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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
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Page 1: Otorinolaringologia MINERVA intratympanic

RIVISTA TRIMESTRALE DIOTORINOLARINGOLOGIA,

AUDIOLOGIAFONIATRIA, CHIRURGIA

CERVICO-FACCIALEMAXILLO-FACCIALE

PLASTICA RICOSTRUTTIVAOTONEUROCHIRURGIA

VOL.60 No.3SETTEMBRE 2010

Intratympanic therapies for inner ear disorders

Guest Editors: A. De Stefano, F. Dispenza

Page 2: Otorinolaringologia MINERVA intratympanic

This journal is PEER REVIEWED and is quoted in: EEMMBBAASSEE//EExxcceerrppttaa MMeeddiiccaaRedazione - Edizioni Minerva Medica - Via Lamarmora 3 - 20122 Milano - Tel. (02) 55.18.43.79 - 59.90.00.41 - Fax (02) 55.18.09.54Direzione, ufficio grafico, ufficio pubblicità, fotocomposizione, amministrazione - Edizioni Minerva Medica - Corso Bramante 83-85 - 10126 Torino - Tel. (011) 67.82.82 - Fax (011) 67.45.02 - E-mail: [email protected] Site: www.minervamedica.itStampa - Edizioni Minerva Medica - Tipografia di Saluzzo - Corso IV Novembre 29-31 - 12037 Saluzzo (CN) - Tel. (0175) 249405 - Fax (0175) 249407Abbonamento 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, INTESASANPAOLO Agenzia n. 18 Torino. IBAN: IT45 K030 6909 2191 0000 0002 917 c) conto corrente postale 00279109 intestato a Edizioni MinervaMedica, Corso Bramante 83-85, 10126 Torino; d) carte di credito Diners Club International, Master Card, VISA, American ExpressI cambi di indirizzo di spedizione, e-mail o di qualsiasi altro dato di abbonamento vanno segnalati tempestivamente inviando i nuovi e vecchi dati perposta, fax, e-mail o direttamente sul sito www.minervamedica.it alla sezione “I tuoi abbonamenti - Contatta ufficio abbonamenti”. I reclami per i fascicolimancanti 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 può essere riprodotta, trasmessa e memorizzata in qualsiasi forma e con qualsiasimezzo Pubblicazione trimestrale. Autorizzazione del Tribunale di Torino n. 553 del 19-5-1981. Iscrizione nel registro nazionale della stampa di cui alla legge 5-8-1981 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. 2comma 20/b legge 662/96 aut. 605/dc/dci/cn

OOTTOORRIINNOOLLAARRIINNGGOOLLOOGGIIAARRiivviissttaa ttrriimmeessttrraallee ddii oottoorriinnoollaarriinnggoollooggiiaa,, aauuddiioollooggiiaa,, ffoonniiaattrriiaacchhiirruurrggiiaa cceerrvviiccoo--ffaacccciiaallee,, mmaaxxiilllloo--ffaacccciiaallee,, ppllaassttiiccaa--rriiccoossttrruuttttiivvaa,, oottoonneeuurroocchhiirruurrggiiaa..CCoonnttiinnuuaazziioonnee ddii::MMiinneerrvvaa OOttoorriinnoollaarriinnggoollooggiiccaa,, NNuuoovvoo AArrcchhiivviioo IIttaalliiaannoo ddii OOttoollooggiiaa,, RRiinnoollooggiiaa ee LLaarriinnggoollooggiiaa,,BBoolllleettttiinnoo ddeellllee mmaallaattttiiee ddeellll’’oorreecccchhiioo,, ddeellllaa ggoollaa,, ddeell nnaassoo,, LL’’OOttoorriinnoollaarriinnggoollooggiiaa IIttaalliiaannaa

DDiirreettttoorriiA. OTTAVIANI - O. PIGNATARO

CCoonnssuulleennttii ee RReevviissoorrii

Otorinolaringologiae chirurgia cervico-facciale

A. ANTONELLIA. BOSATRAM. BUSSIC. CENACCHIG. CERVELLERAA. CIMINOV. COLLETTIS. CONTICELLOG. CORTESINAI. DE VINCENTIISC. GIORDANOA. DI GIROLAMOP. FERRARAP. FILIPPIG. GALETTIB. GALIOTOC. GALLETTIG. MAFFEIT. MARULLOM. MAURIZI

P. MIANIE. MIRAG. MOTTAF. PIRAGINEE. PIRODDAP. PUXEDDUG. RALLIV. RICCIO. SALAA. SARTORISG. SULSENTIC. ZINI

Anatomia patologicaH. E. KAISER (USA)

AudiologiaG. GRISANTI

FoniatriaL. CROATTOM. IENGOO. SCHINDLER

Chirurgiamaxillo-faccialeR. BRUSATIC. CURIONI

Chirurgiaplastica-ricostruttivaA. AZZOLINIL. DONATIG. ZAOLI

OtoneurochirurgiaA. MAZZONIR. VILLANI

OtoneurologiaA. DE STEFANOF. DISPENZAE. MIRA

RinologiaD. PASSALI

DDiirreettttoorree RReessppoonnssaabbiilleeA. OLIARO

Studio grafico della copertina: Eleonora Garosci

Page 3: Otorinolaringologia MINERVA intratympanic

La rivista Otorinolaringologia pubblica articoli scientifici su argomentidi otorinolaringologia, chirurgia capo-collo, chirurgia plastica ricostrut-tiva, otoneurochirurgia. I contributi possono essere redatti come editoria-li, articoli originali, review, casi clinici, note di terapia, articoli speciali,lettere alla direzione. I manoscritti devono essere preparati seguendo rigorosamente le normeper gli Autori, che sono conformi agli Uniform Requirements forManuscripts Submitted to Biomedical Editors editi a curadell’International Committee of Medical Journal Editors(www.icmje.org). Non saranno presi in considerazione gli articoli che nonsi uniformano agli standard internazionali. I lavori redatti in lingua italiana o inglese o duplice versione inglese eitaliana devono essere inviati alla redazione online raggiungibile dal sitodelle Edizioni Minerva Medica:

L’invio del manoscritto sottintende che il lavoro è originale e non è anco-ra stato pubblicato né totalmente né in parte e che, se accettato, non verràpubblicato altrove né integralmente né in parte. Tutto il materiale icono-grafico deve essere originale. L’iconografia tratta da altre pubblicazionideve essere corredata da permesso dell’Editore. Gli Autori accettano ditrasferire la proprietà dei diritti di autore alla rivista Otorinolaringologianell’eventualità che il lavoro sia pubblicato. La rivista recepisce i principipresentati nella Dichiarazione di Helsinki e ribadisce che tutte le ricercheche coinvolgano esseri umani siano condotte in conformità ad essi. Larivista recepisce altresì gli International Guiding Principles forBiomedical Research Involving Animals raccomandati dalla WHO erichiede che tutte le ricerche su animali siano condotte in conformità adessi. Gli Autori, se necessario, devono indicare che lo studio è statoapprovato dal comitato etico e che i pazienti hanno dato il loro consensoinformato. Gli Autori devono inoltre indicare se hanno un accordo finan-ziario con organizzazioni coinvolte nella ricerca compilando il relativomodulo. Il lavoro deve essere accompagnato dalla seguente dichiarazionerelativa ai diritti d’autore, aspetti etici e conflitti di interesse, firmata datutti gli Autori: “I sottoscritti Autori trasferiscono la proprietà dei diritti diautore alla rivista Otorinolaringologia, nella eventualità che il loro lavorosia pubblicato sulla stessa rivista. Essi dichiarano che l’articolo è origina-le, non è stato inviato per la pubblicazione ad altra rivista e non è statogià pubblicato né integralmente né in parte. Essi dichiarano di essereresponsabili della ricerca, che hanno progettato e condotto, e di aver par-tecipato alla stesura e alla revisione del manoscritto presentato, di cuiapprovano i contenuti. Nel caso di studi condotti sugli esseri umani gliAutori riferiscono che lo studio è stato approvato dal comitato etico e chei pazienti hanno sottoscritto il consenso informato. Dichiarano inoltre chela ricerca riportata nel loro lavoro è stata eseguita nel rispetto dellaDichiarazione di Helsinki e dei Principi internazionali che regolano laricerca sugli animali. Si impegnano, infine, a segnalare alle EdizioniMinerva Medica eventuali conflitti di interesse, in particolare accordifinanziari con ditte farmaceutiche o biomedicali i cui prodotti siano perti-nenti all’argomento trattato nel manoscritto”. Gli Autori accettano implicitamente che il lavoro venga sottoposto apeer-review. Tutti i lavori saranno esaminati dal Comitato di Lettura chesi riserva il diritto di rifiutare il lavoro senza sottoporlo a revisione nelcaso che l’argomento, il formato o gli aspetti etici siano inadeguati. Tuttii manoscritti accettati saranno sottoposti a revisione editoriale. In caso dirichiesta di modifiche, la nuova versione corretta deve essere risottopo-sta alla redazione online sottolineando ed evidenziando le parti modifi-cate. La nuova versione deve essere accompagnata da una lettera con lerisposte punto per punto ai commenti dei revisori. La correzione delle bozze di stampa dovrà essere limitata alla semplicerevisione tipografica; eventuali modifiche del testo saranno addebitateagli Autori. Le bozze corrette dovranno essere restituite entro 3 giornilavorativi alla redazione online di Otorinolaringologia. In caso di ritardo,la redazione della rivista potrà correggere d’ufficio le bozze sulla basedel manoscritto originale. I moduli per la richiesta di estratti vengonoinviati insieme alle bozze.Per ulteriori informazioni sulle condizioni di pubblicazione contattare laredazione di Otorinolaringologia, Edizioni Minerva Medica, CorsoBramante 83-85, 10126 Torino - Tel. 011 678282 - Fax 011 674502 -E-mail [email protected]

TIPI DI ARTICOLI SCIENTIFICI

Istruzioni per i più 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 l’Autore espri-me la sua opinione personale. Sono ammesse non più di 1000 parole (3pagine dattiloscritte con spaziatura doppia) e fino a 15 citazioni biblio-grafiche.

Articolo originale. Deve portare un contributo originale all’argomentotrattato. Il testo deve essere di 3000-5500 parole (8-16 pagine dattilo-scritte con spaziatura doppia) escluse bibliografia, tabelle e figure. Sonoammesse fino a 50 citazioni bibliografiche. L’articolo deve essere suddi-viso nelle sezioni: introduzione, materiali e metodi, risultati, discussio-ne, conclusioni. Nell’introduzione sintetizzare chiaramente lo scopo del-lo studio. Nella sezione dei materiali e metodi descrivere in sequenzalogica come è stato impostato e portato avanti lo studio, come sono statianalizzati i dati (quale ipotesi è stata testata, tipo di indagine condotta,come è stata fatta la randomizzazione, come sono stati reclutati e scelti isoggetti, fornire dettagli accurati sulle caratteristiche essenziali del trat-tamento, sui materiali utilizzati, sui dosaggi di farmaci, sulle apparec-chiature non comuni, sul metodo statistico ...). Nella sezione dei risultatidare le risposte alle domande poste nell’introduzione. I risultati devonoessere presentati in modo completo, chiaro, conciso eventualmente cor-relati di figure, grafici e tabelle. Nella sezione discussione riassumere irisultati principali, analizzare criticamente i metodi utilizzati, confronta-re i risultati ottenuti con gli altri dati della letteratura, discutere le impli-cazioni dei risultati. Nelle conclusioni riassumere brevemente il signifi-cato dello studio e le sue implicazioni future.

Review. Preferibilmente su invito (del Redattore Capo, del DirettoreResponsabile), deve trattare un argomento di attualità ed interesse, pre-sentare lo stato delle conoscenze sull’argomento, analizzare le differentiopinioni sul problema trattato, essere aggiornata con gli ultimi dati dellaletteratura. Il testo deve essere di 6000-12000 parole (17-34 pagine datti-loscritte 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 testodeve essere di 2000-3000 parole (6-8 pagine dattiloscritte con spaziaturadoppia) escluse bibliografia, tabelle e figure. Sono ammesse fino a 30citazioni bibliografiche. L’articolo deve essere suddiviso nelle sezioni:introduzione, caso clinico o casistica clinica, discussione, conclusioni.

Nota di terapia. Presentazione e valutazione di nuovi farmaci e tratta-menti chirurgici. Il testo deve essere di 3000-5500 parole (8-16 paginedattiloscritte con spaziatura doppia) escluse bibliografia, tabelle e figure.Sono ammesse fino a 30 citazioni bibliografiche. L’articolo deve esseresuddiviso nelle sezioni: introduzione, materiali e metodi, risultati,discussione, conclusioni.

Articolo speciale. L’articolo deve trattare argomenti di storia della medi-cina, organizzazione sanitaria, etica, politiche economiche e legislativeriguardanti l’otorinolaringologia. 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. Può far riferimento ad articoli precedentementepubblicati sulla rivista o ad osservazioni e dati scientifici che gli autoriintendano portare all’attenzione dei lettori in forma sintetica. Il testodeve essere di 500-1000 parole (1-3 pagine dattiloscritte con spaziaturadoppia) escluse bibliografia, tabelle e figure. Sono ammesse fino a 5citazioni 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 allalunghezza del lavoro.

PREPARAZIONE DEL MANOSCRITTO

File del testoPer la preparazione del manoscritto si prega di utilizzare il modello predi-sposto per il tipo di lavoro prescelto (editoriale, articolo originale, review,caso clinico, , nota di terapia, articolo speciale, lettera alla direzione).

NORME PER GLI AUTORI

www.minervamedica.it

Page 4: Otorinolaringologia MINERVA intratympanic

L’articolo dovrà essere dattiloscritto con spaziatura doppia e con marginidi almeno 2,5 cm su cartelle del formato 212×297 mm (ISOA4). I for-mati accettati sono Word e RTF. Il file del manoscritto deve contenere iltitolo, i dati autori, le note, il riassunto, le parole chiave, il testo, labibliografia, le didascalie delle tabelle e delle figure. Tabelle e figuredevono 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 già stato presentato. • Menzione di eventuali finanziamenti o contratti di ricerca o conflitti

di interesse.• Ringraziamenti. • Nome, cognome, indirizzo, e-mail dell’autore di contatto.

Riassunto e parole chiaveIl riassunto (in inglese e in italiano) non deve superare né essere inferio-re 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 è sta-to trovato), conclusioni (significato dello studio). Per le parole chiave (ininglese e in italiano) usare i termini del Medical Subjects Heading(MeSH) di MEDLINE/PubMed. Gli editoriali e le lettere alla direzionenon necessitano di riassunto.

TestoPer i lavori presentati in duplice versione, il testo in lingua inglese deveessere speculare al testo in lingua italiana. Identificare metodologie,apparecchiature (nome e indirizzo del costruttore tra parentesi) e proce-dure con dettaglio sufficiente a permettere ad altri studiosi di riprodurre irisultati. Menzionare le metodologie già definite, incluse quelle statisti-che; menzionare e fornire brevi descrizioni circa metodologie che sonostate pubblicate ma non sono ben conosciute; descrivere metodologienuove o modificate in modo sostanziale; giustificare il loro utilizzo evalutarne i limiti. Di tutti i farmaci si deve citare nome generico, dosag-gio e vie di somministrazione. I nomi commerciali dei farmaci vannocitati tra parentesi. Unità di misura, simboli, abbreviazioni devono essereconformi agli standard internazionali. Le misure di lunghezza, altezza,peso e volume dovrebbero essere riportate in unità del sistema metrico(metro, chilogrammo, litro) o in loro multipli decimali. Le temperaturedovrebbero essere espresse in gradi Celsius. Le pressioni arteriose in mil-limetri di mercurio. Tutte le misurazioni di chimica clinica dovrebberoessere espresse in unità del sistema metrico nei termini dell’InternationalSystem of Units (SI). Si scoraggia l’uso di simboli e sigle poco comuni.Essi vanno comunque spiegati alla prima apparizione nel testo.

BibliografiaÈ sottointeso che gli articoli citati in bibliografia siano stati letti dagliautori. La bibliografia, che deve comprendere i soli Autori citati neltesto, va numerata con numeri arabi in ordine consecutivo di prima cita-zione nel testo. Il richiamo delle voci bibliografiche nel testo deve esserefatto con numeri arabi in apice. La bibliografia deve essere citata nellostile standardizzato approvato dall’International Committee of MedicalJournals Editors (www.icmje.org).

RIVISTE

Per ogni voce si devono riportare il cognome e l’iniziale del nome degliAutori (elencare tutti gli Autori fino a sei, se sette o più elencare solo iprimi sei nomi seguiti da: et al.), il titolo originale dell’articolo, il titolodella rivista (attenendosi alle abbreviazioni usate di MEDLINE/PubMed), l’anno di pubblicazione, il numero del volume, il numero dipagina iniziale e finale.Nelle citazioni bibliografiche seguire attentamente la punteggiatura stan-dard internazionale.Esempi:– Articolo standard.Sutherland DE, Simmons RL, Howard RJ. Intracapsular technique oftransplant nephrectomy. Surg Gynecol Obstet 1978; 146:951-2.– Articolo a nome di una commissione. International Committee of Medical Journal Editors. Uniform require-ments for manuscripts submitted to biomedical journals. Ann Int Med1988;108:258-65.

– Supplemento ad un fascicoloPayne DK, Sullivan MD, Massie MJ. Women’s psychological reactionsto breast cancer. Semin Oncol 1996;23(1 Suppl 2):89-97.LIBRI E MONOGRAFIE

Per pubblicazioni non periodiche dovranno essere indicati i nomi degliAutori, il titolo, l’edizione, il luogo di pubblicazione, l’editore e l’annodi pubblicazione.Esempi:– Libro di uno o più Autori. Rossi G. Manuale di otorinolaringologia. Torino: Edizioni MinervaMedica; 1987. – Capitolo di un libro. De Meester TR. Gastroesophageal reflux disease. In: Moody FG, CareyLC, Scott Jones R, Kelly KA, Nahrwold DL, Skinner DB, editors.Surgical treatment of digestive diseases. Chicago: Year Book MedicalPublishers; 1986. p. 132-58.– Atti congressuali. Kimura J, Shibasaki H, editors. Recent advances in clinical neurophy-siology. Proceedings of the 10th International Congress of EMG andClinical Neurophysiology; 1995 Oct 15-19; Kyoto, Japan. Amsterdam:Elsevier; 1996.MATERIALE ELETTRONICO

– Articolo standard di rivista su InternetKaul S, Diamond GA. Good enough: a primer on the analysis and inter-pretation 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 DVDKacmarek 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 homepageAMA: helping doctors help patients [Internet]. Chicago: AmericanMedical 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 paginae le note di chiusura di Word. Le voci bibliografiche citate per la prima volta in una tabella o nelladidascalia di una figura devono essere numerate in sequenza con le vocibibliografiche citate nel testo tenendo conto del punto in cui la tabella ola figura è richiamata per la prima volta. Di conseguenza tali voci biblio-grafiche non devono essere elencate in fondo alla bibliografia ma secon-do l’ordine di citazione nel testo.Didascalie delle tabelle e delle figurePer i lavori presentati in duplice versione le didascalie delle tabelle edelle figure devono essere redatte in lingua inglese.Le didascalie di tabelle e figure devono essere inserite sia nel file di testosia nel file delle tabelle e delle figure.File delle tabelleLe tabelle devono essere inviate come file separati. I formati accettatisono Word e RTF. Ogni tabella deve essere correttamente dattiloscritta,preparata graficamente secondo lo schema di impaginazione della rivi-sta, numerata in cifre romane, corredata dal rispettivo titolo. Eventualiannotazioni devono essere inserite al piede della tabella e non nel titolo.Le tabelle devono essere richiamate nel testo in ordine consecutivo. Per ilavori presentati in duplice versione, le tabelle e le didascalie delle tabel-le devono essere redatte in lingua inglese.File delle figureLe figure devono essere inviate come file separati. Formati accettati: pre-feribilmente JPEG con risoluzione di 300 dpi; altri formati accettati sonoTIFF, PNG, PDF (alta qualità) e Word (per i grafici). Le figure devonoessere numerate in cifre arabe e corredate dalla rispettiva didascalia. Lefigure devono essere richiamate nel testo in ordine consecutivo. Per i lavo-ri presentati in duplice versione, le didascalie delle figure devono essereredatte in lingua inglese. La riproduzione deve essere limitata alla parteessenziale ai fini del lavoro. Le foto istologiche devono sempre essere accompagnate dal rapporto diingrandimento e dal metodo di colorazione. Per le figure a colori specificare sempre se si desidera la riproduzione acolori o in bianco e nero. Il costo della riproduzione delle figure a colorisarà 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.

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The journal Otorinolaringologia publishes scientific papers on oto-laryngology, head and neck surgery, plastic and reconstructivesurgery, otoneurosurgery. Manuscripts may be submitted in the formof editorials, original articles, review articles, case reports, therapeu-tical notes, special articles and letters to the Editor. Manuscripts are expected to comply with the instructions to authorswhich conform to the Uniform Requirements for ManuscriptsSubmitted to Biomedical Editors by the International Committee ofMedical Journal Editors (www.icmje.org). Articles not conformingto international standards will not be considered for acceptance. Papers should be submitted directly to the online Editorial Office atthe Edizioni Minerva Medica website:

Submission of the manuscript means that the paper is original and hasnot yet been totally or partially published and, if accepted, will not bepublished elsewhere either wholly or in part. All illustrations should beoriginal. Illustrations taken from other publications must be accompa-nied by the publisher’s permission. The Authors agree to transfer theownership of copyright to Otorinolaringologia in the event the manu-script is published. The journal adheres to the principles set forth inthe Helsinki Declaration and states that all reported research concern-ing human beings should be conducted in accordance with such prin-ciples. The journal also adheres to the International Guiding Principlesfor Biomedical Research Involving Animals recommended by theWHO and requires that all research on animals be conducted in accor-dance with these principles. The Authors, if necessary, must indicatethat the study has been approved by the ethics committee and thatpatients have given their informed consent. Authors must also indicatewhether they have any financial agreement with any organization thatwere involved in the research by filling the relevant form. Papers mustbe accompanied by the following authors’ statement relative to copy-right, ethics and conflicts of interest, signed by all authors: “Theundersigned authors transfer the ownership of copyright toOtorinolaringologia should their work be published in this journal.They state that the article is original, has not been submitted for publi-cation in other journals and has not yet been published either whollyor in part. They state that they are responsible for the research that theyhave designed and carried out; that they have participated in draftingand revising the manuscript submitted, whose contents they approve.In the case of studies carried out on human beings, the authors confirmthat the study was approved by the ethics committee and that thepatients gave their informed consent. They also state that the researchreported in the paper was undertaken in compliance with the HelsinkiDeclaration and the International Principles governing research on ani-mals. They agree to inform Edizioni Minerva Medica of any conflictof interest that might arise, particularly any financial agreements theymay have with pharmaceutical or biomedical firms whose products arepertinent to the subject matter dealt with in the manuscript. “ The authors implicitly agree to their paper being peer-reviewed. Allmanuscripts will be reviewed by Editorial Board members whoreserve the right to reject the manuscript without entering the reviewprocess in the case that the topic, the format or ethical aspects areinappropriate. Once accepted, all manuscripts are subjected to copyediting. If modifications to the manuscript are requested, the correct-ed version should be sent to the online Editorial Office with themodified parts underlined and highlighted. The revised versionshould be accompanied by a letter with point-by-point responses tothe reviewers’ comments. Correction of proofs should be limited to a simple check of the print-ing; any changes to the text will be charged to the authors. Correctedproofs must be sent back within 3 working days to the online EditorialOffice of Otorinolaringologia. In case of delay, the editorial staff ofthe journal may correct the proofs on the basis of the original manu-script. Forms for ordering reprints are sent together with the proofs. For further information about publication terms please contact theEditorial Office of Otorinolaringologia, Edizioni Minerva Medica,Corso Bramante 83-85, 10126 Torino, Italy – Phone +39-011-678282 – Fax +39-011-674502 –E-mail [email protected].

ARTICLE TYPES

Instructions for the most frequent types of articles submitted to thejournal.

Editorials. Commissioned by the Editor in Chief or the ManagingEditor, editorials deal with a subject of topical interest about which theauthor expresses his/her personal opinion. No more than 1000 words (3typed, double-spaced pages) and up to 15 references will be accepted.

Original articles. These should be original contributions to the sub-ject. The text should be 3000-5500 words (8 to 16 typed, double-spaced pages) not including references, tables, figures. No more than50 references will be accepted. The article must be subdivided into thefollowing sections: introduction, materials and methods, results, dis-cussion, conclusions. In the introduction the aim of the study shouldbe clearly summed up. The materials and methods section shoulddescribe in a logical sequence how the study was designed and carriedout, how the data were analyzed (what hypothesis was tested, whattype of study was carried out, how randomization was done, how thesubjects were recruited and chosen, provide accurate details of themain features of treatment, of the materials used, of drug dosages, ofunusual equipments, of the statistical method ...). In the results sectionthe 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 sectionshould sum up the main results, critically analyze the methods used,compare the results obtained with other published data and discuss theimplications of the results. The conclusions should briefly sum up thesignificance of the study and its future implications.

