.

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Anatomy of cochlea andround window

S. DAVID, F. BUCCHIERI, F. CAPPELLO, G. ZUMMO

One of the most important functions of the ear is sound reception, particularly the detection of amplitude and frequency of the sound waves by Cortis organ. The latter is a sensory structure located in the cochlear duct (middle scale), consisting of hair cells lying above the basilar membrane. The cochlear duct is surrounded by two cavities containing perilymph: the scala vestibularis and the scala tympani. The sound reception mechanism involves several other components of the ear such as malleus, incus and stapes, in the tympanic cavity, and the oval and round windows. The movement of the stapes on the oval window, that is adjacent to the scala vestibularis, generates pressure waves in the perilymph along the vestibular canal. The round window, that separates the scala tympani from the tympanic cavity, moves to compensate for oval window movements. The malfunction of the inner ear, due to specific diseases, could be corrected by use of the drugs such as gentamicin that reaches the cochlea through the round window. This brief paper reviews the main anatomical knowledge on the inner ear, with particular attention to the structures of interest for otolaryngologists treating ear disorders by inoculation of drugs into the tympanic cavity. Key words: Inner ear Cochlea - Organ of Corti - Round window.

Department of Experimental Biomedicine and Clinical Neurosciences Section of Human Anatomy E. Luna University of Palermo, Palermo, Italy

Overview of the ear

he ear has three parts: external, middle and inner ear. The external ear transmits sound waves toward the middle ear in the tympanic cavity of the temporal bone. The external ear consists of the auCorresponding author: Dr. F. Cappello, Section of Human Anatomy E. Luna, Via del Vespro 129, 90127, Palermo, Italy. E-mail: francapp@hotmail.com

ricle and the external acoustic meatus. The auricle is a thin plate of elastic fibro-cartilage covered by skin. It is irregularly concave with eminences and depressions (helix, antihelix, tragus and antitragus, triangular fossa, scaphoid fossa, concha of auricle, intertragic notch, auricle tubercle and lobule) and is connected with surrounding tissues by means of ligaments and muscles, both extrinsic and intrinsic.1 The external acoustic meatus extends from the concha to the tympanic membrane, that separates the external ear from the middle ear (Figure 1). It consists of a lateral (cartilaginous) part and a medial (osseous) part. Along its route, it forms a S-shaped curve. The auricle and the external acoustic meatus develop as modifications of the first branchial groove and the branchial arches which bound it. The tympanic membrane is thin and semi-transparent. Its lateral surface is concave. The deepest point, the umbo, contacts the manubrium of malleus. It has a two parts, a pars flaccida and a pars tensa.2 The middle ear or tympanic cavity is a pneumatic chamber localized between the bottom of the external meatus and the internal ear. It consists of an upper part, the epitympanic recess, the proper tympa-

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the hearing organs of the internal ear. The footplate of the stapes is connected to an oval orifice, the vestibular window. Below, there is the cochlear or round window 3 (Figure 2). The cochlea and the round window The inner ear has a bony labyrinth whose outer wall is merged with the surrounding temporal bone. The otic capsule is that portion of the petrous part of the temporal bone which surrounds the internal ear. It derives from the mesenchyma, turned into precartilage and cartilage to change into bone. The bony labyrinth surrounds and protects the membranous labyrinth, a complex of canals and cavities filled with endolymph. The perilymph runs between the bony labyrinth and the membranous labyrinth. The sensory receptors responsible for the equilibrium and hearing sensitivity are located in the membranous labyrinth.4 The bony labyrinth consists of three parts: the vestibule, periotic semicircular canals and a cochlear portion. The vestibule has two membranous sacs: the saccule and the utricle, whose receptors provide information about gravity and linear acceleration. The semicircular canals have ducts whose receptors are stimulated by the rotation of the head. The cochlea lies in front of the vestibule (Figure 1). The cochlea is shaped like a snail and contains the cochlear duct (middle scale), surrounded by two cavities containing perilymph: the scala vestibularis and the scala tympani (Figure 3). The scala tympani is separated from the tympanic cavity by the round window (Figure 2). It lies under the overhanging edge of the promontory in a niche and it is oblique. It is closed by a membrane called the secondary membrane of the tympanum. The complex (middle scale, scala vestibularis and scala tympani) is coiled to spiral around a central spool of bone, the modiolus2. The cochlear duct is blind and ends at the apex of the cochlea and communicates with the other channels at the modiolar apex, the helicotrema (Figure 2). The cochlear duct forms three turns: basal, middle and apical turns. The external wall of the cochlear duct is merged with the periosteum, with a spiral prominence to the cochlear duct and above the vascular stria, that secretes the endolymph. The regulation of inner-ear fluid homeostasis, regarding volume, concentration, osmolarity and pressure, is induced by structures such as the

Figure 1.Structures of inner, middle and external ear. 1. Mastoid air cells; 2. Tympanic antrum; 3. External acoustic meatus; 4. Malleus; 5. Incus; 6. Stapes; 7. Vestibule; 8. Saccule; 9. Utricle; 10. Ampullae; 11a. Sup. semic. duct; 11b. Sup. semic. canal; 12. Horizontal duct; 13a. Inf. semic. duct; 13b. Inf. semic. canal; 14. Endolymph sac; 15. Endolymph duct; 16. Fossula fenestrae cochlea; 17. Scala vestibularis; 18. Cochlear duct; 19. Scala tympani; 20. Auditory tube; 21. Perilymph duct; 22. Dura mater; 23. Arachn. Spaces; 24. Brain.

Figure 2.Middle and inner ear and round window. 1. Tympanic membrane; 2. Malleus; 3. Incus; 4. Stapes; 5. Oval window; 6. Round window; 7. Scala vestibularis; 8. Scala tympani; 9. Middle scale.

num, that posteriorly communicates with tympanic antrum, and the mastoid air-cells, and continuing anteriorly with the auditory tube (Figure 1). The medial wall has eminences and depressions; particularly, the anterior part forms the promontory.2 The tympanic cavity is crossed by a chain of three small bones, malleus, incus and stapes, that harvest and amplify the sound waves to retransmit them to

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Figure 3.Cross section of the cochlea and organ of Corti. 1. Bone wall; 2. Scala vestibularis; 3. Cochlear duct; 4. Scala tympani; 5. Tectorial membrane; 6. Basilar membrane; 7. Spiral ganglion; 8. VIII encephalic nerve, cochlear branch.

stria vascularis and vestibular dark cells, responsible for endolymph secretion.5, 6 The vestibular wall, or Reissner membrane, extends obliquely from the spiral ligament to the spiral strip of the tympanic wall. It converts the movements of the perilymph (induced by movement of the stapes) in movements of the endolymph. The tympanic wall extends straight from the osseous spiral lamina to the spiral ligament. It has two parts, an internal spiral strip and an external basilar membrane. The latter contains an internal arcuate zone and an external combed area. The organ of Corti is located in the cochlear duct (Figure 3). It is a sensory structure above the basilar membrane that separates the cochlear duct from the tympanic duct below. The organ of Corti contains hair cell receptors arranged in longitudinal rows contacting the overlying tectorial membrane.7 These cells collectively detect the amplitude and frequency of the sound waves that enter the cochlea.8-10 Functional anatomy Sound reception takes place through various steps. The sound waves reach the tympanic membrane causing vibration of the membrane. This causes the displacement of malleus, incus and stapes. The

movement of the stapes on the oval window generates pressure waves in the perilymph in the vestibular canal. The round window moves to compensate. when the stapes moves toward the internal of cochlea, the window protrudes outward. The pressure waves induced by the stapes cause distortion and vibration of the basilar membrane, determining vibration of the hair cells. This triggers solicitation of the tectorial membrane, implying the activation of sensory nerves within the cell bodies in the spiral ganglion of the central part of the cochlea (Figure 3). From there the axons (afferent fibres of the VIII encephalic nerve, cochlear branch) reach the bulbar nuclei (cochlear nuclei) to be sorted to other encephalic centres.11 The cochlear nuclei sends fibres that cross the midline and ascend on the opposite side until the midbrain (inferior colliculus), the coordination centres that respond to acoustic stimuli, like auditive reflexes, involving skeletal muscles of the head, face and trunk. The fibres make synapses with the neurons of the thalamus to reach the acoustic cortex in the temporal lobe. The stimulus becomes conscious. Therapeutic modalities that block pro-cell-death pathways are being developed and evaluated for hearing preservation. Because they have both antiinflammatory and anti-apoptotic actions, corticosteroids have long been used to protect against several types of acute sensory-neural hearing loss.12 Areas of research covered include hair cell protection, hair cell regeneration and spiral ganglion cell regeneration.13 The hair cells can be easily damaged by excessive stimulation by ototoxic drugs and by the effects of aging. In mammals, auditory hair cells are never replaced, causing damage to the ear with progressive and permanent deafness. In contrast, nonmammalian vertebrates are capable of replacing lost hair cells.4, 14 Studies in both lower vertebrates and mammals have suggested that the sensory epithelia could be manipulated to achieve hair cell regeneration. These approaches include the use of inner ear stem cells, trans-differentiation of non-sensory cells, and induction of a proliferative response in the cells that can become hair cells.15-17 Oto-acoustic emissions (OAEs) differ between sexes. Prenatal exposure to high levels of androgens can weaken the cochlear amplifiers, thereby weakening oto-acoustic emissions (OAEs).18 During the perinatal period, the brainstem reaches a mature state, and brainstem activity is reflected in behavioral responses to sound (phonetic discrimination).19

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Vascularization of inner ear The inner ear is vascularised by the labyrinthine artery. This artery passes through the internal auditory meatus, dividing into three branches: the vestibular artery, the vestibule-cochlear artery and the cochlear artery. The first supplies the vestibular nerve, the utricle, the saccule and the semicircular ducts. The second supplies the basal turn of the cochlea, most of the saccule, the body of the utricle, the posterior semicircular duct and parts of the lateral and superior semicircular ducts. The third, at the level of the modiolus, gives rise to spiral arteries.2 The venous drainage occurs through three main veins. The internal auditory vein drains the apical and the middle turns of the cochlea. The vein of the cochlear aqueduct arises from the capillaries of the basal turn, saccule and part of the utricle. It passes in the otic capsule to enter into the inferior petrosal sinus. The vein of the vestibular aqueduct drains blood from the semicircular ducts and part of the utricle. It opens into the lateral sinus receiving small veins from the plexus around the endolymphatic sac.1 Conclusions From the current anatomical knowledge provided above, we can determine the effect of drugs in the treatment of pathologies of the inner ear. In general, chemical perfusion therapy of inner ear disease is safe, inexpensive and easy to perform. High inner ear medication concentrations can be achieved while minimizing systemic side effects.20 For example, the intratympanic gentamicin or the transtympanic steroids are an effective procedure for the control of cochleo-vestibular disorders, such as Mnires disease and sudden deafness, acting on the cochleo-vestibular system. These drugs probably passes through the round window, reaching the complex, middle scale, scala vestibularis and scala tympani of the inner ear. Future research could increase the indications for steroids and gentamicin treatment, as well as introducing new drugs and gene therapy.21 Riassunto
Anatomia della coclea e della finestra rotonda Una delle pi importanti funzioni dellorecchio la ricezione del suono, particolarmente il rilevamento dellam-

piezza e della frequenza delle onde sonore da parte dellorgano di Corti. Questultimo una struttura sensoriale localizzata nel dotto cocleare (scala media), costituito da cellule ciliate disposte sulla membrana basilare. Il dotto cocleare circondato da due cavit conteneti perilinfa: la scala vestibularis e la scala tympani. Il meccanismo di ricezione del suono coinvolge diverse altre componenti dellorecchio, come il martello, lincudine e la staffa, nella cavit timpanica e le finestre ovale e rotonda. Il movimento della staffa sulla finestra ovale, che adiacente alla scala vestibularis, genera onde pressorie nella perilinfa lungo il canale vestibolare. La finestra rotonda, che separa la scala tympani dalla cavit timpanica, si muove a compensare i movimenti della finestra ovale. Il malfunzionamento dellorecchio interno, a causa di particolari patologie, pu essere corretto dallimpiego di farmaci come la gentamicina che raggiunge la coclea attraverso la finestra rotonda. Questo breve articolo propone una revisione delle principali conoscenze anatomiche dellorecchio interno, con particolare attenzione alle strutture di interesse otorinolaringoiatrico per il trattamento di disordini dellorecchio attraverso linstillazione di farmaci nella cavit timpanica. Parole chiave: Orecchio interno - Coclea - Organo di Corti Finestra rotonda.

References
1. Bast TH, Anson BJ. The temporal bone and the ear. Illinois (USA): Springfield; 1949. 2. Standring S. Grays Anatomy. The anatomical basis of clinical practice. Edimburgh (UK): Elsevier; 2005. 3. Harada y. Atlas of the ear by scanning electron microscopy. Lancaster (England): MTP Press Limited International Medical Publisher; 1983. 4. Kwan T, white PM, Segil N. Development and regeneration of the inner ear. Ann N y Acad Sci 2009; 1170:28-33. 5. Ciuman RR. Communication routes between intracranial spaces and inner ear: function, pathophysiologic importance and relations with inner ear diseases. Am J Otolaryngol 2009a;30:193-202. 6. Ciuman RR. Stria vascularis and vestibular dark cells: characterisation of main structures responsible for inner-ear homeostasis, and their pathophysiological relations. J Laryngol Otol 2009b;123:15162. 7. Grillet N, Kazmierczak P, Xiong w, Schwander M, Reynolds A, Sakaguchi H et al. The mechanotransduction machinery of hair cells. Sci Signal 2009;2:5. 8. Beisel K, Hansen L, Soukup G, Fritzsch B. Regenerating cochlear hair cells: quo vadis stem cell. Cell Tissue Res 2008; 333:373-9. 9. Hudspeth AJ. Making an effort to listen: mechanical amplification in the ear. Neuron 2008; 59:530-45. 10. Phillips KR, Biswas A, Cyr JL. How hair cells hear: the molecular basis of hair-cell mechanotransduction. Curr Opin Otolaryngol Head Neck Surg 2008;16:445-51. 11. Simon E, Perrot X, Mertens P. Functional anatomy of the cochlear nerve and the central auditory system. Neurochirurgie 2009;55:1206. 12. Dinh CT, Van De water TR. Blocking pro-cell-death signal pathways to conserve hearing. Audiol Neurootol 2009;14:383-92. 13. Diaz RC. Inner ear protection and regeneration: a historical perspective. Curr Opin Otolaryngol Head Neck Surg 2009;17:363-72.

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14. Groves AK. The challenge of hair cell regeneration. Exp Biol Med 2010;235:434-46. 15. Edge AS, Chen Zy. Hair cell regeneration. Curr Opin Neurobiol 2008;18:377-82. 16. Martinez-Monedero R, Edge AS. Stem cells for the replacement of inner ear neurons and hair cells. Int J Dev Biol 2007;51:655-61. 17. Vlastarakos PV, Nikolopoulos TP, Tavoulari E, Papacharalambous G, Tzagaroulakis A, Dazert S. Sensory cell regeneration and stem cells: what we have already achieved in the management of deafness. Otol Neurotol 2008;29:758-68.

18. McFadden D. Masculinization of the mammalian cochlea. Hear Res 2009;252:37-48. 19. Moore JK, Linthicum FH Jr. The human auditory system: a timeline of development. Int J Audiol 2007;46:460-78. 20. Jackson LE, Silverstein H. Chemical perfusion of the inner ear. Otolaryngol Clin North Am 2002;35:639-53. 21. Herraiz C, Miguel Aparicio J, Plaza G. Intratympanic drug delivery for the treatment of inner ear diseases. Acta Otorrinolaringol Esp 2010;61:225-32.

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Pharmacokinetics of drugs in transtympanic administration

F. DISPENZA 1, G. KULAMARVA 2, A. DE STEFANO 3

There are two possible ways to deliver drugs in cases of inner ear diseases: via the bloodstream through systemic administration and through the two windows of the inner ear by application into the middle ear cleft. Efforts to find the strategies to deliver drugs to the inner ear are continuously made by Researchers worldwide. This brief description of inner ear will show the fate of drugs after transtympanic administration, discussing the anatomic and physiologic key point to understand the inner ear pharmacokinetics. Key words: Ear, inner - Pharmacokinetics - Cochlea - Round window, ear.

1Department

of Surgical and Oncological Disciplines University of Palermo, Palermo, Italy 2ENT Clinic, Nayaks Road, Kasaragod Kerala, India 3ENT Institute, Department of Surgical Clinical and Experimental Sciences, G. dAnnunzio University of Chieti and Pescara Chieti, Italy

herapeutic management of inner ear diseases is a contemporary challenge in constant evolution. Researchers in general have focused their efforts on the pharmacological management of inner ear diseases and specifically on the strategies used to deliver drugs to the inner ear. Inner ear contains both the auditory and vestibular systems. Being a very delicate region of the body, it is naturally well protected inside a hard bony capsule leaving only microscopic gaps communicating with the outer structures. This system of protection provides the inner ear with a good defense mechanism from infective agents and toxic substances. Unfortunately, the main disadvantage of such a closed system is its limitation in allowing evaluation of inner ear diseases in vivo, in delivering therapeutic substances and in directly evaluating the efficacy of treatment. That perilymph originated as an ultrafiltrate of blood was already assumed by Schnieder in 1974, based on the ionic composition which was found to

Corresponding author: Dr. F. Dispenza, Via Oreto 339, 90124 Palermo, Italy, E-mail: francesco.dispenza@gmail.com

be similar to that of plasma.1 However, the endothelial cells of inner ear capillary complex form a barrier with tight-junction, morphologically similar to the blood-brain barrier, and anatomic studies showed that there were no fenestrations between the endothelial cells of inner ear.2 The presence of a blood-labyrinth barrier was postulated also after noting that the entry rates of administered drugs decrease in direct proportion with increasing molecular size.3 Effects of drugs, when administered into the body, depend generally on two main factors: concentration (at the site of action) and the amount of time available for it to act. The concentration is influenced mainly by dosage as well as by the clearance of the drug from the body. Because the clearance is often a standard value depending on several local and systemic factors, we can vary the systemic dosage of a drug so as to reach a useful concentration at the intended site of action. However, side effects can increase in direct proportion to the increase in dosage and limit the ability to increase it beyond a certain level.4 There are two possible ways to deliver drugs in cases of inner ear diseases: via the bloodstream through systemic administration and through the two windows of the inner ear by application into the middle ear cleft.

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The systemic route generally requires high dosages to reach useful concentrations in the inner ear. Achieving this while administering the drugs systemically is limited by the adverse systemic events it would cause. For this reason alternative ways were explored to deliver the drugs in the form of transtympanic administration (TTA). Potential drawbacks of TTA include anatomic barriers to absorption, loss of drug down into the eustachian tube, and variable or unknown pharmacokinetic profiles of medications currently delivered via this route. Transtympanic administration: notes on pharmacokinetics The basis of TTA resides in the anatomy of the ear and upon the pharmacokinetics into inner ear spaces. This route of administration has two theoretical advantages. First, there is a potential for direct drug uptake through the round window membrane (RWM), resulting in higher perilymph levels. Second, this route of administration may cause reduced systemic adverse effects. The round and oval windows are situated on the medial wall of the middle ear. Oval window receives mechanical energy by the action of the conduction apparatus of middle ear and transfers the energy of sound waves into fluids of the cochlea. On the further side, round window with its membrane plays a role in acoustic dynamics by allowing the release of mechanical energy passing through the cochlea. Without this outlet no waves could pass into the perilymph. The round window lays posteroinferiorly to the promontory. It is visible through an intact tympanic membrane at an average distance from the umbo of 3.44 (0.68) mm, at an angle of 113.2 (9.8) degrees from the long process of the malleus.4 The round window membrane (RWM) works as a semi permeable membrane. As showed in numerous animal experiments, substances placed in the round window niche can be recovered in perilymph and/or can cause inner ear cell changes.5-7 Variables that affect the amount of drugs entering the cochlea include: 1) amount of drug applied, which in turn depends on the concentration of drug in the solution and on the volume of solution injected; 2) duration of contact between the drug and round window membrane; 3) total number of drug application sessions 4) method of application; 5) presence

of facilitating molecules in the drug-containing solution, which may influence the permeability of the round window membrane, such as the osmolarity and the pH; 6) alteration of permeability of the round window membrane; 7) Molecular size of the drug. The time of contact between drugs and the RWM is influenced by drainage through the eustachian tube during head movements and swallowing. For this reason the patients must lie supine with the head rotated towards the opposite side and have to hold the position for at least 20 minutes, avoiding swallowing if possible during this period. The amount of drug available for absorption depends on solution concentration and volume injected. The volume has to be less than that of middle ear cleft which generally varies between 0.3 to 0.7 mL.8 Air contained in the middle ear can present an obstacle to drug injection and can limit the final volume of drug inoculated. The RWM is sensitive to insults with consequent alteration of the permeability. It is one of the most important parameter that may influence the drugs passage into inner ear fluids. It may be changed by anatomical factors and acquired alterations. The most frequent anatomical variation is the presence of a second membrane at the entrance of the round window niche, it consist of folds of middle ear mucosa. It is also called false round window membrane,9 and may impede or reduce the drug contact with the true membrane. Acquired alteration may be induced by several factors such as: infection, previous operation for middle ear diseases and drugs additives present in injected solution. Treatment with a drug and its carrying solution modifies the appearance of the round window on histopathology and perhaps affect the permeability to future drug applications.10 In otitis media, the RWM may gradually change similar to the mucoperiostium of the middle ear.11 At an early stage of inflammation there may be an increase in permeability, but, as the inflammatory process progress, the changes go in to fibrosis becoming protective to inner ear in terms of decreased permeability.4 The drugs permeate through RWM by pinocytosis and intercellular diffusion. Size of the drug particles and molecules has an effect on the passage through RWM. In an animal model it was reported that 1mm microspheres go across the membrane, but a 3mm microsphere do not.5 Molecule with less than 1000 kD weight pass across RWM rapidly, if the weight is over 1000 kD a pinocytosis mechanism provides

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for the drugs passage.12 Liposolubility of substances is also a factor in regulation of RWM permeability. In fact, although cationic substances have been observed to pass easily through a normal RWM, some authors reported that anionic substances do not pass.9 Acute and chronic inflammatory conditions can double the thickness of RWM and as a consequence it will decrease the permeability of substances through it. As well as inflammation, surgeries in the middle ear can obstruct the round window niche with either cicatrisation or bone dust deposits, reducing the efficacy of transtympanic treatment in such patients.13 Cochlear endolymphatic ions homeostasis is maintained by stria vascularis in the lateral wall of cochlea and by the dark cells in the vestibular system. These systems contain a variety of potassium and sodium transporters. The ions are recycled between endolymph and perilymph without a considerable movement of water, given that the rate of longitudinal flow is near to zero.14 Passage of substances into endolymph occurs indirectly, via the perilymph.15 The movements of charged molecules between endolymph and perilymph are therefore influenced by the endocochlear potential. Substances with a negative charge have a natural gradient to pass from the perilymph to endolymph, because of the considerable positive endocochlear potential. In contrast, cationic molecules in perilymph do not easily enter the endolymph. Therapeutic agents passed across the RWM show a non-uniform distribution in the perilymph along the cochlea. The concentrations of substances delivered are usually higher in the basal turn of cochlea than in the apical turn. To follow the drug movements into inner ear, Salt and Ma conducted an experimental study using the trimethylphenylammonium (TMPA) as ionic marker. It was possible to determine parameters of the RWM permeability, the rate of longitudinal flow, and the rate of clearance from the perilymph.16 The drug diffusion into cochlear fluid was always assumed in a linear model, along the scala tympani and then down the scala vestibuli, through the helicotrema. This movement is certainly present, but, by such route, the concentration obtainable is very low and the time course far too slow. A radial exchange of drug between each of the scalae was then hypothesized and demonstrated by several studies.17, 18 With these findings it was possible to understand the high concentration observable in the

basal portion of two scalae, earlier than the expected passage through helicotrema. Similar to all spaces containing fluids in the body, the inner ear too has a clearance mechanism that removes the drugs from the fluids. The drug level decreases with time as a result of the clearance. Clearance may be the combined effects of numerous processes: diffusion into contiguous compartments of the ear, passage into bloodstream across the vascular endothelial cells, accumulation of drugs by tissues of the ear. The clearance of drugs from perilymph is supposed to be the determinant factor in reaching the stable decreasing gradient of drug concentration from basal turn of the cochlea to the apical turn.8 A drug that is quickly cleared will not progress along the scalar fluid. A steady state may be obtained only by further application. The clearance includes also the passage of drug from the outer space to the intracellular compartments (site of action of the great part of drug used for inner ear diseases). The molecule may bind intracellularly with proteins, with receptors or may be metabolized by intracellular mechanisms. Metabolism of drugs, including uptake and elimination, is different in cochlear tissues as compared with other organs.19 The steroids behavior can be a good example: Methylprednisolone had the highest concentration and longest duration in perilymph and endolymph among all the other steroids (Dexamethasone and Hydrocortisone).20 Therapeutic agents should also reach the posterior labyrinth to act, for example in cases of chemical labyrintectomy. The utriculo-endolymphatic valve maintains anatomical and humoral independence of the pars superior (utricle and canals) from the pars inferior (cochlear duct and saccule) and protects the vestibular apparatus from the hydropic condition,21 but may represent an obstacle to drug diffusion into vestibular compartment. To improve the drug delivering into inner ear fluids, efforts were done to find some facilitating agents. Animal experiments showed that histamine added to drugs may improve the penetration into inner ear fluid, without cochlear cell damage.22 The ultimate frontier of inner ear drug application is the direct delivery into inner ear. Investigators have attempted to modify the electrode of cochlear implant to deliver medications.23, 24 A direct drug delivery by an osmotic pump was experimented to permit longer drug infusion times and bolus dosing25.

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Conclusions In conclusion this brief description of inner ear pharmacokinetics shows the fate of drugs after transtympanic administration. Several emerging themes arise. First of all, the numerous determining factors that influence the action of drug into inner ear, differently from other region of the body, are in reality not modifiable, except for the delivering system. The second major difficulty is the inaccessibility of inner ear without making permanent damages, which keeps the physician between the less invasive TTA producing variable drug levels into inner ear fluids and the more invasive direct injection into the inner which should apply drugs in a more consistent manner. The topic of drug delivery to the inner ear is in its early life, and there is no single standard method to obtain a controlled drug concentration keeping the ear safe, but this therapeutic approach is in development and has the prospective to solve a number of previously challenging clinical problems. Riassunto
Farmacocinetica dei farmaci dopo somministrazione transtimpanica Per il trattamento di alcune patologie dellorecchio interno esistono due possibili vie di somministrazione: via sistemica, attraverso la distribuzione ematica, ed attraverso le due finestre dellorecchio interno mediante applicazione diretta nella cassa timpanica. Numerosi sono gli studi e i tentativi di trattamento compiuti dai ricercatori di ogni Paese, al fine di trovare le corrette strategie terapeutiche nella somministrazione transtimpanica. Questa breve descrizione mostra il destino dei farmaci dopo soministrazione transtimpanica, discutendo i punti chiave anatomici e fisiologici che consentono di comprendere la farmacocinetica dellorecchio interno. Parole chiave: Orecchio interno - Framacocinetica - Coclea - Finestra rotonda, orecchio.

References
41. Schnieder EA. Contribution to the physiology of perilymph. Part I: the origin of perilymph. Ann Otol 1974;83:76-83. 42. Jahnke K. The blood-perilymph barrier. Arch Otolaryngol 1980;228:29-34.

43. Juhn SK, Rybak LP. Labyrinthine barriers and cochlear homeostasis. Acta Otolaryngol 1981;91:529-534. 44. Goycoolea MV, Lundman L. Round window membrane. Structure function and permeability: a review. Microsc Res Tech\ 1997;36\:201-211\. 45. Goycoolea MV, Muchow D, Schachern PA. Experimental studies on round window membrane structure function and permeability. Laryngoscope 1988;98 (Suppl):1-20. 46. Tanaka K, Motomura S. Permeability of the labyrintine windows in guinea pigs. Arch Otolaryngol Head Neck Surg 1981;233:67-75. 47. Lundman L, Holmquist L, Bagger-Sjoback D. Round window membrane permeability. An in vitro model. Acta Otolaryngol 1987;104 (Suppl.):472-80. 48. Haynes DS, OMalley M, Cohen S, Watford K, Labadie RF. Intratympanic dexamethasone for sudden sensorineural hearing loss after failure of systemic therapy. Laryngoscope 2007;117:3-15. 49. Goycoolea MV. Clinical aspects of round window membrane permeability under normal and pathological conditions. Acta Otolaryngol 2001;121:437-47. 10. Nordang L, Linder B, Anniko M. Morphologic changes in the round window membrane after topical hydrocostidone and dexametasone treatment. Otol Neurotol 2003;24:339-43. 11. Ikeda K, Morizono T. Round window permeability during experimental purulent otitis media altered by cortisporin ototoxicity. Ann Otol Rhinol Laryngol 1990;99:46-8. 12. Juhn SK, Hamguchi y, Goycoolea MV. Review of round window membrane permeability. Acta Otolaryngol 1988;457:43. 13. Silverstein H, Rowan PT, Olds MJ. Inner ear perfusion and the role of round window patency. Am J Otol 1997;586:18. 14. Salt AN, Thalmann R, Marcus DC, Bohne BA. Direct measurement of longitudinal endolymph flow rate in the guinea pig cochlea. Hear Res 1986;23:141-51. 15. Sterkers O, Ferrary E, Amiel C. Production of inner ear fluids. Physiol Rev 1988;68:1083-128. 16. Salt AN, Ma y. Quantification of solute entry into cochlear perilymph through the round window membrane. Hear Res 2001;154:8897. 17. Saijo S, Kimura RS. Distribution of HRP in the inner ear after injection into the middle ear cavity. Acta Otolaryngol 1984;97:593-610. 18. Salt AN, Ohyama K, Thalmann R. Radial communication between the perilymphatic scalae of the cochlea. I. Estimation by tracer perfusion. Hear Res 1991;56:29-36. 19. Tobita T, Senarita M, Hara A. Determination of prednisolone in the cochlear tissue. Hear Res 2002;165:30. 20. Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids: an animal study followed by clinical application. Laryngoscope 1999;109:1-17. 21. Schuknecht HF, Belal AA. The utriculo-endolymphatic valve: its functional signifcance. J Laryngol Otol 1975;89:985-96. 22. Chandrasekhar SS, Rubinstein Ry, Kwartler JA, Gatz M, Connely PE, Huang E et al. Dexamethasone pharmacokinetics in the inner ear: Comparison of route of administration and use of facilitating agents. Otolaryngol Head Neck Surg 2000;122:521-8. 23. Paasche G, Bogel L, Leinung M, al. e. Substance distribution in a cochlea model using different pump rates for cochlear implant drug delivery electrode prototypes. Hear Res 2006;212:74-82. 24. Richardson RT, Wise AK, Thompson BC, Flynn BO, Atkinson PJ, Fretwell NJ et al. Polypyrole-coated electrodes for the delivery of charge and neurotrophins to cochlear neurons. Biomaterials 2009;30:2614-24. 25. Prieskorn DM, Miller JM. Technical report: chronic and acute intracochlear infusion in rodents. Hear Res 2000;140:212-5.

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Intratympanic steroids for sudden sensorineural hearing loss

A review
G. JEREMIC, L.S. PARNES

Background/Aim. Local steroid treatment via intratympanic injection has been suggested to achieve a significant rate of hearing improvement in cases of idiopathic sudden sensorineural hearing loss (SSNHL). The aim of this study was to review the current evidence for and future direction of intratympanic steroid (ITS) therapy. Methods. PubMed and Ovid Medline databases were investigated from 1966 to present for clinical trials on ITS in the treatment of Idiopathic SSNHL. Studies were evaluated based on comparability, and internal and external validity. Results. Thirty-four studies were identified in total. Only two studies were double-blinded, randomized prospective trials. Overall, there were variable definitions of disease and improvement, steroid doses, pre-study treatments, and treatment protocols. Conclusion. There are limited concrete studies on ITS that meet the criteria of comparability, internal validity, and external validity. More research is needed using uniform, standardized definitions and protocols to determine the efficacy of ITS for treatment of idiopathic SSNHL. Key words: Intratympanic steroids - Sudden sensorineural hear-ing loss - Deafness

Department of Otolaryngology Head and Neck Surgery, Schulich School of Medicine & Dentistry University of Western Ontario London, Ontario, Canada

diopathic sudden sensorineural hearing loss (SSNHL) is the most common cause of sudden sensorineural hearing loss, and necessitates urgent intervention as an otologic emergency. It is characterized by new onset unilateral hearing loss of greater than 20-30 dB (depending on the study) over 3 contiguous test frequencies on the audiogram that occurs in less than 72 hours. Estimates
Corresponding author: Dr. Lorne S. Parnes, Department of Otolaryngology Head & Neck Surgery, University Hospital, 339 Windemere Road, London, ON, N6A 5A5 Canada, Tel. +1 519 663 3604, Fax. + 1 519 663 3916, Email. parnes@uwo.ca

of the overall incidence of SSNHL range from 5 to 20 per 100,000 persons per year 1. Treatment of SSNHL is broad with no universally accepted standard protocol. Currently, the most employed treatment of SSNHL worldwide is that of systemic steroids, through either the oral or intravenous route 2. Although often considered to be the standard, treatment with systemic steroids has been scrutinized with respect to its efficacy due to study variability in definitions and outcomes. Alternatively, local administration of steroids via intratympanic injection was introduced as a means of delivering higher concentrations into the inner ear, while sparing the side-effects of high-dose systemic steroids. In addition to avoiding the side-effects of systemic steroids, there are several advantages to using intratympanic steroids (ITS). Intratympanic injections are typically well tolerated, and can be done as an office procedure under local anesthesia. Treatment is directed to the affected inner ear only via the round window membrane, with minimal systemic absorption 3. Several clinical reports have explored the use of ITS in various methods to treat idiopathic SSNHL as a salvage therapy to other means such as systemic steroids, with only a few focusing on ITS as a primary treatment modality. Although these studies have

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shown ITS to be relatively safe, efficacy is difficult to assess because of the heterogeneous treatment protocols and variable study designs. Our goal then with this review of the literature was to assist clinicians in clarifying the current evidence and direction of ITS therapy for idiopathic SSNHL. Methods We used the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) proposed guidelines for reporting the methods 4. While this literature review is not a meta-analysis, certain aspects of the MOOSE guidelines are applicable. One author (G.J.) reviewed all the studies. Ovid Medline and PubMed databases were searched for clinical trials on ITS from 1966 to June 1, 2010. We used the following search terms: intratympanic steroids, sudden hearing loss, sensorineural hearing loss. Clinical trials investigating ITS therapy for Idiopathic SSNHL were selected. Articles excluded were those published in a language other than English, abstracts, and unpublished studies. Additional studies were identified by hand searching the references of recognized studies. The author was not blinded to the authors, institutions, journals of publication, or study results. In a study of blinding authors of meta-analyses, masking made no difference to the summary odds ratio 5. The evaluation criteria of these clinical studies were similar to the recent review of Alles et al. 6: Comparability. Were the patients receiving the drug of study compared to a reference control group (eg. Placebo)? Internal Validity. What was the level of evidence for the study? We used the Oxford Centre for Evidencebased Medicine guidelines 7, which grades studies from levels 1-5. Level 1 is the highest level of evidence (e.g. randomized controlled trial); level 5 is the lowest level of evidence (e.g. Expert opinion). Was the study prospective or retrospective? Which therapy was evaluated? External Validity. Which criteria were used to confirm the diagnosis of SSNHL? How long was the follow-up? Which criteria were used to evaluate the results? Results Thirty-four studies were identified in total, with the study designs listed in Table I. Table II lists the

results for the clinical trials. Studies varied with respect to steroid doses, treatment protocols, and definitions of SSNHL, outcome criteria, and follow-up. Comparability. Were the patients receiving the drug of study compared to a reference control group (eg. Placebo)? According to the guidelines of the German Society of OtorhinolaryngologyHead and Neck Surgery, systemic treatment with high dose glucocorticoids is suggested as a primary intervention option in idiopathic SSNHL 42. Consequently, most studies utilized ITS as salvage or concurrent treatment to oral steroids. In reviewing the SSNHL studies in Tables I and II, 18 studies had controls 8, 9, 11, 12, 15-27, 29; only the study by Plontke et al. compared the ITS intervention group to a placebo injection of normal saline 8. The remainder of studies employed systemic steroids as controls groups. With-holding a treatment such as systemic steroids, considered by many clinicians to be the gold standard, presents ethical dilemmas in designing a study with placebo as the control. Nevertheless, a shift in the literature has brought to light the several adverse side-effects of systemic treatment outweighing the little-proven benefits. In fact, a study by Han et al. enrolled patients with Type 2 Diabetes Mellitus and difficult glycemic control to stress the moral use of ITS over systemic management, showing ITS to be at least as effective without the systemic adverse effects 12. Several studies reported confounding factors including most commonly a large range of spontaneous recovery rate, initial degree of hearing loss, and the duration between the time of the hearing loss and the onset of treatment. The reported spontaneous recovery rate of SSNHL ranges from 32 to 70% 43, 44. Many studies stratified patients by the extent of hearing loss on presentation, acknowledging its prognosticating value without agreement on exactly how much hearing loss was beyond improvement with ITS. Similarly, patients were stratified to onset of ITS treatment favoring earlier therapy without accord on when ITS become more effective than other treatments such as systemic steroids. Internal Validity. What was the level of evidence for the study? We used the Oxford Centre for Evidence-based Medicine guidelines, which grades studies from levels 1-5. Level 1 is the highest level of evidence (e.g. randomized controlled trial); level 5 is the lowest level of evidence (e.g. Expert opinion). Was the study prospective or retrospective? Which

