Issuu on Google+

Issue 4

Volume 20

October - November - December 2016

INTERNATIONAL ARCHIVES OF

ISSN 1809-9777

OTORHINOLARYNGOLOGY Official Publication of the Otorhinolaryngology Foundation and Societas Oto-Rhino-Laryngologia Latina

Editor-in-Chief Geraldo Pereira Jotz

Co-Editor Aline Gomes Bittencourt

e first Rapid online publication www.thieme-connect.com/products www.thieme.com/iao ISSN 1809-9777


AF_Anuncio_ReSound_Mapa.pdf

1

9/5/16

11:18 AM

TECNOLOGIA, CONFIANÇA E SEGURANÇA. TUDO ISSO É RESOUND. Seus pacientes merecem sempre o melhor. Por isso, conte com a linha completa de produtos da ReSound. Nossas soluções estão conquistando o Brasil com conexão verdadeiramente sem fio, inovação e experiência sonora natural.

C

M

Y

CM

MY

CY

CMY

K

Cada vez mais ampliamos nossa presença em todas as regiões do País.

Surpreenda seus pacientes com os aparelhos auditivos ReSound. Visite agora mesmo: www.resound.com.br


ISSN 1809-9777

International Archives of Otorhinolaryngology Editor

Domingos Hiroshi Tsuji USP, São Paulo, Brazil

Minoru Hirano Kurume University, Kurume, Japan

Geraldo Pereira Jotz UFRGS, Porto Alegre, Brazil

Eduardo Crema

Nédio Steffen PUC, Porto Alegre, Brazil

Co-Editor

Eliane Schochat

Aline Gomes Bittencourt UFMA, São Luís, Brazil

Elisabete Carrara de Angelis

Associated Editors

Fabrizio Ricci Romano

Desiderio Passáli University Hospital, Siena, Italy

Fayez Bahmad Junior

João Ferreira de Mello Junior USP, São Paulo, Brazil

Filipe Matuba

Luiz Paulo Kowalski H. AC Camargo, São Paulo, Brazil

Fernando Luis Dias

Marcelo M. Hueb UFTM, Uberaba, Brazil

Francini Grecco de Melo Pádua

Marcos Mocelin UFPR, Curitiba, Brazil

Francisco Verissimo de Mello Filho

Marcus Miranda Lessa UFBA, Salvador, Brazil

Gerson Schulz Maahs

Michiel W. M. Van den Brekel Netherlands Cancer Institute, Amsterdam, Netherlands

Giovanni Danesi

Priscila Bogar Rapoport FMABC, Santo André, Brazil

Héctor Rondón Cardoso

Ricardo Ferreira Bento USP, São Paulo, Brazil

UFTM, Uberaba, Brazil USP, São Paulo, Brazil Hospital AC Camargo, São Paulo, Brazil USP, São Paulo, Brazil UNB, Brasília, Brazil Agostinho Neto University, Luanda, Angola INCA, Rio de Janeiro, Brazil UNIFESP, São Paulo, Brazil USP-RP, Ribeirão Preto, Brazil UFRGS, Porto Alegre, Brazil Ospedali Riuniti di Bergamo, Bergamo, Italy Universidad Nacional de San Agustín, Arequipa, Perú

Ricardo L. Carrau Ohio State University, OH, USA

Heinz Stammberger

Richard Voegels USP, São Paulo, Brazil

Jacques Magnan

Robert T. Sataloff Drexel University College of Medicine, Philadelphia, USA

Jair Cortez Mantovani

Graz University, Graz, Austria Université dAix-Marseille, Marseille, France UNESP, Botucatu, Brazil Jeferson S. D’Avila

Editorial Board

UFSE, Aracajú, Brazil Jesús Algaba Guimera Hospital Donostia de San Sebastián, San Sebastián, Spain

Adriana Brondani da Rocha Conselho de Informações sobre Biotecnologia, São Paulo, Brazil

José Faibes Lubianca Neto

Adriane Teixeira UFRGS, Porto Alegre, Brazil

Jose N. Fayad Keck School of Medicine, USC, California USA

Agrício Crespo UNICAMP, Campinas, Brazil

Karine Schwarz UFRGS, Porto Alegre, Brazil

Agustin del Canizo Universidad de Salamanca, Salamanca, Spain Alberto Alencar Nuldelmann PUC, Porto Alegre, Brazil Alejandro Rivas Vanderbilt University Medical Center, Tennessee, USA

UFCSPA, Porto Alegre, Brazil

Lídio Granato FCMSCSP, São Paulo, Brazil Lilian Muniz Universidade Federal de Recife, Recife, Brazil Luiz Antonio Guerra Bernd UFRS, Porto Alegre, Brazil Luiz Lavinsky UFRGS, Porto Alegre, Brazil

Alexandre Felippu Neto Instituto Felippu, São Paulo, Brazil

Luiz Ubirajara Sennes

Alfio Ferlito Udine School of Medicine, Unide, Italy

Maira Rozenfeld Olchik

Ana Cristina H. Hoshino USP, São Paulo, Brazil

Manuel Manrique Rodríguez

André Luiz Lopes Sampaio UNB, Brasília, Brazil

Marcelo Lazzaron Lamers

Antonio Celso Nassif Filho PUC, Curitiba, Brazil

Marcelo Ribeiro de Toledo Piza

Badr Eldin Mostafa Ain-Shams University, Cairo, Egypt

Márcio Abrahão

Bernard Fraysse Hôpital PURPAN, Toulouse, France

Márcio Nakanishi

Carlos Augusto Pires de Oliveira UNB, Brasília, Brazil

Marcos Vial Goycoolea

Carlos Curet Universidad Nacional de Córdoba, Córdoba, Argentina

Maria Valéria Schimidt Goffi Gómez

Carlos Diógenes Pinheiro Neto Albany Medical College, New York, USA

Mario Andréa Lisboa University, Lisboa, Portugal

Celso Gonçalves Becker UFMG, Belo Horizonte, Brazil

Mario Svirsky New York University, New York, USA

Domenico Cuda Guglielmo da Saliceto Hospital, Piacenza, Italy

USP, São Paulo, Brazil UFRGS, Porto Alegre, Brazil Universidad de Navarra, Navarra, España UFRGS, Porto Alegre, Brazil Associação Paparella, Ribeirão Preto, Brazil UNIFESP, São Paulo, Brazil

Nelson Rosário UFPR, Curitiba, Brazil O. Nuri Özgirgin Başkent University Faculty of Medicine, Ankara, Turkey Olivier Sterkers Université Paris Diderot, Paris, France Onivaldo Cervantes UNIFESP, São Paulo, Brazil Otávio Bejzman Piltcher UFRGS, Porto Alegre, Brazil Paulo Sérgio Lins Perazzo UNEB, Salvador, Brazil Pedro L. Coser UFSM, Santa Maria, Brazil Pedro Luiz Mangabeira Albernaz UNIFESP, São Paulo, Brazil Regina Helena Garcia Martins UNESP, Botucatu, Brazil Richard Harvey University of New South Wales, New South Wales, Australia Robert Sweet McGill University, Montreal, Canada Robert Vincent Causse Ear Clinic, Colombiers, France Roberto Campos Meirelles UERJ, Rio de Janeiro, Brazil Roberto Dihl Angeli UFRGS, Porto Alegre, Brazil Roberto Eustáquio Guimarães UFMG, Belo Horizonte, Brazil Roberto Filipo Sapienza Università di Roma, Roma, Italy Rodrigo de Paula Santos UNIFESP, São Paulo, Brazil Ronaldo Frizzarini USP, São Paulo, Brazil Sady Selaimen da Costa UFRGS, Porto Alegre, Brazil Salvatore Conticello Università degli Studi di Torino, Turin, Italy Shiro Tomita UFRJ, Rio de Janeiro, Brazil Silvia Dornelles UFRGS, Porto Alegre, Brazil Silvio Antonio Monteiro Marone PUCCAMP, Campinas, Brazil Silvio da Silva Caldas Neto UFPE, Recife, Brazil Tania Maria Sih FMUSP, São Paulo, Brazil Thomas Linder Luzerner Kantonsspital, Luzern, Switzerland Wytske Fokkens Academic Medical Center, Amsterdam, Netherlands Zelita Ferreira Guedes UNIFESP, São Paulo, Brazil

Librarian Adilson Montefusco (e-mail: iaorl@iaorl.org)

UNB, Brasília, Brazil Clinic of Las Condes, Santiago, Chile USP, São Paulo, Brazil

Maurizio Barbara Sapienza University, SantAndrea Hospital, Rome, Italy

Affiliation


Chegou o Ciclo da Saúde Nasal Diário. Começa com a higienização, passa pela hidratação e termina com conforto e proteção nasal.1-3,5,6

Higienização e hidratação todo dia: um novo hábito diário de saúde. 1-3,5,6

Setembro/2016

Cuidado completo. Higienizar com Salsep ou Salsep 360 para remover impurezas, vírus e bactérias. Hidratar com Maxidrate nova fórmula para evitar o ressecamento da mucosa nasal, prevenindo contra infecções respiratórias e proporcionando conforto e qualidade de vida para o paciente.1-8

Indicado para crianças de até 4 anos.1 Único spray nasal (não jato) que pode ser aplicado em qualquer posição.1,9

Pensado e desenvolvido para higienização nasal e conforto de crianças e adultos.2

O único hidratante nasal em gel do mercado.3,9

SALSEP®0,9% - cloreto de sódio - Solução nasal com 9 mg/mL em frasco spray com 30 ou 50 mL. Cada nebulização (puff) libera 0,1 mL de solução. USO NASAL. USO ADULTO E PEDIÁTRICO. Indicações: como fluidificante e descongestionante nasal. age na mucosa nasal fluidificando a secreção, facilitando assim a eliminação do muco. Salsep® pode ser usado como fluidificante das secreções nasais em resfriados, rinites, sinusites e quaisquer outras condições relacionadas ao ressecamento da mucosa nasal, como baixa umidade do ar, exposição ao ar condicionado e poluição. Pode ser utilizado também para limpeza delicada das secreções em pós-operatórios nasossinusais. Contraindicações: para pacientes com antecedentes de hipersensibilidade (alergia) aos componentes da fórmula. Precauções e advertências: Não há registros de reações adversas relacionadas ao uso deste medicamento. Gravidez e lactação: Apesar de não existirem estudos específicos durante a gestação e amamentação o uso de Salsep® é considerado seguro, não existindo contraindicação ao seu uso nessas situações. Interações com medicamentos, alimentos e álcool: Não há registros de interações clinicamente relevantes relacionadas ao uso de Salsep®. Reações adversas: Ainda não foram relatadas reações adversas específicas com o uso do medicamento. Posologia: Aplique a solução nas narinas, conforme necessidade. MEDICAMENTO DE NOTIFICAÇÃO SIMPLIFICADA RDC Nº 199/2006. AFE Nº 1.0033-3. Farm. Resp.: Cintia Delphino de Andrade CRF-SP nº 25.125. LIBBS FARMACÊUTICA LTDA. CNPJ 61.230.314/0005-07. Rua Alberto Correia Francfort, 88. Embu das Artes-SP. Indústria Brasileira. SALSEP-MB01-15. Serviço de Atendimento LIBBS: 08000-135044. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. SALSEP® É UM MEDICAMENTO. SEU USO PODE TRAZER RISCOS. PROCURE O MÉDICO E O FARMACÊUTICO. LEIA A BULA. Documentação Científica e informações adicionais estão à disposição da classe médica, mediante solicitação.

SALSEP® 360 0,9% - cloreto de sódio - Solução nasal com 9 mg/mL em frasco spray com 15 ou 50 mL. Cada nebulização (puff) libera 0,05 mL de solução. USO NASAL. USO PEDIÁTRICO (Entre 0 e 4 anos de idade). Indicações: como fluidificante e descongestionante nasal. Salsep®360 age na mucosa nasal fluidificando a secreção, facilitando assim a eliminação do muco. Salsep®360 pode ser usado como fluidificante das secreções nasais em resfriados, rinites, sinusites e quaisquer outras condições relacionadas ao ressecamento da mucosa nasal, como baixa umidade do ar, exposição ao ar condicionado e poluição. Pode ser utilizado também para limpeza delicada das secreções em pós-operatórios nasossinusais. Contraindicações: para pacientes com antecedentes de hipersensibilidade (alergia) aos componentes da fórmula. Precauções e Advertências: Não há registros de reações adversas relacionadas ao uso deste medicamento. Gravidez e lactação: Apesar de não existirem estudos específicos durante a gestação e amamentação o uso de Salsep®360 é considerado seguro, não existindo contraindicação ao seu uso nessas situações. Interações com medicamentos, alimentos e álcool: Não há registros de interações clinicamente relevantes relacionadas ao uso de Salsep®360. Reações adversas: Ainda não é conhecida a intensidade e a frequência das reações adversas específicas deste medicamento devido à ausência de relatos científicos a respeito dele. Informe seu médico o aparecimento de reações desagradáveis. Posologia: Aplique a solução nas narinas, conforme necessidade. MEDICAMENTO DE NOTIFICAÇÃO SIMPLIFICADA RDC Nº 199/2006. AFE Nº 1.0033-3. Farm. Resp.: Cintia Delphino de Andrade CRF-SP nº 25.125. LIBBS FARMACÊUTICA LTDA. CNPJ 61.230.314/0005-07. Rua Alberto Correia Francfort, 88. Embu das Artes-SP. Indústria Brasileira. SALSEP 360-MB01-15. Serviço de Atendimento LIBBS: 08000-135044. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. SALSEP® 360 É UM MEDICAMENTO. SEU USO PODE TRAZER RISCOS. PROCURE O MÉDICO E O FARMACÊUTICO. LEIA A BULA. Documentação Científica e informações adicionais estão à disposição da classe médica, mediante solicitação. MAXIDRATE® - cloreto de sódio 6,0 mg/g. Gel nasal contendo 1 frasco aplicador em frascos com 10 g ou 30 g. USO TÓPICO NASAL. USO ADULTO E PEDIÁTRICO. Indicações: Hidratação da mucosa nasal ressecada devido a condições climáticas de baixa temperatura ou baixa umidade; condições ambientais como exposição ao ar condicionado; utilização de betabloqueadores ou das seguintes substâncias: alprazolam, perfenazina, amitriptilina, tioridazina e isotretinoína; resfriados, alergias e sinusite crônica; senilidade; pós-radioterapia, reduzindo a formação de crostas. Reg. MS 1.0033.0126. Farm. Resp.: Cintia Delphino de Andrade CRF-SP nº 25.125 Libbs Farmacêutica Ltda. CNPJ 61.230.314/0001-75. Rua Alberto Correia Francfort, 88. Embu das Artes-SP. Indústria Brasileira. MAXIDRATE-MB10-15. Serviço de Atendimento Libbs: 0800-0135044. SE PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO. MAXIDRATE É UM MEDICAMENTO. SEU USO PODE TRAZER RISCOS. PROCURE O MÉDICO E O FARMACÊUTICO. LEIA A BULA. Documentação Científica e informações adicionais estão à disposição da classe médica, mediante solicitação. Referências: 1. SALSEP 360®. São Paulo: Libbs Farmacêutica Ltda. Bula do medicamento. 2. SALSEP®. São Paulo: Libbs Farmacêutica Ltda. Bula do medicamento. 3. MAXIDRATE®. São Paulo: Libbs Farmacêutica Ltda. Bula do Medicamento. 4. TANO, L.; TANO, K. A daily nasal spray with saline prevents symptoms of rhinitis. Acta Otolaryngol., v.124, p.1-4, 2004. 5. MION, O.; MELLO JUNIOR, J.F. O uso das soluções salinas no nariz e seios paranasais. RBM-ORL, v.2, n.3, p.77-83, 2007. 6. JEFFE, J.S. et al. Nasal saline irrigation in children: a study of compliance and tolerance. Int. J. Pediatr. Otorhinolaryngol., v.76, n.3, p.409-13, 2012. 7. HENKIN, R.I. et al. The role of nasal mucus in upper airways function. In: SIH, T.; CLEMENT, P.A.R. Pediatric nasal and sinus disorders: lung biology in health and disease. Flórida: Taylor & Francis, 2005. p. 24. cap. 2. (Book 199). 8. SLAPAK, I. et al. Efficacy of isotonic nasal wash (seawater) in the treatment and prevention of rhinitis in children. Arch. Otolaryngol. Head Neck Surg., v.134, n.1, p.67-74, 2008.9. GUIA DA FARMÁCIA. São Paulo: Contento, v.23, n.283, jun. 2016. (Suplemento Lista de Preços).


Volume 20, Number 4/2016

International Archives of Otorhinolaryngology Editorial

291

Prof. Dr. Aroldo Miniti – A Great Master Ricardo Ferreira Bento

Original Research

294

Influence of Hormonal Changes on Audiologic Examination in Normal Ovarian Cycle Females: An Analytic Study Indri Adriztina, Adlin Adnan, Ichwanul Adenin, Siti Hajar Haryuna, and Sorimuda Sarumpaet

300

Newborn Hearing Screening in a Public Maternity Ward in Curitiba, Brazil: Determining Factors for Not Retesting Idalina Luz, Angela Ribas, Lorena Kozlowski, Mariluci Willig, and Ana Paula Berberian

305

Comparison of Pre-Attentive Auditory Discrimination at Gross and Fine Difference between Auditory Stimuli Himanshu Kumar Sanju, and Prawin Kumar

310

Temporal Resolution and Active Auditory Discrimination Skill in Vocal Musicians Prawin Kumar, Himanshu Kumar Sanju, and J. Nikhil

315

Relationship between Speech Perception and Level of Satisfaction of Hearing Aid Users Erika Barioni Mantello, Carla Dias da Silva, Eduardo Tanaka Massuda, Miguel Angelo Hyppolito, and Ana Cláudia Mirândola Barbosa dos Reis

321

Pitch and Loudness Tinnitus in Individuals with Presbycusis Bruna Macangnin Seimetz, Adriane Ribeiro Teixeira, Leticia Petersen Schmidt Rosito, Leticia Sousa Flores, Carlos Henrique Pappen, and Celso Dall’igna

327

Auditory Temporal Resolution in Individuals with Diabetes Mellitus Type 2 Rajkishor Mishra, Himanshu Kumar Sanju, and Prawin Kumar

331

Workplace Activity in Health Professionals Exposed to Chemotherapy Drugs: An Otoneurological Perspective Natália Martinez Fernandes, Isadora Gonçalves Pelissari, Licia Assunção Cogo, and Valdete Alves Valentins dos Santos Filha

339

The Influence of Tinnitus on the Audiometric Threshold of Sufferers Onyinye Ukaegbe, Basil Ezeanolue, and Foster Orji

344

“Positive to Negative” Dix-Hallpike test and Benign Paroxysmal Positional Vertigo recurrence in elderly undergoing Canalith Repositioning Maneuver and Vestibular Rehabilitation Karyna M. O. B. de Figueiredo Ribeiro, Lidiane Maria de Brito Macedo Ferreira, Raysa Vanessa de Medeiros Freitas, Camila Nicácio da Silva, Nandini Deshpande, and Ricardo Oliveira Guerra

Thieme Publicações Ltda online

www.thieme-connect.com/products


International Archives of Otorhinolaryngology

353

Volume 20, Number 4/2016

Residual Hearing Preservation with the Evo® Cochlear Implant Electrode Array: Preliminary Results Ricardo Ferreira Bento, Fabiana Danieli, Ana Tereza deMatosMagalhães, Dan Gnansia, and Michel Hoen

359

Early and Delayed Effect of Functional Endoscopic Sinus Surgery on Intraocular Pressure Mohammad Waheed El-Anwar, Mohammad Abdelhady, Hazem Saeed Amer, and Manar A. Ghali

364

Granulocyte-Macrophage Colony-Stimulating Factor Production and Tissue Eosinophilia in Chronic Rhinitis Aleksandar Peric, Cveta Spadijer-Mirkovic, Svjetlana Matkovic-Jozin, Ljiljana Jovancevic, and Danilo Vojvodic

370

Curcumin Reduces the Noise-Exposed Cochlear Fibroblasts Apoptosis Tengku Siti Hajar Haryuna, Wibi Riawan, Ardyansyah Nasution, Suprapto Ma’at, Juliandi Harahap, and Indri Adriztina

377

Evaluation of the Effects of Bismuth Subgallate on Wound Healing in Rats. Histological Findings Rafaela Mabile Ferreira dos Santos, Claudia Paraguaçu Pupo Sampaio, Daniela Pache de Moraes, and Rubianne Ligório de Lima

Systematic Reviews

382

Clinical Value of High Mobility Group Box 1 and the Receptor for Advanced Glycation End-products in Head and Neck Cancer: A Systematic Review Austin Nguyen, Sheila Bhavsar, Erinn Riley, Gabriel Caponetti, and Devendra Agrawal

390

Supra-auricular versus Sinusectomy Approaches for Preauricular Sinuses Mohammad Waheed El-Anwar, and Ahmed Shaker ElAassar

394

Treatment and Prognosis of Facial Palsy on Ramsay Hunt Syndrome: Results Based on a Review of the Literature Rafael da Costa Monsanto, Aline Gomes Bittencourt, Natal José Bobato Neto, Silvia Carolina Almeida Beilke, Fabio Tadeu Moura Lorenzetti, and Raquel Salomone

The colored content of this issue is available online at www.thieme.com/iao.

Copyright © 2016 by Thieme Publicações Ltda Inc. International Archives of Otorhinolaryngology is published four times a year in January, April, July, and October by Thieme Publicações Ltda, Argentina Building 16th floor, 228 Praia do Botafogo, Rio de Janeiro 22250-040, Brazil. Editorial comments should be sent to journals@thieme.com. Articles may be submitted to this journal on an open-access basis. For further information, please send an e-mail to openaccess@thieme.com. The content of this journal is available online at www.thieme-connect.com/products. Visit our Web site at www. thieme.com and the direct link to this journal at www.thieme.com/iao.

International Archives of Otorhinolaryngology is listed in PubMed and PubMed Central – PMC, LILACS and LILACS-Express (Latin-American and Caribbean Center on Health Sciencies Information), Latindex (Regional Cooperative Online Information System for Scholarly Journals from Latin America, the Caribbean, Spain and Portugal), DOAJ (Directory of Open Access Journals), FUNPEC-RP (Foundation for Scientific Research of Ribeirão Preto), SciELO (Scientific Electronic Library Online), and Scopus (SciVerse). Thieme Medical Publishers is a member of the CrossRef initiative.

Some of the product names, patents, and registered designs referred to in this publication are in fact registered trade marks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the Publisher that it is in the public domain. All rights, including the rights of publication, distribution, and sales, as well as the right to translation, are reserved. No part of this work covered by the copyrights hereon may be reproduced or copied in any form or by any means— graphic, electronic, or mechanical, including photocopying, recording, taping, or information and retrieval systems—without written permission of the Publisher. Important Note: Medical knowledge is ever-changing. As new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may be required. The authors and editors of the material herein have consulted sources believed to be reliable in their efforts to provide information that is complete and in accord with the standards accepted at the time of publication. However, in view of the possibility of human error by the authors, editors, or publisher of the work herein, or changes in medical

knowledge, neither the authors, editors, or publisher, nor any other party who has been involved in the preparation of this work, warrants that the information contained here in is in every respect accurate or complete, and they are not responsible for any errors or omissions or for the results obtained from use of such information. Because of rapid advances in the medical sciences, independent verification of diagnoses and drug dosages should be made. Readers are encouraged to confirm the information contained herein with other sources. For example, readers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this publication is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this journal does not constitute a guarantee or endorsement of the quality or value of such product or of claims made by its manufacturer.


THIEME

Editorial

Editorial

Prof. Dr. Aroldo Miniti – A Great Master Ricardo Ferreira Bento, MD, PhD1 1 Department of Otorhinolaryngology, Universidade de São Paulo,

School of Medicine, São Paulo, SP, Brazil Int Arch Otorhinolaryngol 2016;20:291–293.

Medicine is truly a unique art and is undoubtedly the synthesis of a triple humanizing and ethical role, translated as personally helping older colleagues perform a therapeutic act and teaching younger ones to do the same. People who know Professor Aroldo (►Fig. 1) will aver that he was the embodiment of that maxim. Born on December 29, 1935, in São Paulo, Brazil, he pursued his studies at the Rio Branco de São Paulo College and graduated as a physician from the USP Faculty of Medicine in 1960, undergoing the Otorhinolaryngology residency training at the HCFMUSP. He defended his doctoral thesis titled “Closure of perforations of the tympanic membrane using dura mater: experimental study in mice,” and applied for the position of Associate

Fig. 1 Prof. Dr. Aroldo Miniti.

Fig. 2 Prof. Miniti attending one of many congresses along side with Prof. Alexandre Medicis da Silveira and Prof. Ricardo Bento.

Address for correspondence DOI http://dx.doi.org/ Ricardo Ferreira Bento, MD, PhD, 10.1055/s-0036-1592419. Otorhinolaryngology, ISSN 1809-9777. Universidade de São Paulo, Av. Dr. Enéas de Carvalho Aguiar 255, sala 6167, São Paulo, SP 05403-000, Brazil (e-mail: rbento@gmail.com).

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil

291


292

Editorial

Fig. 3 Prof. Miniti with Prof. Lamartine Paiva, then Chairman Otorhinolaryngology Department and Clinic assistants.

Professor in 1970.1,2 He did his internship in Chicago, U.S.A., with David Austin, one of the most notable otologists of the time, wherein he developed techniques that he learned from Professor Correia, his mentor in middle ear surgery. The technique of using dura mater was practiced for many years in Brazil. An outstanding ear surgeon, he leaves behind a teaching legacy in HC and in Brazil, after teaching hundreds of surgeons not only the art of medicine but, most importantly, the ethical and moral principles of the profession. He chaired numerous conferences and always participated spiritedly in all events and congresses in Brazil (â–şFig. 2).

A disciplinarian, but with a big heart, Professor Aroldo was revered by the medical residents and assistants and held in high esteem by otorhinolaryngologists from across the country. Despite his generosity, he always imposed strict discipline at the workplace, but strived to ease differences and maintain harmony in the Clinic. He treated everyone equally, from the humblest to the most important, and was generous toward all those seeking his help (â–şFig. 3). Professor Aroldo Miniti was the person who initiated the modernization of the ORL clinic of the FMUSP and of our specialty in Brazil. The unique aspect of this clinic was to

Fig. 4 Prof. Miniti in 2005 with colleagues. From left to right: Domingos Tsuji, Perboyre Sampaio, Aroldo Miniti, Ricardo Bento, Luiz Ubirajara Sennes, Silvio Antonio Marone, Ivan Miziara.

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016


Editorial

Fig. 5 Staff of ENT Department in December 2006.

encourage formation of groups of various specialty areas, which were then expanding, and give them the freedom to perform. This helped create a generation of great names who are today opinion leaders in their fields (►Fig. 4). Having performed the first ear homograft, he would always say that the ORL was once again a pioneer in that it was the first specialty to perform an “organ transplant,” which came into practice only much later in other specialties such as kidney and heart transplants, among others. He said that the Clinical Hospital had built an Institute (INCOR – Heart Institute) for the first heart transplant in Brazil not knowing that the ORL had already performed transplants many years previously! Otorhinolaryngology was experiencing a golden moment with the expansion of its areas of action beyond the classic ear, nose, and throat to sleep medicine, facial plastic surgery, facial nerve diseases, and electrophysiology and modern otoneurology. With these developments, the ORL was no longer treated as the hospital “basement,” looked down upon by other specialties as a “minor” field, and began to gain status. This was a worldwide phenomenon. In the career history book of Dr. William House, one of the main, if not the main, otologists of the 20th century, states that in choosing this specialty, he was criticized by his colleagues and professors who said, “You are doing ORL? It’s a sub-area and its only purpose is to remove tonsils! Choose something else.” There were even unfilled vacancies for ORL residencies in the 1950s. In such a context, Professor Aroldo proved his worth by initiating the development of the sub-areas of the specialty

and, with that, there were many among his assistants who gained experience abroad and later developed their respective groups. Professor Aroldo was one of the founders of the International Archives of Otorhinolaryngology and was part of its Editorial Board for several years. He retired from his academic career in 2006, and I had the privilege and the difficult job of succeeding him; in every decision, until this day, I still think of his teachings (►Fig. 5). Sadly, Professor Aroldo, our dear master, is no longer with us today and his journey has ended. More important than the sadness of this moment is the knowledge that the path he showed us still bears the fruits, wisdom, and teachings of his life. We are glad that he was able to fulfill his mission among us and are certain that wherever he is, he is looking after his friends and disciples who are following his footsteps. Professor Aroldo, thank you for everything! “To teach is to learn twice.”

References 1 Miniti A. Fechamento de perfurações da membrana do tímpano com

dura-máter: estudo experimental em ratos [thesis]. Universidade de São Paulo; São Paulo, Brazil; 1969 2 Miniti A. Estudo das concentrações de doxiciclina e estearato de eritromicina na secreção do seio maxilar de doentes portadores de sinusite maxilar crônica [thesis]. Universidade de São Paulo; São Paulo, Brazil; 1970

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

293


THIEME

294

Original Research

Influence of Hormonal Changes on Audiologic Examination in Normal Ovarian Cycle Females: An Analytic Study Indri Adriztina1

Adlin Adnan1

Ichwanul Adenin2

1 Department of Otorhinolaryngology, Universitas Sumatera Utara,

Medan, North Sumatera, Indonesia 2 Department of Obstetrics and Gynecology, Universitas Sumatera Utara, Medan, North Sumatera, Indonesia 3 Department of Epidemiology training research advocacy and teaching, Universitas Sumatera Utara, Medan, North Sumatra, Indonesia

Siti Hajar Haryuna1

Sorimuda Sarumpaet3

Address for correspondence Indri Adriztina, MD, ENT specialist, Department of Otorhinolaryngology, Universitas Sumatera Utara, jln dr Mansyur no 9, Medan, Sumatera Utara 20155, Indonesia (e-mail: adriztina@yahoo.com).

Int Arch Otorhinolaryngol 2016;20:294–299.

Abstract

Keywords

► ► ► ► ►

menstrual cycle ovulation luteal phase follicular phase DPOAE

Introduction There is only limited information from previous studies that suggest that auditory function may be influenced by hormones. Recent advances in the field have exposed the potential role of hormones in modulating the auditory system. Objective This study aims to investigate the relationship between menstrual cycle and outer hair cell function with audiological examination. Methods This is an analytic study with a cross-sectional design. The sampling was a systematic random sampling. We found 49 women with normal menstrual cycle and collected their data through interviews, physical examination, and examination of the ear, with otoscopic and other routine otorhinolaryngology examinations. We evaluated Tympanometry, distortion-product otoacoustic emissions (DPOAE), and pure tone audiometry. Results We found the audiometric threshold worse in the follicular phase than other phases at 4000 Hz of the right ear, and in the ovulation was found best than any other phases at 1000 Hz of the left ear with significant difference. We found significant difference of DPOAE between ovulation time and follicular phase at 3000 Hz and 1000 Hz in the left ear and between ovulation and luteal phased at 2000 Hz, 3000 Hz and 5000 Hz in the right ear and at 1000 Hz in the left ear with p < 0.05. Conclusion The result of this study showed that only a small part of audiometry threshold had a significant difference between each menstrual phase. In other words, we found no correlation between menstrual and audiometry threshold. Nonetheless, there is a correlation between menstrual cycle phase and DPOAE amplitude.

Introduction Some researchers have proposed that women with hormonal changes may experience alterations in auditory functions, such as in menopause woman, woman with hormonal contraceptive, or even during the ovarian cycle. Previous studies

received August 19, 2015 accepted September 28, 2015 published online October 29, 2015

DOI http://dx.doi.org/ 10.1055/s-0035-1566305. ISSN 1809-9777.

suggest that even the physiological fluctuation in reproductive hormones - estrogen and progesterone - during the ovarian cycle may influence auditory function.1–3 Homeostasis and the biochemical status of inner ear fluid are essential for balance and for hearing. Changes in sodium and water reabsorption that take place during the ovarian cycle may

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil


Influence of Hormonal Changes in Normal Ovarian Cycle Females affect the functioning of this part of the peripheral auditory system, which could in turn affect homeostasis, causing auditory and labyrinthic symptoms.4 The ovarian cycle is divided into three phases: • The follicular phase begins with menstrual bleeding and lasts, on average, 15 days. It is more variable in length than the other phases. Hormone levels are at their lowest point during this phase, especially during the first five days. Then, estrogen levels begin to rise until about day 13 to 14, when ovulation occurs. • The ovulatory phase lasts about three days, culminating in ovulation, with the release of an ovule. Estrogen reaches its peak level just before ovulation. Several studies found the estrogen receptor α (ERα) and β estrogen β (ERβ) in the adult human cochlea (ERα in the spiral ganglion, and ERβ in the stria vascularis) and animal models with immunohistochemistry. • The luteal phase lasts 14 days and ends with the beginning of menstruation, when a new cycle begins. It does not vary much from month to month. In this phase, blood supply to the endometrium continues to increase due to the rising level of progesterone produced by the corpus luteum of the ovary, reaching its highest level around day 7, after ovulation. Progesterone levels peak in the luteal phase as LH/FSH levels decrease even further. High progesterone may increase sodium, chloride, and water reabsorption. Changes in sodium and water reabsorption that take place during the ovarian cycle may affect the function of this part of peripheral auditory system. Most of the changes in women take place in the luteal phase; these changes include fluid retention, weight gain, increased energy demands, changes in glucose uptake, a slower gastrointestinal transit time, and hydrops of the labyrinth (due to sodium retention and the resulting endolymph hypertension).4–10 Previous studies have reported on changes in auditory function during the ovarian cycle, focusing on various aspects such as auditory threshold and otoacoustic emission. Nonetheless, there has not been a reliable solution. The aim of this research is to investigate the influence of hormonal variation during the ovarian cycle on auditory threshold and outer hair cell function through the audiometry and distortion product otoacoustic emission (DPOAE) test and the correlation between both examinations, based on a relatively larger sample size.3,4,11–15

Material and Methods Subjects This is an analytic study with a cross-sectional design. We recruited forty-nine patients of reproductive age (20 to 40 years old) by systematic random sampling from the entire population of residents at Adam Malik General Hospital in North Sumatera, Indonesia, with an interval of 10. The Health Research Ethical Committee granted approval for the study. All women reported a regular menstrual cycle ranging between 24 and 35 days. We documented positive LH surge

Adriztina et al.

using a commercial ovulatory kit in all women three months prior to the research, indicating they all had a normal ovulatory cycle. None of the women had been taking hormonal contraceptive or other drug treatment that could alter their auditory function (such as Cisplatin, aminoglycoside, hemodialysis). They had no history of endocrine pathology, hypertension, or otological conditions. All women had normal otoscopy, normal hearing and middle ear function, assessed by pure tone audiometry and tympanometry.

Clinical Protocol The subjects underwent tests three times during one ovarian cycle, as follows: • Follicular phase: Third day after menstruation, indicating the estrogen and progesterone are in the lowest level. • Ovulation phase: After the ovulation times tested with the ovulatory kit, indicating the estrogen at a high level. • Luteal phase: Seventh day after the ovulation, indicating the progesterone at a high level. During each test session, the subjects underwent auditory tests including audiometry, tympanometry, and DPOAE. All auditory tests were held at the same time of the day for each subject, to control for the influence of physiological circadian variation.

Material The same audiologist performed each test. For pure tone audiometry, to assess the hearing threshold, the audiologist used Audio Traveler AA222 (Interacoustics, Denmark). The tone pulses were 1–2 seconds in duration to avoid adaptation with ascending sound technique, according to the recommendation from the American Speech-language Hearing Association.16 The tests were at the frequencies of 250 Hz, 500 Hz, 1000 Hz, 2000 Hz, 4000 Hz, and 8000 Hz. We excluded patients with conductive hearing loss. The patients underwent tympanometry to determine the function of middle ear. Using 226-Hz probe tone, the middle ear pressure had to be between 100 Pa and þ50 Pa. The peak value of compliance was in the range between 0.3 and 1.6 cm3. This indicated good tympanic membrane mobility and normal middle ear pressure, enabling a valid otoacoustic emission recording. For the test, we used the Audio Traveler AA222 tympanometer (Interacoustics, Denmark). As for the DPOAE, to assess outer hair cell of the cochlea function, the examiner recorded DPOAE via an ear canal probe inserted into the ear canal. The examination was done at the frequencies of 1000 Hz, 2000 Hz, 3000 Hz, 4000 Hz, and 5000 Hz. Signal-to-noise ratio had to be 3 dB or higher at each frequency. The device used in this test was the Elios (Echodia, France).

Statistical Analysis We analyzed all of the data with SPSS (Statistical Package for the Social Science), adopting a 0.05 significance level for statistical purposes. Using the paired sample t-test, we observed the effect of the menstrual cycle phase on OAE and audiometry. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

295


296

Influence of Hormonal Changes in Normal Ovarian Cycle Females

Result The sample consisted of 49 women of reproductive age. Patientś ages ranged from 24 to 36 years, with a mean of 27.35 years. We found a bigger sample size in the age group of 20–30 years old (85.7%) than in the age group of 31–40 years (14.3%).

Pure Tone Audiometry The difference between pure tone audiometry threshold of follicular and ovulation phase was found significant at 1000 Hz on the left ear (p ¼ 0.005) and at 4000 Hz on the right ear (p ¼ 0.008), as shown in ►Table 1. We also found a significant difference between pure tone audiometry threshold of ovulation and luteal phase at 1000 Hz (p ¼ 0.003) on the left ear, as shown in ►Table 2, and between follicular and luteal phase at 4000 Hz (p ¼ 0.013) on the right ear, as shown in ►Table 3. Based on this result, we found that right ear pure-tone audiometry at the frequency of 4000 Hz in the follicular phase presents the worst hearing threshold (9.08 dB), in comparison with the ovulation period (7.35 dB) and luteal phase (7.00 dB). Although the hearing threshold was in the normal range, we found significant differences (p < 0.05) between follicular phases and between other phases at the frequency of 4000 Hz, showing a slight fluctuation of the hearing function. Furthermore, left ear pure-tone audiometry at the frequency

Adriztina et al.

of 1000 Hz produced the best results (16.33 dB), in comparison with the follicular phase (18.67 dB), and luteal phase (18.57 dB), with significant differences (p < 0.005).

DPOAE A significant difference was found between DPOAE amplitudes of the follicular phase and ovulation, at 1000 Hz (p ¼ 0.022) and 3000 Hz (p ¼ 0.000) on the left ear, as shown in ►Table 4. Between the DPOAE amplitudes of ovulation and luteal phase, there were several significantly different frequencies found, including 2000 Hz, 3000 Hz, and 5000 Hz in the right ear (p < 0.05) and 1000 Hz, 2000 Hz, and 3000 Hz at the left ear (p < 0.05), as shown in ►Table 5. We found no significant differences between DPOAE amplitudes of follicular phase and luteal phase, as shown in ►Table 6.

Discussion Several hormones have been known to modulate auditory function. Many studies have found that several different hormone receptors are located in the mammalian cochlea. This condition may cause alteration of auditory function in patient who suffer hormone deficiency, hormone hypersecretion or patient that have hormonal replacement therapy.17–20 Interestingly, alteration in auditory function also occurs during physiological changes such as the ovarian cycle. Previous data found different hearing sensitivity levels in

Table 1 Pure-tone audiometry analysis results, considering mean hearing threshold at each frequency and comparison between the follicular phase and ovulation for each ear Frequency

Right ear (dB)

Left ear (dB)

Follicular Phase

Ovulation

p-value

Follicular Phase

Ovulation

p-value

250 Hz

19.90

19.08

0.315

19.59

19.39

0.808

500 Hz

19.90

19.29

0.518

19.29

18.57

0.376

1000 Hz

18.00

18.39

0.593

18.67

16.33

0.005

2000 Hz

11.12

11.22

0.898

11.63

10.00

0.051

4000 Hz

9.08

7.35

0.008

7.55

7.45

0.908

8000 Hz

4.59

4.29

0.764

6.22

4.59

0.125

Table 2 Pure-tone audiometry analysis results, considering mean hearing threshold at each frequency and comparison between ovulation and luteal phase for each ear Frequency

Right ear (dB)

Left ear (dB)

Ovulation

Luteal Phase

p-value

Ovulation

Luteal Phase

p-value

250 Hz

19.08

18.47

0.508

19.39

18.00

0.521

500 Hz

19.29

19.49

0.808

18.57

18.88

0.700

1000 Hz

18.39

17.14

0.114

16.33

18.57

0.003

2000 Hz

11.22

10.10

0.140

10.00

10.51

0.390

4000 Hz

7.35

7.00

0.625

7.45

7.14

0.679

8000 Hz

4.29

5.82

0.104

4.59

5.71

0.242

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016


Influence of Hormonal Changes in Normal Ovarian Cycle Females

Adriztina et al.

Table 3 Pure-tone audiometry analysis results, considering mean hearing threshold at each frequency and comparison between follicular and luteal phases for each ear Frequency

Right ear (dB)

Left ear (dB)

Follicular Phase

Luteal Phase

p-value

Follicular Phase

Luteal Phase

p-value

250 Hz

19.90

18.47

0.142

19.59

18.00

0.442

500 Hz

19.90

19.49

0.667

19.29

18.88

0.633

1000 Hz

18.00

17.14

0.052

18.67

18.57

0.904

2000 Hz

11.12

10.10

0.207

11.63

10.51

0.154

4000 Hz

9.08

7.00

0.013

7.55

7.14

0.622

8000 Hz

4.59

5.82

0.248

6.22

5.71

0.694

Table 4 DPOAE analysis, considering mean amplitudes at each frequency and comparison between follicular phase and ovulation for each ear Frequency

Right ear (dB)

Left ear (dB)

Follicular Phase

Ovulation

p-value

Follicular Phase

Ovulation

p-value

1000 Hz

4.55

5.35

0.181

5.02

6.61

0.022

2000 Hz

7.27

7.96

0.170

6.33

7.51

0.060

3000 Hz

2.78

4.22

0.070

2.22

5.67

0.000

4000 Hz

4.59

4.20

0.690

5.08

6.57

0.263

5000 Hz

5.14

7.14

0.063

5.82

7.02

0.218

Table 5 DPOAE analysis, considering mean amplitudes at each frequency and comparison between ovulation and luteal phase for each ear Frequency

Right ear (dB)

Right ear (dB)

Ovulation

Luteal Phase

p-value

Ovulation

Luteal Phase

p-value

1000 Hz

5.35

4.55

0.295

6.61

5.18

0.013

2000 Hz

7.96

6.29

0.003

7.51

5.69

0.005

3000 Hz

4.22

2.16

0.003

5.67

3.71

0.014

4000 Hz

4.20

3.47

0.417

6.57

4.67

0.064

5000 Hz

7.14

5.29

0.034

7.02

5.53

0.113

Table 6 DPOAE analysis, considering mean amplitudes at each frequency and comparison between follicular phase and luteal phase for each ear Frequency

Right ear (dB)

Left ear (dB)

Follicular Phase

Luteal Phase

p-value

Follicular Phase

Luteal Phase

p-value

1000 Hz

4.55

4.55

1.000

5.02

5.18

0.782

2000 Hz

7.27

6.29

0.167

6.33

5.69

0.260

3000 Hz

2.78

2.16

0.445

2.22

3.71

0.112

4000 Hz

4.59

3.47

0.249

5.08

4.67

0.713

5000 Hz

5.14

5.29

0.872

5.82

5.53

0.726

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

297


298

Influence of Hormonal Changes in Normal Ovarian Cycle Females each phase of the ovarian cycle with various parameters, from peripheral to the central auditory system.3,14,21–24 It also has been reported that sensorineural deafness in high frequency can occur with the onset of menstruation.15 We found that hearing threshold at the frequency of 4000 Hz of the right ear in the follicular phase was worse than in ovulation and luteal phase. Whereas, hearing threshold at ovulation at the frequency of 1000 Hz of the left ear was better than in the follicular and luteal phases. At follicular phase, we know that estrogen level is at the lowest point. The condition seemed to cause the alteration in auditory function. Previous studies showed a worsening of hearing threshold in the follicular phase or in the early days of menstruation. Conversely, estrogen during ovulation is high, which may cause a better hearing threshold. Swanson and Dengerink found better hearing thresholds during ovulation at the frequency of 4000 Hz.12,14 Previous studies have found estrogen receptors in the cochlea by immunohistochemistry. In a study on animals, if severe progressive hearing loss occurred in the inner ear ERβ knock-out mice. These receptors maintain fluid and electrolyte balance in cochlea. This condition could cause alteration in fluid and electrolyte balance, leading to a disturbance of estrogen level that results in auditory alteration.17,25–27 In this study, we found that only limited frequencies were disturbed by the hormone fluctuation in ovarian cycle. This shows that the ovarian cycle generally does not influence hearing function. In this research, we also conducted DPOAE examination to evaluate cochlear function. Otoacoustic emissions (OAE) are sounds that arise in the ear canal when the tympanum receives vibration transmitted backward through the middle ear from the cochlea. Distortion product otoacoustic emissions (DPOAE), detected using two stimulus tones from the ear canal, and non-linear intermodulation between the two stimuli, generate several new acoustic frequency components inside the healthy cochlea, which can travel to the ear canal. Therefore, DPOAE can detect abnormalities of the cochlear function.28 We found a significant difference between DPOAE amplitudes during ovulation time and the follicular phase at the frequencies of 1000 Hz and 3000 Hz in the left ear (p < 0.05). We also found significant differences between ovulation time and the luteal phase at the frequencies of 2000 Hz, 3000 Hz, and 5000 Hz in the right ear, and 1000 Hz, 2000 Hz, and 3000 Hz in the left ear. Our study was similar to Al-Mana’s, which found a significant different between OAE amplitude of early follicular phase and the luteal phase, both early and late.3 The result of DPOAE examination was the representation of well-integrated outer hair cells in the cochlea. There were higher DPOAE amplitudes during ovulation in comparison to any other phase. This may be a result of a higher estrogen level at ovulation time, which has a positive effect on auditory function. Estrogen, aside from maintaining the balance of fluid and electrolytes in the cochlea, facilitates auditory information by enhancing glutamatergic neurotransmission, playing a role in neuroprotection. In a recent study, Wang and colleagues reported that estrogen has a protective effect International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Adriztina et al.

against noise exposure. Studies have found that estrogen relates to caspase-3 intensity. Caspase-3 are pro-apoptotic agents which become a precursor to the hair cell apoptotic process in the cochlea upon noise exposure.3,4,13,29 We found no significant difference of DPOAE amplitude in the luteal phase in comparison to the follicular phase. In the luteal phase, we know that progesterone is at a high level; whereas in the follicular phase, both estrogen and progesterone are low. This fact showed that physiological changes in progesterone did not affect auditory function. Previous research reports that progesterone replacement therapy has a detrimental effect on hearing function, as unnatural levels of progesterone could be detrimental to hearing in females. However, our findings show that the fluctuation of progesterone level in normal ranges has no effect on auditory function.18,30,31

Conclusion Pure tone audiometry is an examination to evaluate hearing function in general, while DPOAE is a test for evaluating integration of outer hair cell of the cochlea. The result of this study showed that only a small part of audiometry threshold had a significant difference between each phase of ovarian cycle; whereas the DPOAE product shows statistically significant differences at several frequencies between the phases. In other words, we found no correlation between menstrual and auditory threshold. There is, however, a correlation between phases of ovarian cycle and outer hair cell function.

References 1 Hederstierna C, Hultcrantz M, Collins A, Rosenhall U. Hearing in

2

3

4 5 6

7

8

9

10

women at menopause. Prevalence of hearing loss, audiometric configuration and relation to hormone replacement therapy. Acta Otolaryngol 2007;127(2):149–155 10.1080/00016480600794446 Mitre EI, Figueira AS, Rocha AB, Alves SMC. Audiometric and vestibular evaluation in women using the hormonal contraceptive method. Braz J Otorhinolaryngol 2006;72(3):350–354 Al-Mana D, Ceranic B, Djahanbakhch O, Luxon LM. Alteration in auditory function during the ovarian cycle. Hear Res 2010;268; (1–2):114–122 Arruda PO, Silva IMC. Study of otoacoustic emissions during the female hormonal cycle. Braz J Otorhinolaryngol 2008;74(1):106–111 Ishii C, Nishino LK, Campos CAH. Vestibular characterization in the menstrual cycle. Braz J Otorhinolaryngol 2009;75(3):375–380 Mtawalli G, Pina M. Angle, Murphy C. The menstrual cycle and its relation to contraceptive methods: a reference for reproductive health trainers. INTRAH. University of North Caroline; 1997:14 Farage MA, Neill S, MacLean AB. Physiological changes associated with the menstrual cycle: a review. Obstet Gynecol Surv 2009; 64(1):58–72 10.1097/OGX.0b013e3181932a37 Poromaa IS, Gingnell M. Menstrual cycle influence on cognitive function and emotion processing – from a reproductive perspective. Front Neurosci 2014;8:1–16 10.3389/fnins.2014.00380 Stenberg AE, Wang H, Fish J III, Schrott-Fischer A, Sahlin L, Hultcrantz M. Estrogen receptors in the normal adult and developing human inner ear and in Turner’s syndrome. Hear Res 2001; 157(1–2):87–92 Charitidi K, Meltser I, Canlon B. Estradiol treatment and hormonal fluctuations during the estrous cycle modulate the expression of


Influence of Hormonal Changes in Normal Ovarian Cycle Females

11 12 13

14

15

16

17

18

19 20

estrogen receptors in the auditory system and the prepulse inhibition of acoustic startle response. Endocrinology 2012; 153(9):4412–4421 Yellin MW, Stillman RD. Otoacoustic emissions in normal-cycling females. J Am Acad Audiol 1999;10(7):400–408 Cox JR. Hormonal influence on auditory function. Ear Hear 1980; 1(4):219–222 Gurbuzler L, Yelken K, Aladag I, Eyibilen A, Koc S. Comparison of transient and distortion-product otoacoustic emissions during the luteal and follicular phases of the menstrual cycle. Ear Nose Throat J 2012;91(8):322–334 Swanson SJ, Dengerink HA. Changes in puretone threshold and temporary shifts as a function of menstrual cycle and oral contraceptive. J Speech Hear Res 1988;31(4):569–574 Souaid JP, Rappaport JM. Fluctuating sensorineural hearing loss associated with the menstrual cycle. J Otolaryngol 2001;30(4): 246–250 American Speech-Language Hearig Association. Guidelines for Manual Pure-Tone Threshold Audiometry [Guidelines]. 2005. Available at: www.asha.org/policy. Accesed 15 Jan 2012 Al-Mana D, Ceranic B, Djahanbakhch O, Luxon LM. Hormones and the auditory system: a review of physiology and pathophysiology. Neuroscience 2008;153(4):881–900 Price K, Zhu X, Guimaraes PF, Vasilyeva ON, Frisina RD. Hormone replacement therapy diminishes hearing in peri-menopausal mice. Hear Res 2009;252(1–2):29–36 Malik V, Shukla GK, Bhatia N. Hearing profile in hypothyroidism. Ind J Otolaryngol Head Neck Surg 2002;54(4):285–290 Kucur C, Kucur SK, Gozukara I, et al. Extended high frequency audiometry in polycystic ovary syndrome. Scientific World Journal 2013;2013:482689

Adriztina et al.

21 Walpurger V, Pietrowsky R, Kirschbaum C, Wolf OT. Effects of the

22

23

24

25 26

27

28 29

30 31

menstrual cycle on auditory event-related potentials. Horm Behav 2004;46(5):600–606 Serra A, Maiolino L, Agnello C, Messina A, Caruso S. Auditory brain stem response throughout the menstrual cycle. Ann Otol Rhinol Laryngol 2003;112(6):549–553 Yadav A, Tandon OP, Vaney N. Auditory evoked responses during different phases of menstrual cycle. Indian J Physiol Pharmacol 2002;46(4):449–456 Mann N, Sidhu RS, Babbar R. Brainstem auditory evoked responses in different phases of menstrual cycle. J Clin Diagn Res 2012;6(10): 1640–1643 Simonoska RSex steroid hormone receptors: Inner Ear Hearing, Karolinska Insitute, Stockholm, 2009:31 Hultcrantz M, Simonoska R, Stenberg AE. Estrogen and hearing: a summary of recent investigations. Acta Otolaryngol 2006;126(1): 10–14 Nolan LS, Maier H, Hermans-Borgmeyer I, et al. Estrogen-related receptor gamma and hearing function: evidence of a role in humans and mice. Neurobiol Aging 2013;2077:1–9 Kemp DT. Otoacoustic emissions, their origin in cochlear function, and use. Br Med Bull 2002;63:223–241 Wang H, Wu W, Han H, Li B, Wang G, Yu M. Estrogen reduces caspase-3 expression in the inner ear of guinea pigs exposed to stimulated microgravity and inboard noises of spaceship. Int Adv Otol 2014;10(10):25–29 10.5152/lao.2014.005 Frisina RD. Hormones and hearing: too much or too little of good thing can be ototoxic. Semin Hear 2012;33(3):231–241 Guimaraes P, Frisina ST, Mapes F, Tadros SF, Frisina DR, Frisina RD. Progestin negatively affects hearing in aged women. Proc Natl Acad Sci U S A 2006;103(38):14246–14249

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

299


THIEME

300

Original Research

Newborn Hearing Screening in a Public Maternity Ward in Curitiba, Brazil: Determining Factors for Not Retesting Idalina Luz1

Angela Ribas2

Lorena Kozlowski2

Mariluci Willig3

1 Phonoaudiology, Universidade Tuiuti do Paraná, Curitiba,

Paraná, Brazil 2 Master’s and Doctoral Program in Communication Disorders, Universidade Tuiuti do Paraná, Curitiba, PR, Brazil 3 Nursing, Hospital de Clínicas do Paraná, Curitiba, Paraná, Brazil

Ana Paula Berberian2

Address for correspondence Angela Ribas, PhD, Universidade Tuiuti do Paraná - Programa de Mestrado e Doutorado em Distúrbios da Comunicação, Universdidade Tuiuti do Paraná, Rua Jose Isidoro Biazetto 845, Curitiba, PR 81200240, Brazil (e-mail: angela.ribas@utp.br).

Int Arch Otorhinolaryngol 2016;20:300–304.

Abstract

Keywords

► hearing ► deafness ► speech-language pathology ► pediatric nursing

Introduction Law 12.303/10 requires hearing screening in newborns before hospital discharge to detect possible hearing problems within the first three months after birth. If the newborn fails the test or presents signs of risk for hearing loss, it must undergo a retest and monitoring during the first year of life. In practice, this often does not happen. Objective To identify, in a group of mothers of children with risk factors for hearing loss, the determining reasons for non-compliance with the auditory retest. Method This is a cross-sectional quantitative study. For data collection, we handed a semi-structured questionnaire to 60 mothers of babies at risk for hearing loss who did not attend the hearing retest after hospital discharge. The questionnaire investigated their age, education, marital status, level of knowledge about the hearing screening, and reasons for non-compliance with the retest. We compared and analyzed data using the Chi-square test at a significance level of 0.05%. Results Our study found that 63% of the respondents were unaware of the hearing screening and most did not receive guidance on testing during prenatal care; 30% of participants stated forgetting as the reason for not attending the retest. There was no significant relationship between age, education, and marital status regarding knowledge about the test and the non-compliance with the retest. Conclusion Identified as the most significant determining factors for non-compliance with the newborn hearing screening retest were the surveyed mothers’ forgetting the date, and their ignorance as to the importance of retesting.

Introduction It is a global consensus that hearing loss of early childhood onset negatively impacts the child’s development.1,2 Early diagnosis of hearing loss allows phonoaudiologists to take educational and clinical measures to minimize the effects of such loss.1,3 A speech-language therapy referral geared to the specific needs of the child, such as hearing rehabilitation through

received April 10, 2015 accepted September 6, 2015 published online November 16, 2015

DOI http://dx.doi.org/ 10.1055/s-0035-1567866. ISSN 1809-9777.

electronic devices, as well as to the development of oral, written, or sign language may promote more effective participation of these children in different social contexts (such as with family, at school, at work and in the community at large) when performed in early childhood.4 In 2010, the Brazilian government approved Federal Law number 12.303, which mandates Newborn Hearing Screening (NHS) in newborns before hospital discharge, to ensure effective access to hearing health programs.

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil


Newborn Hearing Screening in a Public Maternity Ward in Brazil: Determining Factors for Not Retesting Nonetheless, it is worth noting that when the NHS results present inconsistencies, babies should be re-evaluated (retested).5 Given that deafness incidence is higher in children with risk factors, according to the recommendations of the Joint Committee of Infant Hearing (JCIH), audiological monitoring is essential for all at-risk infants presenting high-risk indicators for hearing loss (HRIHL), starting with NHS. This also applies to infants at risk of neural conduction disorders and/ or dysfunction of the auditory pathway in the brainstem, other hearing disorders, and/ or delayed development of speech and language.3 Currently, it is up to the speech-language therapist who performs the NHS to guide the family towards retesting, thereby ensuring accurate and early diagnosis of deafness and allowing full treatment to the child. Despite all the progress already achieved in the field, Brazilian studies show that the retesting compliance rate is low, which undermines the effectiveness of NHS programs.2,6–10 In this regard, we emphasize the need to implement actions developed by multidisciplinary teams that aim to sensitize the baby’s mother and other relatives to the importance of following up the NHS with a retest. In this context, it is worth noting the relevance of actions undertaken by speech-language therapists and nurses, both being directly involved with the postpartum period. It is especially important that nurses work directly with those under their care, spending significant time in contact with patients hospitalized due to illness or childbirth.11 According to COREN,12 nurses, as educators and professionals who work directly in maternal and child health, can contribute to raising awareness and guiding the people involved in processes where health monitoring occurs. Considering the above, the present study aims to identify and analyze determining reasons for non-compliance with the auditory retest, according to a group of mothers of children with risk factors for hearing loss.

Materials and Methods The Human Research Ethics Committee from the authors’ institution approved this study, under registration number 830071, according to resolution 466/2012. This is a quantitative cross-sectional study conducted in a public maternity hospital in Curitiba, in the state of Paraná, during the sample period from July to December 2013. The research sample consisted of 60 mothers of newborns with HRIHL who did not attend the hearing retest appointment. All newborns in this sample should have had audiological monitoring for one year based on risk indicators. The inclusion criteria of the mothers in the study were being over the age of 18 years, having babies born between July and December 2013, having not attended the NHS retest, agreeing to participate in the study, and signing the consent form. Excluded from the study were mothers under 18 years of age and those who were not able to understand the proposed questionnaire.

Luz et al.

It is routine in the women and newborn healthcare unit of Curitiba to actively search for mothers who do not follow the regulations established for monitoring at-risk infants. Thus, mothers who composed the sample for this study received a phone call reminding them to return to the Unit to perform various procedures, including the auditory retest. On the day set for the evaluation, after receiving guidance on the purpose of the research and its protocols, the interviewer invited the mothers to participate in the study. Next, the mothers answered a semi-structured questionnaire that collected data on their age profile, marital status, educational level, knowledge of NHS, and reasons for noncompliance with the retest. The level of knowledge about NHS and the reasons for noncompliance were cross-referenced with some variables: mother’s age, education level, and marital status. Then, the answers were subjected to a statistical Chi-square test for a level of significance with p values < 0.05, which were considered statistically significant.