Review articles. Generally commissioned by the Editor in Chief orthe Managing Editor, review articles should discuss a topic of cur-rent interest, outline current knowledge of the subject, analyze differ-ent opinions regarding the problem discussed, be up-to-date on thelatest data in the literature. The text should be 6000-12000 words (17to 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 interestingcases. The text should be 2000-3000 words (6 to 8 typed, double-spaced pages) not including references, tables, figures. No more than30 references will be accepted. The article must be subdivided intothe following sections: introduction, case report or clinical series,discussion, conclusions.

Therapeutical notes. These are intended for the presentation andassessment of new medical and surgical treatments. The text shouldbe 3000-5500 words (8 to 16 typed, double-spaced pages) not includ-ing references, tables, figures. No more than 30 references will beaccepted. 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, healthcare delivery, ethics, economic policy and law concerning otolaryn-gology. The text should be 3000-7000 words (8 to 20 typed, double-spaced pages) not including references, tables, figures. No more than50 references will be accepted.

Letters to the Editor. These may refer to articles already publishedin the journal or to a subject of topical interest that the authors wishto present to readers in a concise form. The text should be 500-1000words (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 orauthoritative sources.

The number of figures and tables should be appropriate for the typeand length of the paper.

Preparation of manuscripts

Text fileManuscripts must be drafted according to the template for each typeof paper (editorial, original article, review, case report, therapeuticalnote, special article, letter to the Editor).

NOTICE TO AUTHORS

www.minervamedica.it

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The paper should be type written double spaced with margins of atleast 2.5 cm on 212×297 mm format sheets (ISOA4). The formatsaccepted are Word and RTF. The text file must contain title, authors’details, notes, abstract, key words, text, references and titles of tablesand 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.

Notes

• Dates of any congress where the paper has already been presen-ted.

• Mention of any funding or research contracts or conflict of inte-rest.

• 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 bestructured as follows: aim (aim of the study), methods (experimentaldesign, patients and interventions), results (what was found), conclu-sion (meaning of the study). Key words should refer to the termsfrom Medical Subject Headings (MeSH) of MEDLINE/PubMed. Noabstracts are required for editorials or letters to the Editor.

Text

Identify methodologies, equipment (give name and address of manu-facturer in brackets) and procedures in sufficient detail to allow otherresearchers to reproduce results. Specify well-known methodsincluding statistical procedures; mention and provide a brief descrip-tion of published methods which are not yet well known; describenew or modified methods at length; justify their use and evaluatetheir limits. For each drug generic name, dosage and administrationroutes should be given. Brand names for drugs should be given inbrackets. Units of measurement, symbols and abbreviations mustconform 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 indegrees Celsius. Blood pressure must be expressed in millimeters ofmercury. All clinical chemistry measurements should be expressed inmetric units using the International System of Units (SI). The use ofunusual symbols or abbreviations is strongly discouraged. The firsttime an abbreviation appears in the text, it should be preceded by thewords for which it stands.

References

It is expected that all cited references will have been read by theauthors. The references must contain only the authors cited in thetext, be numbered in Arabic numerals and consecutively as they arecited. Bibliographical entries in the text should be quoted usingsuperscripted Arabic numerals. References must be set out in thestandard format approved by the International Committee of MedicalJournal Editors (www.icmje.org).JOURNALS

Each entry must specify the author’s surname and initials (list allauthors when there are six or fewer; when there are seven or more,list only the first six and then “et al.”), the article’s original title, thename of the Journal (according to the abbreviations used by MED-LINE/PubMed), the year of publication, the volume number and thenumber of the first and last pages. When citing references, pleasefollow the rules for international standard punctuation carefully. Examples:– Standard article. Sutherland DE, Simmons RL, Howard RJ. Intracapsular technique oftransplant nephrectomy. Surg Gynecol Obstet 1978;146:951-2. – Organization as authorInternational Committee of Medical Journal Editors. Uniformrequirements for manuscripts submitted to biomedical journals. AnnInt Med 1988;108:258-65.

– Issue with supplement Payne DK, Sullivan MD, Massie MJ. Women’s psychological reac-tions 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 MinervaMedica; 1987. – Chapter from book De Meester TR. Gastroesophageal reflux disease. In: Moody FG,Carey LC, Scott Jones R, Ketly KA, Nahrwold DL, Skinner DB, edi-tors. Surgical treatment of digestive diseases. Chicago: Year BookMedical Publishers; 1986. p. 132-58. – Congress proceedings Kimura J, Shibasaki H, editors. Recent advances in clinical neuro-physiology. Proceedings of the 10th International Congress of EMGand Clinical Neurophysiology; 1995 Oct 15-19; Kyoto, Japan.Amsterdam: Elsevier; 1996.

ELECTRONIC MATERIAL

– Standard journal article on the InternetKaul S, Diamond GA. Good enough: a primer on the analysis andinterpretation 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 DVDKacmarek 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 homepageAMA: helping doctors help patients [Internet]. Chicago: AmericanMedical Association; ©1995-2007 [cited 2007 Feb 22]. Availablefrom: http://www.ama-assn.org/.

Footnotes and endnotes of Word must not be used in the preparationof references.References first cited in a table or figure legend should be numberedso that they will be in sequence with references cited in the text tak-ing into consideration the point where the table or figure is first men-tioned. Therefore, those references should not be listed at the end ofthe 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 fileand in the file of tables and figures.

File of tables

Each table should be submitted as a separate file. Formats acceptedare Word and RTF. Each table must be typed correctly and preparedgraphically in keeping with the page layout of the journal, numberedin Roman numerals and accompanied by the relevant title. Notesshould be inserted at the foot of the table and not in the title. Tablesshould 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 areTIFF, PNG, PDF (high quality) and Word (for graphs). Figuresshould be numbered in Arabic numerals and accompanied by the rel-evant title. Figures should be referenced in the text sequentially. Reproductions should be limited to the part that is essential to thepaper.Histological photographs should always be accompanied by themagnification ratio and the staining method.If figures are in color, it should always be specified whether color orblack and white reproduction is required. The cost of color figureswill 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.

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Vol. 60 - N. 3 OTORINOLARINGOLOGIA IX

Vol. 60 Settembre 2010 Numero 3

OOTTOORRIINNOOLLAARRIINNGGOOLLOOGGIIAA

INDICE

Pag. XIICongressi

125PresentazioneDe Benedetto M.

127IntroduzioneSerra A.

129Storia dei trattamenti intratimpanici dei disordini del-l’orecchio internoMankekar G., Kirtane M. V., Chavan K., Pachauri S.

135Anatomia della coclea e della finestra rotondaDavid S., Bucchieri F., Cappello F., Zummo G.

141Farmacocinetica dei farmaci dopo somministrazionetranstimpanicaDispenza F., Kulamarva G., De Stefano A.

145Steroidi intratimpanici per la perdita di udito neuro-sensoriale improvvisa: una revisioneJeremic G., Parnes L. S.

155Trattamento intratimpanico della patologia autoim-mune dell’orecchio internoDe Stefano A., Kulamarva G., Dispenza F.

165Somministrazione intratimpanica di gadolinio per lavalutazione delle dimensioni dello spazio endolinfati-co e il movimento dei farmaci nell’orecchio internoNakashima T., Naganawa S., Sone M., Teranishi M.

171Gentamicina intratimpanica per la malattia diMenière monolateraleSlattery III W. H., Teufert K. B.

183La gentamicina intratimpanica: suo effetto sull’uditoe strategie per minimizzare il danno all’orecchiointernoCitraro L., De Stefano A., Kulamarva G., Dispenza F., Croce A.

TERAPIE INTRATIMPANICHE PER I DISORDINI DELL’ORECCHIO INTERNOGuest Editors: A. De Stefano e F. Dispenza

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INDICE

X OTORINOLARINGOLOGIA September 2010

189Trattamento della malattia di Menière con steroidiintratimpaniciPistorio V., Achilli V.

195Trattamento intratimpanico degli acufeni: illusioni esperanzeOliveira C. A., Araújo M. F. S., Sampaio A. L. L.

207Trattamento intratimpanico dell’ototossicità correla-ta a chemioterapiaParham K.

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

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Vol. 60 - No. 3 OTORINOLARINGOLOGIA XI

CONTENTS

Vol. 60 September 2010 No. 3

OOTTOORRIINNOOLLAARRIINNGGOOLLOOGGIIAA

Pp.XIICongresses

125PrefaceDe Benedetto M.

127ForewordSerra A.

129History of intratympanic managements for inner eardisordersMankekar G., Kirtane M. V., Chavan K., Pachauri S.

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

141Pharmacokinetics of drugs in transtympanic adminis-trationDispenza F., Kulamarva G., De Stefano A.

145Intratympanic steroids for sudden sensorineuralhearing loss. A reviewJeremic G., Parnes L. S.

155Intratympanic management for autoimmune innerear diseaseDe Stefano A., Kulamarva G., Dispenza F.

165Intratympanic gadolinium administration for evalu-ation of endolymphatic space size and drug move-ment into the inner earNakashima T., Naganawa S., Sone M., Teranishi M.

171Intratympanic gentamicin for unilateral Menière’sdiseaseSlattery III W. H., Teufert K. B.

183Intratympanic gentamicin: its effect on hearing andstrategies to minimize inner ear damageCitraro L., De Stefano A., Kulamarva G., Dispenza F., Croce A.

INTRATYMPANIC THERAPIES FOR INNER EAR DISORDERSGuest Editors: A. De Stefano and F. Dispenza

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CONTENTS

XII OTORINOLARINGOLOGIA September 2010

189Management of Menière’s disease with intratympan-ic steroidsPistorio V., Achilli V.

195Intratympanic management of tinnitus: illusionsand hopesOliveira C. A., Araújo M. F. S., Sampaio A. L. L.

207Intratympanic treatment for chemotherapy-relatedototoxicityParham K.

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

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February 28-March 2, 2011Wurzburg (Germany)

23rd Course on Microsurgeryof the Middle Ear

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

March 1-4, 2011Auckland (New Zealand)

12th Asia-OceaniaORL Congress

Contact:Website: www.asia-oceania2011.org

March 25-29, 2011 Milano (Italy)

6th Biennal InternationalMilano Masterclass

Contact:Website: www.milanomasterclass.it

April 28-29, 2011Utrecht (The Netherlands)

IntercontinentalRhinoplasty Course Higlights of functional andesthetic rhinoplastic surgery

Contact:Website: www.intercontinental-rhino-plasty.com

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

COSM CombinedOtolaryngological SpringMeeting

Contact:Website: www.cosm.md

May 12-15, 2011Athens (Greece)

10th European Symposiumon Pediatric CochlearImplantation

Contact:Website: www.espci2011.com

May 25-28, 2011Brussels (Belgium)

International Mastercourseon Endoscopic Sinus Surgery(IMESS)

Contact:Website: www.everyoneweb.com/imess

June 5-9, 2011New Orleans (LA, USA)

10th International Symposiumon Recent Advancesin Otitis Media

Contact:Website: www.om2011.com

July 2-6, 2011Barcelona (Spain)

1st Congress of theConfederation of the EuropeanORL-HNS (CE-ORL-HNS)

Contact:Website:www.ceorlhnsbarcelona2011.org

July 14-17, 2011Singapore

3rd World Congress of theInternational Academy of OralOncology IAOO

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

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

Annual Meetingof the American Academyof Otolaryngology Headand Neck surgery

Contact:Website: www.entnet.org

October 21-22, 2011 Naples (Italy)

6th International Symposiumon Childhood Deafness

Contact:Website: www.chdeaf.org

June 3-7, 2012Nagasaki (Japan)

CholesteatomaConference 20129th InternationalConferenceon Cholesteatomaand Ear Surgery

Contact:Website: www.chole2012.jp

June 17-21, 2012Toulouse (France)

24th Congressof the European RhinologicSociety

Contact:Website: www.ers-isian2012.com

CONGRESSES

[to be continued at page XXI]

XII OTORINOLARINGOLOGIA September 2010

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Vol. 60 - No. 3 OTORINOLARINGOLOGIA 125

Corresponding author. Prof. M. De Benedetto, Unit of Otolaryngology, Vito Fazzi Hospital, Lecce, Italy. E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1937-OTtitolo breve: FOREWORDprimo autore: De Benedettopagine: 125

Over the past 10 years several improvements have been re-corded 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 tran-stympanic administration of drugs, an irreversible damage of inner ear neural epithelium in order to obtain a comparable re-sult as well as what surgically achieved, but in a much more conservative way.

Subsequently, the transtympanic route has progressed to-gether with clinical indications, changing the goal of treatment: obtaining not only the damage of inner ear cells, but also a cura-tive 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 av-erage retard of about five years from the beginning of clinical use.

The great value of De Stefano and Dispenza’s 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, con-tributes 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 re-searchers 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 BenedettoPresident of Societas ORL Latina

Chief of Otolaryngology Department“Vito Fazzi” Hospital, Lecce, Italy

Negli ultimi 10 anni, nell’ambito delle terapie mediche per pa-tologia dell’orecchio interno, notevoli novità si sono regi-

strate grazie al sempre maggiore ricorso a somministrazione di farmaci all’interno dell’orecchio medio.

All’inizio l’obiettivo 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 più conservativo.

Successivamente, tale via di somministrazione si è sempre più ampliata, di pari passo con le indicazioni cliniche, per cui è cambiato l’obiettivo del trattamento: non ottenere più solo un danno irreversibile del neuroepitelio ma cercare di ottenere un’azione 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, è stato stimato in almeno 5 anni rispetto all’inizio dell’utilizzo clinico.

Il grande merito dei colleghi De Stefano e Dispenza è stato quello di aver sistematizzato tutto ciò che attualmente viene effettuato ricorrendo alla terapia topica intratimpanica, dando la possibilità a tutti gli specialisti di avere un quadro completo delle possibilità terapeutiche per le numerose patologie che è 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, è certamente un’opportunità di grande utilità.

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 l’entusiasmo 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 BenedettoPresidente Societas ORL Latina

Direttore U. O. OtorinolaringoiatriaOspedale “Vito Fazzi”, Lecce, Italia

INTRATYMPANIC THERAPIES FOR INNER EAR DISORDERSGuest Editors: A. De Stefano and F. Dispenza

OTORINOLARINGOL 2010;60:125

M. DE BENEDETTO

Preface - Presentazione

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Anno:2010Mese:SeptemberVolume:60No:3Rivista:OTORINOLARINGOLOGIACodRivista:OTORINOLARINGOL

Lavoro:titolobreve:xxxxprimoautore:yyyyypagine:1-2

Vol.60-No.3 OTORINOLARINGOLOGIA 127

A.SERRA

OTORINOLARINGOL2010;60:1-2

Foreword - Prefazione

FrancisBacon,EnglishphilosopherofXVIIcentury,inhisreflection on the sense and the meaning of scientific in-

novations, 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 I’m going topresent thisworkonintratympanic therapyof innereardis-eases:theevolutionofknowledgeandthedevelopmentofthetechniques,infact,allowedtodelivermedicinalsubstancesinsitesbelieved“inaccessible”astheinnerear.

Changesandimprovementsinintratympanictherapeuticap-proachhavebeennumerousifcomparedwithfirstapplications:atypicalexampleisSchuknecht’sattempttoobtainthechemi-cal labyrinthectomy inpatientsaffectedbyMenière’sdiseasebyintratympanicadministrationofstreptomycinin1957.

Theseinitialintuitionshaveopeneddoorstonewtherapeu-ticfrontiersnowrepresentingactualclinicalevidences(evenifSchuknecht’streatmentunfortunatelyresultedinsomein-conveniencesforpatients,suchasaseverehearingloss).

It ispossible toassert that the treatmentof innereardis-easeshasfoundavalidscientificandpracticalsupportintheintratympanic therapy, especially in Menière’s disease, sud-denhearing loss,presbiacusisand tinnitus,characterizedbynotalwayswell-definedevolutionandprognosis.

TheworkoftheAuthors,comingfromdifferentcountriesandculturalbackgrounds, isentirelyfittedoncurrentscien-tificstandardanditalsohasallmultidisciplinarycharactersofbothmodernscientificthoughtandclinicalresearch.

ItthereforegivesmegreatpleasuretocongratulatetheAu-thorsand,applaudingthisinitiativeandwishingall thesuc-cessitdeserves,Ihopethiseffortwillopenthedoortofurtherpossibilitiesforscientificresearchandwiderclinicalapplica-tions.

Prof. Agostino SerraAUORL President

Chief of Otolaryngology DepartmentUniversity of Catania, Italy

Correspondingauthor.Prof.A.Serra,DepartmentofOtolaryngology,AziendaOspedaliero-Universitaria“PoliclinicoVittorioEmaluele”,UniversityofCatania,Catania,Italy.E-mail:[email protected]

Francis Bacon, filosofo inglese del XVII secolo, in una sua rifles-sione sul senso ed il significato delle innovazioni scientifiche

ebbe a dire. “Chi non applica nuovi rimedi deve essere pronto a nuovi mali; perché il tempo è il più grande degli innovatori”.

È proprio tale frase che mi si presenta alla mente mentre mi accingo a presentare questo testo sulla terapia intratimpanica delle patologie dell’orecchio 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 l’orecchio 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 l’ablazione 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 all’ablazione vestibolare determinò 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 utilità ed efficacia rappresentano oggi delle vere e proprie evidenze cliniche.

E’ possibile affermare, infatti, che il trattamento di patologie dell’orecchio interno, ad andamento evolutivo e prognostico non sempre ben definibile, quali la malattia di Meniere, l’ipoacusia 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 modernità e di interdisciplinarietà di cui si avvale la evoluzione del pensiero scientifico e della ricerca clinica.

È con vivo piacere, quindi, che mi complimento per il lavoro svolto dagli Autori e nel plaudire all’iniziativa e nell’augurare tutto il successo che merita, spero che questo sforzo compiuto possa aprire le porte ad ulteriori possibilità di ricerca scientifica e a consentire più ampie applicazioni cliniche.

Prof.AgostinoSerraPresidenteAUORL

DirettoreU.O.diOtorinolaringoiatria,UniversitàdegliStudidiCatania,Catania,Italia

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smaller quantity of medication besides avoiding the systemic side-effects of the medications. Intratym-panic drug therapy has been described for the treat-ment of Menière’s disease;1, 2 sudden sensorineural hearing loss,3 tinnitus 4 and even facial palsy.5 A va-riety of drugs have been used intratympanically from steroids, aminoglycosides to lignocaine. According to Lustig and Carey,6 the treatment potential of intra-tympanic 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 oto-toxic 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 Menière’s disease

Harold Schuknecht should be the first to be cred-ited for the modern attempt at transtympanic treat-ment of Menière’s disease by injecting streptomycin as an alternative to unilateral surgical ablation of the affected labyrinth.1 According to Schuknecht the

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

According to Dictionary.com “intratympanic “ means “situated or occurring within the middle

ear”. Although intratympanic therapy was first de-scribed 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”, intratym-panic + gentamicin showed up 216 articles with 34 review articles. Intratympanic therapy has several ad-vantages over systemic or intravenous medications: being focused, it can achieve higher local therapeu-tic concentration of the drugs with the use of much

1PD Hinduja Hospital, Mahim, Mumbai, India2Seth GS Medical College and KEM Hospital

Mumbai, India 3PD Hinduja Hospital, Saifee Hospital, Breach Candy

Hospital and Cumballa Hospital, Mumbai, India

REVIEWSOTORINOLARINGOL 2010;60:129-33

G. MANKEKAR 1, M. V. KIRTANE 1, 3, K. CHAVAN 1, S. PACHAURI 1

History of intratympanic managements for inner ear disorders

Corresponding author: Dr. G. Mankekar, MS, PhD, ENT Consul-tant, PD Hinduja Hospital, Mahim, Mumbai, 400016, India. E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1928-OTtitolo breve: INTRATYMPANIC MANAGEMENTS FOR INNER EAR DISORDERSprimo autore: MANKEKARpagine: 129-33

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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 re-moved at autopsy. The efficiency of this method for preserving the inner ear was further proven by a con-trolled experiment in animals. Thus it seemed pos-sible 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 meth-od 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 stud-ies in cats showing loss of hair cells in the cristae, maculae and the organ of Corti following intratym-panic 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 Menière’s 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 intratym-panic 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 aver-age total dose of 90 mg to achieve total vertigo con-trol 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 intratym-panic gentamicin also caused postablative disequi-librium and vertigo recurrences. Nedzelski et al.15-

17 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, nystag-mus 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 com-pared 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 ti-tration 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 Menière’s disease with intratympanic gentamicin has become standard therapy there are still conflict-ing 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 in-tratympanic gentamicin. They conclude that there is significant variability in gentamicin outcomes sug-gesting that the technique requires further refine-ment 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 hear-ing 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 Menière’s dis-ease 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 Menière’s dis-ease. Lidocaine’s 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 path-ways 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 re-ported 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 gener-ally 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 var-ious causes of inner ear disease and tinnitus in 46 patients found improvement in tinnitus in 47% pa-tients; of these 60% were patients with Menière’s disease. Shea and Ge 28 reported that 82% patients with Menière’s disease experienced reduction in tin-nitus following IT dexamethasone along with oral dexamathasone. However in the only prospective randomized double blind cross-over trial for IT per-fusion, Silverstein et al.29 could not show any signifi-cant changes in hearing, tinnitus, caloric vestibular responses or in patients’ responses over a 6 week study period. Hicks 30 reported complete improve-ment of tinnitus in 3 patients with Menière’s 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 pa-tients, 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 af-ter otoendoscopy, laser assisted tympanostomy and placement of gelfoam in the round window niche. Tinnitus improved in three of six patients after sin-gle gentamicin injection, five of eight patients after two injections and in three of nine patients after re-peated injections. In 2002. Jackson and Silverstein 32

reported on 92 patients with Menière’s 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 Menière’s patients with about 50% patients experiencing con-trol of their vertigo, some experiencing improvement in hearing and decrease in tinnitus within 72 hours following perfusion. They suggest that patients with Menière’s 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 SS-NHL 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 ster-oids 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 cerebrospi-nal 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 clini-cal 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 sys-temic 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 µL/h continu-ous 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 improve-ment 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. How-ever, 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 lo-cal (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 sal-vage therapy in refractory cases of SSNHL which have not improved with conventional systemic ster-oids.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 con-centration 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 ex-ternal validity. It is difficult to compare studies due to the heterogeneous nature of the data. More rigor-ously 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 Menière’s disease and intratympanic steroids for SSNHL, newer tech-nologies like hydrogels and nanoparticles are being explored. Intracochlear devices that use recent ad-vances in microsystems technology are being devel-oped to apply medications directly in to the inner ear. Such devices could be used to deliver neurotrophic factor and steroid delivery with cochlear implanta-tion, RNA interference technologies and stem cell therapy.50

Riassunto

Storia dei trattamenti intratimpanici dei disordini dell’orec-chio interno

Il trattamento delle patologie dell’orecchio è variato nei secoli dagli spicchi di aglio schiacciati all’olio fino alla bile dei buoi. Tuttavia, il classico “trattamento intratimpanico” si è diffuso soltanto circa mezzo secolo fa, dopo lo svilup-po del microscopio e la visualizzazione della membrana timpanica. Inoltre, vi è stato un miglioramento nella tec-nologia diagnostica, con l’audiometria tonale pura, e nella disponibilità di diverse formulazioni farmacologiche. Que-sta revisione storica descrive le diverse modalità di tratta-mento intratimpanico per le patologie dell’orecchio interno come la malattia di Menière, il tinnito e la sordità improv-visa, nell’ultima metà secolo.Parole chiave: Intratimpanico - Gentamicina - Steroidi - Li-docaina - Malattia di Menière - Sordità neurosensoriale - Acufene.

References

1. Schuknecht H. Ablation therapy for the relief of Menière’s disease. Laryngoscope 1956;66:859-70.

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2. Schuknecht H. Ablation therapy in the management of Menière’s 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 coch-lear 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 Menière. Therapie Woche Wochenschrift Fur Praktische Medizin 1976;26:1-6.

8. Lange G. The intratympanic treatment of Menière’s 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 intratympani-cally applied streptomycin (gentamicin) in the therapy of Morbus Menière. Arch of Otolaryngol 1978;221:149-52.

10. Katzke D. treatment of Menière’s disease with intratympani-cally applied gentamicin sulphate. Laryngol Rhinol Otol (Stuttg) 1982;61:4-8.

11. Blessing RE, Schlenter WW. Long term results of gentamicin therapy of Menière’s disease. Laryngorhinootologie 1989;68:657-60.

12. Moller C, Odkvist LM, Thell J et al. Vestibular and audiologic functions in gentamicin treated Menière’s 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 Menière’s 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 Menière’s disease. Am J Otol 1992;13:18-22.

16. Nedzelski JM, Bryce GM, Pfleiderer AG. Treatment of Menière’s 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 Menière’s disease:update of an ongoing study. Am J Otol 1993;14:278-82.