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Table I.Study design of clinical trials on SSNHL

First Author Level of evidence Definition of SSNHL Study type Steroid & dose (mg/ml) Previous or concurrent treatment other than ITS Treatment protocol

Plontke, 2009 8

She, 2010 9

SSNHL within 72h & hearing threshold of >50 dB HL for 3 freq. or >60 dB for 2 or >70 dB HL for any frequency or a SRT 70 dB SPL or a speech discrimination score of 30% SSNHL 30 dB for 3 freq. over 3 days

Salvage

dex. (4)

Prednisolone i.v., pentoxifylline for 10 days

RW Microcatheter Dex-P. & NS (6 ul/h) for 14 days, up to 28 days

Salvage

MP(40)

Dallan, 2010 10

Idiopathic SSNHL

Salvage

MP(20)

Hong, 2009 11 Han, 2009 12 Zernotti, 2009 13

1 2 4

SSNHL 30 dB in 3 contiguous freq. in 3 days SSNHL 30 dB in 3 contiguous freq. in 3 days

initial initial

dex.(5) dex. (5)

Systemic steroid (dex), vasodilators, antivirals, thrombolytic anti- coagulant (defibrin), Vit. B1 and mecobalamin, and hyperbaric oxygen therapy MP i.v. 1 mg/kg/d, pentoxyfylline i.v. (200 mg/d); 8 patients LMWH heparin (0.4 ml, s.c. bid) for 7-10 d None Trimetazidine (50 mg tid); Gingkobiloba extracts (80 mg bid) None

Microcatheter MP (0.5 mL per day) for 10 days

1 injection

0.3 to 0.4 cc / d for 8 d 1 injection 3 (1 cc) weekly injections

Fitzgerald, 2007 14 Ahn, 2008 15 Lee, 2008 16

4 3 2

SSNHL >30 dB in at initial dex. (4) least 3 contiguous audiometric frequencies, over a period of 72 h or less 20 dB SSNHL in 3 Initial or MP (62.5) contiguous freq. occursalvage ring w/in 72 h or less SSNHL 30 dB in 3 con- Salvage dex. (5) tiguous freq. over several days 20 dB SSNHL in 3 Salvage dex. (5) contiguous freq. occurring w/in 72 h or less 20 dB of unilateral initial SSNHL in 3 freq. occurring w/in 3 days SSNHL 30 dB in 3 conInitial tiguous freq. over several days SSNHL 30 dB in 3 con- Salvage tiguous freq. in 3 days Unilateral severe or pro- Salvage found idiopathic SSNHL over 24 h Sudden onset HL history Unilateral deafness, w/ in 3 days, 30 dB at 3 consecutive freq. SSNHL 30 dB at 3 subsequent 1-octave steps in freq. w/in 3 days

Oral steroids MP p.o. for 14 days with vitamins and lipo-PGE1

3 injections (0.4 cc each) over 3 weeks 2 injections (0.3-0.4 cc) / week for 2 weeks

Battaglia, 2008 17 Ahn, 2008 18 Xenellis, 2006 19 Ho, 2004 20

1 1 1 1

MP p.o. for 14 days + dex- 4 injections within 2 tran i.v. and lipo-PGE1 i.v weeks for 5 days + famci-cyclovir for 7 days dex. (12) Prednisone p.o. concurrently 3 weekly injections for 14 days dex. (5) MP p.o. concurrently for 14 d 3 injections (days 1, 3, 5) 4 injections over 15 days 1 injection/week for 3 weeks 5 injections at 3-day intervals 3 weekly injections

Kilic, 2007 21 Plaza, 2007 22 Van Wijck, 2007 23

2 2 2

MP (80 Prednisolone i.v. for 10 d; mg/2ml) acyclovir dex. (4) MP p.o. for 10 d, vasodilators, vit. B, benzodiazepines for 10 d, carbogen inhalation for 5 d Salvage MP (62.5) MP i.v. for 3 days, prednisolone p.o. for 21 d Salvage MP (20) MP (120 mg) i.v. for 5 d

Salvage MP (62.5) MP i.v. for 1 day, then MP Microcatheter 3 drops p.o. for 9 days; naftidrofuryl, bid for 3 weeks diazepam, LMWH

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Table I [continued]
First Author Level of evidence Definition of SSNHL Steroid & or concurrent Study type dose (mg/ Previous other than ITStreatment ml) Treatment protocol

Kakehata, 2006 24 Lauterman, 2005 25 Roebuck, 2006 26 Choung, 2006 27

2 2 3 3

n.a.(1) Monoaural sudden idiopathic profound HL SSNHL 20 dB over 3 freq. in 72 h Idiopathic SSNHL

Initial Initial Salvage Salvage

dex. (4) MP (32) dex. (24) dex. (5)

Haynes, 2007 28 Plontke, 2005 29 Dallan, 2006 30 Banerjee, 2005 31 Slattery, 2005 32 Herr, 2005 33

3 3 4 4 4 4

Decline over 3 days, 3 freq. affected by 30 dB SSNHL w/in 72h

Salvage Salvage

dex. (24)

20 dB SSNHL in 3 Salvage contiguous freq. occurring w/in 3 days SSNHL at least 30 dB Initial or in 3 contiguous freq. in salvage 3 days SSNHL at least 30 dB in Salvage 3 contiguous freq. over 24h >20 dB SSNHL at any Salvage dex. (10) High-dose systemic steroids freq. w/in 72h or MP (62.5)

MP (40) or dex. (4) MP (40) MP i.v. for 10 d + pentoxifylline for 10 d; 2 patients received LMWH MP (40) Depends on outside referring or dex. ENT specialist (4) MP (62.5) Prednisone for 14 days

Dex. i.v. for 10 d in comparative group Concurrent prednisolone i.v. for 10 d + rheologic infusion therapy Medrol dosepak for 5-7 d before, controls received prednisolone for 20 days Prednisolone p.o. for 10 d and other medication (gingko, antiviral, hydrochlorothiazide) Systemic steroids (85% antiviral, 27% diuretics) Prednisolone i.v. for 10 d, pentoxifylline for 10 d

1 injection/day for 8 days 5 injections on 5 consecutive days via ventilation tube 1 injection 2 injections / week for 2 weeks 1 injection RW microcatheter MP (10 ul/h) or dex. (5 ul/h) for 4 weeks 1 injection 2 injections/week until plateau in hearing; average 3.8 (2-11) 4 injections, 4 days apart, w/in 2 weeks Microwick dex. (3 drops/day) for 1 week; if not better, RW microcatheter infusion MP or dex. (10 ul/h for 10-13 d) 4 injections over 2 weeks Average 2.7 injections (range 1-7) every 2 d RW microcatheter infusion 10 ul/h for 8-10 d 1-15 injections

Battista, 2005 34 Gouveris, 2005 35 Lefebvre, 2002 36

4 4 4

PTA >90 dB

Initial

HL w/in >3 days, >30 dB Salvage SSNHL SSNHL >30 dB for 3 consecutive 1-octave freq. steps w/in 24h Change in hearing w/in 12h to 3 days(1) >20 dB SSNHL in 3 contiguous audiometric freq. occurring w/in 3 days HL on awakening or w/ in 72 h n.a. n.a. Salvage

Chandrasekhar, 2001 37 Gianoli, 2001 38

Salvage

Salvage

Kopke, 2001 39 Parnes, 1999 40 Silverstein, 1996 41

4 4 4

Salvage or initial Salvage

dex. (24) Concurrent MP p.o. for 11 days dex. (8) Prednisone i.v. and vasoactive agents (pentoxifylline and HES) MP (62.5) MP i.v. for 1 day, then MP p.o. for 15 d; carbogen, nafhydrofuryl, diazepam, LMWH dex. (4) other meds, suboptimal doses of either Medrol dosepak or p.o. prednisone, or no treatment dex. (25) High-dose systemic steroids or MP (prednisone 1 mg/kg/day) (125) for min. 1 week or equivalent MP (62.5) Prednisone p.o. for 2 weeks

4 injections over 10-14 days RW microcatheter infusion 10 ul/h for 14 days 2-29 injections Every Monday, Wednesday and Friday for 2-4 weeks

MP (40) conventional medical or dex. measures depending on referring physician Salvage MP (80), conventional treatment dex. Eye solution (1) or i.v. dex (4)

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Table II.Results of clinical trials on SSNHL

First Author Definition of improvement Sample size Hearing loss improvement Follow-up Pos./ neg.

Plontke, 2009 8

She, 2010 9 Dallan, 2010 10

Hong, 2009 11

Han, 2009 12

Zernotti, 2009 13 Fitzgerald, 2007 14 Ahn, 2008 15 Lee, 2008 16

1. 6 PTA25 dB CR, 6 PTA >30 dB MR, 6 PTA 10-30 dB SI, and 6 PTA <10 dB NI. 2. Recovery of 50% of the max possible recovery using the unaffected ear as baseline Decrease of PTA 15 dB at all affected frequencies (from 0.25 kHz to 8 kHz) Good (RG >50%), significant (25% RG 50%), and insignificant (RG <25%), RG = PTA / HL Complete recovery: w/in 25 dB of unaffected ear; partial recovery: >15 dB gain and final hearing 25-45 dB; slight improvement: >15 dB gain and final hearing poorer than 45 dB; no recovery: <15-dB gain and final hearing poorer than 75 dB Decrease in the four-frequency (0.5, 1, 2, and 3 kHz) PTA of 15 dB or more, at least eight weeks later A mean hearing recovery of 25 dB. 10 dB PTA, 15% SDS >15 dB PTA 10 dB PTA, 15% SDS

12 ITS 11 Placebo

4/11 (PTA criteria); 3/11 (max recovery criteria) 1/9 (PTA criteria); 1/9 (max recovery criteria) 50% (61.9 % with time-to-treat 60 d) 21.7% 55.6%

98-112 d

26 ITS 23 controls 27

3 months 6 months

32 ITS 31 controls

No significant differences were noted among the hearing recovery rates between the ITS group and the oral (control) group

3 months

34 ITS 32 i.v. 48 p.o. 18 ITS 21 ITS 49 ITS 50 controls 34 ITS 18 controls 17 ITS 18 p.o. prednisone 16 ITS + p.o. prednisone 60 ITS 60 controls 19 ITS 18 controls 15 ITS 14 controls 19 ITS 18 controls 9 ITS 9 controls 12 ITS 12 controls 10 ITS 21 controls 13 ITS 14 controls

79.4% 66.7% 72.3% 72.2% 67% 30.6% 16.0% 47.1% 44.4% 31 dB PTA, 36% SDS, 12/17 patients 21 dB PTA, 20% SDS, 8/18 patients 40 dB PTA, 44% SDS, 14/16 patients 73.3% 70% 47% 0% 53% 7.1% 73.6% 0% 55% (44 dB PTA) 0% (2.3 dB PTA) 66% (24.5 dB PTA) 8.3% (1.1 dB PTA) 70% 62% 15 dB PTA 11 dB PTA

2 months

At least 1 month n/a(1) 3 months 2-4 weeks 4 weeks

+ + + +

Battaglia, 2008 17 15 dB PTA

Ahn, 2008 18 Xenellis, 2006 19 Ho, 2004 20

>15 dB + final hearing < 45 dB 10 dB PTA 30 dB PTA

3 months 1.5 months 2.61.6 months (ITS) 2.31.7 months (control) 24.9 (7-30) months 6 months 30 days 10 days(1) 10 days(1)

+ +

Kilic, 2007 21 Plaza, 2007 22

10 dB PTA 15 dB PTA, 15% SDS

+ + + + -

Van Wijck, 2007 23 10 dB PTA Kakehata, 2006 24 Complete recovery, or at least 30 dB Lauterman, Calculated PTA gains; full, 2005 25 partial and none recovery scales

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Table II [continued]
First Author Definition of improvement Sample size Hearing loss improvement Follow-up Pos./ neg.

Roebuck, 2006 26 10 dB PTA, 15% SDS

31 ITS 30 controls 33 ITS 33 controls 40

Choung, 2006 27 Haynes, 2007 28 Plontke, 2005 29 Dallan, 2006 30 Banerjee, 2005 31 Slattery, 2005 32

10 dB PTA, 15% SDS 20 dB PTA, 20% SDS

30% (PTA criteria); 38.7% (SDS criteria) 17% (PTA criteria); 10% (SDS criteria) 39.4% 6.1% 27.50% 15 dB PTA 11 dB PTA 75% 27.2 5.7 dB PTA 25.46.2% SDS 5% improved to near-normal hearing 55% significant improvement in PTA and SDS 53% 8% full, 12% partial

4 weeks

8 weeks 271 (22-1460) days control 1 year 6 months 5.4 (1-52) months 3 months

+ + + + + +

Herr, 2005 33 Battista, 2005 34

Gouveris, 2005 35

Lefebvre, 2002 36 Chandrasekhar, 2001 37 Gianoli, 2001 38 Kopke, 2001 39

Calculated PTA improve23 ITS ment 23 controls 15 dB PTA 8 Calculated dB and % SDS 26 improvement Improvement in treated ear 20 to 50% of baseline difference between the treated and untreated ear; 10 dB PTA, 12% SDS 10 dB PTA, 20% SDS 17 Complete = final PTA w/ 25 in 10 dB of baseline; partial = final PTA w/in >50% of hearing Complete recovery: w/in 10 9 high freq. ISdB of unaffected ear; partial SHL; 10 sudrecovery: >10 dB improveden deafness or ment; no recovery: <10 dB profound SHL; 21 improvement pantonal ISSHL 16.25 25 dB PTA 6 Increase in SDS, decrease in PTA 10 dB PTA, 10% SDS 10 dB PTA, 15% SDS 10 (11 ears) 23

6 weeks 6 months

+ -

High freq: 33.3% CR, 39.1% PR, Last audio test 28.6% NR at the end of Profound: 0% CR, 60% PR, 40% NR intratympanic Pantonal: 0% CR, 31% PR, 55.5% NR steroid therapy 100% 73% 44% improved in PTA 21% improved in SDS 83% (5/6 early) 0% (late group) 5 days after completion of treatment 3 weeks to 4 years 1-2 weeks n/a(1)

+ + + +

Parnes, 1999 40 Silverstein, 1996 41

normal thresholds, serviceable hearing 10 dB PTA, 15% SDS

6 (early group, w/in 6 weeks of SSNHL), 3 (late group, >6 weeks) 37 (20 dex., 17 13/37 = 35.1% overall MP) 7/13 = 54% SSNHL 46 (8 SSNHL) 41%

n/a 12 months

+ +

therapy was evaluated? Among the 34 studies, 6 had level one evidence, 9 level two, 5 level three, and the remaining 14 were at level four. Only two studies, Plontke et al. 8, and Battaglia et al. 17 were completed in a double-blinded fashion. The goal of the Plontke et al. study was to determine the efficacy of ITS compared to controls using normal saline (0.9%) injections as placebo. For none of the comparisons, however, were statistically significant differences between the two

groups found. This conservative study focused on patients only with severe to profound SSNHL with a relatively short placebo-controlled study phase for ethical consideration. Despite this, and small sample sizes, this study was the first to compare ITS to a placebo control. The goal of the Battaglia et al. study was to evaluate the combination therapy of ITS and oral steroids. Patients were distributed among three groups including a control group that received ITS and oral placebo

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pills; a second group receiving oral steroids and intratympanic saline; and finally a group that received ITS + oral steroids. Results showed that patients treated with the combination of ITS + oral steroids had a higher probability of hearing recovery than those treated with oral steroids alone. Some limitations of the study include small sample sizes of 17, 18 and 16 in each group, which were much smaller than their original design. In addition, the primary outcome measure of improved pure-tone average was negative for all three groups. Thus, by initial design, their study outcome was negative and there may be flaws with the reassignment of their outcome criteria. In spite of its weaknesses, this level one evidence-based study was well-designed and comprehensive. A positive SSNHL study is considered to be one which exhibits significant overall hearing improvement following ITS compared to pretreatment hearing. Nevertheless, amongst the published studies there is no uniform definition on improvement. The 6 level one evidence studies were all prospective randomized studies 8, 11, 17-20. Three of these studies were positive 17, 19, 20, while three were negative 8, 11, 18. The sample sizes for these studies varied (Table II). Among the 34 SSNHL studies in total, 26 were positive and 8 were negative. Tables I and II address the various therapies evaluated, underlining the heterogeneous nature of the steroids used and treatment protocols. There is no consensus between the use of dexamethasone or methylprednisolone, while doses ranged from 4 10 mg/ml and 20 80 mg/ml, respectively. In a comparison of intracochlear concentrations of these steroids as well as hydrocortisone, Parnes et al. 40 demonstrated via animal models that methylprednisolone (MP) had a higher concentration and longer duration in perilymph after transtympanic administration than hydrocortisone or dexamethasone. Unfortunately, application of MP has found no standard protocol with respect to duration, frequency, or quantity. The majority of studies reviewed (23/34) focused on ITS for salvage therapy while a smaller proportion (8/34) initiated ITS as a primary treatment. Three studies included both salvage and initial (primary) therapy. Previous treatments that patients received before ITS therapy were assorted ranging from steroids, to vasodilators, antivirals, anticoagulants, and vitamins. The interval time-to-treat following the inciting SSNHL event varied among studies, showing mixed degrees of significance on the effects of therapy. In general though, a tendency for

better improvement in those patients with an earlier onset and longer duration of continuous intratympanic salvage treatment has been demonstrated. Much as there exists differences in treatment protocol, ITS administration has found limited uniformity. This has previously been reviewed by Alles et al. 6. In the majority of studies, local anesthesia was applied prior to administering steroids by transtympanic injection. Delivery techniques varied from simple injection, to inner ear medical delivery devices such as the Round Window Microcatheter or the Silverstein Microwick (Table I). Occasionally, simple injections involved a second myringotomy to permit middle ear air to escape 34. Unfortunately, the absence of a consensual method of delivery prevents sound comparison from study-to-study. External Validity. Which criteria were used to confirm the diagnosis of SSNHL? How long was the follow-up? Which criteria were used to evaluate the results? The US National Institute for Deafness and Communication Disorders (NIDCD) defines SSNHL as the idiopathic loss of hearing of at least 30 dB over at least 3 contiguous test frequencies occurring within 3 days 1. Only 9 of the 34 studies reviewed used the NIDCD definition of SSNHL 9, 11, 12, 18, 19, 22, 23, 28, 31. Four studies neglected to define the audiologic parameters of patients with SSNHL 10, 24, 40, 41. Also, there is no uniform definition of improvement among the studies. In the study by Plontke et al., two different definitions of success were used to assess hearing improvement. In addition to that described by Ho et al. 20, success was also defined as recovery of at least 50% of the maximum possible recovery using the unaffected ear as baseline according to the following formula: Improvement [%] 100*(PTApre PTApost)/(PTApre PTAcontralateral), (6 PTA) 8. Many considered the difficulties in discerning therapy effect from the natural course of resolution in patients. Moreover, follow-up in the studies also varied from 10 days to 24.9 months. Overall, the heterogeneity of improvement hinders comparison of the studies. Discussion This systematic review has revealed an assortment of studies involving intratympanic steroid injection with intentions of demonstrating its efficacy in the treatment of idiopathic SSNHL. Unfortunately,

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these studies do not meet the criteria of comparability, internal validity, and external validity. Although more recent studies have conformed to standardizing definitions of disease and improvement, there continues to lack homogeneity with respect to steroid doses, treatment protocols, and pre-study treatments. A common challenge faced by clinicians is the natural history of SSNHL towards spontaneous resolution, variably reported to occur in 58 to 65 percent of patients; a quality difficult to distinguish in the absence of placebo controls 43. Results are also weakened by small sample sizes influenced by selection bias. A true meta-analysis of the literature is complex given the wide variance in treatment protocols, patient data, and reporting of data. This wide-ranging systematic review of all the clinical trials to date for ITS in the treatment of SSNHL is not without its own limitations. Firstly, only articles published in the English language were included in the review. The English-language bias is remarkable to the extent that there are known regional differences in treatment practices between North America and Europe. Moreover, the review is inherently limited by the type and quality of studies. In addition to RCT, several retrospective studies were reviewed due to their valuable impact on clinical practice. To date, there have been a number of studies where intratympanic steroid injections achieved a significant rate of hearing improvement in SSNHL cases that failed to recover with primary oral steroid treatment. Furthermore, it has been suggested that local steroid treatment delivery may have better efficacy than systemic administration. Unfortunately, it cannot be determined from the majority of uncontrolled studies whether IT steroids are more effective than oral steroids or whether they are beneficial to a different cohort of SSNHL patients. Despite the lack of prospective controlled trials of IT steroid therapy, this treatment is being adopted by clinicians who are seeking means of obtaining further hearing improvements in SSNHL. More research needs to be performed using uniform and standardized definitions of disease and improvement. The results of one such investigation are on the horizon, in the form of a multi-center trial which was completed in the early part of 2010. This prospective randomized clinical trial was a head-to-head comparison of oral prednisone against IT methylprednisolone 45. By means of its set protocol and suf-

ficient sample size, this non-inferiority study will attempt to compare the efficacy of these two therapies in the treatment of idiopathic SSNHL. Riassunto
Steroidi intratimpanici per la perdita di udito sensorineurale improvvisa: revisione La somministrazione locale di steroidi per via intratimpanica permetterebbe di ottenere un tasso significativo di miglioramento delludito nei casi di perdita di udito sensorineurale improvvisa idiopatica (SSNHL). Lobiettivo di questo studio era di rivedere lattuale evidenza e i futuri sviluppi della terapia steroidea intratimpanica (SIT). Sono stati analizzati i database PubMed e Ovid Medline dal 1966 ad oggi alla ricerca di studi clinici sulla SIT nel trattamento della SSNHL idiopatica. Gli studi sono stati valutati sulla base della comparabilit, e validit interna ed esterna. Complessivamente, sono stati identificati 34 studi. Soltanto due studi erano trials prospettici randomizzati in doppio cieco. Globalmente, vi erano variabili definizioni della patologia e di miglioramento, delle dosi di steroidi, dei trattamenti prestudio e dei protocolli di trattamento. Pochi studi sulla SIT soddisfano i criteri di comparabilit, validit interna e validit esterna. Sono necessari ulteriori studi con definizioni e protocolli uniformi, standardizzati per determinare lefficacia della SIT nel trattamento della SSNHL idiopatica. Parole chiave: Perdita dudito - Steroidi intratimpanici.

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36. 37. 38. 39. 40. 41. 42.

43. 44. 45.

sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2006;135(2):276279. Choung yH, Park K, Shin yR, Cho MJ. Intratympanic dexamethasone injection for refractory sudden sensorineural hearing loss. Laryngoscope 2006;116(5):747752. Haynes DS, OMalley M, Cohen S, Watford K, Labadie RF. Intratympanic dexamethasone for sudden sensorineural hearing loss after failure of systemic therapy. Laryngoscope 2007;117(1):3 15. Plontke S, Lowenheim H, Preyer S, Leins P, Dietz K, Koitschev A et al. Outcomes research analysis of continuous intratympanic glucocorticoid delivery in patients with acute severe to profound hearing loss: basis for planning randomized controlled trials. Acta Otolaryngol 2005;125(8):830839. Dallan I, Bruschini L, Nacci A, Bruschini P, Traino C, Rognini F et al. Transtympanic steroids as a salvage therapy in sudden hearing loss: preliminary results. ORL J Otorhinolaryngol Relat Spec 2006;68:247y52. Banerjee A, Parnes LS. Intratympanic corticosteroids for sudden idiopathic sensorineural hearing loss. Otol Neurotol. 2005 Sep;26(5):878-81. Slattery WH, Fisher LM, Iqbal Z, Liu N. Oral steroid regimens for idiopathic sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2005;132:510. Herr BD, Marzo SJ. Intratympanic steroid perfusion for refractory sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2005;132:527531. Battista RA. Intratympanic dexamethasone for profound idiopathic sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2005;132:902905. Gouveris H, Selivanova O, Mann W. Intratympanic dexamethasone with hyaluronic acid in the treatment of idiopathic sudden sensorineural hearing loss after failure of intravenous steroid and vasoactive therapy. Eur Arch Otorhinolaryngol 2005;262(2):131 134. Lefebvre PP, Staecker H. Steroid perfusion of the inner ear for sudden sensorineural hearing loss after failure of conventional therapy: a pilot study. Acta Otolaryngol 2002; 122(7):698702. Chandrasekhar SS. Intratympanic dexamethasone for sudden sensorineural hearing loss: clinical and laboratory evaluation. Otol Neurotol 2001;22:18y23. Gianoli GJ, Li JC. Transtympanic steroids for treatment of sudden hearing loss. Otolaryngol Head Neck Surg 2001;125:142y6. Kopke RD, Hoffer ME, Wester D, OLeary MJ, Jackson RL. Targeted topical steroid therapy in sudden sensorineural hearing loss. Otol Neurotol 2001;22(4):475479. Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids: an animal study followed by clinical application. Laryngoscope 1999;109(7 Pt 2):117. Silverstein H, Choo D, Rosenberg SI, Kuhn J, Seidman M, Stein I. Intratympanic steroid treatment of inner ear disease and tinnitus (preliminary report). Ear Nose Throat J 1996;75:468471. Ganzer U, Albegger KW, Arnold W, et al. Leitlinie Horsturz der Deutschen Gesellschaft fur Hals-Nasen-Ohren-Heilkunde, Kopfund Hals-Chirurgie. [Guideline on idiopathic sudden sensorineural hearing loss of the German Society of Otorhinolaryngology, Head and Neck Surgery]. version Nr. 017/010, January 2004, available from www.hno.org. Mattox DE, Simmons FB: Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977; 86: 463-80. Jones N, Ludman H: Acquired sensorineural hearing loss; in Ludman H, Wright t (eds): Diseases of the Ear, ed 6. London, Arnold, 1998, pp 495-97. National Institute of Health. (In Review) Sudden Hearing Loss Multicenter Treatment Trial 2010.

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Intratympanic management for autoimmune inner ear disease

A. DE STEFANO 1, G. KULAMARVA 2, F. DISPENZA
3

Autoimmune inner ear disease (AIED) is a rare condition that accounts for less than 1% of hearing loss or dizziness. Patients generally have aural fullness as well as tinnitus which may precede the hearing loss. One ear is usually involved first and worsens ahead of the contralateral side. Therefore patients may have only unilateral involvement on initial presentation. A spontaneous improvement or resolution of untreated hearing loss in patients affected by AIED does not often occur. For this reason when an AIED is suspected prompt management should be established in order to stop the steady deterioration of hearing function. Intratympanic management of AIED with methylpredinosolone or and recently with Infliximab has been shown to be safe, easy and useful in the therapy of refractory immune-mediated inner ear disease. For all the above reasons management of AIED with intratympanic steroids may be recommended as the first line of treatment for these patients, while in the near future transtympanic management with TNF- antibody is likely to come into the fore. Key words: Autoimmune inner ear disease - Intratympanic steroids Infliximab - Hearing loss - HSP-70 - Inner ear.

Institute, Department of Surgical, Clinical and Experimental Sciences G.dAnnunzio University of Chieti and Pescara Chieti, Italy 2ENT Clinic, Nayaks Road, Kasaragod, Kerala, India 3Department of Surgical and Oncological Disciplines University of Palermo, Palermo, Italy

1ENT

or associated with a concurrent systemic autoimmune illness (secondary). Its incidence is often overlooked because of the absence of a specific diagnostic test. Majority of the cases of AIED are patients without other systemic illnesses (70%). Therefore it is difficult to separate this illness from other forms of progressive hearing loss (viral, genetic, toxic, metabolic) that may have similar presentation. Clinical presentation Autoimmune inner ear disease seems to be more common in females between 20-50 years of age and manifests itself with the occurrence of a rapidly progressive, often fluctuating, bilateral SNHL over a period of weeks to months. The progression of hearing loss is very rapid and can mimic a sudden SNHL or too slow to be concluded as presbyacusis.4 Patients generally have aural fullness as well as tinnitus which may precede the hearing loss. One ear is usually involved first and worsens ahead of the contralateral side. Therefore patients may have only unilateral involvement on initial presentation.

utoimmune Inner Ear Disease (AIED) is a rare condition that accounts for less than 1% of hearing loss or dizziness.1 In 1979, McCabe first described a cohort of patients with idiopathic, rapidly progressive bilateral Sensorineural Hearing Loss (SNHL). These patientss hearing improved after treatment with corticosteroids, thereby suggesting an autoimmune origin.2 Although the peak age of incidence is in the 5th decade of life, AIED can present at any age.3 It is a disease that can occur either in isolation (primary)
Corresponding author: A. De Stefano MD, PhD, FAINOT, Via F. Di Palma 10, 74100 Taranto, Italy. E-mail: dr.adestefano@gmail.com

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Table I.In 30% of patients a systemic autoimmune disorder can be associated and it may aid in the diagnosis.
Systemic diseases associated with AIED

Polyarteritis nodosum Cogans Syndrome Behets disease Wegeners granulomatosis Relapsing polycondritis Sjgrens syndrome Systemic lupus erythematosus Inflammatory bowel disease Rheumatoid arthritis Susacs Syndrome Idiopathic thrombocytopenic purpura Polymiositis Dermatomyositis Scleroderma

Generalized imbalance, ataxia, motion intolerance, positional vertigo, and episodic vertigo are often present in almost 50% of the patients.5 Twenty percent of the patients experiencing vertigo crisis have symptoms consistent with those seen in Menires disease.6 Immune-mediated inner ear disorders presenting with Menires disease-like symptoms generally affect both ears simultaneously causing asymmetrical bilateral audiovestibular dysfunction. The hearing loss observed in AIED is in the lowmedium frequencies. High frequency hearing loss appears to be more common when vasculitis is the suggested etiopathology. Systemic Lupus Erythematosus, Behets disease, Sjgrens syndrome, Wegeners granulomatosis, Thyroiditis of Hashimoto, Cogans syndrome and antiphospholipid/anticardiolipin syndrome are some of the systemic autoimmune disorders associated with AIED (Table I). Pathogenesis Autoimmune inner ear disease implies antibodies to an inner ear antigen. Viral infection, inner ear trauma, neoplastic and neurologic diseases or vascular diseases may be triggers for AIED. Perhaps antibodies or T-cells cause accidental inner ear damage because inner ear tissue shares common antigens with potentially harmful substances. Analogous to the central nervous system, inner ear too is separated from the systemic circulation

by a blood-labyrinthine barrier that allows the inner ear to have separate compartments containing endolymph and perilymph. These are critical for the correct functioning of both auditory and vestibular systems. Although passage of immunoglobulins through the blood-labyrinthine barrier is restricted, immunoglobulins can be found in the inner ear. IgG is the most abundant immunoglobulin found within the inner ear, followed by IgA and IgM. However because of the presence of blood-labyrinthine barrier, the inner ear has long been considered to be incapable of participating in an immune response. In 1983 Harris showed that the inner ear does not represent an immune privileged site protected by the blood-labyrinthine barrier but can generate a local immune response, release pro-inflammatory cytokines and recruit immuno-competent cells from the systemic circulation, after either local or systemic presentation of antigens.7 Further he showed in a 1989 study that antibodies can be produced locally in the inner ear and the secondary response to an antigen previously processed by the inner ear leads to a much higher systemic antibody level than is seen with the primary response.8 These immune responses were dependent on the presence of an intact endolymphatic sac.7, 8 In fact endolymphatic sac and the surrounding perisaccular tissues are the main antigen processing centres of the inner ear. This anatomical structure is responsible for generation of both the local response of inner ear as well as the subsequent recruitment of the systemic response.7, 8 Several facts indicate this. The required cells for immunologic processing and presentation (T-cells, Macrophages, B-cells bearing IgM, IgG and IgA) are present in the endolymphatic sac and its perisaccular tissue and obliterating the endolymphatic sac or the endolymphatic duct results in a much decreased immune response of the inner ear.9 When the antigen has been processed by immunological cells of the endolymphatic sac, proinflammatory cytokines (including IL-1, Tumor Necrosis Factor-, IL-6) are released which results in the recruitment of a variety of cells and further elaborates cytokines like IL-2 and platelet endothelial cell adhesion molecule 1. These steps attract specific cells from the systemic circulation like macrophages and polymorphonuclear cells which then enter the inner ear. In the cochlea the main conduit for entry for the pro-inflammatory cells has been identified in the spiral modiolar vein with additional contributions from the surrounding dilated bone marrow channels. The

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Saccular duct Utricular duct Petrous bone Sinus of endolymphatic duct Endolymphatic duct Intraosseous part of endolymphatic sac External aperture of vestibular aqueduct Extraosseous part of endolymphatic sac

Internal auditory canal External aperture of vestibular aqueduct

Groove of sigmoid sinus

Jugular foramen

Figure 1.Endolymphatic sac and the surrounding perisaccular tissues is the main antigen processing centre of the inner ear. As showed by Harris in 1983 this anatomical structure is responsible for the generation of both the local response of the inner ear as well as the subsequent recruitment of systemic response.7 Modified from Lonser RR et al.38

ensuing labyrinthitis results in a physiologic dysfunction, loss of sensory cells and fibrosis and osteogenesis within the cochlea.6 This process is very quick. In the cochlea the immunoglobulin-bearing cells are seen as early as the first day after antigen challenge. A cochlear innate immunity has been proposed to contribute to the initiation of an adaptive immune response in the cochlea by promoting a response to antigen challenge.10 Particularly the up-regulation of IL-1 in the fibrocytes of the spiral ligament primes the inner ear to allow a small number of leucocytes to enter. Subsequently, in an individual with lymphocytes primed to react against inner ear antigens, an immune response may be started.10

Animal and human models for AIED A variety of experimental approaches have been used to gain insight into the pathogenesis of AIED. Unfortunately none of these studies have yielded an animal model that is definitely analogous to the human condition. For years it has been very difficult to create an animal model for AIED. Yoo was the first in 1983 to develop a model for immune-mediated hearing loss based on type II collagen that clearly showed an immune response of inner ear.11 He demonstrated perivascular lesions within the cochlear artery including a mononuclear cell infiltration around the

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artery with thickening of the endothelial cells of the vessel in rats immunized with native bovine type II collagen.11 However the organ of Corti, the stria vascularis and the cochlear nerve did not show any evidence of injury. Studies of Zajic and Ptok in 1991 and successively studies of Nair and Discher in animal models suggested a probable etiopathogenesis of AIED.12-15 They created monoclonal antibodies against inner ear cells. A particular antibody called Kresge Hearing Research Institute-3 (KHRI-3) binds to supporting cells of the organ of Corti and induces hearing loss when infused into live guinea pigs. There is strong evidence that KHRI-3 and human antibodies derived from patients affected by AIED recognize the same inner ear antigen. This supporting cell antigen has been suggested to correspond to choline trasporter-like protein 2 (CTL-2). Autoantibodies against CTL-2 have been identified with immune mediated inner ear disorders. KHRI-3 localizes to the 68-to 72 kDa region on western blot of inner ear extract and it does not appear to be the Heat Shock Protein 70 (HSP-70).12 HSP-70 was the suspected inner ear antigen in previous bovine inner ear models of AIED and it localized the 68kDa in western-blot evaluation. HSPs are ubiquitous cytoplasmic proteins known to be up-regulated with various forms of stress, and different HSPs have been reported in a number of autoimmune diseases. Further studies have indicated that elevated levels of anti- HSP-70 antibodies are not the underlying cause of hearing loss but rather a non pathogenic epiphenomenon.16, 17 However these results do not rule out the possibility that autoantibodies to HSP70 may contribute to or enhance pre-existing inner ear pathology. A 30kDa protein also has received particular attention. This protein was demonstrated to be major Peripheral Myelin Protein 0 (P0) possibly an autoantigen in autoimmune inner ear disease. Despite the initial enthusiasm a recent study showed that in patients with rapidly progressive hearing loss, P0 positive bands were statistically similar to the control group.18 To date recognition of antibodies against myelin P0 is not useful for AIED diagnosis. Finally, some of the animal models used to study other systemic autoimmune diseases were also also detected to have audio-vestibular dysfunctions. Particularly the MRL-Fas mouse model used for

Systemic Lupus Erythematosus developed significant degree of hearing loss. The MRL-Fas mice lost the ability to eliminate autoimmune T-Cells by apoptosis. When these cells accumulate, various endorgans are injured and we can observe the degeneration of stria vascularis and antibody deposition within the strial capillaries.6 However these changes take place in the absence of inflammatory response and the etiology of the strial degeneration is unknown.6 Limited studies have been performed in human temporal bone derived from patients affected by AIED and two mechanisms are reported. Some bones demonstrate fibrosis and osteoneogenesis within the scalae, findings consistent with the end stages of inflammation. Other bones show changes consistent with ischemia without evidence of inflammation.19, 20 Today the primary antigenic epitope against the antibody is unknown and its role in mediating AIED is unclear 6 and therefore this pathology remains a clinical diagnosis based on history and audiometric criteria. Diagnosis Diagnosis of AIED is most often made using a combination of clinical findings combined with disease-non-specific routine immunological laboratory tests and responses to immunotherapy. Imaging studies (CT and MRI) are recommended in order to rule out a cerebello-pontine tumor or an inflammatory lesion involving the auditory pathways. A typical patient with AIED has bilateral fluctuating sensori-neural hearing loss and a variable degree of vestibulopathy. There is no specific pattern of hearing loss in AIED. Electronystagmography may reveal decreased responses on caloric test, rotational chair testing may show an asymmetrical gain with unilateral loss of vestibular function or reduced gain with phase lag consistent with bilateral vestibular loss. In 30% of patients a systemic autoimmune disorder can be associated and it may aid in the diagnosis. Routine serologic tests in patients with suspected AIED include complete blood count with differential white cell count, erythrocyte sedimentation rate, antiphospholipid/anticardiolipin antibodies, anti thyroid antibodies and rheumatoid factor,

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Antineutrophil Cytoplasmic Antibodies (ANCA). Anti-double-stranded DNA antibodies and Anti Nuclear Antibodies (ANA) are present in patients affected by systemic lupus erythematosus while the prevalence of ANA in patients with sudden sensori-neural hearing loss is 14-43%.21 Antineutrophil cytoplasmic antibodies is associated with small vessel vasculitis and has been shown to be positive in Wegeners granulomatosis, where it is reported to be positive in 50-95% of the patients.21 Anti endothelial Cell Antibody (AECA) have also been associated with immune-mediated vasculitis. This antibody is present in various systemic autoimmune diseases and 47-53% of patients with SSNHL are AECA positive. Diagnosis of primary AIED is more difficult because no serologic test has yet demonstrated any diagnostic accuracy to allow for the establishment of a definitive diagnosis.6 Over the past decade more attention has been focused on Western Blotting for detection of an antibody that binds to a 68kDa antigen. The Western Blot technique has been reported to have a sensitivity of 42% and a specificity of 90%. When a characteristic band at 68 kDa is showed it is considered a positive test demonstrating antibodies to an inner ear antigen. However the antigen used in this method is often the HSP-70 from bovine kidney tissue and therefore lacks ear specificity.21 Also it is well demonstrated that HSP-70 antibodies are no more prevalent in sera of AIED patients than in sera from control groups.16, 17 In summary, the diagnosis of AIED (overall the primary AIED) is always difficult and it is based on clinical history and demonstration of progressive hearing loss and/or vestibular dysfunction and most importantly positive response to the administration of corticosteroids. Classification of AIED is reported in Table II.
Table II.Harris-Keithley classification of AIED.
Type Condition

Treatments A spontaneous improvement or resolution of untreated hearing loss in patients affected by AIED does not often occur. For this reason when an AIED is suspected prompt medical treatment should be established in order to stop the steady deterioration of hearing function and avoid a subsequent surgical management (cochlear implant). Treatment can be broadly classified into two types namely systemic and intratympanic therapies. Systemic therapy can be either parenteral or oral administrations of various drugs like corticosteroids and other immunosuppressants whereas in the transtympanic therapy it consists usually of injecting corticosteroids or other immunomodulators into the middle ear space directly through the tympanic membrane. Systemic therapies McCabe first reported the benefits of using prednisolone and cyclophosphamide in 1979 2 and to date the mainstay of treatment of AIED has been corticosteroids administered systemically. Currently the oral dose of prednisone is given as 1 to 2 mg/kg/ die for 4 weeks as initial therapeutic trial. Patients with benefit should continue for another 1-2 months and tapered slowly. If the hearing remains stable, the dose should be tapered to 10mg every day for at least one year.22 Patients, in whom steroid treatment fails, are rapidly tapered off the drug over a course of 7-10 days. Patients with recurrent disease are placed on a repeat course of steroids but when the improvement of hearing is not sustained and side effects from corticosteroids appear the use of alternative drugs are recommended. Methotrexate, a folic acid antagonist, has been found to be an effective treatment as well, with less potential long-term systemic side effects.22 Roland in 2000 and Garcia-Berrocal et al. in 2006 recommended an oral dose of 7.5 mg/week, increased to 15 mg/week over the ensuing 4-8 weeks for at least 12 months.22, 23 Methotrexate is given with folic acid and the patient is monitored for toxicity by means of blood, platelet counts, blood urea nitrogen and levels of creatinine, liver function determination and urinalysis. In 1997 Sismanis reported success of this therapy in AIED and immune-mediated Menires disease patients.24 But, in a 2003 study of Harris con-

1 2 3 4 5

Organ specific (ear) Rapidly bilateral SNHL with associated systemic immunemediated disease Immune mediated Menires Disease Rapidly bilateral SNHL with associated inflammatory disease (Lymes disease, chronic otitis media, otosyphilis, serum sickness) Cogans Syndrome

SNHL: sensorineural hearing loss.