Results The maternity ward where this study was developed is a leader in the city of Curitiba in caring for high-risk pregnancies. Between the months of July and December 2013, the period for data collection, 733 babies were born in this hospital, all with some HRIHL. Before hospital discharge, all infants underwent a hearing screening and were expected to return for retesting within 15 days. According to the hospital data, 89% of the babies returned for retesting. Of the 82 (11%) mothers who did not return with their infants, 60 were selected for the study as they fell within the listed inclusion criteria. ►Table 1 shows the socio-demographic characteristics of the sample. Regarding the level of mothers’ knowledge regarding NHS, we observed that: 38 (63%) mothers did not know about the infant hearing test or NHS; 100% of the sample believed their child could hear well; 17% had a close relative with hearing loss and knew its harmful effects; 90% reported that they did not receive information on NHS during the prenatal period; 90% knew that their infant had undergone NHS before hospital discharge. but only 38% reported knowing the test result; 62% of mothers did not know who the health professional was who performed the examination on the child; 91% of mothers received guidance on doing the hearing retest, but 90% did not know why it should be done. Considering that none of the interviewed mothers took their infants to the hearing retest, we investigated the reasons for non-compliance. ►Table 2 lists the most frequent responses. The majority of the sample reported not knowing what the infant hearing test was (63%) and most of the sample forgot about the retest or claimed to have forgotten the date (50%). Thus, we analyzed the relationship between maternal age, education level, and marital status as variables. We applied the Chi-square test and ►Tables 3, 4, and 5 describe the results. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

301


302

Newborn Hearing Screening in a Public Maternity Ward in Brazil: Determining Factors for Not Retesting Table 1 Description of sample according to age, education level, and marital status (N ¼ 60) Variable

Frequency

%

Age Under 20 years

7

11.67

20 to 29

25

4.67

30 to 39

21

35.00

40 years older

7

11.67

Primary incomplete

13

21.67

Primary

18

30.00

High School

28

46.67

College

1

1.67

Single

37

61.67

Married

18

30.00

Divorced

4

6.67

Widowed

1

1.67

Education level

Marital status

Table 2 Reasons for non-compliance with NHS retest (N ¼ 60) Variable

Frequency

%

Forgot appointment

18

30.0

Did not know

12

20.0

Mother’s health problems

05

8.3

Health unit on strike

04

6.6

No one to accompany them

04

6.6

Family health problems

03

5.0

Transportation problems

03

5.0

Too much information upon discharge

02

3.3

Bad weather

02

3.3

Scheduling conflict

02

3.3

Death in the family

01

1.6

Could not miss work

01

1.6

Lack of time

01

1.6

Personal issues

01

1.6

Baby’s health problems

01

1.6

Total

60

100

Abbreviations: NHS, newborn hearing screening.

Discussion The NHS program aims at early detection of hearing loss in children and directing toward appropriate treatment to minimize the effects of deafness. Thus, to achieve satisfactory results, it is essential to have the families’ adhesion.8 International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Luz et al.

During the period for the data collection for the study, 733 babies with HRIHL were born in the maternity ward and 89% returned for retesting at the scheduled date, which is considered high when compared with similar studies.8,13,14 The predominant age distribution of the sample was 20–39 years old, however 23% of mothers were outside of this range (older than 39 or younger than 20). Pregnancies at the extremes of reproductive life of women have higher risk of adverse outcomes and complications during pregnancy and childbirth, as well as during the neonatal period.15 Regarding level of education, most mothers (51.67%) had only a primary level of education. One study that researched the reasons for non-attendance of the retest by mothers and their newborns showed a series of reasons, among which was low parental education levels as one of the key factors that limited the mothers’ understanding of the importance of NHS.16 With regard to marital status, 70% of the sample at the time of hospital discharge did not live with a spouse. In one study,10 authors examined the marital status of mothers in a database of 27,817 live births at a maternity ward, and they concluded that the probability of retest non-compliance for single mothers was 1.4 times higher than those who lived with a spouse. On matters relating to knowledge about NHS, the number of mothers who did not know about the procedure was considered high – a fact confirmed in other research,15 where only 34% of mothers reported knowing about NHS during pregnancy, from a total of 1022 mothers surveyed. In our study’s sample, 17% of mothers reported having someone in the family with hearing loss, and yet the mothers still did not return for the hearing retest. Among the possible reasons for such a result, is that a mother’s fear of obtaining confirmation of her child’s hearing problem in the retest, considering the possibility of such loss to be hereditary. It is worth noting that studies8 point to the recurrence of resistant attitudes as part of a process of denial, and only later will come acceptance of the fact that the child has organic and/ or sensory impairment. Despite the high rate of ignorance, 90% of mothers reported knowing that their child had undergone a hearing test before hospital discharge. However, over 60% were unable to provide the test results. The distribution of educational material can act not only to help mothers recognize the test’s importance, but also to arouse greater interest in parents about the hearing health of their children.10 In addition to informative actions such as orientation with health service policies, the need for actions focused on health education is emphasized. These actions should be developed by professional teams aimed at encompassing the different aspects and dimensions involved in health and disease. In this sense, the work of nurses is important. It is important to note that 62% of respondents did not know who the professional was that performed the NHS on their baby. It is necessary that health professionals promote dialogical relations to listen and engage the mothers, so that it is possible to exchange knowledge and empower the patient. This is one of the conditions needed for the mother to assume


Newborn Hearing Screening in a Public Maternity Ward in Brazil: Determining Factors for Not Retesting

Luz et al.

Table 3 Knowledge about NHS and reasons for non-compliance in relation to mother’s age Variable

Answer

p

Age (years) < 20

20–29

30–39

 40

Do you know what the NHS is?

yes

3

9

8

2

0.8861

Did you forget the retest appointment?

yes

4

4

8

2

0.2326

Were you unaware of the retest?

yes

1

5

4

2

0.3651

Abbreviations: NHS, newborn hearing screening.

Table 4 Knowledge about NHS and reasons for non-compliance in relation to mother’s marital status Variable

Answer

p

Marital Status Single

Married

Divorced

Widowed

Do you know what the NHS is?

yes

16

3

3

0

0.1800

Did you forget the retest appointment?

yes

11

5

1

1

0.1573

Were you unaware of the retest?

yes

7

5

0

0

0.2499

Abbreviations: NHS, newborn hearing screening.

Table 5 Knowledge about NHS and reasons for non-compliance in relation to mother’s education level Variable

Answer

p

Education Level Primary Incomplete

Primary Complete

High School Incomplete

High School Complete

Do you know what the NHS is?

yes

6

6

1

9

0.2581

Did you forget the retest appointment?

yes

6

4

0

7

0.2993

Were you unaware of the retest?

yes

3

4

0

5

0.7953

Abbreviations: NHS, newborn hearing screening.

the responsibility for their child’s health care and act in a more constructive manner with respect to it. When asked about the reason that led them to fail to return for the hearing retest, 30% reported having forgotten and 20% said they had no knowledge of it. Researchers in another study7 with similar data indicated that these attitudes are directly related to the absence of appropriate guidance given to mothers and caregivers, and to awareness of the damage that hearing loss can cause children. The available literature9,13,14 explains that an increase in compliance depends on some strategies that encourage greater participation in the Program. Among these strategies, is health care professionals working to guide mothers and parents of newborns, as well as monitoring the families of babies that failed the NHS. Ignorance over the need for retesting, as pointed out in this survey, is mirrored in publications on the topic.8,9,13 According to the authors, there is a contradiction between what health professionals say they tell mothers about the NHS, and what

mothers report hearing from the professionals. While the multidisciplinary team reported knowing about the importance of early detection of hearing impairment and advising mothers about NHS, most mothers claimed they had not received any information during their pregnancy or during their stay in the maternity ward. The authors understand the difficulty may be that mothers receive a lot of new information about examinations and their newborns, and they are not always able to assimilate this information because mothers perceive only what they can understand. This study could not establish a significant relationship between a mother’s age, education level, and marital status and the level of knowledge about the NHS or on the reasons for non-compliance to the hearing retest, although other studies affirm a relation between retest non-compliance and marital status10 and socio-cultural level8 of the mother and family. In this sense, retest non-compliance, despite recommendations given as to its importance, reflects the lack of awareness among the population about the need to monitor International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

303


304

Newborn Hearing Screening in a Public Maternity Ward in Brazil: Determining Factors for Not Retesting child development for hearing loss prevention. We believe that the support of the interdisciplinary team is essential for targeting educational development and guidance for this population, especially from the nurse who spends more time at mothers’ bedsides in maternity wards. An American study in a maternity ward with more than 50% absenteeism in NHS follow-up17 used a nurse at the bedside to perform targeted educational intervention for mothers whose babies failed their NHS. They found a significant improvement in the number of mothers who joined the program and concluded that the nurse is one of the health professionals who can contribute to and actively participate in hearing health projects in maternity wards. It is important to analyze the concept of retest compliance in a multidisciplinary way, for although mothers are the main target of the compliance process, success depends not only on them, but also on various participants, such as family, health professionals, and the health system itself, which must be integrated. By relying on technical-scientific and popular knowledge and a professional dialogue, users can build knowledge and health education in an integrated way, which covers health-disease and care to strengthen confidence in the services received and provided.

Conclusions

4

5

6

7

8

9

10

11

12

The most significant determining factors for non-compliance to NHS retesting identified among the surveyed mothers were forgetting the date and ignorance of the importance of the retest. The level of ignorance about NHS was high in the studied sample. Our research found no correlation between mother’s age, education level, and marital status with knowledge of the NHS and reasons for non-adherence to retest.

13

References

15

14

1 Gaffney M, Green DR, Gaffney C. Newborn hearing screening and

follow-up: are children receiving recommended services? Public Health Rep 2010;125(2):199–207 2 Lima MCMP, Marba ST, Santos MFC, Lima GML, Rossi TRF, Françozo MFC. Detecção de perdas auditivas em neonatos de um hospital público. Rev Soc Bras Fonoaudiologia. 2010;15(1):1–6 3 American Academy of Pediatrics, Joint Committee on Infant Hearing. Year 2007 position statement: Principles and guidelines

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

16

17

Luz et al.

for early hearing detection and intervention programs. Pediatrics 2007;120(4):898–921 Bevilacqua MC, Formigoni GMO. Audiologia educacional: uma opção terapêutica para a criança deficiente auditiva. 3. ed. Carapicuíba. Pro Fono 2012 Presidência da República BL. Lei n° 12.303, de 2 de agosto de 2010. Dispõe sobre a obrigatoriedade de realização do exame denominado Emissões otoacústicas evocadas. Available at: www.planalto.gov.br/ ccivil_03/_Ato2007-2010 /2010/Lei/L12303.htm. Accessed on April 20. 2014. Frederico M. Adesão de mães de lactentes a um programa de monitoramento do desenvolvimento auditivo e de linguagem [Dissertation]. Campinas: Faculdade de Ciências Médicas; 2013:98 Mello JM, Silva EC, Ribeiro VP, Moraes AMSM, Della-Rosa VA. Índice de retorno ao reteste em um programa de triagem auditiva neonatal. Rev Cefac. 2013;15(4):764–772 Alvarenga KF, Gradet JM, Araújo ES, Bevilacqua MC. Triagem auditiva neonatal: motivos da evasão das famílias no processo de detecção precoce. Rev Soc Bras Fonoaudiol. 2012;17(3): 241–247 Françozo MFC, Masson GA, Rossi TRF, Lima MCMP, Santos MFC. Adesão a um programa de triagem auditiva neonatal. Saúde Soc. 2010;19(4):910–918 Fernandes JC, Nozawa MR. Estudo da efetividade de um programa de triagem auditiva neonatal universal. Cien Saude Colet 2010; 15(2):353–361 Marziale MHP. Produção científica da enfermagem brasileira: a busca pelo impacto internacional. Rev Latino-am Enfermagem. 2005;13(3):285–286 Conselho Regional de Enfermagem (COREN). Lei N° 7.498/86. Dispõe sobre a regulamentação do exercício da Enfermagem e dá outras providências. Available at: <http://www.abennacional.org.br/download/LeiPROFISSIONAL. Accessed on October 4 2014 Berni PS, Almeida EO, Amado BC, Almeida Filho N. Triagem auditiva neonatal universal: índice de efetividade no reteste de neonatos de um hospital da rede pública de Campinas. Rev CEFAC. 2010;12(1):122–127 Liu CL, Farrell J, MacNeil JR, Stone S, Barfield W. Evaluating loss to follow-up in newborn hearing screening in Massachusetts. Pediatrics 2008;121(2):e335–e343 Kunst LR, Didoné DD, Moraes SC, et al. Fedosse, E. Perfil sóciodemográfico de mães atendidas em um serviço de triagem auditiva neonatal. Distúrb Comum. 2013;25(3):328–335 Fernandes JC. Estudo da efetividade de um programa de Triagem Auditiva Neonatal Universal [Dissertação]. Campinas: Universidade Estadual de Campinas; 2005:201 Cockfield CM, Garner GD, Borders JC. Follow-up after a failed newborn hearing screen: a quality improvement study. ORL Head Neck Nurs 2012;30(3):9–13


THIEME

Original Research

Comparison of Pre-Attentive Auditory Discrimination at Gross and Fine Difference between Auditory Stimuli Himanshu Kumar Sanju1

Prawin Kumar1

1 Department of Audiology, All India Institute of Speech and Hearing,

Mysore, Karnataka, India

Address for correspondence Himanshu Kumar Sanju, MD, Department of Audiology, AIISH, Mysore, Karnataka, India 570006 (e-mail: himanshusanjuaiish@gmail.com).

Int Arch Otorhinolaryngol 2016;20:305–309.

Abstract

Keywords

► auditory evoked potential ► event related potential ► attention

Introduction Mismatch Negativity is a negative component of the event-related potential (ERP) elicited by any discriminable changes in auditory stimulation. Objective The present study aimed to assess pre-attentive auditory discrimination skill with fine and gross difference between auditory stimuli. Method Seventeen normal hearing individual participated in the study. To assess preattentive auditory discrimination skill with fine difference between auditory stimuli, we recorded mismatch negativity (MMN) with pair of stimuli (pure tones), using /1000 Hz/ and /1010 Hz/ with /1000 Hz/ as frequent stimulus and /1010 Hz/ as infrequent stimulus. Similarly, we used /1000 Hz/ and /1100 Hz/ with /1000 Hz/ as frequent stimulus and /1100 Hz/ as infrequent stimulus to assess pre-attentive auditory discrimination skill with gross difference between auditory stimuli. The study included 17 subjects with informed consent. We analyzed MMN for onset latency, offset latency, peak latency, peak amplitude, and area under the curve parameters. Result Results revealed that MMN was present only in 64% of the individuals in both conditions. Further Multivariate Analysis of Variance (MANOVA) showed no significant difference in all measures of MMN (onset latency, offset latency, peak latency, peak amplitude, and area under the curve) in both conditions. Conclusion The present study showed similar pre-attentive skills for both conditions: fine (1000 Hz and 1010 Hz) and gross (1000 Hz and 1100 Hz) difference in auditory stimuli at a higher level (endogenous) of the auditory system.

Introduction Electrophysiological measures are one of the objective modes of assessment to check the functioning of the auditory function. These measures complement the information provided by the behavioral measures, which are Differential Limen of Frequency (DLF) and Differential Limen of Intensity. An auditory evoked potential assessment with electrophysiological measures describes as series of electrical changes occurring in the peripheral and central nervous system,

received July 4, 2015 accepted September 14, 2015 published online December 8, 2015

DOI http://dx.doi.org/ 10.1055/s-0035-1570071. ISSN 1809-9777.

usually related to the sensory pathways. The auditory evoked potential is further classified as endogenous and exogenous. The exogenous potentials are primarily evoked by some external event-related to the dimension of the stimulus. Studies considered the possibility of studying auditory discrimination using event-related potentials.1,2 The endogenous potentials, similar to mismatch negativity (MMN), are responses resulting from internal events, such as cognition or perception. The mismatch negativity (MMN) is a component of event-related potential that has been extensively used to

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil

305


306

Comparison of Pre-Attentive Auditory Discrimination at Gross and Fine Difference in Auditory Stimuli study the pre-attentive auditory discrimination skill and storage of regularities in stimulus features.3 Pre-attentive processing is the unconscious accumulation of information from the environment. All available information is pre-attentively processed. Then, our brain filters and processes the important information. We select information that has the highest salience (a stimulus that stands out the most) or relevance to what we are thinking about for a further and more complete analysis through conscious (attentive) processing.4,5 Our auditory system plays a very important role in collecting information for pre-attentive processing. When auditory stimuli or soundwaves strike the eardrum, they send a message to the brain via auditory nerves for preattentive processing. The skill to adequately filter information from pre-attentive auditory processing to attentive auditory processing is important for normal development.6 For acoustic pre-attentive auditory processing, the temporal cortex is the main site of activation; however, recent literature and research also showed the involvement of the frontal cortex.7,8 Literature also reports that detection of slight variation in complex musical pattern activates the right ventromedial prefrontal cortex.7 Mismatch Negativity (MMN) was first described by Naatanen et al. in 1978.9 Our brain is able to perceive even a minute change in the acoustic environment, which can be in terms of intensity (loudness), phase, frequency (pitch), and location of auditory stimuli. MMN has been gaining importance as a measure to assess discrimination (i.e., minute change) in the acoustic environment. Naatanen and Escera defined MMN as “an electric brain response, a negative component of the event-related potential (ERP), elicited by any discriminable change (deviant) in some repetitive aspect of auditory stimulation (standard), usually peaking at around 100-200 ms from onset.”10 Mismatch Negativity is a negative component of event-related potential (ERP) elicited by any discriminable changes in auditory stimulation (Naatanen & Alho, 1997)11 MMN can be evoked even in the absence of attention and is easy to administer.12 It can occur when the difference between the standard and deviant stimuli is as small as 8 Hz, or even when stimulus differences are near psychophysical threshold.13 Sams et al. also showed that MMN were present when deviant stimuli were barely discriminable from the standard stimuli, even though the differences were not perceptible.14 MMN reflects the central code of stimulus change; its amplitude and latency relate to the degree to which deviant stimuli differ from standard stimuli, not to absolute levels of deviant/standard stimuli. Thus, MMN is considered an objective neurophysiological test of auditory discrimination. Moreover, it appears that MMN reflects neuronal representation of the discrimination of numerous auditory stimulus attributes. If MMN reflects the ability to discriminate between acoustic stimuli, it is of clinical importance as well, since speech perception inherently depends on neuronal responses to changes in stimulus.15 Based on the literature, we observed that there is a dearth of literature that compares pre-attentive auditory discrimination skill with fine and gross difference of acoustic stimuli. Therefore, the present study aims to fill this gap. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Sanju, Kumar

Method Participants Seventeen normal hearing individuals from a private science college participated in the study with informed consent. Their age range was 18–25 years (mean age 21.5 years).

Participant Selection Criteria All the participants had normal hearing thresholds as defined by pure tone thresholds of < 15 dBHL at 250 Hz to 8000 Hz. Further, they had normal middle ear function as revealed by the middle ear analyzer. Participants presenting any other otological, neuromuscular, or neurological problem were excluded from the study.

Testing Environment We performed electrophysiological tests in a sound treated room where the noise level was as per the guidelines in ANSI S3.1 (1999). The testing rooms were well lit and air-conditioned for the comfort of the examiner, as well as the participant.

Instrumentation Calibrated double-channel clinical audiometer Orbiter 922 (MADSEN-GN Otometrics, Denmark) was used for pure tone audiometry. Calibrated GSI Tympstar immittance meter (Grason-Stadler, U.S.A) was used for tympanometry and reflexometry. We used the Intelligent Hearing System (Miami, USA) with smart EP to record Mismatch Negativity.

Procedure We obtained pure tone thresholds using a modified version of the Hughson and Westlake procedure across octave frequencies from 250 to 8000 Hz for air conduction and 500, 1000, 2000, and 4000 Hz for bone conduction. The middle ear analyzer (GSI-Tympstar) was used to carry out the tympanometry using a probe tone frequency of 226 Hz and to obtain ipsilateral and contralateral acoustic reflex thresholds at 500, 1000, 2000, and 4000 Hz. To assess pre-attentive auditory discrimination skill with fine difference between auditory stimuli, we recorded Mismatch negativity (MMN) with pairs of stimuli (pure tones). We used /1000 Hz/ and /1010 Hz/ with /1000 Hz/ as frequent stimulus and /1010 Hz/ as infrequent stimulus. Similarly, /1000 Hz/ and /1100 Hz/ with /1000 Hz/ as frequent stimulus and /1100 Hz/ as the infrequent stimulus, were used to assess pre-attentive auditory discrimination skill with gross difference between auditory stimuli. The total duration of the stimuli was 200 milliseconds with 30 milliseconds of rise-fall and a plateau of 140 milliseconds. We emitted the stimuli aided by the Aux Viewer program. We converted the wave file to a stimulus file for AEPs using the Stimconv software (Intelligent Hearing System, Miami, U.S.A.). We then recorded MMN in a vertical montage with ‘Fz’ as the positive electrodes referenced to the nape of the neck. We placed the ground electrode on the lower forehead. A second channel recorded eye blink response. The sweeps with large eye blink artifacts were eliminated from the averaging. Stimuli were presented in the oddball


Comparison of Pre-Attentive Auditory Discrimination at Gross and Fine Difference in Auditory Stimuli paradigm with the probability of standard and deviant stimulus of 80% and 20% at 70 dBnHL, respectively. We presented stimuli in the rarefaction polarity with a repetition rate of 1.1/ second. The responses were averaged for 150 sweeps (150 infrequent stimuli þ the corresponding number of frequent stimuli) from -50 to 500 milliseconds (with reference to stimulus onset). The band pass filter was set to the frequency range of 0.1 to 30 Hz, while amplified up to 50,000 times. We presented stimuli binaurally. Participants sat comfortably to avoid muscular artifacts and watched a silent movie to promote passive listening. The subjects were instructed not to pay attention to the auditory stimuli. We cleaned and placed disc electrodes on the skin surface of the target electrode sites. The absolute impedance was less than 5 kΩ and inter-electrode impedance was less than 2 kΩ while recording MMN. Aside from recording MMN in the conventional paradigm for each stimulus pair, we also recorded LLRs (Long Latency Responses) for the infrequent stimulus for 150 presentations, keeping the same recording parameter used for MMN.

Response Analysis We obtained pure tone thresholds using a modified version of the Hughson and Westlake procedure across octave frequencies from 250 to 8000 Hz for air conduction and 500, 1000, 2000, and 4000Hz for bone conduction. The middle ear analyzer (GSITympstar) was used to carry out the tympanometry using a probe tone frequency of 226 Hz and to obtain ipsilateral and contralateral acoustic reflex thresholds at 500, 1000, 2000, and 4000 Hz. To assess pre-attentive auditory discrimination skill with fine difference between auditory stimuli, we recorded Mismatch negativity (MMN) with pairs of stimuli (pure tones). We used /1000Hz/ and /1010Hz/ with /1000Hz/ as frequent stimulus and /1010Hz/ as infrequent stimulus. Similarly, /1000Hz/ and /1100Hz/ with /1000Hz/ as frequent stimulus and /1100Hz/ as the infrequent stimulus, were used to assess pre-attentive auditory discrimination skill with gross difference between auditory stimuli. The total duration of the stimuli was 200 milliseconds with 30 milliseconds of rise-fall and a plateau of 140 milliseconds. We emitted the stimuli aided by the Aux Viewer program. We converted the wave file to a stimulus file for AEPs using the Stimconv software (Intelligent Hearing System, Miami, U.S.A.). We then recorded MMN in a vertical montage with ‘Fz’ as the positive electrodes referenced to the nape of the neck. We placed the ground electrode on the lower forehead. A second channel recorded eye blink response. The sweeps with large eye blink artifacts were eliminated from the averaging. Stimuli were presented in the oddball paradigm with the probability of standard and deviant stimulus of 80% and 20% at 70 dBnHL, respectively. We presented stimuli in the rarefaction polarity with a repetition rate of 1.1/second. The responses were averaged for 150 sweeps (150 infrequent stimuli þ the corresponding number of frequent stimuli) from -50 to 500 milliseconds (with reference to stimulus onset). The band pass filter was set to the frequency range of 0.1 to 30 Hz, while amplified up to 50,000 times. We presented stimuli binaurally. Participants sat comfortably to avoid muscular artifacts and watched a silent movie to promote passive

Sanju, Kumar

listening. The subjects were instructed not to pay attention to the auditory stimuli. We cleaned and placed disc electrodes on the skin surface of the target electrode sites. The absolute impedance was less than 5 kΩ and inter-electrode impedance was less than 2 kΩ while recording MMN. Aside from recording MMN in the conventional paradigm for each stimulus pair, we also recorded LLRs (Long Latency Responses) for the infrequent stimulus for 150 presentations, keeping the same recording parameter used for MMN.

Waveform Analysis For the identification of the MMN true response through visual detection, MMN should be the first negative trough in the latency range of the N1-P2 or P2-N2 complex of LLR of amplitude greater than -0.3 µV and the positive peak should follow the negative peak. If the extra negativity occurred in the P1 area, it was ignored. To analyze the data collected from musicians and nonmusicians, we extracted the following response measures from the MMN for each participant: i. Onset Latency: It is the time, in milliseconds, when negativity started in the subtracted waveform. ii. Offset Latency: It is the time, in milliseconds, when the negativity reached the baseline activity in the subtracted waveform. iii. Peak Latency: It is the time, in milliseconds, at which negativity reached its peak in the subtracted waveform.

Statistical Analysis We used descriptive statistics to find out mean and standard deviation (SD) for all the parameters of MMN (onset latency, offset latency, peak latency, peak amplitude, and area under the curve). We conducted a Multivariate Analysis of Variance (MANOVA) to compare each measure (onset latency, offset latency, peak latency, peak amplitude, and area under the curve) under two conditions: gross difference in auditory stimuli and fine difference in auditory stimuli.

Result To analyze the data collected, we conducted a descriptive statistics and a Multivariate Analysis of Variance (MANOVA). Out of 17 individuals, MMN was present in only 11 of them (64%). Descriptive statistics showed similar outcomes for both the condition shown in ►Table 1 for onset, offset, and peak latency and that shown in ►Table 2 for peak amplitude and area under the curve. We extracted the different measures of MMN, such as onset latency, offset latency, peak latency, peak amplitude, and area under curve from the MMN waveform through visual inspection for all 11 participants. We applied MANOVA to compare between two conditions (gross and fine) for each measure of MMN. Sample waveforms of mismatch negativity is shown in ►Fig. 1.

Onset Latency, Offset Latency, and Peak Latency MANOVA showed no significant difference between both conditions, fine (/1000 Hz/ and /1010 Hz/) and gross (/1000 Hz/ and /1100 Hz/) in terms of onset latency [F (1, 20) ¼ 0.77; International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

307


308

Comparison of Pre-Attentive Auditory Discrimination at Gross and Fine Difference in Auditory Stimuli

Sanju, Kumar

Table 1 Mean and standard deviation (SD) of onset latency, offset latency, and peak latency for the fine and gross conditions Parameters

Onset Latency (ms)

Offset Latency (ms)

Peak Latency (ms)

Mean

SD

Mean

SD

Mean

SD

Fine Difference

161.54

28.02

287.72

23.86

213.27

24.36

Gross Difference

173.36

34.65

261.54

37.63

216.45

37.16

Table 2 Mean and standard deviation (SD) of peak amplitude and area under curve for the fine and gross conditions Parameters

Peak Amplitude(µv)

Groups

Mean

SD

Mean

SD

Fine Difference

2.63

1.08

176.17

55.14

Gross Difference

2.93

0.84

131.58

45.77

p > 0.05; n2 ¼ 0.03], offset latency [F (1, 20) ¼ 3.79; p > 0.05; n2 ¼ 0.16], and peak latency [F (1, 20) ¼ 0.05; p > 0.05; n2 ¼ 0.00].

Peak Amplitude and Area under Curve MANOVA showed no significant difference between both conditions, fine (/1000 Hz/ and /1010 Hz/) and gross (/1000 Hz/ and /1100 Hz/) difference in terms of peak amplitude [F (1, 20) ¼ 0.52; p > 0.05; n2 ¼ 0.02] and area under curve [F (1, 20) ¼ 4.25; p > 0.05; n2 ¼ 0.17].

Discussion The present study showed no significant difference in measures of mismatch negativity in both the fine condition (/1000 Hz/ and /1010 Hz/) as well as gross condition (/1000 Hz/ and /1100 Hz/), which showed similar auditory discrimination skill at pre-attentive level (discrimination skill without giving attention). Lang, Nyrke, Aaltonen, Raimo, and Naatanen

Fig. 1 Sample waveform of mismatch negativity.

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Area under Curve (µVµsec)

recorded MMN to a frequency deviance and correlated it to a behavioral discrimination task.16 They divided their participants into three groups (good, poor, and intermediate) based on their performance in the behavioral discrimination task. They found that MMN was present for a smaller frequency deviance (fine) in the good performers group. On the other hand, in the group of poor performers, MMN was elicited with a greater frequency deviance (gross).16 Sams et al also reported that MMN were present when the deviant stimuli were just discriminable from the standard stimuli, even though the differences were not perceptible.14 According to Kraus et al., MMN can occur even when the difference between the standard and deviant stimuli is as small as 8 Hz or even when stimulus differences are near psychophysical threshold.13 The present study is in contrast with the study done by Picton et al, which stated that MMN reflect the central code of stimulus change (i.e., its amplitude increases and latency decreases with increase in the difference


Comparison of Pre-Attentive Auditory Discrimination at Gross and Fine Difference in Auditory Stimuli between standard and deviant stimuli). Generally, the larger the difference between standard and deviant stimuli, the earlier the latency and larger the amplitude of MMN, although there may be a ceiling effect in amplitudes with a larger difference.17 This studý s outcomes showed that, at the pre-attentive level of auditory processing, the processing of auditory stimuli (infrequent), which differs slightly from the other (frequent), is almost similar when compared with the processing of auditory stimuli (infrequent), which differs grossly from other (frequent). Thus, we may conclude there is no difference in pre-attentive auditory discrimination when the infrequent differs slightly from frequent or when it differs grossly from frequent. The current study highlights that MMN was present in only 64% of the normal population. Therefore, the finding of MMN in clinical population should be interpreted cautiously, as there is a chance of absence of MMN even in normal hearing individuals.

4 Atienza M, Cantero JL, Escera C. Auditory information processing

5 6

7

8

9

10 11

Conclusion The present study showed that our auditory system has similar auditory discrimination skill with gross as well as fine difference in auditory stimuli at pre-attentive level (discrimination without attention).

12 13

14

References

15

1 Ceponiene R, Kushnerenko E, Fellman V, Renlund M, Suominen K,

Näätänen R. Event-related potential features indexing central auditory discrimination by newborns. Brain Res Cogn Brain Res 2002;13(1):101–113 2 Chang M, Iizuka H, Naruse Y, Ando H, Maeda T. Unconscious learning of auditory discrimination using mismatch negativity (MMN) neurofeedback. Sci Rep 2014;4:6729 3 Paavilainen P. The mismatch-negativity (MMN) component of the auditory event-related potential to violations of abstract regularities: a review. Int J Psychophysiol 2013;88(2):109–123

Sanju, Kumar

16

17

during human sleep as revealed by event-related brain potentials. Clin Neurophysiol 2001;112(11):2031–2045 Van AH. Two stages in visual information processing and visual perception? Vis Cogn 1996;3(4):325–362 Seri S, Pisani F, Thai JN, Cerquiglini A. Pre-attentive auditory sensory processing in autistic spectrum disorder. Are electromagnetic measurements telling us a coherent story? Int J Psychophysiol 2007;63(2):159–163 Habermeyer B, Herdener M, Esposito F, et al. Neural correlates of pre-attentive processing of pattern deviance in professional musicians. Hum Brain Mapp 2009;30(11):3736–3747 Klamer D, Svensson L, Fejgin K, Pålsson E. Prefrontal NMDA receptor antagonism reduces impairments in pre-attentive information processing. Eur Neuropsychopharmacol 2011;21(3):248–253 Näätänen R, Gaillard AW, Mäntysalo S. Early selective-attention effect on evoked potential reinterpreted. Acta Psychol (Amst) 1978;42(4):313–329 Näätänen R, Escera C. Mismatch negativity: clinical and other applications. Audiol Neurootol 2000;5(3–4):105–110 Näätänen R, Alho K. Mismatch negativity—the measure for central sound representation accuracy. Audiol Neurootol 1997;2(5): 341–353 Näätänen R, Paavilainen P, Tiitinen H, Jiang D, Alho K. Attention and mismatch negativity. Psychophysiology 1993;30(5):436–450 Kraus N, McGee T, Micco A, Sharma A, Carrell T, Nicol T. Mismatch negativity in school-age children to speech stimuli that are just perceptibly different. Electroencephalogr Clin Neurophysiol 1993; 88(2):123–130 Sams M, Paavilainen P, Alho K, Näätänen R. Auditory frequency discrimination and event-related potentials. Electroencephalogr Clin Neurophysiol 1985;62(6):437–448 Kraus N, McGee T, Carrell T, King C, Littman T, Nicol T. Discrimination of speech-like contrasts in the auditory thalamus and cortex. J Acoust Soc Am 1994;96(5 Pt 1):2758–2768 Lang H, Nyrke T, Aaltonen O, Raimo I, Näätänen R. Pitch discrimination performance and auditory event-related potentials. In C. H. M. Brunia, A. W. K. Gaillard, A. Kok, G. Mulder, & M. N. Verbaten (Eds.), Psychophysiological brain research (Vol. 1). Tilburg: Tilburg University Press; 1990:294–298 Picton TW, Alain C, Otten L, Ritter W, Achim A. Mismatch negativity: different water in the same river. Audiol Neurootol 2000;5; (3–4):111–139

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

309


THIEME

310

Original Research

Temporal Resolution and Active Auditory Discrimination Skill in Vocal Musicians Prawin Kumar1

Himanshu Kumar Sanju1

J. Nikhil1

1 Department of Audiology, All India Institute of Speech and Hearing,

Mysore, Karnataka, India

Address for correspondence Himanshu Kumar Sanju, Post Graduate in Audiology, Department of Audiology, AIISH, Manasagangothri, Mysore, Karnataka, India 570006 (e-mail: himanshusanjuaiish@gmail.com).

Int Arch Otorhinolaryngol 2016;20:310–314.

Abstract

Keywords

► singing ► auditory stimulation ► temporal auditory area

Introduction Enhanced auditory perception in musicians is likely to result from auditory perceptual learning during several years of training and practice. Many studies have focused on biological processing of auditory stimuli among musicians. However, there is a lack of literature on temporal resolution and active auditory discrimination skills in vocal musicians. Objective The aim of the present study is to assess temporal resolution and active auditory discrimination skill in vocal musicians. Method The study participants included 15 vocal musicians with a minimum professional experience of 5 years of music exposure, within the age range of 20 to 30 years old, as the experimental group, while 15 age-matched non-musicians served as the control group. We used duration discrimination using pure-tones, pulse-train duration discrimination, and gap detection threshold tasks to assess temporal processing skills in both groups. Similarly, we assessed active auditory discrimination skill in both groups using Differential Limen of Frequency (DLF). All tasks were done using MATLab software installed in a personal computer at 40dBSL with maximum likelihood procedure. The collected data were analyzed using SPSS (version 17.0). Result Descriptive statistics showed better threshold for vocal musicians compared with non-musicians for all tasks. Further, independent t-test showed that vocal musicians performed significantly better compared with non-musicians on duration discrimination using pure tone, pulse train duration discrimination, gap detection threshold, and differential limen of frequency. Conclusion The present study showed enhanced temporal resolution ability and better (lower) active discrimination threshold in vocal musicians in comparison to non-musicians.

Introduction Auditory temporal processing is defined as perception of sound or alternation of sound within a restricted time duration.1 Temporal resolution ability allows us to detect small and sudden change in sound stimuli. Good auditory temporal resolution ability is important for understanding speech in noise in listeners with normal hearing, hearing aid users,

received July 23, 2015 accepted October 4, 2015 published online December 17, 2015

DOI http://dx.doi.org/ 10.1055/s-0035-1570312. ISSN 1809-9777.

individuals with cochlear implant, and language disorder groups. Temporal processing is a fundamental ability in the perception of both verbal and non-verbal stimuli.2 Previous literature also reported the importance of temporal processing in the perception of music, rhythm, periodicity, phoneme discrimination, duration discrimination, and pitch discrimination.3,4 According to Parbery et al5, musical training and

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil


Temporal Resolution and Active Auditory Discrimination in Vocal Musicians exposure enhances one’s ability to code sudden change in stimuli. Music is one of the most demanding cognitive and neural challenges, which requires very precise and accurate timing of many actions, exact interval control of pitch not involved in language, and producing sound in many different ways. Enhanced auditory perception in musicians is likely to result from auditory perceptual learning during several years of training and practice. Moreover, music contains fine modulation of amplitude, frequency, and temporal aspects, which make the musicians experts in identifying such su0062tle fluctuations. In recent literature of plasticity dependent on experience, two studies explained some of the pre-requisites for inducing neuroplasticity, which include complexity, intensity, and repetition of training.6,7 Another voxel-based morphometric study by Abdul et al showed significantly increased gray matter volume in musicians compared with non-musicians.8 Results were positively correlated with years of music experience.8 This study also showed the change due to musical training in middle and superior cerebellar peduncle in trained musicians.8 Most trained and professional musicians are involved in intensive practice from many years in terms of both intense and repetitive to attain a high level of expertise. In case of vocal singers control of pitch is a complex biomechanical and aerodynamic system. Researchers agree that the musician’s ability to produce a precise pitch is very important for the professional vocal musician. Literature also showed that accurate pitch control is mainly dependent on auditory perceptual monitoring, proprioceptive feedback of the laryngeal system and phonatory reflex systems.9–11 Professional singers consistently control fundamental frequency and maintain targeted pitch better than non-singers. Thus, there must be a better temporal resolution ability and active auditory discrimination threshold in vocal musicians compared with non-musicians. Many studies have focused on biological processing of auditory stimuli among musicians.12–14 However, there is a lack of literature on temporal resolution and active auditory discrimination skills in vocal musicians. The effect of musical training and experience on temporal processing has not been studied using a combination of tasks i.e., duration discrimination using pure tones, pulse train duration discrimination, and gap detection threshold. Hence, the aim of the present study is to assess temporal resolution and active auditory discrimination skill in vocal musicians.

Method Participants Two groups of subjects (15 experimental and 15 in the control group) within the age range of 20–30 years participated in the study. The subjects with minimum professional experience of 5 years of vocal musical exposure participated in experimental group. Age-matched participants without any formal training of music qualified as non-musicians (control group). All the participants provided informed written consent.

Participant Selection Criteria All the participants were having normal hearing thresholds as defined by pure tone thresholds of < 15 dBHL at 250 Hz,

Kumar et al.

500 Hz, 1000 Hz, 2000 Hz, 4000 Hz, and 8000 Hz. Further, they had normal middle ear functioning, as revealed by the middle ear analyzer. We used click-evoked auditory brainstem response (ABR) to rule out any retrocochlear pathology. Participants who had any other otological, neuromuscular, and neurological problem were excluded from the study based on structured case history.

Testing Environment All the behavioral tests were performed in a sound treated room where noise levels were in accordance with the guidelines in ANSI S3.1. The testing rooms were well illuminated and air-conditioned for the comfort of the experimenter as well as of participants.

Procedure Pure tone thresholds was obtained using a modified version of Hughson and Westlake procedure across octave frequencies from 250, 500, 1000, 2000, 4000 Hz, and 8000 Hz for air conduction and frequencies from 500, 1000, 2000, and 4000 Hz for bone conduction.15 We used a middle ear analyzer to carry out tympanometry using a probe tone frequency of 226 Hz and to obtain ipsilateral and contralateral acoustic reflexes thresholds at 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz. We administered duration discrimination using pure tone, pulse train duration discrimination, and gap detection threshold tasks on both groups of participants to assess temporal resolution ability. Similarly, differential limen of frequency tasks were given to both groups of participants to assess active auditory discrimination skill with MATLab software using maximum likelihood procedure technique through a calibrated headphone (Sennheiser Urbanite XL) attached to a personal computer. The program provided feedback on the computer screen after every response as to whether it was correct or incorrect. We considered an average of three blocks as threshold. We adopted this procedure to obtain more precise and reliable thresholds.

Duration Discrimination using Pure Tone In duration discrimination using pure tone (1000Hz), we measured the minimum difference in duration required to perceive the two otherwise identical stimuli, using maximum likelihood procedure. The duration of the standard tone was 250 milliseconds. The duration of the variable tone was changed based on response of the participants. We used two alternative forced choice procedures in which the participants were asked to indicate which tone was longer in duration.

Pulse Train Duration Discrimination In pulse train duration discrimination, the standard stimulus consists of six 20 milliseconds pulses of 1 KHz tone. These pulses are arranged in three pairs, with 40 milliseconds of silence between each member of a pair and 120 milliseconds between pairs. The temporal structure of the variable sequence is varied by increasing the separation between members of each pair, with a corresponding decrease in the between-pair time and, thus, a constant interval between International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

311


312

Temporal Resolution and Active Auditory Discrimination in Vocal Musicians

Kumar et al.

Table 1 Mean and standard deviation (SD) of duration discrimination using pure tone, pulse train duration discrimination, gap detection threshold, and differential limen of frequency Pure Tone Duration Discrimination

Pulse train duration discrimination

Gap Detection Threshold

Differential Limen of Frequency

Mean

SD

Mean

SD

Mean

Mean

Vocal Musicians

23.13

10.16

19.30

5.29

1.81

0.39

5.86

1.64

Non-Musicians

38.93

13.18

35.17

13.76

2.47

0.48

10.33

1.34

SD

SD

Abbreviation: SD, standard deviation.

the first tones in each of the successive pairs. Thus, the first, third, and fifth tones are fixed in time, while the onsets of the second, fourth, and sixth tones are delayed by a varying amount. The parameters that varied adaptively were duration of gap within or between pairs of the variable stimulus to make different rhythm from standard stimuli. The subject task was to identify odd rhythm in a group of two standard and one variable stimuli.

Gap Detection Threshold Gap detection threshold was assessed using 750 milliseconds of Gaussian noise with gap in the center. Gap duration was varied according to listener performance using maximum likelihood procedure. The noise had 0.5 milliseconds cosine ramps at the beginning and end of the gap. In the three alternative forced choice task, the reference stimulus was always a 750-millisecond white noise without gap, whereas the variable stimulus contained a gap. We took the minimum gap duration required to perceive a gap in noise as the threshold.

Differential Limen of Frequency We assessed differential limens of frequency at 1000 Hz with the help of MATLab software using the maximum likelihood procedure technique. Three number of blocks were taken for differential limen of frequency. Each block contained 35 trials. We adopted three alternative forced choice procedures for response. The clients were instructed to discriminate highest pitch among three tones (250 milliseconds) presented one after the other.

differential limen of frequency (►Table 1). Results revealed lower threshold for all tasks in vocal musicians compared with non-musicians. Independent t-test showed that vocal musicians have a significantly lower threshold compared with non-musicians in duration discrimination using pure tone (t ¼ 3.67; df ¼ 28; p ¼ 0.001), pulse train duration discrimination (t ¼ 4.16; df ¼ 28; p ¼ 0.00), gap detection threshold (t ¼ 4.06; df ¼ 28; p ¼ 0.00), and differential limen of frequency (t ¼ 8.15; df ¼ 28; p ¼ 0.00). ►Fig. 1 shows error bar graph of duration discrimination threshold and pulse train duration discrimination threshold for vocal musician and non-musicians. Similarly, ►Fig. 2 and ►Fig. 3 show error bar graph of gap detection threshold and differential limen of frequency, respectively.

Discussion The main aim of the present study is to compare temporal resolution skills in vocal musicians compared with nonmusicians. The present study showed enhanced temporal resolution ability in vocal musicians in comparison to nonmusicians. The better performance of musicians can be attributed to the fact that music exposure helps to develop

Statistical Analysis We performed descriptive statistics to find out mean and standard deviation (SD) for all tasks in vocal musicians and non-musicians. Independent t-test was done to compare between musicians and non-musicians for all task to check any significant difference between groups.

Results To analyze the data collected from vocal musicians and nonmusicians, we performed descriptive statistics and independent t-test using SPSS (version 17.0). The purpose of descriptive statistics was to find out mean and standard deviation of all the tasks: duration discrimination using pure tone, pulse train duration discrimination, gap detection threshold, and International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Fig. 1 Error bar graph of duration discrimination threshold and pulse train duration discrimination threshold for vocal musician and nonmusicians.


Temporal Resolution and Active Auditory Discrimination in Vocal Musicians

Kumar et al.

well as for pulse train duration discrimination, which indicates enhanced temporal resolution ability in musicians compared with non-musicians. This outcome is in consonance with previous literature.18,19 Güçlü et al investigated duration discrimination threshold in musicians and nonmusicians and reported that musicians had better duration discrimination threshold compared with non-musicians.18 The present study finding is similar with a study done by Sangamanatha et al, which reported lower duration discrimination threshold (better) in children with musical training and adults with musical training, when compared with children without any musical training.19

Gap Detection Threshold Fig. 2 Error bar graph of gap detection threshold for vocal musician and non-musicians.

Result showed significantly lower gap detection threshold in vocal musicians compared with non-musicians. Our results are well-supported by other researchers.19–22 However, few studies showed no changes due to musical training.23 Sangamanatha et al investigated gap detection threshold and reported that mean gap detection thresholds were significantly lower for children with musical training and adults with musical training, when compared with children without any musical training.19 Similarly, Mishra, and Panda showed that Carnatic musical training has a significant effect on temporal resolution ability in musicians assessed by gap detection threshold.20 The present study’s finding is in contrast with the study done by Monteiro et al, which reported no significant difference in gap detection threshold between musicians and non-musicians.23

Differential Limen of Frequency

Fig. 3 Error bar graph of differential limen of frequency for vocal musician and non-musicians.

auditory pathways for detecting small change in auditory stimuli. Similarly, the current study also showed better (lower) active discrimination threshold compared with non-musicians, which indicates that musical training and experience has influenced and enhanced active auditory discrimination skills in musicians. Our finding supports those in Fujioka et al and Moreno et al, which reported enhancement of auditory processing with musical training and exposure.16,17 The effect of musical training and experience on temporal processing has not yet been studied using combination of tasks (i.e., duration discrimination using pure tones, pulse train duration discrimination, and gap detection threshold). The present study showed that all these tests are equally sensitive in assessing enhanced temporal resolution ability in musicians.

Duration Discrimination using Pure Train and Pulse Train Duration Discrimination The current study showed lower threshold among vocal musicians for duration discrimination using pure tone as

The current study showed that musicians performed significantly better than non-musicians in differential limen frequency. Threshold of differential limen of frequency for musicians was significantly lower (better) than non-musicians. The finding revealed that musicians have better “active auditory discrimination skill” than non-musicians. Similar, this finding appears in previous literature.24–27 Parbery et al compared frequency discrimination in musicians and non-musicians.25 They reported that musicians have more fine-grained frequency discrimination. In a similar line, Bidelman and Krishnan measured fundamental (F0) and first formant (F1) frequency difference limens (DLs) in musicians and showed DLs 2 to 4 times better than non-musicians.26 In another study, Bidelman et al assessed fundamental frequency discrimination limen between musicians and non-musicians.27 They reported trained musicians having significantly better fundamental frequency differential limen when compared with non-musicians. The findings of the current study showed mean DLF for musicians was almost half of the DLF for non-musicians. This indicates that musical training and experience has influenced and enhanced active auditory discrimination skills in musicians. Thus, musical training can be used to enhance temporal resolution skills and active auditory discrimination skills in the clinical population, such as cases of temporal processing deficit, learning disabilities, Parkinson’s disease, schizophrenia, Alzheimer’s disease, children with developmental International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

313


314

Temporal Resolution and Active Auditory Discrimination in Vocal Musicians

Kumar et al.

language disorder, and children with cochlear implant.28–30 Enhancement of temporal resolution ability and active auditory discrimination skills due to musical training in these populations may result in the improvement of speech perception.

11 Mürbe D, Pabst F, Hofmann G, Sundberg J. Effects of a professional

Conclusion

13

The present study’s outcome showed that vocal music training and experience enhances temporal resolution skill and active auditory discrimination ability. These enhancements may be due the fact that more efficient neural network and connections (neuroplasticity) in vocal musicians results in a better threshold in duration discrimination tasks as well as gap detection tasks. Results from the present study support further exploration into the effectiveness of musical training on children with auditory processing disorder. To conclude, musical training is useful in enhancing temporal resolution and active auditory discrimination skills in normal hearing individuals.

12

14

15 16

17

18 19

References 1 Musiek FE, Shinn JB, Jirsa R, Bamiou DE, Baran JA, Zaida E. GIN

2

3

4

5 6

7

8

9 10

(Gaps-In-Noise) test performance in subjects with confirmed central auditory nervous system involvement. Ear Hear 2005; 26(6):608–618 Bellis TJ. Assessment and management of central auditory processing disorders in the educational setting: from science to practice (2nd ed.). New York: Delmar Learning; 2003 Downie AL, Jakobson LS, Frisk V, Ushycky I. Auditory temporal processing deficits in children with periventricular brain injury. Brain Lang 2002;80(2):208–225 Phillips DP. Central auditory system and central auditory processing disorders: some conceptual issues. Semin Hear 2002;23(2): 251–261 Parbery-Clark A, Skoe E, Lam C, Kraus N. Musician enhancement for speech-in-noise. Ear Hear 2009;30(6):653–661 Kleim JA, Jones TA. Principles of experience-dependent neural plasticity: implications for rehabilitation after brain damage. J Speech Lang Hear Res 2008;51(1):S225–S239 Green CS, Bavelier D. Exercising your brain: a review of human brain plasticity and training-induced learning. Psychol Aging 2008;23(4):692–701 Abdul-Kareem IA, Stancak A, Parkes LM, Sluming V. Increased gray matter volume of left pars opercularis in male orchestral musicians correlate positively with years of musical performance. J Magn Reson Imaging 2011;33(1):24–32 Amir O, Amir N, Kishon-Rabin L. The effect of superior auditory skills on vocal accuracy. J Acoust Soc Am 2003;113(2):1102–1108 Jones JA, Munhall KG. Perceptual calibration of F0 production: evidence from feedback perturbation. J Acoust Soc Am 2000;108(3 Pt 1):1246–1251

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

20

21 22

23

24

25

26

27

28 29

30

solo singer education on auditory and kinesthetic feedback—a longitudinal study of singers’ pitch control. J Voice 2004;18(2): 236–241 Wong PC, Skoe E, Russo NM, Dees T, Kraus N. Musical experience shapes human brainstem encoding of linguistic pitch patterns. Nat Neurosci 2007;10(4):420–422 Lee KM, Skoe E, Kraus N, Ashley R. Selective subcortical enhancement of musical intervals in musicians. J Neurosci 2009;29(18): 5832–5840 Shahin A, Roberts LE, Pantev C, Trainor LJ, Ross B. Modulation of P2 auditory-evoked responses by the spectral complexity of musical sounds. Neuroreport 2005;16(16):1781–1785 Carhart R, Jerger J. Preferred method for clinical determination of pure-tone thresholds. J Speech Hear Disord 1959;24(4):330–335 Fujioka T, Ross B, Kakigi R, Pantev C, Trainor LJ. One year of musical training affects development of auditory cortical-evoked fields in young children. Brain 2006;129(Pt 10):2593–2608 Moreno S, Marques C, Santos A, Santos M, Castro SL, Besson M. Musical training influences linguistic abilities in 8-year-old children: more evidence for brain plasticity. Cereb Cortex 2009;19(3): 712–723 Güçlü B, Sevinc E, Canbeyli R. Duration discrimination by musicians and nonmusicians. Psychol Rep 2011;108(3):675–687 Sangamanatha AV, Fernandes J, Bhat J, Srivastava M, Prakrithi SU. Temporal resolution in individuals with and without musical training. J Ind Sp Hear Assoc 2012;26(3):27–35 Mishra SK, Panda MR. Experience-dependent learning of auditory temporal resolution: evidence from Carnatic-trained musicians. Neuroreport 2014;25(2):134–137 Kuman PV, Rana B, Krishna R. Temporal processing in musicians and non-musicians. J Hear Sci 2014;4(3):35–42 Mishra SK, Panda MR, Herbert C. Enhanced auditory temporal gap detection in listeners with musical training. J Acoust Soc Am 2014; 136(2):EL173–EL178 Monteiro RAM, Nascimento FM, Soares CD, Ferreira MIDC. Temporal Resolution Abilities in Musicians and No Musicians Violinists. Int Arch Otorhinolaryngol 2010;14(3):302–308 Kishon-Rabin L, Amir O, Vexler Y, Zaltz Y. Pitch discrimination: are professional musicians better than non-musicians? J Basic Clin Physiol Pharmacol 2001;12(2, Suppl)125–143 Parbery-Clark A, Skoe E, Kraus N. Musical experience limits the degradative effects of background noise on the neural processing of sound. J Neurosci 2009;29(45):14100–14107 Bidelman GM, Krishnan A. Effects of reverberation on brainstem representation of speech in musicians and non-musicians. Brain Res 2010;1355:112–125 Bidelman GM, Hutka S, Moreno S. Tone language speakers and musicians share enhanced perceptual and cognitive abilities for musical pitch: evidence for bidirectionality between the domains of language and music. PLoS ONE 2013;8(4):e60676 Overy K. Dyslexia and music: From timing deficits to musical intervention. Ann N Y Acad Sci 2003;999:497–505 Walker KM, Hall SE, Klein RM, Phillips DP. Development of perceptual correlates of reading performance. Brain Res 2006; 1124(1):126–141 Tallal P, Gaab N. Dynamic auditory processing, musical experience and language development. Trends Neurosci 2006;29(7):382–390


THIEME

Original Research

Relationship between Speech Perception and Level of Satisfaction of Hearing Aid Users Erika Barioni Mantello1 Carla Dias da Silva1 Ana Cláudia Mirândola Barbosa dos Reis1

Eduardo Tanaka Massuda1

1 Department of Ophthalmology, Otorhinolaryngology and Head and

Neck Surgery, Ribeirão Preto Medical School, Universidade de São Paulo, Ribeirão Preto, São Paulo, Brazil Int Arch Otorhinolaryngol 2016;20:315–320.

Abstract

Keywords

► ► ► ► ►

hearing perception patient satisfaction hearing loss hearing aids questionnaires

Address for correspondence Erika Barioni Mantello, Fga, PhD, Department of Ophthalmology, Otorhinolaryngology and Head and Neck Surgery, Ribeirão Preto Medical School,University of São Paulo, Av Bandeirantes 3600, Campus Ribeirão Preto, São Paulo 14049-900, Brazil (e-mail: erikafga@yahoo.com.br).

Introduction Hearing difficulties can be minimized by the use of hearing aids. Objective The objective of this study is to assess the speech perception and satisfaction of hearing aids users before and after aid adaptation and to determine whether these measures are correlated. Methods The study was conducted on 65 individuals, 54% females and 46% males aged 63 years on average, after the systematic use of hearing aids for at least three months. We characterized subjectś personal identification data, the degree, and configuration of hearing loss, as well as aspects related to adaptation. We then applied a satisfaction questionnaire and a speech perception test (words and sentences), with and without the use of the hearing aids. Results Mean speech recognition with words and sentences was 69% and 79%, respectively, with hearing aids use; whereas, without hearing aids use the figures were 43% and 53%. Mean questionnaire score was 30.1 points. Regarding hearing loss characteristics, 78.5% of the subjects had a sensorineural loss, 20% a mixed loss, and 1.5% a conductive loss. Hearing loss of moderate degree was present in 60.5% of cases, loss of descending configuration in 47%, and plain loss in 37.5%. There was no correlation between individual satisfaction and the percentages of the speech perception tests applied. Conclusion Word and sentence recognition was significantly better with the use of the hearing aids. The users showed a high degree of satisfaction. In the present study, there was no correlation observed between the levels of speech perception and levels of user satisfaction measured with the questionnaire.

Introduction Hearing disability derives from a deficiency in hearing ability and the performance of an individual in communication. The severity of the disability depends on the nature and magnitude of hearing loss and, consequently, on the hearing difficulties experienced by the listener.2

received September 24, 2015 accepted November 6, 2015 published online December 17, 2015

Miguel Angelo Hyppolito1

DOI http://dx.doi.org/ 10.1055/s-0035-1570315. ISSN 1809-9777.

Hearing disability derives from a deficiency in hearing ability and the performance of an individual in communication. The severity of the disability depends on the nature and magnitude of hearing loss and, consequently, on the hearing difficulties experienced by the listener.2 Thus, one of the objectives of a hearing aid is to reduce or eliminate the limitations caused by hearing loss.1 Over the

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil

315


316

Relationship between Speech Perception and Level of Satisfaction of Hearing Aid Users last few years, hearing aids (HA) have been used as a primary intervention option for users with hearing loss who cannot be treated clinically or surgically.1 Tests such as detection of hearing thresholds with the use of electronic devices and measures with a probe microphone are not always sufficient to assess and ensure the adaptation of HA in daily communication situations. Over the past decades, there has been increased interest in the development of verification and validation procedures to assess the benefits and user satisfaction outside the clinical environment, through self-assessment questionnaires.3 Although HAs minimize the impact of hearing loss in affected subjects, their use cannot restore normal hearing. They are meant to provide the largest possible amount of acoustic information, but they do not always contribute to improving speech intelligibility with a consequent effective communication.4 The benefit obtained by the use of these devices can be measured as positive, negative or neutral, depending on the effect the device has on each individuaĺs performance.5 For an efficient fitting of the HA, it is of primary importance to apply guidance and monitoring programs to their users, with active user participation whenever possible. Selfassessment questionnaires are important instruments that help speech therapists to monitor the users of these devices and provide information about the difficulties of HA use.6,7 One example is the self-assessment questionnaire called International Outcome Inventory for Hearing Aids (IOI-HA),8,9 whose goal is to document the user’s progress, the limitations of core activities, the restriction of participation, and the impact of the hearing problem to others, and to the quality of life.8–11 The application of the IOI-HA questionnaire allows the documentation of success and the monitoring of the progress of HA use in userś daily routine, in addition to the benefit and the degree of user satisfaction. Also, it can assess the benefit in of listening in unfavorable situations such as noisy environments and helps to reduce the impact of the individuaĺs hearing loss over others.12 As the population ages, the number of candidates for HA fitting will significantly increase over the next years.13 It is essential to develop diagnostic and rehabilitation programs for the elderly with hearing loss to foster their participation in social relations.14 Studies have demonstrated the need to assess speech perception and user satisfaction after HA fitting, with several investigations contributing to the adaptation and validation of speech perception tests to different listening situations and to the improvement of satisfaction questionnaires. The primary objective of the present study was to assess the speech perception and level of satisfaction of HA users before and after fitting for the device and to determine whether these measurements are correlated. Specific objectives were to determine the association between sex and degree of hearing loss and each question of the IOI-HA, as well as to relate patient age and time of HA use with each IOI-HA question. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Mantello et al.

Methods This study was a cross-sectional, prospective study of a descriptive nature, with approval from the institutioń s Research Ethics Committee (protocol n°. 7629/2008). The selected subjects gave written informed consent to participate. Inclusion criteria were: age of at least 18 years, use of HA with at least three months of adaptation, and HA purchased through the program of Attention to Hearing Health of the institution, according to ordinances SAS–MS n°. 587 and 589 of October 7 and 8, 2004, in effect at the time of the study.15,16 Exclusion criteria were patients with auditory neuropathy spectrum, neurological, psychological, and cognitive impairments, or any problems that could affect the accuracy of the answers in the procedure used after evaluation by a multidisciplinary team. The study was conducted during a monitoring visit in the speech therapy sector of the institution and the data obtained included identification information, data related to the degree and configuration of hearing loss, and aspects related to HA fitting. We then applied a questionnaire as a face-to-face directed interview with the patient. The speech therapist would orally present the questions in the questionnaires, noting the answer, avoiding irrelevant comments to preserve the accuracy of the responses. We used the IOI-HA questionnaire12 because it allows the documentation of the performance of the HA in use, in terms of daily use, benefit, limitation of basic activities, satisfaction, restriction of participation, impact on other persons and quality of life. The IOI-HA contains a total of seven questions, with five optional responses to each one and with a score ranging from one to five, from the worst answer to the best. The maximum score (the sum of all items) is 35 points. Thus, a higher score indicates a positive assessment of the performance of the HA user and a lower score indicates a negative assessment.11 We analyzed the survey responses considering the total score and the scores of the two factors.17,18 The factor number one reflects the interaction of the patients with their HA (questions 1, 2, 4, and 7; with a score that varies between 4 to 20) and the factor number two evaluated patient interaction with others in their environment (questions 3, 5, and 6; score ranging from 3 to 15). Then, we presented the the recognition list disyllables and Lacerda phrases19 through the speakerphone, with and without HA, in an acoustically treated room at a distance of 50 cm from the individual’s ear, the 0 ° azimuth, and an intensity of 65 dB SPL (measured with a decibel meter (make and model).