18. Magnusson M, Padoan S. delayed onset of ototoxic effects of gen-tamicin in treatment of Menière’s disease. Rationale for extremely low dose therapy. Acta otolaryngol 1991;111:671-6.

19. Toth AA, Parnes LS. Intratympanic gentamicin for Menière’s disease:preliminary comparison of two regimes. J Otolaryngol 1995;24:340-4.

20. Nguyen KD, Minor LB, Santina CC, Carey JP. Time course of re-peated intratympanic gentamicin for Menière’s disease. Laryngo-scope 2009;119:792-8.

21. Derebery MJ, Fisher LM, Berliner K, Chung J, Green K. Outcomes of endolymphatic shunt surgery for Menière’s 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 Menière’s syn-drome. Z. Laryngol Rhinol Otol 1960;39:190-5.

24. Shulman A. Neuroprotective drug therapy:a medical and pharmaco-logical 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 Lar-ynx 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

I. Intratympanic steroid treatment of inner ear disease and tinnitus (prelim report). Ear Nose and Throat J 1996;75:468-71;474-476.

28. Shea JJ Jr, Ge X. Dexamethasone perfusion of the labyrinth plus intravenous dexamethasone for Menière’s disease. Otolaryngol Clin North Am 1996;29:353-8.

29. Silverstein H, Isaacson JE, Olds MJ, Rowan PT, Rosenberg S. Dexamethasone inner ear perfusion for the treatment of Menière’s disease:a prospective randomized double blind cross –over trial. Am J Otol 1998;122:143-8.

30. Hicks GW. Intratympanic and round window drug therapy: effect on cochlear tinnitus. Int Tinnitus J 1198;4:144-7.

31. Silverstein H, Arruda J, Rosenberg SI, Deems D, Hester TO. Direct round window membrane application of gentamicin in the treatment of Menière’s disease. Otolaryngol Head Neck Surg 1999;120:649-55.

32. Jackson LE, Silverstein H. Chemical perfusion of the inner ear. Otolaryngol Clin North Am 2002;35:639-53.

33. Dodson K, Woodson E, Sismanis A. Intratympanic perfusion for Menière’s disease. Presented at the meeting of the American Neuro-tology society, Nashville (TN), May 3, 2003.

34. DeKleyn A. Sudden complete or partial loss of function of the octavus-system in apparently normal persons. Acta Otolaryngol 1944;32:407-29.

35. Simmons FB. Sudden idiopathic sensorineural hearing loss:some observations. Laryngoscope 1973;83:1221-7.

36. 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.

37. Mattox DE, Simmons FB. Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977;86(4 Pt 1):463-80.

38. Rauch SD. Intratympanic steroids for sensorineural hearing loss. Otolaryngol Clin N Am 2004;37:1061-74.

39. Sekula J, Wlodyka J. 20% Mannitol in the treatment of sudden hear-ing loss. Otolaryngol Pol 1975;29:129-36.

40. Martin G, Jacobs P. Clinical comparison of dextran 40 and xan-tinol nicotinate in the treatment of sudden deafness caused by shock waves (author’s transl) Laryngol Otolog Rhinlog (Stuttg) 1977;56:860-3.

41. Haug O, Draper WL, Haug SA. Stellate ganglion blocks for idi-opathic sensorineural hearing loss. Arch Otolaryngol 1976;102:5-8.

42. 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.

43. Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids:an animal study followed by clinical applica-tion. Laryngoscope 1999;109 (7 Pt 2):1-17.

44. Kopke R, Hoffer M, Wester D et al. Targeted topical steroid therapy in suden sensorineural hearing loss. Otol Neurotol 2001;22:475-9.

45. Lefebvre PP, Staecker H:Steroid perfusion of the inner ear for sud-den sensorineural hearing loss after failure of conventional therapy:a pilot study. Acta Otolaryngol 2002;12:698-702.

46. Suckfuell M. Perspectives on the pathophysiology and treatment of sudden idiopathic sensorineural hearing loss. Dtsch Arztebl Int 2009;106:669-75; quiz 676.

47. She W, Dai Y, Du X, Yu C, Chen F, Wang J, Qin X. Hearing evalu-ation of intratympanic methylprednisolone perfusion for refractory sudden sensorineural hearing loss 48. Otolaryngol Head Neck Surg 2010;142:266-71.

49. Dallan I, De Vito A, Fattori B, Casani AP, Panicucci E, Berrettini S et al. Intratympanic methylprednisolone in refractory sudden hear-ing loss:a 27-patient case series with univariate and multivariate analysis. Otol Neurotol 2010;31:25-30.

50. Hu A, Parnes LS. Intratympanic steroids for inner ear disorders-a review. Audiol Neurotol 2009;14:373-82.

51. McCall AA, Swan EE, Borenstein JT, Sewell WF, Kujawa SG, McK-enna MJ. Drug delivery for treatment of inner ear disease:current state of knowledge. Ear Hear 2010;31:156-65.

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Department of Experimental Biomedicine and Clinical Neurosciences

Section of Human Anatomy “E. Luna”University of Palermo, Palermo, Italy

OTORINOLARINGOL 2010;60:135-9

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

Anatomy of cochlea and round window

Corresponding author: Dr. F. Cappello, Section of Human Anatomy “E. Luna”, Via del Vespro 129, 90127, Palermo, Italy. E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1935-OTtitolo breve: Anatomy of cochlea and round windowprimo autore: DAVIDpagine: 135-9

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 tym-panic membrane is thin and semi-transparent. Its lat-eral 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 exter-nal meatus and the internal ear. It consists of an up-per part, the epitympanic recess, the proper tympa-

One of the most important functions of the ear is sound re-ception, particularly the detection of amplitude and frequen-cy of the sound waves by Corti’s organ. The latter is a sensory structure located in the cochlear duct (middle scale), consist-ing of hair cells lying above the basilar membrane. The co-chlear duct is surrounded by two cavities containing peril-ymph: 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 ana-tomical 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 win-dow.

Overview of the ear

The ear has three parts: external, middle and in-ner 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 au-

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num, that posteriorly communicates with tympanic antrum, and the mastoid air-cells, and continuing an-teriorly 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

the hearing organs of the internal ear. The footplate of the stapes is connected to an oval orifice, the ves-tibular 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 pre-cartilage 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 membra-nous labyrinth.4

The bony labyrinth consists of three parts: the ves-tibule, periotic semicircular canals and a cochlear portion. The vestibule has two membranous sacs: the saccule and the utricle, whose receptors provide in-formation 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 tym-pani (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 mem-brane called the secondary membrane of the tympa-num. The complex (middle scale, scala vestibularis and scala tympani) is coiled to spiral around a cen-tral spool of bone, the modiolus2. The cochlear duct is blind and ends at the apex of the cochlea and com-municates 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 home-ostasis, regarding volume, concentration, osmolarity and pressure, is induced by structures such as the

Figure 1.—Structures of inner, middle and external ear. 1. Mas-toid air cells; 2. Tympanic antrum; 3. External acoustic meatus; 4. Malleus; 5. Incus; 6. Stapes; 7. Vestibule; 8. Saccule; 9. Utri-cle; 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 tym-pani; 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.

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stria vascularis and vestibular dark cells, responsible for endolymph secretion.5, 6 The vestibular wall, or Reissner membrane, extends obliquely from the spi-ral 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 en-dolymph. 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 ar-cuate 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 col-lectively 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 gener-ates pressure waves in the perilymph in the vestibu-lar canal. The round window moves to compensate. when the stapes moves toward the internal of co-chlea, the window protrudes outward. The pressure waves induced by the stapes cause distortion and vibration of the basilar membrane, determining vi-bration 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 en-cephalic nerve, cochlear branch) reach the bulbar nu-clei (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 neu-rons 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 anti-inflammatory and anti-apoptotic actions, corticoster-oids 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 regenera-tion.13 The hair cells can be easily damaged by ex-cessive stimulation by ototoxic drugs and by the ef-fects of aging. In mammals, auditory hair cells are never replaced, causing damage to the ear with pro-gressive and permanent deafness. In contrast, non-mammalian 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 regenera-tion. 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 emis-sions (OAEs) differ between sexes. Prenatal expo-sure to high levels of androgens can weaken the co-chlear amplifiers, thereby weakening oto-acoustic emissions (OAEs).18 During the perinatal period, the brainstem reaches a mature state, and brainstem ac-tivity is reflected in behavioral responses to sound (phonetic discrimination).19

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

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Vascularization of inner ear

The inner ear is vascularised by the labyrinthine artery. This artery passes through the internal audito-ry meatus, dividing into three branches: the vestibu-lar artery, the vestibule-cochlear artery and the coch-lear 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 supe-rior 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 si-nus. 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 ster-oids are an effective procedure for the control of co-chleo-vestibular disorders, such as Ménière’s disease and sudden deafness, acting on the cochleo-vestibu-lar 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 intro-ducing new drugs and gene therapy.21

Riassunto

Anatomia della coclea e della finestra rotondaUna delle più importanti funzioni dell’orecchio è la ri-

cezione del suono, particolarmente il rilevamento dell’am-

piezza e della frequenza delle onde sonore da parte dell’or-gano di Corti. Quest’ultimo è una struttura sensoriale localizzata nel dotto cocleare (scala media), costituito da cellule ciliate disposte sulla membrana basilare. Il dotto cocleare è circondato da due cavità conteneti perilinfa: la scala vestibularis e la scala tympani. Il meccanismo di ricezione del suono coinvolge diverse altre componenti dell’orecchio, come il martello, l’incudine e la staffa, nella cavità timpanica e le finestre ovale e rotonda. Il movimento della staffa sulla finestra ovale, che è adiacente alla scala vestibularis, genera onde pressorie nella perilinfa lungo il canale vestibolare. La finestra rotonda, che separa la sca-la tympani dalla cavità timpanica, si muove a compensa-re i movimenti della finestra ovale. Il malfunzionamento dell’orecchio interno, a causa di particolari patologie, può essere corretto dall’impiego di farmaci come la gentami-cina che raggiunge la coclea attraverso la finestra rotonda. Questo breve articolo propone una revisione delle prin-cipali conoscenze anatomiche dell’orecchio interno, con particolare attenzione alle strutture di interesse otorino-laringoiatrico per il trattamento di disordini dell’orecchio attraverso l’instillazione di farmaci nella cavità 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. Gray’s Anatomy. The anatomical basis of clinical prac-tice. Edimburgh (UK): Elsevier; 2005.

3. Harada y. Atlas of the ear by scanning electron microscopy. Lancas-ter (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: characterisa-tion of main structures responsible for inner-ear homeostasis, and their pathophysiological relations. J Laryngol Otol 2009b;123:151-62.

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 molecu-lar 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;55:120-6.

12. Dinh CT, Van De water TR. Blocking pro-cell-death signal path-ways to conserve hearing. Audiol Neurootol 2009;14:383-92.

13. Diaz RC. Inner ear protection and regeneration: a ‘historical’ per-spective. 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 deaf-ness. 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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be similar to that of plasma.1 However, the endothe-lial cells of inner ear capillary complex form a bar-rier with tight-junction, morphologically similar to the blood-brain barrier, and anatomic studies showed that there were no fenestrations between the endothe-lial cells of inner ear.2 The presence of a blood-laby-rinth 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 depend-ing 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 in-crease in dosage and limit the ability to increase it be-yond 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 mid-dle ear cleft.

There are two possible ways to deliver drugs in cases of inner ear diseases: via the bloodstream through systemic admin-istration and through the two windows of the inner ear by application into the middle ear cleft. Efforts to find the strate-gies 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 administra-tion, discussing the anatomic and physiologic key point to un-derstand the inner ear pharmacokinetics.

Key words: Ear, inner - Pharmacokinetics - Cochlea - Round window, ear.

Therapeutic 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 dis-eases and specifically on the strategies used to de-liver 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 cap-sule leaving only microscopic gaps communicating with the outer structures. This system of protection provides the inner ear with a good defense mecha-nism from infective agents and toxic substances. Un-fortunately, 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

1Department of Surgical and Oncological DisciplinesUniversity of Palermo, Palermo, Italy

2ENT Clinic, Nayak’s Road, KasaragodKerala, India

3ENT Institute, Department of SurgicalClinical and Experimental Sciences,

“G. d’Annunzio” University of Chieti and Pescara Chieti, Italy

OTORINOLARINGOL 2010;60:141-4

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

Pharmacokinetics of drugsin transtympanic administration

Corresponding author: Dr. F. Dispenza, Via Oreto 339, 90124 Paler-mo, Italy, E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: titolo breve: Pharmacokinetics of drugs in transtympanic administrationprimo autore: DISPENZApagine: 141-4

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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 swal-lowing 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 general-ly 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 win-dow 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 fac-tors such as: infection, previous operation for middle ear diseases and drugs additives present in injected solution. Treatment with a drug and its carrying solu-tion 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

The systemic route generally requires high dos-ages to reach useful concentrations in the inner ear. Achieving this while administering the drugs sys-temically 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 transtym-panic 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 pharma-cokinetics

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 ad-vantages. First, there is a potential for direct drug up-take 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 fur-ther side, round window with its membrane plays a role in acoustic dynamics by allowing the release of mechanical energy passing through the coch-lea. Without this outlet no waves could pass into the perilymph. The round window lays posteroin-feriorly 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 enter-ing 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 applica-tion sessions 4) method of application; 5) presence

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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 numer-ous processes: diffusion into contiguous compart-ments of the ear, passage into bloodstream across the vascular endothelial cells, accumulation of drugs by tissues of the ear. The clearance of drugs from peri-lymph is supposed to be the determinant factor in reaching the stable decreasing gradient of drug con-centration 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 compart-ments (site of action of the great part of drug used for inner ear diseases). The molecule may bind in-tracellularly with proteins, with receptors or may be metabolized by intracellular mechanisms.

Metabolism of drugs, including uptake and elimi-nation, 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 (Dexameth-asone 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 in-ner ear fluid, without cochlear cell damage.22

The ultimate frontier of inner ear drug applica-tion 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 de-livery by an osmotic pump was experimented to per-mit longer drug infusion times and bolus dosing25.

for the drugs passage.12 Liposolubility of substances is also a factor in regulation of RWM permeability. In fact, although cationic substances have been ob-served 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 conse-quence it will decrease the permeability of substanc-es through it. As well as inflammation, surgeries in the middle ear can obstruct the round window niche with either cicatrisation or bone dust deposits, re-ducing the efficacy of transtympanic treatment in such patients.13

Cochlear endolymphatic ions homeostasis is main-tained by stria vascularis in the lateral wall of coch-lea 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 longitudi-nal flow is near to zero.14 Passage of substances into endolymph occurs indirectly, via the perilymph.15 The movements of charged molecules between en-dolymph and perilymph are therefore influenced by the endocochlear potential. Substances with a nega-tive charge have a natural gradient to pass from the perilymph to endolymph, because of the consider-able 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 deliv-ered 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 experi-mental study using the trimethylphenylammonium (TMPA) as ionic marker. It was possible to deter-mine 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 obtain-able 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

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43. Juhn SK, Rybak LP. Labyrinthine barriers and cochlear homeosta-sis. Acta Otolaryngol 1981;91:529-534.

44. Goycoolea MV, Lundman L. Round window membrane. Struc-ture 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 mem-brane permeability. An in vitro model. Acta Otolaryngol 1987;104 (Suppl.):472-80.

48. Haynes DS, O’Malley M, Cohen S, Watford K, Labadie RF. Intra-tympanic dexamethasone for sudden sensorineural hearing loss af-ter failure of systemic therapy. Laryngoscope 2007;117:3-15.

49. Goycoolea MV. Clinical aspects of round window membrane per-meability under normal and pathological conditions. Acta Otolaryn-gol 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 experi-mental 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. Phys-iol Rev 1988;68:1083-128.

16. Salt AN, Ma y. Quantification of solute entry into cochlear peril-ymph through the round window membrane. Hear Res 2001;154:88-97.

17. Saijo S, Kimura RS. Distribution of HRP in the inner ear after injec-tion 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 per-fusion. 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 applica-tion. 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 deliv-ery of charge and neurotrophins to cochlear neurons. Biomaterials 2009;30:2614-24.

25. Prieskorn DM, Miller JM. Technical report: chronic and acute intra-cochlear infusion in rodents. Hear Res 2000;140:212-5.

Conclusions

In conclusion this brief description of inner ear pharmacokinetics shows the fate of drugs after tran-stympanic administration. Several emerging themes arise. First of all, the numerous determining factors that influence the action of drug into inner ear, differ-ently from other region of the body, are in reality not modifiable, except for the delivering system. The sec-ond 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 develop-ment and has the prospective to solve a number of previously challenging clinical problems.

Riassunto

Farmacocinetica dei farmaci dopo somministrazione tran-stimpanica

Per il trattamento di alcune patologie dell’orecchio in-terno esistono due possibili vie di somministrazione: via sistemica, attraverso la distribuzione ematica, ed attraverso le due finestre dell’orecchio interno mediante applicazione diretta nella cassa timpanica. Numerosi sono gli studi e i tentativi di trattamento compiuti dai ricercatori di ogni Pa-ese, al fine di trovare le corrette strategie terapeutiche nella somministrazione transtimpanica. Questa breve descri-zione mostra il destino dei farmaci dopo soministrazione transtimpanica, discutendo i punti chiave anatomici e fisio-logici che consentono di comprendere la farmacocinetica dell’orecchio interno.Parole chiave: Orecchio interno - Framacocinetica - Co-clea - 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.

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Vol. 60 - No. 3 OTORINOLARINGOLOGIA 145

Department of Otolaryngology – Head and Neck Surgery, Schulich School of Medicine & Dentistry

University of Western Ontario London, Ontario, Canada

OTORINOLARINGOL 2010;60:145-53

G. JEREMIC, L.S. PARNES

Intratympanic steroids for sudden sensorineural hearing lossA review

Corresponding author: Dr. Lorne S. Parnes, Department of Otolaryn-gology – Head & Neck Surgery, University Hospital, 339 Windemere Road, London, ON, N6A 5A5 Canada, Tel. +1 519 663 3604, Fax. + 1 519 663 3916, Email. [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1933-OTtitolo breve: Intratympanic Steroids for Sudden Hearing Lossprimo autore: JEREMICpagine: 145-53

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 em-ployed treatment of SSNHL worldwide is that of systemic steroids, through either the oral or intra-venous 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. Alternative-ly, local administration of steroids via intratympanic injection was introduced as a means of delivering higher concentrations into the inner ear, while spar-ing the side-effects of high-dose systemic steroids.

In addition to avoiding the side-effects of systemic steroids, there are several advantages to using intra-tympanic steroids (ITS). Intratympanic injections are typically well tolerated, and can be done as an office procedure under local anesthesia. Treatment is direct-ed 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 prima-ry treatment modality. Although these studies have

Background/Aim. Local steroid treatment via intratympan-ic injection has been suggested to achieve a significant rate of hearing improvement in cases of idiopathic sudden sen-sorineural hearing loss (SSNHL). The aim of this study was to review the current evidence for and future direction of in-tratympanic steroid (ITS) therapy.Methods. PubMed and Ovid Medline databases were in-vestigated 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 im-provement, steroid doses, pre-study treatments, and treat-ment protocols.Conclusion. There are limited concrete studies on ITS that meet the criteria of comparability, internal validity, and ex-ternal validity. More research is needed using uniform, stand-ardized definitions and protocols to determine the efficacy of ITS for treatment of idiopathic SSNHL.Key words: Intratympanic steroids - Sudden sensorineural hear-ing loss - Deafness

Idiopathic 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 uni-lateral 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

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146 OTORINOLARINGOLOGIA September 2010

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 clini-cians in clarifying the current evidence and direction of ITS therapy for idiopathic SSNHL.

Methods

We used the Meta-Analysis of Observational Stud-ies 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: in-tratympanic 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 stud-ies 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 Evidence-based 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 pro-spective 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 re-spect to steroid doses, treatment protocols, and defi-nitions 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 So-ciety of Otorhinolaryngology–Head and Neck Sur-gery, systemic treatment with high dose glucocorti-coids is suggested as a primary intervention option in idiopathic SSNHL 42. Consequently, most stud-ies 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 pa-tients 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 in-cluding most commonly a large range of spontane-ous recovery rate, initial degree of hearing loss, and the duration between the time of the hearing loss and the onset of treatment. The reported spontane-ous 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 ac-cord 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 Evi-dence-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 AuthorLevel

of evidence

Definition of SSNHL Study typeSteroid &

dose (mg/ml)

Previous or concurrent treatment other than ITS Treatment protocol

Plontke, 2009 8 1 SSNHL within 72h & hearing threshold of >50 dB HL for3 freq. or >60 dB for 2 or >70 dB HL for any frequency or a SRT ≥70 dB SPL or a speech discriminationscore of ≤30%

Salvage dex. (4) Prednisolone i.v., pento-xifylline for 10 days

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

She, 2010 9 2 SSNHL ≥ 30 dB for ≥ 3 freq. over ≤ 3 days

Salvage MP(40) Systemic steroid (dex), vasodilators, antivirals, thrombolytic anti- coagulant (defibrin), Vit. B1 and meco-balamin, and hyperbaric oxygen therapy

Microcatheter MP (0.5 mL per day) for 10 days

Dallan, 2010 10 2 Idiopathic SSNHL Salvage MP(20) MP i.v. 1 mg/kg/d, pento- xyfylline i.v. (200 mg/d); 8 patients LMWH heparin (0.4 ml, s.c. bid) for 7-10 d

1 injection

Hong, 2009 11 1 SSNHL ≥30 dB in 3 con-tiguous freq. in ≤ 3 days

initial dex.(5) None 0.3 to 0.4 cc / d for 8 d

Han, 2009 12 2 SSNHL ≥30 dB in 3 con-tiguous freq. in ≤ 3 days

initial dex. (5) Trimetazidine (50 mg tid); Gingkobiloba extracts (80 mg bid)

1 injection

Zernotti, 2009 13 4 SSNHL >30 dB in at least 3 contiguous audio-metricfrequencies, over a pe-riod of 72 h or less

initial dex. (4) None 3 (1 cc) weekly injec-tions

Fitzgerald, 2007 14 4 ≥20 dB SSNHL in ≥3 contiguous freq. occur-ring w/in 72 h or less

Initial or salvage

MP (62.5) Oral steroids 3 injections (0.4 cc each) over 3 weeks

Ahn, 2008 15 3 SSNHL 30 dB in 3 con-tiguous freq. over several days

Salvage dex. (5) MP p.o. for 14 days with vitamins and lipo-PGE1

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

Lee, 2008 16 2 ≥20 dB SSNHL in ≥3 contiguous freq. occur-ring w/in 72 h or less

Salvage dex. (5) MP p.o. for 14 days + dex-tran i.v. and lipo-PGE1 i.v for 5 days + famci-cyclovir for 7 days

4 injections within 2 weeks

Battaglia, 2008 17 1 ≥20 dB of unilateral SSNHL in ≥3 freq. oc-curring w/in 3 days

initial dex. (12) Prednisone p.o. concurrently for 14 days

3 weekly injections

Ahn, 2008 18 1 SSNHL 30 dB in 3 con-tiguous freq. over several days

Initial dex. (5) MP p.o. concurrently for 14 d

3 injections (days 1, 3, 5)

Xenellis, 2006 19 1 SSNHL ≥30 dB in 3 con-tiguous freq. in ≤ 3 days

Salvage MP (80 mg/2ml)

Prednisolone i.v. for 10 d; acyclovir

4 injections over 15 days

Ho, 2004 20 1 Unilateral severe or pro-found idiopathic SSNHL over 24 h

Salvage dex. (4) MP p.o. for 10 d, vasodila-tors, vit. B, benzodiazepines for 10 d, carbogen inhalation for 5 d

1 injection/week for 3 weeks

Kilic, 2007 21 2 Sudden onset HL history Salvage MP (62.5) MP i.v. for 3 days, predniso-lone p.o. for 21 d

5 injections at 3-day intervals

Plaza, 2007 22 2 Unilateral deafness, w/in 3 days, ≥30 dB at 3 consecutive freq.

Salvage MP (20) MP (120 mg) i.v. for 5 d 3 weekly injections

Van Wijck, 2007 23 2 SSNHL ≥30 dB at 3 sub-sequent 1-octave steps in freq. w/in 3 days

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

Microcatheter – 3 drops bid for 3 weeks

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148 OTORINOLARINGOLOGIA September 2010

Table I [continued]

First AuthorLevel

of evidence

Definition of SSNHL Study typeSteroid & dose (mg/

ml)

Previous or concurrent treatment other than ITS Treatment protocol

Kakehata, 2006 24 2 n.a.(1) Initial dex. (4) Dex. i.v. for 10 d in com-parative group

1 injection/day for 8 days

Lauterman, 2005 25 2 Monoaural sudden idio-pathic profound HL

Initial MP (32) Concurrent prednisolone i.v. for 10 d + rheologic infusion therapy

5 injections on 5 consecutive days via ventilation tube

Roebuck, 2006 26 3 SSNHL ≥20 dB over 3 freq. in ≤72 h

Salvage dex. (24) Medrol dosepak for 5-7 d before, controls received prednisolone for 20 days

1 injection

Choung, 2006 27 3 Idiopathic SSNHL Salvage dex. (5) Prednisolone p.o. for 10 d and other medication (gingko, antiviral, hydro-chlorothiazide)

2 injections / week for 2 weeks

Haynes, 2007 28 3 Decline over 3 days, ≥3 freq. affected by ≥30 dB

Salvage dex. (24) Systemic steroids (85% antiviral, 27% diuretics)

1 injection

Plontke, 2005 29 3 SSNHL w/in 72h Salvage MP (40) or dex.