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firmed by Ruckenstein in 2004 and Garcia-Berrocal in 2006 showed that methotrexate does not appear to be effective in maintaining the hearing improvement as achieved with steroids therapy in patients affected by AIED.3, 6, 24 Although the controversial outcomes in hearing improvement while maintaining a good control of the vestibular dysfunctions has been observed in patients managed with oral methotrexate.24 Another approach to management of AIED with transoral medicines is the administration of cyclophosphamide. It is a powerful immunosuppressant and this drug administered at doses of 2-5 mg/kg/ die, taken orally, has been used in the past for cases refractory to steroids.25 Unfortunately cyclophosphamide has high toxicity profile and potential for urinary tract malignancy and leukemia induction. A peripheral blood smear must be performed periodically to monitor for development of leukocytopenia.22, 25 Recently Tumor Necrosis Factor (TNF-) antagonists such as Remicamide (Infliximab), Embrecel (Etanercept) and Humira (Adalimumab) as well as the anti-B cell agent Rituxan (Rituximab) were used for investigation in AIED oral therapy. The importance of TNF- was evidenced by Satoh who showed that it is the first cytokine expressed by inner ear infiltrating cells following systemic immunization and antigen infusion into the cochlea.26 TNF- triggers expression of cells adhesion molecules on vascular endothelial cells thus facilitating extravasation of leukocytes and monocytes to the targeted area of inflammation. As a result TNF- is therefore essential for amplification of the adaptive immuneresponse. Etanercept was used in a retrospective review of 12 steroid-responsive patients and it was found that 11 out 12 patients showed improvement in hearing and tinnitus and 8 out 12 patients improved their balance.27 In another study Etanercept was administered at a dose of 25 mg twice weekly with tapering steroids and 30% of the patients showed improvement in hearing loss.28 However, recently Cohen et al. have contradicted these results. Their study concluded that effect of Etanercept was similar to placebo.29 Another approach is based on plasmapheresis. In a long term study of AIED patients managed with plasmapheresis showed improved or stable hearing at six year follow-up but it presents high costs and needs concomitant continued immunosuppression therapy to prevent antibody production.30

Intratympanic therapies Management with intratympanic steroids Intratympanic management of AIED is becoming increasingly common in clinical use for treating patients unresponsive to systemic steroids and methotrexate management. This is more so because of the overall side effects associated with the systemic therapy. Long term steroid treatment for example, has risks and side effects including: peptic ulcer, mood disorders, insomnia, obesity, moon facies, hyperglycemia, hypertension, immunosuppression and avascular necrosis of femoral head. The biggest advantage of intratympanic inner ear perfusion treatment is that it is by design devoid of any of the systemic side effects. It is designed to increase the concentration of medication delivered to the labyrinth by infusing the drugs into spaces in proximity to the labyrinth. Intratympanic management can be achieved through different routes including direct injection and infusion through myringotomy, wick, minipumps and transtympanic ventilation tube.31 To determine the effectiveness of intratympanic injections as a method for successful drug delivery to inner ear, Parnes et al. in 1999 investigated the pharmacokinetics of hydrocortisone, methylprednisolone and dexamethasone into the inner ear following oral, intravenous and intratympanic administration. They were able to show that intratympanic treatment provided the highest inner ear concentration of the three drugs and found that methylpredinsolone achieved the highest concentration for the longest duration within the perilymph when compared with hydrocortisone or dexamethasone.32 The principal paths of communications for drugs between the middle ear and the inner ear are the round window membrane and the annular ligament of the footplate of the stapes.33 Some factors may modify the round window permeability and the most important of these are: middle ear inflammation, Eustachian tube function, the size and the shape of the round window niche, previous surgical managements of the ear.33 Besides these factors, absorption of glucocorticoids within the round window membrane also depends on concentration of the solution and the amount of time the drug remains in contact with the membrane.23 Finally, the effect of glucocorticoids on the inner ear is directly proportional to the presence of the Glucocorticoid Receptors (GCR) expressed in

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the lateral wall of the cochlea and the ampullae of the vestibule. Glucocorticoid receptors are present in highest numbers in the type III fibrocytes of the spiral ligament. Fibrocytes of the spiral ligament play an important role in cochlear fluid and ion homeostasis. They are not prominently expressed in hair cells of the organ of corti. This suggests that intratympanic steroids do not directly act on the hair cells. Whenever there is a metabolic change on the lateral wall of cochlea, induced by immune responses to antigens, it can affect supporting cells of the organ of corti even before the late effect on the hair cells can be seen.23 Intratympanic steroids would act on the supporting cells that express many GCR and this should be capable to stop the immune reaction. Use of intratympanic steroids in the management of AIED is supported by several studies. A clinical study of Silverstein involving five patients suffering from AIED who were treated with intratympanic steroids showed that four out of five patients improved their speech discrimination score by eight to 20%.34 Successively Parnes in a 1999 study, documented that intratympanic management with steroids was capable to restore the hearing function in patients whose initial systemic steroid therapy had produced a good result but had worsened when steroid tapering was attempted.32 Recently Garcia-Berrocal in 2006 used a modified intratympanic steroids techniques reported by Silverstein and managed 11 patients (refractory to systemic treatment) with 0.3-0.5 mL of methylprednisolone solution, 40mg/ml given 1 week apart. He used a tuberculin syringe (27 gauge needle, 1.5 inch long) to inject into the middle ear through the tympanic membrane posterior to the umbo, over the round window niche. Patients were asked to remain supine with the head turned to the opposite side for 20-30 minutes and asked not to swallow in order to avoid the clearance of the drug from middle ear through the eustachian tube. Six patients in this study (68%) improved their hearing function and all showed an improvement of their vestibular system function too.23 These experiences proves that intratympanic management of AIED with corticosteroids is a potential first-line option for AIED. Management with intratympanic TNF- antibody The importance of TNF- in amplifying the immune response in the inner ear allowed developing

a new therapeutic model for the intratympanic management of AIED. Yang et al. in the year 2000 showed the attenuation of hearing loss in an animal model after transtympanic injection of Etanercept.35 Recently in a study of 2006 Van Wijk evaluated the transtympanic perfusion of Infliximab, a humanized TNF- antibody, in patients affected by AIED.36 Nine patients were enrolled in two groups. Group 1 consisted of five patients affected by AIED who could not be tapered of their steroids. This group was initially treated with methylprednisolone 32 mg for one week followed by a two week taper. Group 2 consisted of four patients treated with weekly intratympanic Infliximab for four weeks after completion of initial steroid treatment and having recurrence of hearing loss. In four out of five patients of the first group local administration of Infliximab allowed methylprednisolone to be tapered off with no deterioration in hearing. Three out of four patients in the second group showed an improvement of hearing function at the end of the treatment. Hearing remained stable at the end of last follow up at 22 weeks. One patient had recurrence of hearing loss one week after Infliximab management but was successfully treated with another local application of TNF- monoclonal antibody.36 This research emphasises the efficacy of intratympanic administration of Infliximab in managing AIED by allowing the steroids to be tapered facilitating improvement in the hearing. Conclusions and future perspective Despite numerous clinical and animal studies, an advance in treatment of AIED is complicated by its as yet unknown pathophysiology. To date it is very difficult to diagnose an immune mediated inner ear disease as it is a rare entity with varying clinical presentations resulting in delay in eventual diagnosis. The treatment for AIED can also be based on high dose of systemic corticosteroids. But when faced with a situation where the improvement of hearing is not sustained and side effects from steroids appear, use of other drugs and other methods of administration are worth attempting. Intratympanic management of AIED with meth-

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ylpredinosolone or dexamethasone (which shows a rapid elimination from the cochlea) 37 and recently with Infliximab has been shown to be safe, easy and useful in the therapy of refractory immune-mediated inner ear disease. Furthermore intratympanic management allows recovering the hearing function even in those patients who reduce or stop systemic steroid therapy. Further studies in the future will help establish the correct role of TNF- in the development of AIED. This would eventually allow standardisation of the management of this disease with intratympanic Infliximab. For all the above reasons management of AIED with intratympanic steroids may be recommended as the first line of treatment for these patients, while in the near future transtympanic management with TNF- antibody is likely to come into the fore. Intratympanic treatments for AIED supported by the development of new delivery technologies such as nanoparticles, hydrogels and others is likely to be the future standard of care in managing this debilitating condition. Riassunto
Trattamento intratimpanico della patologia autoimmune dellorecchio interno La patologia autoimmune dellorecchio interno (AIED) una rara condizione responsabile di meno dell1% di sordit o di vertigini. I pazienti solitamente riportano fullness auricolare come pure tinnito, che possono precedere la perdita delludito. Solitamente viene dapprima interessato un orecchio, che peggiora prima del controlaterale. Pertanto, possibile che i pazienti presentino coinvolgimento auricolare monolaterale allo stadio iniziale. Un miglioramento o la risoluzione spontanea della perdita di udito non trattata in pazienti affetti da AIED sono rari. Per tale motivo, quando si sospetta una AIED, si deve impostare un pronto trattamento per interrompere il deterioramento della funzione uditiva. Il trattamento intratimpanico della AIED con metilprednisolone e recentemente con Infliximab si dimostrato sicuro, semplice e utile nella terapia della patologia dellorecchio interno immuno-mediata refrattaria. Per tutti i motivi sopra menzionati, il trattamento di AIED con steroidi intratimpanici raccomandato come prima linea di trattamento per questi pazienti, mentre nel prossimo futuro sar possible utilizzare per via transtimpanica lanticorpo anti TNF-. Parole chiave: Patologia autoimmune dellorecchio interno - Steroidi intratimpanici - Infliximab - Perdita uditiva HSP-70 - Orecchio interno.

References
1. McKean SA, Musheer Hussain SS. Autoimmune Inner Ear Disease. In: De Stefano A, Dispenza F eds. Head & Neck Experimental Medicine; Pescara, Italy, ECA 2009: 25-29. 2. McCabe B. Autoimmune Sensorineural Hearing Loss. Ann Otol 1979;88:585-9. 3. Harris JP, Weisman MH, Dereby JM, Espeland MA, Gantz BJ, Gulya AJ et al. Treatment of corticosteroid responsive autoimmune inner ear disease with methotrexate: a randomized controlled trial. JAMA 2003;290:1875-83. 4. Bovo R, Ciorba A, Martini A. The diagnosis of autoimmune inner ear disease: evidence and clinical pitfalls. Eur Arch Otorhinolaryngol 2009;266:37-40. 5. Hughes G, Kinney S, Barna B, Calabrese L, Hamid M. Autoimmune reactivity in Menires Disease:preliminary report. Laryngoscope 1983;43:410-7. 6. Ruckenstein JM. Autoimmune inner ear disease. Curr opin Otolaryngol Head Neck Surg 2004;12:426-30. 7. Harris JP. Immunology of the inner ear:response of the inner ear to antigen challenge. Otolaryngol Head Neck Surg 1983;91:18-32. 8. Harris JP. Autoimmunity of the inner ear. Am J Otol 1989;10:1935. 9. Takahashi M, Harris JP. Anatomic distribution and localization of immunocompetent cells in normal mouse endolympahtic sac. Acta Otolaryngol 1988:106;1070-5. 10. Hashimoto S, Billings P, Harris JP, Firestein GS, Keithley EM. Innate immunity to cochlear adaptive immune responses. Audiol Neurotol 2005;10:35-43. 11. Yoo TJ, Tomoda K, Stuart JM, Cremer MA, Townes AS, Kang AH. Type II collagen induced autoimmune sensorineural hearing loss and vestibular dysfunction in rats. Ann Otol Rhinol Laryngol 1983;92:267-71. 12. Zajic G, Nair T S, Ptok M, Van Waes C, Altschuler RA, Schacht J, Carey TE. Monoclonal antibodies to inner ear antigens:I Antigens expressed by supporting cells of the guinea pigs cochlea. Hear Res 1991;52:59-71. 13. Ptok M, Nair TS, Altschuler RA, Schacht J, Carey TE. Monoclonal antibodies to inner ear antigens:II. Antigens expressed in sensory cell stereocilia. Hear Res. 1991;57:79-90. 14. Nair TS, Prieskorn DM, Miller JM, Dolan DF, Raphael Y, Carey TE. KHRI-3 monoclonal antibody-induced damage to the inner ear:antibody staining of nascent scars. Hear Res 1999;129:50-60. 15. 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 N Y Acad Sci 1997;830:253-65. 16. Trune DR, Kempton JB, Mitchell CR, Hefeneider SH. Failure of elevated Heat Shock Protein 70 antibodies to alter cochlear functions in mice. Hear Res 1998;116:65-70. 17. Yeom K, Gray J, Nair TS, Arts HA, Telian SA. Disher MJ et al. Antibodies to HSP-70 in normal donors and autoimmune hearing loss patients. Laryngoscope 2003;113:1770-6. 18. McCabe BF. Autoimmune inner ear disease:therapy. Am J Otol 1989;10:196-7. 19. Pham BN, Rudic M, Bouccara D, Sterkers O, Belmatoug N, Bebear JP et al. Antibodies to myelin protein zero (P0) protein as markers of autoimmune inner ear diseases. Autoimmunity 2007;40:202-7. 20. Haynes BF, Kaiser-Kupfer MI, Mason P, Fauci AS. Cogan Syndrome:studies in thirteen patients, long term follow-up and review of the literature. Medicine 1980;59:426-41. 21. Agrup C, Luxon LM. Immune-mediated inner ear disorders in neurotology. Curr Opin Neurol 2006;19:26-32. 22. Roland JT. Autoimmune inner ear disease. Curr Rheumat Rep 2000;2:171-4.

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23. Garcia-Berrocal JR, Ibanez A, Rodriguez A, Gonzalez-Garcia JA, Verdaguer JM, Trinidad A et al. Alternative to systemic steroid therapy for refractory immune mediated inner ear disease:a physiopathologic approach. Eur Arch Otorhinolaryngol 2006;263:97782. 24. Sismanis A, Wise CM, Johnson GD. Methotrexate management of immuno mediated cochleovestibular disorders. Otolaryngol Head Neck Surg 1997;116:146-52. 25. Gopen Q, Harris JP. Diagnosis, evaluation and management of autoimmune disorders of the ear. In:Kirtane MV, Brackmann D, Borkar DM, de Souza C eds. Comprehensive textbook of otology. Mumbay, India, Bhalani 2010:160-4. 26. Satoh H, Firenstein GS, Billings PB, Harris JP, Keithley EM. Proinflammatory cytokine expression in the endolymphatic sac during inner ear inflammation. J Assoc Res Otolaryngol 2003;4: 139-47. 27. Rahman MU, Poe DS, Choi HK. Etanercept therapy for immunomediated cochleo-vestibular disorders:preliminary reports in a pilot study. Otol Neurotol 2001;22:619-24. 28. Matteson EL, Choi HK, Poe DS, Wise C, lowe VJ, McDonald Tj, Rahman MU. Etanercept therapy for immunomediated cochleovestibular disorders:a multicenter open label pilot study. Arthrit Rheum 2005;53:337-42. 29. Cohen S, Shoup A, Weismann MH, Harris JP. Etanercept treatment for autoimmune inner ear disease:results from a pilot placebo-controlled study. Otol Neurotol 2005;26:903-7.

30. Luetje CM, Berliner KI. Plasmapheresis in autoimmune inner ear disease:long term follow up. Am J Otol 1997;18:572-6. 31. Light JP, Silverstein H. Transtympanic perfusion:indications and limitations. Curr Opin Otolaryngol Head Neck Surg 2004;12:378-83. 32. Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluid:an animal study followed by clinical application. Laryngoscope 1999;109:1-17. 33. De Stefano A, Dispenza F, De Donato G, Caruso A, Taibah A, Sanna M. Intraympanic gentamicin:1-day protocol treatment for unilateral Menires disease. Am J Otolaryngol 2007;28:289-93. 34. Silverstein H, Choo D, Rosemberg SI, Kuhn J, Seidman M, Stein I. intratympanic steroid treatment of inner ear disease and tinnitus (preliminary report). Ear Nose Throat J 1996;75:468-71. 35. Yang GS, Song HT, Keithey EM, Harris JP. Intratympanic immunosuppressives for prevention of immune mediated sensorineural hearing loss. Am J Otol 2000;21:499-504. 36. Van Wijk F, Staecker H, Keithley E, Lefebvre PP. Local perfusion of the tumor necrosis factor blocker Infliximab to the inner ear improves Autoimmune Neurosensory Hearing Loss. Audiol Neurotol 2006;11:357-65. 37. Hargunani CA, Kempton JB, DeGagne JM, Trune DR. Intratympanic injection of dexamethasone:time course of inner ear distribution and conversion to its active form. Otol Neurotol 2006;27:564-9. 38. Lonser RR, Baggenstos M, Kim HJ, Butman JA, Vortmeyer AO. The vestibular aqueduct: site of origin of endolymphatic sac tumors. J Neurosurg 2008;108:751-6.

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Intratympanic gadolinium administration for evaluation of endolymphatic space size and drug movement into the inner ear
T. NAKASHIMA 1, S. NAGANAWA 2, M. SONE 1, M. TERANISHI
1

Aim. To evaluate how intratympanically administered drugs move into the inner ear during intratympanic drug therapy of inner ear diseases. Methods. Intratympanic injection of gadolinium (Gd) contrast agents was conducted and magnetic resonance imaging (MRI) was performed 1 day after the injection in 120 patients with inner ear diseases. Results. Gd that entered the perilymphatic space was visualized. However, in 18% of ears Gd enhancement was not present or poor because of the disturbed permeability of the round window membrane. Because the endolymphatic space was not enhanced by Gd, it could also be visualized. Conclusions. Intratympanic Gd injection and MRI provide useful information for intratympanic drug therapy for the treatment of inner ear diseases. Key words: Intratympanic drug therapy Gadolinium Magnetic resonance imaging - Round window membrane permeability - Endolymphatic hydrops.

1Department of Otorhinolaryngology Nagoya University School of Medicine, Japan 2Department of Radiology Nagoya University School of Medicine, Japan

ndolymphatic sac surgery 1-3 or intratympanic gentamicin therapy 4, 5 are now used widely to treat intractable Menires disease. Intratympanic steroid therapy has also been used recently to treat sudden sensory hearing loss.6-8 Several
Acknowledgements.This study was supported by research grants from the Ministry of Health, Labor, and Welfare and from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Conflict of interest.The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. Corresponding author: T. Nakashima, Department of Otorhinolaryngology, Nagoya University School of Medicine, Nagoya, Japan. E-mail: tsutomun@med.nagoya-u.-ac.jp

studies have shown good results after the injection of steroids through the tympanic membrane to treat sudden sensorineural hearing loss. These intratympanic therapies are based on the assumption that the intratympanically administered drug passes into the inner ear through the round window membrane. Silverstein et al.9 reported that the round window membrane is impermeable or its permeability is inhibited markedly in about 20% of cases. They observed the round window itself, but did not measure the actual permeability of the round window membrane. We evaluated movement of intratympanically applied gadolinium (Gd) into the inner ear and reported that the round window permeability was absent in 5% of ears, and 13% of ears had poor round window permeability.10 These results should be considered when planning intratympanic drug administration therapy to treat inner ear diseases. Recently, Crane et al.11 reported middle ear exploration with direct application of gentamicin to the round window in the operating room in 8 patients with persistent Menires disease symptoms after failure of conventional intratympanic administration of gentamicin. In 6 of these patients, symptoms of

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vertigo either resolved with no further therapy (4 patients) or with subsequent intratympanic gentamicin injections in clinic (2 patients). The remaining 2 patients underwent a vestibular nerve section because of persistent vertigo. Anatomic barriers to the round window membrane may be a significant cause of failure of the intratympanic drug therapy. We have performed intratympanic Gd administration and evaluated permeability of the round window membrane in 120 patients with inner ear diseases. Because the intratympanic Gd moves into the perilymph through the round window membrane, discrimination of endolymphatic and perilymphatic spaces is possible with advanced techniques of magnetic resonance imaging (MRI).12 In this paper, endolymphatic space size and the permeability of the round window are shown using MRI performed after intratympanic Gd injection. Materials and methods Patients The subjects for this investigation included 120 patients with inner ear disease. They had idiopathic sudden sensorineural hearing loss, Menires disease, delayed endolymphatic hydrops, fluctuating hearing loss without vertigo, episodic vertigo without hearing loss, nonfluctuating hearing loss with vertigo, or acute hearing deterioration with large vestibular aqueduct syndrome. Most of the patients were candidates for intratympanic steroid therapy or intratympanic gentamicin therapy. Intratympanic Gd injection Gadodiamide hydrate (Gd-DTPA-BMA: Omniscan) or gadopentetate dimeglumine (Gd-DTPA: Magnevist) diluted with saline was injected intratympanically. Fifty-four patients received gadodiamide hydrate and 66 patients received gadopentetate dimeglumine. In each drug group, the Gd was diluted 16-fold with saline in 3 patients. In the other patients, the drug was diluted 8-fold with saline. The diluted Gd was injected through the tympanic membrane using a 23 G needle and a 1 mL syringe.12 In 3 patients, a small hole in the anterior-superior part of the tympanic membrane was made by the needle to vent air during the injection before the intratympanic injection (2-hole method).

To make the solution for the intratympanic injection, we opened a 5 ml or 10 ml commercially available Gd syringe used for intravenous injection. Because the chelator surrounding the free Gd is apt to separate after the syringe is opened, we opened the syringe immediately before it was used for the intratympanic injection. Gd application during exploratory tympanotomy In 2 patients, an exploratory tympanotomy was performed and we tried to increase the permeability of the round window because intratympanic Gd injected through the tympanic membrane showed no or poor permeability of the round window membrane. MRI MRI was performed 1 day after the intratympanic Gd injection. Using a 3-Tesla MRI unit, 3-dimensional fluid attenuated inversion recovery (3D-FLAIR), T1-, and constructive interference in steady state (CISS) MRI were applied in all patients. Three-dimensional real inversion recovery (3D-real IR) MRI was also performed in 107 patients. The methods of MRI were described previously.13-15 Ethics review The protocol for the study was approved by the Ethics Review Committee of the Nagoya University School of Medicine (approval numbers 369, 369-2, 369-3, and 369-4). All patients gave their informed consent to participation in this study. Their written informed consent was attached to the electronic medical record after permission was obtained from the patient. Results Gd signal intensity in the inner ear showed wide individual difference after the intratympanic Gd injection. An example of good Gd signal intensity is shown in Figure 1. The Gd signal intensity was not different between Gd-DTPA-BMA and Gd-DTPA. Using non-ionic Gd contrast agents (Gd-DTPABMA), we reported that the round window permeability was absent in 5% of ears, and 13% of ears had poor round window permeability (10). This ratio was not different after the injection of ionic Gd

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Figure 1.Gd movement into the inner ear after intaratympanic Gd injection (right ear). The right inner ear was enhanced clearly in this 3D-FLAIR MR image taken 1 day after 8-fold diluted Gd was injected intratympanically through the tympanic membrane on the right side. In the upper left corner, the right inner ear was magnified. Asterisks: endolymphatic hydrops in the cochlea. Arrows: Endolymphatic hydrops in the vestibule.

Figure 2.3D-FLAIR MRI (exploratory tympanotomy case). A 3D-FLAIR MR image taken 1 day after 8-fold diluted Gd was applied to the round window membrane observed by exploratory tympanotomy. Asterisks: endolymphatic hydrops in the cochlea. Arrows: Endolymphatic hydrops in the vestibule.

contrast agents (Gd-DTPA). No adverse effect was recognized in either group. Gd signal intensity was fainter with the 16-fold dilution than the 8-fold dilution, although the degree of endolymphatic hydrops could be evaluated with the 16-fold dilution. This tendency was observed with both Gd-DTPA-BMA and Gd-DTPA. Gd signal intensity in the inner ear of 3 patients who received intratympanic Gd injection using the 2-hole method was not better than that in the ordinary single injection method. Two patients underwent exploratory tympanotomy because movement of intratympanic Gd into the inner ear was poor. In 1 patient, the round window niche was narrow, and we used a Skeeter drill to remove the overhanging bone to visualize the round window membrane. After observing a good round window reflex when the stapes was touched, Gd was administered onto the round window during surgery. However, MRI 1 day after the administration showed

no Gd signal in the perilymph. In the other patient, after removing the overhanging bone, a part of the round window membrane close to the bone became red. After observing a good round window reflex when the stapes was touched, Gd was administered onto the round window during the surgery. MRI 1 day after the surgery revealed excellent movement of Gd (Figures 2, 3). To visualize the endolymphatic space, 3D-real IR MRI (Figures 3, 4) was generally better than 3DFLAIR MRI (Figures 2, 5) because 3D-real IR MRI could discriminate the perilymphatic space from the surrounding bone. However, when the Gd concentration was not sufficient in the perilymph, it was more difficult to visualize the Gd using 3D-real IR MRI than using 3D-FLAIR MRI. In patients whose vestibule was occupied by extremely large endolymphatic hydrops, the Gd movement toward the semicircular canal was disturbed because the perilymphatic space was not clearly recognized in the vestibule (Figure 6).

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Figure 3.3D-real IR MRI (exploratory tympanotomy case). A 3D-real IR MR image taken together with Figure 2. Asterisks: endolymphatic hydrops in the cochlea. Arrows: Endolymphatic hydrops in the vestibule.

Figure 5.3D-FLAIR MRI (intratympanic Gd injection through the tympanic membrane). A 3D-FLAIR MR image taken 1 day after 8-fold diluted Gd was injected intratympanically through the tympanic membrane. Asterisks: endolymphatic hydrops in the cochlea. Arrows: Endolymphatic hydrops in the vestibule.

Discussion Intratympanically administered Gd enters the perilymphatic space through the round window membrane and can then delineate the perilymphatic and endolymphatic spaces. This clinical endolymphatic imaging has 2 purposes.16 One is to investigate the relationship between clinical symptoms and endolymphatic hydrops. According to the criteria of the 1995 American Academy of OtolaryngologyHead and Neck Surgery (AAOHNS) guidelines, histopathological confirmation is necessary to diagnose certain Menires disease in addition to definite Menires disease.17 In addition, the diagnosis can be made when endolymphatic hydrops is observed using MRI in patients with probable or possible Menires disease. Thus, visualization of endolymphatic hydrops may be vital for making a new diagnosis of Menires disease. Another purpose of this clinical imaging is to investigate the permeability of the round window

Figure 4.3D-real IR MRI (intratympanic Gd injection through the tympanic membrane). A 3D-real IR MR image taken together with Figure 5. Asterisks: endolymphatic hydrops in the cochlea. Arrows: Endolymphatic hydrops in the vestibule.

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enhance image contrast, we are now using Gd diluted 8-fold as the intratympanic injection method. Because intravenous injection may reveal impairment of the bloodlabyrinth or bloodperilymph barriers,19, 20 the intravenous method has potential for the fine detection of the pathology of various inner ear diseases. Conclusions Using intratympanic Gd administration and MRI, we can investigate how drugs move into the inner ear from the middle ear. The method also enables us to visualize endolymphatic space in the cochlea, vestibule and semicircular canals. This method informs us of the endolymphatic space size and the drug distribution in the inner ear. Riassunto
Figure 6.3D-FLAIR MRI (poor Gd movement case after intartympanic Gd injection through the tympanic membrane). An MR image that shows poor movement of Gd into the semicircular canals. When the endolymphatic space in the vestibule was extremely large and the surrounding perilymphatic space was compressed, Gd movement into the semicircular canals was poor. In this patients with Menires disease, response to intratympanic gentamicin therapy was poor. Asterisks: endolymphatic hydrops in the cochlea. Shape of the semicircular canals was unclear.

membrane and to observe drug distribution inside the inner ear. Our experience of exploratory tympanotomy in 2 patients showed that it was difficult to evaluate the permeability of the round window membrane even though accessibility to the round window can be evaluated during the surgery.18 Accordingly, MRI after intratympanic Gd administration is now the best way to evaluate the permeability of the round window membrane. We have successfully visualized endolymphatic hydrops after intravenous Gd injection.19 However, the Gd concentration in the perilymph was fainter than that observed after intratympanic injection of Gd diluted 8-fold, and seemed to be closer to the concentration observed after intratympanic injection of Gd diluted 16-fold. We were able to evaluate the degree of endolymphatic hydrops after the intratympanic injection of the 16-fold dilution; however, to

Somministrazione intratimpanica di gadolinio per la valutazione delle dimensioni dello spazio endolinfatico e il movimento dei farmaci nellorecchio interno Obiettivo. Valutare come I farmaci somministrati per via intratimpanica si muovano allinterno dellorecchio interno durante la terapia farmacologica intratimpanica per malattie dellorecchio interno. Metodi. Un giorno dopo liniezione intratimpanica del mezzo di contrasto gadolinio (Gd), una risonanza magnetica nucleare (RMN) stata effettuata in 120 pazienti affetti da patologie dellorecchio interno. Risultati. stato visualizzato il Gd che era entrato nello spazio perilinfatico. Tuttavia, nel 18% degli orecchi, lenhancement del Gd era assente o scarso a causa dellalterata permeabilit della finestra rotonda. Poich lo spazio endolinfatico non era contrastato dal Gd, esso poteva essere visualizzato. Conclusioni. Liniezione intratimpanica di Gd e la RMN forniscono utili informazioni per la terapia farmacologica intratimpanica nel trattamento di patologie dellorecchio interno. Parole chiave: Terapia farmacologica intratimpanica Gadolinio Risonanza magnetica Membrana della finestra rotonda, permeabilit - Idrope endolinfatico.

References
1. Huang TS. Endolymphatic sac surgery for Menires disease: experience with over 3000 cases. Otolaryngol Clin North Am 2002;35:591-606.

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2. Tyagi I, Goyal A, Syal R. Sac surgery results as a function of preoperative distress level. Otol Neurotol 2006;27:951-5. 3. Kitahara T, Kubo T, Okumura S, Kitahara M. Effects of endolymphatic sac drainage with steroids for intractable Menires disease: a long-term follow-up and randomized controlled study. Laryngoscope 2008;118:854-61. 4. Lange G, Maurer J, Mann W. Long-term results after interval therapy with intratympanic gentamicin for Menires disease. Laryngoscope 2004;114:102-5. 5. Postema RJ, Kingma CM, Wit HP, Albers FW, Van Der Laan BF. Intratympanic gentamicin therapy for control of vertigo in unilateral Menires disease: a prospective, double-blind, randomized, placebo-controlled trial. Acta Otolaryngol 2008;128:876-80. 6. Ho HG, Lin HC, Shu MT, Yang CC, Tsai HT. Effectiveness of intratympanic dexamethasone injection in sudden-deafness patients as salvage treatment. Laryngoscope 2004;114:1184-9. 7. Plaza G, Herraiz C. Intratympanic steroids for treatment of sudden hearing loss after failure of intravenous therapy. Otolaryngol Head Neck Surg 2007;137:74-8. 8. Hu A, Parnes LS. Intratympanic steroids for inner ear disorders: a review. Audiol Neurootol 2009;14:373-82. 9. Silverstein H, Rowan PT, Olds MJ, Rosenberg SI. Inner ear perfusion and the role of round window patency. Am J Otol 1997;18:586-9. 10. Yoshioka M, Naganawa S, Sone M, Nakata S, Teranishi M, Nakashima T. Individual differences in the permeability of the round window: evaluating the movement of intratympanic gadolinium into the inner ear. Otol Neurotol 2009;30:645-8. 11. Crane BT, Minor LB, Della Santina CC, Carey JP. Middle ear exploration in patients with Menires disease who have failed outpatient intratympanic gentamicin therapy. Otol Neurotol 2009;30:619-24. 12. Nakashima T, Naganawa S, Sugiura M, Teranishi M, Sone M,

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Hayashi H, et al. Visualization of endolymphatic hydrops in patients with Menires disease. Laryngoscope 2007;117:415-20. Naganawa S, Sugiura M, Kawamura M, Fukatsu H, Sone M, Nakashima T. Imaging of endolymphatic and perilymphatic fluid at 3T after intratympanic administration of gadolinium-diethylenetriamine pentaacetic acid. AJNR Am J Neuroradiol 2008;29:724-6. Naganawa S, Satake H, Kawamura M, Fukatsu H, Sone M, Nakashima T. Separate visualization of endolymphatic space, perilymphatic space and bone by a single pulse sequence; 3D-inversion recovery imaging utilizing real reconstruction after intratympanic Gd-DTPA administration at 3 Tesla. Eur Radiol 2008;18:920-4. Naganawa S, T. N. Cutting edge of inner ear MRI. Acta Otolaryngol 2009;129(Suppl 560):15-21. Nakashima T, Naganawa S, Katayama N, Teranishi M, Nakata S, Sugiura M, et al. Clinical significance of endolymphatic imaging after intratympanic gadolinium injection. Acta Otolaryngol 2009;129(Suppl 560):9-14. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Menires disease. American Academy of Otolaryngology-Head and Neck Foundation, Inc. Otolaryngol Head Neck Surg 1995;113:181-5. Nakashima T Naganawa S, Sone M, Teranishi M, Kawauchi H. Round window surgery. Otol Neurotol 2010;31:549-50. Nakashima T, Naganawa S, Teranishi M, Tagaya M, Nakata S, Sone M, et al. Endolymphatic hydrops revealed by intravenous gadolinium injection in patients with Menires disease. Acta Otolaryngol 2010;130:338-43. Yoshida T, Sugiura M, Naganawa S, Teranishi M, Nakata S, Nakashima T. Three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging findings and prognosis in sudden sensorineural hearing loss. Laryngoscope 2008;118:1433-7.