Statistical Analysis We performed an exploratory analysis of the data to summarize the information. We used the Spearman correlation coefficient to correlate the differences in words and sentences with the total result of the IOI-HA questionnaire. We used mixed-effect (random and fixed effects) linear regression


Relationship between Speech Perception and Level of Satisfaction of Hearing Aid Users

Mantello et al.

Table 1 Mean values, confidence interval, and standard deviation of the continuous variables Variable

Mean

95% CI

SD

Minimum

Median

Maximum

LL

UL

Age

62.18

57.02

67.35

20.85

12.00

70.00

89.00

Time of hearing loss (years)

11.08

9.43

12.72

6.64

5.00

10.00

20.00

Time of HA use (months)

46.60

31.94

61.26

59.15

5.00

24.00

396.00

Word recognition with the HA

69.38

63.44

75.33

23.99

0.00

72.00

100.00

Word recognition without the HA

42.89

34.77

51.01

32.76

0.00

52.00

96.00

Sentence recognition with the HA

79.38

72.94

85.83

26.00

0.00

92.00

100.00

Sentence recognition without the HA

52.92

43.79

62.06

36.87

0.00

60.00

100.00

Total IOI-HA score

30.06

29.12

31.01

3.81

21.00

30.00

35.00

Abbreviations: CI, confidence interval; HA, hearing aid; LL, lower limit; SD, standard deviation; UL, upper limit.

models to compare the recognition of words and sentences between patients with and without HA. Mixed-effect linear models are helpful in analyzing data involving grouped responses (repeated measures for the same individual) when the assumption of independence between observations in the same group is inadequate.20 This model is based on the assumption that the residue obtained from the difference between the values predicted by the model and the observed values has a normal distribution, with 0 mean and constant variance. To achieve the specific objectives, we used crossedtabulation of the variables, the Fisher exact test (sex and degree of loss determined by the questions of the IOI-HA) and the Spearman correlation coefficient to compare between age and time of HA use and the questions of the IOI-HA. We considered P values of less than 0.05 and correlation values higher than 0.60 to be significant. We performed all analyses were with the aid of the SAS software version 9.3,21 and plotted the graphs with the aid of the R software. 21–23

Results The study was conducted on 65 adult and elderly users, 54% of them women and 46% men, followed-up in the Hearing Health Program of the institution of origin. Mean patient age was 63 years (range: 18–89 years).

►Table 1 presents the mean values, confidence interval, and standard deviation of the continuous variables. Eighty percent of the subjects had a hearing loss of the sensorineural type, 20% of the mixed type, and 1.5% of the conductive type. Hearing loss of moderate degree prevailed among 60.7% of cases, followed by loss of the severe degree in 23%, profound loss in 14.6%, and mild loss in 1.54%. Configuration was descending in 47.3% of cases, followed by the plain configuration in 34.9, ascending configuration in 3.0%, and other configurations in 14.7%. Sixty percent of the 65 participants had hearing loss of a progressive nature and 40% had stable hearing loss. A HA of the retro auricular type was fitted to 96% of the users, 94% of whom used a bilateral HA. Mean speech recognition was 69% for words and 79% for sentences with the use of the HA, and 43% and 53%, respectively, without the HA. ►Table 2 lists the significant p-values (p < 0001) obtained when we compared word and sentence recognition between the presence and absence of the HA. ►Figs. 1 and 2 respectively illustrate the distribution of word and sentence recognition with and without the use of the HA. The mean score obtained with the IOI-HA questionnaire was 30.1 points (range: 21–35 points). The comparison of the average total score of the IOI-HA with the degree of hearing loss yielded mean values of 31.4 points for the severe degree,

Table 2 Estimated difference and significant p-values for the comparison of word and sentence recognition in the speech recognition test with and without the HA Effect Words

Estimated difference 

Sentences



P value

95% CI LL

UL

26.492

< 0.001

16.526

36.458

26.461

< 0.001

15.387

37.535

Abbreviations: CI, confidence interval; LL, lower limit; UL, upper limit; SD, standard deviation.  word recognition in the presence and absence of the HA  sentence recognition in the presence and absence of the HA. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

317


318

Relationship between Speech Perception and Level of Satisfaction of Hearing Aid Users

Mantello et al.

Discussion

Fig. 1 Boxplot of the distribution of word recognition in the presence and absence of the hearing aid.

Fig. 2 Boxplot of the distribution of sentence recognition in the presence and absence of the hearing aid.

31 points for the mild degree, 29.6 points for the moderate degree, and 29.2 for the profound degree. We considered the correlation coefficient regarding the difference in word recognition (0.21) and sentence recognition (0.20) before and after the use of the HA compared with the results of the IOI-HA weak. There was a moderate correlation between the difference in word recognition and the difference in sentence recognition (0.69). We found no significant results regarding the association of patient gender with each question of the IOI-HA. We detected no correlation between time of HA use and each issue of the IOI-HA, or between patient age and each issue of the IOI-HA. Similarly, there was no significant association detected between the degree of hearing loss in the right and left ears and each question of the IOI-HA. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

The motivation for this study was based on the need to analyze the correlation between speech perception test, commonly used in clinical practice, and the self-perception among subjects, specifically in relation to satisfaction of adults and elderly HA users. Within the process of speech therapy intervention, this is one of the actions that has an interactive and communicative component in the encounter between the specialist and the user, which can either facilitate or hamper the achievement of their objectives. In the present study, there was a high participation of the elderly population (mean age: 63 years), in agreement with other studies.24,25 With increased life expectancy, the elderly population, which is affected by presbyacusis among other changes, has grown.26 Studies have demonstrated that hearing loss starts at 30 years of age, progressively increasing over the years.26–28 We balanced the present sample in terms of sex (54% women and 46% men), reflecting a current trend in health services, as opposed to reports published several years ago,29 which showed a prevalence of females in general, as was the case in hearing health services. We also observed this gender equilibrium in another study, in which 48.54% of the elderly subjects investigated were males and 51.46% were females.30 Although most of the present users were elderly, their mean time of hearing loss was 11 years, with an interval of 7 years before the acquisition of the HA. We conducted this study on subjects covered by a Hearing Health Program accredited by the Unified Health System (SUS), which involved high demand and a waiting line of over two years before the definitive fitting of the HA, in agreement with other studies.25,29 The present study revealed a significant gap between diagnosis and HA fitting. The literature attributes this delay to the reluctance of adult users in accepting their hearing loss while attributing their hearing difficulties to an inappropriate environment or to communication by third parties. Most users had a hearing loss of the sensorineural type of moderate degree, with a descending configuration and of a progressive nature, compatible with the auditory characteristics detected in the population of elderly individuals with presbyacusis. The reduced auditory sensitivity resulting from aging known as presbyacusis, which is characterized by bilateral symmetric sensorineural hearing loss of descending configuration.31,32 We should, however, emphasize an important reduction of speech intelligibility, which may be incompatible with audiometric thresholds in some users, a fact that can also be explained by a decline in auditory processing.31–33 Almost the entire sample evaluated consisted of users of bilateral HA, as also reported in many literature studies.25–29 The advantages of bilateral hearing are well known in the documentation, allowing better localization of the sound source, better speech recognition, and figure-ground relationship, factors that are crucial for individuals with hearing loss.34


Relationship between Speech Perception and Level of Satisfaction of Hearing Aid Users In the present study, there was a predominance of fitting of an HA of the retroauricular type (96%), in agreement with other literature reports on this topic.29,35 The greater indication of retroauricular devices is explained by the fact that they can adapt to all degrees of hearing loss, from mild to profound. Moreover, they offer greater amplification power and increased handling ease.36 Thus, they were more appropriate for the sample studied, as it mainly consisted of elderly subjects with little manual dexterity and with a higher probability of worsening hearing thresholds, especially at high frequencies. In the process of HA fitting, the intention is to provide better audibility of acoustic signals and better speech intelligibility to the patient with hearing deficiency to reduce his hearing disability.37 Thus, the benefit provided by the use of amplification is the difference in individual performance between the presence and the absence of the hearing device. The improvement of communication in daily life and the reduction of hearing disability and handicap of HA users are benefits inherent to the use of the electronic devices.18 This statement agrees with the results of the present study, since the patients had a mean 26% difference in the recognition of words and sentences with and without the use of HA and a high score in the IOI-HA questionnaire. It was also observed in this study a higher percentage of correct responses in the recognition of sentences when comparing to words. Freitas et al38 stated that the use of sentences is more appropriate to assess speech recognition in noise. Sentences are more similar to situations of everyday communication, moving closer to the spectral characteristics and contexts of everyday speech, controlling the duration and semantic content of it. The results obtained in the present study with the use of the IOI-HA demonstrated that satisfaction appears to be a more faithful measure, since it includes a multitude of factors, has a dynamic character, depends on the perception and attitudes of the user, and is not solely related to the performance of the hearing device. The self-assessment questionnaires determine the psychosocial impact of hearing loss or the benefit of sound amplification and evaluate in a standardized manner the results of the speech therapy procedures directed at patient subjectivity, thus, guiding the fitting process.39 Previous studies have demonstrated that the use of HA is essential to maintain the physical and mental health of the elderly, since it allows them to participate more in their community and in family life.40 Despite the significant difference in the rate of recognition of both words and sentences between the use or not of the HA (►Table 2), there was a weak correlation between speech perception before and after the utilization of the HA compared with the results of the IOI-HA. Similarly, other authors did not find a difference in satisfaction with the HA after hearing rehabilitation (training in speech perception).41,42 They explain that the concept of happiness is more frequently employed to justify or criticize the fitting methods, the qualification of the speech therapist, and the practice of the industries who distribute the HA.43

Mantello et al.

This, however, does not necessarily represent device performance, since a patient may have a significant degree of benefit measured by a test with and without HA, but may be dissatisfied with sound amplification.44–47 These results suggest that further research is needed in this sense, seeking instruments and forms of application that can correlate the level of user satisfaction with the clinical audiological assessment performed by the professionals who work with HA fitting. For such, it is important to highlight the importance of audiological monitoring of patients covered by the hearing health services of the Unified Health System (SUS), which involves extensive work that ranges from monitoring hearing loss to fine adjustments of the HA to maximize its benefits, as well as research on how the device improves the patient́ s quality of life.48

Conclusion In our study, we observed a better performance in terms of word and sentence recognition with the use of the HA, with a significant difference between the conditions of device presence or lack thereof, with the percentage of speech perception being higher when the patient tested with sentences. There was no correlation between the results of the speech perception test and the level of HA user satisfaction, although the results of IOI-HA revealed that the users were satisfied with their devices.

References 1 Bento RF, Neto RB, Castilho AM, et al. Resultados auditivos com o

2

3

4 5

6

7

8

9

implante coclear multicanal em pacientes submetidos à cirurgia no Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo. Rev Bras Otorrinolaringol (Engl Ed) 2004; 70:632–637 Frederigue NB, Bevilacqua MC. Otimização da percepção da fala em deficientes auditivos usuários do sistema de implante coclear multicanal. Rev Bras Otorrinolaringol (Engl Ed) 2003; 69:227–233 Almeida K. Avaliação dos resultados da intervenção. In: Almeida K, Iorio MCM. Próteses auditivas: fundamentos teóricos e aplicações clínicas. São Paulo: Lovise; 2003:335–352 Russo ICP. A intervenção fonoaudiológica na terceira idade. Rio de Janeiro: Revinter; 2004:67–78 Fleck MPA, Chachamovich E, Trentini CM. [WHOQOL-OLD Project: method and focus group results in Brazil]. Rev Saude Publica 2003; 37(6):793–799 Mondelli MFCG, Souza PJS. Qualidade de vida em idosos antes e após a adaptação do AASI. Braz J Otorhinolaryngol 2012;78(3): 49–56 Rosa MRD, Dantes GE, Ribas A. Programa de Orientação a Usuários de Prótese Auditiva e Questionários de Auto-avaliação: Importantes Instrumentos para uma Adaptação Auditiva Efetiva. Int Arch Otorhinolaryngol 2006;3:220–227 Cox RM, Alexander GC. The international outcome inventory for hearing aids (IOI-HA): psychometric properties of the English version. Int J Audiol 2002;41(1):30–35 Cox RM. Assessment of subjective outcome of hearing aid fitting: getting the client’s point of view. Int J Audiol 2003;42(1, Suppl 1): S90–S96

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

319


320

Relationship between Speech Perception and Level of Satisfaction of Hearing Aid Users

Mantello et al.

10 Cox RM, Alexander GC, Beyer CM. Norms for the international

30 Gomes MM. Programa de saúde auditiva: perfil dos usuários e

outcome inventory for hearing aids. J Am Acad Audiol 2003;14(8): 403–413 Cox R, Hyde M, Gatehouse S, et al. Optimal outcome measures, research priorities, and international cooperation. Ear Hear 2000; 21(4, Suppl)106S–115S Teixeira CF, Augusto LGS, Caldas Neto SS. Prótese auditiva: satisfação do usuário com sua prótese e com seu meio ambiente. Rev CEFAC 2008;10(2):245–253 Lessa AH, Costa MJ, Becker KT, Vaucher AVA. Satisfação de usuários de próteses auditivas, com perda auditiva de graus severo e profundo. Arq Int Otorrinolaringol 2010;14(3):338–345 Veras RP, Mattos LC. Audiology and aging: literature review and current horizons. Braz J Otorhinolaryngol 2007;73(1): 122–128 Brasil. Ministério da Saúde. Portaria MS/SAS n° 587, de 7 de outubro de 2004. Available at: http://www.saude.mg.gov.br/images/documentos/Portaria_587.pdf. Accessed on February 11, 2014 Brasil. Ministério da Saúde. Portaria MS/SAS n° 589 de 8 de outubro de 2004. Available at: http://www.saude.mg.gov.br/images/documentos/Portaria_589.pdf. Accessed February 11, 2014 Cox RM, Alexander GC, Gray GA. Personality, hearing problems, and amplification characteristics: contributions to self-report hearing aid outcomes. Ear Hear 2007;28(2):141–162 Prates LPCS, Iório MCM. Aclimatização: estudo do reconhecimento de fala em usuários de próteses auditivas. Pró Fono R Atual Cient 2006;18(3):259–266 Lacerda AP. Audiologia clínica. Rio de Janeiro: Guanabara Koogan; 1976:199 Schall R. Estimation in generalized linear models with random Effects. Biometrika 1991;78(4):719–727 SAS Institute Inc. SAS/STAT® User’s Guide, Version 9. Cary, NC: SAS Institute Inc.; 1999 Pagano M, Gauvreau K. Princípios de Bioestatística. São Paulo: Thomson; 2004:320 R Development Core Team. (2011). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3–900051–07–0 Farias RB, Russo ICP. Saúde auditiva: estudo do grau de satisfação de usuários de aparelho de amplificação sonora individual. Rev Soc Bras Fonoaudiol 2010;15(1):26–31 Moda I, Mantello EB, Reis ACMB, et al. Avaliação da satisfação do usuário de aparelho de amplificação sonora. Rev CEFAC 2013; 15(4):778–785 Megighian D, Savastano M, Salvador L, Frigo A, Bolzan M. Audiometric and epidemiological analysis of elderly in the Veneto region. Gerontology 2000;46(4):199–204 Bance M. Hearing and aging. CMAJ 2007;176(7):925–927 Campos CAH, Russo ICP, Almeida KCP. Indicação, seleção e adaptação de próteses auditivas. In: Almeida K, Iorio MCM. Próteses auditivas: fundamentos teóricos e aplicações clínicas. São Paulo: Lovise; 2003:35–53 Antoniossi NM, Reis ACMB. Análise do tipo, adaptação e uso de HAI adquiridos pelo programa de Saúde Auditiva do HCFMRP/USP [Dissertation]. Ribeirão Preto (SP): Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo, Phonoaudiology Department; 2007

avaliação dos resultados obtidos na intervenção fonoaudiológica [Dissertation]. Campinas (SP): Faculdade de Ciências Médicas de Campinas, Universidade Estadual de Campinas; 2014 Russo ICP. Distúrbios da Audição: A Presbiacusia. In: Russo ICP. Intervenção Fonoaudiológica na Terceira Idade. Rio de Janeiro: Revinter; 2004:51–82 Aiello CP, Lima II, Ferrari DV. Validity and reliability of the hearing handicap inventory for adults. Braz J Otorhinolaryngol 2011; 77(4):432–438 Sousa MGC, Russo ICP. Audição e percepção da perda auditiva em idosos. Rev Soc Bras Fonoaudiol 2009;14(2):241–246 Magni C, Freiberger F, Tonn K. Avaliação do grau de satisfação entre os usuários de amplificação de tecnologia analógica e digital. Rev Bras Otorrinolaringol (Engl Ed) 2005;71(5):650–657 Batista ACM, Sampaio FM. Nível de satisfação dos idosos usuários de próteses auditivas doadas pela APAC-NAMI UNIFOR. Rev Bras Prom Saúde 2005;18(1):7–10 Assayag FHM, Russo ICP. Avaliação subjetiva do benefício e dos efeitos proporcionados pelo uso de amplificação sonora em indivíduos idosos. Rev Dist Comun 2006;18(3):383–390 Almeida K. Avaliação objetiva e subjetiva dos benefícios das próteses auditivas em adultos [Thesis]. São Paulo (SP): Universidade Federal de São Paulo, Escola Paulista de Medicina; 1998 Freitas CD, Lopes LFD, Costa MJ. Confiabilidade dos limiares de reconhecimento de sentenças no silêncio e no ruído. Rev Bras Otorrinolaringol (Engl Ed) 2005;71(5):624–630 Macedo LS, Pupo AC, Balieiro CR. Aplicabilidade dos questionários de auto-avaliação em adultos e idosos com deficiência auditiva. Rev Dist Comun 2006;18(1):19–25 Silva BSR, Sousa GB, Russo ICP, Silva JAPR. Characterization of the complaints, kind of hearing loss and treatment for elderly people seen at a private clinic in Belem - PA. Arq Int Otorhinolaryngol 2007;11(4):387–395 Saunders GH, Lewis MS, Forsline A. Expectations, prefitting counseling, and hearing aid outcome. J Am Acad Audiol 2009; 20(5):320–334 Kramer SE, Allessie GH, Dondorp AW, Zekveld AA, Kapteyn TS. A home education program for older adults with hearing impairment and their significant others: a randomized trial evaluating short- and long-term effects. Int J Audiol 2005;44(5):255–264 Ross M, Levitt H. Consumer satisfaction is not enough: Hearing aids still about hearing. Semin Hear 1997;18(1):7–10 Araújo TM, Morettin M, Torres KCC, et al. Auditory Rehabilitation and Life Quality of Individual Hearing Aids Users: Systematic Review. Rev Dist Comun 2010;22(1):25–36 Cox RM, Alexander GC. Measuring satisfaction with amplification in daily life: the SADL scale. Ear Hear 1999;20(4):306–320 Hosford-Dunn H, Halpern J. Clinical application of the satisfaction with amplification in daily life scale in private practice I: statistical, content, and factorial validity. J Am Acad Audiol 2000;11(10): 523–539 Veiga LR, Merlo ARC, Mengue SS. Satisfação com a prótese auditiva na vida diária em usuários do Sistema de Saúde do Exército. Rev Bras Otorrinolaringol (Engl Ed) 2005;71(1):67–73 Oliveira JRM, Lopes ES, Alves AF. Percepção de fala dos deficientes auditivos usando aparelho de amplificação com algoritmo de redução de ruído. Braz J Otorhinolaryngol 2010;76(1):14–17

11

12

13

14

15

16

17

18

19 20 21 22 23

24

25

26

27 28

29

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

31

32

33 34

35

36

37

38

39

40

41

42

43 44

45 46

47

48


THIEME

Original Research

Pitch and Loudness Tinnitus in Individuals with Presbycusis Bruna Macangnin Seimetz1 Adriane Ribeiro Teixeira2 Leticia Petersen Schmidt Rosito3 Leticia Sousa Flores4 Carlos Henrique Pappen5 Celso Dall’igna3 1 Program in Child and Adolescent Health, Universidade Federal do Rio

Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil 2 Department of Developmental Psychology and Personality, Universidade Federal do Rio Grande do Sul, Instituto de Psicologia da UFRGS, Porto Alegre, Rio Grande do Sul, Brazil 3 Department of Otolaryngology - Head and Neck Surgery, Hospital de Clínicas de Porto Alegre, Porto Alegre, Rio Grande do Sul, Brazil 4 Audiologist Clinic, private office, Porto Alegre, Rio Grande do Sul, Brazil 5 Medical School, Universidade Federal do Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

Address for correspondence Bruna Macangnin Seimetz, Program in Child and Adolescent Health, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2400 Porto Alegre, Rio Grande do Sul 90035-003, Brazil (e-mail: bruna.seimetz@gmail.com).

Int Arch Otorhinolaryngol 2016;20:321–326.

Abstract

Keywords

► presbycusis ► tinnitus ► aging

Introduction Tinnitus is a symptom that is often associated with presbycusis. Objective This study aims to analyze the existence of association among hearing thresholds, pitch, and loudness of tinnitus in individuals with presbycusis, considering the gender variable. Methods Cross-sectional, descriptive, and prospective study, whose sample consisted of individuals with tinnitus and diagnosis of presbycusis. For the evaluation, we performed anamnesis along with otoscopy, pure tone audiometry, and acuphenometry to analyze the psychoacoustic characteristics of tinnitus individuals. Results The sample consisted of 49 subjects, with a mean age of 69.57  6.53 years, who presented unilateral and bilateral tinnitus, therefore, a sample of 80 ears. In analyzing the results, as for acuphenometry, the loudness of tinnitus was more present at 0dB and the pitch was 6HKz and 8HKz. Regarding the analysis of the association between the frequency of greater hearing threshold and tinnitus pitch, no statistical significance (p ¼ 0.862) was found. As for the association between the intensity of greater hearing threshold and tinnitus loudness, no statistical significance (p ¼ 0.115) was found. Conclusion There is no significant association between the hearing loss of patients with presbycusis and the pitch and loudness of tinnitus.

Introduction Presbycusis is a word derived from the Greek (presbus ¼ elder þ ákousis ¼ hearing), which means reduced hearing acuity caused by aging.1 Its etiology is multifactorial and is characterized as bilateral, symmetrical, with slow and progressive evolution, mainly affecting high frequencies. It starts usually

received July 26, 2015 accepted October 4, 2015 published online February 1, 2016

DOI http://dx.doi.org/ 10.1055/s-0035-1570311. ISSN 1809-9777.

between 20 and 30 years of age, but becomes socially awkward from 40 to 50 years.2 Studies show that there is an increase in the prevalence of presbycusis according to age, with a greater loss in high frequencies (from 80–89) and flattening out in individuals aged over 90 years.3,4 Presbycusis is a problem associated with senescence, with

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil

321


322

Pitch and Loudness Tinnitus in Individuals with Presbycusis consequences to social and functional activities as well as to the psychological well-being of individuals.3,5,6 Tinnitus is a symptom related to the hearing system, which may be observed in individuals diagnosed with presbycusis.7 This is the conscious perception of sound that originates in the ears or head of the patient without the presence of an external source of sound generator,8 that is, the sensation of sound in the absence of an external sound stimulus.9 Its main origin is in the cochlea, and may be associated with various diseases that may spread to other auditory pathways.7 Ear diseases are the leading causes of tinnitus, but diseases that affect the ear secondarily, such as metabolic, cardiovascular, neurological, psychiatric, dental changes and possibly the consumption of drugs, caffeine, nicotine and alcohol may cause etiology.8 With respect to age, this is a symptom observed in adults and children,10 but its incidence increases with increasing age and also with hearing loss, making it a more common complaint in older individuals7,10 and more common in men11 than women. It may be unilateral or bilateral, but in some cases patients can’t refer to the side that sense, referring to the perception of sound inside the head, or, optionally, on the outside of the head.7,10 Psychoacoustic characteristics of tinnitus, which are frequency (pitch) and intensity (loudness), differ among patients, as well as in location and duration of tinnitus.8 The manner in which this symptom disturbs people’s quality of life also varies from patient-to-patient, as they present different reactions.12 If gender is considered, literature data are controversial, since research shows that gender has no influence on the nuisance caused by tinnitus,13–15 reporting similarities in how men and women feel the symptom. However, there are studies that demonstrate greater nuisance in males,16 while others have reported greater discomfort among women.17,18 A recent study using functional imaging in patients with tinnitus reported differences in the activity of the orbitofrontal cortex extending to the frontopolar cortex of men and women with this symptom.15 The orbitofrontal cortex is an important tool for the emotional processing of sounds, justifying possible gender differences in the perception of tinnitus.15 Previous research have shown a relationship between tinnitus and hearing, which is more common and severe when associated with hearing loss.11,19 Another study also reported this relationship, with influence of frequency band and hearing thresholds.20 As an auditory perception or, in other words, a subjective characteristic, the conditions for research on tinnitus are limited.21 Nonetheless, given that this is a symptom with great impact in the lives of individuals, all scientific contribution in this area becomes important and necessary.8,10 The assumptions described and the scarce national and international literature on research correlating hearing loss and the results found in the psychoacoustic measurements of tinnitus (pitch and loudness) justify the importance of this research. The objective of this study is to analyze the existence of an association between hearing thresholds, pitch, and loudness International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Seimetz et al. of tinnitus in individuals with presbycusis, considering the gender variable.

Methods This is a transversal, descriptive, and prospective study, whose sample consisted of individuals with presbycusis and tinnitus in the Chronic Tinnitus Clinic of the hospital of the institution that hosted this study. The sample included individuals with tinnitus, whether unilateral or bilateral, diagnosed with presbycusis, and who underwent complete otorhinolaryngologic and audiological evaluation, with audiological exams (otoscopy, pure tone audiometry by air and bone conduction, acoustics, and acuphenometry impedance measures). The study excluded patients with a history of cognitive and / or neurological impairment observed during records analysis. Initially, all patients were treated by an otorhinolaryngologist for the investigation of otologic and health history, as well as otoscopy. Afterwards, all patients underwent an audiological evaluation conducted with pure tone audiometry performed in a soundproof booth, with audiometer Siemens, Unity PC model with HDA 200 headphones and bone vibrator B71 for research of the thresholds by air in the frequencies of 250Hz, 500Hz, 1000Hz, 2000Hz, 3000Hz, 4000Hz, 6000Hz, and 8000Hz, and also bone conduction thresholds in the frequencies of 500Hz, 1000Hz, 2000Hz, 3000Hz, and 4000Hz. Subsequently, we performed acuphenometry to analyze the psychoacoustic characteristics of each individual tinnitus, or we observed the sensation of pitch and loudness of the tinnitus. We found that pitch corresponds to the frequency of the symptom (low, medium, or high) and loudness to the intensity of it, which is equivalent to the volume of feeling reported by the pure tone of the patient or narrowband noise.8 The acuphenometry was performed using the procedures described by Branco-Barreiro,22 which initially was made to search for pitch. In all frequencies, we selected the ear of the individual threshold, added another 10 dBHL and presented pure tone or noise, according to the patients’ description on the characteristics of their tinnitus. We requested that the patient raise his or her hand when realizing that the sound presented was similar to his or her tinnitus. Next, we researched loudness. In the frequency indicated by the patient as similar to their tinnitus, the stimulus was presented (pure tone or noise), with initial intensity 10 dBHL below the patient’s threshold. Next, we increased intensity in steps of 2 dBHL, and the patients would raise their hand as soon as they realized that the intensity was similar to the presented tinnitus. This intensity was recorded and subtracted from the individual hearing threshold. This calculation enables the determination level of sensation. After the audiological evaluation, all subjects returned for consultation with the otorhinolaryngologist for the causal diagnosis of hearing loss and tinnitus. The research had the approval of the institution’s Ethics Committee, recorded under number 06026, as well as Informed Consent (IC) of all participating individuals.


Pitch and Loudness Tinnitus in Individuals with Presbycusis For data analysis, the sample was divided into subgroups according to the variable of interest, which were gender, frequency of greater hearing threshold, intensity of greater hearing threshold, pitch, and loudness obtained in acuphenometry. Regarding the frequency of greater hearing threshold and the pitch in acuphenometry, we analyzed the frequency bands analysis according to the following considerations: severe (250Hz and 500Hz), medium (1000Hz, 2000Hz, and 3000Hz), and acute (4000Hz, 6000Hz, and 8000Hz). Regarding the intensity of greater hearing threshold, subgroups were divided according to individual threshold between 0 and 25 dB HL, 26 and 40 dB HL, 41 and 70 dB HL, 71 and 90 dB HL, and above 90 dB HL. As for loudness in acuphenometry, the group was divided into individuals who had tinnitus between 0 and 4 dBSL, 5 to 9 dBSL, 10 to 14 dBSL, 15 to 19 dBSL, 20 to 24 dBSL, 25 to 30 dBSL, and above 30 dBSL. We entered the data into a database built in Microsoft Excel. We performed the analysis using SPSS software version 18, with the correlation analysis through the Pearson correlation coefficient, Student’s t-test for comparison of independent means, and Fisher’s Exact Test. We considered a significance level of 5% (p < 0.05).

Results The study sample consisted of 49 subjects, with a mean age of 69.57  6.53 years, minimum age of 53 years and maximum of 85 years. As for gender, the study included 28 female subjects (57.15%) and 21 male (42.85%). Of these, 7 (14.28%) had tinnitus in the right ear (RE), 11 (22.44%) in the left ear (LE), and 31 (63.26%) in both ears (BE). Thus, for data analysis, we considered only the ears that had tinnitus, totalizing 80 ears, 38 RE and 42 LE. ►Table 1 shows the frequency distribution of the individuals according to the intensity of greater hearing threshold. In analyzing the results, we observed that most of the patients evaluated had their greatest auditory thresholds between 50 and 75 dB HL. The average loudness of tinnitus was 17.9 dB HL. ►Table 2 shows the frequency distribution of the loudness of tinnitus obtained in acuphenometry. Most of the evaluated ears (80.1%) had tinnitus loudness between 0 dB HL and 19 dB HL. ►Table 3 shows the comparison between genders with regards to the characteristics of greater hearing threshold (frequency and intensity) and psychoacoustic characteristics of tinnitus (pitch and loudness). We concluded that there is no significant difference between genders comparing the average frequency of greater hearing threshold (p ¼ 0.889), intensity of greater hearing threshold (p ¼ 0.140), pitch obtained in acuphenometry (p ¼ 0.144), and loudness obtained in acuphenometry (p ¼ 0.139). ►Table 4 shows the analysis between gender and two other variables, loudness and frequency range, obtained in acuphenometry. There was no significant association in both comparisons, with p ¼ 0.603 and p ¼ 0.555, respectively. In ►Table 5, we present the frequency distribution of patients according to frequency of greater hearing threshold

Seimetz et al.

Table 1 Distribution of frequency of ears evaluated according to the intensity of greater hearing threshold Intensity of greater hearing threshold (dB HL)

N

%

30 | - | 35

7

8.8

40 | - | 45

10

12.6

50 | - | 55

17

21.3

60 | - | 65

20

25.1

70 | - | 75

14

17.5

80 | - | 85

6

7.5

90 | - | 95

4

5.1

110

2

2.5

Total

80

100.0

Abbreviations: dB HL, decibel hearing level; N, number; %, percentage.

Table 2 Distribution of frequency of ears evaluated according to the loudness of tinnitus obtained in acuphenometry Acuphenometry - Loudness (dBSL)

N

%

0|-|4

19

23.7

5|-|9

17

21.3

10 | - | 14

12

15.1

15 | - | 19

16

20.0

20 | - | 24

7

8.8

25 | - | 30

6

7.6

< 30

3

3.8

Total

80

100.0

Abbreviation: (dBSL), decibel sensation level; N, number; %, percentage.

and pitch in acuphenometry. We found low correlation (r ¼ 0.080) and no significance (p ¼ 0.478). Regarding the analysis of the frequency range of greater hearing threshold (divided into severe, medium, and high), and pitch obtained in acuphenometry (ranked in the same way), we observed no significant association (p ¼ 0.081) (►Table 6). ►Table 7 demonstrates the analysis of the intensity ratings of greater hearing threshold and loudness in acuphenometry, whereby it is possible to conclude that there was no significant association between these variables (p ¼ 0.115).

Discussion The results of this study show that the mean age observed in the sample (69.57  6.53 years) was consistent with other studies investigating tinnitus in the elderly. Previous research found average ages of 69.53 years23 and 65.5 years.24 As for tinnitus location, some studies corroborate this research, primarily finding bilateral tinnitus, followed by unilateral LE, and, finally, unilateral RE.18,25,27 International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

323


324

Pitch and Loudness Tinnitus in Individuals with Presbycusis

Seimetz et al.

Table 3 Comparison of the gender characteristics of greater hearing threshold (frequency and intensity) and psychoacoustic characteristics of tinnitus (pitch and loudness) Variables

Gender

Often the higher threshold Higher threshold intensity Pitch (acuphenometry) Loudness (acuphenometry)

N

Average

Standard deviation

p-value 0.889

F

48

6791.7

1878.9

M

32

6851.6

1856.6

F

48

58.5

17.2

M

32

64.4

17.1

F

48

3869.8

2597.0

M

32

4781.3

2867.2

F

48

12.3

10.7

M

32

9.1

7.2

0.140 0.144 0.139

Abbreviations: F, female; M, male; N, number. Student t-test, with significance level of 5% (p < 0.05).

Table 4 Analysis of the influence of gender on the acuphenometry loudness and frequency range obtained in acuphenometry Acuphenometry Gender

Loudness (dB HL)

p-value

0| -| 4

5| -| 9

10 | -| 14

15 | -| 19

20 | -| 24

25 | -| 30

< 30

F (n ¼ 48)

11

8

8

9

4

4

4

M (n ¼ 32)

8

9

4

7

3

1

Total

19

17

12

16

7

5

Frequency Range Serious

Medium

Acute

p-value

8

14

26

0.555

0

3

8

21

4

11

22

47

0.603

Abbreviations: dB HL, decibel hearing level: F, female; M, male. Fisher’s exact test with a significance level of 5% (p < 0.05).

Table 5 Frequency analysis of greater hearing threshold and the pitch in acuphenometry Greater frequency hearing threshold

Pitch in Acuphenometry

Frequency

N

%

N

%

250

1

1.3

3

3.8

500

8

10.0

1000

1

1.3

7

8.8

2000

1

1.3

10

12.5

3000

4

5.0

5

6.3

4000

4

5.0

12

15.0

6000

19

23.8

18

22.5

8000

50

62.5

17

21.3

Total

80

100.0

80

100.0

Abbreviations: N, number; %, percentage. Pearson’s correlation coefficient (r), with a significance level of 5% (p < 0.05). r ¼ 0.80. p ¼ 0.478.

Considering gender, we observed that the number of females (57.15%) was higher than men. Previous studies confirm our results, varying between 51% and 64% women International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

in their samples.18,25–29 A possible explanation to be considered is the fact that women are more careful and concerned about their health, seeking further medical care and, thus, show higher prevalence in studies and research.12 Moreover, given that the sample of this study consisted of elderly people, we must mention the higher proportion of senior females in Brazil as a possible factor in female prevalence.30 Research shows that in 2000, for every 100 elderly women there were 81 elderly men. By 2050, this ratio will be 100 elderly women to 76 elderly men.31 We did not find previous literary data to corroborate the findings of this study in terms of psychoacoustic characteristics of tinnitus in patients with presbycusis, comparing gender and pitch and loudness of tinnitus (►Tables 3 and 4). However, a study conducted with 607 women and 573 men with chronic tinnitus with an average age of 50 years observed an average pitch in women of 5.7 Hz and 5.4 Hz for right and left ears, respectively.18 As for men, average pitch was 5.7 Hz for both ears.18 This is gender indifference is in accordance with the present study. More recent research, however, differs from our data, finding higher pitch value in women (average 3963.2 and 3602 Hz for right and left ears, respectively) than in men (3047.6 in RE and 3228Hz in LE).32 Regarding the loudness of tinnitus, we observed differences between this study and previous studies,16,18 where the authors report significantly higher loudness in men


Pitch and Loudness Tinnitus in Individuals with Presbycusis

Seimetz et al.

Table 6 Analysis of the frequency range of greater hearing threshold and pitch obtained in acuphenometry, by frequency bands Frequency range of greater hearing threshold

Acuphenometry - Frequency Range Serious

Average

Acute

Total

p-value

Serious

1

1

0.081

Average

1

4

1

6

Acute

10

18

45

73

Total

11

22

47

80

Fisher’s exact test with a significance level of 5% (p < 0.05).

Table 7 Analysis of the intensity ratings of greater hearing threshold and the loudness in acuphenometry Greater threshold intensity

Acuphenometry - Loudness (dB HL)

Total

0 |-| 4

5 |-| 9

10 |-| 14

15 |-| 19

20 |-| 24

25 |-| 30

< 30

26 |-| 40

1

3



5

2

1



12

41 |-| 70

14

9

12

6

5

3

3

52

71 |-| 90

3

5



3



1

1

13

< 90

1





2







3

Total

19

17

12

16

7

5

4

80

p-value 0.115

Abbreviation: dB HL, decibel hearing level. Fisher’s exact test with a significance level of 5% (p < 0.05).

(42.3 dB for RE and 44.3 dB for LE) compared to women (35.7 dB for RE and 37.3 dB for LE).18 When analyzing frequency of greater hearing threshold (►Tables 5 and 6), we observed higher thresholds at high frequencies. This is in agreement with the audiological profile that characterizes presbycusis, a sensorineural hearing loss with downward audiometric curve. other studies in elderly patients with tinnitus also reported this audiological pattern.3,5,23 Another study performed in the state of Rio Grande do Sul in Brazil involving a sample of 215 elderly also showed that the frequencies with greater hearing thresholds were 6000Hz and 8000Hz.33 Regarding tinnitus pitch, this study found that most of the evaluated ears had a high pitch, which corroborates previous research.26,32,34,35 Despite the fact that frequency of greater hearing threshold and pitch in acuphenometry are located in the range of high frequencies, corroborating the study of Noreña et al.,36 the correlation between these variables is weak. Other studies also report a poor correlation between the pitch of the tinnitus and hearing loss frequencies, or even no correlation,25,29,37–40 although number of ears examined may have an influence in this trend. In fact, some authors found a positive correlation between tinnitus pitch and frequency with greater hearing loss.38 The greater the intensity of the auditory threshold was found that in most of the individuals ranged between 40 and 65dBNA, which is also compatible with presbycusis above and is comparable with previous studies.33 In relation to the loudness of the tinnitus, it was found that the majority of cases varied between 0 and 19 dBSL, corroborated by a recent study where only 8% of the sample had tinnitus loudness equal to or greater than 20 dBSL.32 The average of this feature

(17.9 dBSL) is higher than the value reported in previous research, where the average was 14.1 dB.41 However, the difference between studies may be due to sample average age (32.1 years) was younger than the sample of the present research. The analysis of the intensity of greater hearing threshold and the loudness of tinnitus showed no significant association. In the literature, were not found previous studies correlating these variables. However, this finding may have been due to the fact of acuphenometry be a subjective test that depends on the intellectual capacity and concentration of the patient at the time of performing the test,42 and thus can restrict the results.18

Conclusions This study showed no association between hearing loss, gender, pitch, and loudness of tinnitus in individuals with presbycusis. However, the studied literature still has significantly controversial data on such characteristics, highlighting the importance of further research on the topic.

References 1 Priberam Dictionary of the Portuguese Language (2013). . Avail-

able at: http://www.priberam.pt/dlpo/presbiacusia. Accessed on Oct 11, 2013 2 Roth TN, Hanebuth D, Probst R. Prevalence of age-related hearing loss in Europe: a review. Eur Arch Otorhinolaryngol 2011;268(8): 1101–1107 3 Baraldi GS, de Almeida LC, Borges ACC. Hearing loss in aging. Braz J Otorhinolaryngol 2007;73(1):58–64 International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

325


326

Pitch and Loudness Tinnitus in Individuals with Presbycusis

Seimetz et al.

4 Teixeira AR, Freitas CR, Millão LF, et al. Relationship Among

26 Urnau D, Tochetto TM. Characteristics of tinnitus and hyperacusis

Hearing Loss, Age, Gender and Senior Quality of Life. Int Arch Otorhinolaryngol 2008;12:62–70 Guerra TM, Estevanovic LP, Cavalcante MdeÁ, Silva RCL, Miranda ICC, Quintas VG. Profile of audiometric thresholds and tympanometric curve of elderly patients. Braz J Otorhinolaryngol 2010; 76(5):663–666 Ciorba A, Bianchini C, Pelucchi S, Pastore A. The impact of hearing loss on the quality of life of elderly adults. Clin Interv Aging 2012; 7:159–163 Assumption ARM, Albertino S. Tinnitus Rev. Pedro Ernesto Univ Hosp UERJ 2012;11:19–22 Sanchez TG, Ferrari GMS. What is tinnitus? In: Samelli AG. Tinnitus: assessment, diagnosis and rehabilitation. Current approaches. São Paulo: Lovise; 2004. p. 17–22. Gonçalves MS, Tochetto TM, Rossi AG. Condição auditiva de indivíduos com queixa de zumbido. Saúde 2005;31:5–9 Baguley DM. Mechanisms of tinnitus. Br Med Bull 2002;63: 195–212 Axelsson A, Ringdahl A. Tinnitus—a study of its prevalence and characteristics. Br J Audiol 1989;23(1):53–62 Coelho CCB, Sanchez TG, Bento RF. Características do zumbido em pacientes atendidos em serviço de referência. Int Arch Otorhinolaryngol 2004;8:216–224 Méric C, Gartner M, Collet L, Chéry-Croze S. Psychopathological profile of tinnitus sufferers: evidence concerning the relationship between tinnitus features and impact on life. Audiol Neurootol 1998;3(4):240–252 Pinto PC, Sanchez TG, Tomita S. The impact of gender, age and hearing loss on tinnitus severity. Braz J Otorhinolaryngol 2010; 76(1):18–24 Vanneste S, Joos K, De Ridder D. Prefrontal cortex based sex differences in tinnitus perception: same tinnitus intensity, same tinnitus distress, different mood. PLoS ONE 2012;7(2):e31182 Hiller W, Goebel G. Factors influencing tinnitus loudness and annoyance. Arch Otolaryngol Head Neck Surg 2006;132(12): 1323–1330 Welch D, Dawes PJ. Personality and perception of tinnitus. Ear Hear 2008;29(5):684–692 Seydel C, Haupt H, Olze H, Szczepek AJ, Mazurek B. Gender and Chronic Tinnitus: differences in tinnitus-related distress depend on age and duration of tinnitus. Ear Hear 2013;34:661–672 Lindgren T, Wieslander G, Dammström BG, Norbäck D. Tinnitus among airline pilots: prevalence and effects of age, flight experience, and other noise. Aviat Space Environ Med 2009;80(2):112–116 Brown SC. Older Americans and Tinnitus: A Demographic Study and Chartbook [dissertation]. Washington, USA: Gallaudet University Gallaudet Research Institute; 1990:1–22 Sanchez TG, Zonato AI, Bittar RSM, Bento RF. Controvérsias sobre a fisiologia do zumbido. Int Arch Otorhinolaryngol 1997;1:2–8 White-Barreiro FCA. Basic Audiological Evaluation and Psychoacoustics of Tinnitus. In: Samelli AG. Tinnitus: assessment, diagnosis and rehabilitation. Current approaches. São Paulo: Lovise; 2004. p. 55–9. Ferreira LMBM, Ramos Júnior AN, Mendes EP. Characterization of tinnitus in the elderly and its possible related disorders. Braz J Otorhinolaryngol 2009;75(2):249–255 Moura LOS, Iorio MCM, Azevedo MF. A eficácia da adaptação de prótese auditiva na redução ou eliminação do zumbido. Braz J Otorhinolaryngol 2004;70:624–631 Figueiredo RR, Rates MA, Azevedo AA, Oliveira PM, Navarro PBA. Correlation analysis of hearing thresholds, validated questionnaires and psychoacoustic measurements in tinnitus patients. Braz J Otorhinolaryngol 2010;76(4):522–526

in normal hearing individuals. Int Arch Otorhinolaryngol 2011; 15:468–474 Mondelli MFCG, Rocha AB. Correlation between the audiologic findings and buzz disturbing. Int Arch Otorhinolaryngol 2011; 15:172–180 Lasisi AO, Abiona T, Gureje O. Tinnitus in the elderly: Profile, correlates, and impact in the Nigerian Study of Ageing. Otolaryngol Head Neck Surg 2010;143(4):510–515 Karatas E, Deniz M. The comparison of acoustic and psychic parameters of subjective tinnitus. Eur Arch Otorhinolaryngol 2012;269(2):441–447 Camarano AA. Aging of the population: a demographic contribution. In: EV Freitas, Py G, Neri AL, Cançado FAX, Gorzoni ML, SM Rocha. Treaty of Geriatrics and Gerontology. 2. ed. Rio de Janeiro: Guanabara Koogan; 2006:88–105 Carvalho JAM, Wong LR. The changing age structure of the population in the first half of the XXI century. Cad Saude Publica 2008;24:597–605 Makar SK, Biswas A, Shatapathy P. The impact of tinnitus on sufferers in Indian population. Indian J Otolaryngol Head Neck Surg 2014;66(Suppl 1):37–51 Seimetz BM, Flores LS, Copetti NS, Freitas NB, Gonçalves AK, Teixeira AR. Hearing thresholds of a group of elderly. Proceedings of the 28th International Meeting of Audiology; April 24–27, 2013; Salvador, Brazil. São Paulo, Brazilian Academy of Audiology; 2013. p. 82. Menezes P, Santos Filha VAV. Acuphenometry: the rescue of an assessment instrument of tinnitus and its correlation with sensory hearing loss. Rev Fonoaudiol Bras 2005;3:1–4 Shekhawat GS, Searchfield GD, Stinear CM. The relationship between tinnitus pitch and hearing sensitivity. Eur Arch Otorhinolaryngol 2014;271(1):41–48 Noreña A, Micheyl C, Chéry-Croze S, Collet L. Psychoacoustic characterization of the tinnitus spectrum: implications for the underlying mechanisms of tinnitus. Audiol Neurootol 2002;7(6): 358–369 Sereda M, Hall DA, Bosnyák DJ, et al. Re-examining the relationship between audiometric profile and tinnitus pitch. Int J Audiol 2011; 50(5):303–312 Schecklmann M, Vielsmeier V, Steffens T, Landgrebe M, Langguth B, Kleinjung T. Relationship between Audiometric slope and tinnitus pitch in tinnitus patients: insights into the mechanisms of tinnitus generation. PLoS ONE 2012;7(4):e34878 Silva AL, Butzke BL, Deutsch KM, et al. Correlation between acuphenometry and audiometry in patients with chronic tinnitus. Proceedings of the 32nd Scientific Week of the Porto Alegre University Hospital; 2012 August; Porto Alegre, Brazil. Porto Alegre, Rev. HCPA & Fac. Med. Univ. Fed. Rio Gd. South 2012.; 32 (Suppl.) 100. Pan T, Tyler RS, Ji H, Coelho C, Gehringer AK, Gogel SA. The relationship between tinnitus pitch and the audiogram. Int J Audiol 2009;48(5):277–294 Schecklmann M, Vielsmeier V, Steffens T, Landgrebe M, Langguth B, Kleinjung T. Relationship between Audiometric slope and tinnitus pitch in tinnitus patients: insights into the mechanisms of tinnitus generation. PLoS ONE 2012;7(4):e34878 Morais AA, Gil D. Tinnitus in individuals without hearing loss and its relationship with temporomandibular dysfunction. Braz J Otorhinolaryngol 2012;78:59–65 Aparecida de Azevedo A, Mello de Oliveira P, Gomes de Siqueira A, Figueiredo RR. A critical analysis of tinnitus measuring methods. Braz J Otorhinolaryngol 2007;73(3):418–423

5

6

7 8

9 10 11 12

13

14

15

16

17 18

19

20

21 22

23

24

25

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43


THIEME

Original Research

Auditory Temporal Resolution in Individuals with Diabetes Mellitus Type 2 Rajkishor Mishra1

Himanshu Kumar Sanju2

Prawin Kumar2

1 Department of Audiology, Bloom Senso Hearing Center, Kolkata,

West Bengal, India 2 Department of Audiology, AIISH, Manasagangothri, Mysore, Karnataka, India

Address for correspondence Himanshu Kumar Sanju, MD, Audiology, Department of Audiology, AIISH, Manasagangothri, Mysore, Karnataka, India 570006 (e-mail: himanshusanjuaiish@gmail.com).

Int Arch Otorhinolaryngol 2016;20:327–330.

Abstract

Keywords

► temporal auditory area ► diabetes complications ► auditory stimulation

Introduction “Diabetes mellitus is a group of metabolic disorders characterized by elevated blood sugar and abnormalities in insulin secretion and action” (American Diabetes Association). Previous literature has reported connection between diabetes mellitus and hearing impairment. There is a dearth of literature on auditory temporal resolution ability in individuals with diabetes mellitus type 2. Objective The main objective of the present study was to assess auditory temporal resolution ability through GDT (Gap Detection Threshold) in individuals with diabetes mellitus type 2 with high frequency hearing loss. Methods Fifteen subjects with diabetes mellitus type 2 with high frequency hearing loss in the age range of 30 to 40 years participated in the study as the experimental group. Fifteen age-matched non-diabetic individuals with normal hearing served as the control group. We administered the Gap Detection Threshold (GDT) test to all participants to assess their temporal resolution ability. Result We used the independent t-test to compare between groups. Results showed that the diabetic group (experimental) performed significantly poorer compared with the non-diabetic group (control). Conclusion It is possible to conclude that widening of auditory filters and changes in the central auditory nervous system contributed to poorer performance for temporal resolution task (Gap Detection Threshold) in individuals with diabetes mellitus type 2. Findings of the present study revealed the deteriorating effect of diabetes mellitus type 2 at the central auditory processing level.

Introduction Diabetes mellitus is a multisystem disorder. It is a disorder of carbohydrate metabolism which occurs because of absolute or relative insulin deficiency. Along with metabolic disturbance, various pathologic changes in the human body have been seen. Previous literature reported that the hearing impairment seen in diabetes mellitus is a progressive bilateral sensorineural hearing loss of gradual onset, which mainly affect higher frequencies,

received October 14, 2015 accepted October 28, 2015 published online February 1, 2016

DOI http://dx.doi.org/ 10.1055/s-0035-1571207. ISSN 1809-9777.

similar to age-related hearing loss.1 We also found that hearing loss may be unilateral, sudden, with and without vestibular disorder. Evidence showed that endolymphatic sac vasculature plays an important role in the pathogenesis of sensorineural hearing loss.2,3 The main cause of hearing loss in diabetic patients is vascular insufficiency to the cochlea. Uncontrolled diabetes may cause vasculopathy in stria vascularis of the cochlea. Researchers have reported diffused thickening of basilar membrane observed in vascular endothelium, which is called

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil

327


328

Auditory Temporal Resolution in Individuals with Diabetes Mellitus Type 2 diabetic microangiopathy.4,5 Several studies also reported that microangiopathy is responsible for hearing loss in diabetic individuals6,7 and on the participation of smaller vessels in the inner ear that leads to hypoxia and cause hearing loss.4,8 Maia et al reported that diabetic neuropathy and microangiopathy can cause high frequency hearing loss.9 Moreover, hearing loss was present at all frequencies from 250Hz to 8000Hz in diabetic individuals.8 Studies on hearing thresholds on subjects with diabetes revealed mild to moderate high-frequency sensorineural hearing loss,10 whereas other studies showed higher thresholds in individuals with diabetes mellitus at all frequencies tested. Previous literature also reported no difference in speech discrimination scores among diabetic patients and the normal population.11 A study by Bajaj et al reported poor speech perception in noise among diabetic patients.12 Researchers also reported poor perception of speech in noise in individuals with high frequency hearing loss.13,14 Poor perception of speech in noise in individuals with high frequency hearing loss may be due to poor auditory processing of the signal at a given frequency region due to loss of audibility.15 Cochlear lesion can also affect intensity and frequency coding, as investigated by various researchers.16,17 Previous studies have mostly been conducted with hearing loss evaluation and speech perception ability in diabetic populations. There is a dearth of literature regarding auditory temporal resolution skill in individuals with diabetes mellitus with high frequency hearing loss. Temporal resolution refers to the ability of the auditory system to identify rapid changes in the envelop of a sound stimulus over time.18 The Gap Detection Threshold (GDT) test is a valuable, cost effective tool to assess the ability of an individual to detect minimal small gap between two stimuli of equal characteristics. The GDT can be defined as the shortest duration of gap within a sound that individual can detect. This test is useful and cost effective in assessing auditory temporal resolution skill.19 GDT have been used by previous researchers to study cortical lesion.20 Musiek et al reported GDT is a valuable tool in assessing temporal resolution deficit in brainstem, as well as cortical lesions.21 Therefore, the present study aimed to compare auditory temporal resolution skill in individuals with diabetes mellitus with high frequency hearing loss with agematched normal hearing subjects by assessing Gap Detection Threshold (GDT) between the two groups (experimental and control).

Methods Participants For this study, we recruited thirty participants that provided their informed written consent. We divided them in two groups (Experimental and Control). The experimental group consisted of 15 individuals (8 men and 7 women) with diabetic mellitus type 2 in the age range of 30 to 40 years (mean age of 37.3 years). The control group, in turn, consisted of 15 age-matched non-diabetic individuals (8 men and 7 women) in the age range of 30 to 40 years (mean age of 38.1 years). The rationale behind selecting this age range was to avoid the effect of age related hearing loss. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Mishra et al.

Participants Selection Criteria All the participants in Group 1 (Experimental) had reduced hearing sensitivity (from mild to severe degree) in both ears as defined by pure tone thresholds greater than 15 dBHL at 2000, 4000, and 8000 Hz, with normal hearing sensitivity at 250, 500 and 1000 Hz. Slope was steep when higher than 25dB/octave. All subjects had normal middle ear functioning as revealed by an A-type tympanogram and presence of acoustic reflexes at all frequencies except 2000 Hz and 4000 Hz for both ipsi and contralateral stimulation. There was no history or presence of any other otological, neuromuscular, or neurological problem among both groups. Neither was there any history of noise exposure. As for Group 2 (Control), all the participants had normal air conduction and bone conduction thresholds ( 15 dB HL) at all octave frequencies from 250 Hz to 8000 Hz. They all presented normal middle ear functioning with A-type tympanogram at 226 Hz probe tone having normal acoustic reflexes (Ipsilateral and Contralateral) in both ears.

Test Environment We conducted all the tests in a sound treated.

Instrumentation We used a calibrated dual channel Madsen MA-53 clinical audiometer (Gn Otometrics A/S, Taastrup, Denmark) for pure tone audiometry. We sued a calibrated GSI-Tympstar Immittance meter (GSI, Eden Prairie, U.S.A.) for tympanometry and reflexometry. We used a personal computer loaded with Matlab R 2011a software (Mathworks, Natick, U.S.A.) for GDT (Gap Detection Threshold).

Procedure Pure tone thresholds were obtained using modified versions of the Hughson and Westlake procedure (Carhart & Jerger, 1959) across octave frequencies from 250 Hz to 8000 Hz for air conduction and from 500 to 4000Hz for bone conduction.22 We used the middle ear analyzer (GSI-Tympstar, Eden Prairie, U.S.A.) to carry out tympanometry using a probe tone frequency of 226 Hz and to obtain ipsilateral and contralateral acoustic reflexes thresholds at 500 Hz, 1000 Hz, 2000 Hz, and 4000 Hz. Gap detection threshold was assessed using 750 milliseconds gaussian noise including a gap in its temporal center. Gap duration varied according to listener performance using maximum likelihood procedure. The noise had 0.5 milliseconds cosine ramps at the beginning and end of the gap. In the three alternative forced choice task, the reference stimulus was always a 750 milliseconds white noise without gap, whereas the variable stimulus contained a gap. We took the minimum gap duration required to perceive a gap in noise as threshold.

Statistical Analysis We conducted descriptive statistics to find mean and standard deviation of GDT of the groups. We used an independent t-test to compare between the experimental and the control group for GDT.


Auditory Temporal Resolution in Individuals with Diabetes Mellitus Type 2 Table 1 Mean and SD of gap detection threshold (GDT) for Group 1 (experimental) and Group 2 (control) Measures

GDT (ms)

Groups Group 1 (Experimental)

Group 2 (Control)

Mean

SD

Mean

SD

6.49

0.81

3.33

0.79

Abbreviation: GDT, gap detection threshold; SD, standard deviation.

Results In the present study all participants underwent Gap Detection Threshold test. We analyzed the data using SPSS software Version 18 (IBM Corporation, Armonk, U.S.A.).

Gap Detection Threshold (GDT) Test We conducted the GDT test for both groups. ►Table 1 shows mean and standard deviation (SD) of gap detection threshold. Descriptive statistical analyses showed that GDT was better for Group 2 when compared with Group 1. ►Fig. 1 shows a graphical presentation of the outcome. We administered the independent t-test to compare GDT between two groups. It showed a statistically significant difference between the groups (t ¼ 7.82; df ¼ 28; p < 0.05).

Discussion The results of the present study showed poor auditory temporal resolution skill in patients with diabetes mellitus type 2 having high frequency hearing loss compared with age matched non-diabetic normal hearing subjects. The present study revealed a statistically significant difference in GDT between patients with diabetes mellitus type 2 having high

Mishra et al.

frequency hearing loss (Group 1) and age-matched nondiabetic normal hearing subjects (Group 2). Absence of the specific literature on GDT in diabetic individuals renders it difficult to explain the result found in the present study. However, widened auditory filter at higher frequencies and poor central auditory processing due to diabetes mellitus type 2 could be a possible explanation for poorer gap detection task. The present study showed poor performance in temporal resolution task by diabetic patients which revealed changes in the central auditory system. Previous studies on diabetic humans and rats showed hearing impairment mainly caused by edema in stria vasularis and reduction in number of spiral ganglion cells and outer hair cells.23–25 Hearing loss in HF region suggests that the cochlea may have been damaged by angiopathy in the stria vascularis, spiral ligament, and edema in the stria vascularis, which leads to poor frequency and intensity coding.16,26,27 Previous literature reports poor auditory brainstem response with prolonged latencies of wave III, V and inter-peak I-III in diabetic population. Prolonged latencies were also noted for wave V and interpeak III-V, inter-peak I-III, and I-V in diabetic individuals at 90 dBnHL.28 This possibly suggests the involvement of the relay stations of different order neurons in the central auditory nervous system. The present study supports the study done by McCrimmon et al, which also reported poor temporal and auditory processing in individuals with diabetes mellitus.29 A similar study done by Sommerfield revealed that tests of immediate verbal and immediate visual memory were significantly poor during hypoglycemia.30 The adverse effect of hypoglycemia on working memory and delayed memory was more profound. The present studý s findings showed poor temporal resolution skill can be due to widening of auditory filter and changes in the central auditory nervous system contributing to the poorer performance on the temporal resolution task in diabetic individuals.

Fig. 1 Mean values of Gap Detection Threshold (GDT) for Group 1 (Experimental) and Group 2 (Control).

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

329


330

Auditory Temporal Resolution in Individuals with Diabetes Mellitus Type 2

Conclusion

14 Stuart A, Phillips DP. Word recognition in continuous and inter-

Present study findings showed poor temporal resolution skills in individuals with diabetes mellitus type 2 compared with control group. Poor auditory temporal resolution may cause poor speech perception in these individuals in quiet, as well as in noise. Findings revealed the deteriorating effect of diabetes mellitus type 2 at the central auditory processing level. Thus, we would suggest screening all patients with diabetes for temporal resolution ability to understand the mechanism underlying speech perception in noise.