(4)

Prednisolone i.v. for 10 d, pentoxifylline for 10 d

RW microcatheter MP (10 ul/h) or dex. (5 ul/h) for 4 weeks

Dallan, 2006 30 4 ≥20 dB SSNHL in ≥3 contiguous freq. occur-ring w/in 3 days

Salvage MP (40) MP i.v. for 10 d + pentoxi-fylline for 10 d; 2 patients received LMWH

1 injection

Banerjee, 2005 31 4 SSNHL at least 30 dB in 3 contiguous freq. in ≤3 days

Initial or salvage

MP (40) or dex.

(4)

Depends on outside referring ENT specialist

2 injections/week until plateau in hearing; aver-age 3.8 (2-11)

Slattery, 2005 32 4 SSNHL at least 30 dB in 3 contiguous freq. over 24h

Salvage MP (62.5) Prednisone for 14 days 4 injections, 4 days apart, w/in 2 weeks

Herr, 2005 33 4 >20 dB SSNHL at any freq. w/in 72h

Salvage dex. (10) or MP (62.5)

High-dose systemic steroids Microwick dex. (3 drops/day) for 1 week; if not better, RW micro-catheter infusion MP or dex. (10 ul/h for 10-13 d)

Battista, 2005 34 4 PTA >90 dB Initial dex. (24) Concurrent MP p.o. for 11 days

4 injections over 2 weeks

Gouveris, 2005 35 4 HL w/in >3 days, >30 dB SSNHL

Salvage dex. (8) Prednisone i.v. and vasoac-tive agents (pentoxifylline and HES)

Average 2.7 injections (range 1-7) every 2 d

Lefebvre, 2002 36 4 SSNHL >30 dB for 3 consecutive 1-octave freq. steps w/in 24h

Salvage MP (62.5) MP i.v. for 1 day, then MP p.o. for 15 d; carbogen, nafhydrofuryl, diazepam, LMWH

RW microcatheter infu-sion 10 ul/h for 8-10 d

Chandrasekhar, 2001 37

4 Change in hearing w/in 12h to 3 days(1)

Salvage dex. (4) ‘other meds’, suboptimal doses of either Medrol dosepak or p.o. prednisone, or no treatment

1-15 injections

Gianoli, 2001 38 4 >20 dB SSNHL in ≥3 contiguous audiometric freq. occurring w/in 3 days

Salvage dex. (25) or MP (125)

High-dose systemic steroids (prednisone 1 mg/kg/day) for min. 1 week or equiva-lent

4 injections over 10-14 days

Kopke, 2001 39 4 HL on awakening or w/in 72 h

Salvage or initial

MP (62.5) Prednisone p.o. for 2 weeks RW microcatheter infu-sion 10 ul/h for 14 days

Parnes, 1999 40 4 n.a. Salvage MP (40) or dex.

‘conventional medical measures’ depending on referring physician

2-29 injections

Silverstein, 1996 41 4 n.a. Salvage MP (80), dex. Eye solution (1) or i.v. dex (4)

‘conventional treatment’ Every Monday, Wednes-day and Friday for 2-4 weeks

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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 1. 6 PTA≤25 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

12 ITS11 Placebo

4/11 (PTA criteria); 3/11 (max recov-ery criteria)1/9 (PTA criteria); 1/9 (max recovery criteria)

98-112 d -

She, 2010 9 Decrease of PTA ≥15 dB atall affected frequencies (from 0.25 kHz to 8 kHz)

26 ITS23 controls

50% (61.9 % with time-to-treat ≤60 d)21.7%

3 months -

Dallan, 2010 10 Good (RG >50%), signifi-cant (25% ≤ RG ≤50%), and insignificant(RG <25%), RG = ∆PTA / HL

27 55.6% 6 months +

Hong, 2009 11 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 hearingpoorer than 45 dB; no recov-ery: <15-dB gain and final hearing poorer than 75 dB

32 ITS31 controls

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

3 months -

Han, 2009 12 Decrease in the four-frequen-cy (0.5, 1, 2, and 3 kHz) PTA of 15 dB or more, at least eight weeks later

34 ITS32 i.v.48 p.o.

79.4%66.7%72.3%

2 months -

Zernotti, 2009 13 A mean hearing recovery of ≥25 dB.

18 ITS 72.2% At least 1 month

+

Fitzgerald, 2007 14 10 dB PTA, 15% SDS 21 ITS 67% n/a(1) +

Ahn, 2008 15 >15 dB PTA 49 ITS50 controls

30.6%16.0%

3 months +

Lee, 2008 16 ≥10 dB PTA, 15% SDS 34 ITS18 controls

47.1%44.4%

2-4 weeks -

Battaglia, 2008 17 15 dB PTA 17 ITS18 p.o. prednisone

16 ITS + p.o. prednisone

31 dB PTA, 36% SDS, 12/17 patients21 dB PTA, 20% SDS, 8/18 patients40 dB PTA, 44% SDS, 14/16 patients

4 weeks +

Ahn, 2008 18 >15 dB + final hearing < 45 dB

60 ITS60 controls

73.3%70%

3 months -

Xenellis, 2006 19 10 dB PTA 19 ITS18 controls

47%0%

1.5 months +

Ho, 2004 20 30 dB PTA 15 ITS14 controls

53%7.1%

2.6±1.6 months (ITS)

2.3±1.7 months (control)

+

Kilic, 2007 21 10 dB PTA 19 ITS18 controls

73.6%0%

24.9 (7-30) months

+

Plaza, 2007 22 15 dB PTA, 15% SDS 9 ITS9 controls

55% (44 dB PTA)0% (2.3 dB PTA)

6 months +

Van Wijck, 2007 23 10 dB PTA 12 ITS12 controls

66% (24.5 dB PTA)8.3% (1.1 dB PTA)

30 days +

Kakehata, 2006 24 Complete recovery, or at least 30 dB

10 ITS21 controls

70%62%

10 days(1) +

Lauterman, 2005 25

Calculated PTA gains; full, partial and none recovery scales

13 ITS14 controls

15 dB PTA11 dB PTA

10 days(1) -

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150 OTORINOLARINGOLOGIA September 2010

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-blind-ed fashion. The goal of the Plontke et al. study was to determine the efficacy of ITS compared to con-trols using normal saline (0.9%) injections as pla-cebo. 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 evalu-ate the combination therapy of ITS and oral steroids. Patients were distributed among three groups includ-ing a control group that received ITS and oral placebo

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 ITS30 controls

30% (PTA criteria); 38.7% (SDS criteria)17% (PTA criteria); 10% (SDS criteria)

4 weeks +

Choung, 2006 27 10 dB PTA, 15% SDS 33 ITS33 controls

39.4%6.1%

8 weeks +

Haynes, 2007 28 20 dB PTA, 20% SDS 40 27.50% 271 (22-1460) days control

+

Plontke, 2005 29 Calculated PTA improve-ment

23 ITS23 controls

15 dB PTA11 dB PTA

1 year +

Dallan, 2006 30 15 dB PTA 8 75% 6 months +Banerjee, 2005 31 Calculated dB and % SDS

improvement26 27.2 ±5.7 dB PTA

25.4±6.2% SDS5.4 (1-52) months +

Slattery, 2005 32 Improvement in treated ear to 50% of baseline differ-ence between the treated and untreated ear; 10 dB PTA, 12% SDS

20 5% improved to near-normal hearing55% significant improvement in PTA and SDS

3 months +

Herr, 2005 33 10 dB PTA, 20% SDS 17 53% 6 weeks +Battista, 2005 34 Complete = final PTA w/

in 10 dB of baseline; partial = final PTA w/in >50% of hearing

25 8% full, 12% partial 6 months -

Gouveris, 2005 35 Complete recovery: w/in 10 dB of unaffected ear; partial recovery: >10 dB improve-ment; no recovery: <10 dB improvement

9 high freq. IS-SHL; 10 sud-

den deafness or profound SHL; 21 pantonal ISSHL

High freq: 33.3% CR, 39.1% PR, 28.6% NRProfound: 0% CR, 60% PR, 40% NRPantonal: 0% CR, 31% PR, 55.5% NR

Last audio test at the end of

intratympanic steroid therapy

+

Lefebvre, 2002 36 16.25 – 25 dB PTA 6 100% ≈5 days after completion of

treatment

+

Chandrasekhar, 2001 37

Increase in SDS, decrease in PTA

10 (11 ears) 73% 3 weeks to 4 years

+

Gianoli, 2001 38 10 dB PTA, 10% SDS 23 44% improved in PTA21% improved in SDS

1-2 weeks +

Kopke, 2001 39 10 dB PTA, 15% SDS 6 (early group, w/in 6 weeks of SSNHL), 3 (late group, >6 weeks)

83% (5/6 early)0% (late group)

n/a(1) +

Parnes, 1999 40 ‘normal thresholds’, ‘ser-viceable hearing’

37 (20 dex., 17 MP)

13/37 = 35.1% overall7/13 = 54% SSNHL

n/a +

Silverstein, 1996 41

10 dB PTA, 15% SDS 46 (8 SSNHL) 41% 12 months +

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pills; a second group receiving oral steroids and in-tratympanic saline; and finally a group that received ITS + oral steroids. Results showed that patients treat-ed 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 improve-ment following ITS compared to pretreatment hear-ing. 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 evalu-ated, underlining the heterogeneous nature of the steroids used and treatment protocols. There is no consensus between the use of dexamethasone or meth-ylprednisolone, 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 hydrocorti-sone or dexamethasone. Unfortunately, application of MP has found no standard protocol with respect to du-ration, 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 pri-mary 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, an-ticoagulants, 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 pro-tocol, ITS administration has found limited uniform-ity. This has previously been reviewed by Alles et al. 6. In the majority of studies, local anesthesia was applied prior to administering steroids by transtym-panic injection. Delivery techniques varied from simple injection, to inner ear medical delivery de-vices 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 Com-munication 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 audio-logic 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 [%] ¼ 100*(PTApre – PTApost)/(PTApre –PTAcontralateral), (6 PTA) 8. Many considered the difficulties in discerning therapy ef-fect 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 comparabil-ity, internal validity, and external validity. Although more recent studies have conformed to standardiz-ing definitions of disease and improvement, there continues to lack homogeneity with respect to ster-oid doses, treatment protocols, and pre-study treat-ments. 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, pa-tient 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 ex-tent that there are known regional differences in treatment practices between North America and Eu-rope. 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 signifi-cant rate of hearing improvement in SSNHL cases that failed to recover with primary oral steroid treat-ment. Furthermore, it has been suggested that local steroid treatment delivery may have better efficacy than systemic administration. Unfortunately, it can-not be determined from the majority of uncontrolled studies whether IT steroids are more effective than oral steroids or whether they are beneficial to a dif-ferent 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 improve-ments in SSNHL. More research needs to be per-formed 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 prospec-tive randomized clinical trial was a head-to-head comparison of oral prednisone against IT methyl-prednisolone 45. By means of its set protocol and suf-

ficient sample size, this non-inferiority study will at-tempt to compare the efficacy of these two therapies in the treatment of idiopathic SSNHL.

Riassunto

Steroidi intratimpanici per la perdita di udito sensorineu-rale improvvisa: revisione

La somministrazione locale di steroidi per via intratim-panica permetterebbe di ottenere un tasso significativo di miglioramento dell’udito nei casi di perdita di udito sen-sorineurale improvvisa idiopatica (SSNHL). L’obiettivo di questo studio era di rivedere l’attuale 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 comparabilità, e validità interna ed esterna. Com-plessivamente, 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 pre-studio e dei protocolli di trattamento. Pochi studi sulla SIT soddisfano i criteri di comparabilità, validità interna e vali-dità esterna. Sono necessari ulteriori studi con definizioni e protocolli uniformi, standardizzati per determinare l’effica-cia della SIT nel trattamento della SSNHL idiopatica.Parole chiave: Perdita d’udito - Steroidi intratimpanici.

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delivered via a round window catheter for severe to profound sud-den idiopathic sensorineural hearing loss after failure of systemic therapy. Laryngoscope. 2009 Feb;119(2):359-69.

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12. Han CS, Park JR, Boo SH, Jo JM, Park KW, Lee Wy et al. Clinical efficacy of initial intratympanic steroid treatment on sudden sen-sorineural hearing loss with diabetes. Otolaryngol Head Neck Surg. 2009 Nov;141(5):572-8. Epub 2009 Oct 1.

13. Zernotti ME, Paoletti OA, Zernotti M, Martinez ME, Roques-Revol M, Prina AC. Intratympanic dexamethasone as therapeutic option in sudden sensorineural hearing loss. Acta Otorrinolaringol Esp. 2009;60:99-103.

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16. Lee HS, Kim JM, Kim yJ, Chung DH, Seo BS, Kim SH. Results of intratympanic dexamethasone injection as salvage treatment in idi-opathic sudden hearing loss. J Otolaryngol Head Neck Surg. 2008 Apr;37(2):263-8.

17. Battaglia A, Burchette R, Cueva R. Combination therapy (intratym-panic dexamethasone + high-dose prednisone taper) for the treat-ment of idiopathic sudden sensorineural hearing loss. Otol Neuro-tol. 2008 Jun;29(4):453-60.

18. Ahn JH, yoo MH, yoon TH, Chung JW. Can intratympanic dexam-ethasone added to systemic steroids improve hearing outcome in pa-tients with sudden deafness? Laryngoscope. 2008 Feb;118(2):279-82.

19. Xenellis J, Papadimitriou N, Nikolopoulos T, Maragoudakis P, Segas J, Tzagaroulakis A et al. Intratympanic steroid treatment in idiopathic sudden sensorineural hearing loss: a control study. Otolaryngol Head Neck Surg 2006;134(6):940–945.

20. Ho HG, Lin HC, Shu MT, yang CC, Tsai HT. Effectiveness of in-tratympanic dexamethasone injection in sudden deafness patients as salvage treatment. Laryngoscope 2004;114(7):1184–1189.

21. Kilic R, Safak MA, Oguz H, Kargin S, Demirci M, Samim E et al. Intratympanic methylprednisolone for sudden sensorineural hearing loss. Otol Neurotol 2007;28(3):312–316.

22. Plaza G, Herraiz C. Intratympanic steroids for treatment of sudden hearing loss after failure of intravenous therapy. Otolaryngol Head Neck Surg 2007;137:74y8.

23. Van Wijck F, Staecker H, Lefebvre PP. Topical steroid therapy us-ing the Silverstein Microwick in sudden sensorineural hearing loss after failure of conventional treatment. Acta Otolaryngol. 2007 Oct;127(10):1012-7.

24. Kakehata S, Sasaki A, Oji K. Futai K, Ota S, Makinae K et al. Com-parison of intratympanic and intravenous dexamethasone treatment on sudden sensorineural hearing loss with diabetes. Otol Neurotol 2006;27(5):604–608.

25. Lautermann J, Sudhoff H, Junker R. Transtympanic corticoid ther-apy for acute profound hearing loss. Eur Arch Otorhinolaryngol 2005;262(7):587–591.

26. Roebuck J, Chang Cy. Efficacy of steroid injection on idiopathic

sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2006;135(2):276–279.

27. Choung yH, Park K, Shin yR, Cho MJ. Intratympanic dexametha-sone injection for refractory sudden sensorineural hearing loss. Laryngoscope 2006;116(5):747–752.

28. Haynes DS, O’Malley M, Cohen S, Watford K, Labadie RF. In-tratympanic dexamethasone for sudden sensorineural hearing loss after failure of systemic therapy. Laryngoscope 2007;117(1):3–15.

29. 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):830–839.

30. Dallan I, Bruschini L, Nacci A, Bruschini P, Traino C, Rognini F et al. Transtympanic steroids as a salvage therapy in sudden hear-ing loss: preliminary results. ORL J Otorhinolaryngol Relat Spec 2006;68:247y52.

31. Banerjee A, Parnes LS. Intratympanic corticosteroids for sud-den idiopathic sensorineural hearing loss. Otol Neurotol. 2005 Sep;26(5):878-81.

32. Slattery WH, Fisher LM, Iqbal Z, Liu N. Oral steroid regimens for idiopathic sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2005;132:5–10.

33. Herr BD, Marzo SJ. Intratympanic steroid perfusion for refractory sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2005;132:527–531.

34. Battista RA. Intratympanic dexamethasone for profound idiopathic sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2005;132:902–905.

35. Gouveris H, Selivanova O, Mann W. Intratympanic dexametha-sone 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.

36. Lefebvre PP, Staecker H. Steroid perfusion of the inner ear for sud-den sensorineural hearing loss after failure of conventional therapy: a pilot study. Acta Otolaryngol 2002; 122(7):698–702.

37. Chandrasekhar SS. Intratympanic dexamethasone for sudden sen-sorineural hearing loss: clinical and laboratory evaluation. Otol Neurotol 2001;22:18y23.

38. Gianoli GJ, Li JC. Transtympanic steroids for treatment of sudden hearing loss. Otolaryngol Head Neck Surg 2001;125:142y6.

39. Kopke RD, Hoffer ME, Wester D, O’Leary MJ, Jackson RL. Tar-geted topical steroid therapy in sudden sensorineural hearing loss. Otol Neurotol 2001;22(4):475–479.

40. Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids: an animal study followed by clinical applica-tion. Laryngoscope 1999;109(7 Pt 2):1–17.

41. 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;75:468–471.

42. Ganzer U, Albegger KW, Arnold W, et al. Leitlinie Horsturz der Deutschen Gesellschaft fur Hals-Nasen-Ohren-Heilkunde, Kopf-und 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.

43. Mattox DE, Simmons FB: Natural history of sudden sensorineural hearing loss. Ann Otol Rhinol Laryngol 1977; 86: 463-80.

44. Jones N, Ludman H: Acquired sensorineural hearing loss; in Lud-man H, Wright t (eds): Diseases of the Ear, ed 6. London, Arnold, 1998, pp 495-97.

45. National Institute of Health. (In Review) Sudden Hearing Loss Mul-ticenter Treatment Trial 2010.

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1ENT Institute, Department of Surgical, Clinical and Experimental Sciences

“G.d’Annunzio” University of Chieti and PescaraChieti, Italy

2ENT Clinic, Nayak’s Road, Kasaragod, Kerala, India3Department of Surgical and Oncological Disciplines

University of Palermo, Palermo, Italy

OTORINOLARINGOL 2010;60:155-63

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

Intratympanic management for autoimmune inner ear disease

Corresponding author: A. De Stefano MD, PhD, FAINOT, Via F. Di Palma 10, 74100 Taranto, Italy. E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1932-OTtitolo breve: AUTOIMMUNE INNER EAR DISEASEprimo autore: DE STEFANOpagine: 155-63

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 pro-gressive, often fluctuating, bilateral SNHL over a pe-riod 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 in-volved first and worsens ahead of the contralateral side. Therefore patients may have only unilateral in-volvement on initial presentation.

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 hear-ing loss in patients affected by AIED does not often occur. For this reason when an AIED is suspected prompt manage-ment should be established in order to stop the steady dete-rioration of hearing function. Intratympanic management of AIED with methylpredinosolone or and recently with Inflixi-mab 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 ster-oids may be recommended as the first line of treatment for these patients, while in the near future transtympanic man-agement with TNF-α antibody is likely to come into the fore.Key words: Autoimmune inner ear disease - Intratympanic steroids – Infliximab - Hearing loss - HSP-70 - Inner ear.

Autoimmune Inner Ear Disease (AIED) is a rare condition that accounts for less than 1% of hear-

ing loss or dizziness.1 In 1979, McCabe first described a cohort of patients with idiopathic, rapidly progres-sive bilateral Sensorineural Hearing Loss (SNHL). These patients’s hearing improved after treatment with corticosteroids, thereby suggesting an autoim-mune 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)

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Generalized imbalance, ataxia, motion intolerance, positional vertigo, and episodic vertigo are often present in almost 50% of the patients.5 Twenty per-cent of the patients experiencing vertigo crisis have symptoms consistent with those seen in Menière’s disease.6 Immune-mediated inner ear disorders pre-senting with Menière’s disease-like symptoms gen-erally affect both ears simultaneously causing asym-metrical bilateral audiovestibular dysfunction.

The hearing loss observed in AIED is in the low-medium frequencies. High frequency hearing loss appears to be more common when vasculitis is the suggested etiopathology.

Systemic Lupus Erythematosus, Beçhet’s disease, Sjögren’s syndrome, Wegener’s granulomatosis, Thyroiditis of Hashimoto, Cogan’s syndrome and antiphospholipid/anticardiolipin syndrome are some of the systemic autoimmune disorders associated with AIED (Table I).

Pathogenesis

Autoimmune inner ear disease implies antibod-ies to an inner ear antigen. Viral infection, inner ear trauma, neoplastic and neurologic diseases or vas-cular diseases may be triggers for AIED. Perhaps antibodies or T-cells cause accidental inner ear dam-age 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 in-ner ear to have separate compartments containing endolymph and perilymph. These are critical for the correct functioning of both auditory and vestibu-lar 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 be-cause of the presence of blood-labyrinthine barrier, the inner ear has long been considered to be incapa-ble 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 im-mune response, release pro-inflammatory cytokines and recruit immuno-competent cells from the system-ic circulation, after either local or systemic presenta-tion 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 sys-temic antibody level than is seen with the primary re-sponse.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 en-dolymphatic sac or the endolymphatic duct results in a much decreased immune response of the inner ear.9 When the antigen has been processed by immunolog-ical cells of the endolymphatic sac, proinflammatory cytokines (including IL-1, Tumor Necrosis Factor-α, 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 spi-ral modiolar vein with additional contributions from the surrounding dilated bone marrow channels. The

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 nodosumCogan’s SyndromeBehçet’s diseaseWegener’s granulomatosisRelapsing polycondritisSjögren’s syndromeSystemic lupus erythematosusInflammatory bowel diseaseRheumatoid arthritisSusac’s SyndromeIdiopathic thrombocytopenic purpuraPolymiositisDermatomyositisScleroderma

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ensuing labyrinthitis results in a physiologic dysfunc-tion, loss of sensory cells and fibrosis and osteogen-esis 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-1β 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 lym-phocytes 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 hu-man 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 in-cluding a mononuclear cell infiltration around the

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

Petrous bone

Saccular duct

Sinus of endolymphatic duct

Utricular duct

Endolymphatic duct

Intraosseous part ofendolymphatic sac

Extraosseous part ofendolymphatic sac

External aperture ofvestibular aqueduct

Internal auditory canal

External aperture ofvestibular aqueduct

Groove of sigmoid sinus

Jugular foramen

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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 succes-sively 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 Hear-ing Research Institute-3 (KHRI-3) binds to support-ing 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 an-tigen 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 sus-pected inner ear antigen in previous bovine inner ear models of AIED and it localized the 68kDa in western-blot evaluation. HSPs are ubiquitous cy-toplasmic 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 HSP-70 may contribute to or enhance pre-existing inner ear pathology.

A 30kDa protein also has received particular at-tention. This protein was demonstrated to be ma-jor Peripheral Myelin Protein 0 (P0) possibly an autoantigen in autoimmune inner ear disease. De-spite 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 an-tibodies 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 signifi-cant degree of hearing loss. The MRL-Fas mice lost the ability to eliminate autoimmune T-Cells by apoptosis. When these cells accumulate, vari-ous endorgans are injured and we can observe the degeneration of stria vascularis and antibody depo-sition 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 in-flammation.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 labora-tory tests and responses to immunotherapy. Imaging studies (CT and MRI) are recommended in order to rule out a cerebello-pontine tumor or an inflamma-tory lesion involving the auditory pathways.

A typical patient with AIED has bilateral fluc-tuating sensori-neural hearing loss and a variable degree of vestibulopathy. There is no specific pat-tern of hearing loss in AIED. Electronystagmogra-phy 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 bilat-eral 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 differ-ential white cell count, erythrocyte sedimentation rate, antiphospholipid/anticardiolipin antibod-ies, 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 senso-ri-neural hearing loss is 14-43%.21 Antineutrophil cytoplasmic antibodies is associated with small vessel vasculitis and has been shown to be positive in Wegener’s granulomatosis, where it is reported to be positive in 50-95% of the patients.21 Anti en-dothelial 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 be-cause no serologic test has yet demonstrated any di-agnostic 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 anti-gen. 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.

Treatments

A spontaneous improvement or resolution of un-treated 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 vari-ous drugs like corticosteroids and other immunosup-pressants whereas in the transtympanic therapy it consists usually of injecting corticosteroids or other immunomodulators into the middle ear space direct-ly through the tympanic membrane.