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Intratympanic gentamicin for unilateral Menires disease

W. H. SLATTERY III
1, 2 ,

K. B. TEUFERT

Menires disease is a chronic illness that affects a substantial number of patients every year worldwide. The disease is characterized by intermittent episodes of vertigo lasting from minutes to hours, with uctuating sensorineural hearing loss, tinnitus, and aural pressure. Although there is currently no cure, more than 80% of patients with Menires disease are helped by either changes in lifestyle and medical treatment with another 20% requiring minimally invasive surgical procedures such as intratympanic steroid therapy, intratympanic gentamicin therapy, and endolymphatic sac surgery. Vestibular neurectomy has a very high rate of vertigo control and is available for patients with good hearing who have failed all other treatments. Labyrinthectomy is undertaken as a last resort and is best reserved for patients with unilateral disease and deafness. This paper discusses treatment options of Menires disease, with emphasis on intratympanic gentamicin therapy, including its basic science, experimental studies, and an extensive review of the literature. Key words: Gentamicins - Menire disease - Aminoglycosides Vertigo - Dizziness.

Studies, House Ear Institute, Los Angeles, CA, USA 2House Ear Clinic, University of Southern California, Los Angeles, CA, USA 3House Ear Institute, Los Angeles, CA, USA

1Clinical

Overview of Menires disease enires disease is an idiopathic disease involving the inner ear and is characterized pathologically by progressive endolymphatic hydrops that is probably related to a disturbance in endolymphatic sac function. This condition must be differentiated from non-progressive endolymphatic hydrops in
Corresponding author: W. Slattery, Clinical Studies, House Ear Institute, 2100 W. Third Street, Los Angeles, CA 90057, USA. E-mail: wslattery@hei.org

which the hydrops is the result of a single traumatic or inflammatory insult to the labyrinth, causing a permanent but not progressive endolymphatic hydrops.1 The symptoms of progressive endolymphatic hydrops can be correlated with two principal types of pathologic change: distention and ruptures of the endolymphatic system,2, 3 and alterations in the cytoarchitecture of the auditory and vestibular sense organs, sometimes accompanied by atrophic changes. Coincident with rupture, there is sudden contamination of the perilymphatic fluid with neurotoxic endolymph (140 mEq/L of potassium) that causes paralysis of the sensory and neural structures and is expressed clinically as episodic vertigo, fluctuating hearing loss, or both. The American Academy of Otolaryngology-Head and neck Surgery (AAOHNS) recommended that these episodes be designated the definitive symptoms of Menires disease.4 As the disease progresses, there are changes in the cytoarchitecture of the sense organs that consist of distortion and atrophy of the sensory cells and supporting cells as well as disruption and deformation of their gelatinous aprons. These alterations impair the motion mechanics of the sense organs, resulting in

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permanent functional deficits. The symptoms of the auditory system are hearing loss and tinnitus. The hearing loss is fluctuating, usually low-frequency, often flat, and sensorineural in type. The symptoms of the vestibular system are constant or recurring sensations of vertigo, described as being off-balance, floating, tilting, falling, or spinning, and are often aggravated by head movement. The AAO-HNS recommended that they be known as adjunctive symptoms. These vertigo spells last from minutes to hours, may vary in severity from patient to patient, are often prostrating, and are frequently accompanied by nausea and vomiting. The patient is oriented and conscious throughout the spell, and there are no neurologic sequelae.

Treatment options of Menires disease Medical treatment Medical treatment for Menires disease is effective in controlling vertigo for approximately 85% of patients and forms the primary mode of therapy in managing these patients. There is a lack of understanding regarding the pathophysiology of Menires disease, and hence the pharmacologic therapy lacks the same scientific understanding. This lack of understanding of the exact pathophysiology of Menires disease is partially because of a lack of an animal model. Very few well-controlled clinical trials have been carried out evaluating medical therapy of Menires disease. Most medical therapy is based on clinical experience and many medications were discovered serendipitously. The fluctuant nature of the disease makes it very difficult to conduct well-established controlled trials evaluating medical therapy. Furthermore, Menires disease or symptoms may be the outward expression of different etiologies of a diseased ear, further complicating our understanding of the pathophysiology. The treatment of patients suffering from Menires disease continues to be controversial. The proposed treatments attest to the difficulty in attaining a satisfactory therapeutic result in these patients. In 1977, Nicholas Torok published a 25-year review of 834 papers concerned with the treatment of Menires disease.5 He concluded that although treating the patient was important, the specific nature of the disease bore little relation to the therapeutic out-

come. The ability to control vertiginous attacks with all medical therapies, ranged between 60% and 80%. Only a small number of patients had hearing improvement and tinnitus reduction. The therapeutic results were similar despite multiple medical regimens. The lack of rationale behind many of the proposed treatments supports the concept that Menires disease patients benefit from a nonspecific form of therapy. In 1991, Ruckenstein et al. reviewed a significant body of literature regarding medical and surgical treatment of Menires disease since the Torok study.6 They concluded that no treatment directed at alleviating hydrops had been shown to specifically ameliorate the symptoms of Menires disease, that the pathophysiologic mechanisms involved in a Menires attack had yet to be elucidated, and that although hydrops is the end result, it may not necessarily be the effector of the disease process. They also found that vestibular suppressants are the only medications that have definitely been shown to improve symptoms of Menires disease. They were unable to find any well-controlled study that demonstrated any medications that are able to prevent symptoms of Menires disease. In 2005, Kim et al. carried out a prospective study to determine the practices of the American Neurotology Society (ANS) membership in the evaluation and treatment of the Menires patient.7 Three hundred members of ANS were mailed a 15-item questionnaire, with questions pertaining to the diagnostic and therapeutic practices in the management of Menires disease. Two hundred three responded, for a 67.7% response rate. For the diagnosis of Menires disease, one in three practitioners relied solely on history, physical exam, and audiometry, whereas two in three relied in part on adjunctive tests, such as electrocochleography (ECOG) and electronystagmography (ENG). Two in three practitioners pursued retrocochlear studies on initial evaluation, with the overwhelming majority using MRI. In treating Menires disease, conservative medical management was preferred. For medically refractory Menires disease, endolymphatic sac surgery (ESS) was the most commonly employed initial intervention (50%), followed by transtympanic gentamicin (38%). Currently, <10% routinely recommend the Menietts device. Eighty-three percent include ESS as a therapeutic option for medically refractory Menires disease. The vast majority continues to perform surgical labyrinthectomies

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and vestibular nerve sections for Menires disease. They concluded that Menires disease continues to pose a difficult diagnostic and therapeutic problem, resulting in heterogeneous approaches to both evaluation and treatment. Despite the 1995 American Academy of Otolaryngology guidelines in the diagnosis of Menires disease, most clinicians rely in part on ENG or ECOG in diagnosing Menires disease. They also concluded that despite the passing of 20 years since the publications claiming a purely placebo effect, ESS is the most commonly employed initial surgical treatment for Menires disease. In 2008, Coelho and Lalwani reviewed the literature and found that because of a lack of well-controlled studies, the medical management of Menires disease remains empirical and is largely restricted to lifestyle changes, pharmacotherapy, and office-based procedures.8 They proposed that the development of transtympanic therapies represents a true therapeutic advance that has largely supplanted surgical intervention and concluded that despite absence of a complete understanding of Menires disease, medical management or its natural history leads to control of vertigo in the majority of patients. Basic research is needed to understand its pathophysiology so that directed therapies can be developed and can be tested in well-controlled clinical trials. Medical therapy for Menires disease has classically included dietary modifications, physiotherapy, psychological support, and pharmacologic intervention. Nonspecific modalities, such as physiotherapy, may have some value in teaching patients coping strategies. Patients also invariably benefit from a supportive and reassuring therapeutic environment. Acute episode Vestibular suppressant drugs and antiemetics are used in the acute period. The site of action for control of vertigo of many of these drugs remains unknown. They may act centrally at neurotransmitter sites, or peripherally on the labyrinth. These drugs have a very well established record in controlling acute attacks of vertigo and accompanying nausea and vomiting. They have variable anticholinergic, antiemetic, and sedative properties. These drugs include benzodiazepines (diazepam), meclizine (Antivert, Bonine), prochlorperazine (Compazine), promethazine (Phenergan), diphenhydramine (Benadryl), dimenhydrinate (Dramamine), hyoscine, and metoclopramide.

Maintenance therapy The goal of maintenance therapy is to prevent the acute attacks of vertigo and maintain hearing in Menires disease. Maintenance therapy usually includes diet modifications combined with other pharmacologic interventions. The specific pharmacologic agent used in maintenance therapy may depend upon the patients previous response to therapy. Past experience with certain medications may prove beneficial in the selection of a specific type of maintenance therapy. The duration of maintenance therapy also is selected by the physician based on the patients response to therapy. Because of the fluctuant nature of the disease, long-term maintenance therapy usually is not recommended. However, some patients require continuous maintenance therapy to prevent acute attacks of vertigo and maintain hearing. Diet modifications The mainstay of diet modifications is to reduce sodium intake. A very low sodium intake or low sodium diet is recommended. The definition of a low-sodium diet must be discussed with the patient. A strict low sodium diet with a daily allowance of 1500 mg of sodium per day is advised. This is a very stringent diet, and many patients consider this unpalatable. Patient compliance with this type of diet may be poor. A more practical approach is to ask patients to avoid excessively salty foods, to not add table salt to foods when they are being prepared, and to not add table salt to foods once they are placed on the table. This is a more practical diet that leads to better patient compliance. Encouraging a salt substitute for those with discriminating taste is helpful. Patient compliance with the practical low-sodium diet is usually very well tolerated in Menires disease patients. Some patients who are very compulsive may prefer the 1500 mg per day diet. Restriction in the intake of caffeine, nicotine, and alcohol also is suggested for Menires disease patients. Diuretics The use of diuretics stems from the supposition that these drugs can alter the fluid balance in the inner ear, leading to a depletion of endolymph and a correction of hydrops. In 1934, Furstenberg et al. demonstrated that the

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symptoms of Menires disease were due to retention of sodium.9 They recommended a low salt diet and demonstrated the effects of diuretics in controlling the attacks of vertigo. In1975, Boles et al. described the University of Michigan experience with a lowsalt diet, supplemented when necessary with the use of diuretics.10 Overall they found that most patients had their vertigo attacks controlled with an 800 to 1 000 mg of sodium per day diet. Additional diuretic medical therapy was dictated by the patients response to the low salt diet and diuretics. In 1981 Jackson et al. reported a success rate of 57.9% with sodium restriction therapy.11 Other medications that could be used in the medical treatment of Menires disease include vasodilators, calcium channel blockers, ACE inhibitors, and lipoflavins and vitamins. Ablative therapy Aminoglycosides The ototoxic effects of aminoglycosides are well known. Streptomycin and gentamicin are predominantly vestibulotoxic. Schuknecht established the standard indications and the treatment regimen for systemic streptomycin use.12 Intramuscular injections of streptomycin administered twice daily, for periods of days to weeks have been used in patients with debilitating bilateral disease or unilateral disease in the only hearing ear. Silverstein et al. and Moretz et al. reported control of vertigo in almost all patients using this method.13, 14 Complete ablation has resulted in disabling oscillopsia. Many authors have suggested the use of lower dosages and fewer injections to achieve partial ablation of the labyrinth, reducing the severity of the ataxia but still controlling vertigo attacks and perhaps stabilizing hearing. Intratympanic gentamicin will be discussed further in this chapter. Surgical management Surgery has long been used to control disabling vertigo of Menires disease and other peripheral vestibular disorders refractory to medical measures, with each surgical procedure having many technical variations. The history of vestibular nerve section (VNS) was recently reviewed.15 It was first attempted in 1898,

with microscopic technique later introduced by William House in 1960. The retrolabyrinthine and retrosigmoid-internal auditory canal approaches for VNS were popularized in the 1980s.16-18 Transmastoid labyrinthectomy, the gold standard surgical technique for complete removal of all neuroepithelial elements of the ear causing disabling disequilibrium, was described as early as1904.19-22 When properly performed, transmastoid labyrinthectomy eliminates all vestibular function in the diseased periphery, but at the expense of any remaining cochlear function. Another common treatment option for patients with intractable Menires disease, endolymphatic sac surgery (ES), has stood the test of time for 75 years.23 House 24 described and popularized endolymphatic sac surgery (the shunt procedure) in the early 1960s. For patients with unilateral disease, the procedures of choice are endolymphatic mastoid shunt and vestibular nerve section (translabyrinthine, retrolabyrinthine, retrosigmoid and middle cranial fossa VNS). These procedures are preferred over labyrinthectomy because cochlear nerve integrity is preserved, leaving open the possibility of future cochlear implantation should bilateral profound hearing loss develop. Telischi and Luxford published statistically valid long-term results in endolymphatic sac surgery.25 This is recommended as the surgical procedure of first choice. Sixty-three percent of patients undergoing sac surgery do not require further surgical procedures and an additional 17% has only revisions of the endolymphatic sac shunt. Thus, 80% never require a destructive procedure and 93% report no further dizziness or mild to no disability 13.5 years later. The sac procedure has only a 2% risk of hearing loss or hearing worsening. Patients who fail sac procedures or who are severely symptomatic, show a 90% vertigo cure rate to vestibular neurectomy. The surgeon should take into consideration severity of disease, hearing status and presence of unilateral versus bilateral disease when selecting an approach for the surgical treatment of Menires disease. Endolymphatic drainage procedures can be divided into external shunts that attempt to drain excessive endolymph from the endolymphatic sac into the mastoid or subarachnoid space, i.e, endolymphayic sach shunt, and internal shunts that attempt to drain excessive endolymph into the perilymphatic space, i.e., cochleosacculotomy (labyrinthotomy). To be successful, surgical procedures based on facilitating drainage of endolymph should alleviate definitive

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symptoms and arrest the progression of adjunctive symptoms. Approaches that transverse the labyrinth, such as labyrinthectomy and translabyrinthine vestibular neurectomy, sacrifice hearing and are useful in patients without useful hearing. Posterior approaches that spare the labyrinth provide varying degrees of cerebellopontine angle (CPA) exposure with an opportunity for hearing preservation: retrolabyrinthine (RL) and retrosigmoid (RS) vestibular neurectomy. Superior approaches permit un-roofing of the internal auditory canal (IAC) and an opportunity for hearing preservation, such as middle fossa (MF) vestibular neurectomy; however, this procedure has fallen out of favor due to increased risk of facial nerve injury or transient palsy, compared with the other approaches. Basic science of intratympanic aminoglicosides In 1944, streptomycin was isolated from cultures of a soil organism, Streptomyces griseolus.26 This drug displayed broad-spectrum antibacterial activity and was the first found to be effective against tuberculosis. Because effective treatment of tuberculosis with streptomycin required prolonged therapy, ototoxicity became evident soon after introduction of the drug. As early as 1948, streptomycin was used to treat patients with unilateral Menires disease specifically on the basis of its vestibulotoxic effects.27 Gentamicin was isolated from the actinomycete Micromonospora purpurea in 1963,28 a genus of Grampositive bacteria widely present in the environment (water and soil). Aminoglycosides exert their toxic effects on the hair cells of the inner ear by two general mechanisms. First, aminoglycosides bind to the plasma membrane and displace calcium and magnesium. This event results in acute but reversible interference with calcium-dependent mechanical-electrical transduction channels.29 Second, aminoglycosides are transported into the cell by an energy-dependent process. Within the cell, the drug binds to phosphatidylinositol. This event is associated with progressive disruption of the plasma membrane and inhibition of the second messenger inositol triphosphate. With progressive disruption of the second messenger system and the plasma membrane, cell death occurs.30-32 The disruption of cell membranes and other intracellular components may be mediated by free radi-

cals. Recent studies have shown that aminoglycosides form a complex with iron and that this complex catalyzes the production of free radicals. The combination of iron chelators and free radical scavengers in animal experiments provides complete protection from gentamicin ototoxicity.33 Aminoglycosides do not become concentrated in cochlear fluids, although the elimination half-life increases with chronic administration. These observations suggest that intracellular sequestration of the drug occurs.34 Aran et al. have demonstrated that aminoglycosides undergo a rapid uptake by cochlear and vestibular hair cells and a slow clearance from these cells.35 Amikacin, dihydrostreptomycin, and kanamycin are primarily cochleotoxic, whereas gentamicin and streptomycin are primarily vestibulotoxic. At high doses, streptomycin is also cochleotoxic. For example, streptomycin, 25 mg/kg per day, administered systemically to cats resulted in loss of vestibular hair cells only, but at 100 mg/kg/day, both vestibular and cochlear hair cells were lost.36 Recent animal experiments have tried to model the pharmacokinetics of intratympanic administration of gentamicin applied in a sustained-release vehicle of liquid fibrin glue. High levels of gentamicin were measured in perilymph within 8 hours of administration. These high levels persisted for at least 24 hours, then declined rapidly by 72 hours. The elimination rate for gentamicin was 1.04 mg/mL per hour.37 The hair cells of the cristae, the ampullae, and the cochlea degenerate to different degrees following the administration of aminoglycosides. The primary vestibular neurons, the cochlear nuclei, and the vestibular nuclei are not directly affected, even at high doses.36, 38 The basal turn of the cochlea is the region most susceptible to permanent loss of hair cells, resulting in an initial loss of high-frequency hearing sensitivity. Although the mechanisms of this differential toxicity are incompletely understood, several contributing factors have been identified, including the route of administration, dose variables, and the specific aminoglycoside used. Damage to vestibular dark cells, which are thought to play a role in the production of endolymph, has been reported following administration of doses of aminoglycoside below the threshold for damage to hair cells. It is possible, but unproven, that impaired function of dark cells is beneficial in Menires disease.39, 40

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Intratympanic gentamicin therapy Experimental studies Intratympanic injection of aminoglycosides allows treatment of unilateral Menires disease without producing systemic toxicity or effects on the opposite ear. Tracer studies have demonstrated that the primary route of entry into the inner ear is through the round window membrane.41-45 A secondary route of entry into the inner ear may be through the annular ligament of the stapes.46, 47 Following the intratympanic application of streptomycin to guinea pigs, the cristae of the semicircular canals showed the most degeneration, followed by the utricule, then the saccule and the cochlea.48 The selectivity of the lesion for vestibular versus cochlear hair cells after intratympanic injection, was reduced at higher dosages. For example, the application of 8 mg of streptomycin to the round window membrane of the cat produced only vestibular toxicity, whereas 20 to 40 mg produced both cochlear and vestibular toxicity.49 These experimental results emphasize the potential for cochlear toxicity when the primary route of entry into the inner ear is through the round window membrane. In 2001, Hoffer et al. conducted a study on chinchillas to help elucidate questions regarding the ideal dose of medicine, the best administration paradigm, and the safest treatment end-point in transtympanic gentamicin therapy for Menires disease.50 The goal of the study was to examine the inner ear kinetics of transtympanic gentamicin and compare this with the kinetics of sustained-release delivery in a basic science model. They also examined the relationship of these kinetics curves to the effect of the two treatment modalities on inner ear function and morphology. The study examined perilymph gentamicin concentrations, hearing results, and inner ear morphology in an animal model. Gentamicin was applied to the right ear of chinchillas either through a transtympanic approach or in a sustained-release device. The left ear remained untreated as an internal control. At set time points the animals hearing and balance function was studied and the perilymph was harvested, after which the animal was killed and preserved for histological evaluation. Kinetics curves were constructed for each of the two treatment paradigms and compared with histological and functional outcomes. They found the two groups

yielded dramatically different kinetics curves. The transtympanic curve had a high peak level at 24 hours with rapid fall-off and almost total elimination by 48 hours, whereas the sustained-release curve was characterized by a long, flat plateau phase with a peak that was approximately one-third that of the transtympanic curve. In addition, the variability seen in perilymph concentrations was significantly higher in the transtympanic group than in the sustainedrelease group. Immunohistochemical analysis using antibodies against cleaved caspase-3 and cleaved caspase-7 demonstrated early damage in the spiral ganglion of both groups, before any obvious morphological change in the hair cells. The staining was significantly denser in animals with transtympanic delivery. Cochlear and vestibular hair cell damage was seen at late time points in animals from both groups. Hearing loss progressed in an orderly fashion in the sustained-release group of animals, with no hearing loss seen in the early time points and universal significant threshold shifts present by 72 hours. In the transtympanic group, the hearing loss was more variable, with significant threshold shifts occurring as early as 4 hours after treatment, but with some animals demonstrating preserved hearing at the 72-hour time point. All animals demonstrated profound hearing loss at the 6-day time point. They concluded that there was a significant difference in the shape and variability of the perilymph kinetics curve when comparing sustained-release delivery to transtympanic delivery of gentamicin. High early peak levels of gentamicin seen with transtympanic therapy may have a profound effect on the spiral ganglion and produce early hearing loss before obvious hair cell damage. Sustained delivery of gentamicin produced universal hearing loss at 72 hours. The reliability of sustained-release delivery to the ear reduced functional and morphological variations between animals. Clinical studies The use of intratympanic aminoglycosides to induce a chemical labyrinthectomy for the treatment of unilateral Menires disease was introduced by Schuknecht.51, 52 He reported the results of eight patients given large daily doses of streptomycin (150 to 600 mg/day) for one to seven days. The treatment end-point was the onset of signs and symptoms of vestibular ablation. The treatment was success-

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ful in controlling vertigo in five of eight patients, all of whom lost substantial hearing in the treated ear. Although hearing was preserved in the remaining three of eight patients, persistent vertigo necessitated surgical labyrinthectomy. Schuknecht found that complete control of vertigo with intratympanic streptomycin required abolition of ice water caloric responses, and that when this was accomplished, hearing was also lost. Lange reported an extensive experience using various aminoglycosides to treat Menires disease.53-55 In his group of 92 patients, Lange reported that 90% had no further episodes of severe vertigo and hearing remained unchanged in 76% of patients. Unfortunately, many of the studies reported from 1956 to 1990 did not use standardized reporting methods. Nedzelski et al. developed a fixed-dose protocol, which they applied consistently.56-58 A catheter was attached to a tympanostomy tube, which was placed near the round window. The aminoglycoside solution used was buffered to pH 6.4 with a final concentration of 26.7 mg/mL. Three doses of 0.65 mL were instilled per day for four days. Bone conduction audiometry was performed daily. They studied the patients prospectively using the AAO-HNS guidelines for reporting treatment results of Meneires disease.59, 60 They also monitored post-treatment caloric responses as the best indicator of biologic treatment effect. Results were reported for the first 30 patients followed for at least two years.58 Complete control of vertigo was obtained in 83 per cent and substantial control (vertigo class B) in 17%. Hearing was worse in 27% of patients; 13% sustained a profound hearing loss. Ice water caloric responses were abolished in 53% of patients, all of whom had complete control of vertigo for the first two years at least. Complete control of vertigo was obtained in 80% of patients who had persistent ice water caloric responses. Four patients required retreatment within two years because of persistent attacks. In a study to characterize the delayed effects of intratympanic gentamicin, Magnusson and Padoan treated five patients with a total of two doses of gentamicin (30 mg/mi, pH 6.4), given 12 hours apart.61 The first symptom of an ototoxic reaction noted by the patients was a sensation of unsteadiness occurring 2 to 5 days (mean 3.2 days) after the injections. Vertigo and nystagmus were noted 3 to 8 days (mean 5.1 days) after the injections. With one year of follow-up, vertigo was controlled (with a loss of caloric

responsiveness in the treated ear) and hearing preserved in all five patients.61 This preliminary study raised the question of whether very low intratympanic doses of gentamicin may be effective in controlling vertigo and preserving hearing. Because this technique did not totally ablate vestibular function, vertigo may recur, but hearing was usually preserved. Additional gentamicin could be used if vertigo recurred. Beck and Schmidt administered gentamicin 30 mg/day and stopped after six days or at the slightest indication of ototoxicity.62 In 40 patients treated with their regimen, control of vertigo occurred in 92.5% of patients. Eighty-five percent of patients maintained hearing. Following the work of Beck and Schmidt, several investigators developed the hypothesis that if a titration dosage schedule were adopted, it might be possible to achieve satisfactory rates of control of vertigo while preserving hearing in more patients. Much of the controversy about intratympanic gentamicin treatment has been over the issue of whether such approaches achieve this goal and how various protocols compare with each other. Studies by several authors showed remarkably similar results for control of vertigo, ranging from 86 to 93% of patients treated. Some patients required additional gentamicin injections or surgery. Authors have noted an association between loss of the ice water caloric response and complete control of vertigo.63, 64 On the other hand, reports showed considerable variation in rates of hearing preservation, ranging from 55% to 85%. The results suggest that the administration schedule and total dosage may be significant factors in hearing preservation. The variability in reports may also be due to differences in case selection, because some series have more elderly patients or patients with worse pretreatment hearing levels than other series. It is suspected, but has not been established, that there may be a trade-off between control of vertigo and preservation of hearing. An important indicator for intratympanic gentamicin therapy seems to be the control of vertigo in non-serviceable ears, i.e., speech reception threshold worse than 50 db and speech discrimination score of less than 50%, or in patients who have failed endolymphatic sac surgery.65 Transmastoid labyrinthectomy has traditionally been offered for non-serviceable ears in patients with Menires disease. This method

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has been the gold standard, and it is very effective in eradication of vertigo in more than 94% of patients. However, transtympanic gentamicin therapy can provide a minimally-invasive ambulatory means with low morbidity and few side-effects, which is very cost effective for management of vertigo in these patients with non-serviceable ears.66 Marzo and Leonetti 67 have also shown the efficacy of intratympanic gentamicin therapy for patients who have failed endolymphatic sac surgery, thus reducing the need for vestibular neurectomy in those with intractable disease. In 2004, Carey reviewed the history of intratympanic aminoglycoside treatment since the 1950s, including current treatment protocol and outcomes.68 He found that titration therapy with intratympanic gentamicin offered class A or B control of vertigo in 87% (range, 75-100%) of patients with unilateral Menires disease. The risk of additional hearing loss was about 21% (range, 0-37%).22 Vertigo may recur, however, in nearly one third of patients over time. These recurrences can also be treated by intratympanic gentamicin with a similar risk of hearing loss. The prominent effect of intratympanic gentamicin is probably the reduction of vestibular function through damage to hair cells, but a complete ablation of function does not seem to be necessary for vertigo control. Boleas-Aguirre et al. reported on residual vestibular symptoms and disability in patients with Menires disease who had achieved complete control of vertigo through intratympanic gentamicin treatment.69 The study involved 103 patients with Menires disease treated with intratympanic gentamicin that, after a long-term follow-up, have not suffered new vertigo spells and were not subject to any major modification in their treatment. After a five-year follow-up, complete control of vertigo was obtained in 81% of the patients with Menires disease who were treated with intratympanic gentamicin. Of them, 15.5% still complained of unsteadiness. Bodmer et al. assessed long-term vertigo symptom control in patients after intratympanic gentamicin instillation for incapacitating unilateral Menires disease, and whether an absent caloric response, using electronystagmography after gentamicin treatment, is a good predicator of long-term symptom control.70 Of 63 patients, 44 were vertigo-free, whereas 14 continued to experience some degree of vertigo. Of the 44 patients who were asymptomatic, 35 had an ab-

sent caloric response. Of the14 patients who reported some vertigo, 12 had an absent caloric response post-treatment. These results led them to conclude that complete or substantial vertigo control was achieved in most patients and a significant caloric response reduction was a consequence in almost all patients, although an absent caloric response is not invariably a predictor of long-term symptom control. In another study about long-term results of highdose gentamicin for intractable Menires disease, 27 mg/mL gentamicin were performed three times daily for four days in 14 who had failed medical (12 subjects) or surgical (2 subjects).71 The overall successful vertigo control rate was 92.9% over the two-year follow-up and 85.7% at long-term follow-up (average 10 years). Hearing level as pure-tone average was worse in four patients (28.5%) after two years follow-up and in six patients (42.8%) after longterm follow-up, respectively. Profound sensorineural hearing loss occurred as a result of gentamicin injection in one patient (7%). More recently, Salt et al. used a validated computer model of gentamicin dispersion in the inner ear fluids to calculate cochlear drug levels resulting from specific clinical delivery protocols, with the objective of establishing safe dosing protocols intratympanic gentamicin therapy.72 Dosing in the cochlea was compared with changes of hearing sensitivity for 568 patients reported in 19 publications. Drug levels resulting from single, one- shot injections were typically lower than those from repeated or continuous application protocols. Comparison of hearing sensitivity changes with gentamicin dosing revealed a flat curve with a near-zero mean for lower doses, suggesting that hearing changes with doses over this range were probably unrelated to the applied drug. Higher intracochlear doses were generated with repeated or continuous delivery protocols, which in some cases caused substantial hearing losses and an increased incidence of deafened ears. They concluded that one-shot application protocols produced gentamicin doses in the cochlea that have minimal risk to hearing at the frequencies tested. Repeated or continuous application protocols resulted in higher doses that in some cases damage hearing. Because of the high variability of hearing changes, even with low gentamicin doses, using individual hearing changes to titrate the applied dose should be further investigated. Carey et al. assessed the time course of recurrent

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vertigo and repeated injections using a Kaplan-Meier survival analysis.73 Injections of IT gentamicin were administered for unilateral definite Menires disease. One injection (or rarely more) in a six-week period constituted a round. Repeat rounds were given when needed for control of recurrent vertigo. Of 78 patients, 75 (96%) achieved sufficient vertigo control to avoid ablative surgery, and 42 (54%) required only one round. Thirty-six (46%) required multiple rounds. The probability of needing another round increased with each subsequent one, through four rounds. The median times to the next round after one, two, or three rounds were 148, 118, and 124 days, respectively. More than half of patients needed only one round of IT gentamicin injections. With each additional round through the fourth one, the probability of additional round increased. Nevertheless, the majority (96%) of patients do not need ablative surgery after IT gentamicin. With the objective of understanding the safety and outcomes of intratympanic gentamicin treatment in patients with Mnieres disease with normal hearing, Silverstein et al. analyzed a total of 224 patients with disabling Mnieres disease.74 Patients underwent self-treatment with intratympanic gentamicin (10 mg/mL) three times daily for one to eight weeks. Twenty-two (88%) of 24 patients with stage 1 Mnieres disease showed unchanged or improved speech discrimination score. All 24 patients showed a mean pure-tone average loss of 8 dB. Seventeen (71%) patients reported complete or improved vertigo control. One hundred sixteen (59%) of 200 patients with stage 2 through four Menires disease showed unchanged or improved speech discrimination score. All 200 patients showed a mean puretone average loss of 11 dB. One hundred forty-eight (74%) patients reported complete or improved vertigo control. Patients with stage 1 Menires disease appeared to have similar vertigo control with better hearing preservation than patients with advanced disease when treated with low-dose intratympanic gentamicin (10 mg/mL). Menires disease continues to afflict hundreds of thousands of patients every year. It is true that we still do not have a cure for this disease, as with many other illnesses in medicine. However, substantial improvements have been made over the years, especially in the past decade, as shown by this literature review, and several safe and effective medical and surgical therapies are now available to help patients

coping with the disorders sequelae, including intratympanic gentamicin physicians treating patients who have Menires disease should remain optimistic and convey a positive attitude when dealing with patients afflicted with this illness. Titration method A full diagnostic assessment is made, including a complete history, physical examination, neurologic examination, observation of eye movements, vestibulospinal examination, vestibular function testing (electronystagmography, posturography, rotational chair testing), and audiometric evaluation. Retrocochlear and metabolic disorders are excluded. Given the low total dose of gentamicin used, the need to withhold treatment based on abnormal renal function is rare. Patients are counseled that the purpose of the intratympanic gentamicin injections is to control the recurrent episodes of vertigo typical of Menires disease. The expectation and time course of post-treatment unsteadiness or disequilibrium typical of unilateral vestibular ablation are explained. Moreover, the possibility that additional courses of gentamicin may be needed in the future or that surgical ablation may be required to control vertigo is reviewed. The possibility of increased hearing loss, including a profound loss of hearing that would be unaidable, is reviewed. Hearing preservation results from the literature and personal series are discussed. Potential positive and negative effects on aural fullness and tinnitus are explained. Intratympanic aminoglycoside therapy is considered in any patient with disabling vertigo, sensorineural hearing loss (fluctuating or fixed), tinnitus, and aural fullness consistent with unilateral Menires disease that is persistent and refractory to previous medical or surgical management.59 The gentamicin solution is buffered to a pH of 6.4 to reduce the sting associated with intratympanic injection. A buffered solution is prepared as follows: 1.5 mL of gentamicin solution (40 mg/mL) is injected into a sterile 5-mL vial. A 0.6 M sodium bicarbonate solution is prepared by combining 2 mL of 8.4% sodium bicarbonate and 1.36 mL of sterile water in a 5-mL sterile vial; 0.5 mL of the 0.6 M sodium bicarbonate solution is added to the sterile vial containing 1.5 mL of gentamicin to form 2 mL of a solution of gentamicin (30 mg/mi, pH 6.4) ready for injection.

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Patients are comfortably positioned supine with the head turned away from the ear to be treated. This position is maintained for 30 minutes following the injection. Patients are instructed not to swallow or clear the middle ear during this period. A small injection site on the surface of the tympanic membrane is anesthetized with a small drop of phenol and the gentamicin is injected into the middle ear using a tuberculin syringe and a 27-gauge needle. Typically, about 0.5 mL of solution fills the middle ear. One intratympanic injection of approximately 0.5 mL of gentamicin, 30 mg/mL, pH 6.4, is given per week. If weekly audiograms are unchanged, weekly injections are continued to reach a total of four doses (40 to 60 mg total dose). Treatment is stopped early if auditory toxicity is noted. Additional doses are given if vertigo is not controlled or recurred. Because intratympanic aminoglycoside therapy is a nonsurgical outpatient treatment, elderly patients and those with significant surgical or anesthetic risks may be treated safely and thus are primary candidates. Intratympanic aminoglycoside therapy can also be used to avoid additional surgery in patients with recurrent vertigo and a return of caloric function following previous ablative vestibular surgery. Patients with profound hearing loss are good candidates for intensified treatment. The data on efficacy of intratympanic aminoglycoside therapy to control vertigo and its safety in preservation of hearing are almost exclusively from patients with Menires disease. Most patients with non-Menires vestibulopathy have normal hearing. The non-hydropic ear seems to be relatively resistant to the effects of aminoglycosides. For these reasons we do not currently recommend intratympanic aminoglycoside therapy in the primary treatment of vertigo caused by disorders other than Menires disease. Conclusions Intratympanic application of gentamicin frequently results in treatment-related hearing loss, although vertigo is usually well controlled. Patients with recurrent post-treatment vertigo can be treated again. A trend in intratympanic application is to administer one or two doses rather than treating until ototoxicity is clinically evident. Just enough additional doses are applied to achieve control of attacks. The advan-

tages of such titration protocols over fixed-dosage protocols have not been proven in long-term studies. Intratympanic gentamicin should be reserved for patients with classic Menires disease who meet appropriate treatment criteria. Prolonged disabling disequilibrium occurs about as frequently as following surgical labyrinthectomy or vestibular nerve section. Complete ablation and long-term control of vertigo are not achieved as reliably as with surgical labyrinthectomy or vestibular nerve section.75 Riassunto
Gentamicina intratimpanica per la malattia di Menire monolaterale
La malattia di Menire una patologia cronica che colpisce un gran numero di pazienti ogni anno in tutto il mondo. Questa patologia caratterizzata da episodi intermittenti di vertigini che durano da minuti a ore, con perdita delludito sensorineurale fluttuante, tinnito e fullness auricolare. Sebbene attualmente non vi sia una cura, pi dell80% dei pazienti affetti da malattia di Menire giova di cambiamenti dello stile di vita e trattamento medico, mentre il restante 20% richiede procedure chirurgiche mini-invasive come la terapia steroidea intratimpanica, la terapia intratimpanica con gentamicina, e la chirurgia del sacco endolinfatico. La neurectomia vestibolare ha un elevato tasso di controllo della vertigine ed indicata nei pazienti con un buon udito in cui hanno fallito tutti gli altri trattamenti. La labirintectomia rappresenta lultima possibilit e viene riservata per i pazienti con patologia e sordit monolaterale. Questo articolo discute le opzioni di trattamento della malattia di Menire, con enfasi sulla terapia intratimpanica con gentamicina, valutando le basi scientifiche, gli studi sperimentali e unampia revisione della Letteratura.

Parole chiave: Gentamicina - Sindrome di Menire Aminoglicosidi - Vertigini - Disequilibrio.