15

16

17 18 19

References

20

1 Jorgensen MB, Buch NH. Studies on the sense of smell and taste in

diabetics. Acta Otolaryngol 1961;53(2):539–545 2 Leone CA, Feghali JG, Linthicum FH Jr. Endolymphatic sac: possible

3 4

5

6

7 8

9 10

11 12

13

role in autoimmune sensorineural hearing loss. Ann Otol Rhinol Laryngol 1984;93(3 Pt 1):208–209 Gussen R. Vascular mechanisms in Meniere’s disease. Theoretical considerations. Arch Otolaryngol 1982;108(9):544–549 Malpas S, Blake P, Bishop R, Robinson B, Johnson R. Does autonomic neuropathy in diabetes cause hearing deficits? N Z Med J 1989;102(874):434–435 Konrad-Martin D, Austin DF, Griest S, McMillan GP, McDermott D, Fausti S. Diabetes-related changes in auditory brainstem responses. Laryngoscope 2010;120(1):150–158 Makishima K, Tanaka K. Pathological changes of the inner ear and central auditory pathway in diabetics. Ann Otol Rhinol Laryngol 1971;80(2):218–228 Costa OA. Inner ear pathology in experimental diabetes. Laryngoscope 1967;77(1):68–75 Wackym PA, Linthicum FH Jr. Diabetes mellitus and hearing loss: clinical and histopathologic relationships. Am J Otol 1986;7(3): 176–182 Maia CA, Campos CA. Diabetes mellitus as etiological factor of hearing loss. Braz J Otorhinolaryngol 2005;71(2):208–214 Celik O, Yalçin S, Celebi H, Oztürk A. Hearing loss in insulindependent diabetes mellitus. Auris Nasus Larynx 1996;23(8): 127–132 Cullen JR, Cinnamond MJ. Hearing loss in diabetics. J Laryngol Otol 1993;107(3):179–182 Bajaj G, Puthuchery S, Bhat J, Ranjan R. Effect of type 2 diabetes on speech perception in noise. Int J Innov Res Dev 2014;3(4): 50–54 Dubno JR, Dirks DD, Morgan DE. Effects of age and mild hearing loss on speech recognition in noise. J Acoust Soc Am 1984;76(1):87–96

International Archives of Otorhinolaryngology

Mishra et al.

Vol. 20

No. 4/2016

21

22 23

24

25

26

27

28

29

30

rupted broadband noise by young normal-hearing, older normalhearing, and presbyacusic listeners. Ear Hear 1996;17(6):478–489 Moore BC. Perceptual consequences of cochlear hearing loss and their implications for the design of hearing aids. Ear Hear 1996; 17(2):133–161 Florentine M, Reed CM, Rabinowitz WM, Braida LD, Durlach NI, Buus S. Intensity perception. XIV. Intensity discrimination in listeners with sensorineural hearing loss. J Acoust Soc Am 1993; 94(5):2575–2586 Simon HJ, Yund EW. Frequency discrimination in listeners with sensorineural hearing loss. Ear Hear 1993;14(3):190–201 Plack CJ, Viemeister NF. Suppression and the dynamic range of hearing. J Acoust Soc Am 1993;93(2):976–982 Lister J, Besing J, Koehnke J. Effects of age and frequency disparity on gap discrimination. J Acoust Soc Am 2002;111(6):2793–2800 Efron R, Yund EW, Nichols D, Crandall PH. An ear asymmetry for gap detection following anterior temporal lobectomy. Neuropsychologia 1985;23(1):43–50 Musiek FE, Shinn JB, Jirsa R, Bamiou DE, Baran JA, Zaida E. GIN (Gaps-In-Noise) test performance in subjects with confirmed central auditory nervous system involvement. Ear Hear 2005; 26(6):608–618 Carhart R, Jerger J. Preferred method for clinical determination of pure-tone thresholds. J Speech Hear Disord 1959;24(4):330–335 Raynor EM, Carrasco VN, Prazma J, Pillsbury HC. An assessment of cochlear hair-cell loss in insulin-dependent diabetes mellitus diabetic and noise-exposed rats. Arch Otolaryngol Head Neck Surg 1995;121(4):452–456 Fukushima H, Cureoglu S, Schachern PA, et al. Cochlear changes in patients with type 1 diabetes mellitus. Otolaryngol Head Neck Surg 2005;133(1):100–106 Lee HS, Kim KR, Chung WH, Cho YS, Hong SH. Early sensorineural hearing loss in ob/ob mouse, an animal model of type 2 diabetes. Clin Exp Otorhinolaryngol 2008;1(4):211–216 Nelson DA, Freyman RL. Psychometric functions for frequency discrimination from listeners with sensorineural hearing loss. J Acoust Soc Am 1986;79(3):799–805 Schroder AC, Viemeister NF, Nelson DA. Intensity discrimination in normal-hearing and hearing-impaired listeners. J Acoust Soc Am 1994;96(5 Pt 1):2683–2693 Gupta R, Aslam M, Hasan S, Siddiqi S. Type -2 diabetes mellitus and auditory brainstem responses-a hospital based study. Indian J Endocrinol Metab 2010;14(1):9–11 McCrimmon RJ, Deary IJ, Frier BM. Auditory information processing during acute insulin-induced hypoglycaemia in non-diabetic human subjects. Neuropsychologia 1997;35(12):1547–1553 Sommerfield AJ, Ewing FM, Strachan MW, Deary IJ, Aitken G, Frier BM. Self-treatment of mild symptomatic hypoglycaemia by people with insulin-treated diabetes. Diabet Med 2003;20(8):686–687


THIEME

Original Research

Workplace Activity in Health Professionals Exposed to Chemotherapy Drugs: An Otoneurological Perspective Natália Martinez Fernandes1 Isadora Gonçalves Pelissari1 Valdete Alves Valentins dos Santos Filha1 1 Department of Speech-Language Pathology and Audiology,

Universidade Federal de Santa Maria, RS, Brazil 2 Post-Graduation Student, Department of Speech-Language Pathology and Audiology, Universidade Federal de Santa Maria, RS, Brazil

Licia Assunção Cogo2

Address for correspondence Natália Martinez Fernandes, Department of Speech Language Pathology and Audiology, Universidade Federal de Santa Maria, Avenida Roraima 1000, Santa Maria, RS 97105900, Brazil (e-mail: nataliafernandes.fono@gmail.com).

Int Arch Otorhinolaryngol 2016;20:331–338.

Abstract

Keywords

► hearing ► drug therapy ► occupational health services ► vestibular function tests ► dizziness

Introduction The manipulation of antineoplastic drugs presents high risk for accidents and occupational diseases. Objective To evaluate the auditory and vestibular systems of workers who are exposed to chemotherapeutic treatment in the University Hospital of Universidade Federal de Santa Maria, Brazil, and to identify the use of individual protection equipment, related to the obtained results. Methods This study is a cross-sectional study using a quantitative method. We evaluate 33 male and female workers, ranging from 21–60 years old, of the nursing and pharmacy sectors. The workers underwent conventional Audiologic Assessment; Transient Evoked Otoacoustic Emissions; and Computerized Vectoelectronystagmography. Results The majority of the sample was female (90.9%). Individual protection equipment was used by 90.9% of the workers. Complaints of dizziness were reported by 56.25% of nursing workers and 52.94% of pharmacy workers. Audiological and vestibular assessment results were within normal limits, 96.97% and 74.20%, respectively. However, audiometric configuration of notch type was identified in 75.75% of all workers. Audiometric notches (76%) and altered caloric test (100%) were often associated with decreased use of coal masks. Conclusion Among the workers evaluated, the vestibulocochlear system was within the normal limits. The presence of notch configuration indicates the need to use individual protection equipment.

Introduction Cancer is the name given to different diseases which resemble one another by uncontrolled growth of abnormal cells, with invasive potential and originated by multifactorial causes.1 The disease is considered the second leading cause of death worldwide and is considered a public health problem.2

received September 22, 2015 accepted November 24, 2015 published online February 12, 2016

DOI http://dx.doi.org/ 10.1055/s-0036-1572431. ISSN 1809-9777.

Treatment with chemotherapy, a systemic treatment modality, is considered the major option for cancer control.3 Chemotherapeutic, antineoplastic, or cytostatic agents are drugs used, in combination or alone, with the aim of eliminating neoplasms. These drugs work on the cell level, interfering in the process of cell growth and division. Most of these drugs are not selective in destroying only tumor cells, and, therefore, also interfere in normal cells.4

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil

331


332

Workplace Activity in Health Professionals Exposed to Chemotherapy Drugs As the number of cancer cases increases, so does the demand for professionals involved in the care and treatment of these patients. This, in turn, increases the occupational risks to which these professionals are exposed. The handling of antineoplastic drugs is considered the major occupational exposure to chemical agents in hospitals, and involves a high risk of accidents and work diseases,5 affecting mostly pharmacists, nurses, and nurse technicians, who are constantly involved in preparing and administrating these drugs. This is because the inhalation of aerosol and percutaneous absorption of residues and particles are the main routes of exposure.6 Such agents may go unnoticed, leading to an immediate or delayed health-disease process7 to the worker. Chemotherapeutic agents have been a constant object of research in the areas of pharmacology and nursing.5–11 However, organic reactions after exposure to antineoplastic drugs are still unclear. It is believed that these drugs can harm workers’ health due to their toxicity, and may cause undesirable and irreversible side effects when exposed and manipulated without safety measures. According to the literature,12 gases and vapors present in the hospital environment affect the organism, causing various reactions, such as weakness, fainting, drowsiness, seizure, vomiting, headache, vision disturbances, tremor, cough, conjunctival tearing, and dizziness. Auditory and vestibular disorders can result from the exposure to ototoxic drugs and noise.13 The contact with ototoxic drugs, considered cochleo-toxic (affect hearing) and vestibulartoxic (affect balance),14 can lead to functional changes or cell damage in the inner ear (anterior and posterior labyrinth),15 acting in the brainstem and/or central nervous system.15,16 Hearing is a complex sense that enables us to identify, locate, and process sounds, allowing people to do activities that range from monitoring danger signals and understanding speech to appreciating music. For this system to function properly, all of the path the sound will travel through has to be healthy, from the outer ear to the central auditory pathways.17 Hearing damage from ototoxicity is characterized by cochlear, bilateral, symmetrical, and irreversible hearing loss. It begins by the high frequencies, and its degree depends on the concentration of the ototoxic element. There may also be tinnitus and dizziness.18 In addition to hearing, balance can also be affected by chemotherapy. The vestibular system is responsible for informing about the position and movement of the head, providing us with sense of balance, which assists in the coordination of head and eye movements, as well as in body posture adjustments. When its function is disrupted, unpleasant sensations can occur, such as dizziness, nausea, and a feeling of lack of balance with uncontrollable eye movements.19 Brazil’s Ministry of Labor’s Regulatory Standard number 9 (NR-9) establishes the obligation of the preparation and implementation of Environmental Risk Prevention Programs (ERPP), to preserve the health and integrity of workers. Among the actions of the program are the evaluation and control of risks in the work environment.20 To monitor the ototoxicity in hearing as well as in body balance, it is believed that different procedures can be used. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Fernandes et al.

Audiometry is an effective method, because it assesses the auditory pathway quantitatively. Otoacoustic emissions may also contribute, as they directly evaluate the outer hair cells of the cochlea, working as a predictor for hearing loss.21 On the other hand, the vectoelectronystagmography, crucial in otoneurological evaluation, provides data about the vestibulo-oculomotor function and its correlation with the brainstem, cerebellum and other connections to the central nervous system.22 Another important aspect that should be considered in relation to studies involving chemotherapy handling are the ways to reduce occupational exposure to these agents, in particular the adoption of procedures for prevention and the use of Personal Protective Equipment - PPE (googles, masks, latex gloves, and apron), essential during every stage of drug manipulation.23 The focus of studies concerning the effect of chemotherapy is generally patients in oncological treatment, that is, those who receive medication, disregarding the workers who apply it, and are exposed to the drugs on a daily basis. Thus, the aim of this study was to investigate the health conditions of the auditory and vestibular systems of health care professionals exposed to chemotherapeutic drugs, through conventional hearing evaluation, otoacoustic emissions by transient stimuli, and computerized vectoelectronystagmography; as well as to identify the use of Personal Protective Equipment, connecting it to the results obtained.

Methods This was an observational, descriptive, cross-sectional study, which used a quantitative method. This study was approved by the Research Ethics Committee (CEP) of Universidade Federal de Santa Maria, in section 04.10.2013, under protocol number 306 039, and is part of a project entitled Integrated Otoneurological Evaluation in Individuals Assisted by a University Hospital. The study was conducted at the Ambulatory of Otoneurology - Balance and Audiology sector of a University Hospital. The sample consisted of 33 health professionals in the Nursing and Pharmacy sectors of a University Hospital, exposed to chemotherapy, with ages ranging from 21 to 60 years old, male and female, after agreeing with participating in the research by reading and signing the Free and Informed Consent. The investigation adopted the following inclusion criteria: being in contact with antineoplastic agents - injectable chemotherapy drugs and/or pills - not necessarily having complaints regarding hearing and/or balance disorders. The exclusion criteria involved individuals with neurological, or cognitive impairments, middle ear disorders, and/or significant visual impairments that could prevent vestibular and hearing evaluation. We tested the health professionals by means of audiological evaluations, composed by anamnesis, to obtain previous and current medical and occupational history of the worker concerning auditory and vestibular complaints, data regarding the history of exposure to chemicals and use of Personal


Workplace Activity in Health Professionals Exposed to Chemotherapy Drugs Protective Equipment (PPE). The patients underwent a visual inspection of the external acoustic meatus using a Heidji otoscope; Pure tone audiometry at frequencies of 250 to 8000 Hz by air conduction (AC), and 500 to 4000 Hz by bone conduction (BC) (in frequencies with auditory thresholds of air conduction above 25dB, in both ears); Logoaudiometry - Speech Recognition Threshold (SRT) and Speech Recognition Percentage Index (SRPI), done in an acoustic booth with a pair of TDH-39P headphones (Vitasons, Porto Alegre, Brazil), using a digital two-channel Otometrics audiometer, model Itera II (Telephonics, Taastrup, Denmark), calibrated according to the ANSI-69 standard; Acoustic Immitance Measures (tympanometry with a 226Hz probe tone, and research of the acoustic reflex of the contralateral stapedius muscle – dBNS with research of the thresholds at 0.5; 1; 2 and 4 kHz, using the Interacoustic middle ear analyzer, model AT235 (Middelfart, Denmark), and Transient evoked otoacoustic emissions (TEOAEs), beginning by the right ear. We used parameters for analysis proposed by the authors,24 that is, non-linear clicks with regular pulses lasting 80 microseconds (μs), polarity rarefied, in a series of 260 stimuli in eight-clicks blocks each, with repetition frequency of 50 cycles per second. As for the spectrum of emissions, the standard stimulus contains energy distributed in the frequency bands of 0.7; 1.0; 1.4; 2.0; 2.8; and 4 kHz, using the cochlear analyzer Otoread in an acoustic booth. Then, were evaluated the professionals in terms of vestibular assessment through the computerized Vectoelectronystagmography (VNG), after previous preparation. Initially, their skin was cleaned with alcohol, and then the electrodes were fixed by means of electrolytic paste and adhesive tape (micropore tape) in the periorbital region, disposed as an isosceles triangle: one electrode on each outer eyelid angle of the eye, the other on the front (earth electrode) and the last 2 cm above the glabela (active electrode), enabling the recording of horizontal, vertical, and oblique movements. The individuals were seated in a swivel chair, 1m to the Led’s bar. The VNG comprised calibration (horizontal and vertical); research of spontaneous nystagmus with open and closed eyes; research of semispontaneous or directional nystagmus (right, left, top, and bottom); of pendular tracking; of optokinetic nystagmus (clockwise and counterclockwise); of per-rotatory nystagmus or decrescent rotatory pendular test (head 30° forward), and; research of post-caloric nystagmus with stimulus of water at 30° and 44°C, according to the proposed criteria.22 For the vestibular-oculomotor evaluation, we used the Contronic VNG computerized system, model SCV, version 5.0, and Nistagmus software. At the end of the collection, the data were tabulated in an online Excel spreadsheet and analyzed statistically. Concerning the statistical method used, we performed a descriptive critical analysis on percentage, mean, standard deviation, and median values, as well as the Fisher’s exact test and chisquare statistical analysis.

Results The sample consisted of 33 health professionals exposed to chemotherapy agents, of whom 90.9% were female and 9.1%

Fernandes et al.

male, with an average age of 37.18 years (  13.20). The age group from 20 to 35 represented 54.54% of the population, 18.2% between 35 and 45 years, and between 50 and 60 years of age the percentage was 27.3%, as there were no individuals in the age group between 45 and 50 years. 51.52% of these professionals work in the field of pharmacy and 48.48% in nursing. Considering the professionals exposed to chemotherapy agents working in the areas of nursing and pharmacy, 56.25% and 52.94% reported dizziness, respectively. Upon Chi-square test, there was no statistically significant difference (p ¼ 0.84). Regarding the variable time of service exposed to chemotherapy agents, 51.51% work for less than five years in the field, considering this as the most frequent occurrence; with an average time of 10.66 years ( 10.54). Concerning the presence of dizziness, 54.54% had some type of dizziness, from which 61.12% was non-rotatory and 38.88% rotatory, in addition to 75.75% of neurovegetative symptoms. The main extra-hearing complaints reported in the anamnesis were anxiety (69.7%), stress (56.6%), nervousness (51.5%), headache (45.5%), and depression (30.3%). In the audiological assessment, 96.97% of the participants had hearing thresholds within the normal range according to the tritone average (0.5, 1 and 2 kHz), and 3.03% had mild sensorineural hearing loss; identifying notch configuration in 75.75% of the individuals; 40% notched at a frequency of 6 kHz (eight RE, two LE), 24% at a frequency of 4 kHz (three RE, three LE), and 36% in both ears at 6 kHz. All evaluated subjects (100%) presented tympanometry curve type A, and the contralateral acoustic reflex was present in 87.87% in the right ear and 93.93% in the left ear. In addition, there were otoacoustic emissions by transient stimuli in 100% of the assessed individuals. ►Table 1 indicates the distribution of absence and presence of notch in the audiometric configuration of the workers with and without dizziness complaint. The distribution of presence and absence of notch in the audiometric configuration of Pharmacy and Nursing workers is shown in ►Table 2. The association between the occurrence of normal and abnormal results in research of the post-caloric nystagmus and the presence and absence of notch in the audiometric configuration is identified in ►Table 3. In the vestibular assessment, 31 professionals were submitted to VNG. From the results, 100% of the participants had regular calibration, absence of spontaneous and semi-spontaneous nystagmus with eyes open and closed; 83.87% showed horizontal pendular tracking type I, and 16.13% type II; 70.97% showed vertical pendular tracking type I, 16.13% type II, and 12.90% of the subjects type III; symmetry was present in 90.32% in the optokinetic nystagmus test, and 96.77% in the decrescent rotatory pendular test. In the research of post-caloric nystagmus, we observed the diagnosis of normal reflexes in 74.20% of the participants, hyperreflexia in 12.90%, labyrinth predominance in 9.68%, and 3.22% with hyporreflexia. From the analysis of the results found in vestibular tests, we identified that 74.20% of the International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

333


334

Workplace Activity in Health Professionals Exposed to Chemotherapy Drugs

Fernandes et al.

Table 1 Distribution of absence and presence of notch in the audiometric configuration in workers with and without dizziness Group

Notch absence N (%)

Notch presence N (%)

Total N (%)

With dizziness

7 (87.50)

11 (44.00)

18 (54.54)

Without dizziness

1 (12.50)

14 (56.00)

15 (45.45)

Total

8 (100.00)

25 (100.00)

33 (100.00)

p-value

0.04

Fisher’s exact test  p < 0.05.

Table 2 Association between the occurrence of normal and abnormal results of the post-caloric nystagmus and the presence and absence of notch in the audiometric configuration Group

Total N (%)

p-value

23 (74.19)

23 74,19

0.15

4 (17.40)

8 (25.81)

8 25,81

23 (100.00)

31 (100.00)

31 100,00

Notch YES N (%)

NO N (%)

Normal

19 (82.60)

Altered Total Fisher’s exact test.

subjects were diagnosed as within the normal range, one (12.90%) subject presented peripheral vestibular deficit dysfunction, and another (12.90%), vestibular dysfunction. ►Table 4 shows the distribution of occurrence of normal and abnormal results in the research of post-caloric nystagmus in pharmacy and nursing workers. Considering the health professionals investigated, we observed that 90.9% use some kind of Personal Protective Equipment (PPE): 90.9% wear gloves; 84.84% wear aprons; 69.69% wear common masks; 24.24% wear caps; 21.21% wear activated coal masks, and 9.09% wear goggles. We present the association between the occurrence of normal and abnormal results in the research of post-caloric nystagmus and whether workers of pharmacy and nursing wear coal masks and gloves or not in ►Table 5. ►Table 6 shows the association between the occurrence of notch in the audiometric configuration and whether workers of pharmacy and nursing wear coal masks and gloves or not.

Discussion The population of this study was mostly female. This is similar to the data obtained by other authors,5–10 who had 63.3%,

70%, and 88% of female subjects, respectively. Health practices are closely related to the act of caring, and this is historically linked to the female gender; therefore, it is natural to find a higher incidence of women in participants of the health sector, especially in nursing.5 As regards to age, there was a prevalence of young adults, with 70% of the population aged 20–35 years old.5 Another author8 studied a 21–47-year-old age group in this occupation. The study’s data are similar to those found in our study. In the current study, health professionals exposed to chemotherapy agents are categorized in the areas of pharmacy and nursing, corroborating a study9 that identified such as the areas with higher exposure to such chemical agents in a hospital. As for the duration of exposure to chemotherapy drugs, we observed in this study that most professionals have been working in the field for less than five years. Such results corroborate other studies found in the literature,8 in which the time of professional experience of the nursing staff in the chemotherapy sector was higher than two years (76.70%). In contrast, another study10 found that 67% of the nurses working in the chemotherapy sector had been in the job for more than five years.

Table 3 Distribution of the presence and absence of notch in the audiometric configuration on workers of Pharmacy and Nursing Group

Notch

Total N (%)

p-value

0.11

YES N (%)

NO N (%)

Pharmacy

15 (60.00)

2 (25.00)

17 (51.51)

Nursing

10 (40.00)

6 (75.00)

16 (48.49)

Total

25 (100.00)

8 (100.00)

33 (100.00)

Fisher’s exact test. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016


Workplace Activity in Health Professionals Exposed to Chemotherapy Drugs

Fernandes et al.

Table 4 Distribution of occurrence of normal and abnormal results in the post-caloric nystagmus of workers of Pharmacy and Nursing Group

Normal N (%)

Altered N (%)

Total N (%)

p-value

Pharmacy

13 (56.52)

2 (25.00)

15 (48.39)

0.21

Nursing

10 (43.48)

6 (75.00)

16 (51.61)

Total

23 (100.00)

8 (100.00)

31 (100.00)

Fisher’s exact test.

Table 5 Association between the occurrence of normal and abnormal results in the post-caloric nystagmus and the use or not of coal masks and gloves by workers of Pharmacy and Nursing PPE

Group

Normal N (%)

Altered N (%)

Total N (%)

p-value

Coal Mask

Yes

7 (30.43)

0 (0.00)

7 (22.58)

0.14

No Total Glove

16 (69.57)

8 (100.00)

24 (77.42)

23 (100.00)

8 (100.00)

31 (100.00)

22 (96.65)

6 (75.00)

28 (90.32)

Yes No

Total

1 (4.35)

2 (25.00)

3 (9.68)

23 (100.00)

8 (100.00)

31 (100.00)

0.15

Fisher’s exact test. Abbreviations: PPE, personal protective equipment.

Table 6 Association between the occurrence of notch in the audiometric configuration and the use or not of coal masks and gloves by workers of Pharmacy and Nursing PPE

Group

Notch/yes N (%)

Notch/no N (%)

Total N (%)

p-value

Coal Mask

Yes

6 (24.00)

1 (12.50)

7 (21.22)

0.65

No Total Glove

19 (76.00)

7 (87.50)

26 (78.78)

25 (100.00)

8 (100.00)

33 (100.00)

25 (100.00)

5 (62.50)

28 (84.84)

Yes No

Total

0 (0.00)

3 (37.50)

3 (15.16)

25 (100.00)

8 (100.00)

33 (100.00)

0.01

Fisher’s exact test;  p < 0.05. Abbreviations: PPE, personal protective equipment.

There is a scarcity of epidemiological studies addressing the time of occupational exposure to chemotherapy agents that can cause hearing loss or balance disorders; however, research25 indicates that individuals in contact with ototoxic chemical products may begin to show hearing loss as early as two or three years of exposure to these substances, while noise exposure would take four to five years. According to that, the population of this study is already within the risk range, considering that hearing loss can be triggered by the ototoxic chemical process. The current study also highlighted the prevalence of nonrotating dizziness associated with neurovegetative symptoms. In a study26 conducted with nurses who had direct contact with medications, solutions, antiseptics, chemother-

apy agents, etc., dizziness complaints were reported, but not specified, and persisted even with the use of PPE. Regarding the neurovegetative symptoms, a study8 identified that 10% of the nurses evaluated showed symptoms such as nausea and heat in the face when in contact with the chemotherapy drug. In the current study, there were extra-auditory complaints, shown in decreasing order herein: anxiety, stress, nervousness, headache, and depression. This corroborates research27 conducted with workers of a hospital, which found that headache was the fourth symptom related to work, pointing out the relationship between hospital work and extra-auditory complaints. Such symptoms can be observed either in the preparation or in the administration of antineoplastic drugs without the use of collective or personal International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

335


336

Workplace Activity in Health Professionals Exposed to Chemotherapy Drugs protective equipment, which implies a significant and inappropriate absorption of such substances.28 In the same study,28 risks caused by handling antineoplastic drugs result from the inherent toxicity of the drug and the time of exposure to them. Moreover, the authors report that the extra-auditory complaints can be compared with those presented by patients being treated with these substances. In the present study, we observed that most professionals in nursing and pharmacy had complaints of dizziness. Despite the lack of studies showing the percentage of occurrence of dizziness in these occupations, it is important to highlight that occupational exposure to antineoplastic drugs can cause immediate (headache, vertigo, dizziness, and vomiting), or late effects (carcinogenesis, mutagenic, and teratogenic).29 Among the main drugs used by the population evaluated are carboplatin, cyclophosphamide, cisplatin, doxorubicin, gentamicin, vinblastine, fluorouracil, vincristine, among others. These drugs are causers of reactions that are toxic to the inner ear structures, and could harm the auditory and/or vestibular system, either centrally and/or peripherally.15–30 The exposure to these drugs can cause various effects, including vertigo, which was observed in professionals responsible for the preparation or administration of antineoplastics without the use of protective equipment.9 The same author points out that the effects caused by the contact with these substances can be compared with those presented by patients undergoing antineoplastic treatment. According to the literature,31 the use of aminoglycosides and platinum derivatives such as cisplatin have been pointed as the most common cause of permanent hearing loss by ototoxic drugs. The incidence of hearing loss induced by cisplatin ranges from three to 100% in the literature. This data does not differ from those of a study32 that evaluated children undergoing cisplatin treatment, and identified that ototoxic effects initially affect high frequencies, with subsequent impairment of medium and, subsequently, of low frequencies, according to the cumulative dose of the drug, characterizing the cisplatin-induced hearing loss as sensorineural, bilateral, symmetrical, and irreversible. In the audiological evaluation of the current study, most workers presented hearing thresholds within the normal limits according to the tone average (0.5, 1, and 2 kHz) and notch configuration in high frequencies. When evaluating the hearing of patients undergoing treatment with cisplatin, authors33 state that hearing loss induced by the use of this drug can occur even after the interruption of the treatment, showing the prolonged and cumulative effect of chemotherapy in the human organism. This study also establishes the importance of the audiologic routine test battery in patients undergoing chemotherapy. Due to the intense exposure, it is understood that this monitoring should be expanded to professionals who come into contact with these substances. In the present study, even though lowered tone thresholds were not found, the presence of notch could be identified as an indicator for taking control and prevention measures in relation to the damage caused by ototoxicity. For this reason, International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Fernandes et al.

the auditory and vestibular monitoring is believed to be of great importance for early detection of the effects of ototoxicity on workers. During the audiological assessment, we found a tympanometric curve of type A and contralateral acoustic reflex. Studies34,35 have shown that the majority of workers exposed to chemical agents have tympanometry curve of type A in both ears; in 75% of subjects in the right ear, and 100% in the left ear, respectively; however, there was a prevalence of bilaterally absent contralateral acoustic reflexes. Regarding transient otoacoustic emissions, we identified in this study that optoacoustic emissions by transient stimuli were present in the whole population studied, indicating normal cochlear function of outer hair cells. Similar results were found in 100% of the patients treated with cisplatin.31,32 Otoacoustic emissions (OAEs) are used to monitor hearing in individuals exposed to ototoxic drugs,36 since they could be a predictor for hearing loss in occupational cases.21 Concerning the distribution of presence or absence of a notch in the audiometric configuration of the workers with and without dizziness complaint, in addition to observing statistically significant differences, a positive association was found, since most individuals with dizziness complaints had notch configuration, indicating that there is an association of the facts in this population. Regarding other associations focusing on clinical exams, no significant differences were found. However, the presence of notch in the hearing configuration could be observed regardless of occupation, as well as a higher percentage of normal results, while in the group of nursing workers there was a higher percentage of abnormal results, respectively; even though we observed no statistically significant difference. In both occupations, there was a higher percentage of normal results (►Table 2); and a higher percentage of workers with notch configuration and normal results in post-caloric nystagmus (►Table 3). According to authors,37 most drugs are damaging to the cochlea and, to a lesser extent, the vestibule. In the literature studied, we did not identify research that made similar associations to those described in the previous paragraph, nor studies using VNG as an evaluation method in the population studied. Therefore, we decided to compare the results obtained in this study with those found through other evaluation methods, as well as those of studies with workers exposed to other chemicals considered potentially damaging to the vestibular system. Authors38 evaluating the vestibular system through cephalic auto-rotation in the horizontal plane of patients before and after cisplatin use, concluded that the reduction in the performance of the vestibulo-ocular reflex observed in these patients could be due to chemotherapy, confirming that this instrument is effective for monitoring vestibulotoxicity. By evaluating workers exposed to organophosphorus compounds, researchers39 identified 88% of alterations of irritative peripheral vestibular syndrome in VNG, nine by changes in caloric tests, with hyperreflexia in absolute values. Regarding the use of PPE, gloves were the most common equipment, followed by the apron and common mask. Activated carbon masks and goggles, essential equipment for


Workplace Activity in Health Professionals Exposed to Chemotherapy Drugs handling chemotherapy drugs as they reduce the penetration of aerosols by the worker,23–40 are used by a smaller share of the population, and the difficulty of access is the justification reported by the workers in this study. In line with a study41 that asked workers about the availability of PPE, we found that 41.80% of the professionals considered access to these devices as insufficient. These data were also similar to those found in another study,8 in which 23.3% of the nurses surveyed did not use goggles, coal mask, or disposable apron; another study5 also identified that 35% of the subjects did not use goggles. The use of PPE in the professional practice should be investigated and demanded by supervisors and also by employees. The national literature42 points out that the greater vulnerability of the nursing staff in relation to accidents at work, when compared with staffs of other fields, may be linked to the organizational process and the unavailability of personal protective equipment. While identifying the hazards of exposure to chemotherapy drugs by nurses, a study8 observed a higher risk among workers who do not use PPE, or do not use it properly. According to authors,11 there is still a low usage of PPE among healthcare professionals, which constitutes a barrier to the adoption of preventive measures. We found that there is no association between normal and abnormal results in post-caloric nystagmus and use or not of coal mask in the healthcare professions evaluated. The same was true for the occurrence of notch configuration on audiometry and use of PPE (gloves and coal mask). Although there is no association, one should take into consideration that the professionals who wear gloves achieved a higher incidence of normal results in post-caloric nystagmus, corroborating a study39 that linked the possible difference in the outcomes of VNG and non-use of PPE, once 77.8% of the research subjects who do not use PPE showed changes in vectoelectronystagmography. In addition, there is a higher incidence of notch in the professionals who did not use coal mask. Researchers9 pointed out that exposure to these substances without precautions can cause risk of contact and/or absorption to workers, be it in the activities which involve handling the substance for preparation, in the administration of the drug, or during the contact with excretions of the patient. Authors43 detected the presence of antineoplasic drugs in the urine of health professionals who manipulated these drugs without the use of PPE, suggesting that the use of the equipment could prevent such contamination. It is important to emphasize that the lack of use of PPE may cause the alterations to become even more severe. Due to this, particular attention is needed to the providing of PPE by employers, and its effective usage by workers exposed to chemotherapy drugs when handling, administrating, or applying them, so that possible injuries to the vestibular and hearing health are prevented. It was possible to notice that the majority of the population studied showed a higher occurrence of normal results on hearing and vestibular evaluation of workers exposed to chemotherapy drugs, but we cannot ignore this small percentage of abnormal findings, since they can provide clinically significant data, especially when used with other procedures.

Fernandes et al.

Furthermore, we believe in the importance of continuing research so as to obtain more information on this topic, once there is a scarcity of studies that discuss it, and the diseases caused by exposure can lead to irreversible consequences for hearing and vestibular health as well as for health conditions in general.

Conclusion The pharmacists and nurses exposed to chemotherapy drugs evaluated in this study are mostly young adult women, who have been exposed to the chemical agent at work for less than five years, and who make greater use of gloves, aprons, and common masks as PPE. They have non-rotatory dizziness and neurovegetative symptoms, and anxiety and stress are their most frequent extra-hearing complaints. Health conditions of the auditory and vestibular systems were within the normal range in most of the evaluated professionals, but with the presence of notch thresholds in pure tone audiometry, commonly identified in workers who reported not having dizziness and had normal caloric test. The association of notch configuration, abnormal caloric test results, and not using coal mask was frequent when compared with the use of gloves; emphasizing the importance of using PPE to maintain the health conditions of these professionals.

References 1 INCA – Instituto Nacional do Câncer. Estimativa 2014: Incidência

2

3

4

5

6

7

8

9

de Câncer no Brasil/Instituto Nacional de Câncer José Alencar Gomes da Silva, Coordenação de Prevenção e Vigilância [Internet]. Rio de Janeiro: INCA, 2014. Available at http://www.inca.gov.br/ estimativa/2014/index.asp?ID¼2. Acessed August 25, 2015 Statistical WHO. Information System (WHOSIS). Cancer. [Denmark]: World Health Organization, Regional Office for Europe; 2010. Available at: http://www.euro.who.int/en/what-we-do/healthtopics/diseases-and-conditions/cancer Accessed May 13, 2014 Rombaldi F, Cassini C, Salvador M, Saffi J, Erdtmann B. Occupational risk assessment of genotoxicity and oxidative stress in workers handling anti-neoplastic drugs during a working week. Mutagenesis 2009;24(2):143–148 Bonassa EMA. Conceitos gerais em terapia antineoplásica. In: Bonassa EMA, Santana TR, ed. Enfermagem em terapêutica oncológica. São Paulo: Atheneu; 2005:3–19 Morais E. Riscos ocupacionais para enfermeiros quando manuseiam quimioterápicos antineoplásicos [dissertation]. Rio de JaneiroUniversidade Federal do Estado do Rio de Janeiro, Centro de Ciências Biológicas e da Saúde2009:73 Villarini M, Dominici L, Piccinini R, et al. Assessment of primary, oxidative and excision repaired DNA damage in hospital personnel handling antineoplastic drugs. Mutagenesis 2011;26(3):359–369 Saleh JH, Cummings AM. Safety in the mining industry and the unfinished legacy of mining accidents: Safety levers and defensein-depth for addressing mining hazards. Saf Sci 2011;49(6): 764–777 Rocha FLR, Marziale MHP, Robazzi MLCC. Potential risks nursing workers are exposed to in handling antineoplastic drugs: know ledge for prevention. Rev Lat Am Enfermagem 2004;12(3):511–517 Martins I, Rosa HVD, Della HC. Considerações toxicológicas da exposição ocupacional aos fármacos antineoplásicos. Rev Bras Med Trab 2004;2(2):118–125

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

337


338

Workplace Activity in Health Professionals Exposed to Chemotherapy Drugs

Fernandes et al.

10 Baroni FCAL, Oliveira JCM, Guimarães GL, Matos SS, Carvalho DV. O

27 Gondim KM, Miranda MDC, Guimarães JMX, D’alencar BP. Avalia-

trabalhador de Enfermagem frente ao gerenciamento de resíduo químico em unidade de quimioterapia antineoplásica. Rev Min Enferm 2013;17(3):554–559 Oliveira ADS, Alves AEC, Silva JA, Oliveira SLF, Medeiros SM. Occupational risks of the nursing team’s exposure to chemotherapeutic agents: integrative literature review. Rev Enferm UFPE 2013;7(3):788–796 Carvalho PR. O ambiente laboratorial. In: Carvalho PR, ed. Boas práticas químicas em biossegurança. Rio de Janeiro: Interciência; 1999:10–26 Jacob LCB, Aguiar FP, Tomiasi AA, Tschoeke SN, Bitencourt RF. Monitoramento auditivo na ototoxicidade. Braz J Otorhinolaryngol 2006;72(6):836–844 Schacht J, Talaska AE, Rybak LP. Cisplatin and aminoglycoside antibiotics: hearing loss and its prevention. Anat Rec (Hoboken) 2012;295(11):1837–1850 Bernardini APA. Testes utilizados na avaliação de trabalhadores expostos a níveis de pressão sonora elevados e solventes. In: Bernardini APA, ed. Conhecimentos essenciais para atuar bem em empresas: audiologia ocupacional. São José dos Campos: Pulso; 2003:67–80 Bellé M, Sartori SA, Rossei AG. Alcoholism: effects on the cochleovestibular apparatus. Braz J Otorhinolaryngol 2007;73(1): 106–116 Fernandes AS. Estudo das características auditivas e vestibulares em indivíduos expostos ocupacionalmente a mercúrio metálico e ruído [dissertação]. Rio de Janeiro: Universidade Federal do Rio de Janeiro, Instituto de Estudos em Saúde Coletiva; 2009:84 Rademaker-Lakhai JM, Crul M, Zuur L, et al. Relationship between cisplatin administration and the development of ototoxicity. J Clin Oncol 2006;24(6):918–924 Afifi AK, Bergman RA. Sentidos especiais: correlatos clínicos. In: Afifi AK, Bergman RA, ed. Neuroanatomia Funcional: texto e atlas. São Paulo: Roca; 2008:252–255 MT-Ministério do Trabalho [internet]. Brasília: Portal do Trabalho e Emprego; Available at: http://portal.mte.gov.br/data/files/ FF8080812BE914E6012BEF1CA0393B27/nr_09_at.pdf. Accessed Jan 11,2014 Marques FP, da Costa EA. Exposure to occupational noise: otoacoustic emissions test alterations. Braz J Otorhinolaryngol 2006; 72(3):362–366 Mor T, Fragoso M. Exame vestibular. In: Mor R, Fragoso M, ed. Vestibulometria na prática fonoaudiológica. São Paulo: Pulso; 2012:43–99 Odraska P, Dolezalova L, Kuta J, Oravec M, Piler P, Blaha L. Evaluation of the efficacy of additional measures introduced for the protection of healthcare personnel handling antineoplastic drugs. Ann Occup Hyg 2013;57(2):240–250 Kemp DT, Ryan S, Bray P. A guide to the effective use of otoacoustic emissions. Ear Hear 1990;11(2):93–105 Costa KCF, Silva SMR, Ganança CF. Estudo das provas oculomotoras e vestibulares por meio da vectonistagmografia digital. Distúrb Comum 2005;17(3):315–322 Ribeiro EJG, Shimizu HE. Work accidents involving nursing workers. Rev Bras Enferm 2007;60(5):535–540

ção da prática de ginástica laboral pelos funcionários de um hospital público. Rev Rene 2009;10(2):95–102 Silva LF, Reis PED. Avaliação do Conhecimento da Equipe de Enfermagem sobre Riscos Ocupacionais na Administração de Quimioterápicos. Rev Bras Cancerol 2010;56(3):311–320 Lima IS, Clementino FS, Miranda FAN, Souza CSM, Brandão ICA, Brasil SKD. Equipe de enfermagem: conhecimentos acerca do manuseio de drogas antineoplásicas. Rev Enferm UERJ 2011; 19(1):40–45 Schweitzer VG. Ototoxicity of chemotherapeutic agents. Otolaryngol Clin North Am 1993;26(5):759–789 Garcia AP, Iório MCM, Petrilli AS. Monitoramento da audição de pacientes expostos à cisplatina. Rev Bras Otorrinolaringol (Engl Ed) 2003;69(2):215–221 Amorim AM, Azevedo MF, Carvalho CAF, Macedo CRPD. Emissões Otoacústicas Evocadas por Estímulo Transiente em Crianças Portadoras de Retinoblastoma Submetidas a Tratamento Quimioterápico com Carboplatina. Int Arch Otorhinolaryngol 2007;11(4):375–379 Crepaldi de Almeida EO, Umeoka WG, Viera RC, de Moraes IF. High frequency audiometric study in cancercured patients treated with cisplatin. Braz J Otorhinolaryngol 2008;74(3):382–390 Ribas A, Schmitz D, Duarte N, Gutierrez L. Achados audiológicos de trabalhadores expostos ao ruído e ao agente químico Arclean SDI. Tuiuti: Cienc Cult 2010;43:23–36 Rankel ADC. Roggia Simone. Perfil audiológico de funcionários de uma imprensa universitária [monography]. Florianópolis: Universidade Federal de Santa Catarina, Centro de Ciências da Saúde; 2013:64 Azevedo MF. Emissões Otoacústicas. In: Figueiredo MS, ed. Emissões otoacústicas e BERA. São José dos Campos: Pulso; 2003:35–71 Silva MLG, Munhoz MSL, Ganança MM, Caovilla HH. Ototoxicoses. In: Silva MLG, Munhoz MSL, Ganança MM, Caovilla HH, ed. Quadros Clínicos Otoneurológicos Mais Comuns. São Paulo: Atheneu; 2000:119–130 Kitsigianis GA, O’Leary DP, Davis LL. Active head-movement analysis of cisplatin-induced vestibulotoxicity. Otolaryngol Head Neck Surg 1988;98(1):82–87 Hoshino AC, Pacheco-Ferreira H, Taguchi CK, Tomita S, Miranda MdeF. Ototoxicity study in workers exposed to organophosphate. Braz J Otorhinolaryngol 2008;74(6):912–918 Manfredo FS, Elias SC. Manipulação de agentes antineoplásicos: a questão da biossegurança. Rev HUPE 2005;4:54–61 De Souza RJ. A percepção de profissionais de enfermagem quanto aos riscos ocupacionais que podem gerar doenças/agravos ao seu estado de saúde [dissertation]. Campina Grande: Universidade Estadual da Paraíba, Centro de Ciências Biológicas e da Saúde; 2011:70 Santos EI. Vulnerabilidade de enfermeiros no cuidado a pacientes com HIV/Aids: Um estudo de representações sociais [dissertation]. Rio de Janeiro: Universidade do Estado do Rio de Janeiro, Centro Biomédico; 2012:229 Clark BA, Sessink PJ. Use of a closed system drug-transfer device eliminates surface contamination with antineoplastic agents. J Oncol Pharm Pract 2013;19(2):99–104

11

12

13

14

15

16

17

18

19

20

21

22

23

24 25

26

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

28

29

30 31

32

33

34

35

36

37

38

39

40 41

42

43


THIEME

Original Research

The Influence of Tinnitus on the Audiometric Threshold of Sufferers Onyinye Ukaegbe1

Basil Ezeanolue1

Foster Orji1

1 Department of Otorhinolaryngology, University of Nigeria Teaching

Hospital, Ituku-Ozalla Enugu, Enugu, Nigeria Int Arch Otorhinolaryngol 2016;20:339–343.

Abstract

Keywords

► tinnitus ► hearing threshold ► audiometry

Introduction Tinnitus is a worldwide problem. Objective The objective of this study is to evaluate the audiometric hearing thresholds of adult patients with ongoing tinnitus as their only otological symptom. Methods We evaluated the hearing thresholds of 43 adult patients with ongoing tinnitus and no history of hearing loss from the otolaryngology department of a tertiary health institution at speech and high frequencies. A total of 56 tinnitus ears were compared against 30 contralateral normal ears as well as with the 100 ears of 50 healthy volunteers. Results The study group consisted of 11 (25.6%) males and 32 (74.4%) females with a mean age of 40.9  11.7. The mean Pure Tone Average of the 56 tinnitus ears was 14.8  9, while that of the 100 control ears was 11.2  6 (U ¼ 2078, p ¼ 0.008). The mean pure tone average of the control was also significantly lower than that of the 30 contralateral normal ears of the tinnitus sufferers (U ¼ 1136, p ¼ 0.02). We observed mild to moderate hearing loss in 10 (23%) of the participants. We observed no hearing loss among the control group. Conclusion A proportion of tinnitus sufferers with self-professed normal hearing are likely to have mildly elevated pure tone audiometric thresholds. In patients with unilateral tinnitus, such elevated pure tone hearing thresholds are likely to be in the tinnitus ear and the contralateral non-tinnitus ear.

Introduction Tinnitus is a worldwide problem and is estimated to affect 12% to 15% of the adult population, with a male preponderance.1 Studies indicate that approximately one third of the global population will experience tinnitus in their lifetime, but tinnitus as a symptom remains a challenge to most clinicians.2,3 Tinnitus is usually described as a buzzing, ringing, humming, clicking, blowing or drum-like sound and involves the perception of pure tones or frequency ranges of noise similar to white noise with no particular pattern of organization.4,5 As much as 80% of patients seen in the otorhinolaryngology clinic may have tinnitus, and it has been associated with a variety of ear pathologies among which hearing loss remains

received September 6, 2015 accepted October 23, 2015 published online February 15, 2016

Address for correspondence Onyinye Ukaegbe, FWACS, MSc Audiology for ENT Practice, MBBS, Department of Otorhinolaryngology, University of Nigeria Teaching Hospital, ItukuOzalla Enugu, Enugu, Nigeria (e-mail: onyikasi@yahoo.com).

DOI http://dx.doi.org/ 10.1055/s-0035-1571271. ISSN 1809-9777.

the most common.3,6–9 Tinnitus has been cited as a potentially debilitating symptom and can be a source of distress to the affected individual especially in cases where there is an associated hearing loss.3,10,11 Tinnitus is believed to be generated from several disorders of the physiological mechanism of hearing.12 These disorders are believed to exist in the peripheral sensorineural activity of the peripheral auditory system or in the central neural pathways.12 Tinnitus may also arise from the interaction between a defective peripheral input and a dysfunctional central neural pathway.12 The progress in tinnitus management has been slow especially in developing countries like Nigeria and there is a paucity of data on the hearing thresholds of tinnitus patients with self-professed normal hearing and no

Copyright © 2015 by Thieme Publicações Ltda, Rio de Janeiro, Brazil

339


340

The Influence of Tinnitus on the Audiometric Threshold additional otological symptoms, probably due to the fact that most of these patients may not present to otorhinolaryngologists. It is important to determine the pure tone audiometric hearing thresholds of these patients who present with tinnitus as their only otological symptom, to find out how it defers from that of healthy controls, as well as to evaluate the hearing thresholds in the contralateral non-tinnitus ears of patients with unilateral tinnitus for better counselling of the patient and overall management of the tinnitus patient.

Materials and Methods We conducted the study in the outpatient otorhinolaryngology clinics of a tertiary hospital over a year period ending in May 2014. We obtained approval from the Ethics review committee of our institution and informed consent from each participant. We recruited for the study forty-three consecutive patients aged 21 - 58 years with a mean age of 40.9  11.7 who had self-reported normal hearing and ongoing tinnitus as their only otorhinolaryngology complaint. Thirteen (30.2%) of the patients had bilateral tinnitus, thereby making a total of 56 ears with ongoing tinnitus available for analysis, while 30 contralateral ears were symptom free in the 30 (69.8%) unilateral tinnitus sufferers. We excluded subjects from the study if they had a prior history of hearing loss, or had any debilitating illness. The average duration of tinnitus was 17.3 months  20.3. Persistent tinnitus was observed in 20 (46.5%) of the participants while 23 (53.5%) had intermittent tinnitus. We obtained a history of noise exposure from 8 (18.6%) of the participants, while 14 (32.6%) of the participants had been exposed to drugs likely to cause tinnitus. Two of the subjects were diabetic, one was hypertensive and diabetic, seven of the subjects were hypertensive, and all were on medication. The control group consisted of 50 healthy volunteers (100 ears) aged 21 to 57 years with a mean of 38.7  9.7 years, who were pooled from the hospital staff, as well as the medical and nursing students of the institution. Eighteen (36%) were male and 32 (64%) were female. A comprehensive history and detailed ear, nose, and throat examination was performed in both groups.

Pure Tone Audiometry All the participants in the study and control group underwent pure tone audiometry using an Amplivox 260 diagnostic audiometer (Amplivox Limited, Oxforshire, England).

Ukaegbe et al. Tests were conducted in a sound proof booth and using circumaural head phones. We assessed the frequencies of 500Hz, 1000Hz, 2000Hz, 3000Hz, 4000Hz, 6000Hz, and 8000Hz for the air conduction thresholds while 500Hz, 1000Hz, 2000Hz, and 4000Hz were assessed for the bone conduction thresholds with the use of a bone vibrator placed on the appropriate mastoid process. The three standard rules of masking were applied. We calculated the Pure Tone Average (PTAv) from the average of the four air conduction speech frequencies of 500Hz, 1000Hz, 2000Hz, and 4000Hz. We calculated the high frequency pure tone average from the average of 6KHz and 8KHz. Audiometric results were graded as: normal hearing (25 dBHL), mild hearing loss (26–40 dBHL), moderate hearing loss (41–60 dBHL), severe hearing loss (61–80 dBHL), and profound hearing loss (81 dBHL).13 The hearing loss was classified as “Sensorineural” if both the air and bone conduction thresholds were above 25 dBHL or “Conductive” in cases with air-bone gaps of 10 dBHL or more or “Mixed” if both the air and bone conduction thresholds were above 25 dBHL with air-bone gaps of 10 dBHL or more.14 We used the Statistical Package for Social Sciences version 15 (IBM, Armonk, U.S.A.) in the statistical analysis. We applied the independent samples t-test and Mann Whitney U test in comparing the mean pure tone thresholds for the 56 tinnitus ears, 30 non-tinnitus ears, and the 100 control ears. The results are single-tailed and the significance level was set at less than 0.05.

Results ►Table 1 outlines the age and gender distribution of the participants. The differences in the mean age between the study group and the control, as well as their gender distributions, were not significant (p ¼ 0.3 and 0.1, respectively). We observed bilateral tinnitus in 13 (30.2%) of subjects. Fourteen (32.6%) had tinnitus in their right ear only, while 16 (37.2%) of the subjects had tinnitus in the left ear only.

Hearing Threshold of 43 Tinnitus Sufferers and 50 Normal Volunteers Concerning the tinnitus individuals, 10 (23.3%) of them had elevated hearing thresholds within the mild to moderate hearing loss range, with 6 (13.9%) of them being conductive loss, 3 (7%) sensorineural, and 1 patient (2.3%) had mixed

Table 1 Age and sex distribution of the participants

Age group

Study group N ¼ 43

Control group N ¼ 50

P value

< 25 years

3

6



25–45 years

21

31



> 45 years

19

13



40.9  11.7

38.7  9.7

t(82) ¼ 1, p ¼ 0.3

Male

11

18

(x2 ¼ 1.2 (df ¼ 1) p ¼ 0.1)

Female

32

32

Mean age Sex

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016


The Influence of Tinnitus on the Audiometric Threshold

-10

0

0

10

10

20

20

30

30

40 50 60 70 80

40 50 60 70 80

100

110

110

120

120

12 5 25 0

a

Frequency (Hz)

12 5 25 0

90

100

50 0 10 00 20 00 40 00 60 00 80 00

90

50 0 10 00 20 00 40 00 60 00 80 00

Heaaring level(dB)

Heaaring level(dB)

-10

Ukaegbe et al.

b

Frequency (Hz)

Heaaring level(dB)

-10 0 10 20 30 40 50 60 70 80 90 100 110 120 0 1000 2000 4000 6000 8000 8 125 250 500 c Frequency (Hz)

Keys:

= bone conduction right = air conduction right

bone conduction o left air conduction left

Fig. 1 (a) Right audiogram of a 49-year-old female tinnitus sufferer in the study group with mild sensorineural hearing loss. (b) Right audiogram of a 53-year-old female tinnitus sufferer in the study group with conductive hearing loss. (c) Right audiogram of a 38-year-old female tinnitus sufferer in the study group with high frequency hearing loss.

hearing loss. The elevated hearing thresholds were unilateral in 7 patients (16.3%) and bilateral in 3 (7%). All the 50 participants in the control group had normal hearing thresholds within the speech frequencies, but 12 of them had elevated hearing thresholds in the high frequencies (6 and 8 Khz), with 7 (14%) of the individuals being unilateral whereas 5 of them (10%) were bilateral (►Fig. 1a, 1b, 1c).

Pure Tone Average (PTAv) of the Tinnitus Ears and Control Ears The 56 tinnitus ears had a mean PTAv of 14.8  9 while that of the 100 control ears was 11.2  6. The difference was significant (U ¼ 2078; p ¼ 0.008). See ►Table 2.

In the high frequencies, the 56 ears with tinnitus had a mean pure tone threshold of 20.9 dBHL at 6KHz, 19.1dBHL at 8KHz, while the 100 control ears without tinnitus had a mean pure tone threshold of 16.6dBHL at 6KHz, 15dBHL at 8KHz. These differences were not significant (U ¼2366, p ¼ 0.05)

Comparison of the Tinnitus Ears and the Non-Tinnitus Ears in Participants with Unilateral Tinnitus The PTAv for the 30 ears with tinnitus was 17  10.4, while the PTAv of the 30 contralateral ears without tinnitus was 15.7  13.2. The difference was not significant (U ¼ 448; p ¼ 0.5). International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

341


342

The Influence of Tinnitus on the Audiometric Threshold Table 2 The mean pure tone thresholds for the 56 ears with tinnitus among the study group and the 100 control ears Frequency (Hz)

Study ears (n ¼ 56)

Control ears (n ¼ 100)

500

17

11.2

1000

14.4

11

2000

12.8

10.3

4000

14.4

12.5

Comparison of the Contralateral Non-Tinnitus Ears and the Control Ears The PTAv in the 100 ears of the control group without tinnitus was significantly better than the PTAv of the 30 contralateral non-tinnitus ears among the participants with unilateral tinnitus (U ¼ 1136; p ¼ 0.02).

Ukaegbe et al. Comparison of the PTAv between Tinnitus and NonTinnitus Ears in Subjects with Unilateral Tinnitus For the subjects with unilateral tinnitus, the mean pure tone average in the ears with tinnitus was higher than that in the contralateral ears without tinnitus but this was not statistically significant. Park et al made similar observations when they compared the pure tone thresholds in the ears of patients with unilateral tinnitus and did not observe a significant difference between the ears with tinnitus and their contralateral ears without tinnitus. However, with the use of Distortion Product Otoacoustic Emissions (DPOAE), a significant decrease in DPOAE threshold was observed in the ears with tinnitus.14 In studies that relied on otoacoustic emissions to assess tinnitus sufferers, authors observed that a significant proportion of the tinnitus ears with normal pure tone thresholds had defective otoacoustic emissions, which indicates that some patients with tinnitus may have abnormal outer hair cell function despite a normal pure tone average.14,18,19

Discussion

Comparison of the Contralateral Non-Tinnitus Ears and the Control Ears

Pure Tone Average

In this study, we observed that the subjects with unilateral tinnitus had a significantly worse mean PTAv (15.7  13.2) in the 30 contralateral ears without tinnitus than the mean PTAv (11.2  5.3) in the 100 ears of the control group without tinnitus. This indicates that patients with tinnitus are likely to have elevated pure tone thresholds and that this elevated pure tone thresholds are likely to be seen in the contralateral unaffected ears of those with unilateral tinnitus. It appears that the contralateral unaffected ears of the subjects with unilateral tinnitus may have been exposed to the same etiological factor as the ear with tinnitus and may give rise to tinnitus in the future. It could also indicate that the insult to the contralateral ears without tinnitus was not severe enough to give rise to tinnitus. There is paucity of data on the hearing threshold of the contralateral non-tinnitus ear of the unilateral tinnitus sufferer and how it compares to the hearing threshold of healthy individuals without tinnitus. This information will help in the counselling of patients with unilateral tinnitus and will contribute to better patient management.

In this study, 10 (23.3%) individuals with tinnitus were observed to have hearing loss as measured by pure tone audiometry, despite the fact that all of them reported that they had normal hearing. This implies that the hearing impairment was mild enough to have gone unnoticed by the participants or that the participants may have blamed the tinnitus for their difficulties with hearing. The subjects with unilateral tinnitus may also have been compensating with the contralateral ear without tinnitus. Comparison between the 56 ears affected by tinnitus and the 100 ears not affected by tinnitus showed that the ears affected by tinnitus had a higher mean PTAv, which was significantly worse than the mean pure tone average of the ears not affected by tinnitus, this indicates that ears with tinnitus are likely to have elevated pure tone thresholds and hearing loss, even in tinnitus sufferers with self-reported normal hearing. Several other studies made observations similar to those in this study.8,9,11,15,16 Their results indicated that patients with hearing loss are likely to present with tinnitus as their main complaints while majority of tinnitus sufferers may have some degree of hearing loss.8,9,11,15,16 Monzani et al observed that 74 of the 100 tinnitus sufferers in their study had hearing loss.9 Martinesi et al observed that 64.14% of the 312 tinnitus sufferers in their study had varying degrees of hearing loss.17 However, none of these studies focused on determining the hearing thresholds of tinnitus patients with self-perceived normal hearing and none compared them to individuals without tinnitus. The elevated mean PTAv observed among the tinnitus sufferers in this study and in the 56 ears with tinnitus indicate that patients with tinnitus are more likely to have hearing loss than those without tinnitus. Therefore audiometry should be routinely performed for all patients presenting with tinnitus regardless of their self-reported hearing status. None of the subjects in the control group had PTAv greater than 25 dBHL in the speech frequencies. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Type of Hearing Loss In this study, out of the 10 (23.3%) subjects with hearing loss, conductive hearing loss was the commonest type of hearing loss observed in 6 (13.9%), while sensorineural hearing loss was observed in 3 (7%) of the participants and mixed hearing loss in 1 (2.3%). Our results defer from the findings in a study by Martines et al where sensorineural hearing loss was seen in 74.6% of tinnitus sufferers, mixed hearing loss in 14.7%, and conductive hearing loss in 10.7%.3 Monzani et al also observed that sensorineural hearing loss was the commonest hearing loss amongst the tinnitus sufferers in their study.9 The conductive hearing loss observed in these subjects may be attributed to some subclinical middle ear disease such as Eustachian tube dysfunction which implies that these subjects are likely to have some improvement with therapy. The results of further middle ear analysis unfortunately are not available for this research.


The Influence of Tinnitus on the Audiometric Threshold Despite having a normal PTAv, 10 subjects (23.3%) of the study group had worsening hearing thresholds in their high frequency ranges, a fact not taken into account while calculating their standard pure tone hearing thresholds. Similar observations were made in the studies by Martines et al and Monzani et al, where they calculated the threshold in the high frequencies of 4kHz, 6kHz, and 8kHz.3,9 However both studies did not make use of a control group and, therefore, were unable to compare the high frequency hearing thresholds of the tinnitus sufferers to that of healthy controls. When the mean high frequency PTAv of the 56 ears affected by tinnitus was compared with the 100 ears of healthy controls, we observed that tinnitus sufferers had higher mean high frequency PTAv than the control group, but this difference was not significant. This finding implies that high frequency hearing loss is likely to be present in tinnitus sufferers and in those without tinnitus, although tinnitus sufferers may have slightly worse high frequency thresholds.