Systemic therapies

McCabe first reported the benefits of using pred-nisolone 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 cor-ticosteroids 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 recom-mended 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 Menière’s disease patients.24 But, in a 2003 study of Harris con-

Table II.—�Harris-Keithley classification of AIED.

Type Condition

1 Organ specific (ear)2 Rapidly bilateral SNHL with associated systemic immune-

mediated disease3 Immune mediated Menière’s Disease4 Rapidly bilateral SNHL with associated inflammatory

disease (Lyme’s disease, chronic otitis media, otosyphilis, serum sickness)

5 Cogan’s 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 ob-served in patients managed with oral methotrexate.24

Another approach to management of AIED with transoral medicines is the administration of cyclo-phosphamide. 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 cyclophospha-mide has high toxicity profile and potential for uri-nary tract malignancy and leukemia induction. A pe-ripheral blood smear must be performed periodically to monitor for development of leukocytopenia.22, 25

Recently Tumor Necrosis Factor (TNF-α) an-tagonists such as Remicamide (Infliximab), Em-brecel (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-α was evidenced by Satoh who showed that it is the first cytokine expressed by inner ear infiltrating cells following systemic im-munization and antigen infusion into the cochlea.26 TNF-α triggers expression of cells adhesion mol-ecules on vascular endothelial cells thus facilitating extravasation of leukocytes and monocytes to the targeted area of inflammation. As a result TNF-α 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 bal-ance.27 In another study Etanercept was administered at a dose of 25 mg twice weekly with tapering ster-oids 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 pa-tients unresponsive to systemic steroids and meth-otrexate management. This is more so because of the overall side effects associated with the systemic ther-apy. Long term steroid treatment for example, has risks and side effects including: peptic ulcer, mood disorders, insomnia, obesity, moon facies, hypergly-cemia, hypertension, immunosuppression and avas-cular 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 lab-yrinth by infusing the drugs into spaces in proxim-ity 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 phar-macokinetics of hydrocortisone, methylprednisolo-ne and dexamethasone into the inner ear following oral, intravenous and intratympanic administration. They were able to show that intratympanic treat-ment 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 mem-brane.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 liga-ment. Fibrocytes of the spiral ligament play an im-portant 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. When-ever 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 sup-porting 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 ster-oids 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 capa-ble 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 methylpred-nisolone 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 tym-panic 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%) im-proved their hearing function and all showed an im-provement of their vestibular system function too.23

These experiences proves that intratympanic man-agement of AIED with corticosteroids is a potential first-line option for AIED.

Management with intratympanic TNF-α antibody

The importance of TNF-α in amplifying the im-mune response in the inner ear allowed developing

a new therapeutic model for the intratympanic man-agement of AIED.

Yang et al. in the year 2000 showed the attenua-tion of hearing loss in an animal model after tran-stympanic injection of Etanercept.35 Recently in a study of 2006 Van Wijk evaluated the transtympanic perfusion of Infliximab, a humanized TNF-α anti-body, 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 con-sisted of four patients treated with weekly intratym-panic 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 lo-cal administration of Infliximab allowed methyl-prednisolone 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 pa-tient had recurrence of hearing loss one week after Infliximab management but was successfully treated with another local application of TNF-α monoclonal antibody.36

This research emphasises the efficacy of intra-tympanic administration of Infliximab in managing AIED by allowing the steroids to be tapered facilitat-ing 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 diagno-sis.

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 administra-tion 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 man-agement allows recovering the hearing function even in those patients who reduce or stop systemic steroid therapy. Further studies in the future will help estab-lish the correct role of TNF-α in the development of AIED. This would eventually allow standardisation of the management of this disease with intratympan-ic 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-α 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 debilitat-ing condition.

Riassunto

Trattamento intratimpanico della patologia autoimmune dell’orecchio interno

La patologia autoimmune dell’orecchio interno (AIED) è una rara condizione responsabile di meno dell’1% di sor-dità o di vertigini. I pazienti solitamente riportano fullness auricolare come pure tinnito, che possono precedere la per-dita dell’udito. Solitamente viene dapprima interessato un orecchio, che peggiora prima del controlaterale. Pertanto, è possibile che i pazienti presentino coinvolgimento auri-colare monolaterale allo stadio iniziale. Un miglioramento o la risoluzione spontanea della perdita di udito non trat-tata 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 fun-zione uditiva. Il trattamento intratimpanico della AIED con metilprednisolone e recentemente con Infliximab si è di-mostrato sicuro, semplice e utile nella terapia della patolo-gia dell’orecchio interno immuno-mediata refrattaria. Per tutti i motivi sopra menzionati, il trattamento di AIED con steroidi intratimpanici è raccomandato come prima linea di trattamento per questi pazienti, mentre nel prossimo futuro sarà possible utilizzare per via transtimpanica l’anticorpo anti TNF-α.Parole chiave: Patologia autoimmune dell’orecchio inter-no - Steroidi intratimpanici - Infliximab - Perdita uditiva - HSP-70 - Orecchio interno.

References

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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 Otorhinolaryn-gol 2009;266:37-40.

5. Hughes G, Kinney S, Barna B, Calabrese L, Hamid M. Autoim-mune reactivity in Menière’s Disease:preliminary report. Laryngo-scope 1983;43:410-7.

6. Ruckenstein JM. Autoimmune inner ear disease. Curr opin Otolaryn-gol 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;10:193-5.

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. In-nate immunity to cochlear adaptive immune responses. Audiol Neu-rotol 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 phylo-genetically 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 el-evated 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 re-view of the literature. Medicine 1980;59:426-41.

21. Agrup C, Luxon LM. Immune-mediated inner ear disorders in neu-rotology. 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 physi-opathologic approach. Eur Arch Otorhinolaryngol 2006;263:977-82.

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 immuno-mediated 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 cochleo-vestibular 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-con-trolled 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 applica-tion. 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 Menière’s 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 immu-nosuppressives 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 α blocker Infliximab to the inner ear im-proves Autoimmune Neurosensory Hearing Loss. Audiol Neurotol 2006;11:357-65.

37. Hargunani CA, Kempton JB, DeGagne JM, Trune DR. Intratym-panic injection of dexamethasone:time course of inner ear distribu-tion 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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1Department of OtorhinolaryngologyNagoya University School of Medicine, Japan

2Department of RadiologyNagoya University School of Medicine, Japan

OTORINOLARINGOL 2010;60:165-70

T. NAKASHIMA 1, S. NAGANAWA 2, M. SONE 1, M. TERANISHI 1

Intratympanic gadolinium administration for evaluation of endolymphatic space size and drug movement into the inner ear

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 Otorhinolaryn-gology, Nagoya University School of Medicine, Nagoya, Japan.E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1931-OTtitolo breve: EVALUATION OF ENDOLYMPHATIC SPACE AND DRUG MOVEMENTprimo autore: Nakashimapagine: 165-70

studies have shown good results after the injec-tion of steroids through the tympanic membrane to treat sudden sensorineural hearing loss. These intratympanic therapies are based on the assump-tion that the intratympanically administered drug passes into the inner ear through the round win-dow membrane.

Silverstein et al.9 reported that the round win-dow membrane is impermeable or its permeabil-ity 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 in-tratympanically applied gadolinium (Gd) into the inner ear and reported that the round window per-meability was absent in 5% of ears, and 13% of ears had poor round window permeability.10 These results should be considered when planning intra-tympanic drug administration therapy to treat inner ear diseases.

Recently, Crane et al.11 reported middle ear explo-ration with direct application of gentamicin to the round window in the operating room in 8 patients with persistent Menière’s disease symptoms after failure of conventional intratympanic administration of gentamicin. In 6 of these patients, symptoms of

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) con-trast 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 visu-alized. 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 – Mag-netic resonance imaging - Round window membrane permeabil-ity - Endolymphatic hydrops.

Endolymphatic sac surgery 1-3 or intratympanic gentamicin therapy 4, 5 are now used widely

to treat intractable Menière’s disease. Intratym-panic steroid therapy has also been used recently to treat sudden sensory hearing loss.6-8 Several

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vertigo either resolved with no further therapy (4 pa-tients) or with subsequent intratympanic gentamicin injections in clinic (2 patients). The remaining 2 pa-tients 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 administra-tion and evaluated permeability of the round window membrane in 120 patients with inner ear diseases. Be-cause 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 im-aging (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 pa-tients with inner ear disease. They had idiopathic sud-den sensorineural hearing loss, Menière’s disease, de-layed endolymphatic hydrops, fluctuating hearing loss without vertigo, episodic vertigo without hearing loss, nonfluctuating hearing loss with vertigo, or acute hear-ing deterioration with large vestibular aqueduct syn-drome. Most of the patients were candidates for intra-tympanic steroid therapy or intratympanic gentamicin therapy.

Intratympanic Gd injection

Gadodiamide hydrate (Gd-DTPA-BMA: Omnis-can®) or gadopentetate dimeglumine (Gd-DTPA: Magnevist®) diluted with saline was injected intra-tympanically. Fifty-four patients received gadodi-amide 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 nee-dle to vent air during the injection before the intratym-panic 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 che-lator 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 per-formed 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 writ-ten 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 in-jection. 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-DTPA-BMA), we reported that the round window perme-ability was absent in 5% of ears, and 13% of ears had poor round window permeability (10). This ra-tio was not different after the injection of ionic Gd

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contrast agents (Gd-DTPA). No adverse effect was recognized in either group.

Gd signal intensity was fainter with the 16-fold di-lution 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 in-tensity 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 injec-tion method.

Two patients underwent exploratory tympanoto-my 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 re-move 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

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: Endol-ymphatic hydrops in the vestibule.

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: Endol-ymphatic hydrops in the vestibule.

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 3D-FLAIR MRI (Figures 2, 5) because 3D-real IR MRI could discriminate the perilymphatic space from the surrounding bone. However, when the Gd concentra-tion 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 vesti-bule 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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Discussion

Intratympanically administered Gd enters the per-ilymphatic space through the round window mem-brane 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 endol-ymphatic hydrops. According to the criteria of the 1995 American Academy of Otolaryngology—Head and Neck Surgery (AAOHNS) guidelines, his-topathological confirmation is necessary to diagnose ‘certain’ Menière’s disease in addition to ‘definite’ Menière’s disease.17 In addition, the diagnosis can be made when endolymphatic hydrops is observed using MRI in patients with ‘probable’ or ‘possible’ Menière’s disease. Thus, visualization of endolym-phatic hydrops may be vital for making a new diag-nosis of Menière’s disease.

Another purpose of this clinical imaging is to investigate the permeability of the round window

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: Endol-ymphatic 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: Endol-ymphatic hydrops in the vestibule.

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: Endol-ymphatic hydrops in the vestibule.

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membrane and to observe drug distribution inside the inner ear. Our experience of exploratory tympa-notomy in 2 patients showed that it was difficult to evaluate the permeability of the round window mem-brane 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 intratym-panic injection of the 16-fold dilution; however, to

enhance image contrast, we are now using Gd dilut-ed 8-fold as the intratympanic injection method. Be-cause intravenous injection may reveal impairment of the blood–labyrinth or blood–perilymph barri-ers,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, vesti-bule and semicircular canals. This method informs us of the endolymphatic space size and the drug dis-tribution in the inner ear.

Riassunto

Somministrazione intratimpanica di gadolinio per la va-lutazione delle dimensioni dello spazio endolinfatico e il movimento dei farmaci nell’orecchio interno

Obiettivo. Valutare come I farmaci somministrati per via intratimpanica si muovano all’interno dell’orecchio inter-no durante la terapia farmacologica intratimpanica per ma-lattie dell’orecchio interno.

Metodi. Un giorno dopo l’iniezione intratimpanica del mezzo di contrasto gadolinio (Gd), una risonanza magneti-ca nucleare (RMN) è stata effettuata in 120 pazienti affetti da patologie dell’orecchio interno.

Risultati. È stato visualizzato il Gd che era entrato nello spazio perilinfatico. Tuttavia, nel 18% degli orecchi, l’en-hancement del Gd era assente o scarso a causa dell’alterata permeabilità della finestra rotonda. Poiché lo spazio en-dolinfatico non era contrastato dal Gd, esso poteva essere visualizzato.

Conclusioni. L’iniezione intratimpanica di Gd e la RMN forniscono utili informazioni per la terapia farmacologica intratimpanica nel trattamento di patologie dell’orecchio interno.Parole chiave: Terapia farmacologica intratimpanica – Ga-dolinio – Risonanza magnetica – Membrana della finestra rotonda, permeabilità - Idrope endolinfatico.

References

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

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 semi-circular 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 Menière’s disease, response to intratympanic gentamicin therapy was poor.Asterisks: endolymphatic hydrops in the cochlea. Shape of the semicircular canals was unclear.

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2. Tyagi I, Goyal A, Syal R. Sac surgery results as a function of preop-erative distress level. Otol Neurotol 2006;27:951-5.

3. Kitahara T, Kubo T, Okumura S, Kitahara M. Effects of endolym-phatic sac drainage with steroids for intractable Menière’s disease: a long-term follow-up and randomized controlled study. Laryngo-scope 2008;118:854-61.

4. Lange G, Maurer J, Mann W. Long-term results after interval ther-apy with intratympanic gentamicin for Menière’s disease. Laryngo-scope 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 Menire’s disease: a prospective, double-blind, randomized, place-bo-controlled trial. Acta Otolaryngol 2008;128:876-80.

6. Ho HG, Lin HC, Shu MT, Yang CC, Tsai HT. Effectiveness of intra-tympanic 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, Na-kashima 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 explo-ration in patients with Menière’s 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,

Hayashi H, et al. Visualization of endolymphatic hydrops in pa-tients with Menière’s disease. Laryngoscope 2007;117:415-20.

13. Naganawa S, Sugiura M, Kawamura M, Fukatsu H, Sone M, Na-kashima T. Imaging of endolymphatic and perilymphatic fluid at 3T after intratympanic administration of gadolinium-diethylene-triamine pentaacetic acid. AJNR Am J Neuroradiol 2008;29:724-6.

14. Naganawa S, Satake H, Kawamura M, Fukatsu H, Sone M, Na-kashima T. Separate visualization of endolymphatic space, peril-ymphatic 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.

15. Naganawa S, T. N. Cutting edge of inner ear MRI. Acta Otolaryngol 2009;129(Suppl 560):15-21.

16. Nakashima T, Naganawa S, Katayama N, Teranishi M, Nakata S, Sugiura M, et al. Clinical significance of endolymphatic imag-ing after intratympanic gadolinium injection. Acta Otolaryngol 2009;129(Suppl 560):9-14.

17. Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Menière’s disease. American Academy of Otolaryngology-Head and Neck Foundation, Inc. Otolaryngol Head Neck Surg 1995;113:181-5.

18. Nakashima T Naganawa S, Sone M, Teranishi M, Kawauchi H. Round window surgery. Otol Neurotol 2010;31:549-50.

19. Nakashima T, Naganawa S, Teranishi M, Tagaya M, Nakata S, Sone M, et al. Endolymphatic hydrops revealed by intravenous gadolin-ium injection in patients with Menière’s disease. Acta Otolaryngol 2010;130:338-43.

20. Yoshida T, Sugiura M, Naganawa S, Teranishi M, Nakata S, Na-kashima T. Three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging findings and prognosis in sudden sen-sorineural hearing loss. Laryngoscope 2008;118:1433-7.

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1Clinical 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

OTORINOLARINGOL 2010;60:171-82

W. H. SLATTERY III 1, 2, K. B. TEUFERT 3

Intratympanic gentamicin for unilateral Menière’s disease

Corresponding author: W. Slattery, Clinical Studies, House Ear Insti-tute, 2100 W. Third Street, Los Angeles, CA 90057, USA.E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1940-OTtitolo breve: Unilateral Menière’s diseaseprimo autore: SLATTERY IIIpagine: 171-82

which the hydrops is the result of a single traumatic or inflammatory insult to the labyrinth, causing a per-manent but not progressive endolymphatic hydrops.1

The symptoms of progressive endolymphatic hy-drops can be correlated with two principal types of pathologic change: distention and ruptures of the endolymphatic system,2, 3 and alterations in the cy-toarchitecture of the auditory and vestibular sense organs, sometimes accompanied by atrophic chang-es. Coincident with rupture, there is sudden contam-ination 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, fluctuat-ing hearing loss, or both. The American Academy of Otolaryngology-Head and neck Surgery (AAO-HNS) recommended that these episodes be designat-ed the “definitive” symptoms of Menière’s 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 sup-porting cells as well as disruption and deformation of their gelatinous aprons. These alterations impair the motion mechanics of the sense organs, resulting in

Menière’s disease is a chronic illness that affects a substan-tial number of patients every year worldwide. The disease is characterized by intermittent episodes of vertigo lasting from minutes to hours, with fluctuating sensorineural hearing loss, tinnitus, and aural pressure. Although there is currently no cure, more than 80% of patients with Menière’s disease are helped by either changes in lifestyle and medical treatment with another 20% requiring minimally invasive surgical procedures such as intratympanic steroid therapy, intratym-panic gentamicin therapy, and endolymphatic sac surgery. Vestibular neurectomy has a very high rate of vertigo con-trol 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 unilat-eral disease and deafness. This paper discusses treatment op-tions of Menière’s disease, with emphasis on intratympanic gentamicin therapy, including its basic science, experimental studies, and an extensive review of the literature.Key words: Gentamicins - Menière disease - Aminoglycosides - Vertigo - Dizziness.

Overview of Menière’s disease

Menière’s disease is an idiopathic disease involv-ing the inner ear and is characterized patho-

logically 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

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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-bal-ance, 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 accompa-nied by nausea and vomiting. The patient is oriented and conscious throughout the spell, and there are no neurologic sequelae.

Treatment options of Menière’s disease

Medical treatment

Medical treatment for Menière’s disease is effective in controlling vertigo for approximately 85% of pa-tients and forms the primary mode of therapy in man-aging these patients. There is a lack of understanding regarding the pathophysiology of Menière’s disease, and hence the pharmacologic therapy lacks the same scientific understanding. This lack of understanding of the exact pathophysiology of Menière’s 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 Menière’s disease. Most medical therapy is based on clinical experience and many medications were discovered serendipi-tously. The fluctuant nature of the disease makes it very difficult to conduct well-established control-led trials evaluating medical therapy. Furthermore, Menière’s disease or symptoms may be the outward expression of different etiologies of a diseased ear, further complicating our understanding of the patho-physiology. The treatment of patients suffering from Menière’s disease continues to be controversial. The proposed treatments attest to the difficulty in attain-ing a satisfactory therapeutic result in these patients.

In 1977, Nicholas Torok published a 25-year re-view of 834 papers concerned with the treatment of Menière’s disease.5 He concluded that although treat-ing 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 improve-ment and tinnitus reduction. The therapeutic results were similar despite multiple medical regimens. The lack of rationale behind many of the proposed treat-ments supports the concept that Menière’s disease patients benefit from a nonspecific form of therapy.

In 1991, Ruckenstein et al. reviewed a signifi-cant body of literature regarding medical and surgi-cal treatment of Menière’s disease since the Torok study.6 They concluded that no treatment directed at alleviating hydrops had been shown to specifi-cally ameliorate the symptoms of Menière’s disease, that the pathophysiologic mechanisms involved in a Menière’s attack had yet to be elucidated, and that although hydrops is the end result, it may not nec-essarily be the effector of the disease process. They also found that vestibular suppressants are the only medications that have definitely been shown to im-prove symptoms of Menière’s disease. They were unable to find any well-controlled study that dem-onstrated any medications that are able to prevent symptoms of Menière’s disease.

In 2005, Kim et al. carried out a prospective study to determine the practices of the American Neuro-tology Society (ANS) membership in the evalua-tion and treatment of the Menière’s patient.7 Three hundred members of ANS were mailed a 15-item questionnaire, with questions pertaining to the diag-nostic and therapeutic practices in the management of Menière’s disease. Two hundred three respond-ed, for a 67.7% response rate. For the diagnosis of Menière’s 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 prac-titioners pursued retrocochlear studies on initial evaluation, with the overwhelming majority using MRI. In treating Menière’s disease, conservative medical management was preferred. For medically refractory Menière’s disease, endolymphatic sac surgery (ESS) was the most commonly employed initial intervention (50%), followed by transtym-panic gentamicin (38%). Currently, <10% routinely recommend the Meniett’s device. Eighty-three per-cent include ESS as a therapeutic option for medi-cally refractory Menière’s disease. The vast major-ity continues to perform surgical labyrinthectomies

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and vestibular nerve sections for Menière’s disease. They concluded that Menière’s disease continues to pose a difficult diagnostic and therapeutic prob-lem, resulting in heterogeneous approaches to both evaluation and treatment. Despite the 1995 Ameri-can Academy of Otolaryngology guidelines in the diagnosis of Menière’s disease, most clinicians rely in part on ENG or ECOG in diagnosing Menière’s 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 Menière’s disease.

In 2008, Coelho and Lalwani reviewed the litera-ture and found that because of a lack of well-control-led studies, the medical management of Menière’s 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 therapeu-tic advance that has largely supplanted surgical in-tervention and concluded that despite absence of a complete understanding of Menière’s disease, medi-cal 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 test-ed in well-controlled clinical trials.

Medical therapy for Menière’s disease has classi-cally included dietary modifications, physiotherapy, psychological support, and pharmacologic interven-tion. 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 at-tacks of vertigo and accompanying nausea and vom-iting. They have variable anticholinergic, antiemetic, and sedative properties. These drugs include benzo-diazepines (diazepam), meclizine (Antivert, Bonine), prochlorperazine (Compazine), promethazine (Phen-ergan), diphenhydramine (Benadryl), dimenhydri-nate (Dramamine), hyoscine, and metoclopramide.

Maintenance therapy

The goal of maintenance therapy is to prevent the acute attacks of vertigo and maintain hearing in Menière’s disease. Maintenance therapy usually in-cludes diet modifications combined with other phar-macologic interventions. The specific pharmacologic agent used in maintenance therapy may depend upon the patient’s previous response to therapy. Past expe-rience with certain medications may prove benefi-cial in the selection of a specific type of maintenance therapy. The duration of maintenance therapy also is selected by the physician based on the patient’s response to therapy. Because of the fluctuant nature of the disease, long-term maintenance therapy usu-ally 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 1 500 mg of sodium per day is advised. This is a very stringent diet, and many patients consider this unpal-atable. 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 bet-ter 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 Menière’s disease pa-tients. Some patients who are very compulsive may prefer the 1 500 mg per day diet. Restriction in the intake of caffeine, nicotine, and alcohol also is sug-gested for Menière’s disease patients.

Diuretics

The use of diuretics stems from the supposition that these drugs can alter the fluid balance in the in-ner 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 Menière’s 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 low-salt 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 diu-retic medical therapy was dictated by the patient’s 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 medi-cal treatment of Menière’s disease include vasodila-tors, calcium channel blockers, ACE inhibitors, and lipoflavins and vitamins.

Ablative therapy

Aminoglycosides

The ototoxic effects of aminoglycosides are well known. Streptomycin and gentamicin are predomi-nantly vestibulotoxic. Schuknecht established the standard indications and the treatment regimen for systemic streptomycin use.12 Intramuscular injec-tions of streptomycin administered twice daily, for periods of days to weeks have been used in patients with debilitating bilateral disease or unilateral dis-ease 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 control-ling vertigo attacks and perhaps stabilizing hearing.

Intratympanic gentamicin will be discussed fur-ther in this chapter.

Surgical management

Surgery has long been used to control disabling vertigo of Menière’s 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 Transmas-toid 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 Menière’s disease, endolymphatic sac sur-gery (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 ves-tibular nerve section (translabyrinthine, retrolabyrin-thine, 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 undergo-ing sac surgery do not require further surgical proce-dures and an additional 17% has only revisions of the endolymphatic sac shunt. Thus, 80% never require a destructive procedure and 93% report no further diz-ziness 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% ver-tigo cure rate to vestibular neurectomy.

The surgeon should take into consideration severi-ty of disease, hearing status and presence of unilateral versus bilateral disease when selecting an approach for the surgical treatment of Menière’s disease.