References
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aminoglycoside ototoxicity demonstrated in outer hair cells. Hear Res 1987;30:11-8. Song B-B, Anderson D, Schacht J. Protection from gentamicin toxicity by iron chelaters in guinea pig in vivo. J Pharmacol Exper Ther 1999;282:369-77. Henley CI, Schacht J. Pharmacokinetics of aminoglycoside antibiotics in inner ear fluids and their relationship to ototoxicity. Audiology 1988;27:137-47. Aran JM, Chappert C, Dulon D, Erre JP, Aurousseau C. Uptake of amikacin by hair cells of the guinea pig cochlea and vestibule and ototoxicity in comparison with gentamicin. Hear Res 1999;82:17983. McGee T, Olszewski J. Streptomycin sulfate and dihydrostreptomycin toxicity. Arch Otolaryngol 1962;75: 295-311. Balough BJ, Hoffer ME, Wester D, OLeary MJ, Brooker CR, Goto M. Kinetics of gentamicin uptake in the inner ear of chinchilla langier after middle-ear administration in a sustained-release vehicle. Otolaryngol Head Neck Surg 1998;119:427-31. Berg K. The toxic effect of streptomycin on the vestibular and cochlear apparatus. Acta Otolaryngol 1951;157:1-77. Park J, Cohen G. Vestibular ototoxicity in the chick: Effects of streptomycin on equilibrium and on ampullary dark cells. Am J Otolaryngol 1982;6:117-27. Pender D. Gentamicin tympanoclysis: effects on the vestibular secretory cells. Am J Otolaryngol 1985;6:358-67. Kimura R, Iverson N, Southard R. Selective lesions of the vestibular labyrinth. Ann Otol Rhinol Laryngol 1988;97:577-84. Smith B, Myers M. The penetration of gentamicin and neomycin into the perilymph across the round window membrane. Otolaryngol Head Neck Surg 1978;87:888-91. Saijo S, Kimura R. Distribution of HRP in the inner ear after injection into the middle ear cavity. Acta Otolaryngol (Stockh) 1999;97:593-610. Goycoolea M, Carpenter A, Muchow D. Ultrastructural studies of the round window membrane of the cat. Arch Otolasyngol 1987;113:617-24. Kawauchi H, DeMaria T, Lim D. Endotoxin permeability through the round window. Acta Otolaryngol (Stockh) Suppl 1988;457:10015. Lundman L, Bagger-Sjbck D, Holmquist L, Juhn S. Round window membrane permeability. Acta Otolaryngol (Stockh) Suppl 1988;457:73-7. Jahnke K. Transtympanic application of gentamicin with cochlea protection. In: Nadol JIB, editor. Second International Symposium on Menires Disease. June 20, 1988. Cambridge, MA, Amsterdam: Kugler & Ghedini; 1988. Lindeman H. Regional differences in sensitivity of the vestibular sensory epithelia to ototoxic antibiotics. Acta Otolaryngol (Stockh) 1969;67:177-89. Cass S, Bouchard K, Graham M. Controlled application of streptomycim to the round window membrane of the cat. Otolaryngol Head Neck Surg 1990;103:223. Hoffer ME, Allen K, Kopke RD, Weisskopf P, Gottshall K, Wester D. Transtympanic versus sustained-release administration of gentamicin: kinetics, morphology, and function. Laryngoscope 2001;111:1343-57. Schuknecht H. Ablation therapy for the relief of Menires disease. Laryngoscope 1956;66:859-70. Schuknecht H. Ablation therapy in the management of Menires disease. Acta Otolaryngol (Stockh) Suppl 1957;132:1-42. Lange G. Gentamicin and other ototoxic antibiotics for the transtympanic treatment of Menires disease. Arch Otorhinolaryngol 1989;246:269-70. Lange G. Isolierte Medikamentose Ausschaltungeines Gleichgewichtsorganes beim Morbus Menire mit Streptomycin-Ozothin. Arch Klin Exp Ohren-Nasen-Kehlkopfheilkd 1999;191:545-9. Lange G. Transtympanic treatment for Menires disease with gen-

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tamicin sulfate. In: Vosteen K-H, Schuknecht HF, Pfaltz CR et al., editors. Menires disease: pathogenesis, diagnosis, and treatment. Stuttgart: Georg Thieme Verlag; 1981. Commins D, Nedzelski J. Topical drugs in the treatment of Menires disease. Curr Opin Otolaryngol Head Neck Surg 1996;4:319-23. Hone S, Nedzelski J. Selective chemical ablation as treatment for Menires disease. In: Harris J, editor. Menires disease. The Hague: Kugler Publications; 1999. p. 381-9. Nedzelski JM, Schessel DA, Bryce GE, Pfleiderer AG. Chemical labyrinthectomy: local application for the treatment of unilateral Menires disease. Am J Otol 1992;13:18-22. Committee on Hearing and Equilibrium. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Menires disease. Otolaryngol Head Neck Surg 1995;113:181-5. Subcommittee on Equilibrium: Menires disease: Criteria for diagnosis and evaluation of therapy for reporting. AAO-HNS Bulletin, 6-7. 7-1985 (Generic). Magnusson M, Padoan S. Delayed onset of ototoxic effects of gentamicin in treatment of Menires disease. Acta Otolaryngol 1991;111:671-6. Beck C, Schmidt C. Ten years of experience with intratympanically applied streptomycin (gentamicin) in the therapy of morbus Menire. Arch Otorhinolaryngol 1978;221:149-52. Youssef T, Poe D. Intratympanic gentamicin injection for the treatment of Menires disease. Am J Otol 1998;19:435-42. Atlas J, Panes L. Intratympanic gentamicin titration therapy for intractable Menires disease. Am J Otol 1999;20:357-63. Driscoll CL, Kasperbauer JL, Facer GW, Harner SG, Beatty CW. Low-dose intratympanic gentamicin and the treatment of Menires disease: preliminary results. Laryngoscope 1997;107:83-9. Bauer PW , MacDonald CB, Cox LC. Intratympanic gentamicin

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therapy for vertigo in nonserviceable ears. Am J Otolaryngol 2001;22:111-5. Marzo SJ, Leonetti JP. Intratympanic gentamicin therapy for persistent vertigo after endolymphatic sac surgery. Otolaryngol Head Neck Surg 2002;126:31-3. Carey J. Intratympanic gentamicin for the treatment of Menires disease and other forms of peripheral vertigo. Otolaryngol Clin North Am 2004;37:1075-90. Boleas-Aguirre MS, Snchez-Ferrandiz N, Guilln-Grima F, Perez N. Long-term disability of class A patients with Mnires disease after treatment with intratympanic gentamicin. Laryngoscope 2007;117:1474-81. Bodmer D, Morong S, Stewart C, Alexander A, Chen JM, Nedzelski JM. Long-term vertigo control in patients after intratympanic gentamicin instillation for Mnires disease. Otol Neurotol 2007;28:1140-4. Hsieh LC, Lin HC, Tsai HT, Ko YC, Shu MT, Lin LH. High-dose intratympanic gentamicin instillations for treatment of Menires disease: long-term results. Acta Otolaryngol 2009;129:1420-4. Salt AN, Gill RM, Plontke SK. Dependence of hearing changes on the dose of intratympanically applied gentamicin: a meta-analysis using mathematical simulations of clinical drug delivery protocols. Laryngoscope 2008;118:1793-800. Nguyen KD, Minor LB, Della Santina CC, Carey JP. Time course of repeated intratympanic gentamicin for Mnires disease. Laryngoscope 2009;119:792-8. Silverstein H, Wazen J, Van Ess MJ, Daugherty J, Alameda YA. Intratympanic gentamicin treatment of patients with Mnires disease with normal hearing. Otolaryngol Head Neck Surg 2010;142:5705. Laitakari K. Intratympanic gentamicin in severe Menires disease. Clin Otolaryngol 1990;15:545-8.

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Intratympanic gentamicin: its effect on hearing and strategies to minimize inner ear damage
L. CITRARO 1, A. DE STEFANO 1, G. KULAMARVA 2, F. DISPENZA 3, A. CROCE
1

Intratympanic gentamicin injection is the easiest and least invasive treatment available for Menires disease as compared to other procedures available today. The most important side effect of this therapy however is sensorineural hearing loss primarily at the high frequencies. Ototoxicity of gentamicin begins at the outer hair cells of the basal turn of cochlea and progresses apically. It can even involve inner hair cells. Hair cell death from ototoxicity can be either necrotic or apoptotic. Many protocols have been developed to reduce gentamicin cochleotoxicity. Among these, low dose and long interval of injections (hybrid) protocols showed the best results with good rates of vertigo control and low rates of hearing loss. Animal experiments have shown many drugs such as iron chelators, antioxidants, and glucocorticoids to be having otoprotective properties. But more research is needed to find reliable otoprotective strategies using these agents. Genetic studies and gene therapy appears to be the new and promising frontier in treating this dreadful sequelae of treating MD. Key words: Gentamicin - Hair cells, auditory - Hearing loss Menires disease.

Istitute, Department of Surgical, Clinical and Experimental Sciences, G. dAnnunzio University of Chieti-Pescara Chieti, Italy 2ENT Clinic, Nayaks Road, Kasaragod, India 3Department of Surgical and Oncological Disciplines University of Palermo, Palermo, Italy

1 ENT

Effect of gentamicin on the inner ear Aminoglycosides are bactericidal aminoglycosidic aminocyclitols. They were the rst class of drugs to have called attention to the problem of ototoxicity.7 Gentamicin, which was discovered in 1963, is one such molecule and is currently the most widely used aminoglycoside.8, 9 Gentamicin, like other aminoglycosides, plays their bactericidal effect by inhibiting bacterial protein synthesis. It binds to the bacterial 30S ribosomal subunit, blocking the initiation of protein synthesis. By doing this, it introduces an error in reading of the mRNA thereby facilitating premature termination of the ongoing translation of mRNA template.10 Individual aminoglycosides differ in their ability to produce cochlear versus vestibular toxicity. Gentamicin, despite the widespread belief that it is selectively toxic to the vestibular system, causes damage to both vestibular and cochlear cells in a dose-dependent manner.11, 12 Plontke 13 established that intratympanically administered gentamicin spreads from the round window membrane to the vestibule via communications

totoxic drugs are frequently used to selectively damage specific cells in the inner ear and thus control the symptoms of Menires disease (MD). Many drugs are known to be having ototoxic properties, such as loop inhibiting diuretics, platinum-based anticancer agents, and aminoglycoside antibiotics. Among these, gentamicin has been the preferred aminoglycoside used for intratympanic administration because of its easy availability, low cost and the low incidence of cochlear damage.1-6
Corresponding author: L. Citraro, MD, Via Sardegna 37, San Cesario di Lecce, Lecce, Italy. E-mail: citraro.leonardo@gmail.com

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Figure 1.Gentamicin hair cell damage (modified from Rybak et al.10). ]). Gentamicin (black) enters into the hair cell and accumulates in lysosome. When lysosomes break, it binds with iron (white box) and produces ROS that activate JNK. JNK activates cell death pathway which in turn triggers explulsion of cyt-c from mitochondria causing apoptosis via caspase.

through the scala rather than by diffusion through the helicotrema. It is cleared from the body via glomerular ltration in the kidney. Gentamicin, in the vestibular part of inner ear, binds with the melanin present in the dark cells of ampullae and stria vascularis.14 Vestibular dark cells are important in creating and maintaining ion homeostasis in the inner ear. In fact, they contain Na-K-adenosine triphosphatase and phospholipids with which gentamicin binds and they play a role in the active transportation of electrolytes in the vestibular labyrinth.15 Gentamicin also alters the permeability of hair cells to Calcium and Magnesium ions, causing their destruction.16, 17 Type I hair cells are damaged more rapidly and severely than type II hair cells.18 These mechanisms are the rationale that justifies use of gentamicin in Menires disease. Inside the cochlea, gentamicin initially damages outer hair cells residing in the basal turn; and then progresses apically eventually damaging the inner hair cells and other supporting cells of the organ of Corti.19 Hair cell damage begins in the base of the cochlea and spreads towards the apex as the dose or duration of treatment increases.20 In other words, dam-

age to the hair cells progresses from an area for high frequency sound detection (the base) to an area for low frequency sound detection (the apex).21 This is followed by retrograde damage to the auditory nerve. Gentamicin enters the hair cells near the apical pole via unknown receptor-mediated endocytosis.22 Action of this specic receptor has been shown to be dependent on the protein- myosin VIIA, a protein involved in cell membrane trafficking.23 Gentamicin accumulates in lysosomes and mitochondria until a cytotoxic level is reached. Lysosomes are cytosolic organelles that serve to incarcerate and digest materials that threaten homeostasis or require recycling. As gentamicin is continuously ingested and collected, the lysosomes may eventually break, allowing cytosolic distribution of the drug to its as yet unknown targets and followed shortly by cell death.24 Hofferw 25 and colleagues 26, 27 explain that there are two different patterns of hair cell death, correlated with the timing and concentration of aminoglycoside delivery: a necrotic pattern associated with rapid and high dose perfusion and an apoptotic pattern associated with slower or chronic perfusion. The aminoglycoside molecule is not toxic by itself but requires the redox-capacity of a transition metal ion in order to induce ototoxicity.7 Several reports have concluded that the generation of reactive oxygen species (ROS), a kind of free radical, is linked to ototoxicity 21 because they induce oxidative damage to biomolecules. Basal outer hair cells appear to be more sensitive to ROS.28, 29 These ROS are thought to be a product of aminoglycosides interaction with iron. Gentamicin binds with iron and the resulting ironaminoglycoside complex is capable of promoting the formation of free radicals from unsaturated fatty acid.30 These ROS are believed to promote apoptotic and necrotic cell death.21 One signaling pathway activated by aminoglycosides via ROS is the c-Jun N-terminal kinase (JNK) pathway that contributes to cell apoptosis by activating genes in the cell death pathway.31 Mitochondria too can be a site of aminglycoside induced damage. In fact their genetic composition suggests that they have evolved from bacteria, possibly making their ribosomes susceptible to injury by aminoglycosides. As an effect of this damage cytochrome c is released, which in turn can trigger apoptosis via caspases.10 Caspases are a family of proteolytic enzymes important in mediating and executing cell death in both the cochlea and vestibular apparatus.

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Mitochondria may also be involved in the patients susceptibility to aminoglycoside ototoxicity. Molecular studies revealed a mitochondrial DNA mutations in the ribosomal RNA and Transfer RNA. Especially, mutations affecting gene 12S rRNA are responsible for a raise in susceptibility to the ototoxicity caused by aminoglycoside antibiotics. Presence or absence of aberrations in this locus play a role both in binding of aminoglycosides and to aminoglycoside resistance.32 These results suggested that certain individuals may be at greater risk of developing hearing loss due to genetic mutations. Hearing loss The prime focus of treatment of Menires disease with intratympanic gentamicin is to control the negative effect the disease has on the quality of life of the sufferer. Hearing loss is an important side effect of this therapy. According to AAO-HNS, hearing deterioration is defined as an increase in pure tone audiogram (PTA) threshold of 10 dB or a 15% deterioration of word recognition in speech audiometry when compared with the pretreatment values.33 Generally, when hearing loss begins to appear treatment with intratympanic gentamicin is stopped. The most appropriate concentration of gentamicin in the inner ear so as to reduce cochleotoxicity may be determined by many factors such as, the frequency of administration, dosage of the drug, delivery methods used, and the end point of gentamicin injections. Based on these reasons several authors have developed different intratympanic gentamicin treatment protocols. In 2004 Chia et al.4 divided the protocols into five different categories: multiple daily dosing technique (delivery, 3 times per day for more than 4 days), weekly dosing technique (weekly injections for 4 total doses), low dose technique (1-2 injections with retreatment for recurrent vertigo), and continuous microcatheter delivery and titration technique (daily or weekly doses until onset of vestibular symptoms, change in vertigo, or hearing loss). They also made a comprehensive comparison of these techniques and found that the titration technique had the best vertigo control rate (effective vertigo control rate:96.3%; complete vertigo control rate: 81.7%) with a moderate rate of hearing loss (24.2%). The weekly technique yielded the lowest hearing loss rate (13.1%) and the

low dose technique also demonstrated a relatively low chance of hearing loss (23.7%). But both these techniques showed worse rates of complete vertigo control and effective vertigo control when compared to the other regimes. It was 75% and 89.3% respectively for weekly technique and 66.7% and 86.8% respectively for low dose techniques. Multiple daily dosing technique resulted in the highest hearing loss rates (34.7%) with comparable results in vertigo control to other techniques. These differences between vestibulotocity and cochleotoxicity are related to death of different cells: in fact at low doses only vestibular hair cells and dark cells are damaged, while at high doses cochear hair cells too are damaged. To obtain a good vertigo control without significant risk to hearing Hybrid protocols have also been introduced.14, 34-37 They combined the features of different standard methods of intratympanic gentamicin administration (i.e. reducing the total dose of gentamicin but increasing the number of the administrations, or reducing the total dose of gentamicin but administering it in 24 hours). These protocols, as reported in the English literature, obtained a good vertigo control (86-90%) and relatively low rate of hearing loss (8-19%). Today these techniques could be a good compromise between vertigo control and risk of hearing loss in the intratympanic gentamicin panorama. The risk of hearing loss is an important problem especially in patients with normal hearing. In 2002 Kaplan et al. described, in a long term period, a better hearing outcome in patients with better pre-treatment hearing.38 Recently Silverstein et al.39 showed that the level of hearing loss after low dose intratympanic gentamicin was lower in patients with better pre-treatment hearing. They found that after treatment, pure tone audiometry was decreased in 33% of patients with pretreatment normal hearing, while in patients with worse pretreatment hearing the decline was demonstrated in 45% of patients. Their results was in accordance with the observations of Kaplan. Otoprotective strategies Once damaged, hair cells do not regenerate. One of the main purposes of research in otology is to find otoprotective strategies to avoid ototoxicity. There is no certain therapy that would alleviate the ototoxic potential of aminoglycosides, but animal experi-

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ments have provided encouraging evidence for the protection of cochlear hair cells.40 Sha and Schacht 41 in 1999 used salicylate to prevent gentamicin damage. Salicylate can act as an iron chelator and antioxidant and in their study they noted that co-treatment significantly reduced outer hair cell loss. Interrupting apoptosis pathways also may protect hair cells. The c-Jun N-terminal kinase (JNK) pathway is one signaling pathway activated by aminoglycosides via ROS. Pirvola et al.42 in 2000 found that a small molecule, CEP-1347, blocks this pathway. Co-treatment with CEP-1347 and aminoglycoside resulted in reduced hair cell DNA fragmentation and thereby in apoptotic cell death. Also dexamethasone, a glucocorticoid, is believed to be useful in preventing aminoglycoside damage. In fact, in 2002 Himeno 43 showed that this drug, co-administred with aminoglycosides, modulate ion transport and immune response in inner ear and reduce outer hair cell death compared to treatment with aminoglycoside alone. A protection from aminoglycoside ototoxicity is possible through reduction of iron availability, using iron chelators like dihydroxybenzoate and desferoxamine. Also antioxidants, such as lipoic acid and d-methionine, showed protection against aminoglycoside induced inner ear damage in experimental animals,44 by preventing free radical formation. Gene therapy is the new frontier in medicine and it also has excellent potential in otoprotective strategies. A variety of neurotrophic factors have been shown to protect cochlear hair cells from aminoglycoside damage. One potential approach for introducing these factors into the inner ear is via gene transfer. Adeno-associated virus-based vectors have been of great interest because they mediate stable transgene expression in a variety of postmitotic cells with minimal toxicity. In 1999 Yagi et al.45 obtained over expression of one of these neurotrophic factors, the glial cell line-derived neurotrophic factor (GDNF), using an adenovirus vector. In this study, ears that were inoculated with the GDNF vector had better hearing and fewer missing hair cells after exposure to the ototoxins, as compared with controls. Another promising study by Pfannenstiel et al.46 showed that bcl-2 delivered in vivo by an adenovector is capable of preventing ototoxicity by aminoglycoside in a mouse model. Bcl-2 gene codes for a

protein that governs the mitochondrial membrane permeability and is involved in matrix ions concentration, pH and mitochondrial voltage. Members of bcl-2 family control the release of cytochrome c into the cytosol, inducing apoptotic cascade. These members of bcl-2 family are divided into 3 subfamilies: Bcl-2, Bax and BH3-only. While Bax and BH3-only subfamilies are responsible for pro-apoptotic effect, Bcl-2 has a pro-survival effect and its overexpression in the auditory system, has been shown to be protective against ototoxicity. Conclusions In conclusion, hearing loss in intratympanic gentamicin therapy is an important side effect which eventually determines the efficacy of the treatment by having to stop the therapy. Risk of hearing loss is present in all protocols, different for dose, mode and frequency of administration. Good results in vertigo control with a low risk of hearing loss has been shown in the hybrid protocols compared to other standard protocols like low dose, weekly dose, titration therapy and others. Therefore they could currently be considered as the best protocols for treating Menires disease even in patients with normal hearing. In any case it is important to emphasize that the treatment is primarily aimed at controlling the vertigo and it is imperative to warn patients about the possibility of side effects, including hearing loss, or the need for further treatment to control vertigo. Furthermore, there are lot of researches currently going on to explore otoprotective strategies that can prevent hair cell death. Many authors have provided encouraging evidence with animal models, using drugs and molecules that stop the mechanism of cochlear cell damage. But probably gene therapy would hold the key for the future in eventually eliminating ototoxicity secondary to the use of aminoglycosides in the inner ear. Riassunto
La gentamicina intratimpanica: suo effetto sulludito e strategie per minimizzare il danno allorecchio interno Liniezione intratimpanica di gentamicina rappresenta il trattamento pi semplice e meno invasivo per la Malattia di Menire, rispetto alle altre procedure ablative chi-

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miche e chirurgiche disponibili. Il pi importante effetto collaterale di questa terapia costituito dallipoacusia neurosensoriale per lo pi sulle frequenze acute. Lototossicit della gentamicina inizia a livello delle cellule ciliate esterne della coclea e si estende verso lapice. Essa pu coinvolgere anche le cellule ciliate interne. La morte delle cellule ciliate pu avvenire per necrosi o apoptosi. Sono stati sviluppati numerosi protocolli per ridurre questa cocleotossicit. Tra questi, i protocolli ibridi (con iniezioni a basse dosi e/o lunghi intervalli di somministrazione) hanno riportato i migliori risultati con buone percentuali di controllo della vertigine e basse percentuali di perdita uditiva. Gli esperimenti animali hanno dimostrato che numerosi farmaci, come i chelanti del ferro, gli antiossidanti e i glucocorticoidi, hanno propriet otoprotettive; tuttavia sono necessari ulteriori studi per identificare sicure strategie otoprotettive utilizzando questi agenti. Oltre a ci, gli studi basati su terapie genetiche potrebbero essere la nuova frontiera nel management delle complicanze uditive della terapia intratimpanica con gentamicina nella Malattia di Menire. Parole chiave: Gentamicina - Cellule ciliate uditive Perdita delludito - Malattia di Menire.

15. 16. 17. 18.

19. 20. 21. 22. 23.

24. 25.

References
1. Fowler E. Streptomycin treatment of vertigo. Trans Am Acad Ophthalmol Otolaryngol 1948;52:239. 2. Schuknect H.Ablation therapy in Mnires disease. Acta Otolaryngol (Stockh) 1957;132(Suppl):1. 3. Beck C, Schmidt CL. 10 years experience with intratympanically applied streptomycin (gentamicin) in the therapy of morbus Mnire. Arch Otolaryngol 1978;221:149. 4. Chia SH, Gamst AC, Anderson JP, Harris JP. Intratympanic gentamicin therapy for Mnires disease: a meta-analysis. Otol Neurotol 2004;25:544-52. 5. Schwaber MK. Transtympanic gentamicin perfusion for the treatment of Menires disease. Otolaryngol Clin North Am 2002;35:287-95, vi. 6. Hirsch BE, Kamerer DB. Intratympanic gentamicin therapy for Mnires disease. Am J Otol 1997;18:44-51. 7. Schacht J. Biochemical basis of aminoglycoside ototoxicity. Otolaryngol Clin North Am 1993;26:845-56. 8. Santucci RA, Krieger JN. Gentamicin for the practicing urologist: review of efficacy, single daily dosing and switch therapy. J Urol 2000;163:1076-84. 9. Minor LB. Gentamicin-induced bilateral vestibular hypofunction. JAMA 1998;279:541-4. 10. Rybak LP, Ramkumar V. Ototoxicity. Kidney Int 2007;72:931-5. 11. Hilton M, Chen J, Kakigi A, Hirakawa H, Mount RJ, Harrison RV. Middle ear instillation of gentamicin and streptomycin in chinchillas: electrophysiological appraisal of selective ototoxicity. Clin Otolaryngol Allied Sci 2002;27:529-35. 12. Wanamaker HH, Slepecky NB, Cefaratti LK, Ogata Y. Comparison of vestibular and cochlear ototoxicity from transtympanic streptomycin administration. Am J Otol 1999;20:457-64. 13. Plontke SK, Wood AW, Salt AN. Analysis of gentamicin kinetics in fluids of the inner ear with round window administration. Otol Neurotol 2002;23:967-74. 14. De Stefano A, Dispenza F, De Donato G, Caruso A, Taibah A, Sanna

26. 27. 28. 29. 30. 31. 32. 33.

34. 35. 36. 37.

M. Intratympanic gentamicin: a 1-day protocol treatment for unilateral Menires disease. Am J Otolaryngol 2007;28:289-93. Hiraide F. The histochemistry of dark cells in the vestibular labyrinth. Acta Otolaryngol 1971;71:40-8. LaFerriere KA, Arenberg IK, Hawkins JE Jr, Johnsson LG. Melanocytes of the vestibular labyrinth and their relationship to the microvasculature. Ann Otol Rhinol Laryngol 1974;83:685-94. Merchant SN, Rauch SD, Nadol JB Jr. Mnires disease. Eur Arch Otorhinolaryngol 1995;252:63-75. Lopez I, Honrubia V, Lee SC, Schoeman G, Beykirch K. Quantification of the process of hair cell loss and recovery in the chinchilla crista ampullaris after gentamicin treatment. Int J Dev Neurosci 1997;15:447-61. Hawkins JE, Johnson LG. Histopathology of cochlear and vestibular ototoxicity in laboratory animals in aminoglycoside ototoxicity. Boston: Little, Brown and Co; 1981. p. 327-39. Forge A, Schacht J. Aminoglycoside antibiotics. Audiol Neurootol 2000;5:3-22. Chen Y, Huang WG, Zha DJ, Qiu JH, Wang JL, Sha SH, Schacht J. Aspirin attenuates gentamicin ototoxicity: from the laboratory to the clinic. Hear Res 2007;226:178-82. Hashino E, Shero M. Endocytosis of aminoglycoside antibiotics in sensory hair cells. Brain Res 1995;704:135-40. Richardson GP, Forge A, Kros CJ, Marcotti W, Becker D, Williams DS et al. A missense mutation in myosin VIIA prevents aminoglycoside accumulation in early postnatal cochlear hair cells. Ann N Y Acad Sci 1999;884:110-24. Hashino E, Shero M, Salvi RJ. Lysosomal targeting and accumulation of aminoglycoside antibiotics in sensory hair cells. Brain Res 1997;777:75-85. Hoffer ME, Balough B, Henderson J, DeCicco M, Wester D, OLeary MJ et al. Use of sustained release vehicles in the treatment of Menires disease. Otolaryngol Clin North Am 1997;30:115966. Li L, Nevill G, Forge A. Two modes of hair cell loss from the vestibular sensory epithelia of the guinea pig inner ear. J Comp Neurol 1995;355:405-17. Lang H, Liu C. Apoptosis and hair cell degeneration in the vestibular sensory epithelia of the guinea pig following a gentamicin insult. Hear Res 1997;111:177-84. Sha SH, Taylor R, Forge A, Schacht J. Differential vulnerability of basal and apical hair cells is based on intrinsic susceptibility to free radicals. Hear Res 2001;155:1-8. Hirose K, Hockenbery DM, Rubel EW. Reactive oxygen species in chick hair cells after gentamicin exposure in vitro. Hear Res 1997;104:1-14. Priuska EM, Schacht J. Formation of free radicals by gentamicin and iron and evidence for an iron/gentamicin complex. Biochem Pharmacol 1995;50:1749-52. Davis RJ. Signal transduction by the JNK group of MAP kinases. Cell 2000;103:239-52. Rizzi MD, Hirose K. Aminoglycoside ototoxicity. Curr Opin Otolaryngol Head Neck Surg 2007;15:352-7. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Menires disease. American Academy of Otolaryngology-Head and Neck Foundation, Inc. Otolaryngol Head Neck Surg 1995;113:181-5. Sala T. Transtympanic gentamicin in the treatment of Menires disease. Auris Nasus Larynx 1997;24:239-46. Atlas JT, Parnes LS. Intratympanic gentamicin titration therapy for intractable Menires disease. Am J Otol 1999;20:357-63. Minor LB. Intratympanic gentamicin for control of vertigo in Menires disease: vestibular signs that specify completion of therapy. Am J Otol 1999;20:209-19. Zhai F, Liu JP, Dai CF, Wang Q, Steyger PS. Evidence-based modification of intratympanic gentamicin injections in patients with intractable vertigo. Otol Neurotol 2010;31:642-8.

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38. Kaplan DM, Nedzelski JM, Al-Abidi A, Chen JM, Shipp DB. Hearing loss following intratympanic instillation of gentamicin for the treatment of unilateral Menires disease. J Otolaryngol 2002;31:106-11. 39. Silverstein H, Wazen J, Van Ess MJ, Daugherty J, Alameda YA. Intratympanic gentamicin treatment of patients with Mnires disease with normal hearing. Otolaryngol Head Neck Surg 2010;142:570-5. 40. Guthrie OW. Aminoglycoside induced ototoxicity. Toxicology 2008;249:91-6. 41. Sha SH, Schacht J. Salicylate attenuates gentamicin-induced ototoxicity. Lab Invest 1999;79:807-13. 42. Pirvola U, Xing-Qun L, Virkkala J, Saarma M, Murakata C, Camoratto AM et al. Rescue of hearing, auditory hair cells, and neurons byCEP-1347/KT7515, an inhibitor of c-Jun N-terminal kinase activation. J Neurosci 2000;20:43-50.

43. Himeno C, Komeda M, Izumikawa M, Takemura K, Yagi M, Weiping Y et al. Intra-cochlear administration of dexamethasone attenuates aminoglycoside ototoxicity in the guinea pig. Hear Res 2002;167:61-70. 44. Lesniak W, Pecoraro VL, Schacht J. Ternary complexes of gentamicin with iron and lipid catalyze formation of reactive oxygen species. Chem Res Toxicol 2005;18:357-64. 45. Yagi M, Magal E, Sheng Z, Ang KA, Raphael Y. Hair cell protection from aminoglycoside ototoxicity by adenovirus-mediated overexpression of glial cell line-derived neurotrophic factor. Hum Gene Ther 1999;10:813-23. 46. Pfannenstiel SC, Praetorius M, Plinkert PK, Brough DE, Staecker H. Bcl-2 gene therapy prevents aminoglycoside-induced degeneration of auditory and vestibular hair cells. Audiol Neurootol 2009;14:254-66.

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Management of Menires disease with intratympanic steroids

V. PISTORIO, V. ACHILLI

We made a review of the english-language literature to evaluate the efficiency, optimum dosage and administration schedule of intratympanic corticosteroid therapy in Menires disease patients as an alternative to more aggressive therapies, given the evidence that in many cases the underlying etiology and pathophisiology is inflammatory. Results of the up to now published studies are difficult to interpret in that none of them completely meets the requirements of a clinical drug study. For this reason, even if a certain efficacy of intratympanic corticosteroid administration is likely, further investigations are required with controlled, randomised, double-blind trials to get more precise data. Key words: Menires disease - Intratympanic corticosteroid Endolymphatic hydrops.

Division of Otolaryngology Ospedale Maggiore, Lodi, Italy

enires disease is a clinical disorder of the inner ear whose underlying pathophysiologic condition is endolymphatic hydrops and whose major clinical signs and symptoms are recurrent, spontaneous spells of vertigo of at least 20 minutes or longer, associated with nausea, retching and vomiting, progressive sensorineural hearing loss which is often fluctuating and sometimes associated with diplacusis and intolerance of loudness, tinnitus and aural fullness or aural pressure. At the end of vertigo spells a disequilibrium that may last several days is usually present. Most of the times all these symptoms are present simultaneously, whereas in some patients auditory or vestibular symptoms alone can represent the
Corresponding author: dr. V. Pistorio, Division of Otolaryngology, Ospedale Maggiore di Lodi, Viale Savoia 2, 26900 Lodi, Italy. E-mail: vpistorio@yahoo.it

one and only clinical manifestation of the disease for a long time until a full-blown Menires syndrome appears. For this reason it is possible to separate two subsets of the disease: a typical one in which the patient presents with the complete clinical manifestations and an atypical one whose clinical presentation is limited to the vestibular or cochlear compartment. No single test has enough sensitivity and specificity to definitively allow its identification, thus Menires disease diagnosis is mainly anamnestic and made after exclusion of a multitude of central and peripheral lesions causing vertigo and perceptive hearing impairment (Tables I, II). Pathophisiology The pathophysiologic basis of this syndrome seems to be an endolymphatic hydrops which likely develops in genetically predisposed patients on a multifactorial basis. A genetic predisposition with an autosomal dominant pattern with 61% penetrance in 41 families with more than one member affected by Menires disease has been demonstrated by Morrison.1 Endolymph is mainly produced in the stria vascularis and slowly absorbed in the endolymphatic duct and sac by a biologically active transport sys-

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Table I.Central lesions responsible of vertigo and/or tinnitus and/or hearing loss. Inflammatory Meningitis Encephalitis Cerebral abscesses Expansile lesions Tumours of the CNS Arachnoid cysts Congenital cholesteatomas Vascular AICA aneurisms PICA lesions Basilar artery insufficiency Traumatic Systemic Toxins Multiple sclerosis

Table II.Peripheral lesions responsible of vertigo and/or tinnitus and/or hearing loss. Middle ear otitis Labyrinthitis Vestibular neuronitis Cochlear ischemia Otosclerosis Benign tumors such as glomus Temporal bone fractures Labyrinthine concussion BPPV

tem. (An anatomic description of the inner ear is beyond the purpose of this article). The most popular etiopathogenetic theory sees Menires disease as the consequence of a hydrops of the membranous labyrinth due to excessive endolymphatic fluid. This is Paparellas lake, river, pond concept 2, 3 also exemplified by the faucet, sink and drain analogy of da Costa et al.4 This hydrops of the membranous structures of the inner ear could be attributable either to a mechanical obstruction (which could be congenital as in the case of Mondinis dysplasia, or acquired as it is after some kind of head trauma with temporal fracture or secondary to endoluminal deposition of cellular debris) or to a chemical-based alteration of the productionreabsorption mechanism of the endolymph. In both cases, as a direct consequence of an overdistension of the membranous labyrinth, a progressive thinning, atrophy and rupture of its walls would develop with spillage of the neurotoxic potassium-rich endolymph

in the perilymphatic space, where the delicate neural structures would suffer so that sudden hearing loss and vertigo would appear. Restoration of the normal chemical composition of the perilymph would be followed by spontaneous healing of the fistulae and resolution of the clinical symptomatology.5 Currently there is no large agreement on this topic, because the pathophysiology of this syndrome is still largely unclear. Some have contested this theory arguing that this mechanism would need simultaneous ruptures in both the anterior and posterior membranous labyrinth to justify concurrent perceptive hearing loss and vertigo seen in the full-blown Menires disease, and many histopathologic reports do not show this. An alternative explanation is that of Vosteen and Morgensteen,6 who considered the altered equilibrium between produced and reabsorbed endolymph to be the primum movens in the genesis of the clinical signs and symptoms of the disease, suggesting that ruptures could alleviate, rather than precipitate vertiginous crises. A more interesting and recent pathophysiologic theory for Menires disease describes the endolymphatic sac as being able to sense changes in volume and pressure of its endoluminal fluids, whose longitudinal flow towards the sac is normally regulated by osmotic gradients, and secretion of a natriuretic hormone called saccin, as well as glycoprotein conjugates and proteoglycans.7 The latter would act by an osmotic mechanism, attracting endolymph before a narrowing of the endolymphatic duct due to cellular debris deposition.8 The saccin would, conversely, augment the production of endolymph. As a direct consequence there would be a progressive increase of the pressure behind the obstruction, and eventually, the debris would be cleared. The abrupt movement of the endolymph would likely generate the acute vestibular symptoms. Late stage resolution of vertigo attacks would depend on ceasing of endolymphatic sac function. For this reason the endolymphatic sac appears as a very complex structure of the inner ear, provided with a very active ultrastructure to guarantee a high endolymph turnover rate, which is necessary to remove debris from its lumen and from the cochlea. Similarly, nowadays the old belief that the endolymphatic sac is an organ devoid of immune-response has been totally changed, since its ability to process antigens and locally mount an antibody and cellular