3 Martines F, Bentivegna D, Martines E, Sciacca V, Martinciglio G.

4 5

6

7

8

9

10

Conclusion Tinnitus sufferers with self-professed normal hearing are more likely to have hearing loss than none sufferers; however, high frequency hearing loss is likely to be observed in the tinnitus sufferer and in those without tinnitus. The pure tone audiometric thresholds of the unaffected non-tinnitus ear in those with unilateral tinnitus is likely to be elevated when compared with that of individuals without tinnitus, indicating that these may also have a similar pathology as the tinnitus ear. Tinnitus sufferers should therefore undergo routine audiometric evaluation even in cases where they report normal hearing.

11

12 13

14

15

16

Conflict of Interest There is no conflict of interest to declare and no external source of funding used in the research.

17

18

References 1 Axelsson A, Ringdahl A. Tinnitus—a study of its prevalence and

characteristics. Br J Audiol 1989;23(1):53–62 2 Aaron GB, Wayne KR. Inner ear: tinnitus. Emed 2013

Ukaegbe et al.

19

Assessing audiological, pathophysiological and psychological variables in tinnitus patients with or without hearing loss. Eur Arch Otorhinolaryngol 2010;267(11):1685–1693 Frank M, Marie BT, Barry L, et al. Auditory hallucinations: An audiological perspective. Hearing J 2007;60:32–52 Santos RMR, Sanchez TG, Bento RF, Lucia MC. Auditory hallucinations in tinnitus patients: Emotional relationships and depression. Int Arch Otorhinolaryngol 2012;16(3):322–327 Cima R, Joore M, Maes I, et al. Cost-effectiveness of multidisciplinary management of Tinnitus at a specialized Tinnitus centre. BMC Health Serv Res 2009;9:29 Ogunleye AO, Labaran AO. Presbycusis in Nigerians at the University College Hospital, Ibadan. Afr J Med Med Sci 2005;34(3): 293–296 Adobamen PO, Ogisi FO. Symptoms Associated With Hearing Loss As Seen In the University Of Benin Teaching Hospital, Benin City, Nigeria. Gomal J Med Sci 2011;9:159–162 Monzani D, Genovese E, Marrara A, et al. Validity of the Italian adaptation of the Tinnitus Handicap Inventory; focus on quality of life and psychological distress in tinnitus-sufferers. Acta Otorhinolaryngol Ital 2008;28(3):126–134 Snow JB. Tinnitus: theory and management. Hamilton, London: BC Decker; 2004:16–63 Schlee W, Kleinjung T, Hiller W, Goebel G, Kolassa IT, Langguth B. Does tinnitus distress depend on age of onset? PLoS ONE 2011; 6(11):e27379 Bauer CA. Mechanisms of tinnitus generation. Curr Opin Otolaryngol Head Neck Surg 2004;12(5):413–417 World Health Organization. Prevention of Blindness and deafness: Grades of HearingImpairment. http://www.who.int/pbd/deafness/hearing_impairment_grades/en/index.html2002(accessed 17th April 2012). Park JP, Lim HW, Shim BS, et al. Interaural differences of distortion product otoacoustic emission amplitudes in patients with unilateral tinnitus. Otolaryngol Head Neck Surg 2013;148(3):456–459 Gopinath B, McMahon CM, Rochtchina E, Karpa MJ, Mitchell P. Incidence, persistence, and progression of tinnitus symptoms in older adults: the Blue Mountains Hearing Study. Ear Hear 2010; 31(3):407–412 Shargorodsky J, Curhan GC, Farwell WR. Prevalence and characteristics of tinnitus among US adults. Am J Med 2010;123(8):711–718 Martines F, Bentivegna D, Di Piazza F, Martines E, Sciacca V, Martinciglio G. Investigation of Tinnitus Patients in Italy: Clinical and Audiological Characteristics. Int J Otolaryngol 2010;20(10): 265861 Granjeiro RC, Kehrle HM, de Oliveira TS, Sampaio ALL, de Oliveira CA. Is the degree of discomfort caused by tinnitus in normalhearing individuals correlated with psychiatric disorders? Otolaryngol Head Neck Surg 2013;148(4):658–663 Ami M, Abdullah A, Awang MA, Liyab B, Saim L. Relation of distortion product otoacoustic emission with tinnitus. Laryngoscope 2008;118(4):712–717

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

343


THIEME

344

Original Research

“Positive to Negative” Dix-Hallpike test and Benign Paroxysmal Positional Vertigo recurrence in elderly undergoing Canalith Repositioning Maneuver and Vestibular Rehabilitation Karyna M. O. B. de Figueiredo Ribeiro1 Lidiane Maria de Brito Macedo Ferreira2 Raysa Vanessa de Medeiros Freitas1 Camila Nicácio da Silva1 Nandini Deshpande3 Ricardo Oliveira Guerra1 1 Department of Physiotherapy, Universidade Federal do Rio Grande do

Norte, Natal, Rio Grande do Norte, Brazil 2 Post-Graduation Program in Public Health, Universidade Federal do Rio Grande do Norte, Natal, Brazil 3 Faculty of Health Sciences, School of Rehabilitation Therapy, Queen’s University, Kingston, Canada

Address for correspondence Karyna M. O. B. de Figueiredo Ribeiro, PhD, Department of Physiotherapy, Universidade Federal do Rio Grande do Norte, Senador Salgado Filho Avenue, n 3000, Campus Natal, Rio Grande do Norte 59078-970, Brazil (e-mail: karynamy@hotmail.com).

Int Arch Otorhinolaryngol 2016;20:344–352.

Abstract

Keywords

► elderly ► vestibular diseases ► rehabilitation

received September 15, 2015 accepted November 15, 2015 published online February 16, 2016

Introduction Benign Paroxysmal Positional Vertigo is the most common cause of dizziness in elderly people. Recent studies have shown that the elderly present higher Benign Paroxysmal Positional Vertigo recurrence and that vertiginous symptomatology remission varies according to comorbidities and the therapeutic techniques applied. Objective To assess the short-term effectiveness of Vestibular Rehabilitation in addition to Canalith Repositioning Maneuver on positive to negative Dix-Hallpike test, on recurrence and number of maneuvers to achieve a negative test in elderly patients with chronic Benign Paroxysmal Positional Vertigo. Methods In this randomized controlled trial, 7 older adults (median age: 69 years, range 65–78) underwent Canalith Repositioning Maneuver and Vestibular Rehabilitation for thirteen weeks. Seven older adults (median age: 73 years, range 65–76) in the control group received only Canalith Repositioning Maneuver. The participants were assessed at baseline (T0), one (T1), five (T5), nine (T9), and thirteen weeks (T13). We assessed the differences between the groups by Mann-Whitney and Fisher exact tests, and used the Friedman and Wilcoxon tests to determine the intragroup differences. Results No significant differences were found between groups for the positive to negative Dix-Hallpike test, recurrence, and number of maneuvers to achieve a negative test. The number of maneuvers to achieve negative Dix-Hallpike test was lower in intragroup comparisons in the experimental group. Conclusion The findings suggest that additional Vestibular Rehabilitation did not influence the positive to negative Dix-Hallpike test, recurrence, or number of maneuvers to achieve a negative test in elderly patients with chronic Benign Paroxysmal Positional Vertigo.

DOI http://dx.doi.org/ 10.1055/s-0036-1572528. ISSN 1809-9777.

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil


“Positive to Negative” Dix-Hallpike test and Benign Paroxysmal Positional Vertigo recurrence in elderly undergoing Canalith Repositioning Maneuver and Vestibular Rehabilitation Ribeiro et al.

Introduction Dizziness is a common symptom, especially in the elderly. It is estimated that 30% of people over the age of 65 complain of dizziness. The rate of annual consultations due to dizziness in primary care increases from 8% for individuals aged 65 years or older to 18% among those aged 85 or older.1,2 In elderly patients, this symptom is considered a geriatric multifactorial syndrome, caused by the physiological processes of aging and/or pathological processes.3–6 Benign Paroxysmal Positional Vertigo (BPPV) is the most common cause of dizziness in the adult population; 30% of seniors over the age of 70 will experience at least one episode of BPPV throughout their life.7,8 BPPV is classified according to its nature, in primary or idiopathic (considered the most common form of the disease),9 or secondary. The main causes for secondary BPPV are: traumatic brain injury, post-operative ear surgery, vertebrobasilar insufficiency, vestibular neuronitis, Ménière’s disease or metabolic disorders.10 BPPV recurrences are associated with known risk factors such as diabetes mellitus, hypertension, osteoporosis and osteoarthritis.11 Posterior canal BPPV is considered the most common type of the disease, and is diagnosed by Dix-Hallpike test.12 The treatment can be based on non-pharmacological measures, highlighted by the Canalith Repositioning Maneuver (CRM) or modified Epley maneuver, a therapeutic recommendation with strongly proven evidence, and Vestibular Rehabilitation (VR) as a secondary option.13,14 The objectives of the study were to analyze the effectiveness of VR associated with the CRM compared with CRM in a “positive to negative” Dix-Hallpike test, BPPV recurrence, and the number of maneuvers to achieve a negative test in elderly patients with chronic BPPV. In addition, we aimed to trace the clinical profile of elderly with chronic BPPV and descriptively evaluate the associations of this (profile) with risk factors described in the literature.

Method This is a randomized, single-blind, two-arm controlled trial that followed the recommendations established by the CONSORT (Consolidated Standards of Reporting Trials), 2010,15 recorded in the REBEC (Registro Brasileiro de Ensaios Clínicos) under code: RBR-7jkbyg. It was approved by the local Ethics Committee in Research, protocol 543/11, in accordance to resolution 196/96. Seniors with chronic BPPV (minimum of 6 months) were referred from the otoneurology outpatient clinic of Hospital Universitário Onofre Lopes, Natal, RN, Brazil and from other public and private services of medical specializations that treat patients with complaints of dizziness. The study included individuals aged 65 years and older; having a positive Dix-Hallpike test with vertigo accompanied or not with positional nystagmus (objective or subjective BPPV). Exclusion criteria were: presence of cervical neurological symptoms; limited cervical amplitude of movement and instability for the implementation of both the diagnostic

Dix-Hallpike test and CRM; systemic diseases (such as hypertension, diabetes mellitus, and thyroid dysfunction) with no medication control; motor, hearing, or visual restrictions that prevent proper conduction of body balance evaluation and VR protocol; subjects not being able to understand and respond to simple verbal commands; having undergone previous treatment with CRM; and that had been performing some physical activity such as muscle strengthening, pilates, yoga, or high intensity aerobic exercises. Seniors who had some serious health complications which prevented the continuation of treatment or who did not want to continue the instituted therapy were also excluded from the study. Participants were informed about the procedures and objectives of the study and those who agreed to participate were asked to sign the Informed Consent Form. After screening for the definition of the inclusion and exclusion criteria, the randomization process was performed in blocks with a sequence generated by a computer program (www.randomization.com). Patients were then randomized into two groups: 1 - Control Group (CG) - CRM; and 2 - Experimental group (EG) - CRM and additional VR. An independent researcher not involved with clinical trial did the process of randomization and allocation. Blinded investigators, different from those who performed the VR protocol performed the evaluations. Participants were assessed at baseline (T0) and at one (T1), five (T5), nine (T9), and thirteen (T13) weeks. A multidimensional clinical questionnaire was used to collect sociodemographic (age and sex) and anthropometric data (body mass index in kg/m2); anamnesis for BPPV with questions about nature (primary or secondary) and type of dizziness16 (vertigo, floating sensation, disequilibrium or presyncope), dizziness time onset, Dix-Hallpike test (positive or negative), presence of nystagmus, affected side (right, left, or bilateral), number of maneuvers, associated symptoms such as tinnitus; related health data, including comorbidities and medication use. We evaluated BPPV recurrence taking into account the “positive to negative” Dix-Hallpike test with subsequent positive results in the 13-week assessment period. The classification for drug use was performed using the Anatomical Therapeutic Chemical Classification System (ATC), an alphanumeric coding system developed by the World Health Organization (WHO) for the classification of drugs and other medical products. The classification was in accordance with the second level.17 Polypharmacy occurrence was defined by concomitant use of five or more medications.18 Regarding the associated diseases, the classification system we used was the International Classification of Diseases (ICD - 10). This is the international standard diagnostic classification for epidemiological and health administrative purposes, including analysis of the general situation of population groups and monitoring of incidence and prevalence of diseases and other health problems.19 Seniors were submitted to the Dix-Hallpike test20,21 with the aid of a Computerized Videonystagmoscopy Infrared System (SVNC, Contronic, Brazil), introduced to the least symptomatic side, according to information obtained from International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

345


346

“Positive to Negative” Dix-Hallpike test and Benign Paroxysmal Positional Vertigo recurrence in elderly undergoing Canalith Repositioning Maneuver and Vestibular Rehabilitation Ribeiro et al. each patient. If patients failed to report which position was responsible for triggering vertigo, the test started on the right side. Hence, the side that should be treated by CRM was identified. We observed eye movement for 1 minute in search of nystagmus and the patient was asked about the presence of vertigo. The same procedure was repeated with the head rotated to the other side. To confirm the involvement of the posterior semicircular canal, nystagmus should last less than one minute and be of the superior torsional type for canalithiasis cases; and one minute or slightly more for cupulolithiasis.22–24 Cases where dizziness during testing was present with or without positional nystagmus association were accepted. We conducted the Epley maneuver in accordance with the description of Epley (1992), but none of the patients received premedication prior to treatment or applied mastoid bone vibration.25,26 CRM was performed up to 3 times in the same session if signs and symptoms persisted.22,23 Patients were warned that treatment could cause dizziness and nausea prior to each maneuver and they were asked to relax their neck muscles to prevent injury to the area. Orientations were given after completing the maneuvers. Next, CRM seniors were instructed to avoid rotation and extreme flexion-extension head movements, to avoid lying down on the affected side for 48 hours, and to elevate the head of the bed while sleeping for 24 hours.26 The medical assistant consented to suspend the anti-vertigo and anti-emetic preparations a week before the start of treatment. After one week (T1), the seniors performed the same initial evaluation protocol, and those who had positive Dix-Hallpike test underwent CRM again, in addition to VR protocol for seniors belonging to the EG. The same happened at five (T5), nine (T9) and thirteen (T13) weeks after the initial assessment, totaling 5 assessments. The subjects of the EG performed customized VR based on other publications in the field,27,28 twice a week for a period of twelve weeks, supervised by trained physiotherapists. The sessions lasted an average of 50 minutes. The main deficits and functional limitations were identified in the initial assessment and the prescribed exercises were addressed to specific problems of the elderly.29 In customized exercise programs, the therapist regularly assesses the patient’s progress and promotes feedback to the patient about the proper way to carry out the exercises. It is believed that this type of exercise increases patient adherence to treatment.30 VR included adaptation exercises (VORx1) and vestibular habituation (head and trunk repeated movements), static and dynamic balance training, and lower limb muscle strengthening exercises. The exercise program aimed to stimulate the vestibular system and promote sensory recalibration. During VR, therapists supervised exercises to ensure proper head and body movement for enhanced results (according to the habituation precepts) and monitored wrong posture, promoting greater patient safety.27,28 For each prescribed exercise, a universal series containing 10 modifiers and progression patterns was followed to achieve the most challenging exercises. For more information, please see the detailed description previously published.27 Participants were instructed to report all complaints (for example dizziness, nausea, or pain) during International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

or after the exercises, which justified modifying the exercises, and to not do any other physical activity during the study. They were also encouraged to perform the exercises described in a booklet at home once a day.

Statistical Analysis The normality of the data was analyzed using the ShapiroWilk test. Fisher’s exact test was used to analyze the differences between groups at baseline regarding the distribution of sex, physical exercises performance and the presence of nystagmus, while the Mann-Whitney test was used to analyze differences between groups according to age, number of comorbidities, medication and dizziness time onset. We analyzed the differences between groups regarding numerical results obtained at baseline (T0), one (T1), five (T5), nine (T9), and thirteen (T13) weeks using the Mann-Whitney test. Fisher’s exact test was also used for dichotomous variables (positive or negative Dix-Hallpike and recurrence). We used the non-parametric Friedman test to elucidate the differences in repeated intragroup measurements over time. We used the Wilcoxon test to compare intragroup improvement. We performed all statistical tests using version 20.0 of the Statistical Package for Social Sciences (SPSS) with statistical significance set at p < 0.05.

Result Fourteen subjects were randomly allocated to one of the two groups. In the experimental group, 6 women (6/7, 85.7%) and 1 man (1/7, 14.3%) with a median age of 69 years (65–78) underwent CRM whenever necessary and VR for thirteen weeks whereas, five women (5/7, 71.4%) and 2 men (2/7, 28.6%) with a median age of 73 years (65–76) received only CRM in the control group. The research flowchart is shown in ►Fig. 1. There were no statistical differences between groups at baseline for BPPV sociodemographic and clinical characteristics (p < 0.05). Body Mass Index (p ¼ 0.720), dizziness time onset (p ¼ 0.169), presence of tinnitus (p ¼ 1.000), presence of nystagmus (p ¼ 1.000), number of medications used by the elderly (p ¼ 0.386), as well as the number of comorbidities (p ¼ 1.000) were also statistically similar for both groups at baseline. The median for the number of comorbidities in the experimental group was 4 (3–6) and 4 (2–6) in the control group. The median number of drugs used was 3 (1–6) in the experimental group and 3 (3–7) in the control group. Other clinical characteristics of seniors participating in the study are presented in ►Table 1. In assessing the “positive to negative” Dix-Hallpike test, it was observed that all seniors in the EG obtained negative results after 13 weeks. In contrast, the CG showed treatment failure in 2/7 (28.6%) patients. Though, there was no difference (p > 0.05) between both groups throughout the testing period (►Fig. 2). Regarding the number of maneuvers performed in each session, we found no differences between the groups at baseline (T0), first (T1), fifth (T5), ninth (T9), and thirteenth (T13) week of assessment (p > 0.05). Only in the EG it is possible to observe significant improvement gradient, with a


“Positive to Negative” Dix-Hallpike test and Benign Paroxysmal Positional Vertigo recurrence in elderly undergoing Canalith Repositioning Maneuver and Vestibular Rehabilitation Ribeiro et al.

Enrollment

Assessed for eligibility (n=35) Excluded (n= 19) Did not meet inclusion criteria (n= 19) Other reason (n=0)

Screening

Allocation

Randomized (n= 16)

Allocated to intervention group (n=08) Received VR in addition to CRM (n=08) Did not receive allocated intervention (n=0)

Allocated to CG (n=08) Received CRM (n=08) Did not receive allocated control (n=0)

Baseline Assessment

F o

CRM

CRM

l l o w u p

Analysis

Follow-up in: Additional VR and CRM, if necessary 1 week (n= 08) 5 weeks (n= 08) 9 weeks (n=07) 13 weeks (n=07) Lost to follow-up (n = 01) 1. Personal problems

Follow-up in: (No additional treatment and CRM if necessary) 1 week (n= 08) 5 weeks (n= 07) 9 weeks (n=07) 13 weeks (n=07) Lost to follow-up (n = 01) 1. Fall

Discontinued intervention (n=0)

Discontinued intervention (n=0)

Analyzed (n= 7) Excluded from analysis (n= 0)

Analyzed (n= 7) Excluded from analysis (n= 0)

Fig. 1 Flowchart of the study. CRM, Canalith Repositioning Maneuvers; VR, Vestibular Rehabilitation.

progressive decrease in the number of maneuvers necessary for the treatment (►Table 2). Two patients (2/7, 28.3%) in the control group and 1 (1/7, 14.7%) in the experimental group had recurrence of BPPV in the 13-week period. However, this fact did not favor the statistically significant difference between groups (p ¼ 1.000). Among the seniors who had recurrence, Senior 1 had bilateral BPPV, hypertension as a risk factor for the disease, and used 6 daily medications. Senior 6 had diabetes as a risk factor and used 3 daily medications. Senior 8 had secondary BPPV and remained feeling dizziness (floating sensation) after 13 weeks. There were no adverse events or complications of treatment, such as posterior canal BPPV being converted to horizontal canal BPPV.

Discussion Vestibular dysfunction is a major cause of dizziness in the elderly and represents 40–50% of the causes of dizziness in

elderly patients referred to the otorhinolaryngologist. It is also described as an important differential diagnosis when the elderly falls without apparent cause.30 Chronically dizzy elderly have 53.3% of falls per year,31 and, although vertigo corresponds to 25% of falls, it is separately disclosed as the most common cause.7 In a recent cohort study,32 it was observed that BPPV elderly patients exhibited 1.14-fold higher risk to fracture compared with healthy elderly, when adjusted for age, sex, and comorbidities. Non-pharmacological alternatives for the treatment of BPPV, including CRM, represent an important therapeutic opportunity for not presenting risks of adverse effects usually present in the elderly that use pharmacological products. The treatment may be associated with VR, which includes vestibular adaptation, habituation, and substitution exercises, associated with a set of procedures linked to changes in habits and postural improvement,21,30,33 despite the lack of substantial scientific evidence that VR enhances the effect of CRM or provides any benefit whatsoever.13,14 International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

347


International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

73

76

74

72

65

65

Pat 4

Pat 5

Pat 6

Pat 7

Pat 8

74

Pat 2

Pat 3

72

Pat 1

Age

F

F

F

F

M

M

F

F

Sex

EG

CG

CG

CG

CG

CG

CG

CG

Group

Yes

No

Yes

No

No

No

No

Yes

Recurrence

Secondary

Primary

Primary

Primary

Primary

Primary

Primary

Primary

Type of BPPV

Table 1 Characteristics of the elderly with BPPV sample during 13 weeks

Right

Right

Right

Left

Right

Right

Right

Bilateral

Affected side

Vertigo

Vertigo

Vertigo

Vertigo

Vertigo

Vertigo

Vertigo

Vertigo

Type of dizziness Baseline

Floating sensation

Vertigo

Vertigo

No dizziness

Floating sensation

Floating sensation

No dizziness

No dizziness

Type of dizziness 13th week

E07 F32 H40

I10 M81

M19 E11 F32 E78

I10 M19 I48 G47.3 M81 H40

N40 E11 M19 J32 E78 K-29

I10 N40 E78

I10 E11 M81 M19 E02

I10 J45 E78

Diseases 

N06 S01

C08 M05 A11

A10 N02 N06

C03 C07 S01

A02 C02 C10

C03 C07 C09 C10 G03

A10 A11 B01 C03 C09 H03 M05

A11 B01 C03 C10 R01 R03

Medications#

348 â&#x20AC;&#x153;Positive to Negativeâ&#x20AC;? Dix-Hallpike test and Benign Paroxysmal Positional Vertigo recurrence in elderly undergoing Canalith Repositioning Maneuver and Vestibular Rehabilitation Ribeiro et al.


66

73

78

70

69

Pat 10

Pat 11

Pat 12

Pat 13

Pat 14

F

F

F

F

F

F

Sex

EG

EG

EG

EG

EG

EG

Group

No

No

No

No

No

No

Recurrence

Primary

Primary

Primary

Primary

Primary

Primary

Type of BPPV

Right

Right

Right

Bilateral

Left

Right

Affected side

Vertigo

Vertigo

Vertigo

Vertigo

Vertigo

Vertigo

Type of dizziness Baseline

Floating sensation

No dizziness

No dizziness

Floating sensation

No dizziness

No dizziness

Type of dizziness 13th week

M79.7 F32 E78

M19 J45 K29.3 E16 E78

I10 M19 I49

M19 M81 E02 K74

I10 M81 F32 J42 K29.3 I87.2

I10 M81 E78 F32 M79.7

Diseases 

C10 N05 N06

A02 A10 C10 M05 R01 R03

C01 C03 C09

H03

A11 M05 N03 R01 R03

A11 C09 C10 N06

Medications#

Abbreviations: Pat, patient; CG, Control Group; EG, Experimental Group.  E02–Subclinical iodine-deficiency hypothyroidism, E07–Other disorders of thyroid, E11–Type 2 diabetes mellitus, E 16 - Other disorders of pancreatic internal secretion, E78–Hypercholesterolemia, F32Depressive episode, G47.3–Sleep apnoea, H40–Glaucoma, I10–Essential hypertension, I48–Atrial fibrillation and flutter, I49–Other cardiac arrhythmias, I87.2–Venous insufficiency (chronic)(peripheral), J32– Chronic sinusitis, J42–Unspecified chronic bronchitis, J45–Asthma, K29.3–Chronic superficial gastritis, K74–Fibrosis and cirrhosis of liver, M19–Other arthrosis, M32–Systemic lupus erythematosus, M79.7– Fibromyalgia, M81–Osteoporosis without pathological fracture, N40–Hyperplasia of prostate. # A02–Drugs for acid related disorders, A10–Drugs used in diabetes, A11–Vitamins, B01–Antithrombotic agents, C01–Cardiac therapy, C02–Antihypertensives, C03–Diuretics, C07–Beta blocking agents, C08– Calcium channel blockers, C09–Agents acting on the renin-angiotensin system, C10–Lipid modifying agents, G03–Sex hormones and modulators of the genital system, H03–Thyroid therapy, M05–Drugs for treatment of bone diseases, N02–Analgesics, N03–Antiepileptics, N05–Psycholeptics, N06–Psychoanaleptics, R01–Nasal preparations, R03–Drugs for obstructive airway, S01–Ophthalmologicals.

65

Pat 9

Age

Table 1 (Continued)

“Positive to Negative” Dix-Hallpike test and Benign Paroxysmal Positional Vertigo recurrence in elderly undergoing Canalith Repositioning Maneuver and Vestibular Rehabilitation Ribeiro et al.

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

349


International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

0.073

p

0 (0–3)

0 (0–3)

a

T13 T9

0 (0–3) 2 (0–3) 2 (2–3) 0.0001

T5

a

0 (0–0) 0 (0–2) Significant intragroup difference compared with T0, p < 0.05. Significant intragroup difference compared with T1, p < 0.05.  Intragroup comparison. b

a

0 (0–3) 3 (0–3) 3 (2–3) Number of Maneuvers

Our findings revealed that negative Dix-Hallpike test results or number of maneuvers to achieve it over the 13 weeks were not significantly different regardless of patients having performed additional VR therapy. However, it is important to mention that all patients in the EG obtained negative test results with consequent remission of vertigo after treatment with additional VR, unlike in the control group, which was unsuccessful with two seniors. It might be suggested that these findings occurred due to the habitual performance of exercises incorporated into the VR program. Previous studies23,34 that performed vestibular habituation exercises in patients who had persistent BPPV symptoms after treatment through CRM reported good results with this combination therapy. BPPV recurrence is set at 1.7-fold higher risk in elderly patients with BPPV than in younger individuals suffering with the same disease.35 In this study, the prevalence of symptoms recurrence over the 13-week follow-up was 21.4%, corroborating with Dorigueto et al.34 In the literature, however, the recurrence rate variability shows a result of 26%34 to 50%,36,37 which can be explained by the difference in time and patient follow-up mode. Choi et al38 observed that patients with BPPV presenting recurrence needed longer follow-up and CRM treatment periods when compared with groups that achieved rapid remission or symptom persistence. Of the three seniors who presented recurrence in this study, one had hypertension and one had associated osteoarthritis and diabetes. A recent multicenter study11 demonstrated that the association between two or more comorbidities such as hypertension, diabetes, and osteoarthritis are able to significantly influence the number of BPPV recurrences and that osteoporosis is associated with a higher risk for such condition. Since this was a study conducted with elderly who have more comorbidities than the general population,39 the likelihood of recurrence is higher because these associated diseases, recognized as BPPV triggers, are more present in such individuals. BPPV can recur when secondary to some neurological or otological event. In this study, the only senior who had secondary BPPV (which was due to prolonged bed rest from being in a coma, also considered a triggering event to BPPV)40 had recurrence. Cases of recurrence and persistence of BPPV mostly result from the idiopathic form of the disease.

T1

Fig. 2 Descriptive analysis of the "positive to negative" Dix-Hallpike test at baseline (T0), first (T1), fifth (T5), ninth (T9) and thirteenth week (T13) of assessment.

T0

T13

p

T9

ab

T5 Follow-up

T13

T1

ab

T0

T9

0

a

1

T5

Control Group

2

T1

Experimental Group

3

T0

4

Control Group (n ¼ 7)

5

Experimental Group (n ¼ 7)

6

Outcome Measures Median (range)

7

Table 2 Number of maneuvers performed per session in experimental and control groups at baseline (T0), first (T1), fifth (T5), ninth (T9) and thirteenth (T13) week of assessment

“Positive to Negative” Dix-Hallpike test and Benign Paroxysmal Positional Vertigo recurrence in elderly undergoing Canalith Repositioning Maneuver and Vestibular Rehabilitation Ribeiro et al.

Number of elderly with posive Dix-Hallpike

350


“Positive to Negative” Dix-Hallpike test and Benign Paroxysmal Positional Vertigo recurrence in elderly undergoing Canalith Repositioning Maneuver and Vestibular Rehabilitation Ribeiro et al. Additionally, individuals suffering from secondary BPPV are more likely to present vertigo symptoms for a longer time, and even after dizziness remission, may have disease recurrence.38,41 It was found that more than half of the elderly were suffering from hypertension, hypercholesterolemia, and arthritis, and that most also had osteoporosis and diabetes. Patients with BPPV have more vascular risk factors when compared with patients suffering from other vestibular diseases.42,43 Furthermore, elderly patients with BPPV have 1.3fold higher risk, adjusted by age and sex, to develop acute ischemic stroke than seniors who do not have the disease.44 Cardiovascular, metabolic, and osteoarticular diseases, and osteoporosis are risk factors for the onset of BPPV, and may also be related to its genesis.7,45–47 A considerable number of comorbidities per elderly was found. This may explain the low resolution of the symptomatology, since most of the surveyed elderly suffer from comorbidities that directly interfere with dizziness symptoms. The greater the number of associated diseases, the greater the risk for dizziness, especially if that number is greater than three.48,49 The high number of associated diseases may be related to the fact that some seniors improved the vertigo symptom related to BPPV, but remain feeling another type of dizziness. This occurred in five patients in this study (35.7%). Those participants remained with floating sensation dizziness even after a negative Dix-Hallpike test. The low number of subjects involved in the study can be considered as a potential limitation on the extrapolation of results found. However, the form of selection, and type (randomized controlled clinical trial) are considered strengths of the study. The findings of the intervention and its clinical implications must be wisely considered for making therapeutic decisions in elderly patients with BPPV. Despite the fact that we did not find differences between groups, VR should be considered as an important adjuvant therapeutic tool, since the consequences arising out of BPPV such as falls and fractures in the elderly can be potentially avoided through CRM associated with postural balance training exercises.32 We suggest further studies to evaluate the effectiveness of VR with larger sample sizes and longer-term follow-up, as vestibular functions may be influenced by confounding factors, which may cause a change in the health status of the elderly throughout treatment.

References 1 Maarsingh OR, Dros J, Schellevis FG, van Weert HC, Bindels PJ,

2 3

4

5 6

7

8 9

10

11

12

13

14

15

16 17

Conclusion In the present study, elderly patients with BPPV were mostly women and had a considerable number of comorbidities. The findings suggest that “positive to negative” Dix-Hallpike test, BPPV recurrence, and the number of maneuvers to achieve negative results were not influenced by additional VR to CRM in the elderly with chronic BPPV.

Conflicts of Interest The authors declare no conflicts of interest.

18 19

20

21

Horst HE. Dizziness reported by elderly patients in family practice: prevalence, incidence, and clinical characteristics. BMC Fam Pract 2010;11:2 Sloane PD, Coeytaux RR, Beck RS, Dallara J. Dizziness: state of the science. Ann Intern Med 2001;134(9 Pt 2):823–832 Horak FB. Postural orientation and equilibrium: what do we need to know about neural control of balance to prevent falls? Age Ageing 2006;35(2, Suppl 2):ii7–ii11 Jönsson R, Sixt E, Landahl S, Rosenhall U. Prevalence of dizziness and vertigo in an urban elderly population. J Vestib Res 2004; 14(1):47–52 Kutz JW Jr. The dizzy patient. Med Clin North Am 2010;94(5): 989–1002 Tinetti ME, Williams CS, Gill TM. Dizziness among older adults: a possible geriatric syndrome. Ann Intern Med 2000;132(5): 337–344 Ganança FF, Gazzola JM, Ganança CF, Caovilla HH, Ganança MM, Cruz OL. Elderly falls associated with benign paroxysmal positional vertigo. Braz J Otorhinolaryngol 2010;76(1):113–120 Cho EI, White JA. Positional vertigo: as occurs across all age groups. Otolaryngol Clin North Am 2011;44(2):347–360, viii Moreno NS, André AP. Number of maneuvers need to get a negative Dix-Hallpike test. Braz J Otorhinolaryngol 2009;75(5): 650–653 Caldas MA, Ganança CF, Ganança FF, Ganança MM, Caovilla HH. Clinical features of benign paroxysmal positional vertigo. Braz J Otorhinolaryngol 2009;75(4):502–506 De Stefano A, Dispenza F, Suarez H, et al. A multicenter observational study on the role of comorbidities in the recurrent episodes of benign paroxysmal positional vertigo. Auris Nasus Larynx 2014; 41(1):31–36 Kerber KA, Burke JF, Skolarus LE, et al. Use of BPPV processes in emergency department dizziness presentations: a population-based study. Otolaryngol Head Neck Surg 2013;148(3): 425–430 Bhattacharyya N, Baugh RF, Orvidas L, et al; American Academy of Otolaryngology-Head and Neck Surgery Foundation. Clinical practice guideline: benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg 2008;139(5, Suppl 4):S47–S81 Fife TD, Iverson DJ, Lempert T, et al; Quality Standards Subcommittee, American Academy of Neurology. Practice parameter: therapies for benign paroxysmal positional vertigo (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2008; 70(22):2067–2074 Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: updated guidelines for reporting parallel group randomized trials. Ann Intern Med 2010;152(11):726–732 Drachman DA, Hart CW. An approach to the dizzy patient. Neurology 1972;22(4):323–334 WHO Collaborating Centre for Drug Statistics Methodology. (2012) Guidelines for ATC Classification and DDD Assignment 2013. 16th ed. WHO Collaborating Centre for Drug Statistics Methodology, Oslo. Flores LM, Mengue SS. Uso de medicamentos por idosos em região do sul do Brasil. Rev Saude Publica 2005;39(6):924–929 Saúde. OMd. CID–10, tradução do Centro Colaborador da OMS para a Classificação de Doenças em Português. 2003. 9ª ed. São Paulo: EDUSP Gold DR, Morris L, Kheradmand A, Schubert MC. Repositioning maneuvers for benign paroxysmal positional vertigo. Curr Treat Options Neurol 2014;16(8):307 Silva AL, Marinho MR, Gouveia FM, Silva JG, Ferreira AdeS, Cal R. Benign Paroxysmal Positional Vertigo: comparison of two recent

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

351


352

“Positive to Negative” Dix-Hallpike test and Benign Paroxysmal Positional Vertigo recurrence in elderly undergoing Canalith Repositioning Maneuver and Vestibular Rehabilitation Ribeiro et al.

22

23

24

25

26

27

28

29

30 31

32

33 34

international guidelines. Braz J Otorhinolaryngol 2011;77(2): 191–200 Helminski JO, Zee DS, Janssen I, Hain TC. Effectiveness of particle repositioning maneuvers in the treatment of benign paroxysmal positional vertigo: a systematic review. Phys Ther 2010;90(5): 663–678 Angeli SI, Hawley R, Gomez O. Systematic approach to benign paroxysmal positional vertigo in the elderly. Otolaryngol Head Neck Surg 2003;128(5):719–725 Herdman SJ, Tusa RJ. Physical Therapy Management of Benign Positional Vertigo. In: Herdman SJ. Vestibular Rehabilitation. 3rd ed. Philadelphia, PA: F. A. Davis Company; 2007:233–60 Epley JM. The canalith repositioning procedure: for treatment of benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg 1992;107(3):399–404 Bruintjes TD, Companjen J, van der Zaag-Loonen HJ, van Benthem PP. A randomised sham-controlled trial to assess the long-term effect of the Epley manoeuvre for treatment of posterior canal benign paroxysmal positional vertigo. Clin Otolaryngol 2014;39(1):39–44 Alsalaheen BA, Whitney SL, Mucha A, Morris LO, Furman JM, Sparto PJ. Exercise prescription patterns in patients treated with vestibular rehabilitation after concussion. Physiother Res Int 2013; 18(2):100–108 Chang WC, Yang YR, Hsu LC, Chern CM, Wang RY. Balance improvement in patients with benign paroxysmal positional vertigo. Clin Rehabil 2008;22(4):338–347 Herdman SJ, Whitney SL. Interventions for the Patient with Vestibular Hypofunction. In: Herdman SJ. Vestibular Rehabilitation. 3rd ed. Philadelphia, P.A.: f.a. Davis Company; 2007: 3009– 37Herdman SJ WS. Interventions for the patient with Vestibular Hypofunction. 2007:309–37 Alrwaily M, Whitney SL. Vestibular rehabilitation of older adults with dizziness. Otolaryngol Clin North Am 2011;44(2):473–496, x Gazzola JM, Ganança FF, Aratani MC, Perracini MR, Ganança MM. Circumstances and consequences of falls in elderly people with vestibular disorder. Braz J Otorhinolaryngol 2006;72(3):388–392 Liao WL, Chang TP, Chen HJ, Kao CH. Benign paroxysmal positional vertigo is associated with an increased risk of fracture: a population-based cohort study. J Orthop Sports Phys Ther 2015;45(5): 406–412 Whitney SL, Sparto PJ. Principles of vestibular physical therapy rehabilitation. NeuroRehabilitation 2011;29(2):157–166 Dorigueto RS, Mazzetti KR, Gabilan YP, Ganança FF. Benign paroxysmal positional vertigo recurrence and persistence. Braz J Otorhinolaryngol 2009;75(4):565–572

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

35 Kao CL, Hsieh WL, Chern CM, Chen LK, Lin MH, Chan RC. Clinical

36

37 38

39

40

41

42 43

44

45

46

47

48

49

features of benign paroxysmal positional vertigo (BPPV) in Taiwan: differences between young and senior age groups. Arch Gerontol Geriatr 2009; 49(2, Suppl 2):S50–S54 Baloh RW, Honrubia V, Jacobson K. Benign positional vertigo: clinical and oculographic features in 240 cases. Neurology 1987; 37(3):371–378 Brandt T, Daroff RB. Physical therapy for benign paroxysmal positional vertigo. Arch Otolaryngol 1980;106(8):484–485 Choi SJ, Lee JB, Lim HJ, et al. Clinical features of recurrent or persistent benign paroxysmal positional vertigo. Otolaryngol Head Neck Surg 2012;147(5):919–924 Batuecas-Caletrio A, Trinidad-Ruiz G, Zschaeck C, et al. Benign paroxysmal positional vertigo in the elderly. Gerontology 2013; 59(5):408–412 Charles C, Santina D, Minor LB, Carey JP In: Lee KJ. Princípios de Otorrinolaringologia: cirurgia de cabeça e pescoço. 9th ed. Porto Alegre, RS: AMGH editora; 2010:94–134 Tanimoto H, Doi K, Nishikawa T, Nibu K. Risk factors for recurrence of benign paroxysmal positional vertigo. J Otolaryngol Head Neck Surg 2008;37(6):832–835 De Reuck J. Vascular risk factors in patients with peripheral vestibular disorders. Acta Neurol Belg 2010;110(4):303–305 Wada M, Naganuma H, Tokumasu K, Hashimoto S, Ito A, Okamoto M. Arteriosclerotic changes as background factors in patients with peripheral vestibular disorders. Int Tinnitus J 2008;14(2):131–134 Kao CL, Cheng YY, Leu HB, et al. Increased risk of ischemic stroke in patients with benign paroxysmal positional vertigo: a 9-year follow-up nationwide population study in taiwan. Front Aging Neurosci 2014;6(2):108 Gazzola JM, Ganança FF, Aratani MC, Perracini MR, Ganança MM. Clinical evaluation of elderly people with chronic vestibular disorder. Braz J Otorhinolaryngol 2006;72(4):515–522 Bittar RS, Pedalini ME, Ramalho JO, Yoshimura R. Critical analysis of vestibular rehabilitation outcome according to dizziness etiology. Braz J Otorhinolaryngol 2007;73(6):760–764 Yu S, Liu F, Cheng Z, Wang Q. Association between osteoporosis and benign paroxysmal positional vertigo: a systematic review. BMC Neurol 2014;14:110 Gassmann KG, Rupprecht R. Dizziness in an older community dwelling population: a multifactorial syndrome. J Nutr Health Aging 2009;13(3):278–282 Gomez F, Curcio CL, Duque G. Dizziness as a geriatric condition among rural community-dwelling older adults. J Nutr Health Aging 2011;15(6):490–497


THIEME

Original Research

Residual Hearing Preservation with the Evo® Cochlear Implant Electrode Array: Preliminary Results Ricardo Ferreira Bento1

Fabiana Danieli2

Ana Tereza de Matos Magalhães3

1 Department of Otolaryngology, Universidade de São Paulo,

São Paulo, Brazil 2 Clinical Department, Oticon Medical, São Paulo, Brazil 3 Department of Audiology, Universidade de São Paulo, São Paulo, Brazil 4 Department of Scientific and Clinical Research, Oticon Medical, Vallauris, France

Dan Gnansia4

Michel Hoen4

Address for correspondence Michel Hoen, PhD, Department of Scientific and Clinical Research, Oticon Medical, 2720 Chemin St., Bernard Porte 14, Vallauris 06220, France (e-mail: mhoe@oticonmedical.com).

Int Arch Otorhinolaryngol 2016;20:353–358.

Abstract

Keywords

► cochlear implantation ► cochlear round window ► residual hearing ► hearing preservation ► dexamethasone

received October 6, 2015 accepted November 15, 2015 published online February 16, 2016

Introduction The preservation of residual hearing is currently an important challenge for cochlear implant surgeries. Indeed, if patients exhibit functional hearing after cochlear implantation, they can benefit from the combination of acoustical stimulation, usually in the low-frequencies and electrical stimulation in the high-frequencies. This combined mode of stimulation has proven to be beneficial both in terms of speech perception and of sound quality. Finding the right procedures for conducting softsurgeries and designing electrode arrays dedicated to hearing preservation is an open issue. Objective The objective of this study is to evaluate the combination of a soft-surgery procedure implicating round-window insertion and the use of dexamethasone and hyaluronic acid during surgery, with the use of a specifically designed straight soft electrode array, on hearing preservation in patients with functional hearing in the low frequencies. Methods This pre-clinical trial was conducted on seven patients with residual hearing in the low frequencies. The surgical method used employed a round window insertion and the use of topical dexamethasone. Results The soft-surgery protocol could be successfully followed in five patients. In this group, the average hearing threshold shift compared with pre-operative values was of 18.7 þ/ 16.1 dB HL up to 500 Hz and 15.7 þ/ 15.1 up to 1 kHz, demonstrating satisfying levels of hearing preservation. Conclusion We were able to demonstrate the possibility of preserving residual hearing in most of the patients using the EVO electrode. Significant residual hearing preservation levels were was obtained when a soft surgical approach involving round window insertion, dexamethasone and hyaluronic use during the surgery.

DOI http://dx.doi.org/ 10.1055/s-0036-1572530. ISSN 1809-9777.

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil

353


354

Residual Hearing Preservation with the Evo Cochlear Implant Electrode Array

Introduction Cochlear implants (CI) nowadays constitute a method of choice for the rehabilitation of hearing function in patients with severeto-profound hearing loss and congenital deafness. Thanks to proven benefits in terms of quality of life and speech and communication, CI indication was progressively extended to patients presenting significant levels of functional residual hearing. Provided cochlear implantation can preserve this residual hearing, these patients can benefit from the combination of electrical stimulation provided by the CI over mid- to high frequencies and of amplified acoustic stimulation over the low-frequencies. This stimulation mode was shown to improve speech understanding in various listening situations.1,2 These advantages have highlighted the importance of preserving residual hearing during CI surgery. Recent developments in this area followed mainly three lines of research. The first series of improvements concerned the surgery itself with the refining of soft-surgical approaches, seeking to minimize intracochlear trauma due to the opening of the internal ear and the insertion of the electrode array. In this context, the round-window (RW) surgical approach is often thought to be less traumatic than the cochleostomy. With the RW approach, the entry into the cochlea happens through a membrane, not requiring added bone drilling and can thus potentially lead to less trauma.3,4 Therefore, the RW approach today constitutes the favored approach for soft-surgeries and is still widely preferred over cochleostomy. The second line of developments concerned the use of pharmacological support to diminish the acute insertion trauma as well as postimplantation inflammation, and lubricating substances, to diminish the mechanical trauma caused during the electrode insertion. Dexamethasone was proven to be efficient under systemic administration. The injection of intravenous dexamethasone one hour prior to the surgery lead to reduced surgery-induced hearing loss.5 Preoperative local administration of steroids directly on the RW was shown to significantly reduce post-operative thresholds shifts.6 In addition to steroids, the use of lubricating fluids or gels applied onto the electrode array, such as Hyaluronic acid was shown to reduce friction forces during electrode insertion, potentially limiting the insertion trauma.7,8 Finally, the combination of both steroids and hyaluronic acid was sometimes more efficient than the use of either solution alone.9 The last line of research developed in this context was the improvement and specific design of electrode arrays optimized for less traumatic insertions. Shorter electrode arrays, meant to cover only the high-frequency regions of the cochlea were developed, but presented very limited interest because of the frequent progressive nature of the hearing-loss affecting patients and the high risk of reimplantation associated. Moreover, residual hearing preservation was shown to be possible with long electrodes, provided they have a soft surface and a limited tip diameter.10,11 Despite these results, the efficiency of combining softsurgical approaches with specific pharmacological treatment procedures to prevent loss of residual hearing using long electrode arrays can still be optimized and specific protocols International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Bento et al.

should be tested to develop clear guidelines. The objective of the present study was to evaluate the combination of a softsurgery procedure implicating round-window insertion and the use of dexamethasone and hyaluronic acid during surgery, with the use of a specifically designed soft electrode array (EVO, Oticon Medical, Vallauris, France), on hearing preservation in a group of CI candidates with residual hearing in the low frequencies.

Method Participants Seven participants from the Department of Otolaryngology of the Universidade de São Paulo (São Paulo, Brazil) were included in this preliminary clinical study. Participants were all post-lingual deaf adults, aged 23 to 83 years, with an average age of 52.43 þ/- 20.85 years. Patient’s demographic details are provided in ►Table 1. All but one patient had a history of progressive hearing loss from unknown etiology. The last patient had a sudden ototoxic loss. Presurgical imaging revealed no cochlear abnormalities or ossifications of the internal ear in any patient. All presented with profound hearing loss thresholds starting from 1000 Hz, with averaged pure-tone thresholds between 1 and 8 kHz of 119.7 þ/12.8 dB HL. See ►Fig. 1 for detailed pure-tone audiometry. Patients were included in the study because they presented residual hearing over the low frequencies, with averaged pure-tone thresholds at 750 Hz ¼ 86.1 þ/- 14.85 dB HL; 500 Hz¼ 67.9 þ/- 12.5 dB HL; 250 Hz¼ 46.4 þ/- 10.7 dB HL and 125 Hz ¼ 38.6 þ/- 10.7 dB HL). Despite these favorable low-frequency thresholds, all patients had limited benefit of hearing aids (Sentence recognition scores lower than 50% with amplification), and were thus candidates for cochlear implantation and received an Oticon Medical Neurelec (Vallauris, France) CI system (Digisonic SP). If residual hearing was preserved, these patients would be candidates for Table 1 Patients’ demographics Subject id

Gender

Age at Implantation (years)

Implanted Side

Etiology

P1

F

83

Left

Progr. Unknown

P2

F

41

Left

Progr. Unknown

P3

F

72

Right

Progr. Unknown

P4

F

49

Left

Progr. Unknown

P5

F

23

Left

Progr. Unknown

P6

M

38

Right

Sudden Ototoxic

P7

F

61

Left

Progr. Unknown

Abbreviations: id, identification; F, female; M, male; Progr, progressive.


Residual Hearing Preservation with the Evo Cochlear Implant Electrode Array

Bento et al.

Fig. 1 Top panel: Averaged free-field warble-tone thresholds measured pre- (blue) and post-operatively (orange) in the five patients who had successful soft-surgery with the Evo® electrode array. The shaded areas represent the standard deviation of mean. Bottom-panel: graphical representation of the median loss across frequencies for the same patients.

combined electric and acoustic stimulation using the Zebra (Oticon Medical, Vallauris, France) speech processor.12 Before inclusion, volunteers were fully informed about the goals and procedures of the study and provided written consent. This study was performed in accordance with the Declaration of Helsinki, and was approved by the Ethics Committee for the Analysis of Research projects of the Universidade de São Paulo (São Paulo, Brazil).

Hearing Preservation Soft-Surgery Protocol and Electrode Array The soft surgical procedure employed a classical trans-mastoid approach and a round-window insertion of the electrode array.9 Pre-operatively, patients received a weight-adjusted intravenous dose of hydrocortisone (4 mg/kg) and a single dose of preventive antibiotic treatment (cefazolin, 1 g), before intubation and general anesthesia. The surgeon then performed a wide posterior tympanotomy via facial recess, allowing exposure of the round window membrane. The middle ear cavity was then filled with a dexamethasone solution (4 mg/ml), while the receiver was placed in the subperiosteal pocket and secured with two titanium screws, without drilling a bony well.13,14 The steroid solution was then removed, the anterior border of the round window

membrane was delicately perforated and no suctioning of the perilymph was performed. Hyaluronic acid (Provisc, Alcon Laboratories Inc., Puurs, Belgium) was then placed over the membrane and along the electrode array, before slow insertion of the electrode. After insertion, the electrode insertion site was sealed using a small collar of temporalis fascia positioned around the electrode array and the middle ear cavity was again filled with dexamethasone (4 mg/ml). If the soft-surgery was compromised (difficult insertion of electrode array), the procedure would be abandoned and a cochleostomy performed to warranty the best insertion ratio and the best cochlear implant outcomes for the patient despite the risk of not preserving residual hearing.

The EVO® Electrode Array The EVO® electrode array (Oticon Medical, Vallauris, France) was especially designed to respond to the constraints of soft surgeries for hearing preservation. It is a long (24 mm), thin (proximal diameter ¼ 0.5 mm; distal diameter ¼ 0.4 mm), and flexible device, with a smooth surface silicone array carrying 20 micro-machined titanium-iridium electrodes (►Fig. 2). This specific design demonstrated low insertion forces compared with classical electrode array designs,15 and is associated to low levels of intracochlear traumas.16 International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

355


356

Residual Hearing Preservation with the Evo Cochlear Implant Electrode Array

Bento et al.

Fig. 2 The EVO® electrode-array for residual hearing preservation. The electrode array was designed for maximized hearing preservation with a smooth surface and a soft, less traumatic tip.

Evaluation of Residual Hearing Preservation To evaluate residual hearing preservation, we evaluated pre- and post-surgical pure-tone audiometry using a calibrated clinical AC33 audiometer (Interactoustics, Assens, Denmark), in a double-walled sound-booth. We measured warble-tone thresholds under free-field listening conditions, using only the cochlear implant system (contralateral ear plugged). Post-operative thresholds were measured on average 3.14 þ/- 1.5 months after surgery.

Results Surgeries The round-window soft surgery approach was possible only in five out of seven patients (P1; P4-P7). Unfortunately, electrode insertion through the RW appeared to be difficult and remained partial in two patients (P2 & P3). These two patients required a cochleostomy to obtain a more favorable insertion angle and ensure a fuller insertion. Therefore, we will first report separate results for the 5 patients who had a successful soft-surgery and round window insertion, which represent our best case scenario. We will then report on the complete group by including the two patients who had a cochleostomy.

Hearing Preservation with Soft-Surgery and Round Window Insertion The different thresholds measured pre- and post-surgery in the group of patients who had successful soft-surgery are represented in ►Fig. 1. In this group, the average hearing threshold shift compared with pre-operative values was of 18.7 þ/- 16.1 dB HL up to 500 Hz and 15.7 þ/- 15.1 up to 1 kHz (►Fig. 1–Top panel). The observed median loss at 500 Hz was 15 dB HL (►Fig. 1–Bottom panel). The averaged residual thresholds after surgery in this group of patients were 73 þ /- 24 dB HL up to 500 Hz and 87 þ/- 26.7 up to 1 kHz. However, these group’s results hide a relatively important interindividual variability as can shown in ►Fig. 3, showing the pre- versus post-surgery thresholds diagram at 500 Hz. Among the five patients, 3 (P1, P5 & P7) had post-operative thresholds in the þ10 dB HL range and one more (P4) was between þ10 and þ20 dB HL. One patient (P6) showed an important threshold shift of þ40 dB HL at 500 Hz.

Complete Group Analysis When considering the data from the complete patients group, results showed that the two patients (P2 & P3, triangles on ►Fig. 3), who could not have a full-insertion through

Fig. 3 Pre- versus post-surgery input/output chart. For each individual patient included in the study, pre- (x-axis) and post-operative (y-axis) thresholds are plotted on the same graph. The diagonal (black line) of this graph represents the no-difference line the dotted lines represent the þ / - 10 dB HL (light gray) or þ/ - 20 dB HL difference lines (dark gray). Circles represent patients from the round-window insertion group and triangles represent patients P2 and P3, who had to undergo cochleostomy because of difficult insertion (partial ossification). International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016


Residual Hearing Preservation with the Evo Cochlear Implant Electrode Array the round-window showed worst results than the patients from the round-window insertion group, with individual threshold increases at 500 Hz of respectively 40 and 65 dB HL. However, even for these two patients, some residual hearing could be preserved as their averaged thresholds below 500 Hz were of 81.7 þ/- 19.7. Including these two patients, the group-averaged hearing threshold shift compared with pre-operative values was of 24.5 þ/- 18.2 dB HL up to 500 Hz and 21.8 þ/- 19.2 up to 1 kHz.

Discussion This preliminary clinical study demonstrated the possibility of preserving residual hearing using the 24 mm long EVO® soft electrode array combined with a soft-surgery protocol including the usage of dexamethasone and hyaluronic acid.9 The results, however, also highlighted potential caveats of this approach, regarding the selection of candidate patients and the surgical approach employed. In a first sub-group of five patients, thresholds compatible with the use of combined electric and acoustic stimulation could be achieved. Although the number of patients included in the present study do not allow us to generalize from our current observations, these preliminary observations are very promising and would encourage the conducting of larger scale, multi-centric clinical trials including larger numbers of patients. In 3 out of 5 patients (60%), who had successful softsurgery with round-window insertion, the hearing preservation was complete, with a post-surgery loss at 500 Hz of 10 dB and moderate (loss of 11–20 dB) in one other patient (20%) and one presented only partial hearing preservation (loss of 40 dB), bringing the total count of partial preservations to 100%. When including the two patients who could not have soft-surgery and who had to have a cochleostomy after several attempts of RW insertion, the number is 71.4% of successful hearing preservation over the sample. Our preliminary observations are well in line with data reported in the literature regarding hearing preservation. Reported distributions in the literature vary with the study and are in about the same range: 45.2% of complete preservation and 90.3% of partial loss in 31 children, mean threshold shift of 18.5 dB HL with standard electrode arrays and full-length insertions17; 71–86% hearing preservation using the Nucleus 24 Contour Advance electrode.18 In a recent study comparing hearing preservation with the Hybrid-L24 and the CI 422 from Cochlear, Jurawitz and colleagues19 reported 54.6% and 49.0% of subjects showed a mean threshold shift < 15 dB. Another aspect which would be interesting to monitor is the evolution over time of the hearing preservation scores, several authors having shown that sometimes scores obtained pre-operatively decrease during the following months.20,21 Our data also suggest that hearing preservation can be achieved with a straight electrode with full insertion (21 mm), provided a soft-surgical procedure can be achieved. The round-window surgical approach led to good hearing preservation results in our case, however, we cannot be conclusive regarding the difference between the RW and a

Bento et al.

cochleostomy approach, because of the small numbers of patients included in the present study and because a cochleostomy was performed only if the RW approach could not be conducted properly. Former work in this domain have shown that both approaches could lead to satisfying hearing preservation levels provided both are conducted appropriately. In a systematic literature review including 170 patients, Havenith and colleagues,22 could not find clear evidence for a superiority of the RW approach compared with cochleostomy. Other authors reported that similar levels of lowfrequency hearing preservation could be achieved using straight narrow electrode inserted with either approaches.23–25 One possible difference contrasting both approaches is the relatively important anatomical variability of the round window itself, which could compromise insertion in certain cases and would make the cochleostomy a better option.26 Extensive studies including more patients and looking at the detailed relationship between ore-operative anatomical characteristics of the RW region and how these should constrain the choice of the surgical approach are necessary. Our study also provides evidence for the use of steroids such as Dexamethasone, combined with Hyaluronic acid to ease atraumatic electrode insertion.9 These observations constitute arguments in favor of improving the way drugs can be delivered to the inner ear to favor long-term residual hearing preservation in patients candidates for combined electrical and acoustical stimulation. One option in this domain would be to develop drug-eluting electrode arrays, made with dexamethasone loaded silicones, which could deliver steroids to the inner ear over longer post-surgery periods.27,28 Further work will be dedicated to the amelioration of these treatment options to maximize hair-cell survival rate after CI surgery. The preservation of residual hearing in CI surgeries will allow patients to benefit from combined acoustical and electrical stimulation, allowing for better functional outcomes compared with electrical stimulation alone, in particular concerning speech perception and speech-in-noise comprehension. This combined mode of stimulation was indeed shown to increase the perception of low-frequency cues (F0, f1) in speech. F0 was shown to play a crucial role in voice separation and auditory stream segregation,29 and lowfrequency cues are also crucial for phoneme categorization in normal listeners30 and CI users.31 Follow-up experiments will therefore measure the speech perception and speech in noise intelligibility outcomes in the patients who had successful residual hearing preservation, using a sound processor designed to deliver both acoustical and electrical stimulations. Altogether, the benefits of soft surgery techniques and the ameliorations observed regarding the levels of residual hearing preservation consecutively to a cochlear implantation are progressively broadening the indications of cochlear implants.

Conclusions In this preliminary clinical study involving seven CI patients, we could demonstrate the possibility of preserving residual International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

357


358

Residual Hearing Preservation with the Evo Cochlear Implant Electrode Array hearing in most of the patients using a specifically designed straight soft electrode (EVO, Oticon Medical, Vallauris, France). Residual hearing preservation was obtained in those patients in which a soft surgical approach involving round window insertion, pre-surgical dexamethasone, and topical dexamethasone use during the surgery, as well as the coating of the electrode array using hyaluronic acid. In certain cases, due to anatomical variations in the round widow region and to partial intracochlear ossification, this surgery was not possible and hearing preservation could not be achieved. These results shed light on the importance of the surgical approach combined to electrode array specificities for successful hearing preservation in CI patients.