Endolymphatic drainage procedures can be divid-ed into external shunts that attempt to drain exces-sive 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 pa-tients without useful hearing. Posterior approaches that spare the labyrinth provide varying degrees of cerebellopontine angle (CPA) exposure with an op-portunity 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 tuber-culosis. Because effective treatment of tuberculosis with streptomycin required prolonged therapy, oto-toxicity became evident soon after introduction of the drug. As early as 1948, streptomycin was used to treat patients with unilateral Menière’s disease spe-cifically on the basis of its vestibulotoxic effects.27 Gentamicin was isolated from the actinomycete Mi-cromonospora purpurea in 1963,28 a genus of Gram-positive 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 re-sults in acute but reversible interference with calci-um-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 intra-cellular components may be mediated by free radi-

cals. Recent studies have shown that aminoglyco-sides form a complex with iron and that this complex catalyzes the production of free radicals. The combi-nation 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 in-creases with chronic administration. These observa-tions 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 exam-ple, 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 administra-tion. 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 ves-tibular 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, re-sulting in an initial loss of high-frequency hearing sensitivity. Although the mechanisms of this differ-ential 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 Menière’s dis-ease.39, 40

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Intratympanic gentamicin therapy

Experimental studies

Intratympanic injection of aminoglycosides al-lows treatment of unilateral Menière’s disease with-out producing systemic toxicity or effects on the op-posite 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 annu-lar ligament of the stapes.46, 47

Following the intratympanic application of strep-tomycin to guinea pigs, the cristae of the semicircu-lar canals showed the most degeneration, followed by the utricule, then the saccule and the cochlea.48 The selectivity of the lesion for vestibular versus co-chlear hair cells after intratympanic injection, was reduced at higher dosages. For example, the applica-tion of 8 mg of streptomycin to the round window membrane of the cat produced only vestibular toxic-ity, whereas 20 to 40 mg produced both cochlear and vestibular toxicity.49 These experimental results em-phasize 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 chin-chillas 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 Menière’s 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 relation-ship of these kinetics curves to the effect of the two treatment modalities on inner ear function and mor-phology. The study examined perilymph gentamicin concentrations, hearing results, and inner ear mor-phology in an animal model. Gentamicin was ap-plied to the right ear of chinchillas either through a transtympanic approach or in a sustained-release device. The left ear remained untreated as an inter-nal 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 treat-ment 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 sustained-release 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 mor-phological 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 fash-ion 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 ob-vious hair cell damage. Sustained delivery of gen-tamicin 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 in-duce a chemical labyrinthectomy for the treatment of unilateral Menière’s disease was introduced by Schuknecht.51, 52 He reported the results of eight pa-tients 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 remain-ing three of eight patients, persistent vertigo neces-sitated 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 var-ious aminoglycosides to treat Menière’s disease.53-55 In his group of 92 patients, Lange reported that 90% had no further episodes of severe vertigo and hear-ing remained unchanged in 76% of patients. Unfor-tunately, 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 pro-spectively using the AAO-HNS guidelines for report-ing treatment results of Meneire’s 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 fol-lowed 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 hear-ing 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 be-cause 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 gen-tamicin (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 occur-ring 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 fol-low-up, vertigo was controlled (with a loss of caloric

responsiveness in the treated ear) and hearing pre-served 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 gen-tamicin 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 ver-tigo.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 ad-ministration schedule and total dosage may be sig-nificant factors in hearing preservation. The variabil-ity in reports may also be due to differences in case selection, because some series have more elderly patients or patients with worse pretreatment hear-ing 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 hear-ing.

An important indicator for intratympanic gen-tamicin 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 endol-ymphatic sac surgery.65 Transmastoid labyrinthecto-my has traditionally been offered for non-serviceable ears in patients with Menière’s 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 pa-tients. 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 intra-tympanic gentamicin therapy for patients who have failed endolymphatic sac surgery, thus reducing the need for vestibular neurectomy in those with intrac-table disease.

In 2004, Carey reviewed the history of intratym-panic aminoglycoside treatment since the 1950s, in-cluding 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 Menière’s 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 intratym-panic 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 abla-tion of function does not seem to be necessary for vertigo control.

Boleas-Aguirre et al. reported on residual vestibu-lar symptoms and disability in patients with Menière’s disease who had achieved complete control of vertigo through intratympanic gentamicin treatment.69 The study involved 103 patients with Menière’s 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 modifica-tion in their treatment. After a five-year follow-up, complete control of vertigo was obtained in 81% of the patients with Menière’s 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 in-stillation for incapacitating unilateral Menière’s dis-ease, 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 con-tinued to experience some degree of vertigo. Of the 44 patients who were asymptomatic, 35 had an ab-

sent caloric response. Of the14 patients who report-ed 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 high-dose gentamicin for intractable Menière’s disease, 27 mg/mL gentamicin were performed three times daily for four days in 14 who had failed medical (12 sub-jects) or surgical (2 subjects).71 The overall success-ful vertigo control rate was 92.9% over the two-year follow-up and 85.7% at long-term follow-up (aver-age 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 long-term follow-up, respectively. Profound sensorineural hearing loss occurred as a result of gentamicin injec-tion in one patient (7%).

More recently, Salt et al. used a validated com-puter model of gentamicin dispersion in the inner ear fluids to calculate cochlear drug levels result-ing 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 sen-sitivity for 568 patients reported in 19 publications. Drug levels resulting from single, “one- shot” injec-tions were typically lower than those from repeated or continuous application protocols. Comparison of hearing sensitivity changes with gentamicin dos-ing 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 gen-erated with repeated or continuous delivery proto-cols, 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. Re-peated 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-Mei-er survival analysis.73 Injections of IT gentamicin were administered for unilateral definite Menière’s 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%) re-quired 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. Never-theless, 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 Méniere’s disease with normal hear-ing, Silverstein et al. analyzed a total of 224 patients with disabling Méniere’s disease.74 Patients under-went 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 Méniere’s 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 ver-tigo control. One hundred sixteen (59%) of 200 pa-tients with stage 2 through four Menière’s disease showed unchanged or improved speech discrimina-tion score. All 200 patients showed a mean pure-tone average loss of 11 dB. One hundred forty-eight (74%) patients reported complete or improved ver-tigo control. Patients with stage 1 Menière’s 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).

Menière’s 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, espe-cially 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 disorder’s sequelae, including in-tratympanic gentamicin physicians treating patients who have Menière’s disease should remain optimis-tic 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, vesti-bulospinal examination, vestibular function testing (electronystagmography, posturography, rotational chair testing), and audiometric evaluation.

Retrocochlear and metabolic disorders are exclud-ed. 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 intra-tympanic gentamicin injections is to control the recur-rent episodes of vertigo typical of Menière’s disease. The expectation and time course of post-treatment unsteadiness or disequilibrium typical of unilateral vestibular ablation are explained. Moreover, the pos-sibility that additional courses of gentamicin may be needed in the future or that surgical ablation may be required to control vertigo is reviewed. The possibil-ity 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), tin-nitus, and aural fullness consistent with unilateral Menière’s 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 intratym-panic 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 so-dium 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 in-jection 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 tu-berculin 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 candi-dates. Intratympanic aminoglycoside therapy can also be used to avoid additional surgery in patients with recurrent vertigo and a return of caloric func-tion following previous ablative vestibular surgery. Patients with profound hearing loss are good candi-dates for intensified treatment.

The data on efficacy of intratympanic aminogly-coside therapy to control vertigo and its safety in preservation of hearing are almost exclusively from patients with Menière’s disease. Most patients with non-Menière’s vestibulopathy have normal hearing. The non-hydropic ear seems to be relatively resist-ant to the effects of aminoglycosides. For these rea-sons we do not currently recommend intratympanic aminoglycoside therapy in the primary treatment of vertigo caused by disorders other than Menière’s dis-ease.

Conclusions

Intratympanic application of gentamicin frequent-ly results in treatment-related hearing loss, although vertigo is usually well controlled. Patients with re-current post-treatment vertigo can be treated again. A trend in intratympanic application is to administer one or two doses rather than treating until ototoxic-ity 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 pa-tients with classic Menière’s disease who meet ap-propriate treatment criteria. Prolonged disabling dis-equilibrium 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 laby-rinthectomy or vestibular nerve section.75

Riassunto

Gentamicina intratimpanica per la malattia di Menière monolaterale

La malattia di Menière è una patologia cronica che colpi-sce un gran numero di pazienti ogni anno in tutto il mondo. Questa patologia è caratterizzata da episodi intermittenti di vertigini che durano da minuti a ore, con perdita dell’udito sensorineurale fluttuante, tinnito e fullness auricolare. Sebbe-ne attualmente non vi sia una cura, più dell’80% dei pazienti affetti da malattia di Menière 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 è indicata nei pazienti con un buon udito in cui hanno fallito tutti gli altri trattamenti. La labirintectomia rappresenta l’ultima possibilità e viene riservata per i pazienti con patologia e sordità mono-laterale. Questo articolo discute le opzioni di trattamento della malattia di Menière, con enfasi sulla terapia intratimpanica con gentamicina, valutando le basi scientifiche, gli studi speri-mentali e un’ampia revisione della Letteratura.

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

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54. Lange G. Isolierte Medikamentose Ausschaltungeines Gleichge-wichtsorganes beim Morbus Menière mit Streptomycin-Ozothin. Arch Klin Exp Ohren-Nasen-Kehlkopfheilkd 1999;191:545-9.

55. Lange G. Transtympanic treatment for Menière’s disease with gen-

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tamicin sulfate. In: Vosteen K-H, Schuknecht HF, Pfaltz CR et al., editors. Menière’s disease: pathogenesis, diagnosis, and treatment. Stuttgart: Georg Thieme Verlag; 1981.

56. Commins D, Nedzelski J. Topical drugs in the treatment of Menière’s disease. Curr Opin Otolaryngol Head Neck Surg 1996;4:319-23.

57. Hone S, Nedzelski J. Selective chemical ablation as treatment for Menière’s disease. In: Harris J, editor. Menière’s disease. The Hague: Kugler Publications; 1999. p. 381-9.

58. Nedzelski JM, Schessel DA, Bryce GE, Pfleiderer AG. Chemical labyrinthectomy: local application for the treatment of unilateral Menière’s disease. Am J Otol 1992;13:18-22.

59. Committee on Hearing and Equilibrium. Committee on Hear-ing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Menière’s disease. Otolaryngol Head Neck Surg 1995;113:181-5.

60. Subcommittee on Equilibrium: Menière’s disease: Criteria for diag-nosis and evaluation of therapy for reporting. AAO-HNS Bulletin, 6-7. 7-1985 (Generic).

61. Magnusson M, Padoan S. Delayed onset of ototoxic effects of gentamicin in treatment of Menière’s disease. Acta Otolaryngol 1991;111:671-6.

62. Beck C, Schmidt C. Ten years of experience with intratympani-cally applied streptomycin (gentamicin) in the therapy of morbus Menière. Arch Otorhinolaryngol 1978;221:149-52.

63. Youssef T, Poe D. Intratympanic gentamicin injection for the treat-ment of Menière’s disease. Am J Otol 1998;19:435-42.

64. Atlas J, Panes L. Intratympanic gentamicin titration therapy for in-tractable Menière’s disease. Am J Otol 1999;20:357-63.

65. Driscoll CL, Kasperbauer JL, Facer GW, Harner SG, Beatty CW. Low-dose intratympanic gentamicin and the treatment of Menière’s disease: preliminary results. Laryngoscope 1997;107:83-9.

66. Bauer PW , MacDonald CB, Cox LC. Intratympanic gentamicin

therapy for vertigo in nonserviceable ears. Am J Otolaryngol 2001;22:111-5.

67. Marzo SJ, Leonetti JP. Intratympanic gentamicin therapy for per-sistent vertigo after endolymphatic sac surgery. Otolaryngol Head Neck Surg 2002;126:31-3.

68. Carey J. Intratympanic gentamicin for the treatment of Menière’s disease and other forms of peripheral vertigo. Otolaryngol Clin North Am 2004;37:1075-90.

69. Boleas-Aguirre MS, Sánchez-Ferrandiz N, Guillén-Grima F, Pe-rez N. Long-term disability of class A patients with Ménière’s dis-ease after treatment with intratympanic gentamicin. Laryngoscope 2007;117:1474-81.

70. Bodmer D, Morong S, Stewart C, Alexander A, Chen JM, Nedzel-ski JM. Long-term vertigo control in patients after intratympanic gentamicin instillation for Ménière’s disease. Otol Neurotol 2007;28:1140-4.

71. Hsieh LC, Lin HC, Tsai HT, Ko YC, Shu MT, Lin LH. High-dose intratympanic gentamicin instillations for treatment of Menière’s disease: long-term results. Acta Otolaryngol 2009;129:1420-4.

72. 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.

73. Nguyen KD, Minor LB, Della Santina CC, Carey JP. Time course of repeated intratympanic gentamicin for Ménière’s disease. Laryngo-scope 2009;119:792-8.

74. Silverstein H, Wazen J, Van Ess MJ, Daugherty J, Alameda YA. In-tratympanic gentamicin treatment of patients with Ménière’s disease with normal hearing. Otolaryngol Head Neck Surg 2010;142:570-5.

75. Laitakari K. Intratympanic gentamicin in severe Menière’s disease. Clin Otolaryngol 1990;15:545-8.

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1 ENT Istitute, Department of Surgical, Clinical and Experimental Sciences,

“G. d’Annunzio” University of Chieti-PescaraChieti, Italy

2ENT Clinic, Nayak’s Road, Kasaragod, India3Department of Surgical and Oncological Disciplines

University of Palermo, Palermo, Italy

OTORINOLARINGOL 2010;60:183-8

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

Intratympanic gentamicin: its effect on hearing and strategies to minimize inner ear damage

Corresponding author: L. Citraro, MD, Via Sardegna 37, San Cesario di Lecce, Lecce, Italy. E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1941-OTtitolo breve: INTRATYMPANIC GENTAMICINprimo autore: CITRAROpagine: 183-8

Effect of gentamicin on the inner ear

Aminoglycosides are bactericidal aminoglycosidic aminocyclitols. They were the first 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 pro-tein 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. Gen-tamicin, despite the widespread belief that it is selec-tively toxic to the vestibular system, causes damage to both vestibular and cochlear cells in a dose-de-pendent manner.11, 12

Plontke 13 established that intratympanically ad-ministered gentamicin spreads from the round win-dow membrane to the vestibule via communications

Intratympanic gentamicin injection is the easiest and least invasive treatment available for Menière’s disease as com-pared to other procedures available today. The most im-portant 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 re-sults with good rates of vertigo control and low rates of hear-ing 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 promis-ing frontier in treating this dreadful sequelae of treating MD.Key words: �Gentamicin - Hair cells, auditory - Hearing loss - Menière’s disease.

Ototoxic drugs are frequently used to selectively damage specific cells in the inner ear and thus

control the symptoms of Menière’s disease (MD). Many drugs are known to be having ototoxic proper-ties, such as loop inhibiting diuretics, platinum-based anticancer agents, and aminoglycoside antibiotics. Among these, gentamicin has been the preferred aminoglycoside used for intratympanic administra-tion because of its easy availability, low cost and the low incidence of cochlear damage.1-6

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through the scala rather than by diffusion through the helicotrema. It is cleared from the body via glomeru-lar filtration in the kidney.

Gentamicin, in the vestibular part of inner ear, binds with the melanin present in the dark cells of ampul-lae and stria vascularis.14 Vestibular dark cells are im-portant in creating and maintaining ion homeostasis in the inner ear. In fact, they contain Na-K-adenosine triphosphatase and phospholipids with which gen-tamicin binds and they play a role in the active trans-portation 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 Menière’s 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 co-chlea and spreads towards the apex as the dose or du-ration 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 specific 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 materi-als that threaten homeostasis or require recycling. As gentamicin is continuously ingested and collected, the lysosomes may eventually break, allowing cy-tosolic 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 associ-ated 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 rad-ical, 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 iron–aminoglycoside complex is capa-ble 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, possi-bly making their ribosomes susceptible to injury by aminoglycosides. As an effect of this damage cyto-chrome c is released, which in turn can trigger apopto-sis via caspases.10 Caspases are a family of proteolytic enzymes important in mediating and executing cell death in both the cochlea and vestibular apparatus.

Figure 1.—Gentamicin hair cell damage (modified from Rybak et al.10). ]). Gentamicin (black) enters into the hair cell and ac-cumulates 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.

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Mitochondria may also be involved in the patient’s susceptibility to aminoglycoside ototoxicity. Molecu-lar 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 bind-ing of aminoglycosides and to aminoglycoside resist-ance.32 These results suggested that certain individu-als may be at greater risk of developing hearing loss due to genetic mutations.

Hearing loss

The prime focus of treatment of Menière’s disease with intratympanic gentamicin is to control the nega-tive 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 dete-rioration is defined as an increase in pure tone audio-gram (PTA) threshold of 10 dB or a 15% deteriora-tion 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 frequen-cy of administration, dosage of the drug, delivery methods used, and the end point of gentamicin injec-tions. Based on these reasons several authors have developed different intratympanic gentamicin treat-ment 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 verti-go 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 tech-niques showed worse rates of complete vertigo con-trol 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% respec-tively 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 vestib-ulotocity 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 signifi-cant risk to hearing “Hybrid” protocols have also been introduced.14, 34-37 They combined the features of different standard methods of intratympanic gen-tamicin administration (i.e. reducing the total dose of gentamicin but increasing the number of the admin-istrations, 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-treat-ment 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 pre-vent 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) path-way is one signaling pathway activated by aminogly-cosides 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 desfer-oxamine. Also antioxidants, such as lipoic acid and d-methionine, showed protection against aminogly-coside 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 strate-gies.

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 trans-gene 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 adenovec-tor is capable of preventing ototoxicity by aminogly-coside in a mouse model. Bcl-2 gene codes for a

protein that governs the mitochondrial membrane permeability and is involved in matrix ions concen-tration, pH and mitochondrial voltage. Members of bcl-2 family control the release of cytochrome c into the cytosol, inducing apoptotic cascade. These mem-bers 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 overexpres-sion in the auditory system, has been shown to be protective against ototoxicity.

Conclusions

In conclusion, hearing loss in intratympanic gen-tamicin 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 ver-tigo 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, ti-tration therapy and others. Therefore they could cur-rently be considered as the best protocols for treat-ing Menière’s 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 co-chlear 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 sull’udito e strategie per minimizzare il danno all’orecchio interno

L’iniezione intratimpanica di gentamicina rappresenta il trattamento più semplice e meno invasivo per la Malat-tia di Menière, rispetto alle altre procedure ablative chi-

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miche e chirurgiche disponibili. Il più importante effetto collaterale di questa terapia è costituito dall’ipoacusia neurosensoriale per lo più sulle frequenze acute. L’ototos-sicità della gentamicina inizia a livello delle cellule ciliate esterne della coclea e si estende verso l’apice. Essa può coinvolgere anche le cellule ciliate interne. La morte delle cellule ciliate può avvenire per necrosi o apoptosi. Sono stati sviluppati numerosi protocolli per ridurre questa co-cleotossicità. Tra questi, i protocolli ibridi (con iniezio-ni 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 nu-merosi farmaci, come i chelanti del ferro, gli antiossidanti e i glucocorticoidi, hanno proprietà otoprotettive; tuttavia sono necessari ulteriori studi per identificare sicure stra-tegie otoprotettive utilizzando questi agenti. Oltre a ciò, gli studi basati su terapie genetiche potrebbero essere la nuova frontiera nel management delle complicanze uditi-ve della terapia intratimpanica con gentamicina nella Ma-lattia di Menière. Parole chiave: Gentamicina - Cellule ciliate uditive - Perdita dell’udito - Malattia di Menière.

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43. Himeno C, Komeda M, Izumikawa M, Takemura K, Yagi M, Weip-ing Y et al. Intra-cochlear administration of dexamethasone at-tenuates aminoglycoside ototoxicity in the guinea pig. Hear Res 2002;167:61-70.

44. Lesniak W, Pecoraro VL, Schacht J. Ternary complexes of gen-tamicin 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 overex-pression of glial cell line-derived neurotrophic factor. Hum Gene Ther 1999;10:813-23.

46. Pfannenstiel SC, Praetorius M, Plinkert PK, Brough DE, Stae-cker H. Bcl-2 gene therapy prevents aminoglycoside-induced de-generation of auditory and vestibular hair cells. Audiol Neurootol 2009;14:254-66.

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one and only clinical manifestation of the disease for a long time until a full-blown Menière’s syndrome appears. For this reason it is possible to separate two subsets of the disease: a typical one in which the pa-tient presents with the complete clinical manifesta-tions and an atypical one whose clinical presentation is limited to the vestibular or cochlear compartment.

No single test has enough sensitivity and spe-cificity to definitively allow its identification, thus Menière’s disease diagnosis is mainly anamnestic and made after exclusion of a multitude of central and peripheral lesions causing vertigo and percep-tive 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 Menière’s disease has been demonstrated by Mor-rison.1 Endolymph is mainly produced in the stria vascularis and slowly absorbed in the endolymphatic duct and sac by a biologically active transport sys-

We made a review of the english-language literature to evalu-ate the efficiency, optimum dosage and administration sched-ule of intratympanic corticosteroid therapy in Menière’s disease patients as an alternative to more aggressive thera-pies, 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 clini-cal drug study. For this reason, even if a certain efficacy of intratympanic corticosteroid administration is likely, further investigations are required with controlled, randomised, dou-ble-blind trials to get more precise data.Key words: Menière’s disease - Intratympanic corticosteroid - Endolymphatic hydrops.

Menière’s disease is a clinical disorder of the in-ner ear whose underlying pathophysiologic

condition is endolymphatic hydrops and whose major clinical signs and symptoms are recurrent, spontane-ous spells of vertigo of at least 20 minutes or longer, associated with nausea, retching and vomiting, pro-gressive sensorineural hearing loss which is often fluctuating and sometimes associated with diplacusis and intolerance of loudness, tinnitus and aural full-ness 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 au-ditory or vestibular symptoms alone can represent the

Division of Otolaryngology Ospedale Maggiore, Lodi, Italy

OTORINOLARINGOL 2010;60:189-94

V. PISTORIO, V. ACHILLI

Management of Menière’s disease with intratympanic steroids

Corresponding author: dr. V. Pistorio, Division of Otolaryngology, Ospedale Maggiore di Lodi, Viale Savoia 2, 26900 Lodi, Italy.E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1934-OTtitolo breve: INTRATYMPANIC STEROIDS IN Menière’S DISEASEprimo autore: PISTORIOpagine: 189-94

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tem. (An anatomic description of the inner ear is be-yond the purpose of this article).

The most popular etiopathogenetic theory sees Menière’s disease as the consequence of a hydrops of the membranous labyrinth due to excessive endol-ymphatic fluid. This is Paparella’s “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 Mondini’s dysplasia, or acquired as it is after some kind of head trauma with temporal fracture or sec-ondary to endoluminal deposition of cellular debris) or to a chemical-based alteration of the production-reabsorption 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 ar-guing that this mechanism would need simultaneous ruptures in both the anterior and posterior membra-nous labyrinth to justify concurrent perceptive hear-ing loss and vertigo seen in the full-blown Menière’s disease, and many histopathologic reports do not show this.

An alternative explanation is that of Vosteen and Morgensteen,6 who considered the altered equilibri-um between produced and reabsorbed endolymph to be the “primum movens” in the genesis of the clini-cal signs and symptoms of the disease, suggesting that ruptures could alleviate, rather than precipitate vertiginous crises.

A more interesting and recent pathophysiologic theory for Menière’s disease describes the endolym-phatic sac as being able to sense changes in volume and pressure of its endoluminal fluids, whose longi-tudinal flow towards the sac is normally regulated by osmotic gradients, and secretion of a natriuretic hormone called saccin, as well as glycoprotein con-jugates and proteoglycans.7 The latter would act by an osmotic mechanism, attracting endolymph before a narrowing of the endolymphatic duct due to cellu-lar 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 eventu-ally, the debris would be cleared. The abrupt move-ment of the endolymph would likely generate the acute vestibular symptoms. Late stage resolution of vertigo attacks would depend on ceasing of endol-ymphatic 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 re-move debris from its lumen and from the cochlea.

Similarly, nowadays the old belief that the endol-ymphatic 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

Table I.—�Central lesions responsible of vertigo and/or tinnitus and/or hearing loss.

InflammatoryMeningitisEncephalitisCerebral abscesses

Expansile lesionsTumours of the CNSArachnoid cystsCongenital cholesteatomas

VascularAICA aneurismsPICA lesionsBasilar artery insufficiency

Traumatic

SystemicToxinsMultiple sclerosis

Table II.—�Peripheral lesions responsible of vertigo and/or tin-nitus and/or hearing loss.

Middle ear otitisLabyrinthitisVestibular neuronitisCochlear ischemiaOtosclerosisBenign tumors such as glomusTemporal bone fracturesLabyrinthine concussionBPPV

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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 autoantibod-ies to the endolymphatic sac 13 are, together with the demostration of IgG deposits in endolymphatic sac 14 and experimental description of corticosteroid re-ceptors within the inner ear,15 among the most inter-esting elements for hypothesising that Menière’s dis-ease could be caused by immunological alterations.