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reaction has been definitely demonstrated.9-11 Focal inflammation sustained by mononuclear cells (the so called endolymphatic sacitis),12 and by autoantibodies to the endolymphatic sac 13 are, together with the demostration of IgG deposits in endolymphatic sac 14 and experimental description of corticosteroid receptors within the inner ear,15 among the most interesting elements for hypothesising that Menires disease could be caused by immunological alterations. Under these premises many authors are studying Menires disease as an autoimmune pathology, whose inflammatory pathophysiology would also be suggested by some other considerations, such as the frequent bilaterality, the wax and wane tendency, the strict association with psycho-physical stress. McCabe was the first who suggested an immunologic pathogenetic mechanism for Menires hydrops 16 and clinical and laboratory results have supported this concept, by demonstrating circulating immune complexes of inner ear antigens and their antibody counterparts in 55% of Menires patients and in only 3% of controls. Some investigators have also reported allergy as an etiologic factor.9, 10 Other investigators try to relate hydrops in Menires disease with some inflammatory toxin generated during chronic otitis media and passed to the inner ear via the round window membrane. Moreover, chronic otitis media could lead to developmental anomalies such as periaqueductal hypocellularity, reduced mastoid-air complex and dimensional reduction of Trautmanns triangle with a possible displacement and a stricture of the endolymphatic duct and sac and alteration of their blood supply.2 Intratympanic management with corticosteroids In the light of increased evidence of Menires disease inflammatory autoimmune phatophysiology, corticosteroid intratympanic therapy is appealing as a valid alternative to systemic treatment and most of all, as an effective substitute for chemical or surgical labyrinthectomy and vestibular neurectomy. The conceptual basis of this way of infusion is the existence of a blood-labyrinth barrier which would be comparable to the blood-brain barrier. The most popular and cited studies related to direct application of corticosteroid drugs into the middle ear are those of Shea and Silverstein.17, 18 They postulated the possibility of having an en-

hanced clinical effect based on the semipermeability of the round window membrane within which the transport of the steroid would take place by means of a pinocytoic mechanism. Alternative routes of entrance could be the annular ligament of the oval window, and blood and lymphatic vessels. The perilymphatic concentration of dexametasone after intratympanic administration is much higher than that after systemic injection.19 An ion or water transport mechanism could be responsible for the amelioration of hearing loss and vertigo after topical intratympanic corticosteroid therapy as was suggested by True et al.16 in their study on mice with a genetically-based progressive stria vascularis dysfunction and hearing loss which improved after corticosteroid injection. The main advantages of intratympanic corticosteroids compared to endovenous infusion are low complication rate, higher inner ear concentration, higher selectivity of action, given the possibility of acting just on the single ear in monolateral cases, and avoidance of its systemic side effects. It is also less expensive than endolymphatic sac shunt and seems to be a good therapeutical choice for patients whose initial dietary and medical treatment have failed, and for those who are in a poor general condition and refuse a surgical operation. The steroid most frequently used for intratympanic injections is dexamethasone. Some studies evaluated the efficacy of dexamethasone, hydrocortisone and methylprednisolone in guinea pigs.20 Even if methylprednisolone reached the highest concentrations for the longest time both in endolymph and perilymph, on clinical application its use was often negatively affected by the burning discomfort many patients referred in the ear or the throat after its administration. Moreover, dexamethasone is preferred to methylprednisolone in that it is one of the most powerful corticosteroids, it is the longest acting, and causes less sodium retention. Usually the amount of drug instilled in the middle ear is between 0.5 and 0.8 ml, which means the quantity necessary to completely fill the tympanic cavity. Reports in the international literature not only differ about the type of steroid tested but also the injection technique applied and the strength of the solution. The latter can vary significantly among different studies: from 2-4 mg/mL 19 to 24 mg/mL dexametasone 21 and from 32 mg/mL 22 to 62.5 mg/mL methylprednisolone.23

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Intratympanic administration of steroids can be done by one of several techniques available. The patient is usually kept in a supine position with the head turned to the contralateral side and specifically requested not to swallow if not strictly necessary, thus maintaining the steroid in the middle ear as long as possible. The most popular technique of administration allows tympanic cavity filling under microscopic vision through a transtympanic injection with local anaesthesia and a 1 mL tuberculintype syringe loaded with the drug and a 23-25-gauge needle attached to it. A second tympanic incision is sometimes done to allow the air to escape. Some authors prefer to insert a T-type transtympanic pressure equalizing tube into the miringotomy incision, to allow multiple injections into the middle ear, thus alleviating the necessity to perform a new miringotomy incision for each subsequent administration.24 Delivery can also be accomplished through a wick placed in a myringotomy or through an implantable pump which guarantees a constant infusion. Sometimes corticosteroid were directly injected onto an absorbable gelatin sponge positioned in the round window niche, as carried out by Arriaga and Goldman,25 and Silverstein et al.26 Another way of administration is opening the middle ear either with a laser-assisted-tympanostomy as described in Sheas and Silversteins original reports, or by a tympanomeatal flap. Both modalities allow a direct inspection of the round window region which was reported to be completely obstructed by fibrotic adherences in 12% of cases.27 These adhesions, which required removal in Silversteins experience, were, by contrast, not removed by other authors, who did not consider them an obstacle to the diffusion of the drug.20 Similarly, a large difference in the literature exists between the length of time and number of injections of the treatment, ranging from a single day 24 to multiple weeks with self-administered drops 29 based on variations of the audiograms. Results of corticosteroid injection as reported in literature are difficult to interpret as published protocols of transtympanic treatment are not uniform in that no study strictly meets the requirements of a clinical drug trial due to the small population size or differences in inclusion-exclusion criteria and study set-up. For this reason the role and efficacy of corticosteroid for intratympanic injection in Menires disease therapy is still a matter of debate, Sheas and

Silversteins initial enthusiasm in 1996 has gradually been substituted by a more prudent attitude. In his 1996 original series Shea reported an overall 68% hearing improvement after combined treatment with intratympanic and intravenous dexametasone with 98% vertigo control.17 One year later, his updated series showed less efficacy since vertigo control decreased to 63% and, more evident, hearing improvement dropped to 35%.30 Similarly, after an initial reported 43% hearing improvement in nine patients treated with intratympanic steroids for inner ear disease and tinnitus in 1996,18 the results of a prospective, randomised, double-blind, crossover trial in 20 patients with stage IV unilateral Menires disease in 1997 conducted by Silverstein were less encouraging, showing no benefit over placebo for treatment of the same symptoms.26 In 1998 Arriaga and Goldman conducted a retrospective study on 14 patients who, after failure of a low-salt, low-caffeine diet and diuretic therapy, were offered intratympanic steroids as an alternative to endolymphatic-mastoid shunt, labyrintectomty and vestibular neurectomy for uncompensated Menires disease. They were injected into the middle ear with a mixture of 8 mg dexametasone in hyaluronan with a total volume of approximately 1 mL through a tympanomeatal flap elevation in a single application. Short-term outcomes of this study, evaluated in relation to post-treatment results, did not show any dramatic improvement. However, as suspected by the same authors, it is probable that the results could be related to the extremely short duration of treatment and, in fact, after 5 years another report from the same group 31 showed hearing improvement in 40% of 50 patients affected by cochlear hydrops and treated with one to three intratympanic injections of dexamethasone with an average of 14.2 decibels hearing gain. A retrospective chart review published in 2003 32 showed a low rate (24%) of control of 34 patients affected by Menires disease treated with intratympanic highly concentrated dexamethasone (10 mg/ mL) with a single course of weekly injections over a month, versus 47% of long-term vertigo control after repeated injections were performed from the first month on, suggesting that multiple courses of intratympanic administration of steroids, together with diet restrictions and diuretics, are necessary for a large part of patients with Menires disease, but

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also not ruling out a placebo effect or that the natural history of the disease (which improves over time) could itself be responsible for the amelioration. The most adequate duration of therapy is, in fact, one of the most debated issues. Better results are documented in the literature for a more prolonged therapeutic protocol as reported in the 2005 prospective double blind study of Garduno-Anaya MA et al.,33 who achieved complete control of vertigo spells in 82% of 22 patients with unilateral Menires disease after 5 consecutive days of once a day intratympanic injection of a dexamethasone solution 4 mg/mL versus 57% of patients in the control group. Subjective improvement in hearing loss and tinnitus was more disappointing, because it was obtained only in 37% and 48% of patients respectively. The same authors suggest that inner ear perfusion should be repeated every year on average. Similar results on vertigo control were obtained in another study about effects of the same concentration dexamethasone injection as the only drug employed intratympanically once or twice a week for 4-5 weeks.34 However, in that case, tinnitus ameliration was reported as excellent in 45% of patients and good in 29%. Another cause of debate is the optimal concentration of the steroid. It seems that, the more concentrated the steroid solution, the bigger its impact on both vestibular and cochlear functions, as could be argued by 90% reported hearing improvement and vertigo control in a study made by Hamid et al., who used a 24 mg/mL dexamethasone solution on 60 patients affected by Menires disease.35 Moreover, taking into consideration the longitudinal follow-up of the pathology, the real efficacy of any treatment is doubtful with respect to its natural history.36-38 In the literature there are many confounding variables that make the interpretation of data difficult and disturb the comparison of results between different studies. Among these there are the significant differences related to the modality of administration, since many studies add to the intratympanic injection also an oral or intravenous perfusion, and some tricks in intratympanic topical applying of the steroid, as for example, the application of a ventilation tube. Montandon et al, in fact, stated that there is a placebo effect of the ventilation tube insertion in the affected ear, preventing vertigo spells in 71% of patients and reducing the frequency of attacks in 11%.39

Conclusions Globally, evidence from literature suggests that intratympanic steroid infusion (mostly dexamethasone) is a valid and practical therapeutic alternative to most ablative and invasive treatments such as endolymphatic-mastoid shunts, labyrinthectomy and even intratympanic gentamicin administration. An attractive therapeutic algorithm is that proposed by Sennaroglu,40 for whom initial treatment of a Menire patient should be a conventional medical one. Non responding patients should then undergo intratympanic infusion of corticosteroid after 6 months. If, after 3 more months of steroid administration no significant improvement is reported, then an intratympanic gentamicin infusion is to be done, particularly in those patients with a profound perceptive hearing loss. Endolymphatic sac decompression is suggested for patients with a good, serviceable hearing, who, in case of failure of the sac shunt, can be addressed to vestibular nerve section. On the contrary, patients with non serviceable hearing should benefit from a labyrinthectomy. Riassunto
Trattamento della malattia di Menire con steroidi intratimpanici Gli autori hanno condotto una revisione della letteratura di lingua inglese per valutare lefficacia, il dosaggio ottimale e la modalit di somministrazione della terapia corticosteroidea intratimpanica in pazienti affetti dalla malattia di Menire, in alternativa a terapie pi aggressive, poich in numerosi casi la sottostante etiologia e fisiopatologia infiammatoria. I risultati degli studi finora pubblicati sono difficili da interpretare poich nessuno di questi soddisfa completamente le richieste di uno studio clinico farmacologico. Per tale motivo, sebbene sia probabile una certa efficacia della somministrazione intratimpanica di corticosteroidi, ulteriori studi controllati, randomizzati, in doppio cieco sono necessari per ottenere dati pi precisi. Parole chiave: Malattia di Menire - Corticosteroidi intratimpanici - Idrope endolinfatico.

References
1. A.W. Morrison, Anticipation in Menires disease. J Laryngol Otol 1995;109:499-502. 2. Paparella MM, Costa SS, Fox R, Yoo TH. Menires disease and other labyrinthine diseases. In: Paparella MM, Shumrick DA,

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3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16.

17. 18. 19. 20. 21. 22.

Gluckmann J, Meyerhoff WL, editors. Otolaryngology, vol. II: Otology. 3rd edition. Philadelphia: WB Saunders; 1991. p. 1689714. Paparella MM. The natural course of Menires disease. In: Filipo R, Barbara M, editors. Proceedings of the Third International Symposium on Menires Disease. Amsterdam: Kugler; 1994. p. 9-20. Da Costa SS, Alves de Sousa LC, Ribeiro de Toledo Piza Marcelo. Menires disease: overview, epidemiology and natural history. Otolaryngol Clin N Am 2002;35:455-95. Schuknecht HF. Pathology of the ear. Cambridge (MA): Harvard University Press 1991. Vosteen KH, Morgensteen C. Biochemical aspects of inner ear pathophysiology. In: Pfaltz CR, editor. Controversial aspects of Menires disease. New York: George Thieme; 1986 pp. 688-705. Wackym PA, Sando I. Molecular and cellular pathology of Menires disease. Otolaryngol Clin N Am 1997;30:947-60. Gibson WPR, Arenberg K. Pathophysiologic theories in the etiology of Menires disease. Otolaryngol Clin N Am 1997;30:961. Derebery J. Allergic management of Menires disease: an outcome study. Otolaryngol Head Neck Surg 2000;174-82. Derebery J, Rao S, Siglock TJ, Linthicum FH, Nelson RA. Menires disease: an immune complex-mediated illness? Laryngoscope 1991;101:225-9. Ruckenstein MJ. Imunologic aspects of Menires disease. Am J Otolaryngol 1999;20:161-5. Danckwardt-Lilliestrm N, Friberg U, Kinnefors A. Endolymphatic sacitis in a case of active Mnires disease. A TEM histopathological investigation. Ann Otol Rhinol Laryngol 1997;106:190-8. Alleman AM, Dornhoffer JL, Arenberg K. Demonstration of autoantibodies to the endolymphatic sac in Mnires disease. Laryngoscope1997;107:211-5. Dornhoffer JL, Waner M, Arenberg IK. Immunoperoxidase study of the endolymphatic sac in Mnires disease. Laryngoscope 1993;103:1027-34. Rarey KE, Lohius PJ. Response to the stria vascularis to corticosteroids. Laryngoscope 1991;101:1081-4. True DR, Kempton JB, Kessi M. Aldosterone (mineralcorticoid) equivalent to prednisolone (glucocorticoid) in reversing hearing loss in MRL/MpJ-Fas 1 pr autoimmune mice. Laryngoscope 2000;110:1902-6. Shea JJ, Ge X. Dexamethasone perfusion of the labyrinth plus intravenous dexamethasone for Menires disease. Otolaryngol Clin North Am 1996;29:353-8. Silverstein H, Choo D, Rosenberg SI, Kuhn J, Seidman M, Stein I. Intratympanic steroid treatment of inner ear disease and tinnitus (preliminary report). Ear Nose Throat J 1996;75:468-71. Chandrasekhar SS. Intratympanic dexamethasone for sudden sensorineural hearing loss: clinical and laboratory evaluation. Otol Neurotol 2001;22:18-23. Parnes LS, Sun AH, Freeman DJ. Corticoisteroid Pharmacokinetics in the inner ear fluids: an animal study followed by clinical application. Laryngoscope 1999; Suppl 91:1-17. Gianoli GJ, Li JC. Transtympanic steroids for treatment of sudden hearing loss. Otolaryngol Head Neck Surg 2001; 125:142-6. Lautermann J, Sudhoff H, Junker R. Transtympanic corticoid therapy

23. 24. 25. 26.

27. 28. 29. 30. 31. 32. 33.

34. 35. 36. 37. 38. 39. 40.

for acute profound loss. Eur Arch Otorhinolaryngol 2005;262:58791. Lefebvre PP, Staecker H. Steroid perfusion of the inner ear for sudden sensorineural hearing loss after failure of conventional therapy: a pilot study. Acta Otolaryngol 2002;122:698-702. Barrs DM, Keyser JS, Stallworth C, McElveen JT. Laryngoscope 2001;111:2100-4. Arriaga M, Goldman S. Hearing results of intratympanic steroid treatment of endolymphatic hydrops. Laryngoscope 1998;108(11 Pt 1):1682-85. Silverstein H, Isaacson J, Olds M, Rowan P, Rosenberg S Dexamethasone inner ear perfusion for the treatment of Menires disease: a prospective, randomized, double-blind, crossover trial. Am J Otol 1998;19:196-201. Silverstein H, Rowan P. Inner ear injection and and the role of round window patency. Am J Otol 1997;18:586-9. Slattery WH, Fisher LM, Iqbal Z, Friedman RA, Liu N. Intratympanic steroid for the treatment of sudden hearing loss. Otolaryngol Head Neck Surg 2005;133:251-9. Herr BD, Marzo SJ. Intratympanic steroid perfusion for refractory sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2005;132:527-31. Shea JJ. The role of dexametasone or streptomycin perfusion in the treatment of Menires disease. Otolaryngol Clin North Am 1997;30:1051-9. Hillman TM, Arriaga MA, Chen DA. Intratympanic steroids: do they acutely improve hearing in cases of cochlear hydrops? Laryngoscope 2003;113:1903-7. David M. Barrs. Intratympanic Injections of Dexamethasone for Long-Term Control of Vertigo. Laryngoscope 2004;114:1910-4. Garduo-Anaya MA, Couthino De Toledo H, Hinojosa-Gonzlez R, Pane-Pianese C, Ros-Castaeda LC, PhD. Dexamethasone Inner Ear Perfusion by Intratympanic Injection in Unilateral Mnires Disease: A Two-year Prospective, Placebo-Controlled, Doubleblind, Randomized Trial. Otolaryngology-Head and Neck Surgery 2005;133:285-294. Itoh A, Sakata E. Treatment of vestibular disorders Acta Otolaryngol 1991;481(suppl):617-23. Hamid MA. Intratympanic dexamethasone perfusion in Mnires disease. Presented at the spring meeting of the American Neurotology Society, Palm Desert, CA, May 2001:12. Quaranta A, Marini F, Sallustio V. Long-term outcome of Mnire disease: endolymphatic mastoid shunt versus natural history. Audiol Neurootol 1998;3:54-60. Green JD Jr, Blum DJ, Harner SG. Longitudinal follow-up of patients with Mnire disease. Otolaryngol Head Neck Surg 1991;104:7838. Silverstein H, Smouha E, Jones R. Natural history vs. surgery for Mnire disease. Otolaryngol Head Neck Surg 1989;100:6-16. Montandon P, Guillemin P, Husler R. Prevention of vertigo in Mnires syndrome by means of transtympanic ventilation tubes. ORL J Otorhinolaryngol Relat Spec 1988;50:377-81. Sennaroglu L. Intratympanic dexamethasone, intratympanic gentamicin, and endolymphatic sac surgery for intractable vertigo in Mnires disease. Otolaryngol Head Neck Surg 2001;125:537-43.

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Intratympanic management of tinnitus: illusions and hopes

C. A. OLIVEIRA, M. F. S. ARAJO, A. L. L. SAMPAIO

Claudius Galeno of Pergamus who was a master in anatomy and physiology advocated delivering medications to the outer and middle ear to treat diseases of the ear (130-200 AD). In our time Schuknecht in 1956 was the first to use streptomycin intratympanic for the treatment of Menires disease. However, the incidence of deafness was very high. Two decades later Beck and Schmidt used gentamycin for vestibular ablation in Menires disease patients and by carefully titrating the dosis they were able to low the incidence of hearing loss. This and others reported successes led investigators to use several intratympanic drug injections to treat tinnitus. Lidocaine, had been shown to suppress tinnitus when injected systemically and was also tried in the intratympanic route. Aminoglicosides and steroids, were also tried for treatment of tinnitus, sudden sensori-neural hearing loss and autoimmune deafness. Neuroactive drugs also have been used to treat tinnitus using the intratympanic route. While there have been many reports optimistic about the intratympanic route for drug delivery in the treatment of tinnitus up to now this method of treatment is still controversial and no specific drug has been shown to be consistently effective when injected intratympanically. This report will present the evidences reported in the literature and try to sort out what is illusion what is supported by facts and what hopes we can have for the future in this field. Key words: Ear diseases - Lidocaine - Tinnitus.

Department of Otolaryngology, Braslia University Medical School, Braslia, DF, Brasil

innitus is a complex symptom that may have different causes both peripheral and central.1 It is important however to recognize objective and subjective tinnitus as these two categories have different etiologies and the former is caused by identifiable
Corresponding author: C. A. Oliveira MD, PhD, SHIS QL 22 Conjunto 4 Casa 9, Braslia, DF, Brasil. E-mail: cacpoliveira@brturbo.com.br

and treatable causes while the latter usually has no clear cut etiology and involves complex interactions in the central nervous system.2 Next it is necessary to separate the symptom that has low intensity and low level of annoyance and is present in over 90% of the population when placed in a soundproof room3 from the tinnitus that is intense, annoying and disrupts the normal activities of the patient lowering his quality of life. The latter Shullman called severe disabling tinitus (SDT).4 It stands to reason that the great majority of patients who will say they have tinnitus if you ask them do not need any specific treatment for the symptom. We have made a study in our Otology Clinic at Hospital Universitrio de Braslia trying to identify all patients with tinnitus visiting the clinic in 2 years time interval. Of 500 patients with tinnitus only 5% had the symptom in the severe disabling level.5 The great majority of them would not mention the symptom spontaneously. This is said in order to make a point which we believe is fundamental: tinnitus treatment have to be tested on patients with SDT in order to be recognized as an effective one. Intratympanic drug injection was already mentioned by Claudius Galeno of Pergamo in the ancient Rome (130-200 AD) as reported by Politzer

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in 1981.6 However Schuknecht in 1956 was the first Otologists of our days to use the intratympanic route to treat Menires disease.7 He used streptomycin and obtained good results in relieving vertigo but severe hearing loss occurred in the majority of treated patients. In 1957 Schuknecht 8 treated 8 patients with Menires disease using streptomycin by the intratympanic route. He cured the vertigo in 5 patients but all of them developed severe sensorineural hearing loss. The intratympanic route was then put to rest for the next two decades. In 1978 Beck and Schmidt 9 reported their results with gentamycin using the intratympanic route for vestibular ablation in Menires disease patients. They cured 98% of the patients of their vertigo but 58% of them had severe sensorineural hearing loss. They then adjusted the dosis of gentamycin controlling the effects in the vestibule and in the hearing as they went along. This time they obtained 92.5% of cure of vertigo and only 15% of sensorineural hearing loss. Today intratympanic drug injections to treat inner ear diseases has become a popular method.10-18 Indeed intratympanic gentamycin injection is today the first line of treatment for vertigo in Menires disease patients.19 By injecting a drug into the middle ear one treats directly the affected ear, obtains a higher concentration of the drug in the inner ear, systemic efects of the drug are avoided. The technique is easy to perform, minimally invasive and can be performed in the Office. One must have in mind however that the drug will affect only the inner ear so that in order to be succesfull the pathologic process must be occuring in the inner ear only. As vertigo in Menires disease is indeed due to pathological process in the labyrinth gentamycin destroying the labyrinth cures the symptom. Based on the succes in treating vertigo in Menires disease intratympanic drug injections have been used to treat other diseases of the inner ear: sudden sensorineural hearing loss, autoimmune sensorineural hearing loss, and hearing loss associated with Menires disease 19 with some success. All these diseases display strong evidence for being strictly inner ear pathological processes. Based on the evidences reported above tinnitus has also been treated with intratympanic drug injections. The drugs used to treat tinnitus are lidocaine, gentamycin, steroids and neuroactives agents.20 Ster-

oids and gentamycin have been the foremost drugs used for intratympanic injections in the treatment of tinnitus. The techniches used for intratympanic injections of drugs vary from simple injection of the drug with a needle into the middle ear to the use of sustained release devices, like the Silverstein MicroWick (Micromedics, Eaton, MN, USA) and the round window Microcatheter (Durect Corporation, Cupertino CA, USA). The general idea is to deliver the drug to the round window niche so it can reach the inner ear in the most effective way.19 Round window membrane (rwm) permeability It is pertinent to understand the permeability of the round window membrane (RMW) in order to understand the inner ear concentration of drugs injected in the middle ear. Being the only membranous structure separating the midle ear from the inner ear the RWM is the obvious point of entry for substances to the inner ear. The permeability of the RWM is regulated by factors related to the structure of the RWM like its thickness, its structural components and the charge barrier in the cell surface of the membrane.21 Also the characeristics of the substances like their molecular weight, their concentration in the middle ear space and their electrical charges are important. Scar tissue from previous infections and granulation tissue in the RWM niche also are important in determining RWM permeability. Saijo 21 injected horseraddish peroxidase (HRP) in the middle ear of guinea pigs and showed that HRT reaction products were not only in the sensori cells of the vestibule and cochlea but also in the lumen of the endolymphatic sac (ELS). Goycoolea in 1978 22 described the normal RWM structure in the cat and later described the changes occurring in this structure in otitis media.23 Goycoolea ET AL. in 198024 studied in detail the permeability of the RWM of cats in otitis media. These studies showed clearly that the RWM is indeed permeable to substances injected into the middle ear and that: 1) this permeability depends on the struture of the menbrane and; 2) the characteristics of the substance injected. Even macromolecules (HRP) were shown to cross the RMW from the middle to the inner ear.

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Although the intratympanic route was used before these studies came out7,8,9 they established scientific basis for the intratympanic route of medications to the inner ear. Techniques used for the intratympanic delivery of drugs Many protocols exist for repeated injections of medicines into the middle ear. The patient is placed supine with the head turned away from the ear to be treated. Anesthesia can be achieved with topical tetracaine solution mixed with alcohol and applied to the ear canal for some 8 minutes,25 by topical phenol applied to the posterior central part of the tympanic membrane 26 or by ear canal injection with 1% lidocaine with 1:100000 epinephrine buffered in 10% sodium bicarbonate to reduce stinging. The treating solution is then injected into the middle ear using a tubercilin syringe with a long 25 or 27 gauge needle. A volume of 0.3 to 0.5 mL usually fills the middle ear and the injection is made in the postero-inferior region of the tympanic membrane. A hole can be made in other place to allow air to leave the middle ear but this is not consensual. The patient must remain for 30 to 45 minutes supine with the head turned away from the ear treated. Some use an indwelling tympanostomy tube in the posterio-inferior quadrant of the tympanic membrane, others 13, 14 make a myringotomy in the posterior inferior quadrant and insert a T tube connected to a butterfly catheter that stays for the duration of the treatment. According to the protocol of Nedzelski et al.14, 15 the medicine is delivered once daily in the office and twice daily at home for four consecutive days. The patient is examined on a daily basis for nystagmus, deterioration of tanden gait, and worsening of the bone conduction audiometry of more than 10 db in three consecutive frequencies. Other protocols are designed for long term follow up. Harner et al.24 recommend to see the patient on a biweekly to monthly basis and question the patients about changes in the symptoms and do an audiometry and electronystagmography (ENG) during each visit. A judgement about the need for further courses of treatment can be then made. Injections onto materials placed in the round window niche can be made.19 This technique requires a

formal tympanotomy with exposure of the round window niche, removal of adhesions and pseudomembranes of the niche and placement of dry gelfoam in the round window niche. The middle ear space is then filled with 0.3 to 0.5 mL of the medicine being used. The Idea is to concentrate the substance in the niche and deliver more of the medicine to the inner ear in a sustained way. The microcatheter sustained delivery system aims at maintaining a Constant and uniform delivery of the medicine to the round window so that the concentration of the drug in the iner ear is kept constant and peaks of concentration that could be ototoxic are avoided. In order to insert the microcatheter the patient has to be taken to the operating room and be submitted to general anesthesia.27 A tympanomeatal flap is elevated and the round window niche is exposed and cleared of pseudomembranes or fibrosis so that the appropriately sized microcatheter can be locked in the niche. The catheter attached to the niche is left laying in the external canal and the tympanomeatal flap is replaced over the catheter. The catheter is connected to an electronic pump that will pump the microdosis of medicine in a constant and sustained way. The Silverstein MicroWick is also conceived to deliver medicine to the round window in a sustained and constant way. The placement of this device do not require general anesthesia and can be done in an ofice minor surgery room and delivers the medicine to the round window membrane in a precise and direct way.28-30 The micro wick is made of polyvinyl acetate and has a diameter of 1 mm and is 9 mm long. It can be delivered to the round window niche through a special silicone vent tube that has appropriate dimensions to allow the pasage of the wick into the tympanic cavity. This method allows self medication: the patient can lay down at home with the ear to be treated upwards and drop the medicine in the external canal. It will go through the ventilation tube and reach the micro wick.19 Because there are many variables that can influence the deliver of drugs to the round window by intratympanic injections (midde ear volume, clearing of the substance via auditory tube, pseudo membrane and fibrosis in the round window niche) 31 the search for better and more precise ways to deliver medications by intratympanic injection is justified but there is no consensus about the best way to achieve this goal. Certainly simple injection of the medication

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into the middle ear space as described above is the most popular method because it is simple and do not require any expensive devices in order to be done. Some studies on the absortion and distribution of solutes delivered by the intratympanic route in the inner ear structures Salt and Ma 32 developed a model for studying the permeability and the distribution of solutes delivered to the RWM. The cochlear perilymph shows a higher concentration of the solute in the basal turn and there is a gradient of concentration along the midde and upper turns. This gradient was shown to persist after hours from the intratympanic injection. The molecular weight, the charge, concentration and volumes of the injected substance plus the RWM characteristics, the lenght of the cochlea, perilymnph flow patterns and speed of absortion of the cochlear cells are important in determining the gradient. All these details are far from being well studied and understood but it is established that drugs delivered through the intratympanic route reach higher concentrations in the inner ear than when delivered systemically.32 Drugs used for tinnitus control through the intratympanic route Lidocaine In 1935 Barany 33 reported that the tinntus of some of his patients stopped when he injected procaine hydrochloride to the inferior turbinate as a local anesthetic for intranasal surgery. Inspired by Baranys report Lewy 34 did a formal study to investigate the use of local anesthetic for control of tinnitus. He tested procaine, dibucaine hydrochloride and quinine combined with urethan by the intravenous route of administration. He claimed that all of these drugs could aleviate tinnitus but the last one was ototoxic and should be discarded. Subsequently many authors 35-37 repported relief of tinnitus with the use of local anesthetics. In 1976 Sakata and Umeda 38 reported on 58 patients with tinnitus treated by an intratympanic injection of lidocaine. Of these 48 reported an improve-

ment of their tinnitus. Melding et al.39 reported that some of their chronic pain patients treated with IV lidocaine reported improvement of their coexisting tinnitus. Shea and Harell 40 reported similar results in their patients after IV lidocaine injections. None of these studies presented a control group and no placebo was used in any case. In 1982 Israel et al.41 conducted a double blind experimental study using lidocaine in one group and sterile saline in another both substances by the intravenous route. The difference between the two groups was statistically significant with more patients having tinnitus relief in the lidocaine group. Sakata et al.42 published another larger series of tinnitus patients treated with intratympanic lidocaine and reported complete resolution of the symptom in 34% of the patients, great amelioration in 50% and no response to the treatment in 16%. It has been proposed that the action of lidocaine in tinnitus would be analogous to its action on pain: the drug would block the central hyperfunctional neuronal pathways responsible for the generation of noise as it does in the pain central pathways.43 Fradis et al.44 reported a study in which he treated Menires disease patients with intratympanic lidocaine injections (1 mL of 1% solution of lidocaine intratympanic) and saline solution was used in the control group. He reported total remission of SDT in 10.7% of the patients in the study group, significant improvement of the symptom in 57.1% and no change in 32.2% one week after the injection. No patient in the control group showed any improvement of the SDT. However six months later 74% of the responding patients were experiencing gradual return of their tinnitus. Itoh and Sakata in 1991 44 treated 322 patients with vestibular disorders and tinnitus with lidocaine (4% solution) and dexamethasone (4 mg/4 mL solution) by the intratympanic route. They reported improvement of tinnitus in Menires disease patients (61%) that varied from good to excelent result. In other groups of patients with tinnitus and vertigo he obtained good results for tinnitus in 76% of patients. Nausea and vomiting were immediate side effects of lidocaine. Haginomori et al. in 1995 45 studied evoked otoacoustic emissions (EOAE) in 30 patients with tinnitus before and after lidocaine intravenous injections (1 mg/kg dosis). The treatment resulted in suppres-

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sion of tinnitus in 32 (73%) of the treated ears and changes in EOAE (increase or decrease) in 18 (60%) of the patients. Of 18 ears with EOAE changes improvement or remission of tinnitus occurred in 17 (94%). In 12 ears with no change in EOAE amplitude only 5 (42%) patients have tinnitus remission. One can then speculate that there is a relation between tinnitus suppression and changes in the cochlea micromechanics. It is well known that in experimental animals cochlea physiology is affected by topical lidocaine and that this effect is dose depending and specific. To clarify this subject Laurikainen et al.46 injected lidocaine in highly concentrated solution into the tympanic cavity of 6 patients with tinnitus and normal hearing. Pure tone audiometrys, auditory evoked brain stem potentials (ABR) and transient evoked otoacoustic emissions (TEOAE) were recorded following the injections. In control group (5 patients) normal saline was injected intratympanically before the lidocaine solution. The saline injection did not cause any change in the three tests. The lidocaine injection caused a two to 10 db reduction in the amplitude of TEOAE at the 1 to 3 khz frequency interval.This effect peaked at 30 minutes after the injection and started to decrease thereafter. After two hours the TEOAE was still two to four dB below baseline. A discrete increase in pure tone thresholds was observed peaking at 30 minutes after the lidocaine injection but there was full recovery after one hour. ABR waves did not show any change after the lidocaine injections. These results show that lidocaine acts in the cochlea structures and do not have any effect in the 8th nerve and brainstem auditory strutures. Knowing where the drug acts might help to localize the disorder (tinnitus) affected by the drug. Because of the short relieve time of tinnitus and significant side effects with high dosis lidocaine has been largely abandoned as pharmacologic treatment for SDT. Aminoglicosides Most of the reports regarding the efect of aminoglicosides in tinnitus concern patients with Menires disease treated primarly for relief of vertigo. Gentamycin is now the prefered agent because it is primarily vestibulotoxic.47 Moller et al.48 reported reduction of tinnitus in a

group of 15 patients with disabling Menires disease treated with intratympanic administration of gentamycin once daily during 3 to 11 days. They followed the patients for 1 to 6 years and the effect was long lasting. Magnusson and Padoan 49 administred gentamycin intratympanically twice a day to a small group of Menires disease patients untill they became irresponsive to caloric stimulation. They did not have any significant hearing loss and their tinnitus were untouched up to one year later. Gentamycin intratympanic injection seems much less effective in tinnitus control than in controlling severe vertigo. Kaasinen et al.50 used gentamycin intratympanic to treat 69 patients with difficult to treat Menires disease. Sixty six of them had tinnitus before treatment. Four percent had their tinnitus suppressed, 30% remained with slight tinnitus, 27% persisted with moderate tinnitus. Twenty eight percent of the patients continued with severe and handicapping tinnitus. Some of them had significant hearing loss as a consequence of the treatment. Silverstein et al.51 tried to improve drug delivery throuh the round window using direct inspection of the niche and removal of mucosal excesses or adhesions and placement of a piece of gelfoam in the round window niche.They used different protocols: 1) a single intratympanic infusion; 2) two infusions (five days apart with revaluation at one month); 3) multiple infusions (1 to 4 weeks apart). The dosis was 0.2 to 0.3 mL of a buffered gentamycin solution (26.7 mg/mL). Vertigo was controlled in 75%, tinnitus improved in 48% and aural fullness in 62.5% of patients. Ninety percent of the patients had hearing preservation. The best control of tinnitus was obtained with two gentamycin injections (62.5% control) followed by one gentamycin injection (50% control). Repeated injections resulted in 33,3% of patinets with tinnitus control. Eklund et al.52 in 1999 treated 93 patients with intractable Menires disease with intratympanic gentamycin injection and examined the results concerning tinnitus and hearing loss. The Tinnitus Handicap Inventory (THI) was used to evaluate tinnitus improvement. The pretreatment THI score was 2.92 and posttreatment the ndex was 2,26 indicating significant tinitus reduction after the treatment. Many of the patients also had hearing losses. Quaranta et al.53 treated 15 patients with Menires disease with low dosis intratympanic gentamycin and

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compared tinnitus improvement in the treated group with another group who refused any treatment. The treated group received 0.5 mL of a 20 mg/mL gentamycin solution once a week for two consecutive weeks. When there was recurrence of vertigo the patients received another injection. Using the American Academy of Otolaryngology Head and Neck Surgery criteria for reporting results of treatment for Menires disease 93% of the treated patients had complete control of vertigo. However 20% of the patients reported resolution of tinnitus in the treated group and 27% had the same result in the untreated group. Hoffer et al.54 treated 27 patients with Menires disease using microdosis of gentamycin intratympanic delivered by microcatheter to the RWM. Continuous infusion of a solution of gentamycin (10 mg/ mL) during 10 days was used. The treatment resulted in elimination of vertigo in 92.6% of the patients and 3.7% had mild permament hearing threshold shift. Sixty six percent of the patients reported significant reduction of tinnitus and aural fullness. Jackson and Silverstein 19 treated 92 patients with Menires disease using the MicroWick device we have mentioned earlier in this communication. The method allows self medication by the patients at home. The treatment duration was 18 months. Eighty five percent of the patients reported relief of vertigo and 57% reported relief of tinnitus. Comparing these results with the ones from the same group 51 the MicroWick technique improved the results regarding vertigo control with preservation of hearing but had no effect on tinnitus control. Yetizer and Kertmen 55 used intratympanic gentamycin injection to treat 25 patients with Menires disease for the control of vertigo. Tinnitus was evaluated before and after the treatment with a visual analog scale (VAS) from 1 to 10 and by a questionnaire. According to these parameters tinnitus improved in 4 patients (16%) and resolved completely in 3 (12%) patients. They found no correlation between the dosis of gentamycin used and the results on tinnitus control so they found it difficult to recommend gentamycin intraympanic for tinnitus treatment. Seidman 56 in 2002 studied the effect of continuous intratympanic injection of gentamycin using an Intra Ear catheter placed in the round window niche and conected to a microinfusion pump. They used a 10 mg/mL gentamycin solution. Ninety percent of 86 patients had either total control or significant im-

provement of vertigo. Tinnitus improved in 69%, aural fullness in 77% and 23% referred hearing loss. Lange et al.57 in 2004 in order to reduce the hearing loss caused by intratympanic gentamycin injection tried to treat vertigo and tinnitus with a single injection and when a new injection was needed they kept an interval of one week between treatments. He treated 90 patients and tinnitus control was reported in 50% of the patients. He had no hearing loss in his patients and stated that this method was safe and effective. The evolution of the intratympanic gentamycin injection seeks to diminishe the hearing loss as a side effect of treating severe intractable vertigo in Menires disease. Silverstein et al.19 treated 90 patients with Menires disease using a single shot of gentamycin and when needed a second shot would be done one week apart. Fifty three percent of the patients had control of vertigo with a single shot. They claimed tinnitus control in 50% of the patients using this protocol. The low incidence of hearing loss led the authors to state that a one week interval between shots might prevent hearing loss. Treatment of tinnitus with aminoglicosides (gentamycin) intratympanic is a side product of the treatment of vertigo in Menires disease. The studies reported above are concerned with the treatment of vertigo and report as a side effect the tinnitus results. None has control groups of tinnitus patients to compare with the treated (study) group and it is well known that a 30% placebo effect is to be expected when treating tinnitus. The only work reported here 53 who compared the effect of gentamycin intratympanic on tinnitus with no treatment at all showed no difference between the groups. It is fair to conclude that aminoglicosides (gentamycin) injected intratympanically is by no means an established and effective treatment for tinnitus. Steroids Itoh and Sakata in 1991 44 reported their experience with the treatment of 136 patients with Menires disease and 186 patients with labyrinthine vertigo using dexamethasone and lidocaine by the intratympanic route. All these patients had failed conservative treatments. Using the American Academy of Otolaryngology and Ophtalmology (AAOO-1972), American Academy of Otolaryngology Head and Neck Surgery (AAO-HNS, 1985) and Sakatas cri-

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teria (1987) for results evaluation they concluded that dexamethasone was more effective in Menire`s disease while lidocaine was better for other causes of labyrinthine vertigo. Both showed effectiveness in the control of vertigo and tinnitus. There was no control group, it was a retrospective study and the follow up was not standardized. Sakata 58 in 1996 treated 1214 patients affected by what he classified as cochlear tinnitus. There were 1466 ears affected. The patients had many different otologic diagnosis. They used intratympanic dexamethasone (2 or 4 mg/mL) repeated four times at one or two weeks interval. They measured improvement using a 10 points VAS pre and post treatment. They found improvement of tinnitus in 71% regardless of age group. When the otologic diagnosis was Menires disease and chronic otitis media the results were better (82% and 77% respectively). The improvement tended to fade away during follow up. Silverstein et al.59 in 1996 used intratympanic injection of depo-Medrol (80 mg/mL), dexamethasone ophtalmic solution (1mgm/ml) and dexamethasone IV (4 mg/mL) and obtained improvement of cochlear function in some patients with Menires disease, autoimmune ear disease and sudden sensorineural hearing loss. Tinnitus improved in 60% of Menires patients and 47% overall. They used the MicroWick method of infusion. Interestingly there was no improvement in patients with presbyacusis. Shea and Ge 60 in 1996 based on the autoimmune hypothesis for the etiology of Menires disease injected 0.5 mL of a 16 mg/mL dexamethasone solution directly into the round window niche through a laser myringotomy followed by a 16 mg IV injection of dexamethasone in Menires disease patients. Vertigo control, aural fullness reduction and low frequency tinnitus improvement were reported. In some patients hearing improvement also occurred. Low frequency tinnitus improved in 82% of the patients. They proposed as site of action of the dexamethasone the endolymphatic sac, the stria vascularis and the spiral ligament so the action of the drug would reduce endolymphatic hydrops and restore fluid dynamics in the inner ear. Sakata et al.61 in 1997 used dexamethasone (2 mg/ mL and 4 mg/mL) by the intratympanic route as an office procedure in 3978 ears of 3041 patients. They reported immediate improvement of tinnitus after the injections in 75% of the patients and after 6 months 68% of them were still having tinnitus reduction.