14 Carvalho GM, Guimarães AC, Danieli F, et al. Evaluation of the

15

16

17

18

19

References 1 Gantz BJ, Turner C, Gfeller KE, Lowder MW. Preservation of hearing in

2

3

4

5

6

7

8

9

10

11

12

13

cochlear implant surgery: advantages of combined electrical and acoustical speech processing. Laryngoscope 2005;115(5):796–802 Gifford RH, Dorman MF, Skarzynski H, et al. Cochlear implantation with hearing preservation yields significant benefit for speech recognition in complex listening environments. Ear Hear 2013; 34(4):413–425 Richard C, Fayad JN, Doherty J, Linthicum FH Jr. Round window versus cochleostomy technique in cochlear implantation: histologic findings. Otol Neurotol 2012;33(7):1181–1187 Nordfalk KF, Rasmussen K, Bunne M, Jablonski GE. Deep round window insertion versus standard approach in cochlear implant surgery. Eur Arch Otorhinolaryngol 2014 Kuthubutheen J, Coates H, Rowsell C, Nedzelski J, Chen JM, Lin V. The role of extended preoperative steroids in hearing preservation cochlear implantation. Hear Res 2015;327:257–264 Chang A, Eastwood H, Sly D, James D, Richardson R, O’Leary S. Factors influencing the efficacy of round window dexamethasone protection of residual hearing post-cochlear implant surgery. Hear Res 2009;255(1–2):67–72 Laszig R, Ridder GJ, Fradis M. Intracochlear insertion of electrodes using hyaluronic acid in cochlear implant surgery. J Laryngol Otol 2002;116(5):371–372 Miroir M, Nguyen Y, Kazmitcheff G, Ferrary E, Sterkers O, Grayeli AB. Friction force measurement during cochlear implant insertion: application to a force-controlled insertion tool design. Otol Neurotol 2012;33(6):1092–1100 Ramos BF, Tsuji RK, Bento RF, et al. Hearing preservation using topical dexamethasone alone and associated with hyaluronic acid in cochlear implantation. Acta Otolaryngol 2015;135(5):473–477 Nguyen Y, Mosnier I, Borel S, et al. Evolution of electrode array diameter for hearing preservation in cochlear implantation. Acta Otolaryngol 2013;133(2):116–122 Brown KD, Melton MF, Shonfield H, Kraskin M, Wolf J. Preserved low-frequency hearing following 20-mm cochlear implantation. Otol Neurotol 2015;36(2):240–243 Vaerenberg B, Péan V, Lesbros G, et al. Combined electric and acoustic hearing performance with Zebra® speech processor: speech reception, place, and temporal coding evaluation. Cochlear Implants Int 2013;14(3):150–157 Guevara N, Sterkers O, Bébéar JP, et al. Multicenter evaluation of the digisonic SP cochlear implant fixation system with titanium screws in 156 patients. Ann Otol Rhinol Laryngol 2010;119(8):501–505

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Bento et al.

20

21

22

23

24

25

26

27

28

29

30

31

Digisonic® SP cochlear implant: patient outcomes and fixation system with titanium screws. Braz J Otorhinolaryngol 2012;78(6): 56–62 Nguyen Y, Miroir M, Kazmitcheff G, et al. Cochlear implant insertion forces in microdissected human cochlea to evaluate a prototype array. Audiol Neurootol 2012;17(5):290–298 Martins GdeS, Brito Neto RV, Tsuji RK, Gebrim EM, Bento RF. Evaluation of intracochlear trauma caused by insertion of cochlear implant electrode arrays through different quadrants of the round window. Biomed Res Int 2015;2015:236364 Brown RF, Hullar TE, Cadieux JH, Chole RA. Residual hearing preservation after pediatric cochlear implantation. Otol Neurotol 2010;31(8):1221–1226 Garcia-Ibanez L, Macias AR, Morera C, et al. An evaluation of the preservation of residual hearing with the Nucleus Contour Advance electrode. Acta Otolaryngol 2009;129(6):651–664 Jurawitz MC, Büchner A, Harpel T, et al. Hearing preservation outcomes with different cochlear implant electrodes: Nucleus® Hybrid™-L24 and Nucleus Freedom™ CI422. Audiol Neurootol 2014;19(5):293–309 Santa Maria PL, Domville-Lewis C, Sucher CM, Chester-Browne R, Atlas MD. Hearing preservation surgery for cochlear implantation —hearing and quality of life after 2 years. Otol Neurotol 2013; 34(3):526–531 Bruce IA, Felton M, Lockley M, et al. Hearing preservation cochlear implantation in adolescents. Otol Neurotol 2014;35(9): 1552–1559 Havenith S, Lammers MJ, Tange RA, et al. Hearing preservation surgery: cochleostomy or round window approach? A systematic review. Otol Neurotol 2013;34(4):667–674 Adunka OF, Dillon MT, Adunka MC, King ER, Pillsbury HC, Buchman CA. Cochleostomy versus round window insertions: influence on functional outcomes in electric-acoustic stimulation of the auditory system. Otol Neurotol 2014;35(4):613–618 Hassepass F, Aschendorff A, Bulla S, et al. Radiologic Results and Hearing Preservation With a Straight Narrow Electrode via Round Window Versus Cochleostomy Approach at Initial Activation. Otol Neurotol 2015;36(6):993–1000 Sun CH, Hsu CJ, Chen PR, Wu HP. Residual hearing preservation after cochlear implantation via round window or cochleostomy approach. Laryngoscope 2015;125(7):1715–1719 Zhou L, Friedmann DR, Treaba C, Peng R, Roland JT Jr. Does cochleostomy location influence electrode trajectory and intracochlear trauma? Laryngoscope 2015;125(4):966–971 Nguyen Y, Bernardeschi D, Kazmitcheff G, et al. Effect of embedded dexamethasone in cochlear implant array on insertion forces in an artificial model of scala tympani. Otol Neurotol 2015;36(2): 354–358 Sircoglou J, Gehrke M, Tardivel M, Siepmann F, Siepmann J, Vincent C. Trans-Oval-Window Implants, A New Approach for Drug Delivery to the Inner Ear: Extended Dexamethasone Release From Silicone-based Implants. Otol Neurotol 2015;36(9):1572–1579 Bronkhorst AW. The cocktail-party problem revisited: early processing and selection of multi-talker speech. Atten Percept Psychophys 2015;77(5):1465–1487 Varnet L, Knoblauch K, Serniclaes W, Meunier F, Hoen M. A psychophysical imaging method evidencing auditory cue extraction during speech perception: a group analysis of auditory classification images. PLoS ONE 2015;10(3):e0118009 Goldsworthy RL. Correlations Between Pitch and Phoneme Perception in Cochlear Implant Users and Their Normal Hearing Peers. J Assoc Res Otolaryngol 2015;16(6):797–809


THIEME

Original Research

Early and Delayed Effect of Functional Endoscopic Sinus Surgery on Intraocular Pressure Mohammad Waheed El-Anwar1

Mohammad Abdelhady1

1 Department of Otorhinolaryngology - Head and Neck Surgery,

Faculty of Medicine, Zagazig University, Zagazig, Egypt 2 Department of Ophthalmology, School of Medicine, Zagazig University, Zagazig, Egypt

Hazem Saeed Amer1

Manar A. Ghali2

Address for correspondence Hazem Saeed Amer, MD, Department of Otorhinolaryngology, Head and Neck Surgery, School of Medicine, Zagazig University, Zagazig 0020552322665, Egypt (e-mail: hazemamerent@yahoo.com).

Int Arch Otorhinolaryngol 2016;20:359–363.

Abstract

Keywords

► sinusitis ► nose ► endoscopy

Introduction Due to the close anatomical relationship between the paranasal sinuses and the orbit, involvement or injury of the orbit from paranasal sinuses procedures may occur. Objectives We aimed to study the early and delayed effect of endoscopic sinus surgery on intraocular pressure (IOP). Methods We included in the study 38 patients with chronic rhinosinusitis (CRS), undergoing FESS. We performed FESS with the standard anterior to posterior approach. We measured IOP at the same time one day before surgery as well as day 1 and 6 weeks after surgery. Results One day after surgery, mean IOP in the right eye was 14.176  1.91 mm Hg and in the left eye was 13.79  2.42 mm Hg with statistically non-significant difference from preoperative values. Six weeks postoperative, the mean IOP in the right eye was 15.14  2.28 mm Hg. The difference between the mean preoperative and postoperative IOP values was found to be statistically significant (p ¼ 0.0012). While in the left eye, mean postoperative IOP was 15.14 þ 2.23mm Hg. The difference between the mean preoperative and postoperative IOP values was also found to be highly statistically significant (p ¼ 0.0005). Conclusion Delayed significant increase in IOP can occur after FESS, Thus, special measures must be taken to reduce IOP to protect the patient́ s eye from the risk of increased IOP, especially in patients with glaucoma.

Introduction Chronic rhinosinusitis (CRS) is one of the most common diseases in the otolaryngologic field. Functional endoscopic sinus surgery (FESS) represents the preferred surgical treatment for CRS.1 FESS was initially driven by Messerklinger’s work in the late 1970s.2 It was then popularized and standardized in the beginning of the 1980s, particularly by Kennedy et al3 and

received September 1, 2015 accepted December 11, 2015 published online February 26, 2016

DOI http://dx.doi.org/ 10.1055/s-0036-1579663. ISSN 1809-9777.

Stammberger4 with their studies regarding the philosophy of clearing the natural ostium of the diseased sinus. Due to the close anatomical relationship between the paranasal sinuses and the orbit, involvement or injury of the orbit from procedures the paranasal sinuses may occur.5 The ocular complications after FESS include: nasolacrimal duct injury, extraocular muscle injury; periorbital, intraorbital, or retrobulbar hematoma; and even optic nerve injury. The risk of injury is correlated to the anatomical variations, the history of

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil

359


360

Effect of FESS on Intraocular Pressure

El-Anwar et al.

previous surgery, the extent of the disease, and the skills of the surgeon.6,7 Normal intraocular pressure (IOP) is essential for normal eye structure and function. When the balance of aqueous formation and drainage is altered, IOP changes. The IOP elevation results in corneal edema, iris atrophy, cataract and optic nerve atrophy. The common symptoms of increased IOP are blurred vision, epiphora, headache, nausea, vomiting, or a sensation of pressure in the eyes.1 Some studies have described the relationships between conventional sinus surgery and IOP.8,9 A previous research1 described the early effect of FESS on IOP; however, in the current study, we aimed at detecting whether or not there is a delayed effect for this type of surgery on IOP.

Patients and Methods Thirty-eight patients were included in this prospective study. All included patients were suffering from nasal polypi refractory to medical treatment (according to Lanza and Kennedy10) and had been scheduled for FESS. Exclusion criteria included patients that had diabetes mellitus, hypertension, glaucoma, ocular hypertension, previous ocular trauma, history of ocular surgery, defect in lamina paperatia, and patients within two days of using topical corticosteroid eye drops. Any systemic conditions, such as carotid-cavernous fistula and pulmonary hypertension, which may induce changes in episcleral venous pressure were also excluded because the fluctuation of episcleral venous pressure results in changes in IOP. All patients included in this study signed an informed consent. All patients underwent medical history analysis, examination, diagnostic nasal endoscopy, and CT. We classified nasal polyps following the staging classification proposed by Johansson et al11; level 0 - absent, level I - polyp in the middle meatus, level II - polyp going through the middle turbinate with clear nasal floor, level III - polyp filling up the entire nasal cavity.

Surgical Procedure Each nasal cavity was packed (in middle meatus) with a piece of gauze soaked with topical vasoconstrictor (with adrenaline dissolved in saline in a concentration of 1:200,000.) fifteen minutes before surgery, to be removed at the beginning of surgery. We performed all surgeries under general anesthesia with oral endotracheal tube with the standard anterior to posterior approach for FESS (middle meatal antrostomy, anterior ethmoidectomy, posterior ethmoidectomy, sphenoidotomy, skull base clearance, and/or frontal sinus clearance). Used intranasal packing was removed on the first morning after surgery. We prescribed postoperative antibiotics and analgesics. IOP was measured for both eyes in all patients using Goldmann applanation tonometry, and dilated funduscopy as baseline data one day before surgery. Then, we measured IOP on day 1 postoperatively and, lastly, at 6 weeks after surgery. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Statistical Analysis We used the SPSS statistical software package (version 18.0; SPSS, Inc., Chicago, IL, USA) for statistical comparisons and descriptive statistics. A p value < 0.05 was considered statistically significant.

Results This study included 38 patients: 22 males (57.9%) males and 16 females (42.1%). Their ages ranged from 16 to 56 years with a mean of 35.3 years. All patients underwent preoperative endoscopic nasal examination (76 nasal sides) and various grades of nasal polyposis were detected. Grade 0 was detected in 12 nasal sides (15.8%), grade 1 in 18 sides (23.7%), grade 2 in 28 sides (36.8%), and grade 3 in 18 sides (23.7%) (►Table 1). No major complications were observed in this study; only minor complications in the form of nasal adhesions between the inferior turbinate and septum (in two cases). Moreover, we found no significant correlation between the postoperative changes in IOP values and the grades of nasal polyposis (R value ¼ 0.3521; R2, the coefficient of determination, was 0.124). We found that the mean preoperative pressure was 13.1  2.5 mm Hg (range, 10 - 18 mm Hg) in the right eye and 12.89  2.23 mm Hg (range, 10 - 17 mm Hg) in the left eye, and the difference between the mean IOP values between the two sides was found to be statistically non-significant (p ¼ 0.7862, t ¼ 0.2732) (►Tables 2 and 3). One day after surgery, the mean postoperative IOP in the RT eye was 14.176  1.91 mm Hg (range 10 -17 mm Hg) and the difference between the mean preoperative and postoperative IOP values was statistically non-significant (p ¼ 0.1589, t ¼ 1.4403), whereas in the left eye mean postoperative IOP was 13.79  2.42 mm Hg (range 10 - 19 mm Hg). The difference between the mean preoperative and postoperative IOP values was also statistically non-significant (p ¼ 0.0961, t ¼ 1.6859). Also, we observed that the difference in the postoperative IOP values between both eyes one day after surgery was statistically non-significant (p ¼ 0.4428, t ¼ 0.7718) (►Table 2). Six weeks after surgery, the mean postoperative IOP in the right eye was 15.14  2.28 mm Hg (range 10–18 mm Hg) and the difference between the mean preoperative and postoperative IOP values was found to be statistically significant (p ¼ 0.0012, t ¼ 3.4027), whereas in the left eye the mean postoperative IOP was 15.14286  2.23 mm Hg (range 11 - 18 mm Hg). The difference between the mean

Table 1 Results of endoscopic nasal examination Grade of nasal polyp

Number of nasal sides

%

0

12

15.8

1

18

23.7

2

28

36.8

3

18

23.7


Effect of FESS on Intraocular Pressure

El-Anwar et al.

Table 2 Difference in IOP between preoperative and 1 day postoperative Pre-operative IOP (38 patients)

1 day post-operative IOP (38 patients)

Mean

Mean

SD

t test

p value

Significance

SD

Right

13.1

2.5

14.176

1.91

1.4403

0.1589

Non-Significant

Left

12.89

2.23

13.79

2.42

1.6859

0.0961

Non-Significant

Abbreviations: IOP, intraocular pressure; SD, standard deviation.

Table 3 Difference in IOP between preoperative and 6 weeks postoperative t test

p value

Significance

2.28

3.4027

0.0012

Significant

2.34872

3.6808

0.0005

Extremely statistically significant

Pre-operative IOP (38 patients)

6 w post-operative IOP (28 patients)

Mean

SD

Mean

SD

Right

13.1

2.5

15.14

Left

12.89

2.23

15.14

Abbreviations: IOP, intraocular pressure; SD, standard deviation; w, week.

preoperative and postoperative IOP values was also highly statistically significant (p value ¼ 0.0005, t ¼ 3.6808). Moreover, the difference in the postoperative IOP values between right and left eyes 6 weeks after surgery was statistically non-significant. We also performed endoscopic nasal examination during follow-up until 6 weeks after surgery for a second-look evaluation. The results presented no significant findings.

Discussion Functional endoscopic sinus surgery (FESS) has gained popularity in the diagnosis and treatment of paranasal sinus diseases.12 However, orbital negative sequels may occur due to its close anatomical relation with the paranasal sinuses.5 The incidence of serious complications of endoscopic sinus surgery reportedly reaches 0.5%. Orbital injuries can range from eye pressure, pain, retrobulbar hemorrhage, and compromised extraocular muscle movement with sequential binocular diplopia to blindness.13–16 Intraocular pressure (IOP) may be defined as the resulting balance between aqueous humor production and removal. Its increase is considered to be one of the main risk factors leading to the development of glaucoma. IOP is a variable value affected by multiple factors: age, gender, race, tobacco consumption, local ocular problems, obesity, hormonal changes, and physical exercise, among others.17–19 No clear line exists between safe and unsafe IOPs. In general, in cases in which the IOP is less than 30 mm Hg, the eye can be observed, and in cases in which the IOP is more than 40 mm Hg, a poor vision result may ensue. The IOP can be measured clinically by various types of tonometers, including the Goldmann applanation tonometer, noncontact tonometer, and Tonopen. The Goldmann applanation tonometer is the most valid and reliable.20 That is why we used it in current study.

In the current study, the mean preoperative IOP rose 1 day postoperatively, but this increase was found to be statistically non-significant. In contrast, six weeks after surgery, we had noticed that the mean IOP increased in both eyes and this increase, surprisingly, was statistically significant in both eyes. The postoperative results one day after surgery of this study agree with the results of Lin et al,1 who found also that the postoperative increase in the average IOP values is statistically non-significant, taking into consideration that Lin et al1 studied the early effect of FESS on IOP as they measured IOP in three consecutive days after surgery. The mechanism by which IOP is raised post-FESS whether in the early or late postoperative period is not clearly understood. Vascular mechanism is one of the proposed mechanisms for increased IOP post FESS. The eyes and paranasal sinuses are anatomically, neighboring structures. The eyeball, orbit, and parts of the sinonasal areas share the same vascular supply from the ophthalmic artery. The venous drainage of the orbit and ocular structures is via the central retinal vein (drains into the superior ophthalmic vein) and the vortex vein (drains into the inferior ophthalmic vein). The vascular supplies of the sinuses are partial from the anterior and posterior ethmoidal arteries those are also derived from the ophthalmic artery, and the anterior and posterior ethmoidal veins drain into the superior ophthalmic vein.21 Lin et al1 observed that the post-FESS symptoms of epiphora and eye pressure were similar to the symptoms of increased IOP. Given that the eyes and sinonasal region have the same origin of vascular supply, they decided to elucidate whether FESS would result in a significant change in the IOP before and after surgery. They detected increased IOP. In the early postoperative period, in agreement with the current study, these changes were statistically insignificant. A possible cause of increased IOP postoperatively could be excessive gauze packing and overinflated antral balloons of the Foley type, after the Caldwell-Luc operation. This may induce International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

361


362

Effect of FESS on Intraocular Pressure

El-Anwar et al.

hypertropia and compression of the central retinal artery. Gelman et al8 reported a case of acute ocular hypertension following the use of an antral balloon after repairing fractures on the floor of the orbit via a Caldwell-Luc antrostomy. Another study was done by Papangelou and Christidis9 to investigate whether there would be any effects on the IOP in patients who underwent a Caldwell-Luc operation for chronic sinusitis or antral polyps. They found that some changes of IOP occurred whether or not the maxillary sinus walls were denuded of mucous membrane. They performed endoscopic grading for nasal polyposis preoperatively and observed various grades; however, when correlating the postoperative changes in IOP values with the grades of nasal polyposis, they found no correlation. Many researchers studied the effect of endotracheal intubation on IOP and found a transient increase in the IOP intraoperatively and in the early postoperative period. Malti and Geeta22 reported that endotracheal intubation is associated with tachycardia, hypertension, and increase in intraocular pressure and that the latter may not have any adverse effect in patients with healthy eyes but has deleterious effects on a diseased or an injured eye. They also concluded in their study that laryngeal mask airway insertion is a suitable alternative to endotracheal intubation in patients having penetrating eye injuries, glaucoma, and strabismus in whom elevation of intraocular pressure is likely to be detrimental. Langham et al23 and Murphy24 stated that endotracheal intubation can lead to adrenergic stimulation may cause vasoconstriction and an increase in central venous pressure which has a closer relationship to intraocular pressure than systemic pressure. It can produce an acute increase in intraocular pressure by increasing the resistance to the outflow of aqueous humor in the trabecular meshwork between the anterior chamber and the Schlemm’s canal. In fact, these mechanisms would explain the early increase in IOP. Nonetheless, the cause of delayed increase in IOP remains unclear, so further studies are needed to explain the effect in IOP post-FESS. To the best of our knowledge, this the first study to deal with the delayed effect of FEES on IOP. However, further studies are still needed to study the delayed effect of FESS on IOP in unilateral cases, as our study only included cases with bilateral sinonasal pathology. It is important to note the risk of potential rise of IOP after surgery in patients scheduled for FESS and that had preoperative increase IOP, such as patients of glaucoma. Thus, preoperative ophthalmological consultation is important to protect the patient from the hazard of possible increased IOP.

Conclusion

Financial Support The authors declare no financial support or interest to this study.

References 1 Lin PW, Lin HC, Chang HW, Su CY. Effects of functional endoscopic

2 3

4

5

6

7

8

9

10 11

12

13

14

15

16

Delayed significant increase in IOP can occur after FESS. Therefore, special measures are necessary preoperatively to reduce IOP and protect the patient’s eye from the hazard of increased IOP, especially in patients with glaucoma. Further studies are still needed to explain the cause of this delayed significant rise in IOP post-FESS.

International Archives of Otorhinolaryngology

Conflict of Interest The authors declare no conflict of interest.

Vol. 20

No. 4/2016

17 18 19

sinus surgery on intraocular pressure. Arch Otolaryngol Head Neck Surg 2007;133(9):865–869 Messerklinger W. [Endoscopy of the nose]. Monatsschr Ohrenheilkd Laryngorhinol 1970;104(10):451–456 Kennedy DW, Zinreich SJ, Rosenbaum AE, Johns ME. Functional endoscopic sinus surgery. Theory and diagnostic evaluation. Arch Otolaryngol 1985;111(9):576–582 Stammberger H. Endoscopic endonasal surgery—concepts in treatment of recurring rhinosinusitis. Part I. Anatomic and pathophysiologic considerations. Otolaryngol Head Neck Surg 1986; 94(2):143–147 Colclasure JC, Gross CW, Kountakis SE. Endoscopic sinus surgery in patients older than sixty. Otolaryngol Head Neck Surg 2004; 131(6):946–949 Bhatti MT, Giannoni CM, Raynor E, Monshizadeh R, Levine LM. Ocular motility complications after endoscopic sinus surgery with powered cutting instruments. Otolaryngol Head Neck Surg 2001; 125(5):501–509 Stankiewicz JA. Blindness and intranasal endoscopic ethmoidectomy: prevention and management. Otolaryngol Head Neck Surg 1989;101(3):320–329 Gelman HK, Janzen WR, Skolnik EM. Ocular hypertension following use of an antral balloon. Arch Otolaryngol 1974; 99(6):449–450 Papangelou L, Christidis M. Positive intramaxillary sinus pressure and intraocular pressure. J Laryngol Otol 1978; 92(12):1071–1074 Lanza DC, Kennedy DW. Adult rhinosinusitis defined. Otolaryngol Head Neck Surg 1997;117(3 Pt 2):S1–S7 Johansson L, Akerlund A, Holmberg K, Melén I, Stierna P, Bende M. Evaluation of methods for endoscopic staging of nasal polyposis. Acta Otolaryngol 2000;120(1):72–76 Weber R, Draf W, Keerl R, Schick B, Saha A. Endonasal microendoscopic pansinusoperation in chronic sinusitis. II. Results and complications. Am J Otolaryngol 1997;18(4):247–253 Cumberworth VL, Sudderick RM, Mackay IS. Major complications of functional endoscopic sinus surgery. Clin Otolaryngol Allied Sci 1994;19(3):248–253 Graham SM, Nerad JA. Orbital complications in endoscopic sinus surgery using powered instrumentation. Laryngoscope 2003; 113(5):874–878 Huang CM, Meyer DR, Patrinely JR, et al. Medial rectus muscle injuries associated with functional endoscopic sinus surgery: characterization and management. Ophthal Plast Reconstr Surg 2003;19(1):25–37 Stankiewicz JA. Complications in endoscopic intranasal ethmoidectomy: an update. Laryngoscope 1989;99(7 Pt 1):686–690 Fernández PC. Glaucoma. Medicine 1998;7:4770–4777.1987; 97: 1270–1273 Qureshi IA. Intraocular pressure: a comparative analysis in two sexes. Clin Physiol 1997;17(3):247–255 Passo MS, Goldberg L, Elliot DL, Van Buskirk EM. Exercise conditioning and intraocular pressure. Am J Ophthalmol 1987;103(6): 754–757


Effect of FESS on Intraocular Pressure

El-Anwar et al.

20 Liesegang TJ, Skuta GL, Cantor LB. Basic and Clinical Science

22 Malti PJ, Agarwal Geeta A. Comparative study of intraocular pressure

Course, Section 10 Glaucoma: Intraocular Pressure and Aqueous Humor Dynamics. San Francisco, CA: American Academy of Ophthalmology; 2003:14–24 21 Harris A, Jonescu-Cuypers CP, Kagemann L, Ciulla TA, Krieglstein GK. Atlas of Ocular Blood Flow: Vascular Anatomy, Pathophysiology, and Metabolism. Philadelphia, PA: Butterworth Heinemann; 2003

changes with laryngeal mask airway and endotracheal tube. National Journal of Community Medicine 2012;3(2):279–282 23 Langham ME, Kitazawa Y, Hart RW. Adrenergic responses in the human eye. J Pharmacol Exp Ther 1971;179(1):47–55 24 Murphy DF. Anesthesia and intraocular pressure. Anesth Analg 1985;64(5):520–530

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

363


THIEME

364

Original Research

Granulocyte-Macrophage Colony-Stimulating Factor Production and Tissue Eosinophilia in Chronic Rhinitis Aleksandar Peric1 Danilo Vojvodic4

Cveta Spadijer-Mirkovic1

Svjetlana Matkovic-Jozin2

1 Department of Otorhinolaryngology, Military Medical Academy,

Belgrade, Serbia 2 Department of Otorhinolaryngology, Stavanger University Hospital, Stavanger, Norway 3 Department of Otorhinolaryngology, Clinical Center of Vojvodina, Novi Sad, Serbia 4 Institute of Medical Research, Division of Clinical and Experimental Immunology, Military Medical Academy, Belgrade, Serbia

Ljiljana Jovancevic3

Address for correspondence Aleksandar Peric, MD, PhD, Department of Otorhinolaryngology, Military Medical Academy, Crnotravska 17, Belgrade, Belgrade 11000, Serbia (e-mail: alexneta@orion.rs).

Int Arch Otorhinolaryngol 2016;20:364–369.

Abstract

Keywords

► ► ► ► ► ►

rhinitis allergic perennial nasal lavage fluid eosinophilia cytokines

received October 19, 2015 accepted November 6, 2015 published online February 26, 2016

Introduction Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a strong proinflammatory cytokine that takes part in allergic nasal inflammation as an eosinophil colony-stimulating factor. However, the role of GM-CSF in non-allergic rhinitis has not been fully explored. Objectives The aim of this investigation was to assess the concentration of GM-CSF in nasal secretions of patients with non-allergic rhinitis with eosinophilia syndrome (NARES) in comparison to patients with perennial allergic rhinitis (PAR) and healthy subjects, as well as to assess the relationship with the degree of eosinophilic inflammation and clinical characteristics of the patients. Methods Fourteen patients with diagnosis of NARES, 14 PAR patients, and 14 healthy subjects were included in this cross-sectional study. All patients underwent symptom score assessment, nasal endoscopy, allergy testing, and cytological evaluation. The concentration of GM-CSF in nasal secretions of all participants was measured by enzyme-linked immunosorbent assay (ELISA). Results We found significantly higher levels of GM-CSF in patients with NARES than in the control group (p ¼ 0.035). The percent of eosinophils in nasal mucosa was higher in NARES patients in comparison to patients with PAR (p < 0.001) and control patients (p < 0.0001). We found positive correlations between GM-CSF levels and eosinophil counts only in NARES patients. Conclusion The concentrations of GM-CSF in nasal secretions correlate well with eosinophil counts in the nasal mucosa of NARES patients. These facts indicate a possible role of GM-CSF as a favorable marker for assessment of nasal disease severity and the degree of chronic eosinophilic inflammation in the nasal mucosa.

DOI http://dx.doi.org/ 10.1055/s-0035-1570746. ISSN 1809-9777.

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil


GM-CSF Production and Tissue Eosinophilia in Chronic Rhinitis

Introduction Unlike allergic rhinitis (AR), there are no specific diagnostic tests for non-allergic rhinitis (NAR). Diagnosis is primarily based on rhinitis symptoms, which include nasal congestion, rhinorrhea, sneezing, itching, and impaired sense of smell, for greater than one hour most days in the absence of identifiable allergy by allergy testing.1 AR is an immunoglobulin E (IgE)-mediated noninfectious disease of the nasal mucosa following contact with allergens. Previous studies have demonstrated that imbalance of T helper 1 / T helper 2 (Th1/Th2) cell-mediated immunity plays an important role in the pathogenesis of AR, which is characterized by the Th2 cell mediated inflammation.2 Although chronic inflammation has proven to be an integral component of AR, there is great debate regarding this facet in NAR, since some studies have suggested that exclusion of inflammation is indicative in vasomotor rhinitis. Other studies have demonstrated that all patients with non-allergic rhinitis with eosinophilia syndrome (NARES) have high degree of chronic eosinophilic inflammation.3,4 NARES, which accounts for 14% of rhinitis patients, is defined by a syndrome of nasal hyper-reactivity for more than three months, the absence of atopic factor, and a profound nasal eosinophilia with more than 20% eosinophils in the total granulocytic or mononuclear cell population.4 It is well-known that many cytokines play a role in the manifestation of nasal allergic reaction through the activation and proliferation of migrating cells, such as eosinophils, mastocytes, and lymphocytes, as well as nasal mucosa epithelial cells. These cells produce a variety of cytokines that, in turn, regulate the immunological reaction and inflammatory process.5 Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor, which was originally recognized as a stimulator of the proliferation of granulocytes and macrophages from bone marrow precursor cells.6 The main sources of GM-CSF in allergic rhinitis include epithelial and endothelial cells, activated eosinophils, T and B cells, monocytes, and macrophages.6,7 GM-CSF also reportedly takes part in Th2 response in allergic nasal inflammation as an eosinophil colony-stimulating factor and by activation of dendritic cells.7 On the other hand, in non-allergic and aspirin tolerant patients with chronic polypous rhinosinusitis, eosinophils appear to be recruited mainly by the release of GM-CSF.8 However, the role of GM-CSF in pathogenesis of NARES has not been fully explored. The aim of this investigation was to assess the concentration of GM-CSF in nasal secretions in patients with NARES in comparison to patients with perennial allergic rhinitis (PAR) and healthy subjects, and to assess the relationship with the degree of eosinophilic inflammation and clinical characteristics of these patients.

Materials and Methods Participants We recruited 14 patients with diagnosis of NARES (9 men and 5 women, mean age 42.38  11.18 years) and 14 patients with diagnosis of PAR (8 men and 6 women, mean age 41.05  9.78 years) for participation in this cross-sectional

Peric et al.

study, which was performed in accordance with the Declaration of Helsinki. The protocol and methods received approval from our institutioń s Ethics Committee. We obtained written informed consent from all patients. This study was performed in the Rhinology Unit of the Department of Otorhinolaryngology between May 2013 and April 2015. As controls in the study, we included fourteen healthy subjects without symptoms, medical history, or endoscopic findings of nasal/paranasal sinus inflammation. The main age in the control group (7 male and 7 female subjects) was 40.58  13.37 years. Following the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines,9 we divided patients with AR into two categories: intermittent and persistent. We only included patients with persistent symptoms (more than 4 days a week and for more than 4 weeks) in the study to avoid differences due to actual allergen exposure between seasonal and non-seasonal subjects. The patients with PAR had typical nasal symptoms (rhinorrhea, sneezing, itching, nasal obstruction, hyposmia) for at least 12 weeks. They had the confirmation of atopic status, negative nasal endoscopy for polyps, and negative computed tomography (CT) scan of paranasal sinuses for mucosal swelling. The patients with NARES complained about typical symptoms of PAR (rhinorrhea, sneezing, itching, nasal obstruction, and hyposmia) for more than 12 weeks. However, all allergy tests were negative for atopy. Nasal hypereosinophilia was found by scraping of nasal mucosa of the inferior turbinate and more than 20% eosinophils in the total granulocyte and mononuclear cell population, excluding respiratory epithelium cells, was the criteria for a NARES diagnosis. CT scan was negative in all subjects. We evaluated the presence of micropolyposis by nasal endoscopy. An endoscopic finding was understood as characteristic of chronic rhinosinusitis (CRS) and we excluded such patients for further investigation. Exclusion criteria were: chronic polypous rhinosinusitis (including endoscopic evidence of micropolyposis), bronchial asthma, systemic diseases affecting the nose (sarcoidosis, primary ciliary dyskinesia, Wegener’s granulomatosis, cystic fibrosis, Churg-Strauss syndrome). Also, the patients with a history of cigarette smoking and previous nasal and paranasal sinus surgery were excluded. None of the patients had any acute upper and lower respiratory tract infections, use of antibiotics, oral or intranasal antihistamines, and systemic or topical corticosteroids within three weeks before the start of this investigation.

Allergy Determination The atopic status was evaluated in all participants at the start of the study by an allergist on the basis of clinical symptoms, medical history of allergic rhinitis, positive skin-prick tests, and positive serological test. Skin-prick tests were performed on the volar part of the forearm with a standard battery of common aeroallergens including house dust mite (Dermatophagoides farinae, Dermatophagoides pteronyssinus), fungus (Alternaria alternata, Aspergillus fumigatus), dogs, and cats. We also included negative (0.9% natrium-chloridum solution) and positive (1 mg/ml histamine dihydrochloride solution) controls with each skin-prick tests. After 15 minutes, we read International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

365


366

GM-CSF Production and Tissue Eosinophilia in Chronic Rhinitis the reactions. We considered the test positive if the diameter of wheal was greater than 3mm with respect to the negative control. We measured total serum IgE level by enzyme-linked immunosorbent assay (ELISA) kit (Elitech Diagnostics, Salonde-Provence, France) and an ELISA reader (Spectra III, Austria). We then collected venous blood and centrifuged it, and stored the serum at -70°C until testing. Subjects were considered allergic if they had a serum IgE level > 100 IU/mL.

Symptoms The same rhinologist examined all the patients. The examiner asked all NARES and PAR patients to assess their symptoms (nasal obstruction, rhinorrhoea, hyposmia, sneezing, and itching). The symptoms were scored from 0 to 3: 0 for no symptoms, 1 for mild symptoms, 2 for moderate symptoms, and 3 for severe symptoms, resulting in a maximum nasal symptom score of 15, as previously described.10

Peric et al.

of detection was < 2 pg/mL and assay ranged from 15.4 pg/ mL to 600 pg/mL. According to the producer’s declaration, overall intra-assay and inter-assay coefficient of variation should not exceed 10%.

Statistical Analysis We expressed data as mean  standard deviation (SD). We analyzed comparisons between the groups using the nonparametric Mann-Whitney U-test. We explored the strength of the correlation between different parameters using the Spearman’s rank correlation test. P values < 0.05 were considered significant. We performed the analysis using the SPSS software (Statistical Package for the Social Sciences, version 15.0, SPSS Inc., Chicago, U.S.A.).

Results Patients’ Characteristics

Nasal Cytology We counted the number of granulocytes on nasal scraped tissue obtained from the inferior turbinate bilaterally by rhinoprobe. The cupped tip of the disposable probe was gently passed over the mucosal surface. Two or three short scrapes of the epithelial layer are made to obtain a sample. The specimen was spread onto a plain slide and immediately fixed for at least one minute in 95% ethyl alcohol and stained with May Grünwald-Giemsa. An experienced cytologist blindly examined the samples, unaware of the clinical status of participants. We counted the percentage of eosinophils by microscopic cytological examination. The slides were examined under oil immersion by light microscopy at a magnification of × 400. We expressed eosinophil counts as a percentage of cells of the granulocytic or mononuclear type, without nasal epithelial cells, per high-power field, from a mean of at least 10 fields observed.

Sampling of Nasal Secretions and GM-CSF Determination We collected nasal secretion samples from nasal cavities of all 42 subjects, 14 with PAR, 14 with NARES, and 14 healthy subjects, using the absorption technique. We used cottonwool sticks (length 10 mm, diameter 4 mm; Institute of Virology, Vaccines and Sera, Torlak, Belgrade, Serbia). We inserted them for 5 minutes into the middle meatus, under the endoscopic guidance, as previously described.11,12 We placed all samples in a 2 mL Eppendorf tube containing 1 mL of transfer medium (phosphate-buffered saline with gentamicin 50 μg/mL, penicillin G 340 IU/mL, fungizone 500 μg/mL) for 30 minutes. It allowed the diffusion of cytokines into the medium and then stored at 4°C for a maximum of 2 hours until processed. We centrifuged nasal fluid at 1000 g for 10 minutes to separate the cellular components. After centrifugation, we portioned supernatants and stored at -70°C for no more than two months, pending cytokine determination. We measured levels of GM-CSF in all of the 42 samples using the commercial human ELISA kit (Thermo Fisher Scientific Inc., Waltham, MA, U.S.A.). We expressed the concentrations of GM-CSF in picograms per milliliter (pg/mL). The sensitivity International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

A statistically significant difference between NARES and PAR patients was found in the nasal symptom score (p ¼ 0.047). On the other hand, we found significantly higher concentrations of total serum IgE in patients with PAR than in patients with NARES (148.98  67.25 IU/ mL versus 87.35  27.48 IU/mL) (p ¼ 0.029). The patients’ characteristics are presented in ►Table 1.

GM-CSF Levels and Eosinophil Counts We detected GM-CSF in 13 of 14 nasal secretion samples of patients with NARES. However, we could not detect such cytokine in samples of 5 patients with PAR and 6 controls. The mean concentration of GM-CSF in nasal secretions was significantly higher in NARES patients (33.01  23.45 pg/mL) compared with control patients (21.35  23.28 pg/ mL) (p ¼ 0.035). We observed no significant difference in GM-CSF levels between PAR patients (26.08  27.92 pg/ mL) and patients with diagnosis of NARES (p ¼ 0.064). We also found no significant difference in the GM-CSF concentration between PAR patients and healthy subjects (p ¼ 0.127) (►Fig. 1). The mean eosinophil percentage observed in the PAR patients, NARES patients, and control patients were 27.88  8.73, 51.85  11.82, and 5.92  2.97, respectively. The highest eosinophil count was found in the patients with NARES with significant differences compared with PAR patients (p < 0.001) and control patients (p < 0.0001).

Table 1 Patients’ characteristics

Number of patients Age/Years



Men/Women Nasal symptom score



Total serum IgE (IU/ml)



NARES

PAR

14

14

42.38  11.18

41.05  9.78

9/5

8/6

11.45  2.37

8.47  1.95

87.35  27.48

148.98  67.25

Abbreviations: NARES, non-allergic rhinitis with eosinophilia syndrome; PAR, perennial allergic rhinitis; IgE, immunoglobulin E.  Mean  standard deviation.


GM-CSF Production and Tissue Eosinophilia in Chronic Rhinitis

Peric et al.

Table 2 Correlations GM-CSF concentration

Nasal symptom score

Eosinophil counts

NARES

R ¼ 0.318 p ¼ 0.084

R ¼ 0.552 p ¼ 0.01

PAR

R ¼ 0.327 p ¼ 0.089

R ¼ 0.348 p ¼ 0.069

Abbreviations: GM-CSF, Granulocyte-Macrophage Colony-Stimulating Factor; NARES, non-allergic rhinitis with eosinophilia syndrome; PAR, perennial allergic rhinitis.  Correlation is significant at the 0.01 level (2-tailed).

Fig. 1 Concentrations of GM-CSF in nasal secretions of patients with non-allergic rhinitis with eosinophilia syndrome (NARES), perennial allergic rhinitis (PAR), and in healthy subjects.

Therefore, PAR patients have higher eosinophil count in the nasal mucosa than healthy subjects (p < 0.001). We only found a significant positive correlation between GM-CSF levels in nasal secretions and eosinophil counts in the nasal mucosa (r ¼ 0.552, p ¼ 0.01) in patients with NARES (►Fig. 2). There were no significant correlations found between GM-CSF concentrations in nasal secretions and symptoms/eosinophil percentage in patients with PAR (►Table 2). In control subjects, we also found no correlation between GM-CSF levels and eosinophil counts.

Discussion Nasal secretions are a mixture of plasma exudation and mucus produced by goblet cells and seromucous glands, together with plenty of epithelial and migrating cells such as granulocytes, lymphocytes, and mononuclear cells with immunocompetent activities. The biochemical and cytological exploration of nasal secretions may provide additional information on mucosal activity.13 Studies have shown that contents of nasal secretions reflect the inflammatory status of

Fig. 2 Correlation between GM-CSF levels in nasal secretions and eosinophil counts in nasal mucosa was found only in NARES patients.

the nasal mucosa, paralleling the evolution of mucosal disease.14 Previous investigations showed that cytokine and chemokine levels in nasal secretions correlate well with clinical parameters and cytological findings in patients with chronic upper airway inflammatory diseases.11,12,15 On the other hand, cytological examination of the nasal secretions and nasal mucosa is a helpful path towards better knowledge of the pathophysiology of chronic inflammatory diseases and correct differential diagnosis.16,17 NARES is a chronic inflammatory disease of unknown origin. It is characterized by nasal symptoms consistent with allergic rhinitis in which an absence of atopy has been demonstrated by allergen skin testing and serological testing. The pathophysiology of NARES is poorly understood, but a key component involves a self-perpetuating, chronic eosinophilic nasal inflammation with development of nasal micropolyposis during the transformation in chronic polypous rhinosinusitis.4 The high level of release of substance P in the nasal mucosa lead to the hypothesis of a neurogenic origin of NARES.18 This disease is a risk factor for the development of nasal polyposis associated with aspirin sensitivity. Treatment consists mainly of intranasal corticosteroid drops and sprays, with or without the addition of oral second-generation antihistamines and/or leukotriene-receptor antagonists.1,4 Our results showed significantly higher production of cytokine GM-CSF in the nasal mucosa of patients with NARES than in the control group. The level of eosinophilic infiltration of the nasal mucosa in NARES patients is two times higher than in the patients with PAR and almost ten times higher than in the control patients. Ohkubo et al19 demonstrated that epithelial cells are a main source of CM-CSF in nasal secretions of healthy subjects, whereas in patients with allergic rhinitis, the main sources are migrating cells (eosinophils and lymohocytes) and epithelial cells, induced by antigen stimulation. In our results, for NARES patients, GM-CSF concentration in nasal fluid correlates well with eosinophil counts in the nasal mucosa. This finding suggests that the main source of the cytokine in patients with NARES are activated eosinophils. The fact that basal secretions of GM-CSF were greater in NARES patients than in the patients with PAR (although without significant difference) may explain the higher abundance of eosinophils in the nasal mucosa of NARES patients. This proinflammatory cytokine may influence the growth, differentiation, proliferation, and activation of eosinophils, International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

367


368

GM-CSF Production and Tissue Eosinophilia in Chronic Rhinitis which explain the good correlation between GM-CSF levels in nasal secretions and eosinophil counts in our results. The results of a previous study showed that GM-CSF is the main cytokine in the process of eosinophil activation in chronic rhinosinusitis with nasal polyps (CRSwNP).20 Moreover, the receptor affinity of GM-CSF is almost 10 times stronger than that of interleukin-3 (IL-3) or IL-5.20 Many facts indicate that chronic eosinophilic inflammation in patients with NARES have similar characteristics to those found in CRSwNP. According to the results presented by Moneret-Vautrin et al,18 NARES seems to evolve in three stages: (1) migration of eosinophils from the vessels of the nasal mucosa to the nasal secretions; (2) retention of eosinophils in the mucosa, which might be linked to activation of unknown origin; and (3) nasal polyposis. However, relatively frequent association with aspirin sensitivity implies that this disease should be understood as a distinct entity among the different types of chronic sinonasal inflammations. In our review of the literature, we found only one recently published study concerning the association between GM-CSF levels in nasal secretions and nasal eosinophilia. De Corso et al21 found detectable levels of this cytokine in 34 of 70 (48.57%) patients, with an average concentration of 2.67 ± 0.8 pg/ml, whereas, only 1 out of 20 individuals in the control group showed detectable GM-CSF levels. In our study, we found detectable levels of GM-CSF in 22 of 28 patients (71.57%). We could not detect cytokine levels in only 6 control subjects. Different methods for nasal secretions sampling could explain the differences between our study and that of De Corso et al regarding the detectability of GM-CSF and average cytokine concentrations. De Corso et al21 performed the nasal lavage dilution technique, whereas we used the absorption technique to collect nasal secretions. In the dilution technique, a liquid is instilled into the nose, recovered with an admixed and sample of epithelial lining fluid. Thus, nasal lavage is associated with a substantial, often unpredictable, dilution of nasal secretions. As a consequence, the concentration of inflammatory mediators may reveal high variability and frequently falls below the lower detection limits. On the other hand, the absorption technique overcomes the problem encountered when only small quantities of spontaneous secretions are available, as it provides sufficient amounts of undiluted nasal secretions. Riechelmann et al,22 for instance, found that analyte concentrations in nasal lavage were 10 times lower than in specimens obtained by the absorption technique.

way to study the pathogenesis of these diseases. Our results indicate a possible role of GM-CSF as a favorable marker for the investigation of pathophysiological mechanisms, which play a role in the development of NARES. Nonetheless, further studies in this direction conducted with a higher number of patients are needed.

Conflict of Interest Statement The authors declare that they have no conflict of interest regarding the publication of this paper.

References 1 Papadopoulos NG, Bernstein JA, Demoly P, et al. Phenotypes and

2

3

4 5

6 7

8

9

10

11

12

13

Conclusions Our results demonstrated that proinflammatory cytokine GM-CSF production and eosinophilic inflammation are higher in patients with NARES than in the patients with PAR and in healthy subjects. The concentrations of this cytokine in nasal secretions correlate well with eosinophils counts in the nasal mucosa only in NARES patients. The measurement of local inflammatory mediators in nasal secretions could be a useful path in the monitoring of the severity of chronic nasal inflammation, as well as a sensitive International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Peric et al.

14

15

16

endotypes of rhinitis and their impact on management: a PRACTALL report. Allergy 2015;70(5):474–494 Huang X, Chen Y, Zhang F, Yang Q, Zhang G. Peripheral Th17/Treg cell-mediated immunity imbalance in allergic rhinitis patients. Braz J Otorhinolaryngol 2014;80(2):152–155 Nguyen KH, Suzuki H, Wakasugi T, et al. Expression of epidermal growth factors and a tight junction protein in the nasal mucosa of patients with chronic hypertrophic rhinitis. Allergol Immunopathol (Madr) 2013;41(4):246–254 Ellis AK, Keith PK. Nonallergic rhinitis with eosinophilia syndrome. Curr Allergy Asthma Rep 2006;6(3):215–220 Scavuzzo MC, Rocchi V, Fattori B, et al. Cytokine secretion in nasal mucus of normal subjects and patients with allergic rhinitis. Biomed Pharmacother 2003;57(8):366–371 Shiomi A, Usui T. Pivotal roles of GM-CSF in autoimmunity and inflammation. Mediators Inflamm 2015;2015:568543 Shiozawa A, Miwa M, Ono N, Homma H, Hirotsu M, Ikeda K. Comparative analysis of cytokine release from epithelial cell cultures of the upper airway. Rhinology 2015;53(2):135–141 Rinia AB, Kostamo K, Ebbens FA, van Drunen CM, Fokkens WJ. Nasal polyposis: a cellular-based approach to answering questions. Allergy 2007;62(4):348–358 Van Hoecke H, Van Cauwenberge P, Thas O, Watelet JB. The ARIA guidelines in specialist practice: a nationwide survey. Rhinology 2010;48(1):28–34 Tsicopoulos A, Shimbara A, de Nadai P, et al. Involvement of IL-9 in the bronchial phenotype of patients with nasal polyposis. J Allergy Clin Immunol 2004;113(3):462–469 Perić A, Baletić N, Sotirović J, Špadijer-Mirković C. Macrophage inflammatory protein-1 production and eosinophil infiltration in chronic rhinosinusitis with nasal polyps. Ann Otol Rhinol Laryngol 2015;124(4):266–272 Perić A, Vojvodić D, Perić AV, Radulović V, Miljanović O. Correlation between cytokine levels in nasal fluid and scored clinical parameters in patients with nasal polyposis. Indian J Otolaryngol Head Neck Surg 2013;65(Suppl 2):295–300 Watelet JB, Gevaert P, Holtappels G, Van Cauwenberge P, Bachert C. Collection of nasal secretions for immunological analysis. Eur Arch Otorhinolaryngol 2004;261(5):242–246 Lü FX, Esch RE. Novel nasal secretion collection method for the analysis of allergen specific antibodies and inflammatory biomarkers. J Immunol Methods 2010;356(1–2):6–17 De Corso E, Baroni S, Romitelli F, et al. Nasal lavage CCL24 levels correlate with eosinophils trafficking and symptoms in chronic sino-nasal eosinophilic inflammation. Rhinology 2011;49(2): 174–179 Jankowski R, Persoons M, Foliguet B, Coffinet L, Thomas C, Verient-Montaut B. Eosinophil count in nasal secretions of subjects with and without nasal symptoms. Rhinology 2000; 38(1):23–32


GM-CSF Production and Tissue Eosinophilia in Chronic Rhinitis 17 de Corso E, Battista M, Pandolfini M, et al. Role of inflammation in

non-allergic rhinitis. Rhinology 2014;52(2):142–149 18 Moneret-Vautrin DA, Jankowski R, Bene MC, et al. NARES: a model of inflammation caused by activated eosinophils? Rhinology 1992;30(3):161–168 19 Ohkubo K, Ikeda M, Pawankar R, Gotoh M, Yagi T, Okuda M. Mechanisms of IL-6, IL-8, and GM-CSF release in nasal secretions of allergic patients after nasal challenge. Rhinology 1998;36(4): 156–161

Peric et al.

20 Shin SH, Lee SH, Jeong HS, Kita H. The effect of nasal polyp epithelial

cells on eosinophil activation. Laryngoscope 2003;113(8):1374–1377 21 De Corso E, Baroni S, Lucidi D, et al. Nasal lavage levels of

granulocyte-macrophage colony-stimulating factor and chronic nasal hypereosinophilia. Int Forum Allergy Rhinol 2015;5(6): 557–562 22 Riechelmann H, Deutschle T, Friemel E, Gross HJ, Bachem M. Biological markers in nasal secretions. Eur Respir J 2003;21(4): 600–605

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

369


THIEME

370

Original Research

Curcumin Reduces the Noise-Exposed Cochlear Fibroblasts Apoptosis Tengku Siti Hajar Haryuna1 Indri Adriztina1

Wibi Riawan2

Ardyansyah Nasution1

1 Department of Otorhinolaryngology-Head and Neck Surgery, Faculty

of Medicine, Universitas Sumatera Utara, Medan 20155, Indonesia 2 Department of Biochemistry, Faculty of Medicine, Universitas Brawijaya, Malang 65145, Indonesia 3 Department of Clinical Pathology, Faculty of Medicine, Universitas Airlangga, Surabaya 60131, Indonesia 4 Department of Community Medicine, Faculty of Medicine, Universitas Sumatera Utara, Medan 20155, Indonesia

Suprapto Ma’at3

Juliandi Harahap4

Address for correspondence Tengku Siti Hajar Haryuna, MD, ENT Specialist, PhD, Department of Otorhinolaryngology - Head and Neck Surgery, Faculty of Medicine, Universitas Sumatera Utara, Jalan Bunga Lau No. 17, Medan Tuntungan Medan, Sumatera Utara 20136, Indonesia (e-mail: tengkusitihajarharyuna@gmail.com).

Int Arch Otorhinolaryngol 2016;20:370–376.

Abstract

Keywords

► ► ► ► ► ►

noise curcumin calcineurin NFATc1 apoptosis cochlea

Introduction The structural changes underlying permanent noise-induced hearing loss (NIHL) include loss of the sensory hair cells, damage to their stereocilia, and supporting tissues within the cochlear lateral wall. Objective The objective of this study is to demonstrate curcumin as a safe and effective therapeutic agent in the prevention and treatment for fibroblasts damage within the cochlear supporting tissues and lateral wall through cell death pathway. Methods We divided 24 Rattus norvegicus into 4 groups, Group 1: control; Group 2: noise (þ); Group 3: noise (þ), 50 mg/day curcumin (þ); Group 4: noise (þ), 100 mg/day curcumin (þ). We provided the noise exposure dose at 100 dB SPL for two hours over two weeks and administered the curcumin orally over two weeks. We examined all samples for the expressions of calcineurin, nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), and apoptotic index of cochlear fibroblasts. Results We found significant differences for the expressions of calcineurin (p < 0.05) in all groups, significant differences for the expressions of NFATc1 (p < 0.05) in all groups, except in Groups 1 and 4, and significant differences for the apoptotic index (p < 0.05) in all groups. Conclusion Curcumin proved to be potentially effective in the prevention and treatment for fibroblasts damage within the cochlear supporting tissues and lateral wall regarding the decreased expression of calcineurin, NFATc1, and apoptotic index of cochlear fibroblasts.

Introduction Exposure to excessive noise is the major avoidable cause of permanent hearing impairment.1 It is mostly found in the developing and industrial countries with bad hearing conservation.2 In 2012, there were 360 million persons in the world with

received October 3, 2015 accepted December 11, 2015 published online March 4, 2016

DOI http://dx.doi.org/ 10.1055/s-0036-1579742. ISSN 1809-9777.

disabling hearing loss, 5.3% of the world’s population, of which 328 million (91%) were adults (183 million men, 145 million women) and 32 (9%) million were children. Sixteen per cent of the disabling hearing loss in the adult population in the world resulted from excessive noise exposure in the workplace, ranging from 7% to 21% in the various subregions.1,3

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil


Curcumin Reduces the Noise-Exposed Cochlear Fibroblasts Apoptosis The cochlear spiral ligament is a connective tissue lining the space between stria vascularis and the bony otic capsule. It plays diverse roles in normal hearing and is composed of sub-populations of specialized fibrocytes, which are suggested to play distinct roles in fluid homeostasis, inflammatory responses, predicted by their protein expression profiles. Certain fibrocyte sub-types express ion transport proteins and, thus, are likely to regulate Kþ and Cl within the lateral wall perilymph.4 Evidence from various cell lines shows that cell death can be stimulated by oxidative stress and excitotoxicity through Ca2þ overload. Acoustic overstimulation increases the Ca2þ concentration in auditory hair cells. Elevated Ca2þ has been implicated in the impairment of hair cell function and may initiate hair cell damage after noise exposure. There are several pathways through which Ca2þ may contribute to cell death, involving activation of nitric oxide synthase (NOS), phospholipase A2, proteases, and calcineurin.5 For years, studies have emerged based on the use of natural compounds plant-derived as potential therapeutic agents for various diseases in humans.6 Curcumin, a yellow pigment obtained from the rhizomes of Curcuma longa Linnaeus (Family: Zingiberaceae), is a major component of turmeric and has been used as a traditional medicine that possesses therapeutic potential against various diseases. Curcumin is capable of modulating numerous molecular targets involved in each stage of disease development by regulating transcription factors, growth factors, receptors, cytokines, kinases, enzymes, cell survival, metastatic, and apoptotic molecules.7 The role of curcumin in the prevention of and treatment of fibroblast damage within the supporting tissues and the cochlear lateral wall through the apoptosis inhibition mechanism contributed by calcineurin in cochlear fibroblasts has never been studied and serves as the focus in this study. The objective of this study is also to demonstrate that higher doses of curcumin (100 mg/day) exert more beneficial effects in inhibiting apoptosis rather than low doses of curcumin (50 mg/day).

Methods This study is an experimental study with randomized posttest-only control group design using male Wistar strain white Rattus norvegicus rats (150 - 250 g, 8 - 12 weeks of age). The dose and frequency of noise exposure was 100 dB SPL and 1 - 10 kHz for 2 hours. Curcumin used in this study was derived from Curcuma longa Linnaeus (Turmeric) with curcumin content levels of 28.1  1.0% w/w compared with standard, suspended in 0.5% carboxymethyl cellulose. Afterwards, we administered the suspension directly to the stomach of each rat via nasogastric tube, once a day for two weeks. The samples were composed of 24 Rattus norvegicus divided into 4 groups. Group 1: the control group; Group 2: noise (þ); Group 3: noise (þ), 50 mg/ day curcumin (þ); Group 4: noise (þ), 100 mg/day curcumin (þ). We provided noise exposure doses of 100 dB SPL for two hours over two weeks.

Haryuna et al.

After two weeks, the rats underwent termination by ether inhalation and necropsy procedure on their temporal bone. All samples underwent standard tissue processing with fixation in buffered formaldehyde, followed by dehydration in graded alcohol solutions. Thereafter, they were embedded in paraffin blocks, serially cut into 4 µm thick sections, and put on glass slides. Representative sections were stained with hematoxylin and eosin (H&E). We performed immunohistochemical staining to examine the expressions of calcineurin and nuclear factor of activated T-cells cytoplasmic 1 (NFATc1) and apoptotic index of cochlear fibroblasts by terminal deoxynucleotidyl transferase (TdT) 2’-deoxyuridine 5′-triphosphate (dUTP) nick-end labeling (TUNEL) Assay. Immunohistochemistry procedures were performed as follows. We cleared the slide in xylene and rehydrated it through graded series of alcohol solutions. Endogenous peroxidase activity was blocked with 3% hydrogen peroxide in absolute methanol. We prevented nonspecific binding of the second layer antibody by incubation with 10% nonimmune serum (0.25% Triton X-100 in phosphate-buffered saline phosphate-buffered saline). Anti-Calcineurin A antibody (abcam ab71149, Abcam plc., Cambridge, USA) and NFATc1 antibody 7A6 (sc-7294, Santa Cruz Biotechnology, Inc., Dallas, Texas, USA) served as the first antibodies and were separately applied to each specimen and incubated in a humid chamber. After rinsing with phosphate-buffered saline, we incubated sections with biotinylated secondary antibody. Later, we washed them once more and incubated with a horseradish streptavidin–peroxidase conjugate. Next, we added a substrate–chromogen solution (3–3′-diaminobenzidine tetrahydrochloride). This reaction involved peroxidase catalysis of the substrate and conversion of the chromogen to a brown deposit that marked the antigen. The final steps included counterstaining with H&E and application of coverslips. The TUNEL assay (The ApopTag Plus Peroxidase In Situ Apoptosis Detection Kit (Merck Millipore Corporation, Darmstadt, Germany) procedures were described as follows. We cleared the slide in xylene and rehydrated by transferring the slides through a graded ethanol series. We blotted away the excess water carefully and added proteinase K solution to cover sections. Afterwards, it was incubated at room temperature. We inactivated endogenous peroxidases by covering sections with 2% hydrogen peroxide. Later, the slide was washed and the excess water also was blotted away carefully. We added TdT equilibration buffer to cover sections and then removed the buffer. TdT reaction buffer was added to cover sections afterwards. The slide was incubated in a humidified chamber. To conserve reagents, a reduced volume of TdT buffer may be carefully covered with a glass coverslip during the incubation. The reaction was stopped by incubating the slide. Then we rinsed it in phosphate-buffered saline and blocked nonspecific binding by covering tissue sections with 2% Bovine Serum Albumin solution. Later, the slide was incubated in working strength stop/wash buffer. After applying stop solution, the sample was washed and incubated with anti-digoxigenin peroxidase conjugate. We developed the slide with 3–3′-diaminobenzidine tetrahydrochloride substrate, counterstained with methyl green, dehydrated, and cover-slipped. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

371


372

Curcumin Reduces the Noise-Exposed Cochlear Fibroblasts Apoptosis

Haryuna et al.

fibroblasts unit with single nucleus expressing calcineurin and NFATc1 (showing brown-colored cytoplasms) and the occurrence of apoptosis (showing brown-colored nucleus). We processed the data using the Statistical Package for the Social Sciences (SPSS) one-way analysis of variance (ANOVA) and used a p value of 0.05 as the cut-off for statistical significance.

Results

Fig. 1 The cochlear supporting tissues and lateral wall with H&E staining (20x zoom).