Under these premises many authors are study-ing Menière’s 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. Mc-Cabe was the first who suggested an immunologic pathogenetic mechanism for Menière’s 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 Menière’s patients and in only 3% of controls. Some investigators have also report-ed allergy as an etiologic factor.9, 10 Other investiga-tors try to relate hydrops in Menière’s disease with some inflammatory toxin generated during chronic otitis media and passed to the inner ear via the round window membrane. Moreover, chronic otitis me-dia could lead to developmental anomalies such as periaqueductal hypocellularity, reduced mastoid-air complex and dimensional reduction of Trautmann’s 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 Menière’s disease inflammatory autoimmune phatophysiol-ogy, corticosteroid intratympanic therapy is appeal-ing 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 semipermeabil-ity 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 peri-lymphatic concentration of dexametasone after in-tratympanic 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 corticos-teroids 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 intratympan-ic injections is dexamethasone. Some studies evalu-ated the efficacy of dexamethasone, hydrocortisone and methylprednisolone in guinea pigs.20 Even if methylprednisolone reached the highest concentra-tions 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 ad-ministration. 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 com-pletely 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 dif-ferent studies: from 2-4 mg/mL 19 to 24 mg/mL dex-ametasone 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 specifi-cally requested not to swallow if not strictly neces-sary, 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 injec-tion with local anaesthesia and a 1 mL tuberculin-type 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 au-thors prefer to insert a T-type transtympanic pressure equalizing tube into the miringotomy incision, to al-low multiple injections into the middle ear, thus alle-viating the necessity to perform a new miringotomy incision for each subsequent administration.24 Deliv-ery 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 absorb-able 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 mid-dle ear either with a laser-assisted-tympanostomy as described in Shea’s and Silverstein’s 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 fibrot-ic adherences in 12% of cases.27 These adhesions, which required removal in Silverstein’s 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 mul-tiple 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 pro-tocols 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 cor-ticosteroid for intratympanic injection in Menière’s disease therapy is still a matter of debate, Shea’s and

Silverstein’s 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 up-dated series showed less efficacy since vertigo con-trol 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 intratym-panic 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 Menière’s disease in 1997 conducted by Silverstein were less encouraging, showing no benefit over placebo for treatment of the same symp-toms.26

In 1998 Arriaga and Goldman conducted a retro-spective 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 Menière’s 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 applica-tion. 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 treat-ment 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 Menière’s disease treated with intratym-panic 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 Menière’s disease, but

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also not ruling out a placebo effect or that the natu-ral 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 doc-umented in the literature for a more prolonged thera-peutic 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 Menière’s disease after 5 consecutive days of once a day intratympanic injection of a dexamethasone solution 4 mg/mL ver-sus 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 concentra-tion dexamethasone injection as the only drug em-ployed intratympanically once or twice a week for 4-5 weeks.34 However, in that case, tinnitus amelira-tion was reported as excellent in 45% of patients and good in 29%.

Another cause of debate is the optimal concentra-tion of the steroid. It seems that, the more concen-trated 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 pa-tients affected by Menière’s disease.35

Moreover, taking into consideration the longitudi-nal 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 varia-bles that make the interpretation of data difficult and disturb the comparison of results between different studies. Among these there are the significant differ-ences 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 dexametha-sone) is a valid and practical therapeutic alternative to most ablative and invasive treatments such as endol-ymphatic-mastoid shunts, labyrinthectomy and even intratympanic gentamicin administration. An attrac-tive therapeutic algorithm is that proposed by Sen-naroglu,40 for whom initial treatment of a Menière patient should be a conventional medical one. Non responding patients should then undergo intratym-panic infusion of corticosteroid after 6 months. If, after 3 more months of steroid administration no sig-nificant improvement is reported, then an intratym-panic 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 Menière con steroidi intra-timpanici

Gli autori hanno condotto una revisione della letteratura di lingua inglese per valutare l’efficacia, il dosaggio otti-male e la modalità di somministrazione della terapia corti-costeroidea intratimpanica in pazienti affetti dalla malattia di Menière, in alternativa a terapie più aggressive, poiché in numerosi casi la sottostante etiologia e fisiopatologia è infiammatoria. I risultati degli studi finora pubblicati sono difficili da interpretare poiché nessuno di questi soddisfa completamente le richieste di uno studio clinico farma-cologico. Per tale motivo, sebbene sia probabile una certa efficacia della somministrazione intratimpanica di cortico-steroidi, ulteriori studi controllati, randomizzati, in doppio cieco sono necessari per ottenere dati più precisi.Parole chiave: Malattia di Menière - Corticosteroidi in-tratimpanici - Idrope endolinfatico.

References

1. A.W. Morrison, Anticipation in Menière’s disease. J Laryngol Otol 1995;109:499-502.

2. Paparella MM, Costa SS, Fox R, Yoo TH. Menière’s disease and other labyrinthine diseases. In: Paparella MM, Shumrick DA,

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Gluckmann J, Meyerhoff WL, editors. Otolaryngology, vol. II: Otology. 3rd edition. Philadelphia: WB Saunders; 1991. p. 1689-714.

3. Paparella MM. The natural course of Menière’s disease. In: Filipo R, Barbara M, editors. Proceedings of the Third International Sym-posium on Menière’s Disease. Amsterdam: Kugler; 1994. p. 9-20.

4. Da Costa SS, Alves de Sousa LC, Ribeiro de Toledo Piza Marcelo. Menière’s disease: overview, epidemiology and natural history. Otolaryngol Clin N Am 2002;35:455-95.

5. Schuknecht HF. Pathology of the ear. Cambridge (MA): Harvard University Press 1991.

6. Vosteen KH, Morgensteen C. Biochemical aspects of inner ear pathophysiology. In: Pfaltz CR, editor. Controversial aspects of Menière’s disease. New York: George Thieme; 1986 pp. 688-705.

7. Wackym PA, Sando I. Molecular and cellular pathology of Menière’s disease. Otolaryngol Clin N Am 1997;30:947-60.

8. Gibson WPR, Arenberg K. Pathophysiologic theories in the etiol-ogy of Menière’s disease. Otolaryngol Clin N Am 1997;30:961.

9. Derebery J. Allergic management of Menière’s disease: an outcome study. Otolaryngol Head Neck Surg 2000;174-82.

10. Derebery J, Rao S, Siglock TJ, Linthicum FH, Nelson RA. Menière’s disease: an immune complex-mediated illness? Laryngo-scope 1991;101:225-9.

11. Ruckenstein MJ. Imunologic aspects of Menière’s disease. Am J Otolaryngol 1999;20:161-5.

12. Danckwardt-Lillieström N, Friberg U, Kinnefors A. Endolymphatic sacitis in a case of active Ménière’s disease. A TEM histopathologi-cal investigation. Ann Otol Rhinol Laryngol 1997;106:190-8.

13. Alleman AM, Dornhoffer JL, Arenberg K. Demonstration of au-toantibodies to the endolymphatic sac in Ménière’s disease. Laryn-goscope1997;107:211-5.

14. Dornhoffer JL, Waner M, Arenberg IK. Immunoperoxidase study of the endolymphatic sac in Ménière’s disease. Laryngoscope 1993;103:1027-34.

15. Rarey KE, Lohius PJ. Response to the stria vascularis to corticoster-oids. Laryngoscope 1991;101:1081-4.

16. True DR, Kempton JB, Kessi M. Aldosterone (mineralcorticoid) equivalent to prednisolone (glucocorticoid) in reversing hear-ing loss in MRL/MpJ-Fas 1 pr autoimmune mice. Laryngoscope 2000;110:1902-6.

17. Shea JJ, Ge X. Dexamethasone perfusion of the labyrinth plus in-travenous dexamethasone for Menière’s disease. Otolaryngol Clin North Am 1996;29:353-8.

18. 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.

19. Chandrasekhar SS. Intratympanic dexamethasone for sudden sen-sorineural hearing loss: clinical and laboratory evaluation. Otol Neurotol 2001;22:18-23.

20. Parnes LS, Sun AH, Freeman DJ. Corticoisteroid Pharmacokinetics in the inner ear fluids: an animal study followed by clinical applica-tion. Laryngoscope 1999; Suppl 91:1-17.

21. Gianoli GJ, Li JC. Transtympanic steroids for treatment of sudden hearing loss. Otolaryngol Head Neck Surg 2001; 125:142-6.

22. Lautermann J, Sudhoff H, Junker R. Transtympanic corticoid therapy

for acute profound loss. Eur Arch Otorhinolaryngol 2005;262:587-91.

23. Lefebvre PP, Staecker H. Steroid perfusion of the inner ear for sud-den sensorineural hearing loss after failure of conventional therapy: a pilot study. Acta Otolaryngol 2002;122:698-702.

24. Barrs DM, Keyser JS, Stallworth C, McElveen JT. Laryngoscope 2001;111:2100-4.

25. Arriaga M, Goldman S. Hearing results of intratympanic steroid treatment of endolymphatic hydrops. Laryngoscope 1998;108(11 Pt 1):1682-85.

26. Silverstein H, Isaacson J, Olds M, Rowan P, Rosenberg S Dexam-ethasone inner ear perfusion for the treatment of Menière’s disease: a prospective, randomized, double-blind, crossover trial. Am J Otol 1998;19:196-201.

27. Silverstein H, Rowan P. Inner ear injection and and the role of round window patency. Am J Otol 1997;18:586-9.

28. Slattery WH, Fisher LM, Iqbal Z, Friedman RA, Liu N. Intratym-panic steroid for the treatment of sudden hearing loss. Otolaryngol Head Neck Surg 2005;133:251-9.

29. Herr BD, Marzo SJ. Intratympanic steroid perfusion for refractory sudden sensorineural hearing loss. Otolaryngol Head Neck Surg 2005;132:527-31.

30. Shea JJ. The role of dexametasone or streptomycin perfusion in the treatment of Menière’s disease. Otolaryngol Clin North Am 1997;30:1051-9.

31. Hillman TM, Arriaga MA, Chen DA. Intratympanic steroids: do they acutely improve hearing in cases of cochlear hydrops? Laryn-goscope 2003;113:1903-7.

32. David M. Barrs. Intratympanic Injections of Dexamethasone for Long-Term Control of Vertigo. Laryngoscope 2004;114:1910-4.

33. Garduño-Anaya MA, Couthino De Toledo H, Hinojosa-González R, Pane-Pianese C, Ríos-Castañeda LC, PhD. Dexamethasone Inner Ear Perfusion by Intratympanic Injection in Unilateral Ménière’s Disease: A Two-year Prospective, Placebo-Controlled, Double-blind, Randomized Trial. Otolaryngology-Head and Neck Surgery 2005;133:285-294.

34. Itoh A, Sakata E. Treatment of vestibular disorders Acta Otolaryn-gol 1991;481(suppl):617-23.

35. Hamid MA. Intratympanic dexamethasone perfusion in Ménière’s disease. Presented at the spring meeting of the American Neurotol-ogy Society, Palm Desert, CA, May 2001:12.

36. Quaranta A, Marini F, Sallustio V. Long-term outcome of Ménière disease: endolymphatic mastoid shunt versus natural history. Audiol Neurootol 1998;3:54-60.

37. Green JD Jr, Blum DJ, Harner SG. Longitudinal follow-up of patients with Ménière disease. Otolaryngol Head Neck Surg 1991;104:783-8.

38. Silverstein H, Smouha E, Jones R. Natural history vs. surgery for Ménière disease. Otolaryngol Head Neck Surg 1989;100:6-16.

39. Montandon P, Guillemin P, Häusler R. Prevention of vertigo in Ménière’s syndrome by means of transtympanic ventilation tubes. ORL J Otorhinolaryngol Relat Spec 1988;50:377-81.

40. Sennaroglu L. Intratympanic dexamethasone, intratympanic gen-tamicin, and endolymphatic sac surgery for intractable vertigo in Ménière’s disease. Otolaryngol Head Neck Surg 2001;125:537-43.

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

OTORINOLARINGOL 2010;60:195-206

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

Intratympanic management of tinnitus: illusions and hopes

Corresponding author: C. A. Oliveira MD, PhD, SHIS QL 22 Conjun-to 4 Casa 9, Brasília, DF, Brasil. E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1930-OTtitolo breve: INTRATYMPANIC MANAGEMENT OF TINNITUSprimo autore: OLIVEIRApagine: 195-206

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 in-tense, 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 pa-tients 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 Hos-pital Universitário de Brasília 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 symp-tom 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 men-tioned by Claudius Galeno of Pergamo in the an-cient Rome (130-200 AD) as reported by Politzer

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 Menière´s disease. How-ever, the incidence of deafness was very high. Two decades later Beck and Schmidt used gentamycin for vestibular abla-tion in Menière´s 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. Lido-caine, 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 auto-immune 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 inject-ed 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.

Tinnitus is a complex symptom that may have dif-ferent causes both peripheral and central.1 It is

important however to recognize objective and sub-jective tinnitus as these two categories have different etiologies and the former is caused by identifiable

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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 Menière´s disease.7 He used streptomycin and obtained good results in relieving vertigo but se-vere hearing loss occurred in the majority of treated patients. In 1957 Schuknecht 8 treated 8 patients with Menière´s disease using streptomycin by the intra-tympanic 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 Menière´s 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 control-ling 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 hear-ing loss.

Today intratympanic drug injections to treat in-ner ear diseases has become a popular method.10-18 Indeed intratympanic gentamycin injection is today the first line of treatment for vertigo in Menière´s disease patients.19

By injecting a drug into the middle ear one treats directly the affected ear, obtains a higher concentra-tion of the drug in the inner ear, systemic efects of the drug are avoided. The technique is easy to per-form, 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 oc-curing in the inner ear only. As vertigo in Menière´s 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 Menière´s 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 associ-ated with Menière´s 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 injec-tions. 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 win-dow 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 under-stand 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 ob-vious 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 thick-ness, it’s structural components and the charge bar-rier 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 tis-sue 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 Goy-coolea ET AL. in 198024 studied in detail the perme-ability of the RWM of cats in otitis media.

These studies showed clearly that the RWM is in-deed permeable to substances injected into the mid-dle 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 tet-racaine 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% lido-caine 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 re-gion 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 mem-brane, others 13, 14 make a myringotomy in the poste-rior 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 audiom-etry 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 win-dow niche can be made.19 This technique requires a

formal tympanotomy with exposure of the round win-dow niche, removal of adhesions and pseudomem-branes 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 con-centration 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 pa-tient 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 ex-posed 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 tym-panomeatal 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 di-rect 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 appro-priate 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 ventila-tion tube and reach the micro wick.19

Because there are many variables that can influ-ence the deliver of drugs to the round window by in-tratympanic 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 medica-tions 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 un-derstood but it is established that drugs delivered through the intratympanic route reach higher con-centrations in the inner ear than when delivered sys-temically.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 an-esthetic for intranasal surgery. Inspired by Barany´s report Lewy 34 did a formal study to investigate the use of local anesthetic for control of tinnitus. He tested procaine, dibucaine hydrochloride and qui-nine 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 pa-tients with tinnitus treated by an intratympanic injec-tion 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 an-other 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 it´s 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 Menière´s disease patients with intratympanic lido-caine 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, signifi-cant improvement of the symptom in 57.1% and no change in 32.2% one week after the injection. No pa-tient in the control group showed any improvement of the SDT. However six months later 74% of the re-sponding 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 solu-tion) by the intratympanic route. They reported im-provement of tinnitus in Menière´s 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 otoa-coustic emissions (EOAE) in 30 patients with tinni-tus 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 im-provement or remission of tinnitus occurred in 17 (94%). In 12 ears with no change in EOAE ampli-tude only 5 (42%) patients have tinnitus remission. One can then speculate that there is a relation be-tween tinnitus suppression and changes in the coch-lea micromechanics.

It is well known that in experimental animals co-chlea 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 nor-mal hearing. Pure tone audiometrys, auditory evoked brain stem potentials (ABR) and transient evoked otoacoustic emissions (TEOAE) were recorded fol-lowing 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 re-duction 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 af-ter 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 audi-tory 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 aminogli-cosides in tinnitus concern patients with Menière´s disease treated primarly for relief of vertigo. Gen-tamycin is now the prefered agent because it is pri-marily vestibulotoxic.47

Moller et al.48 reported reduction of tinnitus in a

group of 15 patients with disabling Menière´s dis-ease treated with intratympanic administration of gentamycin once daily during 3 to 11 days. They fol-lowed the patients for 1 to 6 years and the effect was long lasting.

Magnusson and Padoan 49 administred gentamy-cin intratympanically twice a day to a small group of Menière’s disease patients untill they became ir-responsive to caloric stimulation. They did not have any significant hearing loss and their tinnitus were untouched up to one year later. Gentamycin intra-tympanic injection seems much less effective in tin-nitus control than in controlling severe vertigo.

Kaasinen et al.50 used gentamycin intratympanic to treat 69 patients with difficult to treat Menière´s disease. Sixty six of them had tinnitus before treat-ment. 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 tin-nitus. 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 ad-hesions 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%, tin-nitus improved in 48% and aural fullness in 62.5% of patients. Ninety percent of the patients had hear-ing 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 in-tractable Menière´s disease with intratympanic gen-tamycin injection and examined the results concern-ing tinnitus and hearing loss. The Tinnitus Handicap Inventory (THI) was used to evaluate tinnitus im-provement. The pretreatment THI score was 2.92 and posttreatment the índex was 2,26 indicating sig-nificant tinitus reduction after the treatment. Many of the patients also had hearing losses.

Quaranta et al.53 treated 15 patients with Menière´s 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 gen-tamycin solution once a week for two consecutive weeks. When there was recurrence of vertigo the pa-tients received another injection. Using the Ameri-can Academy of Otolaryngology Head and Neck Surgery criteria for reporting results of treatment for Menière´s 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 Menière´s disease using microdosis of gentamycin intratym-panic delivered by microcatheter to the RWM. Con-tinuous 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 Menière´s 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. Compar-ing these results with the ones from the same group 51 the MicroWick technique improved the results re-garding vertigo control with preservation of hearing but had no effect on tinnitus control.

Yetizer and Kertmen 55 used intratympanic gen-tamycin injection to treat 25 patients with Menière´s disease for the control of vertigo. Tinnitus was evalu-ated before and after the treatment with a visual ana-log 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 do-sis of gentamycin used and the results on tinnitus control so they found it difficult to recommend gen-tamycin intraympanic for tinnitus treatment.

Seidman 56 in 2002 studied the effect of continu-ous 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%, au-ral fullness in 77% and 23% referred hearing loss.

Lange et al.57 in 2004 in order to reduce the hear-ing loss caused by intratympanic gentamycin injec-tion 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 ef-fective.

The evolution of the intratympanic gentamycin injection seeks to diminishe the hearing loss as a side effect of treating severe intractable vertigo in Menière´s disease. Silverstein et al.19 treated 90 pa-tients with Menière´s disease using a single shot of gentamycin and when needed a second shot would be done one week apart. Fifty three percent of the pa-tients 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 (gen-tamycin) intratympanic is a side product of the treat-ment of vertigo in Menière´s disease. The studies reported above are concerned with the treatment of vertigo and report as a side effect the tinnitus re-sults. 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 intratym-panic on tinnitus with no treatment at all showed no difference between the groups.

It is fair to conclude that aminoglicosides (gen-tamycin) 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 Menière´s disease and 186 patients with labyrinthine vertigo using dexamethasone and lidocaine by the intratym-panic route. All these patients had failed conserva-tive treatments. Using the American Academy of Otolaryngology and Ophtalmology (AAOO-1972), American Academy of Otolaryngology – Head and Neck Surgery (AAO-HNS, 1985) and Sakata´s cri-

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teria (1987) for results evaluation they concluded that dexamethasone was more effective in Menière`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 dex-amethasone (2 or 4 mg/mL) repeated four times at one or two weeks interval. They measured improve-ment using a 10 points VAS pre and post treatment. They found improvement of tinnitus in 71% regard-less of age group. When the otologic diagnosis was Menière´s disease and chronic otitis media the re-sults were better (82% and 77% respectively). The improvement tended to fade away during follow up.

Silverstein et al.59 in 1996 used intratympanic in-jection 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 Menière´s disease, autoimmune ear disease and sudden sensorineural hearing loss. Tinnitus improved in 60% of Menière´s patients and 47% overall. They used the MicroWick method of infusion. Interestingly there was no im-provement in patients with presbyacusis.

Shea and Ge 60 in 1996 based on the autoimmune hypothesis for the etiology of Menière´s disease in-jected 0.5 mL of a 16 mg/mL dexamethasone solu-tion directly into the round window niche through a laser myringotomy followed by a 16 mg IV injec-tion of dexamethasone in Menière´s disease patients. Vertigo control, aural fullness reduction and low fre-quency 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 dexametha-sone the endolymphatic sac, the stria vascularis and the spiral ligament so the action of the drug would reduce endolymphatic hydrops and restore fluid dy-namics 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 pa-tients treated with dexamethasone intratympanic in-jections. Fourteen of them (57%) reported improve-ment of tinnitus.

Silverstein et al.51 in 1998 published a prospec-tive randomized double blind and crossover study of the results of dexamethasone intratympanic injection in Menière´s 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 Menière´s disease.They also observed au-ral fullnes and caloric vestibular responses after the treatment. They did three intratympanic injections in three consecutive days of dexamethasone or pla-cebo (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 dexametha-sone from the placebo injections. They concluded that intratympanic administration of dexamethasone solution was no different from placebo in unilateral Menière´s patients.

In order to clarify the pharmacokynetics of ster-oids injected intratympanically Parnes et al.63 us-ing high performance liquid chromatography es-tablished the pharmacokinetics of hydrocortisone, methylprednisolone and dexamethasone in the inner ear fluids of the guinea pig. They compared the con-centrations of the drugs in the inner ear using the intratympanic, oral and intravenous routes and dem-onstrated that much higher concentrations were ob-tained by the first route. They also showed that meth-ylprednisolone 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 hear-ing loss patients with good results also in several cases of sudden deafness. They considered the in-jections safe and highly effective to treat some dis-orders. They did not report any difference between methylprednisolone and dexamethasone in the hu-man 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 systemi-cally and intratympanically to the perilymph. They assessed the role of 3 potential facilitators of dexam-ethasone from the middle ear to the perilymph. Forty guinea pigs (79 ears) were studied. The dexametha-sone concentrations in the perilymph were measured using radioimmunoassay. They found higher con-centrations of dexamethasone in perilymph when the drug was injected intratympanically than by in-travenous injection (P=0.05). Using histamine as fa-cilitator 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 dexametha-sone was high and without systemic effects.

Cesarani et al.65 in 2002 treated patients with idi-ophatic subjective tinnitus with dexamethasone (4 mg/mL) using the intratympanic route. The injec-tions 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 recom-mended 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 in-tratympanic injection of a 62.5 mg/mL methylpred-nisolone 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.

Araújo 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 re-ceive intratympanic isotonic saline injections. Us-ing topical anesthesis they received 0.5ml of either a 4mgm/ml dexamethasone solution or 0.5ml of iso-tonic daline. The injections were performed once a week during four weeks. Improvement of tinnitus

was measured using the VAS from 1 to 10. The two groups did not differ regarding age, sex, average in-tensity of tinnitus in the VAS and main otologic di-agnosis (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 func-tion. These enzymes incitate intracellular proteoili-sis 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

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

Diagnosis Ears N. (%)

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

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

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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 infu-sion 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 stim-ulation by acoustic energy. Shulman 43 in 1998 sug-gested 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 it´s action would also reach the central nervous system´s sites of tinnitus generation. This treatment therefore remains a real possibility to be explored in the future.

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

Patient N. Sex Side of symptomVAS Score*

Complication DiagnosisPretreatment** Posttreatment***

1 2 3 4 5 6 7 8 91011121314

FFMMFFMMMMFFMF

LLLRRRRRRRLLLR

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

VertigoOtalgia

Vertigo

OtotoxicityMenière´s diseaseNIHLNIHLPresbycusisPresbycusisCOMPresbycusisOtosclerosisPresbycusisPresbycusisIdiopathic tinnitusNIHLCOM

COM: chronic otitis media; NIHL: noise-induced hearing loss; VAS: visual analog scale. *Mean score *Mean score improvement = 1.36. **Mean pre-treatment 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).

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

Patient N. Sex Side of symptomVAS Score*

Complication DiagnosisPretreatment** Posttreatment***

1 2 3 4 5 6 7 8 9101112131415161718192021

MMMMMFFFFFFMFFMMMMMFF

RLLLRLRRRLRRLRLRRLRRL

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

OtosclerosisPresbycusisNIHLNIHLOtosclerosisSudden deafnessMenière´s diseaseIdiopathic tinnitusPresbycusisIdiopathic tinnitusSudden deafnessNIHLMenière´s diseaseMenière´s diseaseOtosclerosisOtosclerosisCOMCOMIdiopathic tinnitusCOMCOM

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).

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Conclusions

Lidocaine has showed only transient and inconsist-ent action on tinitus control when injected intratym-panically and is largely abandoned for this purpose.

Steroids are the best studied class of drugs regard-ing intratympanic injection for the control of tinnitus and the best evidences based on prospective, rand-omized single blinded clinical trials point to absence of effective action in tinnitus control.