The best results were seen among endolymphatic hydrops patients. Hicks 62 in 1998 published a small series of 20 patients treated with dexamethasone intratympanic injections. Fourteen of them (57%) reported improvement of tinnitus. Silverstein et al.51 in 1998 published a prospective randomized double blind and crossover study of the results of dexamethasone intratympanic injection in Menires disease patients with special attention to hearing loss and tinnitus. Using the AAO-HNS Committe on Hearing and Equilibrium criteria they selected 20 patients with either definite or problable unilateral Menires disease.They also observed aural fullnes and caloric vestibular responses after the treatment. They did three intratympanic injections in three consecutive days of dexamethasone or placebo (saline or sodium hyaluronate) to the diseased ear. They looked for post-injections change in the pure tone audiometry, speech reception thresholds, caloric vestibular responses and scores in THI. No changes were observed in these parameters and the patients were unable to distinguish the dexamethasone from the placebo injections. They concluded that intratympanic administration of dexamethasone solution was no different from placebo in unilateral Menires patients. In order to clarify the pharmacokynetics of steroids injected intratympanically Parnes et al.63 using high performance liquid chromatography established the pharmacokinetics of hydrocortisone, methylprednisolone and dexamethasone in the inner ear fluids of the guinea pig. They compared the concentrations of the drugs in the inner ear using the intratympanic, oral and intravenous routes and demonstrated that much higher concentrations were obtained by the first route. They also showed that methylprednisolone has the best profile. They then treated 37 patients with several inner ear disorders causing sensorineural hearing loss with dexamethasone (20 patients) and methylprednisolone (17 patients). The best results were obtained in immune mediated hearing loss patients with good results also in several cases of sudden deafness. They considered the injections safe and highly effective to treat some disorders. They did not report any difference between methylprednisolone and dexamethasone in the human study. They did not detect any significant effect of the drugs on endolymphatic hydrops patients. Chandrasekhar et al.64 in 2000 investigated ways

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to improve the transport of steroids injected systemically and intratympanically to the perilymph. They assessed the role of 3 potential facilitators of dexamethasone from the middle ear to the perilymph. Forty guinea pigs (79 ears) were studied. The dexamethasone concentrations in the perilymph were measured using radioimmunoassay. They found higher concentrations of dexamethasone in perilymph when the drug was injected intratympanically than by intravenous injection (P=0.05). Using histamine as facilitator they produced signifficantly higher steroids level in the perilymph than dexamethasone alone (P=0.05). Others facilitators had no effect. They also demonstrated that after 1 hour of the intratympanic injection the perilymph concentration of dexamethasone was high and without systemic effects. Cesarani et al.65 in 2002 treated patients with idiophatic subjective tinnitus with dexamethasone (4 mg/mL) using the intratympanic route. The injections were repeated during three consecutive months. Two weeks ater the end of the treatment 117 of 50 patients (34%) had complete resolution of tinnitus, 20 of 50 patients (40%) had significant reduction of the symptom and 13 of 50 (26%) did not improve. After 6 weeks only 13.5% of the patients continued to have complete resolution of the symptoms. At one year after treatment only 2 patients continued to report complete resolution of tinnitus. They recommended this approach only for patients with inner ear disorders associated with tinnitus. They had no control group. Hoffer et al.66 reported the treatment of 10 patients with subjective idiopathic tinnitus using 0.3 mL intratympanic injection of a 62.5 mg/mL methylprednisolone solution during two weeks. The intensity of tinnitus was measured by a VAS from 1 to 10 and significant tinnitus improvement was considered when there was a four points or more reduction of tinntus in the VAS after treatment. They reported 60% of the patients as having significant reduction of their tinnitus. Arajo et al.67 in 2005 selected 36 patients with SDT presumably of cochlear origin and randomized them in two groups: one to receive intratympanic injections of dexamethasone and the other to receive intratympanic isotonic saline injections. Using topical anesthesis they received 0.5ml of either a 4mgm/ml dexamethasone solution or 0.5ml of isotonic daline. The injections were performed once a week during four weeks. Improvement of tinnitus

Table I.Otologic diagnosis in 35 ears selected for treatment.

Diagnosis Ears N. (%)

Presbycusis Chronic otitis media Noise-induced hearing loss Otosclerosis Menires disease Idiopathic tinnitus Sudden deafness Ototoxicity

7 (20) 6 (17) 6 (17) 5 (14) 4 (11) 4 (11) 2 (06) 1 (03)

was measured using the VAS from 1 to 10. The two groups did not differ regarding age, sex, average intensity of tinnitus in the VAS and main otologic diagnosis (Table I). A two points improvement in the VAS was considered significant. Five patients were excluded from analysis because they did not finish the protocol of treatment. As a final result 29% of the ears treated with intratympanic saline solution and 33% of the ones treated with the dexamethasone solution showed significant improvement of tinnitus immediatly after the treatment plan was completed (Tables II, III). This diference was not statistically significant. They concluded that intratympanic injection of dexametasone (4 mg/mL) was no different from intratympanic injection of isotonic saline solution. This work was randomized, prospective and single blinded. In 2009 two studies prospective, randomized and single blinded were performed: She et al.68 and Topak et al.69 Both of them found no statistically significant effect of intratympanic steroids in the treatment of tinnitus of the SDT type. Neuroprotectors Calpain is a protease normally existent in the inner ear. Proteases are enzymes that attack peptide bonds either in proteins or polypeptides. The calpain family requires the presence of activated calcium to function. These enzymes incitate intracellular proteoilisis and destroys intracellular and membrane proteins leading to cell destruction and death (apoptosis).70, 71 Regulation of calpain activity is tightly controlled by the intracellular concentration of calcium. Another way of controlling calpain activity is by the presence of endogenous calpain inhibitors. Several calpains inhibitors have been shown to be neuroprotective both in vitro and in vivo.43 Stratcher 71

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Table II.Otologic diagnosis in 21 ears in the study group.

Patient N. Sex Side of symptom VAS Score* Pretreatment** Posttreatment*** Complication Diagnosis

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21

M M M M M F F F F F F M F F M M M M M F F

R L L L R L R R R L R R L R L R R L R R L

6 8 7 7 7 10 9 7 9 7 10 10 10 8 8 7 6 5 8 10 10

5 8 6 4+ 6 9 9 6 9 6 10 8+ 8+ 8 8 5+ 2+ 2+ 8 10 8+

Vertigo

Vertigo

Otosclerosis Presbycusis NIHL NIHL Otosclerosis Sudden deafness Menires disease Idiopathic tinnitus Presbycusis Idiopathic tinnitus Sudden deafness NIHL Menires disease Menires disease Otosclerosis Otosclerosis COM COM Idiopathic tinnitus COM COM

COM: chronic otitis media; NIHL: noise-induced hearing loss; VAS: visual analog scale. *Mean score improvement = 1.14. **Mean pretreatment score = 8.04. ***Mean posttreatment score = 6.90. +Improvement was significant (defined as a lowering of tinnitus by at least 2 gradations on the VAS).

Table III.Otologic diagnosis in 14 ears in the control group.

Patient N. Sex Side of symptom VAS Score* Pretreatment** Posttreatment*** Complication Diagnosis

1 2 3 4 5 6 7 8 9 10 11 12 13 14

F F M M F F M M M M F F M F

L L L R R R R R R R L L L R

10 10 7 6 5 9 8 8 7 7 9 7 6 7

10 9 4+ 4+ 5 9 6+ 8 6 6 1+ 7 6 6

Vertigo Otalgia Vertigo

Ototoxicity Menires disease NIHL NIHL Presbycusis Presbycusis COM Presbycusis Otosclerosis Presbycusis Presbycusis Idiopathic tinnitus NIHL COM

COM: chronic otitis media; NIHL: noise-induced hearing loss; VAS: visual analog scale. *Mean score *Mean score improvement = 1.36. **Mean pretreatment score = 7.57. ***Mean posttreatment score = 6.21. +Improvement was significant (defined as a lowering of tinnitus by at least 2 gradations on the VAS).

showed that leupeptin, a calpain inhibitor, administered orally improved muscle recovery and neuron recovery after median nerve section and repair. Experimental work in animal 72 showed that infusion of calpain into the inner ear through a catether in the round window connected to an osmotic pump protected the outter hair cells submitted to over stimulation by acoustic energy. Shulman 43 in 1998 suggested that leupeptin infusion directly into the inner

ear could be usefull in the treatment of tinnitus in humans. Up to now no studies in humans using this method to treat tinnitus has been reported. It is also true that this refers to direct infusion of the drug (leupeptin) into the inner ear hopping that its action would also reach the central nervous systems sites of tinnitus generation. This treatment therefore remains a real possibility to be explored in the future.

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Conclusions Lidocaine has showed only transient and inconsistent action on tinitus control when injected intratympanically and is largely abandoned for this purpose. Steroids are the best studied class of drugs regarding intratympanic injection for the control of tinnitus and the best evidences based on prospective, randomized single blinded clinical trials point to absence of effective action in tinnitus control. Aminoglicosides (gentamycin) have been studied targeting the control of vertigo in Menires disease and the effect of the drug on tinnitus is reported as a secondary result. While intratympanic injection of gentamycin is well established for the treatment of vertigo we lack prospective randomized single blinded clinical trials to clarify their action on tinnitus control. Considering that gentamycin intratympanic injections to treat vertigo produces significant hearing loss in some patients one would expect that this drug used to treat tinnitus would produce an even worse rate of hearing loss being tinnitus a cochlear phenomenon: the cochlea would necessarily have to be hit in order to control tinnitus. The conclusion is that at this time we have no established drug to treat tinnitus by the intratympanic route. Hopes Neuroprotectors (leupeptin) not by intratympanic injection but by direct inner ear perfusion may be looked upon as a hope for the future. The infusion would be necessary in order to reach the tinnitus connected areas of the central nervous system. There is interest in genetic therapy and new technologies such as hydrogel and nanoparticles. Viral vectors and nano particles could difuse through the round window membrane to reach the inner ear. The use of drugs diluted in polymers and hydrogel placed against the RWM may allow better and continuous delivery of the therapeutic agents. Potential uses for such devices include neurotrophic agents, RNA interference agents and stem cells therapy.73 Because SDT is not only a cochlear phenomenon but a mainly a neuroscience issue the treatment of this conditon can not be limited to the cochlea: it must reach the central nervous system areas involved with the maintenance and ampilification of

tinnitus as well as the integration of the acoustic and affective components of the symptom (final common pathway).74 While these hopes do not come through we believe that techniques that act on neuroplasticity (tinnitus retraining therapy and others) are our best bet. These techniques work even better when allied with psycotherapy.75 Riassunto
Trattamento intratimpanico del tinnito: illusioni e speranze Claudio Galeno di Pergamo, maestro di anatomia e fisiologia, sosteneva di somministrare medicamenti nellorecchio esterno e medio per trattare patologie dellorecchio (130-200 AD). Ai nostri tempi, Schuknecht nel 1956 fu il primo a utilizzare la streptomicina intratimpanica per il trattamento della malattia di Menire. Tuttavia, lincidenza di sordit era molto elevata. Nelle due decadi successive Beck e Schmidt utilizzavano la gentamicina per lablazione vestibolare in pazienti affetti dalla malattia di Menire e, titolando attentamente le dosi, essi erano in grado di ridurre lincidenza di sordit. Questi e altri successi hanno permesso ai ricercatori di utilizzare diverse sostanze iniettate in sede intratimpanica per trattare il tinnito. La lidocaina si dimostrata in grado di sopprimere il tinnito quando iniettata per via sistemica ed stata utilizzata anche per via intratimpanica. Anche gli aminoglicosidi e gli steroidi sono stati utilizzati nel trattamento del tinnito, della sordit sensorineurale improvvisa e della sordit autoimmune. Inoltre, sono stati impiegati per via intratimpanica farmaci neuroattivi per trattare il tinnito. Sebbene vi siano numerosi articoli ottimisti circa la via intratimpanica per la somministrazione di farmaci nel trattamento del tinnito, fino ad ora questo metodo di trattamento rimasto controverso e nessun farmaco specifico si dimostrato significativamente efficace quando iniettato per via intratimpanica. Questo articolo presenter le evidenze riportate in Letteratura e cercher di dividere ci che illusione da ci che supportato dai fatti e dalle speranze che abbiamo per il futuro in questo settore. Parole chiave: Disturbi uditivi - Lidocaina - Tinnito.

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30. Silverstein H. The micro wick to deliver medication to the inner ear. Ear Nose Throat J 1999;78:595-600. 31. Wanamaker H. Perfusion of the inner ear: basic sciences considerations. Current Opinion in Otolaryngol Head and Neck Surg 2001;9:329-32. 32. Salt NA, Ma Y. Quantification of solute entryinto cochlear perilymph through the round window membrane. Hear Res 2001;154:88-97. 33. Barany R. Die beeinflussung des ohrensausens durch intravenos injizierte lokalanaesthetica. Acta Otolaryngol 1935;23:201-203. 34. Lewy RB. A treatment of tinnitus aurium by intravenous use of local anesthetic agents. Arch otolaryngol 1937;25:178-83. 35. Fowler EP. Intravenous procaine in the treatment of Menires disease. Ann Otol Rhinol Laryngol 1953;62:1186-201. 36. Gejrot T. Intravenous xylocaine in the treatment of attacks of Menires disease. Acta Otolaryngol Suppl 1963;188:190-5. 37. Gejrot T. Intravenous xylocaine in the treatment of attacks of Menires disease. Acta Otolaryngol 1976;82:301-2. 38-Sakata E, Umeda Y. Treatment of tinnitus by transtympanic injection of lidocaine. Auris Nasus Larynx 1976;3:133-8. 39. Melding P, Goode RJ, Thorne PR. The use of intravenous lidocaine in the diagnosis and treatment of tinnitus. J Laryngol Otol 1978;92:115-21. 40. Shea J, Harell M. Management of tinnitus aurium with lidocaine and carbamazepine. Laryngoscope 1978;88:1477-84. 41. Israel JM, Coinnelly JS, McTigue ST, Brummett RE, Brown J. Lidocaine in the treatment of tinnitus aurium. A Double blind study. Arch Otolaryngol 1982;108:471-3. 42. Sakata E, Nakasawa H, Iwashita N. Therapy of tinnitus. Tympanic cavity infusion of lidocaine and steroid solution. Auris Nasus Larynx 1984;11:11-8. 43. Shulman A. Neuroprotecyive drug therapy: a medical and pharmacological treatment for tinnitus control. Int Tinnitus J 1997;3:7793. 44. Itoh A, Sakata E. Treatment of vestibular disorders. Acta Otolaryngol 1991;Suppl 481:617-23. 45. Haginomori S, Makimoto K, Araki M, Kawakmi M, Takahashi H. Effect of lidocaine injection in evoked otoacoustic emissions (EOAE) in patients with tinnitus. Acta Otolaryngol 1995;115:488-92. 46. Laurikainen EA, Johanson RK, Kileny PR. Effects of intratympanically delivered lidocaine on the auditory system inhumans. Ear Hear 1996. 47. Dodson KM, Sismani A. Intratympanic perfusion for the treatment of tinnitus. Otolaryngol Clin N Am 2004;37:991-1000. 48. Moller C, Odkvist LM, Theil J, Larsby B, Hyden D. Vestibular and audiologic functions in gentamycin treated Menires disease. Am J Otol 1988;9:383-91. 49. Magnusson M, Padoan S. Delayed onset of ototoxic effects of gentamycin in treatment of Menires disease rationale for extremely low dose therapy. Acta Otolaryngol 1991;111:671-6. 50. Kaasinen S, Pyykko I, Ishizaki H, Aalto H. Effect of intratympanically administered gentamycin on hearing and tinnitus in Menires disease. Acta Otolaryngol 1995;Suppl 520 part 1:184-5. 51. Silverstein H, Arruda J, Rosenberg SI, Dems D, Hester T. Direct round window membrane application of gentamycin in the treatment of Menires disease. Otolaryngol Head and Neck Surg 1999;120:649-55. 52. Eklund S, Pyykko I, Aalto H, Ishizaki H, Vasama JP. Effect of intratympanic gentamycin on hearing and tinnitus in Menires disease. Am J Otol 1999;20:350-6. 53. Quaranta A, Scaringi A, Aloidi A, Quaranta N, Salonna I. Intratympanic therapy for Menires disease: effect of administration of low concentration of gentamycin. Acta Otolaryngol 2001;121:387-92. 54. Sakata E, Itoh A, Itoh Y. Treatment of cochlear tinnitus with dexamethasone injection into the tympanic cavity. Int Tinnitus J 1996;2:129-35. 55. Yetiser S, Kertmen M. Intratympanic gentamycin in Menires disease: the impact on tinnitus. Int J Audiol 2002;41:363-70.

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56. Seidman M. Continuous gentamycin therapy using an intraear microcatheter for Menires disease: a retrospective study. Otolaryngol Head and Neck Surg 2002;126:244-56. 57. Lange G, Maurer J, Mann W. Long term results after interval therapy with intratympanic gentamycin for Menires disease. Laryngoscope 2004;114:102-5. 58. Sakata E, Itoh Y. Clinical experience of steroid targeting therapy to iner ear for control of tinnitus. Int Tinnitus J 1997;3:117-21. 59. Silverstein H, Choo D, Rosenberg SI, Kuhn Seidman M, Stein I. Intratympanic steroid treatment of inner ear disease and tinnitus (preliminarys report). Ear Nose Throat J 1996;75:466-71. 60. Shea JJ Jr, Ge X. Dexamethasone perfusion of the labytrinth plus intravenous dexamethason in Menires disease. Otolaryngol Clin N Am 1996;29:352-8. 61. Hicks GW. Itratympanic and round window drug therapy: effect on cochlear tinnitus. Int Tinnitus J;1998, 4:144-7. 62. Silverstein H, Isaacson E, Olds M, Rowan PT, Rosenberg S. Dexamethasone ear perfusion for the treatment of Menires disease: a prospective randomized double blind cross-over trial. Am J Otol 1998;19:196-201. 63. Parnes LS, Aun AH, Freman DJ. Corticosteroid pharmacokinetics in the inner ear fluids: an animal study followed at clinical application. Laryngoscope 1999;Suppl 91:1-17. 64. Chandrasekhar SS, Rubinstein RY, Kwartler JA, Gatz M, Connelly PE, Huang E, Baredes S. Dexamethasone pharmacokinetics in the iner ear: comparison of route of administration and use of facilitating agents. Otolaryngol Head and Neck Surg 2000;212:521-8.

65. Cesarani A, Capobianco S, Sol D, Giuliano DA, Alpini D. Intratympanic dexamethasone treatment for control of subjective idiopathic tinnitus: our clinical experience. Int Tinnitus J 2002;8:111-4. 66. Hoffer ME, Wester D, Kopke RD, Weisskjopf P, Gottshall K. Transtympanic management of tinnitus. Otolaryngol Clin N Am 2003;36:353-8. 67. Arajo MFS, Oliveira CA, Bahmad Jr F. Intratympanic dexamethasone injectio as a treatment for severe disabling tinnitus. Arch Otolaryngol Head and Neck Surg 2005;131:113-7. 68. She W, Da Y, Du X, Chen F, Dig X, Cui X. Treatment of subjective tinnitus: A comparative clincal study of intratympanic steroid injection versus oral carbamazepine. Med Sci Monit 2009;15:35-9. 69. Topak M, Sabin-Yilma A, Ozdoganoglu T, Yilmaz HB, Ozbay M, Kulekci M. Intratympanic methylprednisolone injections for subjective tinnitus. J Laryngol Otol 2009;123:1221-5. 70. Stratcger A. Calpain inhibitors as neuroprotective agents in degenerative disorders. Int Tinnitus J 1997;3:71-5. 71. Brown JN, Miller JM, Altschuler RA et al. Osmotic pumo implant for chronic infusion of drugs into the iner ear. Hear Res 1993;70:167-72. 72. McCall AA, Swan EE, Borenstein JT, Sewell WF, Kujawa SG, McKenna MJ. Ear Hear 2010;31:156-65. 73. Shulman A, Strashun AM, Afriyie M, Aronson F, Abel W, Goldstein B. SPECT Imaging of Brain and tinnitus: neurotologic/neurologia implications. Int Tinnitus J 1995;1:13-29. 74. Holdefer L, Oliveira CA, Venosa AR. Group therapy for patients with tinnitus at the University of Braslia Medical School. Brazilian Journal of Otorhinolaryngology 2010;76:102-6.

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OTORINOLARINGOL 2010;60:207-12

Intratympanic treatment for chemotherapy-related ototoxicity

K. PARHAM

Cisplatin-induced ototoxicity is a common side effect of chemotherapeutic regimens aimed at treating several types of malignant solid tumors. Cisplatin ototoxicity is likely mediated by multiple cellular mechanisms which lead to accumulation of reactive oxygen species (ROS) and apoptosis. Cisplatin targets in the cochlea include the outer hair cells (OHC), spiral ganglion cells and stria vascularis. There are currently a number of clinical trials underway to assess the efficacy of systemic antioxidants in ameliorating ototoxic side effects of cisplatin. However, there is concern that systemic administration of antioxidants may interfere with anti-neoplastic properties of chemotherapeutic regimens. Intratympanic (IT) administration of drugs offer an alternative route of delivery of rescue medications to the cochlea to minimize systemic absorption, thus reducing the risk of altering the efficacy of chemotherapeutic regimens. This article reviews the available experimental evidence on the effectiveness of IT therapy in protecting auditory function from cisplatin ototoxicity. Promising agents include dexamethasone, which is currently in use in treatment of other diseases of the inner ear. Latest research has improved our understanding of the cellular mechanisms that lead to ototoxicity and permitted emergence of targeted therapeutic strategies, such as IT application of short interfering RNA to inhibit NADPH oxidase, a key generator of ROS. The experimental results reviewed in this paper suggest a promising future in protecting hearing against cisplatin-induced ototoxicity. Key words: Cisplatin - Apoptosis - Reactive Oxygen Species.
Acknowledgements.This work was supported by a Jahnigen Career Development Award from the American Geriatrics Society. I am grateful to D. Kent Morest and Julia Gross for their assistance and providing cochlear histology data. Corresponding author: K. Parham, MD, PhD, Assistant Professor, Director of Research, Division of Otolaryngology, Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030-6228, USA. E-mail: parham@neuron.uchc.edu

Division of Otolaryngology Department of Surgery University of Connecticut Health Center Farmington, CT, USA

Cisplatin ototoxicity The problem is-Diamminedichloroplatinum(II), cisplatin, is a common chemotherapeutic agent used to treat many different types of cancer including medulloblastoma, neuroblastoma, osteosarcoma, testicular, ovarian, cervical, bladder, lung, and head and neck cancers. Cisplatin forms a monohydrated complex inside the malignant cell and cross-links DNA thus interfering with DNA replication. The accumulation of these DNA adducts leads to malignant cell death.1 Cisplatin has several side effects stemming from its non-specific cytotoxic action, including neuro-, nephro- and ototoxicity. Cisplatin ototoxicity generally manifests as tinnitus and sensorineural hearing loss 2, 3 which starts in the high frequencies, but extends into lower frequencies that are important for speech perception.4 Sixty-80% of patients treated show elevations of hearing thresholds and nearly 15% sustain significant hearing handicap.5, 6 This hearing impairment is dose related, cumulative, bilateral and usually permanent. A primary target for cisplatin is the cochlear OHCs, with loss starting in the base of the cochlea 7, 8 (Figure 1). In a time course parallel to the OHC loss, the stria vascularis and the spiral ganglion cells are also injured,

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suggesting that cisplatin targets multiple cochlear structures directly.9 There are currently four platinating agents available for treatment of cancer: intravenously administered cisplatin and its analogs carboplatin and oxaplatin and orally available satraplatin. Ototoxicity due to cisplatin analogs is relatively rare but they have inferior efficacy in treatment of some neoplasms.10 Lower ototoxicity of other platinating agent may be due to their lower cochlear uptake.11 Nevertheless, ototoxicity has also been reported for these agents, including both carboplatin 12 and oxaplatin.13 Variability observed in expression of ototoxicity due to platinating agents may be in part based on genotype14 but is also influenced by dose, young age, renal status, history of cranial irradiation and concomitant therapy with other ototoxic agents (e.g., aminoglycosides).10 In this review, we will focus on cisplatin-induced ototoxicity. Cisplatin ototoxicity The mechanism Cisplatin ototoxicity is likely mediated by multiple cellular mechanisms and targets. As noted above, cisplatin binds DNA. This binding affects both replication and transcription of DNA, DNA repair and disrupts signal transduction in proliferating cells leading to apoptosis 15 via mitochondiral death pathway.16 Since hair cells, supporting cells and spiral ganglion cells are postmitotic, ototoxicity is unlikely to be mediated by disruption of DNA replication in these structures. Cell division, however, is a property of the basal layer of stria vascularis.17 Cisplatin

toxicity is more likely to affect the entire cochlea through its action on stria vascularis. For example, at doses where cisplatin induces only basal OHC and SGC apoptosis, apoptosis in stria vascularis is demonstrated in all turns of the cochlea.18 Another mechanism by which cisplatin can disrupt cochlear function, without dependence on proliferating populations, is through generation of reactive oxygen species (ROS),19 such as superoxide anions.20 Mammalian cochlea, particularly stria vascularis, is normally rich in free radical scavengers consisting of antioxidant enzymes superoxide dismutase, glutathione peroxidase and catalase.21, 22 Rybak et al. have suggested that cisplatin-induced cytotoxic mechanisms leading to apoptosis may differ depending on the target cellular element, i.e., OHCs, SGs or stria vascularis.23, 24 ROS are generated through NADPH oxidase which through a chain of molecular events leads to peroxidation of lipids and oxidized proteins and DNA. With increased ROS, glutathione and antioxidant enzymes are depleted 25 and pro-apoptotic Bax proteins are activated leading to mitochondrial release of cytochrome c which in turn activates procaspase-9 and -3 leading to apoptosis.23 Besides NOX family NADPH oxidase isoforms, cisplatin induces transient receptor potential vanilloid 1 (TRPV1) in cochlear hair.26, 27 Suppression of NOX isoforms and TRPV1 by short interfering RNA reduces hair cell damage and cisplatin-induced hearing loss by reducing ROS production.26, 27 Inhibition of caspase-3 activity also produces ototoprotective effects against cisplatin.28

Cisplatin-induced outer hair cell loss

100 90 80 70 60 50 40 30 20 10 0
IHC

No missing IHCs

% Missing hair cells

Missing OHCs

10

20

OHC

30 40 50 60 70 % distance from APEX

80

90

100

Figure 1.Plastic embedded flat preparation of the mouse organ of Corti after administration of cisplatin 14 mg/kg ip demonstrated loss of outer hair cells (OHCs) (left panel). Cochleogram of cisplatin-treated mouse demonstrated OHC loss in the basal, high-frequency region of the cochlea (previously unpublished data). IHC: inner hair cell.

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Cisplatin ototoxicity The treatment In current clinical practice, treatment of cancer with cisplatin is either interrupted when ototoxicity develops (by switching to another less potent antineoplastic agent such as carboplatin) or the resulting hearing impairment is tolerated as an acceptable side effect of cancer treatment. A desired goal is to find a safe therapy that protects the ear from cisplatin ototoxicity without affecting its chemotherapeutic actions. Dozens of experimental studies have attempted to find an ideal otoprotectant by administration of antioxidants against ROS at an early stage in the ototoxic pathways.23 Unfortunately, many of these agents have been found to inhibit the tumoricidal effects of cisplatin and/or have toxicities or unknown effects in humans.2 There are currently several ongoing clinical trials involving lactated ringers, alpha lipoic acid, sodium thiosulfate, aspirin and ginko biloba extract (see www.clinicaltrial. gov) that will provide results that may guide future clinical applications. As yet, no FDA approved treatment for cisplatin ototoxicity is available. One experimental otoprotective strategy that is currently in use for treatment of other otologic disorders, is IT steroid injections. IT administration of drugs is a contemporary method of locally treating inner ear disorders, allowing diffusion across the round window into the inner ear where it can exert its effects (See Chapter 1). Specifically, steroids placed into the middle ear have been shown to diffuse across the round window into the inner ear and bathe the inner ear structures 29-31(See Chapter 2). This method allows concentration of steroid to much higher levels within the inner ear compared to oral or parenteral routes 30-32 (See Chapter 3). Also, local administration prevents systemic absorption avoiding the common systemic side effects of steroids including hyperglycemia, peptic ulcers, hypertension and osteoporosis 30, 33 and more relevant to this topic, reduced efficacy of chemotherapeutic agents34. IT administration of steroids has been used to safely treat other inner ear disorders such as sudden sensorineural hearing loss and Mnieres disease for several years31, 33 (See Chapters 4-9). Corticosteroids have been shown to limit the formation of ROS in the inner ear.35, 36 In animal models, corticosteroids have demonstrated protective benefits against various sources of hearing loss including noise,37,38 ischemia 39,40 and physical trauma
Level (dB SPL)

85 75 65 55 45 35 25 Click 8 kHz 10 kHz Stimulus PostIT DEX 32 kHz Post IT Saline

Pretreatment

Figure 2.Effects of intratympanic (IT) dexamethasone (DEX) and saline on cisplatin ototoxicity. Mice were treated with 14 mg/ kg ip of cisplatin. Before cisplatin injection and for 4 days after, DEX (24 mg/mL) or saline were administered IT once daily. DEX-treated ears were protected against cisplatin ototoxicity at all stimulus conditions except at 32 kHz where the difference did not reach statistical significance (P<0.05). (Data from Hill et al.45).

(e.g., from electrode array insertion into the cochlea Similarly, aminoglycoside ototoxicity, which is believed to have a similar pathogenesis to cisplatin ototoxicity can be ameliorated with steroid treatment.42, 43 The presence of corticosteroid receptors within critical mammalian inner ear structures provides further evidence that steroids can exert an effect on the inner ear.29 Unfortunately, corticosteroids also down-regulate apoptosis genes in tumor cells.34 Therefore, their systemic application to protect against cisplatin ototoxicity may result in decreased efficacy of cisplatins tumoricidal properties. Several experimental studies have demonstrated otoprotective properties of steroids against cisplatin ototoxicity. An early experiment that demonstrated this potential, involved systemic administration of lazaroids, a novel series of 21-aminosteroids without glucocorticoid action that have the properties of free radical scavenging and potent inhibition of lipid peroxidation. Pre-treatment with a lazaroid, U-74389G, PO reduced compound action potential threshold elevation and rate of missing OHCs in rats treated for 7-10 days with cisplatin 0.9 mg/kg i.v.44 Subsequent work has focused on IT application of steroids. Guinea pigs pre-treated with IT dexamethasone (4 mg/mL) who were administered cisplatin 12 mg/kg IP showed preservation of DPOAE am41).

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plitudes 3 days after injection (Daldal et al. 2008). Pre-treatment and 5 days of post-treatment with IT dexamethasone (24 mg/ml) in mice injected with cisplatin (14 mg/kg ip) preserved auditory brainstem response (ABR) thresholds in low frequencies, and partial protection in the high frequencies 45 (Figure 2). Rats treated with cisplatin (20 mg/kg) followed by dexamethasone also demonstrated protection as demonstrated by minimal change in ABR thresholds.46 Not all steroids appear to be efficacious when administered IT in treatment of cisplatin ototoxicity. Guniea pigs who received cisplatin (3 mg/kg ip once weekly for 5 weeks) did not show any ABR threshold preservation when administered methylprednisolone (62.5 mg/ml) IT.47 The beneficial effect of steroids on reducing ROS burden and preserving auditory function may be, at least in part, through inflammatory mediators. Cisplatin increases the early release and de novo synthesis of pro-inflammatory cytokines, including TNF-, IL-1, and IL-6, through the activation of MEK1/ ERK.48 Kim et al. have suggested that the cisplatinmediated secretion of pro-inflammatory cytokines is an upstream signal of ROS production and that ERKs regulate NADPH oxidase activation through the phosphorylation of their regulatory subunit component, as well as, their transcriptional activation in cisplatin-mediated auditory cell death.48 Other IT treatments of cisplatin ototoxicity have also been studied. Adenosine receptor agonists applied directly to the round window membrane (RWM) in chinchilla 90 min before RWM application of cisplatin significantly reduced ABR threshold at all frequencies but the highest frequencies.49 IT 2% N-acetylcysteine (NAC) preserved distortion product ototacoustic emissions (DPOAE) in guinea pigs receiving a cumulative cisplatin dose of 20 mg/kg (10 mg/kg ip on 2 consecutive days) 50 and 4% IT NAC in guinea pigs treated with cisplatin 3 mg/kg ip weekly, for a cumulative dose of 15 mg/kg, resulted in partial protection of ABR thresholds and histologically produced preservation of nuclear and cytoplasmic membranes and stereocila.47 However, 4% IT NAC also produced an external auditory canal and middle ear inflammatory reaction. Lactated Ringers solution when administered IT can induce partial protection in ABR thresholds of guinea pigs treated with weekly with cisplatin 3 mg/ kg up to 24 mg/kg51 and near-complete protection of DPOAE levels in guinea pigs treated with a cumula-

tive cisplatin dose of 20 mg/kg (10 mg/kg ip on 2 consecutive days).50 Rats treated with cisplatin (20 mg/kg) followed by Vitamin E also exhibited protection as demonstrated by minimal change in ABR thresholds.46 In one study, investigators directly applied antioxidants to the round window. D-methionine applied directly to RW before RW application of cisplatin in rat protected against ABR threshold elevation.53 In such studies, it has been observed that pH modulates cisplatin otoxocity: 30 min alkaline PBS (pH=10.2) pretreatment of RWM followed by cisplatin applied to RWM had a protective effect on ABR thresholds 3 days later, but not neutral (pH=7.0) or acidic (pH=6.0) in chinchillas.54 This protective effect was smaller, however, when basic PBS was applied to RWM 30 min before 13 mg/kg of cisplatin was administered IP in rats.55 Guided by improved understanding of cellular mechanisms that lead to cisplatin-induced apoptosis in the cochlea, novel agents are being evaluated for protection against ototoxicity. As noted above, the cochlea expresses a unique isoform of NADPH oxidase, NOX3, which serves as the primary source of ROS generation in the cochlea. IT administration of short interfering (si) RNA, which inhibits NOX3, in rats 48 hours before treatment with cisplatin (11 mg/kg ip) reduced threshold shifts in ABRs and protected OHCs from damage.52 Conclusions and future directions Experimental studies support the effectiveness of IT application of medications to protect inner ear structures and hearing against cisplatin ototoxicity. Options range from medications already in use for IT treatment of other inner ear disorders, such as dexamethasone, to new therapeutic approaches emerging from a better understanding of the pathophysiology of ototoxicity, such as siRNA targeting NADPH oxidases. The results reviewed here suggest a promising future in protecting hearing against cisplatin ototoxicity. Additional experimental studies, however, are needed to address efficacy of above treatment options in the presence of other risk factors, such as pre-existing hearing loss. It is important to recognize that advancing age is a high risk factor for cancer, with persons over 65 accounting for 60% of newly diagnosed malignancies and 70% of all

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cancer deaths.56, 57 The incidence of cancer in those over 65 is 10 times greater than in those younger than 65. A major gap in our knowledge exists on how ototoxicity interacts with presbycusis. A synergistic interaction between presbycusis and cisplatin ototoxicity is likely. Indeed, older cancer patients being treated with cisplatin show statistically significant greater incidence of ototoxicity.58 As the elderly form the majority of cancer patients, the oto-protective effects of corticosteroids against cisplatin would have to be demonstrated in aged models. Importance of such studies is emphasized by the knowledge that the aging process,59 in general, and presbycusis,60 specifically, are associated with generation and accumulation ROS. Due to age-related depletion, the aging cochlea may not have sufficient reserve of antioxidant enzymes, that IT rescue drugs such as dexamethasone have to activate in order to preserve hearing in the face of cisplatin ototoxicity. This work is currently underway in my laboratory. Riassunto
Trattamento intratimpanico dellototossicit correlata a chemioterapia Lototossicit indotta da cisplatino un comune effetto collaterale dei regimi di chemioterapia utilizzati nel trattamento di diversi tipi di tumori maligni solidi. Lototossicit da cisplatino mediata da numerosi meccanismi cellulari che determinano laccumulo di specie reattive dellossigeno (ROS) e lapoptosi. I bersagli del cisplatino nella coclea sono le cellule ciliate esterne (OHC), le cellule spirali ganglionari e la stria vascularis. Attualmente, vi sono numerosi trials clinici atti a valutare lefficacia di sostanze antiossidanti nel migliorare gli effetti collaterali ototossici del cisplatino. Tuttavia, la somministrazione sistemica di antiossidanti potrebbe interferire con le propriet anti-neoplastiche dei regimi chemioterapici. La somministrazione intratimpanica (IT) di farmaci offre una via alternativa per la somministrazione di farmaci rescue a livello della coclea per minimizzare lassorbimento sistemico, riducendo cos il rischio di alterare lefficacia dei regimi di chemioterapia. In questo articolo, lautore fornisce una revisione dellevidenza sperimentale disponibile sullefficacia della terapia IT nella funzione protettiva auricolare dallototossicit del cisplatino. Tra i farmaci promettenti, vi il desametasone, attualmente utilizzato nel trattamento di malattie dellorecchio interno. Le ricerche pi recenti hanno migliorato le nostre conoscenze nei meccanismi cellulari che determinano lototossicit e hanno permesso lemergenza di strategie terapeutiche mirate, come lapplicazione

IT di un breve interfering RNA per inibire la NADPH ossidasi, generatore di ROS. I risultati sperimentali riproposti in questo articolo mostrano un futuro promettente nella protezione dellorecchio dallototossicit indotta dal cisplatino. Parole chiave: Cisplatino - Apoptosi.