Three observers examined the samples in each slide. The fibroblasts within the cochlear supporting tissues and lateral wall, which expressed calcineurin and NFATc1, and apoptotic index in all fields were calculated manually with a hand counter. We calculated the expressions of calcineurin and NFATc1 quantitatively for the average distribution of

We performed H&E staining of rat cochlea to get a detailed view of the tissue (►Fig. 1). The expression of calcineurin, after being evaluated with the immunohistochemistry method, showed an increased expression in Group 2 (►Fig. 2B), compared with other groups. The curcumin-treated groups showed lower density seen in the brown color, and less calcineurin-expressed fibroblasts than Group 2 (►Fig. 2C, D). Data in ►Table 1 show significant differences for the expressions of calcineurin (p < 0.05) in all groups. A dose of curcumin 100 mg per day showed statistically significant decreases in the expressions of calcineurin rather than a dose of curcumin at 50 mg per day. The expression of NFATc1 after being evaluated with the immunohistochemistry method showed an increased expression in Group 2 (►Fig. 3B) compared with other groups. The curcumin-treated groups showed less NFATc1expressed fibroblasts than Group 2 (►Fig. 3C, D).

Fig. 2 The expression of calcineurin in each group (1000x zoom): (A) Group 1/control; (B) Group 2; (C) Group 3; (D) Group 4. The white arrow indicates the expression of calcineurin in cochlear fibroblasts marked by the brown color. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016


Curcumin Reduces the Noise-Exposed Cochlear Fibroblasts Apoptosis Table 1 ANOVA test results in terms of the expressions of calcineurin Mean difference  Standard deviation

P value

Group 2

22.000  1.392

0.000

Group 3

17.500  1.392

0.000

Group 4

12.500  1.392

0.000

Group 3

4.500  1.392

0.025

Group 4

9.500  1.392

0.000

Group 4

5.000  1.392

0.011

Group Group 1

Group 2 Group 3 

Denotes statistically significant.

Data in ►Table 2 above showed significant differences for the expressions of NFATc1 (p < 0.05) in all groups, except in Groups 1 and 4. A dose of curcumin of 100 mg per day showed statistically significant decreases in the expressions of NFATc1, rather than a dose of curcumin 50 mg per day. The apoptotic index, after being evaluated with TUNEL assay showed an increased apoptotic index in group 2 (►Fig. 4 B) compared with other groups. The curcumintreated groups showed less apoptotic cells-expressed fibroblasts than group 2 (►Fig. 4C, D).

Haryuna et al.

Data in ►Table 3 showed significant differences for the apoptotic index (p < 0.05) in all groups. A dose of curcumin 100 mg per day showed statistically significant decreases in the apoptotic index rather than a dose of curcumin 50 mg per day.

Discussion Acoustic overstimulation induces Ca2þ overload and mediated cell death pathways, involving activation of calcineurin.5,8 In this study, we found that the expression of calcineurin statistically increases in the cochlear fibroblast noiseexposed group (Group 2) when compared with the control group. Calcineurin belongs to the family of Ca2þ/calmodulindependent protein phosphatases, protein phosphatase 2B. Calcineurin is activated by binding of Ca2þ/calmodulin and the only protein phosphatase regulated by a second messenger Ca2þ.9,10 It has been recently reported that calcineurin is activated in outer hair cells following noise exposure in mice exposed to broadband noise (2 - 20 kHz).8 In another experimental study in guinea pigs, after intense noise exposure (4 - 10 kHz, 120 dB, for 5 hours), varying degrees of hair cells loss and calcineurin immunoreactivity were detected immunohistochemistrically in outer hair cells and concentrated at the cuticular plate.5

Fig. 3 The expression of NFATc1 in each group (1000x zoom): (A) Group 1/control; (B) Group 2; (C) Group 3; (D) Group 4. The white arrow indicates the expression of NFATc1 in cochlear fibroblasts marked by the brown color. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

373


374

Curcumin Reduces the Noise-Exposed Cochlear Fibroblasts Apoptosis Table 2 ANOVA test results in terms of expressions of NFATc1

Group 1

Group 2 Group 3

Table 3 ANOVA test results in terms of the apoptotic index

Mean difference  Standard deviation

P value

Group

Group 2

10.833  0.792

0.000

Group 1

Group 3

5.667  0.792

Group 4

1.833  0.792

Group

Haryuna et al.

Mean difference  Standard deviation

P value

Group 2

12.333  1.004

0.000

0.000

Group 3

6.833  1.004

0.000

0.189

Group 4

3.667  1.004

0.010

Group 3

5.500  1.004

0.000

Group 4

8.667  1.004

0.000

Group 4

3.167  1.004

0.030



Group 3

5.167  0.792

0.000

Group 4

9.000  0.792

0.000

Group 4

3.833  0.792

0.001

Group 2 Group 3





The expression of NFATc1 was found to be statistically higher in the cochlear fibroblast noise-exposed group (Group 2) compared with the control group. Ca2þ overload activates calcineurin-dephosphorylated NFATs, leading to their translocation to the nucleus. In addition to this first wave of NFAT activation, in a second step of NFATc1/αA generation, a short isoform of NFATc1 is strongly induced.11,12 The apoptotic cochlear fibroblasts were statistically higher in the cochlear fibroblast noise-exposed group (Group 2) compared with the control group. Calcineurin has a dual function and may exert its effects on apoptosis either by the

activation of specific transcriptional pathways or by direct dephosphorylation of proteins including Bad (B cell lymphoma 2 antagonist of cell death) and caspase-9 involved in the apoptotic pathway.10,11 Calcineurin dephosphorylates Bad, resulting in the disruption of the binding of Bax (B cell lymphoma 2 associated x protein) to Bcl-2 (B cell lymphoma 2) or Bcl-xL (B cell lymphoma 2-extra large) at the outer membrane of mitochondria through intrinsic pathway. Free Bax translocate to mitochondria and activate the transport system to release cytochrome c.8,13,14

Denotes statistically significant.

Denotes statistically significant.

Fig. 4 The apoptotic index in each group (1000x zoom): (A) Group 1/control; (B) Group 2; (C) Group 3; (D) Group 4. The white arrow indicates the apoptotic cochlear fibroblasts marked by the brown color. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016


Curcumin Reduces the Noise-Exposed Cochlear Fibroblasts Apoptosis In the extrinsic pathway, outside the mitochondria, it has been previously described that expression of the membranebound death receptor ligand FasL is mediated by NFAT. When FasL binds to its receptor Fas, the intracellular machinery associated with the death receptor Fas is activated and eventually leads to apoptosis by caspase activation and subsequent DNA cleavage.2 Caspase-8 directly cleaves caspase-3 as well as cytosolic Bid (BH-3 interacting domain death agonist), its active fragment (tBid) translocates to mitochondria to release cytochrome c.15 Cytochrome c interacts with proteins such as Apaf-1 (apoptotic protease activating factor-1), dATP, and procaspase-9 to produce apoptosome and then activates caspase9. This complex degrades procaspase-3 to caspase-3.15 In apoptotic cells, activated caspase-3 cleaves inhibitor of caspase activated DNAse (ICAD) to release CAD. CAD then degrades chromosomal DNA within the nuclei and causes chromatin condensation. Caspase-3 also induces cytoskeletal reorganization and disintegration of the cell into apoptotic bodies.14 An experimental study in mice exposed to broadband noise (2 - 20 kHz) has discovered that noise exposure induces activation of mitochondria-mediated cell death pathways in outer hair cells of the cochlea through activation of Bad by calcineurin. The localization of Bad was analyzed by immunohistochemistry. Total Bad was observed both in the sensory cells and in the supporting cells and also in the nerve fibers projecting to the sensory cells. The results of this study strongly support the Bad as a link between Ca2þ influx after noise exposure and the death of outer hair cells.8 In another study, after intense noise exposure (4 - 10 kHz, 120 dB, for 5 hours) in guinea pigs, some calcineurin-immunopositive hair cells demonstrated condensed and swollen nuclei, indicating that calcineurin is related to both apoptosis and necrosis.5 This study proved that curcumin was able to decrease the expression of calcineurin and NFATc1 in cochlear fibroblasts, where a dose of curcumin 100 mg per day showed statistically significant decreases in the expression of calcineurin and NFATc1 compared with a dose of curcumin 50 mg per day. This is due to the speculation that curcumin inhibits the regulation and expression of calcineurin, and prevents the dephosphorylation of NFATc1 by calcineurin, thus, reducing its translocation to the nucleus. The expression of NFATc1 in Group 4 was statistically insignificant compared with the control group, indicating that curcumin administration at higher doses is able to prevent NFATc1 activation, thereby its expression was found to be nearly similar to the control group (without noise exposure). Researchers have recently investigated the therapeutic efficacy of curcumin in attenuation of left ventricular hypertrophy and sought to delineate the associated signaling pathways in blunting the hypertrophic response in nephrectomized rats. Curcumin attenuates cardiac hypertrophy and remodeling through deactivation of multiple hypertrophic signaling pathways. This study reported that cytosolic NFAT was significantly decreased in rats that underwent nephrectomy and was significantly attenuated

Haryuna et al.

by curcumin. NFAT in the nucleus was decreased by curcumin with quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR) analysis. 16 Another study showed an action of curcumin as an NFAT inhibitor through the Ca2þ signaling pathway blocking. This experiment also demonstrates that curcumin inhibits NFAT transcriptional activity by preventing its nuclear translocation from the cytoplasm into the nucleus upon phorbol myristate acetate (PMA)/ionomycin stimulation of Jurkat T-cells with laser scan microscopy (LSM) analysis. 17 Curcumin significantly promoted nonischemic wound healing in a dose–response fashion compared with controls as judged by increased reepithelialization and granulation tissue formation. Improved wound healing was associated with significant decreases in pro-inflammatory cytokines interleukin (IL)-1 and IL-6 as well as the chemokine IL-8. Curcumin also significantly reduced hypertrophic scarring.18 Another study concluded that pre- and coreceiving curcumin can significantly protect the cochlear morphology and functions on paclitaxel-induced ototoxicity in rats using light microscopy and distortion product otoacoustic emissions (DPOAEs) to evaluate histopathological, immunohistochemical, and functional changes in hearing. Curcumin might be considered as a potential dietary supplement from a natural product given to patients undergoing paclitaxel chemotherapy.19 Curcumin can also be used as an efficient adjuvant to cisplatin cancer therapy. This treatment strategy in head and neck cancer could mediate cisplatin chemoresistance by modulating therapeutic targets (Signal transducer and activator of transcription 3 and NF-E2 p45-related factor 2) and, at the same time, reduce cisplatin-related ototoxic adverse effects.20 Preclinical studies demonstrated that systemic curcumin attenuates ototoxicity and provides molecular evidence for a role of hemeoxigenase (HO-1) as an additional mediator in attenuating cisplatin-induced hearing loss.21 A previous study found the effect of curcumin on peroxynitrite (ONOO)-induced damage in rat spiral ganglion neurons. Pretreatment with curcumin abrogated cytochrome c release, blocked activation of caspase-3, and altered the expression of Bcl-2 family triggered by ONOO. Curcumin can attenuate ONOO-induced damage in spiral ganglion neurons by the anti-oxidative activity, as well as protect mitochondria from oxidative stress.22 In the present study, we proved that curcumin is able to decrease the apoptotic cochlear fibroblasts, whereby a dose of curcumin 100 mg per day showed significant decreases in the apoptotic index compared with a dose of curcumin 50 mg per day. This is due to the speculation that curcumin inhibits calcineurin activation, therefore its role in Bad dephosphorylation can be prevented. Furthermore, the complex of Bcl-2 or Bcl-XL remains inseparable and both function in preventing cytochrome c release into cytosol is inhibitable and apoptosis becomes an avoidable process. Curcumin also inhibits the dephosphorylation of NFATc1 leading to reduced translocation to the nucleus, therefore, preventing apoptosis by caspase-8 activation. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

375


376

Curcumin Reduces the Noise-Exposed Cochlear Fibroblasts Apoptosis

Conclusion

10 Zhu H, Gao W, Jiang H, Wu J, Shi YF, Zhang XJ. Calcineurin mediates

This study indicates that curcumin is safe and effective as a therapeutic agent in the prevention and treatment of the damage of fibroblasts within the supporting tissues and the cochlear lateral wall through the cell death pathway. Moreover, the study provides more insight into the mechanism of curcumin against apoptosis and shows that curcumin inhibits multiple apoptosis signaling pathways, including calcineurin and NFATc1. The study may serve as a scientific basis in the traditional systems of medicine for the management of NIHL in the future.

11

12

13

14 15

References 1 Nandi SS, Dhatrak SV. Occupational noise-induced hearing loss in

India. Indian J Occup Environ Med 2008;12(2):53–56

16

2 Harmadji S, Kabullah H. Noise induced hearing loss in steel factory

workers. Folia Medica Indonesiana 2004;40(4):171–174 3 World Health Organization. WHO global estimates on prevalence

4

5

6

7

8

9

of hearing loss. Available at: http://www.who.int/pbd/deafness/ WHO_GE_HL.pdf. Accessed Dec 10, 2014 Kelly JJ, Forge A, Jagger DJ. Contractility in type III cochlear fibrocytes is dependent on non-muscle myosin II and intercellular gap junctional coupling. J Assoc Res Otolaryngol 2012;13(4):473–484 Minami SB, Yamashita D, Schacht J, Miller JM. Calcineurin activation contributes to noise-induced hearing loss. J Neurosci Res 2004;78(3):383–392 Trujillo J, Granados-Castro LF, Zazueta C, Andérica-Romero AC, Chirino YI, Pedraza-Chaverrí J. Mitochondria as a target in the therapeutic properties of curcumin. Arch Pharm (Weinheim) 2014;347(12):873–884 Prasad S, Gupta SC, Tyagi AK, Aggarwal BB. Curcumin, a component of golden spice: from bedside to bench and back. Biotechnol Adv 2014;32(6):1053–1064 Vicente-Torres MA, Schacht J. A BAD link to mitochondrial cell death in the cochlea of mice with noise-induced hearing loss. J Neurosci Res 2006;83(8):1564–1572 Morioka M, Hamada J, Ushio Y, Miyamoto E. Potential role of calcineurin for brain ischemia and traumatic injury. Prog Neurobiol 1999;58(1):1–30

International Archives of Otorhinolaryngology

Haryuna et al.

Vol. 20

No. 4/2016

17

18

19

20

21

22

acetylcholinesterase expression during calcium ionophore A23187-induced HeLa cell apoptosis. Biochim Biophys Acta 2007;1773(4):593–602 Alvarez S, Blanco A, Fresno M, Muñoz-Fernández MA. TNF-α contributes to caspase-3 independent apoptosis in neuroblastoma cells: role of NFAT. PLoS ONE 2011;6(1):e16100 Serfling E, Avots A, Klein-Hessling S, Rudolf R, Vaeth M, BerberichSiebelt F. NFATc1/αA: The other Face of NFAT Factors in Lymphocytes. Cell Commun Signal 2012;10(1):16 Precht TA, Phelps RA, Linseman DA, et al. The permeability transition pore triggers Bax translocation to mitochondria during neuronal apoptosis. Cell Death Differ 2005;12(3):255–265 Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol 2007;35(4):495–516 Maher S, Toomey D, Condron C, Bouchier-Hayes D. Activationinduced cell death: the controversial role of Fas and Fas ligand in immune privilege and tumour counterattack. Immunol Cell Biol 2002;80(2):131–137 Ghosh SS, Salloum FN, Abbate A, et al. Curcumin prevents cardiac remodeling secondary to chronic renal failure through deactivation of hypertrophic signaling in rats. Am J Physiol Heart Circ Physiol 2010;299(4):H975–H984 Kliem C, Merling A, Giaisi M, Kohler R, Krammer PH, Li-Weber M. Curcumin suppresses T cell activation by blocking Ca2þ mobilization and nuclear factor of activated T cells (NFAT) activation. J Biol Chem 2012;287(13):10200–10209 Jia S, Xie P, Hong SJ, et al. Intravenous curcumin efficacy on healing and scar formation in rabbit ear wounds under nonischemic, ischemic, and ischemia-reperfusion conditions. Wound Repair Regen 2015;22(6):730–739 Bucak A, Ozdemir C, Ulu S, et al. Investigation of protective role of curcumin against paclitaxel-induced inner ear damage in rats. Laryngoscope 2015;125(5):1175–1182 Fetoni AR, Paciello F, Mezzogori D, et al. Molecular targets for anticancer redox chemotherapy and cisplatin-induced ototoxicity: the role of curcumin on pSTAT3 and Nrf-2 signalling. Br J Cancer 2015;113(10):1434–1444 Fetoni AR, Eramo SLM, Paciello F, et al. Curcuma longa (curcumin) decreases in vivo cisplatin-induced ototoxicity through heme oxygenase-1 induction. Otol Neurotol 2014;35(5):e169–e177 Liu W, Fan Z, Han Y, et al. Curcumin attenuates peroxynitriteinduced neurotoxicity in spiral ganglion neurons. Neurotoxicology 2011;32(1):150–157


THIEME

Original Research

Evaluation of the Effects of Bismuth Subgallate on Wound Healing in Rats. Histological Findings Rafaela Mabile Ferreira dos Santos1 Rubianne Ligório de Lima1

Claudia Paraguaçu Pupo Sampaio1

1 School of Medicine, Pontifícia Universidade Católica do Paraná,

Curitiba, Paraná, Brazil Int Arch Otorhinolaryngol 2016;20:377–381.

Abstract

Keywords

► bismuth subgallate ► angiogenesis ► wound healing

Address for correspondence Rafaela Mabile Ferreira dos Santos, MS, Pontifícia Universidade Católica do Paraná - School of Medicine, Rua Imaculada conceição n.1155 Curitiba Paraná 80215901, Brazil (e-mail: rafa_mabile@yahoo.com.br; danielapachedemoraes@hotmail.com).

Introduction Bismuth subgallate (BS) is a yellow and odorless powder that has hemostatic astringent properties. Some otorhinolaryngologists and dentists currently use this substance to enhance wound healing. Objective The objective of this study is to evaluate the effects of bismuth subgallate on wound healing, through the analysis of inflammatory process, collagen production, and angiogenesis. Method A standard wound was made on the back of 60 male Wistar rats, using a biopsy punch. We created two groups: the experimental group, which underwent daily application of 0.5mg BS over the entire wound, and the control group, which underwent daily application of sodium chloride 0.9%. We performed a qualitative evaluation of the tissue on the third, seventh, and fourteenth day. We assessed inflammatory markers using Hematoxylin and Eosin (HE) stain, used Picrosirius stain for collagen analysis, and immunohistochemistry was used for angiogenesis analysis through evaluation of smooth muscle proliferation. Results Statistically, we found no significant differences between groups regarding inflammatory response on the third (p ¼ 1), seventh (p ¼ 0.474), and fourteenth day (p ¼ 0.303). Also, collagen type I and III production showed no statistical differences between groups on the third (p ¼ 0.436), seventh (p ¼ 0.853), and fourteenth day (p ¼ 0.436) of analysis. Immunohistochemistry did not present differences on angiogenesis between experimental and control group on the third (p ¼ 0.280), seventh (p ¼ 0.971), and fourteenth day (p ¼ 0.218). Conclusion BS does not promote significant changes in inflammatory response, collagen, and angiogenesis. Thus, it does not influence healing on skin wounds on rats.

Introduction Intra and postoperative hemorrhage are relevant issues for surgeons due to its association with high mortality. Despite the existence of hemostatic agents for years, this subject is not fully elucidated. There are two main types of agents that prevent hemorrhage: hemostatic agents and tissue adhesives. Each of these substances differ in their mechanism of action, cost, and application method.1

received July 17, 2015 accepted March 17, 2016 published online May 4, 2016

Daniela Pache de Moraes1

DOI http://dx.doi.org/ 10.1055/s-0036-1583760. ISSN 1809-9777.

The mechanism of action of hemostatic agents may be mechanical or through action over the coagulation cascade. On the other hand, tissue adhesives are substances that close wound edges. Collagen is considered a topic hemostatic agent, and it is biomaterial derived from organic tissues. It has considerable tension force as a characteristic. Furthermore, it has high affinity for water, low antigenicity, and is absorbed by the body promoting platelet activation. Collagen

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil

377


378

Effects of Bismuth Subgallate on Wound Healing in Rats may be applied on the bleeding site. Although bovine collagen may lead to allergic reactions or immune reactions, the incidence of such events in clinical practice is low.1 Cellulose-based products contain oxidized regenerated cellulose. They trigger coagulation through contact activation; however, the exact mechanism has not been elucidated. Cellulose-based products may be cut in different sizes to adapt to the exact size of the wound. These products are easy to use and do not adhere to surgical instruments. Nonetheless, the body may not absorb oxidized cellulose as well as other products. Differences in biodegradability will depend on the quantity used and place of implantation. This way, a minimal quantity should be used to obtain hemostasis.1 Bismuth subgallate (BS) is a yellow and odorless powder. The compound is stable in air, but suffers discoloration under the influence of sunlight.2 Its homeostatic and astringent properties have led to increasing use by dentists and ear, nose, and throat (ENT) surgeons. Due to these characteristics, its use is diverse and comprises dental surgery, peptic ulcer disease treatment, wound treatment, diarrhea management (0.1–2 g orally), odor control in colostomies (0.1–2 g orally), epistaxis management, as well as, empirical use in adenotonsilectomies.2–4 The recommended dose via rectal route is 0.1–2 g and 20% may be used for topic application. This study addresses BS regarding the fact that published trials addressing the effects of BS on wound healing are limited. Furthermore, there are diverging reports on its use. Whereas some departments of otorhinolaryngology do not encourage the utilization of BS under the premise that its post-operative effect is not significantly beneficial, other departments claim great pro-homeostatic results associated with its topical application. The aim of this study is to evaluate the influence of BS on wound healing phases. Given that BS has low cost and is easily applicable, it could benefit wound healing. The histological analysis of inflammatory process, collagen production, and angiogenesis may demonstrate the benefits of its use, thus, optimizing the wound healing process. Furthermore, BS trials have not specifically explored its wound healing effects. Generally, they have addressed its effects on post-operative immediate bleeding. The classical wound healing phases are: hemostasis, inflammation, proliferation (epithelialization, collagen deposition, angiogenesis, granulation tissue formation, and wound contraction) and remodeling.5–7 The earliest stage is hemostasis and consists of an immediate response to injury, comprising the formation of a clot and a transitional wound matrix, through which cells migrate during repair.8 Inflammation manifestations are due to augmented blood flow and vascular permeability. They consist of: pain, heat, redness, swelling, and loss of function. Substantial effort has been given to elucidating the physical relationships driving wound healing. The utilization of resources to stimulate this process should be applied to acute wounds, thus preventing chronification and its adverse effects. Wounds that do not heal within eight weeks are considered chronic.9 Considering this, the aim of this study is to evaluate the influence that BS may have over any of the wound healing phases. Our research will employ histological International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Santos et al. analysis. Given the fact that BS has low cost and is easily used, its use could benefit wound healing.

Method This study took place at the Surgical Technique Experimental Laboratory. The sample comprised 60 male Wistar rats (n ¼ 60) (Rattus norvegicus albinus, Rodentia mammalia), 110 days old and weighing 250–300 g. Ethical approval was granted by Animals Ethics Committee, under protocol number 720. The animals from this study also participated in the concomitant project: “Evaluation of the effects of bismuth subgallate on myofibroblasts proliferation: an experimental study on rats.” We determined the sample size by literature analysis. We randomly created two groups of 30 animals. We then divided the animals into subgroups of 10. Therefore, the control and experimental group comprised 3 subgroups of 10 rats. Animals in both groups underwent anesthesia with ketamine (50 mg) and xylazine 2% (20 mg), at a concentration of 0.1ml/100 g of animal body weight. Intramuscular application was done on the posterior portion of thigh. Animals were placed in ventral decubitus and had their superior and inferior limbs adhered to a wooden support. We performed a trichotomy of 24 cm2 (6 cm  4 cm) on the ratś backs. This area was demarcated by means of an imaginary line traced between inferior limbs that extended progressively in caudal direction. Subsequently, we performed skin antisepsis with polyvinylpyrrolidone-iodine (PVPI) and delimited the operative area with a fenestrated sterile field. Wounds were standardized with biopsy punches. We made a circular excision and deepened it down until dorsal muscle fascia. Intramuscular Diclofenac Potassium 10mg/Kg was administered, as a post-operative analgesic and anti-inflammatory. The experimental group underwent daily applications of 0.5 mg BS over the entire wound. The control group underwent daily application of sodium chloride 0.9%, as recommended by literature.10 We created subgroups to analyze tissue at different times. To do so, animals were re-operated for wound excision, on the third, seventh, and fourteenth day. The animals underwent anesthesia (as previously described), and the wound was excised with gross margin of 1cm of normal tissue. Incision was deepened until dorsal muscle fascia. We administered intraperitoneal thiopental (120 mg/ kg) to each subgroup after excision of wound for the purpose of euthanasia. No animals were lost throughout this study. We placed excision specimens on a paper card and identified them. Subsequently, we immersed tissues in formaldehyde 10% for 24 hours, and then processed into paraffin. Blocks were sectioned and stained with Hematoxylin and Eosin (HE). Optical microscopy analysis of one section of each rat was then conducted with 40x image magnification. We did cell counts on slides stained with HE to analyze inflammatory process stage. We performed the polymorphonuclear and mononuclear cell count on all slides, then placed the total cells on a table for classification of wounds into acute, subacute, or chronic.11 (►Table 1)


Effects of Bismuth Subgallate on Wound Healing in Rats

Santos et al.

Table 1 Cell count of inflammatory process and characterization of inflammatory process stage according to the final score of each group Cell Count

Polymorphonuclear

Monomorphonuclear

IPS

Classification

<50

-1

1

Acute

-9 to -3

50–100

-2

2

Subacute

-2.9 to 3

>100

-3

3

Chronic

3 to 9

Abbreviation: IPS, inflammatory process stage.

We used Picrosirius red stain to analyze collagen by evaluating differences in intensity of birefringence. We examined sections using a Polarizing microscope. We used the Mann-Whitney nonparametric test to perform quantitative analysis of collagen. We used the Kruskal-wallis nonparametric to analyze variance between different times of the procedure (3rd, 7th, and 14th day). We used Fisher’s exact test to detect differences in inflammation stages between groups and timings. We used IBM SPSS Statistics v.20 system to analyze data. Statistical significance was defined by p-values of 0.05 or less. Specimens also underwent immunohistochemistry evaluation to determine reactivity to factor VIII, CD34, and αsmooth muscle actin (A-SMA). However, only the A-SMA analysis was possible since factor VIII and CD34 presented decreased specificity for staining on the evaluated tissue. Afterwards, we sent all the results for statistical analysis, which was conducted utilizing parametric and nonparametric methods.

Results HE Stain We made comparisons between the groups (control and experimental) regarding stages of inflammatory process (acute, subacute, or chronic) at different times of tissue removal (3rd, 7th, and 14th day). Subsequently, we compared each time separately (3rd day versus 7th day; 3rd day versus

Fig. 1 Picrosirius stain for experimental group (D7) demonstrating mature collagen and immature collagen.

14th day; 7th day versus 14th day). The null hypothesis of distribution equality among inflammation stages in both groups was tested and contrasted to the alternate hypothesis of diverse distribution. No differences were found in the inflammatory process concerning the two analyses on the third day (p ¼ 1), seventh day (p ¼ 0.474), and fourteenth day (p ¼ 0.303).

Picrosirius Red Stain We performed a quantitative comparison of collagen type I between different times of tissue removal for the control group and experimental group separately. We found no differences among the different times of analysis in the control group. Furthermore, we detected no differences within the experimental group: third day (p ¼ 0.436), seventh day (p ¼ 0.853), fourteenth day (p ¼ 0.436) (►Fig. 1) As for collagen type III, we ran the same analysis and the control group had no significant differences; whereas within the experimental group, statistical differences were apparent between subgroups on day 3 and day 14 (p ¼ 0.005) (►Fig. 2).

A-SMA Immunohistochemical analysis revealed brown staining of ASMA. This area highlights the presence of myofibroblasts and allows vessel count for angiogenesis evaluation. We executed an analysis of the presence of myofibroblasts in a delimited area, and then contrasted control and experimental group

Fig. 2 Picrosirius stain for control group (D7) demonstrating mature collagen and immature collagen.

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

379


380

Effects of Bismuth Subgallate on Wound Healing in Rats

Santos et al.

Table 2 Immunohistochemistry results obtained per day and per group of myofibroblasts p value

Evaluation time

Group

Brown colored area myofibroblasts n

Mean

Median

Min

Max

SD

Day 3

Control

10

5118

4867

1867

8542

2478

Experimental

10

5649

5125

3851

9890

1897

Day 7 Day 14

Control

10

6751

6462

3977

8784

1692

Experimental

10

5551

5674

3503

7696

1210

Control

10

6283

6546

2403

11421

2335

Experimental

10

6557

6828

3927

8835

1923

0.684 0.143 0.631



Mann-Whitney non-parametric test; p < 0.05. Abbreviation: SD, standard deviation.

according to the time of tissue removal. Results were not statistically significant by the third day (p ¼ 0.684), seventh day (p ¼ 0.143), and fourteenth day (p ¼ 0.631) (►Table 2). Subsequently, we evaluated the null hypothesis of equal means among all times and contrasted it with the alternate hypothesis of the presence of divergent results on at least one of the timings. The null hypothesis could not be rejected by statistical tests for both control group (p ¼ 0.336) and experimental group (p ¼ 0.4) (►Table 2). When contrasting immunohistochemical analysis of control and experimental group for A-SMA presence, we found no statistical differences. For angiogenesis evaluation, we compared times of tissue removal between groups. We found no statistically significant results on the third day (p ¼ 0.280), seventh day (p ¼ 0.971), and fourteenth day (p ¼ 0.218) (►Table 3). Afterwards, the null hypothesis of equal means was tested versus the alternative hypothesis that at least one of the times presented different results. Statistical testing could not rule out the null hypothesis for the control group (p ¼ 0.389) and the experimental group (p ¼ 0.091). When we evaluated angiogenesis among groups, we did not find statistical difference.

Discussion BS is commonly used in adenotonsillectomies with homeostatic purposes. BS enhances the intrinsic pathway of blood

coagulation by activating factor XII.12,13 Therefore, this study was developed to elucidate its role in wound healing. BS could be of potential benefit considering that several hemostatic techniques are being explored to reveal efficient methods of trans- and postoperative bleeding control. Some trials have described BS as being a heavy metal element that is prohomeostatic and stimulates clot formation.12,13 Nonetheless, there is a lack of studies analyzing its effects on wound healing. Another study developed in the city of Curitiba, Brazil, evaluated the effects of the application of BS over wounds performed on the mucosa on the back of rats. This investigation revealed that BS inhibits fibroplasia and angiogenesis, therefore, delaying the wound healing process.13 Diversely, our study showed no effects of BS on wound healing. Given that both studies performed identical application of 0.5 mg of BS over the wounds, we hypothesize that the divergence was due to the wound being performed in the mucosa that study, whereas, in our study, it was done on the skin. Mucous membrane consists of the combination of an epithelium and a lamina propria of connective tissue, which line some body cavities. The mucosa’s lamina propria consists of a nonkeratinized epithelial tissue, whereas the skin presents keratinized stratified squamous epithelium.14 This could explain differences in wound healing effects on tissues. We hypothesize that the lack of keratinized tissue exposed tissues to a higher concentration of BS, reaching, thus, toxic levels and impairing wound healing. The keratinized surface of skin,

Table 3 Immunohistochemistry results obtained per day and per number of vessels p value

Evaluation time

Group

Number of vessels n

Mean

Median

Min

Max

SD

Day 3

Control

10

2.5

2

0

5

2.0

Experimental

10

1.5

1.5

0

4

1.5

Control

10

3.4

3

1

8

2.5

Experimental

10

3.3

3.5

1

6

1.9

Control

10

2.1

2

0

7

1.9

Experimental

10

2.4

2

1

4

0.8

Day 7 Day 14



Mann-Whitney nonparametric test; p < 0.05. Abbreviation: SD, standard deviation.

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

0.280 0.971 0.218


Effects of Bismuth Subgallate on Wound Healing in Rats however, may have acted as a barrier, preventing BS induced toxicity and, thus, not influencing cicatrization. Notwithstanding, another study presented similar results to the ones described in this project. The research team performed a standard wound with a circular scalpel on the back of 55 Wistar rats to evaluate the effects of BS on tissue regeneration. They traced an imaginary line to divide the wound into two equal parts. The right part was treated with BS and the other one with physiological saline 0.9%. We found no differences between the utilization of these two compounds over different time analyses. Therefore, BS did not enhance tissue regeneration.15 Bias cannot be ruled out in this study, though, since the same wound was used for the analysis of both substances. Nonetheless, the results are similar to ours. Another study also corroborates our findings. Hepatectomies were performed using a metallic scalpel on 30 rats. Animals were divided into two groups. One group utilized an electrosurgical device for hemostatic purposes while the other group used BS. Subsequently, we performed histological analyses to detect: necrosis, fibrosis, thrombosis of the microcirculation, granulomatous reaction, inflammation stage, and adhesions. We found no differences among groups regarding granulomatous reaction, necrosis, fibrosis, inflammation stage, and adhesions.16 This strengthens the notion that BS does not alter the inflammation process and wound healing. This project reveals that the use of BS is tolerable and safe and that it does not remarkably influence the wound healing process. Both wounds on D14 were cicatrized and presented similar ectoscopy. The lack of substantial effects on wound healing was determined by HE stain, picrosirius stain, and immunohistochemistry.17 The findings of this study indicate that BS is neither harmful nor helpful regarding wound healing.

References

Conclusion

14

Based on the data presented here, study limitations that could be addressed in future research is a bigger population of rats and BS absorption characteristics. Future trials comparing other substances with the control group is also warranted to increase the validity of our results. In conclusion, BS does not promote significant changes in the inflammatory process, collagen production, and angiogenesis. Thus, BS is neither harmful nor helpful regarding wound healing on skin wounds of rats.

Santos et al.

1 Brasileiro HMS, Lee IWC, Rapoport A. Uso do subgalato de bismuto

2

3 4

5 6

7

8

9

10 11

12

13

15

16

17

como agente hemostático em tonsiléctomia palatina: Estudo de 201 casos. ACTA ORL 2006;24(3):181–185 Kim SH, Grein RL, Tramontina VA. Aplicação do subgalato de bismuto em cirurgia periodontal. JBC J Bras Odontol Clin. 1997; 1(1):31–34 Pillar RS, Brito EO. Aplicação do subnitrato de bismuto e do subgalato nas amigdaléctomias. Arq Otorrinolaringol. 2003;7(1):28–31 Lazarus GS, Cooper DM, Knighton DR, et al. Definitions and guidelines for assessment of wounds and evaluation of healing. Arch Dermatol 1994;130(4):489–493 Robson MC. Wound infection. A failure of wound healing caused by an imbalance of bacteria. Surg Clin North Am 1997;77(3):637–650 Mandelbaum SH, Di Santis EP, Mandelbaum MHS. Cicatrização: conceitos atuais e recursos auxiliares/ Parte I. An Bras Dermatol 2003;78(4):393–410 Baum CL, Arpey CJ. Normal cutaneous wound healing: clinical correlation with cellular and molecular events. Dermatol Surg 2005;31(6):674–686 Hanson D, Langemo D, Thompson P, Anderson J, Hunter S. Understanding wound fluid and the phases of healing. Adv Skin Wound Care 2005;18(7):360–362 Dieter MF. Ação do medicamento canova na cicatrização do dorso de camundongo após incisão e sutura: avaliação macro e microscópica [dissertation]. Curitiba: University of Parana; 2005 Feridas IG. Novas Abordagens, Manejo Clínico e Atlas em Cores. Rio de Janeiro, Brazil: Editora LAB; 2005:178–179 Vizzotto Junior AO, Noronha L, Scheffel DLH, Campos ACL. Influência da cisplatina administrada no pré e pós-operatório sobre a cicatrização de anastomoses colônicas em ratos. J Bras Patol Med Lab 2003;39(2):143–149 Tramontina VA. Efeito do subgalato de bismuto no processo de reparação de feridas em dorso de rato. Estudo experimental histológico, histométrico e fotográfico. [dissertation]. Campinas: Universidade Estadual de Campinas. Faculdade de Odontologia de Piracicaba. 1997 Seidel KC, Sampaio CPP. Avaliação dos efeitos do subgalato de bismuto na cicatrização: avaliação do processo inflamatório e da proliferação dos miofibroblastos. Poster session presented at: Congresso Brasileiro de Otorrinolaringologia, Nov 20–23, 2013; São Paulo, Brazil Manterola ER, Smerilli AL. Uso del subgalato de bismuto como técnica hemostática en la exodoncia para pacientes dializados. Rev Fac Odontol (UBA) 2007;22:52–5325–27 Tramontina VA. Efeito do subgalato de bismuto no processo de reparação de feridas em dorso de rato. Estudo experimental, histológico, histométrico e fotográgico [dissertation]. Campinas: Universidade Estadual de Campinas. Faculdade de Odontologia de Piracicaba, Piracicaba, Brazil, 1997 Arroyo PC Jr, et al. Uso do subgalato de bismuto para hemostasia local em hepatectomias parciais em ratos. Rev Col Bras Cir 2004; 31(3):165 [online] Feridas IG. Novas Abordagens, Manejo Clínico e Atlas em Cores. Rio de Janeiro, Brazil: Editora LAB; 2005:178–179

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

381


THIEME

382

Systematic Review

Clinical Value of High Mobility Group Box 1 and the Receptor for Advanced Glycation Endproducts in Head and Neck Cancer: A Systematic Review Austin Nguyen1

Sheila Bhavsar1

Erinn Riley1

Gabriel Caponetti2

1 Department of Clinical and Translational Science, Creighton

University School of Medicine, Omaha, Nebraska, United States 2 Department of Pathology, Creighton University School of Medicine, Omaha, Nebraska, United States

Devendra Agrawal1

Address for correspondence Devendra Agrawal, PhD, Department of Clinical and Translational Science, Creighton University School of Medicine, 2500 California Plaza, Omaha, NE 68172, United States (e-mail: DevendraAgrawal@creighton.edu).

Int Arch Otorhinolaryngol 2016;20:382–389.

Abstract

Keywords

► HMGB1 protein ► advanced glycosylation end product-specific receptor ► head and neck neoplasms

Introduction High mobility group box 1 is a versatile protein involved in gene transcription, extracellular signaling, and response to inflammation. Extracellularly, high mobility group box 1 binds to several receptors, notably the receptor for advanced glycation end-products. Expression of high mobility group box 1 and the receptor for advanced glycation end-products has been described in many cancers. Objectives To systematically review the available literature using PubMed and Web of Science to evaluate the clinical value of high mobility group box 1 and the receptor for advanced glycation end-products in head and neck squamous cell carcinomas. Data synthesis A total of eleven studies were included in this review. High mobility group box 1 overexpression is associated with poor prognosis and many clinical and pathological characteristics of head and neck squamous cell carcinomas patients. Additionally, the receptor for advanced glycation end-products demonstrates potential value as a clinical indicator of tumor angiogenesis and advanced staging. In diagnosis, high mobility group box 1 demonstrates low sensitivity. Conclusion High mobility group box 1 and the receptor for advanced glycation endproducts are associated with clinical and pathological characteristics of head and neck squamous cell carcinomas. Further investigation of the prognostic and diagnostic value of these molecules is warranted.

Introduction The high mobility group box 1 protein (HMGB1) is a highly conserved and highly versatile nuclear and extracellular protein found in eukaryotic cells. HMGB1 is a non-histone, chromosomal protein that has been implicated in a variety of biologically important processes, including transcription, DNA repair, and extracellular signaling.1 Structurally, HMGB1 consists of 215-amino acid polypeptide organized into two DNA-binding domains (termed A-box and B-box)

received January 20, 2016 accepted February 28, 2016 published online April 19, 2016

DOI http://dx.doi.org/ 10.1055/s-0036-1583168. ISSN 1809-9777.

and a negatively charged C-terminal tail.2,3 Functionally, HMGB1 appears to have two distinct roles in cellular systems. In the intracellular milieu, HMGB1 localizes to the nucleus and non-specifically binds to the minor groove of DNA, facilitates the assembly of DNA-binding proteins, and is involved in regulating gene transcription.4,5 Following release into the extracellular space, HMGB1 acts as a pro-inflammatory cytokine that is secreted by activated monocytes, macrophages, and natural killer (NK) cells. It is also passively secreted by necrotic cells and is, therefore,

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil


Clinical Value of HMGB1 and RAGE in Head and Neck Cancer referred as an optimal marker of necrosis.6,7 It is involved in the mediation of neurite outgrowth, smooth muscle cell chemotaxis, mesoangioblast migration and proliferation, and tumor growth and metastasis.8–10 The extracellular HMGB1 binds to several cell surface receptors, including the Receptor for Advanced Glycation End-products (RAGE) and the Triggering Receptor Expressed on Myeloid cells 1 (TREM-1).11,12 RAGE is a transmembrane protein that belongs to the immunoglobulin superfamily. It can bind to advanced glycation end-products, the resulting product of nonenzymatic glycation. RAGE is mostly stimulated by cellular stress, such as inflammation and is therefore found to be overexpressed in many diseases, such as different cancers. 13 In certain cells, HMGB1 and its receptor, RAGE, co-localize on the cell surface. Authors have reported that HMGB1 binding to RAGE may activate signaling pathways, such as Ras/MAKP, PI3K/Akt, NF-kB, which leads to overexpression of genes and the change in the biological

Nguyen et al.

behavior of tumor cells.14 Previous studies have found that HMGB1 and RAGE play important roles in the development, growth, and metastasis of multiple tumors.15,16 The RAGE-HMGB1 interaction can diminish host anticancer immunity by inducing apoptosis in antigenpresenting dendritic cells and reprogram immune cells by promoting tumor-infiltrating T cell–expressed lymphotoxin a1b2, which leads to the recruitment of CD11bþF4/ 80þ macrophages (tumor-associated macrophages, TAMs) into the tumor for its promotion (►Fig. 1) by providing growth factors and supporting angiogenesis.17 Furthermore, HMGB1 released from necrotic cancer cells treated with chemotherapy enhances regrowth and metastasis of remnant cancer cells in a RAGE-dependent manner.18,19 Therefore, blocking the HMGB1–RAGE system may increase the effectiveness of chemotherapy.17 In fact, specialists have used soluble RAGE (sRAGE) to prevent the HMGB1RAGE signaling from occurring in animal tumor models by acting as a decoy receptor.20

Fig. 1 A generalized model of HMGB1 and RAGE involvement in cancer progression. Whether released by secretion or necrosis, extracellular HMGB1 acts as a proinflammatory cytokine. Additionally, HMGB1 may reprogram immune cells by supporting recruitment of tumor-associated macrophages (TAM) that promote tumor progression. Soluble RAGE (sRAGE) acts as a decoy receptor by binding HMGB1 without subsequent signaling. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

383


384

Clinical Value of HMGB1 and RAGE in Head and Neck Cancer In comparison to RAGE, HMGB1 has been more extensively studied in various cancers. HMGB1 expression appears to be associated with many different tumor types.21–24 In addition, the association of HMGB1 overexpression and poor prognosis has been reported in patients with various types of cancers.25–29 To our knowledge, however, a systematic evaluation of the clinical value of HMGB1 and RAGE in head and neck squamous cell carcinoma (HNSCC) has not been performed to date. HNSCC, which consists of several different subtypes, is the sixth most common malignancy in the world and the most common cause of cancer-related death in South Asia.30 Despite aggressive treatment approaches, prognosis of patients with HNSCC is quite poor. Due to the poor outcome, it is of particularly high interest to identify any additional biomarkers that allow early detection or implicate prognosis of HNSCC. In this article, we systematically review the available literature regarding HMGB1 and RAGE in HNSCC and evaluate their potential clinical value.

Review of Literature We performed a systematic search of the PubMed Database (through July 2015) of the National Library of Medicine using

Nguyen et al.

the following Medical Subject Headings: HMGB1 protein, advanced glycation end-product receptor, neoplasm, and head and neck neoplasms. The articles included discussed original research on the clinical value of HMGB1 or RAGE, including prognostic and diagnostic concordance, in head and neck neoplasms. We cross-referenced the search results with the Web of Science database, using the same terms. We excluded articles based on the following criteria: not written in English, conference abstract, and not performed on primary human subjects/specimens. An initial search of PubMed and Web of Science retrieved 421 articles (►Fig. 2). After reviewing titles and abstracts, excluding non-English articles and conference abstracts, 16 studies remained as potential candidates for inclusion. Full text review excluded five studies due to presentation of data irrelevant to the present topics. Ultimately, 11 studies were included in this systematic review, encompassing a total of 2,098 patients (►Table 1). Examination of HMGB1 and/or RAGE was predominantly performed in sectioned tissue, whether frozen (one study) or formalin-fixed and embedded in paraffin (7 studies). Four studies investigated expression levels in serum/blood. Studies in the squamous cell carcinoma (SCC) investigated the following malignancy types: general

Fig. 2 Systematic search of PubMed and the Web of Science returned 421 total studies. After review of titles, abstracts, and full-text, 11 studies were included in this review. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016


Clinical Value of HMGB1 and RAGE in Head and Neck Cancer

Nguyen et al.

Table 1 Study design and population characteristics Study

Malignancy

Sample type

N (total)

N (cancer)

Age, mean/median (range)

Sex, M:F

Patient notes

Sasahira et al31

OSCC

FFPE tissue

20

20

69.1 (41–83)

10:10



35

OSCC

FFPE tissue

62

62



35:27

Treatment naive

Wu et al36

NPC

FFPE tissue

166

166

47.7 (13–74)

133:33

Treatment naive

Landesberg et al32

OSCC

FFPE tissue

50

38

A: 69 (28–92). B: 72 (51–88). C: 66 (55–88).

A: 4:7. B: 7:7. C: 6:2

A: Well-differentiated tumor B: Moderately-differentiated tumor C: Poorly-differentiated tumor

Tsuji et al33

NPC

FFPE tissue

42

42







Liu et al37

HNSCC

FFPE tissue

103

103

57.86 (27–80)

99:4



Wild et al38

HNSCC

Serum and frozen tissue

52

35

64  10

29:6

Treatment naive

LSCC

Serum

121

71

54.5  14.0

54:17

Treatment naive

Tongue SCC

FFPE tissue

26

26

69 (29–87)

15:11

Treatment naive

Sasahira et al

Qiu et al39 Hanakawa et al Supic et al

Su et al34

41

40



OSCC

Tumor tissue (unspecified) or blood (controls)

246

93

58 (36–80)

OSCC

Blood

1210

618

54.29  11.28

69:24



596:22

All received primary surgery followed by radiotherapy. 24 received neoadjuvant cisplatin/5-fluorouracil chemotherapy. 

Abbreviations: FFPE, formalin-fixed paraffin-embedded; HNSCC, head and neck squamous cell carcinoma; LSCC, laryngeal squamous cell carcinoma; NPC, nasopharyngeal carcinoma; OSCC, oral squamous cell carcinoma; SCC, squamous cell carcinoma.  Does not include controls.

head and neck SCC (HNSCC, 2 studies), oral SCC (OSCC, 6 studies, including one study specifically on tongue SCC), nasopharyngeal carcinoma (2 studies), and SCC of the larynx (LSCC, 1 study). Of these, five studies indicated their included patients to be treatment naive. The study populations were between 50.0% and 96.3% male, with a mean/median age of 47.7 to 69.1 years.

The Receptor for Advanced Glycation End-products Four studies evaluated RAGE in head and neck cancer patients31–34 (►Table 2). The earliest study to be included31 analyzed samples from 20 patients with OSCC. The study compared expression of RAGE with angiogenesis and lymphangiogenesis, evaluated by microvessel density and lymph vessel density. A significant positive correlation was found between RAGE concentration and microvessel density (p ¼ 0.0123), but not between RAGE and lymph vessel density. Additionally, RAGE expression was significantly associated with concentration of vascular endothelial growth factor (VEGF; p ¼ 0.0344). The only clinic pathological factor to be significantly associated with RAGE expression was T-classification, with an elevated level seen in T3T4 classifications compared with T1-T2 (p ¼ 0.0408). In a study involving 38 OSCC cases, Landesberg et al32 observed RAGE to be associated with tumor differentiation (p < 0.05). RAGE positivity was detected in 100% of welldifferentiated OSCC, 75% of well-to-moderately differentiated OSCC, 33% of moderately differentiated OSCC, 14% of moderate-to-poorly differentiated OSCC, and 0% of poorly differentiated OSCC. Additionally, RAGE expression trended toward decreasing staining intensity with less tumor differentiation.

The most recent and largest study34 included 618 OSCC patients. Blood was collected and analyzed for RAGE gene polymorphism. Five polymorphisms of the RAGE gene were assessed: 374T > A (rs1800624), 429T > C (rs1800625), 1704G > T (rs184003), Gly82Ser (rs2070600), and a 63-bp deletion allele (407 to 345). The heterozygous 429T > C genotype was found to be significantly associated with an increased incidence of oral cancer [odds ratio (OR), 1.870; 95% confidence interval (CI), 1.323 to 2.644], stage III/IV tumors (OR, 1.736; 95% CI, 1.126 to 2.677), and large tumor size (OR, 1.644; 95% CI, 1.083 to 2.493). None of the other polymorphisms were found to be significantly associated with incidence or clinical status of OSCC. Lastly, the clinical value of RAGE was also evaluated in nasopharyngeal carcinoma.33 Analysis of 42 nasopharyngeal carcinoma specimens demonstrated expression of RAGE to be associated with tumor microvessel density (p ¼ 0.0049). Additionally, RAGE expression was significantly higher in cases with lymph node metastasis (N1–3 classification), when compared with that of lymph node metastasis-negative (N0) cases (p ¼ 0.0005).

Evaluation of High Mobility Group Box 1 We found seven studies that investigated the clinical role of HMGB1 in head and neck cancers35–41 (►Table 2). Of these, only one study assessed the diagnostic value of HMGB1.39 Using the cutoff of 4.80 ng/mL, serum HMGB1 was 42.0% sensitive and 88.3% specific (positive predictive value of 52.9%) for the diagnosis of laryngeal SCC. However, high serum HMGB1 was significantly associated with T classification (p ¼ 0.005), N International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

385


386

Clinical Value of HMGB1 and RAGE in Head and Neck Cancer

Nguyen et al.

Table 2 Clinical value of HMGB1 and RAGE Study

HMGB1 or RAGE

Assay

Clinic pathological characteristics or prognosis

RAGE (OSCC)

IHC and ELISA

• Lower in T1-T2 stages than T3-T4 (p ¼ 0.0408). • Correlated with MVD (p ¼ 0.0123) and VEGF expression (p ¼ 0.0344). • No correlation with N stage, age, sex, histological differentiation, LVD.

Sasahira et al35

HMGB1 (OSCC)

IHC

• High expression in cancer cell nuclei and nodal metastatic foci. • Correlated with VEGF-C and VEGF-D expression (p < 0.001)

Wu et al36

HMGB1 (NPC)

IHC

• Detected in 53.6% of cases, higher in malignant tissue. • Correlated with T classification (p ¼ 0.01), N classification (p ¼ 0.003), distant metastasis (p ¼ 0.046), clinical stage (p < 0.001), initial radiotherapy response (p ¼ 0.034), overall survival (p < 0.001), and disease-free survival (p < 0.001).

Landesberg et al32

RAGE (OSCC)

IHC and Western blot

• Expression was significantly different by tumor differentiation (p < 0.05): 100% of well-differentiated, 75% of well-to-moderately differentiated, 14% of moderate-to-poorly differentiated, 0% of poorly differentiated. • RAGE was highest in normal tissue and trended toward decreased levels with less tumor differentiation.

Tsuji et al33

RAGE (NPC)

IHC

• Tumor expression correlated with MVD (p ¼ 0.0049), suggestive of the important role of RAGE in angiogenesis. • Expression was higher with lymph node metastasis (p ¼ 0.0005).

Liu et al37

HMGB1 (HNSCC)

IHC

• Expressed in 88.3% of primary tumor samples and 43.7% in adjacent normal tissue (p < 0.001). • Correlated with tumor T classification (p ¼ 0.001), advanced stage (p < 0.001), lymph node metastasis (p < 0.001) recurrence (p < 0.001), disease-free survival (p < 0.001), and overall survival (p < 0.001). • Was not correlated with age, alcohol intake, smoking, tumor grade, and tumor site.

Wild et al38

HMGB1 (HNSCC)

IF, real-time PCR, and ELISA

• Expressed more strongly in tumor tissue than tumor-adjacent stroma (p ¼ 0.005). • HMGB1 levels were higher in sera of HNSCC patients than controls (p ¼ 0.002).

Qiu et al39

HMGB1 (LSCC)

ELISA

• Associated with T classification (p ¼ 0.005), N classification (p ¼ 0.002), and clinical stage (p ¼ 0.001). • High HMGB1 (cutoff 4.80 ng/mL) was associated with poorer overall survival rate (p ¼ 0.036). • Diagnosis of LSCC: 42.0% sensitive, 88.3% specific, positive predictive value of 52.9% (cutoff 4.80 ng/mL)

Hanakawa et al40

HMGB1 (Tongue SCC)

IHC

• Expression is not significantly associated with late neck metastases.

Supic et al41

HMGB1 (OSCC)

TaqMan genotyping

HMGB1 G/C polymorphism analysis: • 1177GG genotype had higher prevalence of advance tumor stage III (p ¼ 0.016) and significantly lower RFS (p ¼ 0.000). • 3814CC genotype had higher prevalence of nodal metastasis and advance tumor stage III (p ¼ 0.019).

Su et al34

RAGE (OSCC)

TaqMan genotyping

• -429TC genotype was associated with oral cancer incidence (OR, 1.870; 95% CI, 1.323–2.644) and late stage tumors (OR, 1.644; 95% CI, 1.083 to 2.493).

Sasahira et al

31

Abbreviations: 95% CI, 95% confidence interval; HNSCC, head and neck squamous cell carcinoma; LSCC, laryngeal squamous cell carcinoma; LVD, lymph vessel density; MVD, microvessel density; NPC, nasopharyngeal carcinoma; OR, odds ratio; OSCC, oral squamous cell carcinoma; SCC, squamous cell carcinoma; VEGF, vascular endothelial growth factor.

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016


Clinical Value of HMGB1 and RAGE in Head and Neck Cancer classification (p ¼ 0.002), clinical stage (p ¼ 0.001), and poorer overall survival rate (p ¼ 0.036). The study found no association between serum HMB1 level and gender (p ¼ 0.814), age (p ¼ 0.174), tumor site (p ¼ 0.733), and degree of differentiation (p ¼ 0.727). Wild et al38 performed the only other evaluation of serum HGMB1 levels. Sera of 35 HNSCC patients contained significantly higher concentrations of HMGB1 compared with that of controls (p ¼ 0.002). HMGB1 levels of patients’ sera were also analyzed against clinic pathological characteristics of patients (including cancer location, age, sex, therapy, staging, and grading), but they found no significant associations. Further analysis of frozen sections from HNSCC patients demonstrated stronger HMGB1 expression in tumor islands than in tumorsurrounding stroma (p ¼ 0.005). Three studies35,40,41 investigated the role of HMGB1 in OSCC. Sasahira et al35 analyzed 62 specimens of primary OSCC. HMGB1 was found to be highly expressed in cancer cell nuclei and nodal metastatic foci. Comparison with expression of VEGF-C and VEGF-D demonstrated a significant correlation (p < 0.001). Interestingly, analysis of HMGB1 levels in 26 specimens from patients with tongue SCC40 demonstrated no significant association between high HMGB1 expression and late neck metastases. Supic et al41 explored the role of polymorphisms in the HMGB1 gene in OSCC. Using TaqMan genotyping assays, they analyzed four single-nucleotide polymorphisms within the HMGB1 gene in 246 patients: 2262G > A (rs1045411), 1177G > C (rs3742305), 3814C > G (rs2249825), and rs4540927. The 1177G > C polymorphism was associated with longer recurrence-free survival (p ¼ 0.000), but not overall survival (though a trend was noted of worse survival with the GG phenotype, p ¼ 0.104). Additionally, the 1177G > C variation was significantly associated higher histological nucleus grade (wild-type versus combined heterozygote and variant homozygote genotype, p ¼ 0.010), nodal metastasis (p ¼ 0.016), and higher clinical stage (p ¼ 0.030). Additionally, the 3814C > G variant was also significantly associated with nodal metastasis (wild-type versus combined heterozygote and variant homozygote genotype, p ¼ 0.019), and higher clinical stage (wild-type versus combined heterozygote and variant homozygote genotype, p ¼ 0.042). One study analyzed the role of HMGB1 in 166 nasopharyngeal carcinoma specimens from treatment-naive patients.36 HMGB1 was detected in 53.6% of the cases, primarily located in the nuclei and cytoplasm of carcinoma cells and a subset of fibroblasts. HMGB1 was positively correlated with T classification (p ¼ 0.01), N classification (p ¼ 0.003), distant metastasis (p ¼ 0.046), and clinical stage (p < 0.001). Additionally, HMGB1 expression correlated significantly with initial radiotherapy response in NPC patients (p ¼ 0.034). Prognostically, high HMGB1 expression was associated with a poor overall survival (p < 0.001) and disease-free survival (p < 0.001). No significant correlation was found between HMGB1 expression and gender, age, pathological classification, or local relapse. Liu et al37 studied 103 specimens from treatment-naive patients with HNSCC. Tumors were located at superglottic (N ¼ 29), glottic (N ¼ 63), subglottic (N ¼ 1), and hypopharyngeal (N ¼ 10) sites. HMGB1 protein was detected in 88.3%

Nguyen et al.

of cases, but only 43.75% of normal tumor-adjacent tissue controls (p < 0.001), with higher expression (staining graded as 6–7 out of 7) in 43.7% of tumor samples. HMGB1 overexpression was significantly associated with advanced clinical stage, including larger tumor size (p ¼ 0.001) and lymph node metastasis (p < 0.001), and recurrence (p < 0.001). No significant relationship was observed between HMGB1 level and age, alcohol history, smoking, tumor grade, and tumor site. Additionally, high HMGB1 expression was associated with shorter disease-free survival (p < 0.001) and overall survival (p < 0.001). HMGB1 was found to be an independent prognostic factor in HNSCC patients after tumor resection (hazard ratio, 2.133; 95% CI, 1.079–4.218). Further analysis of prognostic value of HMGB1 in patient subgroups demonstrated a high level of HMGB1 expression to be associated with shorter disease-free survival (p ¼ 0.005) and overall survival (p < 0.001) in late stage group (stage III / IV) patients.