Aminoglicosides (gentamycin) have been studied targeting the control of vertigo in Menière´s 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 tin-nitus control. Considering that gentamycin intratym-panic 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 es-tablished 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 tech-nologies 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 in-terference 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 in-volved 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 be-lieve that techniques that act on neuroplasticity (tin-nitus 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 speran-ze

Claudio Galeno di Pergamo, maestro di anatomia e fisio-logia, sosteneva di somministrare medicamenti nell’orec-chio esterno e medio per trattare patologie dell’orecchio (130-200 AD). Ai nostri tempi, Schuknecht nel 1956 fu il primo a utilizzare la streptomicina intratimpanica per il trattamento della malattia di Menière. Tuttavia, l’incidenza di sordità era molto elevata. Nelle due decadi successive Beck e Schmidt utilizzavano la gentamicina per l’ablazio-ne vestibolare in pazienti affetti dalla malattia di Menière e, titolando attentamente le dosi, essi erano in grado di ri-durre l’incidenza di sordità. Questi e altri successi hanno permesso ai ricercatori di utilizzare diverse sostanze iniet-tate in sede intratimpanica per trattare il tinnito. La lidocai-na si è dimostrata in grado di sopprimere il tinnito quando iniettata per via sistemica ed è stata utilizzata anche per via intratimpanica. Anche gli aminoglicosidi e gli steroidi sono stati utilizzati nel trattamento del tinnito, della sordi-tà sensorineurale improvvisa e della sordità autoimmune. Inoltre, sono stati impiegati per via intratimpanica farmaci neuroattivi per trattare il tinnito. Sebbene vi siano numero-si articoli ottimisti circa la via intratimpanica per la som-ministrazione di farmaci nel trattamento del tinnito, fino ad ora questo metodo di trattamento è rimasto controverso e nessun farmaco specifico si è dimostrato significativamen-te efficace quando iniettato per via intratimpanica. Questo articolo presenterà le evidenze riportate in Letteratura e cercherà di dividere ciò che è illusione da ciò che è sup-portato dai fatti e dalle speranze che abbiamo per il futuro in questo settore.Parole chiave: Disturbi uditivi - Lidocaina - Tinnito.

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33. Barany R. Die beeinflussung des ohrensausens durch intravenos in-jizierte lokalanaesthetica. Acta Otolaryngol 1935;23:201-203.

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36. Gejrot T. Intravenous xylocaine in the treatment of attacks of Menière´s disease. Acta Otolaryngol Suppl 1963;188:190-5.

37. Gejrot T. Intravenous xylocaine in the treatment of attacks of Menière´s disease. Acta Otolaryngol 1976;82:301-2.

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39. Melding P, Goode RJ, Thorne PR. The use of intravenous lido-caine 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 Lar-ynx 1984;11:11-8.

43. Shulman A. Neuroprotecyive drug therapy: a medical and pharma-cological treatment for tinnitus control. Int Tinnitus J 1997;3:77-93.

44. Itoh A, Sakata E. Treatment of vestibular disorders. Acta Otolaryn-gol 1991;Suppl 481:617-23.

45. Haginomori S, Makimoto K, Araki M, Kawakmi M, Takahashi H. Ef-fect 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 intratympani-cally 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 Menière´s disease. Am J Otol 1988;9:383-91.

49. Magnusson M, Padoan S. Delayed onset of ototoxic effects of gen-tamycin in treatment of Menière´s disease rationale for extremely low dose therapy. Acta Otolaryngol 1991;111:671-6.

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54. Sakata E, Itoh A, Itoh Y. Treatment of cochlear tinnitus with dex-amethasone injection into the tympanic cavity. Int Tinnitus J 1996;2:129-35.

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56. Seidman M. Continuous gentamycin therapy using an intraear mi-crocatheter for Menière´s disease: a retrospective study. Otolaryn-gol Head and Neck Surg 2002;126:244-56.

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Cisplatin ototoxicity – The problem

Cis-Diamminedichloroplatinum(II), cisplatin, is a common chemotherapeutic agent used to treat

many different types of cancer including medullob-lastoma, 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 accumula-tion 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 ototoxic-ity generally manifests as tinnitus and sensorineural hearing loss 2, 3 which starts in the high frequencies, but extends into lower frequencies that are impor-tant 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, cumu-lative, 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 vas-cularis and the spiral ganglion cells are also injured,

Cisplatin-induced ototoxicity is a common side effect of chem-otherapeutic regimens aimed at treating several types of ma-lignant 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 gan-glion 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) administra-tion 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 chemothera-peutic regimens. This article reviews the available experimen-tal 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 oto-toxicity and permitted emergence of targeted therapeutic strat-egies, 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.

Division of Otolaryngology Department of Surgery

University of Connecticut Health Center Farmington, CT, USA

OTORINOLARINGOL 2010;60:207-12

K. PARHAM

Intratympanic treatment for chemotherapy-related ototoxicity

Acknowledgements.—This work was supported by a Jahnigen Career Development Award from the American Geriatrics Society. I am grate-ful to D. Kent Morest and Julia Gross for their assistance and providing cochlear histology data.

Corresponding author: K. Parham, MD, PhD, Assistant Professor, Di-rector of Research, Division of Otolaryngology, Department of Surgery, University of Connecticut Health Center, Farmington, CT 06030-6228, USA. E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1929-OTtitolo breve: CHEMOTHERAPY-RELATED OTOTOXICITYprimo autore: PARHAMpagine: 207-12

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suggesting that cisplatin targets multiple cochlear structures directly.9

There are currently four platinating agents avail-able for treatment of cancer: intravenously adminis-tered cisplatin and its analogs carboplatin and oxapla-tin and orally available satraplatin. Ototoxicity due to cisplatin analogs is relatively rare but they have infe-rior efficacy in treatment of some neoplasms.10 Lower ototoxicity of other platinating agent may be due to their lower cochlear uptake.11 Nevertheless, ototoxic-ity has also been reported for these agents, including both carboplatin 12 and oxaplatin.13 Variability ob-served 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 re-view, we will focus on cisplatin-induced ototoxicity.

Cisplatin ototoxicity – The mechanism

Cisplatin ototoxicity is likely mediated by multi-ple cellular mechanisms and targets. As noted above, cisplatin binds DNA. This binding affects both rep-lication and transcription of DNA, DNA repair and disrupts signal transduction in proliferating cells leading to apoptosis 15 via mitochondiral death path-way.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 prop-erty 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 dem-onstrated in all turns of the cochlea.18

Another mechanism by which cisplatin can disrupt cochlear function, without dependence on proliferat-ing populations, is through generation of reactive ox-ygen 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, glutath-ione peroxidase and catalase.21, 22 Rybak et al. have suggested that cisplatin-induced cytotoxic mecha-nisms 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 anti-oxidant enzymes are depleted 25 and pro-apoptotic Bax proteins are activated leading to mitochondrial release of cytochrome c which in turn activates pro-caspase-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 re-ducing ROS production.26, 27 Inhibition of caspase-3 activity also produces ototoprotective effects against cisplatin.28

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-frequen-cy region of the cochlea (previously unpublished data). IHC: inner hair cell.

100

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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 anti-neoplastic agent such as carboplatin) or the result-ing 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 cis-platin ototoxicity without affecting its chemothera-peutic actions. Dozens of experimental studies have attempted to find an ideal otoprotectant by adminis-tration of antioxidants against ROS at an early stage in the ototoxic pathways.23 Unfortunately, many of these agents have been found to inhibit the tumo-ricidal effects of cisplatin and/or have toxicities or unknown effects in humans.2 There are currently several ongoing clinical trials involving lactated ringer’s, alpha lipoic acid, sodium thiosulfate, aspi-rin 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 dis-orders, 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 ex-ert its effects (See Chapter 1). Specifically, steroids placed into the middle ear have been shown to dif-fuse 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 avoid-ing the common systemic side effects of steroids in-cluding 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 sen-sorineural hearing loss and Méniere’s disease for several years31, 33 (See Chapters 4-9).

Corticosteroids have been shown to limit the for-mation of ROS in the inner ear.35, 36 In animal mod-els, corticosteroids have demonstrated protective benefits against various sources of hearing loss in-cluding noise,37,38 ischemia 39,40 and physical trauma

(e.g., from electrode array insertion into the cochlea 41). Similarly, aminoglycoside ototoxicity, which is believed to have a similar pathogenesis to cisplatin ototoxicity can be ameliorated with steroid treat-ment.42, 43 The presence of corticosteroid receptors within critical mammalian inner ear structures pro-vides further evidence that steroids can exert an ef-fect 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 cisplatin’s 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 with-out 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 dexameth-asone (4 mg/mL) who were administered cisplatin 12 mg/kg IP showed preservation of DPOAE am-

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 af-ter, 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).

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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 antioxi-dants to the round window. D-methionine applied di-rectly 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 cispla-tin otoxocity: 30 min alkaline PBS (pH=10.2) pretreat-ment 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 chin-chillas.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 apopto-sis 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 pro-tected 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 ototoxic-ity. 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 patho-physiology of ototoxicity, such as siRNA targeting NADPH oxidases. The results reviewed here suggest a promising future in protecting hearing against cis-platin ototoxicity.

Additional experimental studies, however, are needed to address efficacy of above treatment op-tions in the presence of other risk factors, such as pre-existing hearing loss. It is important to recog-nize 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

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 thresh-olds.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. Cis-platin increases the early release and de novo synthe-sis of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, through the activation of MEK1/ERK.48 Kim et al. have suggested that the cisplatin-mediated 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 com-ponent, 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 ap-plied directly to the round window membrane (RWM) in chinchilla 90 min before RWM applica-tion of cisplatin significantly reduced ABR threshold at all frequencies but the highest frequencies.49

IT 2% N-acetylcysteine (NAC) preserved distor-tion 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 Ringer’s 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-

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IT di un breve “interfering RNA” per inibire la NADPH ossidasi, generatore di ROS. I risultati sperimentali ripro-posti in questo articolo mostrano un futuro promettente nella protezione dell’orecchio dall’ototossicità 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 cisplatin-induced 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 ototoxic-ity 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 morpho-logical 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, Bern-dtsson M et al. Cisplatin and oxaliplatin toxicity: importance of co-chlear 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;89:258-61.

14. Ross CJ, Katzov-Eckert H, Dubé MP, Brooks B, Rassekh SR, Barh-dadi A et al.;CPNDS Consortium. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cispla-tin 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. Cis-platin cytotoxicity:DNA and plasma membrane targets. Curr Med Chem 2008;15:2656-63.

17. Dunaway G, Mhaskar Y, Armour G, Withworth C, Rybak L. Migra-tion 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 oxy-gen species on cochlear outer hair cells. Hear Res 1995;84:30-40.

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 syn-ergistic interaction between presbycusis and cis-platin ototoxicity is likely. Indeed, older cancer patients being treated with cisplatin show statisti-cally 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 gen-eral, 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 ac-tivate in order to preserve hearing in the face of cis-platin ototoxicity. This work is currently underway in my laboratory.

Riassunto

Trattamento intratimpanico dell’ototossicità correlata a chemioterapia

L’ototossicità indotta da cisplatino è un comune effetto collaterale dei regimi di chemioterapia utilizzati nel tratta-mento di diversi tipi di tumori maligni solidi. L’ototossicità da cisplatino è mediata da numerosi meccanismi cellulari che determinano l’accumulo di specie reattive dell’ossige-no (ROS) e l’apoptosi. I bersagli del cisplatino nella co-clea sono le cellule ciliate esterne (OHC), le cellule spirali ganglionari e la stria vascularis. Attualmente, vi sono nu-merosi trials clinici atti a valutare l’efficacia di sostanze antiossidanti nel migliorare gli effetti collaterali ototossici del cisplatino. Tuttavia, la somministrazione sistemica di antiossidanti potrebbe interferire con le proprietà anti-neo-plastiche dei regimi chemioterapici. La somministrazione intratimpanica (IT) di farmaci offre una via alternativa per la somministrazione di farmaci ‘rescue’ a livello della co-clea per minimizzare l’assorbimento sistemico, riducendo così il rischio di alterare l’efficacia dei regimi di chemio-terapia. In questo articolo, l’autore fornisce una revisione dell’evidenza sperimentale disponibile sull’efficacia della terapia IT nella funzione protettiva auricolare dall’ototos-sicità del cisplatino. Tra i farmaci promettenti, vi è il de-sametasone, attualmente utilizzato nel trattamento di ma-lattie dell’orecchio interno. Le ricerche più recenti hanno migliorato le nostre conoscenze nei meccanismi cellulari che determinano l’ototossicità e hanno permesso l’emer-genza di strategie terapeutiche mirate, come l’applicazione

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ne prevents transient ischemia-induced cochlear damage in gerbils. Acta Otolaryngol Suppl 2009;562:24-7.

41. James DP, Eastwood H, Richardson RT, O’Leary SJ. Effects of round window dexamethasone on residual hearing in a Guinea pig model of cochlear implantation. Audiol Neurootol 2008;13:86-96.

42. Himeno C, Komeda M, Izumikawa M, Takemura K, Yagi M, Weip-ing Y et al. Intra-cochlear administration of dexamethasone attenuates aminoglycoside ototoxicity in the guinea pig. Hear Res 2002;67:61-70.

43. 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.

44. Hori H, Kanno H. An experimental study of the protective effect of lazaroid (U-74389G) on cisplatin-induced toxicity. Nippon Jibi-inkoka Gakkai Kaiho 1999;102:8-18.

45. Hill GW, Morest DK, Parham K. Cisplatin-induced ototoxicity:Effect of intratympanic dexamethasone injections. Otology & Neurotol-ogy 2008;29:1005-11.

46. Paksoy M, Ayduran E, Sanlı A, Eken M, Aydın 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]).

47. Saliba I, El Fata F, Ouelette V, Robitaille Y. Are intratympanic in-jections of N-acetylcysteine and methylprednisolone protective against Cisplatin-induced ototoxicity? J Otolaryngol Head Neck Surg 2010;39:236-43.

48. So H, Kim H, Lee JH, Park C, Kim Y, Kim E et al. Cisplatin cy-totoxicity of auditory cells requires secretions of proinflamma-tory cytokines via activation of ERK and NF-kappaB. J Assoc Res Otolaryngol 2007;8:338-55.

49. Whitworth CA, Ramkumar V, Jones B, Tsukasaki N, Rybak LP. Biochem Pharmacol. 2004;67:1801-7.

50. Choe WT, Chinosornvatana N, Chang KW. Prevention of cisplatin ototoxicity using transtympanic N-acetylcysteine and lactate. Otol Neurotol 2004;25:910-5.

51. Nader ME, Théorêt Y, Saliba I. The role of intratympanic lactate injection in the prevention of cisplatin-induced ototoxicity. Laryn-goscope 2010;120:1208-13.

52. 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 Cisplatin-Induced Hearing Loss in the Rat. Antioxid Redox Signal [Internet]. 2010 June 6. [Epub ahead of print]).

53. Korver KD, Rybak LP, Whitworth C, Campbell KM. Round win-dow application of D-methionine provides complete cisplatin oto-protection. Otolaryngol Head Neck Surg 2002;126:683-9.

54. Tanaka F, Whitworth CA, Rybak LP. Influence of pH on the oto-toxicity of cisplatin:a round window application study. Hear Res 2003;177:21-31.

55. Tanaka F, Whitworth CA, Rybak LP. Round window pH ma-nipulation alters the ototoxicity of systemic cisplatin. Hear Res 2004;187:44-50.

56. Ries LAG, Eisner MP, Kosary CL, Hankey BF, Miller BA, Clegg LX et al. SEER Cancer Statistics Review, 1973-1998. National In-stitute of Health publication 00-2789, 2000.

57. NIA/NCI Report of the Cancer Center Workshop (June 13–15, 2001). Exploring the Role of Cancer Centers for Integrating Aging and Cancer Research [Internet]. Available from:http://www.nia.nih.gov/Research Information/ConferencesAndMeetings/WorkshopRe-port/ExecutiveSummary.htm.

58. Laurell G. Borg E. Ototoxicity of cisplatin in gynaecological cancer patients. Scandinavian Audiology 1988;17:241-7.

59. Krause KH. Aging:a revisited theory based on free radicals generated by NOX family NADPH oxidases. Exp Gerontol 2007;42:256-62.

60. 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.

20. Dehne N, Lautermann J, Petrat, Rauen U, de Groot H. Cisplatin ototoxicity:involvement of iron and enhanced formation of super-oxide anion radicals. Toxicol Appl Pharmacol 2001;174:27-34.

21. Zelck U, Norwak R, Karnstedt U, Koitschev A, Kacher N. Spe-cific 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 Mn-SOD in rat cochlear tissues. Hear Res 1996;96:199-203.

23. Rybak LP, Whitworth CA, Mukherjea D, Ramkumar V. Mecha-nisms of cisplatin-induced ototoxicity and prevention. Hear Res 2007;226:157-67.

24. Rybak LP, Mukherjea D, Jajoo S, Ramkumar V. Cisplatin ototoxic-ity 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 poten-tial 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. García-Berrocal JR, Nevado J, González-García JA, Sánchez-Ro-dríguez C, Sanz R, Trinidad A et al. Heat shock protein 70 and cel-lular disturbances in cochlear cisplatin ototoxicity model. J Laryn-gol Otol 2010;124:599-609.

29. Hargunani CA, Kempton JB, DeGagne JM, Trune DR. Intratym-panic injection of dexamethasone:time course of inner ear distribu-tion and conversion to its active form. Otol Neurotol 2006;27:564-9.

30. Parnes LS, Sun AH, Freeman DJ. Corticosteroid pharmacokinetics in the inner ear fluids:an animal study followed by clinical applica-tion. 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 ap-optosis 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, Green-berg SSl. Rapid induction of messenger RNA for nitric oxide syn-thase 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. Ef-fects of corticosteroid, contrast medium and ATP on focal microcir-culatory 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;112:599-603.

38. Takemura K, Komeda M, Yagi M, Chiemi H, Izumikawa M, Doi T et al. Direct inner ear infusion of dexamethasone attenuates noise-induced 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-

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(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 de-livery 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, fi-brocytes 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 µm can pass through this layer into the in-ner ear either intercellulary or transcellulary via pino-cytosis. Thus, the round window membrane provides little impediment to the movement of most drugs or other molecules into the inner ear. Although the hu-man round window membrane (60-70 µm) is thicker than most experimental rodents (10-15 µm), they are essentially similar in the fact that the only real barrier is the single layer of epithelial cells on the middle

Division of OtolaryngologyDepartment of Biomedicine and Clinical Neurosciences

University of Palermo, Palermo, Italy

OTORINOLARINGOL 2010;60:213-9

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

Techniques of intratympanic administration

The purpose of this review is to examine the most recent litera-ture regarding the application of transtympanic inner ear per-fusion 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 de-velopment of alternate delivery methodologies involving both transtympanic and direct intracochlear infusions.Key words: Hearing loss - Menière disease - Ear, inner.

Since its original introduction by Schuknecht in 1956 for the treatment of Menière disease,1 inner

ear perfusion has been used in a variety of other dis-orders, 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 ef-fects to the rest of the body are avoided.2 The success-ful 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 Otolaryngo-logy, University of Palermo, Palermo, Italy. E-mail: [email protected]

Anno: 2010Mese: SeptemberVolume: 60No: 3Rivista: OTORINOLARINGOLOGIACod Rivista: OTORINOLARINGOL

Lavoro: 1938-OTtitolo breve: TECHNIQUES OF INTRATYMPANIC ADMINISTRATIONprimo autore: MARCHESEpagine: 213-9

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ear side. Although this minimal anatomical barrier appears to offer little protection to the inner ear, a re-cent study on monkeys 6 suggests that mucous glands around the round window and extensive inflamma-tory cell populations within the round window ves-sels provide a basic immunological defence to the co-chlea. 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 perme-ability. 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 an-other anatomic consideration that can make middle ear application of medication variable.

Transtympanic drug delivery is generally accom-plished 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 pharmacologi-cal agents. These approaches rely on transport through the RWM. No significant clinical difference in these approaches has been observed,11 although animal test-ing and computer modeling provide evidence that sus-tained 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 patient’s ear is anesthetized with local injec-tion or topical anesthetic. Under microscopic visu-alization, a 27-gauge needle is used to inject medi-cation into the inner ear over the area of the round window niche. The head is placed in position 45° to-ward 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 tube’s 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. It’s 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 pa-tients understand the concept of intratympanic injec-tion and readily accept the proposed therapy. Unlike systemic therapies, intratympanic therapy allows for the selection of the affected ear to be treated. In addi-tion, 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 perfora-tion, 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 infu-sions, and periodic infusions have been used exten-sively, with excellent clinical reviews presented by Hoffmann and Silverstein 16 and Hoffer et al.17 Ani-mal studies are used to explore details of drug distri-bution and cellular impact with acute and sustained infusions to the RWM. Roehm et al.18 examined gen-tamicin uptake in the chinchilla inner ear with single injections through the tympanic membrane, and sus-tained 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 apical–basal 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 dexam-ethasone in guinea pig perilymph following adminis-tration 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-

Figure 2.—Introducing the Silverstein MicroWick.

Silverstein microwick

Microwick

Incus

Malieus

Staples

Semicircularcanals

Silicone vent tube Tympanic membraneEustachian tube

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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 posi-tion, 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 anaesthe-sia 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, SD±68 mm) and slightly infe-rior to the umbo of the malleus (113°, SD±9.8°).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 in-sert 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 medica-tion delivering a high concentration of the medica-tion 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 with-out the use of anesthesia. The tympanic membrane is then allowed to heal. This technique of patient self-treatment using the MicroWick to deliver medi-cations to the inner ear is minimally invasive, inex-pensive, safe, effective, and well tolerated for treating Menière’s disease and other inner ear conditions.

Potential drawbacks to the use of the Silverstein MicroWick may include the development of a per-sistent perforation of the tympanic membrane, in-fection of the middle or external ear, and the poten-tial for tissue ingrowth in the middle ear either in the form of fibrosis or epithelial ingrowth leading to cholesteatoma. Despite these potential complica-tions, in a series of 69 patients with Menière’s dis-ease treated with gentamicin delivered through the Silverstein MicroWick, no long -term complications were noted.21

RWM

Despite its invasiveness, the temporary implanta-tion of a microcatheter into the middle ear cavity is

an appropriately safe method for providing continu-ous drug delivery to the inner ear (Figure 3). It has recently been demonstrated that the choice of the drug delivery system influences the pharmacokinet-ics 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 neces-sary to guarantee efficient drug delivery and to avoid unwanted side effects. The standardized surgical im-plantation 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) stabi-lization of the catheter with bone wax and soft tis-sue 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 con-necting line between pump and catheter.9 At the end of the implantation period, the catheter was removed by a second surgical procedure allowing for evalu-ation 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-

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.

Section A-A

Section A-AFluid in Fluid out

Electrode

Tip endview

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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 pro-cedure is expensive.

Stabilizing matrices

The use of stabilizing matrices offers many po-tential benefits over middle ear perfusions. Medi-cations delivered to the middle ear are ultimately dissipated by drainage down the Eustachian tube or absorption by middle ear mucosa unless a stabiliz-ing 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 tech-niques 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 com-bination found to be most effective. Chitosan-glyc-erophosphate hydrogel, a liquid at room tempera-ture 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 dis-ease 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 con-ductive hearing loss if the middle ear is overfilled with hydrogel, and the relatively quick release pro-file 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. Hista-mine 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) concentra-tion 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 media-tors on middle ear vasodilatation: edema and perme-ability 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 con-ducted 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 pro-longing RWM exposure to dexamethasone. Topical dexamethasone application does not result in sys-temic absorption. The clinical implications for treat-ment are considerable. Advantages of such therapy are not yet available in human model, but further studies are required.

Nanoparticles

Nanoparticles are another methodology of medi-cation delivery to the inner ear that has generated considerable interest in the past several years. Na-noparticles 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. Nanoparti-cles 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 as-sumed 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 be-fore 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 deliv-ery 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 ca-nals,33 scala vestibule,34, 35 and most commonly the scala tympani.36-41 Endolymph injections have pro-vided exciting cochlear hair cell regeneration results 30 but generally impact auditory function making them unlikely avenues for clinically relevant thera-pies. 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 admin-istration to the RWM. A perilymphatic inoculation route is technically easier and therefore more fea-sible 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 infu-sions.

Molecular therapies

Molecular therapies for protection of spiral gan-glion 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 fac-tors,45 and glial cell-derived neurotrophic factor.46 Recent work with scala media inoculation demon-strated hair cell regeneration mediated by Math1 overexpression in the intact cochlea,30, 47 providing

favorable evidence of the potential for effective gene-based 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. Effec-tive, 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 through-out 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 dimen-sions less than 50 nm, which distribute quickly and traverse cochlear membranous partitions.

Riassunto

Tecniche di somministrazione transtimpanicaQuesto articolo si propone di esaminare la più recen-

te letteratura riguardante l’applicazione della infusione di farmaci per via transtimpanica nel trattamento delle di-sfunzioni vestibolari e uditive. L’impiego di tale tecnica è un campo in rapida espansione in otorinolaringoiatria, e diverrà clinicamente più rilevante, con l’approfondimen-to delle conoscenze di farmacocinetica. Terapie emergenti quali nanoparticelle e “facilitatori” sono attualmente og-getto di studio. Lo sviluppo di terapie avanzate comporterà l’impiego di farmaci direttamente intracocleari. Potenziali impieghi riguardano anche i fattori neurotrofici. Studi re-centi 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 Menière - Orecchio interno.

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