References
1. Furuta T, Ueda T, Aune G, Sarasin A, Kraemer KH, Pommier Y. Cancer Res 2002; 62:4899-902. 2. Rybak LP, Whitworth CA. Ototoxicity: therapeutic opportunities. Drug Discov Today 2005;10:1313-21. 3. Bokemeyer C, Berger CC, Hartmann JT, Kuczyk MA, Truss MC, Kollmannsberger C et al. Analysis of risk factors for cisplatininduced ototoxicity in patients with testicular cancer. Br J Cancer 1998;77:1355-62. 4. Biro K, Noszek L, Prekopp P, Nagyivanyi K, Geczi L, Gaudi et al. Characteristics and risk factors of cisplatin-induced ototoxicity in testicular cancer patients detected by distortion product otoacoustic emission. Oncology 2006;70:177-84. 5. Laurell G. High-dose cisplatin treatment: hearing loss and plasma concentrations. Laryngoscope 1990;100:724-34. 6. Blakley BW, Gupta AK, Myers SF, Schwan S. Risk factors for ototoxicity due to cisplatin. Arch Otolaryngol Head Neck Surg 1994;120:541-6. 7. Komune S, Asakuma S, Snow JBJ. Pathophysiology of the ototoxicity of cis-diamminedichloroplatinum, Otolaryngol. Head Neck Surg 1981;89:275-82. 8. Nakai Y, Konishi K, Chang KC, Ohashi K, Morisaki N, Minowa Y et al. Ototoxicity of the anticancer drug cisplatin. An experimental study. Acta Otolaryngol (Stockh) 1982;93:227-32. 9. Van Ruijven MWM, de Groot JCMJ, Klis SFL, Smoorenburg G. Cochlear targets of cisplatin: an electrophysiological and morphological time-sequence study. Hear Res 2005;205:241-8. 10. Hartmann JT, Lipp HP. Toxicity of platinum compounds. Expert Opin Pharmacother 2003;4:889-901. 11. Hellberg V, Wallin I, Eriksson S, Hernlund E, Jerremalm E, Berndtsson M et al. Cisplatin and oxaliplatin toxicity: importance of cochlear kinetics as a determinant for ototoxicity. J Natl Cancer Inst 2009;101:37-47. 12. MacDonald MR, Harrison RV, Wake M, Bliss B, MacDonald RE. Ototoxicity of carboplatin: Comparing animal and clinical models at the Hospital for Sick Children. J Otolaryngol 1994;23:151-9. 13. Malhotra NK, Aslam R, Lipman SP, Bilski VJ. Acute ototoxicity from a single infusion of oxaliplatin. Ear Nose Throat J 2010;89:25861. 14. Ross CJ, Katzov-Eckert H, Dub MP, Brooks B, Rassekh SR, Barhdadi A et al.;CPNDS Consortium. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat Genet 2009;41:1345-9. 15. Cepeda V, Fuertes MA, Castilla J, Alonso C, Quevedo C, Perez JM. Biochemical mechanisms of cisplatin cytotoxicity. Anticancer Agents Med Chem 2007;7:3-18. 16. Rebillard A, Lagadic-Gossmann D, Dimanche-Boitrel MT. Cisplatin cytotoxicity:DNA and plasma membrane targets. Curr Med Chem 2008;15:2656-63. 17. Dunaway G, Mhaskar Y, Armour G, Withworth C, Rybak L. Migration of cochlear lateral wall cells. Hear Res 2004;177:1-11. 18. Alam SA, Ikeda K, Oshima T, Suzuki M, Kawase T, Kikuchi T et al. Cisplatin-induced apoptotic cell death in Mongolian gerbil cochlea. Hear Res 2000;141:28-38. 19. Clerici WJ, DiMartino DL, Prasad MR. Direct effect of reactive oxygen species on cochlear outer hair cells. Hear Res 1995;84:30-40.

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20. Dehne N, Lautermann J, Petrat, Rauen U, de Groot H. Cisplatin ototoxicity:involvement of iron and enhanced formation of superoxide anion radicals. Toxicol Appl Pharmacol 2001;174:27-34. 21. Zelck U, Norwak R, Karnstedt U, Koitschev A, Kacher N. Specific activities of antioxidant enzymes in the cochlea of guinea pigs at different stages of development. Eur Arch Otorhinolaryngol 1993;250:218-9. 22. Yao X, Rarey KE. Detection and regulation of Cu/Zn-SOD and MnSOD in rat cochlear tissues. Hear Res 1996;96:199-203. 23. Rybak LP, Whitworth CA, Mukherjea D, Ramkumar V. Mechanisms of cisplatin-induced ototoxicity and prevention. Hear Res 2007;226:157-67. 24. Rybak LP, Mukherjea D, Jajoo S, Ramkumar V. Cisplatin ototoxicity and protection:clinical and experimental studies. Tohoku J Exp Med 2009;219:177-86. 25. Somani SM, Husain K, Jagannathan R, Rybak LP. Amelioration of cisplatin-induced oto- and nephrotoxicity by protective agents. Ann Neurosci 2001;8:101-13. 26. Mukherjea D, Jajoo S, Whitworth C, Bunch JR, Turner JG, Rybak LP et al. Short interfering RNA against transient receptor potential vanilloid 1 attenuates cisplatin-induced hearing loss in the rat. J Neurosci. 2008;28:13056-65. 27. Kim HJ, Lee JH, Kim SJ, Oh GS, Moon HD, Kwon KB et al. Roles of NADPH oxidases in cisplatin-induced reactive oxygen species generation and ototoxicity. J Neurosci. 2010;30:3933-46. 28. Garca-Berrocal JR, Nevado J, Gonzlez-Garca JA, Snchez-Rodrguez C, Sanz R, Trinidad A et al. Heat shock protein 70 and cellular disturbances in cochlear cisplatin ototoxicity model. J Laryngol Otol 2010;124:599-609. 29. Hargunani CA, Kempton JB, DeGagne JM, Trune DR. Intratympanic injection of dexamethasone:time course of inner ear distribution and conversion to its active form. Otol Neurotol 2006;27:5649. 30. Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids:an animal study followed by clinical application. Laryngoscope 1999;109:1-17. 31. Chandrasekhar SS, Rubinstein RY, Kwartler JA, Gatz M, Connelly PE, Huang E et al. Dexamethasone pharmacokinetics in the inner ear:comparison of route of administration and use of facilitating agents. Otolaryngol Head Neck Surg 2000;122:521-8. 32. Bird PA, Begg EJ, Zhang M, Keast AT, Murray DP, Balkany TJ. Intratympanic Versus Intravenous Delivery of Methylprednisolone to Cochlear Perilymph. Otol Neurotol 2007;28:1124-30. 33. Doyle KJ, Bauch C, Battista R, Beatty C, Hughes GB, Mason et al. Intratympanic steroid treatment:a review. Otol Neurotol 2004;25:1034-9. 34. Herr I, Ucur E, Herzer K, Okouoyo S, Ridder R, Krammer PH, von Knebel Doeberitz M et al. Glucocorticoid cotreatment induces apoptosis resistance toward cancer therapy in carcinomas. Cancer Res 2003;63:3112-20. 35. Kolls J, Xie J, LeBlanc R, Malinski T, Nelson S, Summer W, Greenberg SSl. Rapid induction of messenger RNA for nitric oxide synthase II in rat neutrophils in vivo by endotoxin and its suppression by prednisolone. Proc Soc Exp Biol Med 1994;205:220-9. 36. Nagura M, Iwasaki S, Wu R, Mizuta K, Umemura K, Hoshino T. Effects of corticosteroid, contrast medium and ATP on focal microcirculatory disorders of the cochlea. Eur J Pharmacol 1999;366:47-53. 37. Henry KR. Noise-induced auditory loss:influence of genotype, naloxone and methyl-prednisolone. Acta Otolaryngol 1992;112:599603. 38. Takemura K, Komeda M, Yagi M, Chiemi H, Izumikawa M, Doi T et al. Direct inner ear infusion of dexamethasone attenuates noiseinduced trauma in guinea pig. Hear Res 2004;196:58-68. 39. Tabuchi K, Oikawa K, Murashita H, Hoshino T, Tsuji S, Hara A. Protective effects of corticosteroids on ischemia-reperfusion injury of outer hair cells. Laryngoscope 2006;116:627-9. 40. Maetani T, Hyodo J, Takeda S, Hakuba N, Kiyofumi G. Prednisolo-

41. 42. 43. 44. 45. 46.

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ne prevents transient ischemia-induced cochlear damage in gerbils. Acta Otolaryngol Suppl 2009;562:24-7. James DP, Eastwood H, Richardson RT, OLeary SJ. Effects of round window dexamethasone on residual hearing in a Guinea pig model of cochlear implantation. Audiol Neurootol 2008;13:86-96. Himeno C, Komeda M, Izumikawa M, Takemura K, Yagi M, Weiping Y et al. Intra-cochlear administration of dexamethasone attenuates aminoglycoside ototoxicity in the guinea pig. Hear Res 2002;67:61-70. Park SK, Choi D, Russell P, John EO, Jung TT. Protective effect of corticosteroid against the cytotoxicity of aminoglycoside otic drops on isolated cochlear outer hair cells. Laryngoscope 2004;114:768-71. Hori H, Kanno H. An experimental study of the protective effect of lazaroid (U-74389G) on cisplatin-induced toxicity. Nippon Jibiinkoka Gakkai Kaiho 1999;102:8-18. Hill GW, Morest DK, Parham K. Cisplatin-induced ototoxicity:Effect of intratympanic dexamethasone injections. Otology & Neurotology 2008;29:1005-11. Paksoy M, Ayduran E, Sanl A, Eken M, Aydn S, Oktay ZA. The protective effects of intratympanic dexamethasone and vitamin E on cisplatin-induced ototoxicity are demonstrated in rats. Med Oncol. 2010 Mar 19. [Epub ahead of print]). Saliba I, El Fata F, Ouelette V, Robitaille Y. Are intratympanic injections of N-acetylcysteine and methylprednisolone protective against Cisplatin-induced ototoxicity? J Otolaryngol Head Neck Surg 2010;39:236-43. So H, Kim H, Lee JH, Park C, Kim Y, Kim E et al. Cisplatin cytotoxicity of auditory cells requires secretions of proinflammatory cytokines via activation of ERK and NF-kappaB. J Assoc Res Otolaryngol 2007;8:338-55. Whitworth CA, Ramkumar V, Jones B, Tsukasaki N, Rybak LP. Biochem Pharmacol. 2004;67:1801-7. Choe WT, Chinosornvatana N, Chang KW. Prevention of cisplatin ototoxicity using transtympanic N-acetylcysteine and lactate. Otol Neurotol 2004;25:910-5. Nader ME, Thort Y, Saliba I. The role of intratympanic lactate injection in the prevention of cisplatin-induced ototoxicity. Laryngoscope 2010;120:1208-13. Mukherjea D, Jajoo S, Kaur T, Sheehan KE, Ramkumar V, Rybak LP. Transtympanic Administration of Short Interfering (si)RNA for the NOX3 Isoform of NADPH Oxidase Protects Against CisplatinInduced Hearing Loss in the Rat. Antioxid Redox Signal [Internet]. 2010 June 6. [Epub ahead of print]). Korver KD, Rybak LP, Whitworth C, Campbell KM. Round window application of D-methionine provides complete cisplatin otoprotection. Otolaryngol Head Neck Surg 2002;126:683-9. Tanaka F, Whitworth CA, Rybak LP. Influence of pH on the ototoxicity of cisplatin:a round window application study. Hear Res 2003;177:21-31. Tanaka F, Whitworth CA, Rybak LP. Round window pH manipulation alters the ototoxicity of systemic cisplatin. Hear Res 2004;187:44-50. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg LX et al. SEER Cancer Statistics Review, 1973-1998. National Institute of Health publication 00-2789, 2000. NIA/NCI Report of the Cancer Center Workshop (June 1315, 2001). Exploring the Role of Cancer Centers for Integrating Aging and Cancer Research [Internet]. Available from:http://www.nia.nih. gov/Research Information/ConferencesAndMeetings/WorkshopReport/ExecutiveSummary.htm. Laurell G. Borg E. Ototoxicity of cisplatin in gynaecological cancer patients. Scandinavian Audiology 1988;17:241-7. Krause KH. Aging:a revisited theory based on free radicals generated by NOX family NADPH oxidases. Exp Gerontol 2007;42:256-62. Seidman MD, Ahmad N, Joshi D, Seidman J, Thawani S, Quirk WS. Age-related hearing loss and its association with reactive oxygen species and mitochondrial DNA damage. Acta Otolaryngol Suppl 2004;552:16-24.

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Techniques of intratympanic administration

D. MARCHESE, F. RIGGIO, S. GALLINA, R. SPECIALE

The purpose of this review is to examine the most recent literature regarding the application of transtympanic inner ear perfusion in the treatment of auditory and vestibular disfunction. Transtympanic delivery of medications to the inner ear has been a rapidly expanding field in otolaryngology, and clinically more relevant, with understanding of pharmacokinetics becoming more closely studied. Emerging therapy like nanoparticles and facilitators are being explored. Advanced therapy development will likely require direct intracochlear delivery . Potential uses for such devices include neurotrophic factors. Recent studies about nanotechnology and molecular therapy have pushed development of alternate delivery methodologies involving both transtympanic and direct intracochlear infusions. Key words: Hearing loss - Menire disease - Ear, inner.

Division of Otolaryngology Department of Biomedicine and Clinical Neurosciences University of Palermo, Palermo, Italy

ince its original introduction by Schuknecht in 1956 for the treatment of Menire disease,1 inner ear perfusion has been used in a variety of other disorders, including sudden sensorineural hearing loss, tinnitus, and autoimmune inner ear disease. Potential advantages of transtympanic perfusion as compared with systemic drug administration include: higher concentration of medication given in the inner ear, the diseased ear is treated directly without affecting the other ear or other organ systems, and potential side effects to the rest of the body are avoided.2 The successful application of this technique therefore depends not only on the properties of the medication, but also on its diffusion characteristics across the round window
Corresponding author: Dr. D. Marchese, Department of Otolaryngology, University of Palermo, Palermo, Italy. E-mail: marchesedonatella@hotmail.com

(RW). Silverstein demonstrated that in up to 30% of ears the RW membrane is at least partially obscured by mucosal membranes, which can interfere with delivery of medication to the RW membrane (RWM).3 The principal paths of communication for drugs between the middle and the inner ears are the round window membrane and the annular ligament of the footplate of the stapes.4 RWM is a semi-permeable membrane that is lined on the middle ear side with cuboidal epithelial cells joined by tight junctions and lined on the inner ear side with mesothelial cells that often are intermittent.5 Between these lining layers are loosely organized collagen and elastic fibers, fibrocytes and fibroblasts, occasional blood vessels, and nerve fibers. The lack of an organized epithelial barrier on the scala tympani side means the fibrous layer is bathed in perilymph. Although tight junctions join epithelial cells on the middle ear side, molecules as large as 1 m can pass through this layer into the inner ear either intercellulary or transcellulary via pinocytosis. Thus, the round window membrane provides little impediment to the movement of most drugs or other molecules into the inner ear. Although the human round window membrane (60-70 m) is thicker than most experimental rodents (10-15 m), they are essentially similar in the fact that the only real barrier is the single layer of epithelial cells on the middle

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ear side. Although this minimal anatomical barrier appears to offer little protection to the inner ear, a recent study on monkeys 6 suggests that mucous glands around the round window and extensive inflammatory cell populations within the round window vessels provide a basic immunological defence to the cochlea. The glands secrete macromolecules that form a physical barrier to trap pathogens and other toxic agents, which are then degraded and phagocytosed by the immune cells. This mucous membrane over the round window has been discussed as a barrier to intratympanic drug movement into the cochlea.5 Some factors may modify the round window permeability. The most important of these are inflammation of middle ear mucosa,4 the eustachian tube function, the size and the shape of the round window niche, and the thickness of the fibrous membranes overlying the round window, which can be altered from blood and bone dust by a previous transmastoid surgery.7 Loss of medication via the Eustachian tube is another anatomic consideration that can make middle ear application of medication variable. Transtympanic drug delivery is generally accomplished by one of three methods: blind injection into the middle ear cavity through the tympanic membrane,8 sustained or periodic delivery with a microcatheter 9 or MicroWick 10 positioned at the RWM, or placement of a stabilizing matrix within the round window niche to provide passive sustained release of pharmacological agents. These approaches rely on transport through the RWM. No significant clinical difference in these approaches has been observed,11 although animal testing and computer modeling provide evidence that sustained release approaches result in greater control of drug concentration in the inner ear.12, 13 The most commonly used method worldwide is the direct perfusion into the middle ear. Direct intratympanic injection The patients ear is anesthetized with local injection or topical anesthetic. Under microscopic visualization, a 27-gauge needle is used to inject medication into the inner ear over the area of the round window niche. The head is placed in position 45 toward the unaffected ear. On completion of injection, the head is turned toward the affected side and then back away to the original position. This manoeuvre is performed in attempt to maximize exposure of the

solution in middle ear space to the round window membrane. A second injection may be immediately performed if the first was felt to be inadequate or if inspection of the middle ear shows a predominantly air-filled middle ear space. They maintain this position for a specified amount of time, usually 15 to 30 minutes. The decision for 30 min was arbitrary; however, a recent study 14 showed that it is an optimal time for diffusion through the round window membrane. An alternative is to place a tympanostomy tube in the tympanic membrane over the area of the round window. This can be used for performing serial injections through the tubes lumen over several weeks. Placement of a tympanostomy tube (Figure 1) comes with a small, but real, risk of persistent perforation of the tympanic membrane on extrusion of the tube, otorrhea associated with the presence of the tube, and the need to keep the ear dry to avoid a middle ear infection. There are several advantages of intratympanic drugs. The procedure is well tolerated and relatively easy to perform. Its relatively painless and rapidly administrated after diagnosis. As an office-based procedure done under local (topical) anesthesia, there is an avoidance of general anesthesia. Most patients understand the concept of intratympanic injection and readily accept the proposed therapy. Unlike systemic therapies, intratympanic therapy allows for the selection of the affected ear to be treated. In addition, the local application, bypasses the blood-laby-

Figure 1.Placement of a tympanostomy tube.

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rinthine barrier, resulting in higher concentrations in the inner ear fluids despite the lower total amount of drug given, and avoiding major unwanted effects of systemically administered medications. The primary disadvantage of intratympanic drugs (i.e. steroids), is the lack of proven efficacy and/or superiority over systemic steroids. Other potential disadvantages include tympanic membrane perforation, pain, otitis media, vertigo (usually temporary), and the potential for further hearing loss.15 Acute and sustained infusion to the round window membrane Single transtympanic injections, continuous infusions, and periodic infusions have been used extensively, with excellent clinical reviews presented by Hoffmann and Silverstein 16 and Hoffer et al.17 Animal studies are used to explore details of drug distribution and cellular impact with acute and sustained infusions to the RWM. Roehm et al.18 examined gentamicin uptake in the chinchilla inner ear with single injections through the tympanic membrane, and sustained delivery with an osmotic pump with consistent

staining patterns independent of exposure time and cochlear turn. The authors indicate this could be due to saturation of cellular uptake at all sites masking an apicalbasal gradient. Such a gradient was measured in guinea pigs by Plontke et al.19 with continuous gentamicin application to the RWM resulting in scala tympani basal concentration of gentamicin 4000 more than that at the apex. Plontke et al.20 also measured a strong basal-apical concentration gradient of dexamethasone in guinea pig perilymph following administration directly onto the RWM. He predicts a smaller gradient in the mouse, and more significant gradients in the larger human cochlea, which may contribute to variance in clinical treatment efficacy and pose problems for drugs with a narrow therapeutic range. However, animal studies have demonstrated greater hair cell loss throughout the cochlea with single-dose gentamicin application to the RWM than continuous administration at the same dose.13 Silverstein-Micro-Wick The Micro-Wick, designed by Herbert Silverstein (Figure 2), allows self-medication of patients being treated with transtympanic drugs. It comprises a spe-

Silverstein microwick
Semicircular canals Malieus Incus Staples Microwick

Silicone vent tube

Tympanic membrane

Eustachian tube

Figure 2.Introducing the Silverstein MicroWick.

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cial ventilation tube together with a PVA sponge wick, which is placed through the lumen of the ventilation tube and located on the round window membrane. Once the wick is hydrated it becomes locked in position, and when the patient applies the medication it is absorbed by the wick and transported to the round window where it diffuses through the membrane into the inner ear. It can be placed under local anaesthesia in a non-certified office minor surgery room. A vertical myringotomy or a bloodless opening is made with the CO2 laser over the round window niche. Usually, the round window can be seen through a normal tympanic membrane as a shadow beneath the tympanic membrane. The round window niche lies posterior (3.44 mm, SD68 mm) and slightly inferior to the umbo of the malleus (113, SD9.8).20 Any obstructing membranes over the round window niche are removed with a small pick. The MicroWick is made from polyvinyl acetate and measures 1 mm in diameter and 9 mm in length. It is small enough to insert through a 1.42-mm inner diameter vent tube into the round window niche. The MicroWick is saturated, and middle ear is injected with 0.2 cc of the medication delivering a high concentration of the medication to the round window and allowing perfusion into the inner ear. Patients then continue to self-administer the medication on a scheduled basis. When therapy is complete, the MicroWick and tube are removed without the use of anesthesia. The tympanic membrane is then allowed to heal. This technique of patient self-treatment using the MicroWick to deliver medications to the inner ear is minimally invasive, inexpensive, safe, effective, and well tolerated for treating Menires disease and other inner ear conditions. Potential drawbacks to the use of the Silverstein MicroWick may include the development of a persistent perforation of the tympanic membrane, infection of the middle or external ear, and the potential for tissue ingrowth in the middle ear either in the form of fibrosis or epithelial ingrowth leading to cholesteatoma. Despite these potential complications, in a series of 69 patients with Menires disease treated with gentamicin delivered through the Silverstein MicroWick, no long -term complications were noted.21 RWM Despite its invasiveness, the temporary implantation of a microcatheter into the middle ear cavity is

Tip end view

Section A-A

Fluid in

Fluid out

Electrode

Section A-A

Figure 3.Inner ear fluid delivery micro-catheter: Designed to allow controlled delivery of fluid to the round window membrane for the treatment of inner ear disorders. Platinum electrode is for recording electrocochleograghy.

an appropriately safe method for providing continuous drug delivery to the inner ear (Figure 3). It has recently been demonstrated that the choice of the drug delivery system influences the pharmacokinetics in the inner ear. If a continuous drug application over several weeks is required, a secure placement of the delivery device (i.e., the microcatheter) is necessary to guarantee efficient drug delivery and to avoid unwanted side effects. The standardized surgical implantation and fixation technique developed for the microcatheter were characterized by six elements: 1) a medial and a lateral tunnel connected by a groove in the posterior wall of the bony ear canal; 2) stabilization of the catheter with bone wax and soft tissue plugs in the tunnels; 3) an ear canal packing; 4) a series of fixating sutures along the catheter; 5) an adhesive dressing; and 6) additional tapes at the connecting line between pump and catheter.9 At the end of the implantation period, the catheter was removed by a second surgical procedure allowing for evaluation of the catheter position and the condition of the middle ear space. Adverse events includ: catheter dislocation, catheter obstruction, formation of mild granulation tissue in the middle ear cavity, tympanic membrane defects, and ear canal skin defects. With introduction of an improved implantation and fixa-

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tion technique, the number of catheter dislocations could be significantly reduced. The microcatheter technique is performed in the hospital, and the procedure is expensive. Stabilizing matrices The use of stabilizing matrices offers many potential benefits over middle ear perfusions. Medications delivered to the middle ear are ultimately dissipated by drainage down the Eustachian tube or absorption by middle ear mucosa unless a stabilizing matrix is used. For potentially toxic agents, this raises significant concerns regarding isolation to target tissues. This, coupled with superior control of dosing profiles, suggests future transtympanic delivery methodologies are likely to focus on techniques utilizing stabilizing gel matrices for passive sustained release. An excellent review of several different controlled release systems is provided by Nakagawa and Ito.22 Patterns of ototoxic damage in gerbils with sustained delivery of gentamicin using gelfoam, hyaluronic acid, and fibrin were compared by Sheppard et al.23 with a fibrin and gelfoam combination found to be most effective. Chitosan-glycerophosphate hydrogel, a liquid at room temperature and a biodegradable gel at body temperature, allows injection into the round window niche and facilitates close contact between the matrix and the RWM. This material has been used successfully in mouse studies to deliver dexamethasone to the inner ear through the RWM 24 and has tuneable delivery properties. Some potential drawbacks human inner ear disease may include the need for accurate placement directly over the round window to permit transfer of drug to the inner ear, the potential for transient conductive hearing loss if the middle ear is overfilled with hydrogel, and the relatively quick release profile of most hydrogels under study (the majority of drug is released over several days) may not be ideal for chronic conditions.21 Facilitators Uptake of medication through the RWM may be enhanced by the use of certain facilitators. Histamine has potential vasodilatory and increased per-

meability effects on the RWM, hyaluronic acid (HA) has known osmotic effects, and dimethylsulfoxide (DMSO), an organic solvent, may increase solubility of medication in perilymph.25, 26 Injection details The histamine (Sigma Chemical Co) concentration was 1 mg/mL dissolved in 0.9% saline solution. This dose was derived from the concentration used in dogs to study the effect of inflammatory mediators on middle ear vasodilatation: edema and permeability of middle ear mucosa.25, 27 The concentration of the osmotic agent hyaluronic acid (HA) (Sigma Chemical Co), which was 9.5 mg/mL dissolved in 0.9% saline solution, was derived from studies conducted on the fate of HA in the middle ears of rats.28 Dimethylsulfoxide (DMSO) (Sigma Chemical Co) was used without dilution to obtain the maximum benefit from this organic solvent. Histamine appears to be a potent facilitating agent to improve transport of dexamethasone across the RWM. HA as a facilitator has the potential for prolonging RWM exposure to dexamethasone. Topical dexamethasone application does not result in systemic absorption. The clinical implications for treatment are considerable. Advantages of such therapy are not yet available in human model, but further studies are required. Nanoparticles Nanoparticles are another methodology of medication delivery to the inner ear that has generated considerable interest in the past several years. Nanoparticles are particles with diameters 1000 nm and are typically in the size range of 200 nm or less when used for drug deliveryto the inner ear. Nanoparticles have a demonstrated ability to readily cross the RWM and quickly incorporate into membranes and cells of the organ of Corti. Mechanisms of transport have not been fully elucidated although size is assumed to be a key factor enabling rapid diffusion and transport across membanes. Because this technology remains in a very early stage of development and is likely to requie substantial further investigation before human application to treat inner ear disease, an extensive discussion of the potential drawbacks for this application is premature.21

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Intracochlear delivery A more invasive approach with the potential for much greater control is direct intracochlear delivery of therapeutic and curative agents. This method eliminates dependence on RWM permeability and can provide better isolation of the delivered agent to the target tissues. Intracochlear delivery of drugs or genes has been successfully accomplished in animal models by injection through the RWM,29 injection into the endolymphatic space via the scala media 30, 31 and endolymphatic sac,32 and injection or infusion into the perilymphatic space via the semicircular canals,33 scala vestibule,34, 35 and most commonly the scala tympani.36-41 Endolymph injections have provided exciting cochlear hair cell regeneration results 30 but generally impact auditory function making them unlikely avenues for clinically relevant therapies. Protocols involving continous perfusion into the scala tympani will result in expulsion of fluid through the cochlear aqueduct unless a fluidic exit route is provided within the cochlea. This is a clear disadvantage compared with transtympanic administration to the RWM. A perilymphatic inoculation route is technically easier and therefore more feasible for clinical applications. The most promising infusion approaches involve a cochleostomy in the basal turn of the scala tympani with a microcannula connected to a syringe pump for acute infusions or an implantable osmotic pump for more chronic infusions.

favorable evidence of the potential for effective genebased deafness therapies. Staecker et al.48 recently demonstrated regeneration of vestibular hair cells and restoration of balance function in mice with acute injection of Admath1.11D into scala tympani. Effective, specific and safe delivery vectors are critical for gene-based therapies, but therapeutic efficacy will greatly depend on intracochlear delivery providing isolation to target tissues and distribution throughout the cochlea and vestibular system. The authors suggest the small size of the adeno-associated virus (AAV) vectors (11-22 nm) may allow dissemination from perilymph to endolymph whereas larger vector systems such as adenovirus (75 nm) and retrovirus or lentivirus (>100 nm) have not. This observation is consistent with results using nanoparticles of dimensions less than 50 nm, which distribute quickly and traverse cochlear membranous partitions. Riassunto
Tecniche di somministrazione transtimpanica Questo articolo si propone di esaminare la pi recente letteratura riguardante lapplicazione della infusione di farmaci per via transtimpanica nel trattamento delle disfunzioni vestibolari e uditive. Limpiego di tale tecnica un campo in rapida espansione in otorinolaringoiatria, e diverr clinicamente pi rilevante, con lapprofondimento delle conoscenze di farmacocinetica. Terapie emergenti quali nanoparticelle e facilitatori sono attualmente oggetto di studio. Lo sviluppo di terapie avanzate comporter limpiego di farmaci direttamente intracocleari. Potenziali impieghi riguardano anche i fattori neurotrofici. Studi recenti riguardo la nanotecnologia e la terapia molecolare determineranno uno sviluppo di terapie alternative sia per infusioni transtimpaniche che intracocleari. Parole chiave: Perdita di udito - Malattia di Menire Orecchio interno.

Molecular therapies Molecular therapies for protection of spiral ganglion neurons and hair cells in degenerative diseases and ototoxic insult, and auditory and vestibular hair cell regeneration require delivery of target genes and exogenous cells to cochlear structures. Significant work in this area has been reviewed by Staecker et al.42 and Richardson et al.43 Enhanced survival of neurons in the spiral ganglion following ototoxic insult has been demonstrated with overexpression of neurotrophin-3,44 brainderived neurotrophic factors,45 and glial cell-derived neurotrophic factor.46 Recent work with scala media inoculation demonstrated hair cell regeneration mediated by Math1 overexpression in the intact cochlea,30, 47 providing

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29. Staecker H, Li D, OMalley BW, Van De Water TR. Gene expression in the mammalian cochlea: a study of multiple vector systems. Acta Otolaryngol 2001;121:157-63. 30. Izumikawa M, Minoda R, Kawamoto K, Abrashkin KA, Swiderski DL, Dolan DF et al. Auditory hair cell replacement and hearing improvement by Atoh1 gene therapy in deaf mammals. Nat Med 2005;11:271-6. 31. Ishimoto S-i, Kawamoto K, Kanzaki S, Raphael Y. Gene transfer into supporting cells of the organ of Corti. Hear Res 2002;173:18797. 32. Yamasoba T, Yagi M, Roessler BJ, Miller JM, Raphael Y. Inner ear transgene expression after adenoviral vector inoculation in the endolymphatic sac. Hum Gene Ther 1999;10:769-74. 33 Kawamoto K, Oh SH, Kanzaki S, Brown N, Raphael Y. The functional and structural outcome of inner ear gene transfer via the vestibular and cochlear fluids in mice. Mol Ther 2001;4:575-85. 34. Suzuki M, Yagi M, Brown JN, Miller AL, Miller JM, Raphael Y. Effect of transgenic GDNF expression on gentamicin-induced cochlear and vestibular toxicity. Gene Ther 2000;7:1046-54. 35. Bowers WJ, Chen X, Guo H, Frisina DR, Federoff HJ, Frisina RD. Neurotrophin-3 transduction attenuates cisplatin spiral ganglion neuron ototoxicity in the cochlea. Mol Ther 2002;6:12-8. 36. Kingma GG, Miller JM, Myers MW. Chronic drug infusion into the scala tympani of the guinea pig cochlea. J Neurosci Methods 1992;45:127-34. 37. McGuinness SL, Shepherd RK. Exogenous BDNF rescues rat spiral ganglion neurons in vivo. Otol Neurotol 2005;26:1064-72. 38. Chen Z, Mikulec AA, McKenna MJ, Sewell WF, Kujawa SG. A method for intracochlear drug delivery in the mouse. J Neurosci Methods 2006;150:67-73. 39. Wang J, Pignol B, Chabrier P-E, Saido T, Lloyd R, Tang Y, Lenoir M et al. A novel dual inhibitor of calpains and lipid peroxidation (BN82270) rescues the cochlea from sound trauma. Neuropharmacology 2007;52:1426-37. 40. Eshraghi AA, Adil E, He J, Graves R, Balkany TJ, Van De Water TR. Local dexamethasone therapy conserves hearing in an animal model of electrode insertion trauma-induced hearing loss. Otol Neurotol 2007;28:842-9. 41. Stver T, Paasche G, Lenarz T, Ripken T, Breitenfeld P, Lubatschowski H et al. Development of a drug delivery device: using the femtosecond laser to modify cochlear implant electrodes. Cochlear Implants Int 2007;8:38-52. 42. Staecker H, Brough DE, Praetorius M, Baker K. Drug delivery to the inner ear using gene therapy. Otolaryngol Clin North Am 2004;37:1091-108. 43. Richardson RT, Noushi F, OLeary S. Inner ear therapy for neural preservation. Audiol Neurootol 2006;11:343-56. 44. Bowers WJ, Chen X, Guo H, Frisina DR, Federoff HJ, Frisina RD. Neurotrophin-3 transduction attenuates cisplatin spiral ganglion neuron ototoxicity in the cochlea. Mol Ther 2002;6:12-8. 45. Nakaizumi T, Kawamoto K, Minoda R, Raphael Y. Adenovirusmediated expression of brain-derived neurotrophic factor protects spioral ganglion neurons from ototoxic damage. Audiol Neurootol 2004;9:135-43. 46. Liu Y, Okada T, Shimazaki K, Sheykholeslami K, Nomoto T, Muramatsu S et al. Protection against aminoglycoside-induced ototoxicity by regulated AAV vector-mediated GDNF gene transfer into the cochlea. Mol Ther 2008;16:474-80. 47. Kawamoto K, Ishimoto S, Minoda R, Brough DE, Raphael Y. Math1 gene transfer generates new cochlear hair cells in mature guinea pigs in vivo. J Neurosci 2003;23:4395-400. 48. Staecker H, Praetorius M, Baker K, Brough DE. Vestibular hair cell regeneration and restoration of balance function induced by math1 gene transfer. Otol Neurotol 2007;28:223-31.

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