Discussion Overall, there was high variation in the included studies, including sample size (range, 20–1210), presence of controls (range, 0 to 1:1 ratio), and methodology. The majority of studies included treatment-naive patients, with the exception of one study,41 in which neoadjuvant therapy was administered to a fraction of the included patients. Additionally, the total number of investigations is a current limiting factor in determining the true clinical values of HGMB1 and RAGE. We found no studies that investigate the diagnostic potential of RAGE, while only one study39 evaluated the diagnostic value of HMGB1. The low sensitivity of HMGB1 in the diagnosis of LSCC potentially makes HMGB1 a suboptimal marker. However, this study was limited in power (N ¼ 121) and by the small sample size of early-stage LSCC patients. Additionally, the multifaceted role of HMB1 and its broad expression likely contribute to its low diagnostic value. Further studies are required to elucidate the diagnostic value of both RAGE and HMGB1, including the possibility of use in conjunction with other markers to improve diagnostic ability. A total of four studies31–34 investigated the prognostic value of RAGE in head and neck cancers (OSCC, N ¼ 3; nasopharyngeal carcinoma, N ¼ 1). The interaction between HMGB1 and RAGE has been shown to stimulate tumor cell migration and invasion.23 Interestingly, Wild et al38 found tumor-infiltrating Tregs to express RAGE as well. Further in vitro analysis demonstrated HMGB1 to induce migration of Treg cells isolated from PBMC of patients with HSNCC. This indicates a possible role of tumor-derived HMGB1 in recruitment of Treg cells and, ultimately, suppression of T cell proliferation within the tumor microenvironment. According to the available literature reviewed in this article, RAGE appears to be a potential clinical indicator of tumor angiogenesis, differentiation, and staging. Two of the four studies determined RAGE to be correlated with angiogenesis, including tumor microvessel density31,33 and VEGF expression.31 While some inconsistencies among the studies existed, likely due to variation in study methodology, generally RAGE was correlated with some component of staging.31,33,34 Additionally, the International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

387


388

Clinical Value of HMGB1 and RAGE in Head and Neck Cancer analysis on polymorphisms in the RAGE gene34 may indicate the variants to be involved in tumor cell proliferation but not invasion and differentiation. Perhaps some potential exists for the polymorphisms to be used in assessment of risk. Larger studies are required to determine if RAGE is a clinically useful predictor of survival, and further confirm its prognostic value. Substantial evidence support the association of HMGB1 with clinic pathological characteristics of patients with head and neck cancers, including tumor angiogenesis and staging. Three of the seven studies investigating HMGB1 found high protein expression to be significantly associated with lower overall survival.36,37,39 Interestingly, Wu et al36 found high HMGB1 in late-stage nasopharyngeal carcinoma patients (i.e., stages III / IV), to be associated with significantly shorter overall survival when compared with patients with a low level of HMGB1 expression. Conversely, Hanakawa et al40 found HMGB1 to not be significantly associated with late neck metastasis in tongue SCC. This is suggestive of HMGB1 possibly being more valuable in determining the prognosis for late-stage patients. Furthermore, use of HMGB1 in combination with other clinic pathological indicators could improve the prognostic utility. Liu et al37 found the subset of patients with both high HMGB1 expression and positive lymph node metastasis had an even poorer disease-free survival (p < 0.001) and overall survival (p < 0.001) than that of others.

Final Comments

Nguyen et al. 4 Goodwin GH, Sanders C, Johns EW. A new group of chromatin-

5

6

7

8

9

10 11

12

13

14

The diagnostic value of HMGB1 in head and neck cancer, while not exhaustively investigated, may suffer from low sensitivity. No studies were found to evaluate the diagnostic value of RAGE. The demonstrated associations of HMGB1 and RAGE with clinic pathological characteristics of head and neck cancer patients offer a strong basis for further investigation into the prognostic value of both of these molecules. Early investigation has demonstrated HMGB1 to have definite potential as a predictor for survival, while RAGE has not been as extensively evaluated. Further studies are needed to confirm the clinical prognostic utility of both RAGE and HMGB1.

15

16

17

18

19

Acknowledgment This work was supported by research grant R01 HL116042 to DK Agrawal from the National Heart, Lung, and Blood Institute, NIH USA.

20

21

References

22

1 Czura CJ, Wang H, Tracey KJ. Dual roles for HMGB1: DNA binding

and cytokine. J Endotoxin Res 2001;7(4):315–321 2 Cheng BQ, Jia CQ, Liu CT, et al. Serum high mobility group box

chromosomal protein 1 is associated with clinicopathologic features in patients with hepatocellular carcinoma. Dig Liver Dis 2008;40(6):446–452 3 Lee H, Song M, Shin N, et al. Diagnostic significance of serum HMGB1 in colorectal carcinomas. PLoS ONE 2012;7(4):e34318 International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

23 24 25

associated proteins with a high content of acidic and basic amino acids. Eur J Biochem 1973;38(1):14–19 Pallier C, Scaffidi P, Chopineau-Proust S, et al. Association of chromatin proteins high mobility group box (HMGB) 1 and HMGB2 with mitotic chromosomes. Mol Biol Cell 2003;14(8): 3414–3426 Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 2005; 5(4):331–342 Zhang Z, Wang M, Zhou L, et al. Increased HMGB1 and cleaved caspase-3 stimulate the proliferation of tumor cells and are correlated with the poor prognosis in colorectal cancer. J Exp Clin Cancer Res 2015;34(1):51–60 Evans A, Lennard TW, Davies BR. High-mobility group protein 1 (Y): metastasis-associated or metastasis-inducing? J Surg Oncol 2004;88(2):86–99 Palumbo R, Sampaolesi M, De Marchis F, et al. Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol 2004;164(3):441–449 Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med 2004;255(3):320–331 Hori O, Brett J, Slattery T, et al. The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J Biol Chem 1995; 270(43):25752–25761 Nguyen AH, Berim IG, Agrawal DK. Chronic inflammation and cancer: emerging roles of triggering receptors expressed on myeloid cells. Expert Rev Clin Immunol 2015;11(7):849–857 Chuah YK, Basir R, Talib H, Tie TH, Nordin N. Receptor for advanced glycation end products and its involvement in inflammatory diseases. Int J Inflamm 2013;2013:403460 Schlueter C, Weber H, Meyer B, et al. Angiogenetic signaling through hypoxia: HMGB1: an angiogenetic switch molecule. Am J Pathol 2005;166(4):1259–1263 Srinivasan M, Banerjee S, Palmer A, et al. HMGB1 in hormonerelated cancer: a potential therapeutic target. Horm Cancer 2014; 5(3):127–139 Diener KR, Al-Dasooqi N, Lousberg EL, Hayball JD. The multifunctional alarmin HMGB1 with roles in the pathophysiology of sepsis and cancer. Immunol Cell Biol 2013;91(7):443–450 Sasahira T, Sasaki T, Kuniyasu H. Interleukin-15 and transforming growth factor alpha are associated with depletion of tumorassociated macrophages in colon cancer. J Exp Clin Cancer Res 2005;24(1):69–74 Luo Y, Chihara Y, Fujimoto K, et al. High mobility group box 1 released from necrotic cells enhances regrowth and metastasis of cancer cells that have survived chemotherapy. Eur J Cancer 2013;49(3):741–751 Kang R, Tang D, Schapiro NE, et al. The receptor for advanced glycation end products (RAGE) sustains autophagy and limits apoptosis, promoting pancreatic tumor cell survival. Cell Death Differ 2010;17(4):666–676 Taguchi A, Blood DC, del Toro G, et al. Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases. Nature 2000;405(6784):354–360 Campana L, Bosurgi L, Rovere-Querini P. HMGB1: a two-headed signal regulating tumor progression and immunity. Curr Opin Immunol 2008;20(5):518–523 Ellerman JE, Brown CK, de Vera M, et al. Masquerader: high mobility group box-1 and cancer. Clin Cancer Res 2007;13(10): 2836–2848 Kang R, Zhang Q, Zeh HJ III, Lotze MT, Tang D. HMGB1 in cancer: good, bad, or both? Clin Cancer Res 2013;19(15):4046–4057 Tang D, Kang R, Zeh HJ III, Lotze MT. High-mobility group box 1 and cancer. Biochim Biophys Acta 2010;1799(1–2):131–140 Kuniyasu H, Chihara Y, Kondo H, Ohmori H, Ukai R. Amphoterin induction in prostatic stromal cells by androgen deprivation is


Clinical Value of HMGB1 and RAGE in Head and Neck Cancer

26

27

28

29

30 31

32

33

associated with metastatic prostate cancer. Oncol Rep 2003;10(6): 1863–1868 Tarbé N, Evtimova V, Burtscher H, Jarsch M, Alves F, Weidle UH. Transcriptional profiling of cell lines derived from an orthotopic pancreatic tumor model reveals metastasis-associated genes. Anticancer Res 2001;21(5):3221–3228 Maeda S, Hikiba Y, Shibata W, et al. Essential roles of high-mobility group box 1 in the development of murine colitis and colitisassociated cancer. Biochem Biophys Res Commun 2007;360(2): 394–400 Leman ES, Madigan MC, Brünagel G, Takaha N, Coffey DS, Getzenberg RH. Nuclear matrix localization of high mobility group protein I(Y) in a transgenic mouse model for prostate cancer. J Cell Biochem 2003;88(3):599–608 Dolde CE, Mukherjee M, Cho C, Resar LM. HMG-I/Y in human breast cancer cell lines. Breast Cancer Res Treat 2002;71(3): 181–191 Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin 2015;65(1):5–29 Sasahira T, Kirita T, Bhawal UK, et al. The expression of receptor for advanced glycation end products is associated with angiogenesis in human oral squamous cell carcinoma. Virchows Arch 2007; 450(3):287–295 Landesberg R, Woo V, Huang L, et al. The expression of the receptor for glycation endproducts (RAGE) in oral squamous cell carcinomas. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008; 105(5):617–624 Tsuji A, Wakisaka N, Kondo S, Murono S, Furukawa M, Yoshizaki T. Induction of receptor for advanced glycation end products by EBV

34

35

36

37

38

39

40

41

Nguyen et al.

latent membrane protein 1 and its correlation with angiogenesis and cervical lymph node metastasis in nasopharyngeal carcinoma. Clin Cancer Res 2008;14(17):5368–5375 Su S, Chien M, Lin C, Chen M, Yang S. RAGE gene polymorphism and environmental factor in the risk of oral cancer. J Dent Res 2015; 94(3):403–411 Sasahira T, Kirita T, Oue N, et al. High mobility group box-1inducible melanoma inhibitory activity is associated with nodal metastasis and lymphangiogenesis in oral squamous cell carcinoma. Cancer Sci 2008;99(9):1806–1812 Wu D, Ding Y, Wang S, Zhang Q, Liu L. Increased expression of high mobility group box 1 (HMGB1) is associated with progression and poor prognosis in human nasopharyngeal carcinoma. J Pathol 2008;216(2):167–175 Liu Y, Xie C, Zhang X, et al. Elevated expression of HMGB1 in squamous-cell carcinoma of the head and neck and its clinical significance. Eur J Cancer 2010;46(16):3007–3015 Wild CA, Brandau S, Lotfi R, et al. HMGB1 is overexpressed in tumor cells and promotes activity of regulatory T cells in patients with head and neck cancer. Oral Oncol 2012;48(5):409–416 Qiu G, Li Y, Liu Z, Wang M, Ge J, Bai X. Clinical value of serum HMGB1 in diagnosis and prognosis of laryngeal squamous cell carcinoma. Med Oncol 2014;31(12):316 Hanakawa H, Orita Y, Sato Y, et al. Does HMGB1 predict occult neck lymph node metastasis in early tongue carcinoma? A case-control study of 26 patients. J Laryngol Otol 2014;128(10):926–931 Supic G, Kozomara R, Zeljic K, et al. HMGB1 genetic polymorphisms in oral squamous cell carcinoma and oral lichen planus patients. Oral Dis 2015;21(4):536–543

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

389


THIEME

390

Systematic Review

Supra-auricular versus Sinusectomy Approaches for Preauricular Sinuses Mohammad Waheed El-Anwar1

Ahmed Shaker ElAassar1

1 Department of Otorhinolaryngology - Head and Neck Surgery, School

of Medicine, Zagazig University, Zagazig, Egypt Int Arch Otorhinolaryngol 2016;20:390–393.

Abstract

Keywords

► recurrence ► preauricular fistulae ► facial nerve

Introduction Several surgical techniques and modifications have been described to reduce the high recurrence rate after excision of preauricular sinus. Objectives The aim of this study is to review the literature regarding surgical approaches for preauricular sinus. Data Synthesis We performed searches in the LILACS, MEDLINE, SciELO, PubMed databases and Cochrane Library in September, 2015, and the key words used in the search were “preauricular sinus,” “sinusectomy,” “supra-auricular approach,” “methylene blue,” and/or “recurrence.” We revised the results of 17 studies, including 1270 preauricular sinuses that were surgically excised by sinusectomy in 937 ears and by supra-auricular approach in 333 ears. Recurrence with supra-auricular was 4 (1.3%) while sinusectomy was 76 (8.1%) with significant difference (p < 0.0001). There were no reported facial nerve paresis or paralysis in any of the approaches. The sinusectomy approach showed significantly more complications (p ¼ 0.0048). Conclusion Supra-auricular approach had significantly less recurrence rate than tract sinusectomy approaches. Thus, it could be regularly chosen as the standard procedure for preauricular sinus excision. As such, it would be helpful for surgeons to be familiar with this approach.

Introduction Preauricular sinuses (pits) are common congenital abnormalities that were first described in 1864 by Heusinger.1,2 The malformation is associated with either a defect in the first branchial arch development during the sixth week of gestation3 due to incomplete fusion of the six auditory hillocks of His, or with the sinus developing during embryonal auricular development from an isolated ectodermal folding, a less accepted hypothesis.2 Classically, a preauricular sinus presents as a small opening, usually near the anterior limb of the ascending helix, although most preauricular sinuses are found anterior to the external auditory canal.2 A small percentage has been reported and located in other areas such as the superopos-

received October 26, 2015 accepted February 1, 2016 published online April 26, 2016

Address for correspondence Mohammad Waheed El-Anwar, MD, Department of Otorhinolaryngology - Head and Neck Surgery, School of Medicine, Zagazig University, Zagazig, Zip code 0020552309843, Egypt (e-mail: mwenteg@yahoo.com).

DOI http://dx.doi.org/ 10.1055/s-0036-1583305. ISSN 1809-9777.

terior edge of the helix, the tragus, the lobule, the ascending helix crus, supra-auricular area, and the postauricular area.4–8 Preauricular sinuses are usually asymptomatic, isolated, and require no treatment. However, if infected, these sinuses become painfully swollen with offensive discharge. Given that preauricular sinuses may be associated with hearing and renal anomalies, auditory testing and renal ultrasound are useful in patients presenting associated syndromes.9–11 Complete excision of the sinus sac or fistula is ideal in treatment.1,6 However, even if excision is performed by experienced surgeons, recurrence can still occur after excision.4 Several surgical techniques have been used for total excision of preauricular sinuses to avoid recurrence:

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil


Supra-auricular versus Sinusectomy Approaches for Preauricular Sinuses Sinusectomy Approaches (a) Classic simple sinusectomy using lacrimal probe. Under general or local anesthesia, an elliptical incision is done parallel to the edge of the anterior helix including the sinus opening. Gentle probing with a blunt ended malleable probe is done first to delineate the extent and presence of multiple ramifications. All ramifications are meticulously dissected and totally excised.12 (b) Classic simple sinusectomy using methylene blue. Elliptical incision is done parallel to the edge of the anterior helix including the sinus opening. Methylene blue injection is used as a guide for tracing and excising the complete sinus, including its surrounding soft tissue.13 (c) Classic simple sinusectomy using microscopy or magnifying glasses (inside-out technique). This technique was first described in 2005 by Baatenburg de Jong,14 but was first introduced by Jesma in Rottendam in the 1970s (not published at that time). This method involves a small elliptical incision around the sinus pit. Stay sutures are placed to facilitate dissection of the tract and the sinus is opened. The sinus tract and its branches are then followed from the inside and outside.15

Supra-auricular Approaches (a) Parasad technique of supra-auricular approach. The elliptical incision used is extended down to the superior end of the tragus and up parallel to the anterior edge of the anterior helix. The incision is deepened till the temporalis fascia is identified as a medial limit of the dissection. The dissection continues over the cartilage of the anterior helix. The base of the sinus attached to the perichondrium of the anterior helix is excised with the perichondrium to ensure complete excision of the epithelial lining.12 (b) Fig. 8 incision with extended fistulectomy. For cases with fistulae formation, Huang et al13 performed the Fig. 8 incision with extended fistulectomy under general anesthesia. This surgical method consists of two wedge incisions: one includes the sinus opening and the other includes the abscess openings and surrounding necrotic skin. The surgeon then elevates the skin flap and dissects along the perichondria of the ear down to the temporalis fascia and removes all of the inflamed tissue en bloc, including the sinus or fistula tract. The use of microscopy or glasses in this technique is an option. The Fig. 8 incision method can preserve more intact skin than the large wedge excision can, attaining a better cosmetic result.13 The aim of this study was to review, collect, and analyze the published results of each technique.

Review of Literature We conducted a search in the LILACS, MEDLINE, SciELO, PubMed, and Cochrane Library databases in September 2015, and used “preauricular sinus,” “sinusectomy,” “supra-auricular approach,” “methylene blue,” and/or “recurrence.” We searched for studies published after 2001.

El-Anwar, ElAassar

We collected all methods of preauricular tract(s) identification and excision and their modifications and referred to them as sinusectomy approaches. We also gathered studies that used the supra-auricular approach as described by Prasad et al, referring to them as supra-auricular approaches. We collected, tabulated, and analyzed the results. Then, we performed a statistical analysis and comparison using SPSS 14.0 statistical software for Windows (SPSS Inc., Chicago, IL). The significance level was set at p less than 0.05. We revised seventeen studies and the results of 1270 surgically excised preauricular sinuses: 937 by sinusectomy techniques and 303 by supra-auricular approach (►Table 1).4,12–27 Recurrence with supra-auricular was 4 (1.2%) and with sinusectomy was 76 (8.1%) with a highly significant difference (X2 ¼ 19.874; p < 0.0001) (►Table 2). None of the approaches reported major complications such as facial nerve paresis or paralysis. Of the sinusectomy approach cases, there were 4 dehiscent wounds (0.43%), 10 infections (1.06%), 14 bad scars (1.5%) documented, whereas only one operated preauricular sinus (0.3%) by supra-auricular approach reported infection with no scar or wounds. Total reported complications resulting from the sinusectomy approach was 28 ears (3%) and one ear (0.3%) from the supra-auricular approach. Therefore, the sinusectomy approach showed significantly more complications (X2 ¼ 7.955; p ¼ 0.0048).

Discussion Recurrence after excision of preauricular sinus is a result of incomplete excision of the sinus tract and presence of residual viable squamous epithelium.28 The real problem in the surgical removal of preauricular sinus is the high recurrence rate following sinusectomy techniques due to tortuous tract course12 and the high variability and number of sinus ramifications,12,24 particularly of the terminal ramifications, which are difficult for the surgeon to follow,12 and especially upwards and medially.24 Furthermore, infectious episodes, possibly with abscess, can induce scars that further alter the sinus route and courses.18 Recurrences result from the difficulty during sinusectomy to follow the tract and its branches. Pre- and intraoperatory precautions are often not sufficient to guarantee there is no recurrence, which remains high.17 Although there are several tools and methods used for proper tract(s) identification, such as the use of methylene blue, probing, microscope, or magnifying glasses.14,15 Nonetheless, recurrence remains of significant concern. Based on the theory that a preauricular fistula is almost always found in subcutaneous tissues between the temporalis fascia and perichondrium of the helical cartilage, the supraauricular approach proposed by Prasad et al in 1990 is assumed to have a lower recurrence risk.17 The supra-auricular technique is based on identification of the temporalis fascia (medial border of the dissection) and the cartilage of the helix and auditory canal (posterior border of the dissection). Subsequently, the surgeon performs an en bloc resection of the sinus,16 removing all subcutaneous tissue between the temporalis fascia and the helix through a postauricular International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

391


392

Supra-auricular versus Sinusectomy Approaches for Preauricular Sinuses

El-Anwar, ElAassar

Table 1 Recurrence among different studies Study

Year

Number of ears/ approach Sinusectomy or its modifications

Supra auricular

Lam et al12

2001

25

8

27

1

2005

36

0

2005

40

2

2006

206

10

2007

30

10

33

3

2007

73

10

2008

6

0

Vijayendra

16

Baatenburg de Jong14 Yeo et al

4

Hassan and Samir Tang et al18 Leopardi et al

19 20

2009

77

2

2012

101

0

2013

208

5

2013

79

8

30

0

2013

30

3

2013

34

0

2014

15

0

2014

51

0

26

2015

112

18

27

2015

57

0

Bhandary et al Bae et al21 Gan et al15 Huang et al

13

Tariq et al22 Kavuturu et al Mundra et al

23

24

Bhandari et al25 Goel et al Yoo et al

17

Recurrence

extended incision. Thus, there is no need to identify the entire sinus tract and its branches.12,17 Thereafter, Lam et al,12 in his comparative study, found a significant difference in recurrence rates between the classic sinusectomy technique and the supra-auricular approach (32% and 3.7%, respectively). We analyzed the published operated preauricular cases since Lam et al12 and collectively found that recurrence rate was 4/333 (1.2%) with the supra-auricular approach, and 76/937 (8.1%) with various sinusectomy approaches with statistically significant difference in favor of the supraauricular approach (►Table 2). Even though, the sinusectomy relied on magnification,25 which was not employed in any previous study on the supraauricular approach, recurrence was significantly minimized12,17 and even not encountered16,19,21,23–25 after the supra-auricular approach. This demonstrates that the supra-auricular approach is highly effective and successful.

The supra-auricular approach was also described as a simple, less time consuming approach and shows fewer difficulties12,16,17,19,24,29 because it does require the surgeon to isolate and follow the sinus branches, as in the sinusectomy technique and its modifications but simply identify a surgical plane such as the temporalis fascia.25 Moreover, it carries a risk of injury of the facial nerve or any important structure, with a low risk of scar formation. That is why our statistical analysis of reported complications detected that the supraauricular approach causes significantly (p ¼ 0.0048) less complications (0.3%) than sinusectomy (3%). Since this kind of surgery is often performed by relatively inexperienced surgeons, the supra-auricular approach may represent a further guarantee of preventing recurrences as it does not require a learning curve. It is less time consuming and can be done under local anesthesia The supra-auricular approach is simple, effective, with negligible recurrence. Thus, it is better to be used regularly

Table 2 Statistical analysis of recurrence rate difference between supra-auricular and sinusectomy approaches Approach

Number of ears

Recurrence

Chi square test

p value

Supra auricular

333

4 (1.2%)

19.874

< 0.0001 HS

Sinusectomy or its modifications

937

76 (8.1%)

Abbreviations: HS; highly significant. International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016


Supra-auricular versus Sinusectomy Approaches for Preauricular Sinuses as a standard procedure for preauricular sinus excision, especially because it has shown no significant complications and less post-operative scar formation18 with no need for extra tools as microscope and loops. Moreover, it is the ideal technique for recurrent cases or cases undergoing sinusectomy after abscess incision and drainage. Studies to compare supra-auricular approach and sinusectomy approaches for preauricular sinus excision in bilateral cases by the same surgeon are still needed.

Final Comments Supra-auricular approach had a significantly lower recurrence rate than tract sinusectomy approaches. Thus, it is a good option as a standard procedure for preauricular sinus excision, It is especially useful as an alternative in cases where the sinusectomy approaches are difficult to be performed. Therefore, it would be helpful for surgeons to be familiar with this approach.

11

12

13

14 15

16

17

Conflict of Interest and Financial Disclosure Statement The authors declare no financial support or conflict of interest in this study.

18

19

References

20

1 Scheinfeld NS, Silverberg NB, Weinberg JM, Nozad V. The preaur-

2

3 4

5

6

7 8 9

10

icular sinus: a review of its clinical presentation, treatment, and associations. Pediatr Dermatol 2004;21(3):191–196 Tan T, Constantinides H, Mitchell TE. The preauricular sinus: A review of its aetiology, clinical presentation and management. Int J Pediatr Otorhinolaryngol 2005;69(11):1469–1474 Nofsinger YC, Tom LWC, LaRossa D, Wetmore RF, Handler SD. Periauricular cysts and sinuses. Laryngoscope 1997;107(7):883–887 Yeo SW, Jun BC, Park SN, et al. The preauricular sinus: factors contributing to recurrence after surgery. Am J Otolaryngol 2006; 27(6):396–400 Chami RG, Apesos J. Treatment of asymptomatic preauricular sinuses: challenging conventional wisdom. Ann Plast Surg 1989; 23(5):406–411 Choi SJ, Choung YH, Park K, Bae J, Park HY. The variant type of preauricular sinus: postauricular sinus. Laryngoscope 2007; 117(10):1798–1802 Minkowitz S, Minkowitz F. Congenital aural sinuses. Surg Gynecol Obstet 1964;118:801–806 Chang PH, Wu CM. An insidious preauricular sinus presenting as an infected postauricular cyst. Int J Clin Pract 2005;59(3):370–372 Kumar S, Marres HA, Cremers CW, Kimberling WJ. Autosomaldominant branchio-otic (BO) syndrome is not allelic to the branchio-oto-renal (BOR) gene at 8q13. Am J Med Genet 1998;76(5): 395–401 Fraser FC, Aymé S, Halal F, Sproule J. Autosomal dominant duplication of the renal collecting system, hearing loss, and external ear

21

22 23

24

25

26 27 28

29

El-Anwar, ElAassar

anomalies: a new syndrome? Am J Med Genet 1983;14(3): 473–478 Clementi M, Mammi I, Tenconi R. Family with branchial arch anomalies, hearing loss, ear and commissural lip pits, and rib anomalies. A new autosomal recessive condition: branchio-otocostal syndrome? Am J Med Genet 1997;68(1):91–93 Lam HCK, Soo G, Wormald PJ, Van Hasselt CA. Excision of the preauricular sinus: a comparison of two surgical techniques. Laryngoscope 2001;111(2):317–319 Huang WJ, Chu CH, Wang MC, Kuo CL, Shiao AS. Decision making in the choice of surgical management for preauricular sinuses with different severities. Otolaryngol Head Neck Surg 2013;148(6): 959–964 Baatenburg de Jong RJ. A new surgical technique for treatment of preauricular sinus. Surgery 2005;137(5):567–570 Gan EC, Anicete R, Tan HK, Balakrishnan A. Preauricular sinuses in the pediatric population: techniques and recurrence rates. Int J Pediatr Otorhinolaryngol 2013;77(3):372–378 Vijayendra H, Sangeetha R, Chetty KR. A safe and reliable technique in the management of preauricular sinus. Indian J Otolaryngol Head Neck Surg 2005;57(4):294–295 Mohamed EG. Hassan, Ayman Samir. Pre-Auricular sinus: comparative study of two surgical techniques. Ann Pediatr Surg 2007; 3:139–143 Tang IP, Shashinder S, Kuljit S, Gopala KG. Outcome of patients presenting with preauricular sinus in a tertiary centre—a five year experience. Med J Malaysia 2007;62(1):53–55 Leopardi G, Chiarella G, Conti S, Cassandro E. Surgical treatment of recurring preauricular sinus: supra-auricular approach. Acta Otorhinolaryngol Ital 2008;28(6):302–305 Bhandary S, Singh RK, Karki P, Sharma SK, Chettri ST. Preauricular sinus: Prospective study of clinical course and associations. Gujarat Journal of Otorhinolaryngology and Head & Neck Surgery 2009;6(2):6–9 Bae SC, Yun SH, Park KH, et al. Preauricular sinus: advantage of the drainless minimal supra-auricular approach. Am J Otolaryngol 2012;33(4):427–431 Tariq M, Murtaza G, Akram A, Bashir T. Pre-Auricular sinus and its microsurgical excision. Esculapio 2013;9(3):123–125 Kumar Chowdary KV, Sateesh Chandra N, Karthik Madesh R. Preauricular sinus: a novel approach. Indian J Otolaryngol Head Neck Surg 2013;65(3):234–236 Mundra RK, Sinha R, Agrawal R. Supra-auricular approach: a simple recurrence-free technique for pre-auricular sinus. EJNSO 2014;1(1):11–15 Bhandari R, Limbu TR, Parajuli R, Thapa S. Auricular dissection method for treatment of preauricular sinus. Journal of Chitwan Medical College 2014;4(9):21–24 Goel AK, Sylonia SC, Garg A, Rattan K. Preauricular sinus: When to operate? Indian Journal of Otology 2011;17(2):63–65 Yoo H, Park DH, Lee J, Park MC. A Surgical Technique for congenital preauricular sinus. Arch Craniofac Surg 2015;16(2):63–66 Kumar KK, Narayanamurthy VB, Sumathi V, Vijay R. Preauricular sinus: Operating microscope improves outcome. Indian J Otolaryngol Head Neck Surg 2006;58(1):6–8 Prasad S, Grundfast K, Milmoe G. Management of congenital preauricular pit and sinus tract in children. Laryngoscope 1990; 100(3):320–321

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

393


THIEME

394

Systematic Review

Treatment and Prognosis of Facial Palsy on Ramsay Hunt Syndrome: Results Based on a Review of the Literature Rafael da Costa Monsanto1 Aline Gomes Bittencourt1,2 Natal José Bobato Neto1 Silvia Carolina Almeida Beilke1 Fabio Tadeu Moura Lorenzetti1,2 Raquel Salomone1,2 1 Department of Otolaryngology, Banco de Olhos de Sorocaba

Hospital, Sorocaba, São Paulo, Brazil 2 Department of Otolaryngology, School of Medicine, Universidade de São Paulo, São Paulo, Brazil

Address for correspondence Rafael da Costa Monsanto, MD, Centro de Estudos - Departamento de Otorrinolaringologia do Banco de Olhos de Sorocaba (BOS), Praça Nabek Shiroma, 210, Jardim Emília, Sorocaba/SP, Zip code 18031-060, Brazil (e-mail: rafaelmonsanto@hotmail.com).

Int Arch Otorhinolaryngol 2016;20:394–400.

Abstract

Keywords

► prognosis ► facial palsy ► ramsay hunt syndrome ► varicela zoster ► house-brackmann

Introduction Ramsay Hunt syndrome is the second most common cause of facial palsy. Early and correct treatment should be performed to avoid complications, such as permanent facial nerve dysfunction. Objective The objective of this study is to review the prognosis of the facial palsy on Ramsay Hunt syndrome, considering the different treatments proposed in the literature. Data Synthesis We read the abstract of 78 studies; we selected 31 studies and read them in full. We selected 19 studies for appraisal. Among the 882 selected patients, 621 (70.4%) achieved a House-Brackmann score of I or II; 68% of the patients treated only with steroids achieved HB I or II, versus 70.5% when treated with steroids plus antiviral agents. Among patients with complete facial palsy (grades V or VI), 51.4% recovered to grades I or II. The rate of complete recovery varied considering the steroid associated with acyclovir: 81.3% for methylprednisolone, 69.2% for prednisone; 61.4% for prednisolone; and 76.3% for hydrocortisone. Conclusions Patients with Ramsay-hunt syndrome, when early diagnosed and treated, achieve high rates of complete recovery. The association of steroids and acyclovir is better than steroids used in monotherapy.

Introduction Ramsay Hunt syndrome (RHS) is an infectious disease caused by the varicella zoster virus (VZV).1 The main clinical symptoms are facial palsy, inner ear dysfunction, periauricular pain, and herpetiform vesicles on the pinna. J. Ramsay Hunt, in 1907, was the first author to describe the disease, which now represents the second most common cause of peripheral facial palsy. The incidence of RHS is 5 cases/100,000 people.2 It affects mostly patients between the ages of 20 and 30, with no gender predilection.1 Spontaneous remission of the facial

received March 17, 2016 accepted April 12, 2016 published online May 30, 2016

DOI http://dx.doi.org/ 10.1055/s-0036-1584267. ISSN 1809-9777.

palsy caused by VZV occurs only in a few cases - without proper treatment, only 20% achieve complete recovery.3 The physiopathological mechanism is the reactivation of the VZV in the geniculate ganglion, with subsequent inflammation, edema, and compression of the VII cranial nerve.2 Viral demyelination may also contribute to further damage of the nerve.3,4 A viral prodrome or an upper respiratory tract infection might be the first symptoms,5 evolving into severe pain in the pinna, acute facial hypotonia, and a herpetiform vesicular eruption on the pinna, external acoustic meatus, face, tongue, hard palate, neck, larynx, and oral mucosa.2

Copyright © 2016 by Thieme Publicações Ltda, Rio de Janeiro, Brazil


Prognosis of Facial Palsy on Ramsay Hunt Syndrome Cochleovestibular impairment such as hypoacusis, tinnitus, and vertigo may occur. The involvement of other cranial nerves, such as V, IX, X, XI, and XII is rare.1,6–8 Permanent facial deformity and other possible sequelae of RHS substantially impact patientś social life. Thus, early diagnosis and treatment of this clinical entity is essential to avoid such sequels.6 Another clinical presentation of the disease is the “Ramsay Hunt syndrome sine herpete,” characterized by peripheral facial paralysis without ear or mouth rash, and the presence of either a 4-fold rise in antibody to VZV or the detection of VZV DNA in skin, blood mononuclear cells, or middle ear fluid. Thus, some patients diagnosed with idiopathic facial palsy could be suffering from zoster sine herpete.9,10 The objective of this study was to evaluate the prognosis of facial palsy in RHS after different treatments proposed in the literature, and to determine the best treatment option for these patients.

Materials and Methods We performed a systematic review of the literature. The Ethics Committee of the Banco de Olhos de Sorocaba hospital approved this manuscript. We searched the LILACS, SciELO, and PUBMED databases from January to June 2015. The keywords used were: (Ramsay AND hunt) OR (“varicella”) AND (“facial paralysis” OR (“facial” AND “paralysis”) OR “facial paralysis” OR (“facial nerve” OR (“facial” AND “nerve”). Additional filters used were: period of publication: 1995–2014; human subjects; with abstracts available; Spanish, English, and Portuguese languages. We read the resulting studies in full, and the criteria for study selection were as follows:

a) Inclusion Criteria – Case reports and prospective and retrospective studies referring to the prognosis and treatment of facial palsy in RHS.

b) Exclusion Criteria – Studies of patients with tumors; traumatic lesions; ear infections; diseases that cause recurrent facial palsy; facial paralysis secondary to intracranial lesions such as cerebrovascular disease. – Studies that did not classify the facial palsy on the HouseBrackmann (HB) scale. – Studies of patients with RHS that did not mention the type of treatment, results, or prognosis. ►Fig. 1 shows a flowchart of the decision process regarding the study selection.

Review of the Literature

Monsanto et al.

patients with facial paralysis caused by RHS1–8,11–17 (►Table 1). The duration of follow-up extended from 73 days to one year among the different studies. Out of the 882 patients described in these studies, 829 (93.99%) had facial palsy grades III to VI on the HB scale. Following treatment, 621 out of the 882 (70.4%) achieved a score of I–II on the HB scale (“good prognosis”). Regarding the HB graduation before treatment, 53 (6%) were HB II, 150 (17%) HB III, 289 (32.7%) HB IV and 390 (44.2%) HB V or VI. After treatment, 621 (70.4%) achieved HB I or II and 261 (29.6%) achieved HB III, IV, or V. All of the patients were treated with steroids1–8,11–17; however, Furuta et al7 only administered them to patients with facial palsy grades IV–VI at the initial examination. Antiviral agents were used in all patients, in exception of the 47 patients described in Kinishi et al’s study.14 These authors conducted a clinical trial in which 91 patients were treated with steroids (methylprednisolone, 500 mg on day 1, 250 mg on days 2 and 3, and 100 mg/d for 3 days thereafter), aciclovir (4000 mg/d for 7 days), dextran (500 mL/d for 7 days), vitamins B6 and B12 and peripheral vasodilators; another 43 patients received the same treatment but without the antiviral. Among the patients that received acyclovir, 85 (93.4%) achieved a good prognosis for facial palsy (HB I or II), compared with only 32 (68%) of the group that did not receive the antiviral agent (p < 0.05). Some authors treated patients with other drugs or therapies, such as dextran (500 mL for 7 days),6,14 peripheral vasodilators,6 adenosine triphosphate (ATP),14 and vitamins B6 and B12.14 The rate of complete recovery regarding the type of steroid associated with acyclovir varied among the studies.1,4,7,11,14–17 Regarding the patients treated with prednisone, 290 out of the 419 patients (69.2%) achieved a good prognosis; among the 192 patients treated with prednisolone, 118 (61.4%) achieved facial palsy HBI or II, versus 29 out of the 38 (76.3%) that received hydrocortisone, and 118 of the 145 (81.3%) patients treated with methylprednisolone. These results are presented in ►Table 2. Some studies6,16 compared the facial nerve recovery rate in patients with and without metabolic diseases. Patients with diabetes mellitus achieved worse recovery rates than patients without systemic diseases (p < 0.05). Patients older than 60 years with RHS had a delayed recovery of the facial nerve when compared with younger patients (p < 0.05),6,14 probably due to a less efficient cellular immune system, rather than a reduction in humoral immunity.8 Nonetheless, the Uri et al11 study did not evidence differences in the prognosis of facial palsy according to age and gender. Regarding the prognostic factors, the association between facial palsy and cochleovestibular impairment has worse prognosis than isolated facial nerve palsy (p ¼ 0.029).11 Shim et al,15 in a case-control study, observed that the recovery of the facial paralysis was worse when associated with impairment of other cranial nerves, regardless of the initial grade on the HB scale (p < 0.05).15

Results The database search resulted in 259 studies. After reading all the resulting manuscripts in full by two of the authors, we selected 19 studies for appraisal, and included 13 in the quantitative analysis. The studies included a total of 882

Discussion Ramsay Hunt syndrome is responsible for 12% of cases of facial paralysis, with a worse prognosis than Bell’s palsy.11 International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

395


396

Prognosis of Facial Palsy on Ramsay Hunt Syndrome

Monsanto et al.

Fig. 1 Flowchart of the decision criteria involved in the selection of the studies.

Other pathologic changes include damage of the Corti organ and Scarpa ganglion, leading to hearing loss and vertigo.4 Although previous studies have reported a 10% recovery rate of patients with complete facial palsy even with correct treatment,11 in our study, 51.4% of patients with facial palsy graded as HB V to VI treated with steroids plus antiviral agents achieved HB I or II. Treatment of RHS involves high doses of steroids and virostatic agents, especially acyclovir. The drugs, dosages, and period of treatment used by each author are described in ►Table 1. Even though the antiviral agents might theoretically cause several damaging effects, the number of the adverse effects on the selected studies was not significant.3 International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

Some authors treated patients with other drugs or therapies, such as dextran (500 mL for 7 days),6,14 peripheral vasodilators,6 adenosine triphosphate (ATP),14 and vitamins B6 and B12.14 However, many studies did not report the dosage, time of treatment, or period between the initial symptoms of facial palsy and treatment. Thus, it was difficult to define a treatment protocol and to compare the success of the treatments. For comparison purposes, “good prognosis” (adequate response to treatment) was considered when the HB grade increased to I or II after treatment. The percentage of patients with a good prognosis varied from 61.1% to 100% in the different studies.1,2,4,6,11,16,17 In our data, 621 out of the 882 patients (70.4%) achieved HB I or II.1,2,4,6–8,11–17


Prognosis of Facial Palsy on Ramsay Hunt Syndrome Regarding the different treatment regimens proposed, 68% of the patients with III to VI on the HB scale achieved a good prognosis when treated with steroids without the antiviral agent,14 versus 70.5% of patients treated with steroids plus

Monsanto et al.

antiviral agents.1,2,4,6–8,11–17 More specifically, 51.4% of the patients with facial palsy grade V and VI completely recovered the facial motor function (HB I or II)1–3,7,8,11–13,15–17 when treated with steroids plus antiviral agents.

Table 1 Results regarding the evolution of the facial nerve function obtained by different authors on patients with Ramsay Hunt syndrome, by using different treatments Authors

No. of patients

HB scale and patients BT

AT

Ryu et al16

155

HB III – 24

HB I or II – 22

HB IV – 53

HB I or II – 35

HB V or VI – 78

HB I or II – 34

HB III – 1

HB I – 1

HB IV – 8

HB HB HB HB

HB V – 6

HB II – 3 HB V – 3

Zainine et al4

15

I–4 II – 2 III – 1 IV – 1

Treatment

Follow-up

Patients with HB I or II AT

Prednisolone (80 mg oral methylprednisolone per day for 4 days, 60 mg/d for 2 days, 40 mg/d for 2 days, 20 mg/d for 2 days, and 10 mg/d for 5 days); Acyclovir (4000 mg/d for 7 days)

3 months

91 (58.7%)

Hydrocortisone (100 mg 3x/day IV for 8 days) Acyclovir (4000 mg/d PO for 8 days)

8 months

10 (66.6%)

Kansu et al12

01

HB V – 1

HB IV – 1

Corticosteroid (1 mg/kg/d) Acyclovir (90 mg/kg/d)

4 months

00 (0%)

Donati et al2

01

HB V – 1

HB I – 1

Oral valacyclovir (3 g/day, lowered to 1.5 g/day after 1 week) and prednisone 50 mg/day. On day 66–methylprednisolone (1 g/day I.V. for 5 days.

248 days

02 (100%)

01

HB V – 1

HB I – 1

Oral acyclovir (800 mg/day) for 10 days and prednisone 75 mg/d. On day 37–methylprednisolone, 1 g/day I.V. for 3 days

73 days

339

HB II – 40

HB I – 33 HB II – 7

6 months

225 (66.3%)

HB III – 95

HB I – 52 HB II – 34 HB III – 9

Prednisone (1 mg/kg/d orally for 4 days, tapered to zero until day 10) Acyclovir (400 mg/8h for 5 days)

HB IV – 137

HB HB HB HB

I – 30 II – 52 III – 26 IV – 29

HB V – 67

HB HB HB HB HB

I- 12 II – 5 III – 21 IV – 13 V – 16

HB II – 5

HB I – 5

09 (81.8%)

HB II – 1

HB IV – 2

HB II – 2

HB V – 3

HB II – 1 HB III – 2

Steroids (40 to 60 mg of prednisolone, or 48 mg of methylprednisolone, orally, for 10 to 37 days Acyclovir (750 to 4800 mg, intravenously, for 5 to 12 days)

6 months

HB III – 1

Shim et al17

Kim et al13

11

(Continued)

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

397


398

Prognosis of Facial Palsy on Ramsay Hunt Syndrome

Monsanto et al.

Table 1 (Continued) Authors

No. of patients

HB scale and patients BT

AT

Boemo et al1

54

HB II – 4

HB I – 4

HB III – 8

HB I – 8

HB IV – 20

HB I – 10 HB III – 8 HB IV – 2

HB V – 22

HB HB HB HB

I–3 II – 8 III – 6 IV – 5

Treatment

Follow-up

Patients with HB I or II AT

Acyclovir 250 mg/8h and methylprednisolone 120 mg/d IV for 48h; then acyclovir 850 mg/8h for 10 days and methylprednisolone 30mg/d orally, in a decreasing dosage for 16 days

6 months

33 (61.1%)

Gondivkar et al8

01

HB V – 1

HB I – 1

Initial dose of acyclovir and steroids I.V., and a 2-week course of oral acyclovir and steroids after discharge; Transcutaneal electrical nerve stimulation and facial neuromuscular exercise.

5 weeks

01 (100%)

Yeo et al6

26

HB II – 3

HB I – 2 HB II – 1

6 months

22 (84.6%)

HB III – 13

HB I – 7 HB II – 4 HB III – 2

HB IV – 10

HB HB HB HB

Prednisolone (1 mg/kg/d IV for 5 days; then, the dose was tapered for another 5 days); Acyclovir (5 mg/kg/8h IV for 5 days); Famciclovir (500 mg orally for 7 days, after the 5-day cycle of acyclovir); Dextran; Peripheral vasodilators.

HB II – 1

HB I – 1

6 months

27 (72.9%)

HB III – 3

HB I – 3

HB IV – 9

HB I – 9

HB V – 17

HB HB HB HB

I–9 II – 2 III – 5 IV – 1

HB VI – 7

HB HB HB HB

I–2 II – 1 III – 1 IV – 3

Acyclovir (4000 mg in tablet form or 750 mg per day by infusion) or valacyclovir (3000 mg in tablets) was administered to all patients for 5 to 7 days. Patients with grade IV to VI facial paralysis were usually given 40 to 60 mg prednisone for 4 days.

HB IV – 3

HB I – 2 HB III – 1

1 year

19 (82.6%)

HB V – 2

HB I – 2

HB VI – 18

Acyclovir (5 mg/kg/8h intravenously for 7 days) Hydrocortisone (100 mg/8h intravenously for 7 days)

HB HB HB HB HB

Furuta et al7

Uri et al11

37

23

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

I–4 II – 4 III – 1 IV – 1

I – 11 II – 4 III – 1 IV – 1 V–1


Prognosis of Facial Palsy on Ramsay Hunt Syndrome

Monsanto et al.

Table 1 (Continued) Authors

No. of patients

HB scale and patients BT

AT

Kinishi et al14

91

HB III – 2

HB I – 82

HB IV – 17

HB II – 3

47

Murakami et al15

Total

80

882

HB V – 33

HB III – 5

HB VI – 39

HB IV – 1

HB III – 2

HB I – 30

HB IV – 9

HB II – 2

HB V – 17

HB III – 10

HB VI – 19

HB IV – 5

HB III – 1

HB I – 1

HB IV – 21

HB I – 17 HB II – 2 HB III – 2

HB V – 38

HB HB HB HB

HB VI – 20

HB I – 4 HB II – 9 HB III – 7

Treatment

Follow-up

Patients with HB I or II AT

Dextran (500 mL, for 7 days) Methylprednisolone (500 m on day 1, 250 mg on days 2 and 3 and 100 mg for 4 days thereafter Adenosine triphosphate (ATP) and vitamins B6 and B12 Acyclovir, 4000 mg/d, 7 days

6 months

85 (93.4%)

The same protocol described above, but without the acyclovir

I – 20 II – 12 III – 5 IV – 1

32 (68%)

Prednisone (1 mg/kg/d, orally or intravenously for 5 days; then, tapered to zero over the following 10 days); Acyclovir (250 mg/8h for 7 days intravenously or 800 mg 5 times/d orally, for 7 days)

1 year

65 (81.25%)

621 (70.4%)

Abbreviation: AT, after treatment; BT, before treatment; HB, graduation on the House-Brackmann facial palsy scale.

Kinishi et al14 compared the evolution of patients with facial palsy due to RHS treated with corticosteroids with or without antiviral agents. They demonstrated better evolution of patients treated with methylprednisolone and acyclovir (93.4% versus 68% of the patients who did not receive acyclovir) (p < 0.01). De Ru et al3 demonstrated an oddsratio (OR) for a complete recovery of the facial palsy of 5.5 (95% confidence interval [95% CI] ¼ 1.6–18.8) with antiviral

agents, 2.9 (95% CI ¼ 1.6–5.4) with steroids in monotherapy, and 8.4 (95% CI ¼ 3.7–18.9) when both treatments were combined, when compared with no treatment at all. The OR of the combined therapy versus only steroids was 2.8 (95% CI ¼ 1.3–5.8). Although the studies used different kinds of steroids, dosages, and periods of treatment, the treatment proposed by Kinishi et al14 (methylprednisolone at 500 mg on day 1, 250 mg on days 2 and 3, and 100 mg for 4 days

Table 2 Number of patients that achieved a good prognosis of the facial palsy, according to the different classes of steroids associated to acyclovir

Ryu et al16 Zainine et al Shim et al

4

17

Boemo et al1 Furuta et al Uri et al

7

11

Kinishi et al14 Murakami et al Total

15

No. of patients that achieved good prognosis with Prednisone

No. of patients that achieved good prognosis with Prednisolone

No. of patients that achieved good prognosis with Hydrocortisone

No. of patients that achieved good prognosis with Methylprednisolone

91/155

10/15

225/339

33/54

27/37

19/23

85/91

65/80

290/419 (69.2%)

118/192 (61.4%)

29/38 (76.3%)

118/145 (81.3%)

International Archives of Otorhinolaryngology

Vol. 20

No. 4/2016

399


400

Prognosis of Facial Palsy on Ramsay Hunt Syndrome

Monsanto et al.

thereafter, associated with oral acyclovir, 400 mg 5x/d for 7 days) achieved the higher rate of recovery. Nonetheless, the comparison between the results achieved by the different types of steroids did not achieve statistical significance (p > 0.05). A study of the molecular mechanisms of corticosteroids conducted by Tsai18 showed that methylprednisolone has a higher affinity to glucocorticoid receptors, and a higher anti-inflammatory action when compared with the prednisone, prednisolone, or hydrocortisone; these facts might explain the best results achieved by the authors that used methylprednisolone comparing to other steroids. Coulson et al5 showed that the group of patients treated with oral prednisone 1 mg/kg for 14 days, followed by a declining dose of 10 mg/d down to 0 mg, associated with acyclovir 200 mg 5x/d for 21 days 5 days after the onset of the paralysis achieved greater improvement of symptoms than patients treated earlier (p ¼ 0.005). A possible explanation for this is that the antiinflammatory action of the steroids should be present at the moment that the inflammation is most intense to achieve the best efficacy.5 Nonetheless, a study conducted by De Ru3 demonstrated that best results are achieved when the treatment is initiated on the early onset of the disease. Murakami et al15 also showed significant differences in the improvement of facial nerve function depending on the time elapsed between the onset of the symptoms and the start of treatment – the best results are achieved when treatment is introduced before the fifth day of the first symptoms. The same authors indicated that intravenous and oral drugs are equally efficient in terms of the recovery of the function of the facial nerve. They also reported that most of the patients with RHS did not require hospitalization.15 Furuta et al7 observed that patients with VZV in the oropharynx or with a viral load above 10,000 copies per 50 μL in the saliva had a worse recovery of the facial nerve function than patients with the isolated cutaneous form of the zoster infection (p ¼ 0.0019). Thus, the level of VZV DNA in the saliva reflects the kinetics of the viral reactivation in the facial nerve. Other parameters related to worse prognosis were lagophthalmus and dry eye (p < 0.05), which indicates the involvement of the large superficial petrosal nerve.5 None of the selected studies refer to surgical management of the facial palsy in Ramsay Hunt syndrome. Bodénez et al,19 however, proposed a flowchart regarding to the surgical approach – if the patient maintains complete facial palsy (HB V or VI) after the clinical treatment, the electromyography shows axonal loss higher than 95% and a time elapsed since the beginning of the facial palsy of 15 days, a surgical approach may be indicated.

Final Comments

References 1 Boemo RL, Navarrete ML, García-Arumí AM, Copa SL, Graterol D,

2

3

4

5

6

7

8 9 10 11

12

13

14

15

16

17

Overall, patients with Ramsay Hunt syndrome achieved a high rate of complete recovery of the facial nerve function (70.4%) after the different proposed treatments. The combination of steroids and acyclovir reached better recovery rates than steroids in monotherapy. Dosage and period of treatment greatly varied among studies.

International Archives of Otorhinolaryngology

Clinical data such as age, associated metabolic diseases, impairment of the cochleovestibular, or other cranial nerves, oropharynx lesions, dry eye, and lagophthalmus must be assessed at the initial physical examination, since they suggest worse prognosis of the facial palsy secondary to Ramsay Hunt syndrome.

Vol. 20

No. 4/2016

18

19

Scherdel EP. Ramsay Hunt syndrome: our experience. Acta Otorrinolaringol Esp 2010;61(6):418–421 Donati D, De Santi L, Ginanneschi F, Cerase A, Annunziata P. Successful response of non-recovering Ramsay Hunt syndrome to intravenous high dose methylprednisolone. J Neurol Sci 2012; 318(1–2):160–162 de Ru JA, van Benthem PPG. Combination therapy is preferable for patients with Ramsay Hunt syndrome. Otol Neurotol 2011;32(5): 852–855 Zainine R, Sellami M, Charfeddine A, Beltaief N, Sahtout S, Besbes G. Ramsay Hunt syndrome. Eur Ann Otorhinolaryngol Head Neck Dis. Head and Neck Dis 2012;129:22–25 Coulson S, Croxson GR, Adams R, Oey V. Prognostic factors in herpes zoster oticus (ramsay hunt syndrome). Otol Neurotol 2011; 32(6):1025–1030 Yeo SW, Lee DH, Jun BC, Chang KH, Park YS. Analysis of prognostic factors in Bell’s palsy and Ramsay Hunt syndrome. Auris Nasus Larynx 2007;34(2):159–164 Furuta Y, Aizawa H, Ohtani F, Sawa H, Fukuda S. Varicella-zoster virus DNA level and facial paralysis in Ramsay Hunt syndrome. Ann Otol Rhinol Laryngol 2004;113(9):700–705 Gondivkar S, Parikh V, Parikh R. Herpes zoster oticus: A rare clinical entity. Contemp Clin Dent 2010;1(2):127–129 Sweeney CJ, Gilden DH. Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 2001;71(2):149–154 Gilchrist JM. Seventh cranial neuropathy. Semin Neurol 2009; 29(1):5–13 10.1055/s-0028-1124018 Uri N, Greenberg E, Kitzes-Cohen R, Doweck I. Acyclovir in the treatment of Ramsay Hunt syndrome. Otolaryngol Head Neck Surg 2003;129(4):379–381 Kansu L, Yilmaz I. Herpes zoster oticus (Ramsay Hunt syndrome) in children: case report and literature review. Int J Pediatr Otorhinolaryngol 2012;76(6):772–776 Kim YH, Chang MY, Jung HH, et al. Prognosis of Ramsay Hunt syndrome presenting as cranial polyneuropathy. Laryngoscope 2010;120(11):2270–2276 Kinishi M, Amatsu M, Mohri M, Saito M, Hasegawa T, Hasegawa S. Acyclovir improves recovery rate of facial nerve palsy in Ramsay Hunt syndrome. Auris Nasus Larynx 2001;28(3):223–226 Murakami S, Hato N, Horiuchi J, Honda N, Gyo K, Yanagihara N. Treatment of Ramsay Hunt syndrome with acyclovir-prednisone: significance of early diagnosis and treatment. Ann Neurol 1997; 41(3):353–357 Ryu EW, Lee HY, Lee SY, Park MS, Yeo SG. Clinical manifestations and prognosis of patients with Ramsay Hunt syndrome. Am J Otolaryngol 2012;33(3):313–318 Shim HJ, Jung H, Park DC, Lee JH, Yeo SG. Ramsay Hunt syndrome with multicranial nerve involvement. Acta Otolaryngol 2011; 131(2):210–215 Tsai MJ, O’Malley BW. Molecular mechanisms of action of steroid/ thyroid receptor superfamily members. Annu Rev Biochem 1994; 63:451–486 Bodénez C, Bernat I, Willer JC, Barré P, Lamas G, Tankéré F. Facial nerve decompression for idiopathic Bell’s palsy: report of 13 cases and literature review. J Laryngol Otol 2010;124(3):272–278


A-1

Instructions to Authors

Instructions to Authors for International Archives of Otorhinolaryngology Geraldo Pereira Jotz, M.D. Ph.D., Editor-in-Chief Aline Bittencourt, M.D., Ph.D., Co-Editor Editorial Office: Rua Artur de Azevedo 46, Zip code 05404000, São Paulo/SP, Brazil; Phone: +55 (11) 3062-4097; E-mail: iaorl@iaorl.org; www.internationalarchivesent.org International Archives of Otorhinolaryngology (IAORL) is an international peer-reviewed journal dedicated to otolaryngology–head and neck surgery, audiology, and speech therapy. IAORL is published every three months and supports the World Health Organization (WHO) and of the International Committee of Medical Journal Editors (ICMJE) politics regarding registration of clinical trials. Therefore we only accept for publication articles of clinical trials that have been given a number of identification from one of the Clinical Essay Registry validated by the criteria established by the WHO and the ICMJE, the links to which are available at the ICMJE (http://www.icmje.org/). The identification number should be given at the end of the abstract. IAORL reserves the right to exclusive publication of all accepted manuscripts. We will not consider any manuscript previously published nor under review by another publication. Once accepted for review, the manuscript must not be submitted elsewhere. Transfer of copyright to IAORL is a prerequisite of publication. All authors must sign a copyright transfer form. The editors and Thieme combat plagiarism, double publication, and scientific misconduct with the software CrossCheck powered by iThenticate. Your manuscript may be subject to an investigation and retraction if plagiarism is suspected. Authors must disclose any financial relationship(s) at the time of submission, and any disclosures must be updated by the authors prior to publication. Information that could be perceived as potential conflict(s) of interest must be stated. This information includes, but is not limited to, grants or funding, employment, affiliations, patents, inventions, honoraria, consultancies, royalties, stock options/ownership, or expert testimony. Article Categories The journal publishes the types of articles defined below. When submitting your manuscript, please follow the instructions relevant to the applicable article category. Original Research Original, in-depth, clinical or basic science investigations that aim to change clinical practice or the understanding of a disease process. Article types include, but are not limited to, clinical trials, before-and-after studies, cohort studies, casecontrol studies, cross-sectional surveys, and diagnostic test assessments. Components of original research are: ® A title page, including the manuscript title and all authors’ full names, academic degrees (no more than three), institutional affiliations, and locations. Designate one author as the corresponding author. Also indicate where the paper was presented, if applicable. ® A structured abstract of up to 250 words with the headings: Introduction, Objective, Methods, Results, and Conclusion.

● The Manuscript body should be divided as: introduction with objective(s); method; result; discussion; conclusion; references. ● Manuscript length of no more than 24 pages (exclusive of the title page and abstract). ● Studies involving human beings and animals should include the approval protocol number of the respective Ethics Committee on Research of the institution from which the research is affiliated. Systematic Reviews (including Meta-analyses) Critical assessments of literature and data sources on important clinical topics in otolaryngology-head and neck surgery. Systematic reviews that reduce bias with explicit procedures to select, appraise, and analyze studies are highly preferred over traditional narrative reviews. The review may include a meta-analysis, or statistical synthesis of data from separate, but similar, studies leading to a quantitative summary of the pooled results. The components of a systematic review are: ● A title page, including the manuscript title and all authors’ full names, academic degrees, institutional affiliations, and locations. Designate one author as the corresponding author. Also indicate where the paper was presented, if applicable. ● A structured abstract of up to 250 words with the headings: Introduction, Objectives, Data Synthesis, and Conclusion. ● The Manuscript body should be divided as: introduction; review of literature; discussion; final comments; references. ● Manuscript length of no more than 24 pages (exclusive of the title page and abstract). Case Reports Case Reports will no longer be accepted for submission, starting on 2015. Submitted manuscripts until December 2014 will be reviewed and published, if approved. Update Manuscripts The manuscript is an update that explores a particular subject, developed from current data, based on recently published works. ● A title page, including the manuscript title and all authors’ full names, academic degrees, institutional affiliations, and locations. Designate one author as the corresponding author. Also indicate where the paper was presented, if applicable. ● A structured abstract of up to 250 words with the headings: Introduction, Objectives, Data Synthesis, and Conclusion. ● The Manuscript body should be divided as: introduction; review of a particular subject; discussion; final comments; references. ● Manuscript length of no more than 15 pages (exclusive of the title page and abstract). Letters to the Editor and Opinion articles Only by invitation from the Editorial Board. Manuscript length: no more 2 pages.


Instructions to Authors Manuscript Preparation Correct preparation of the manuscript will expedite the review and publishing process. Manuscripts must conform to acceptable English usage. Necessary Files for Submission (each topic should start in a new page): ● Title Page ● Abstract ● Manuscript (main text, references, and figure legends) ● Figure(s) (when appropriate) ● Table(s) (when appropriate) In accordance with double-blind review, author/institutional information should be omitted or blinded from the following submission files: Manuscript, Figure(s), Table(s), Response to Reviewers. The Abstract should be followed by three to six keywords in English, selected from the list of Descriptors (Mesh) created by National Library of Medicine and available at http://www.nlm.nih.gov/mesh/2013/mesh_browser/ MBrowser.html.

● Books: Author/Editor | Title | Edition | Place of Publication | Publisher | Date of Publication. Valente M, Hosford-Dunn H, Roeser RJ. Audiology Treatment. 2nd ed. New York: Thieme; 2008 ● Book chapters: Author of the chapter | Title of chapter | In: Editor(s) of book | Title of chapter | Place of Publication | Publisher | Date of Publication | Pagination. Vilkman E. A survey on the occupational safety and health arrangements for voice and speech professionals in Europe. In: Dejonckere PH, ed. Occupational Voice: Care and Cure. Hague: Kugler Publications; 2001:129-137 ● Electronic material: for articles taken entirely from the Internet, please follow the rules mentioned above and add at the end the web site address. Ex: AMA: helping doctors help patients [Internet]. Chicago: American Medical Association; c1995-2007 Available at: http://www.ama-assn.org/. Accessed Feb 22, 2007 Figures Figures must be uploaded separately. Include the number of the figure in the description box.

Abbreviations

Figure Legends

Do not use abbreviations in the title or abstract. When using abbreviations in the text, indicate the abbreviation parenthetically after the first occurrence and use the abbreviation alone for all subsequent occurrences.

Provide a legend for each figure. List the legends (doublespaced) on a separate text page, after the reference page. Up to 8 pictures will be published at no cost to the authors; color pictures will be published at the editor’s discretion. Acceptable submissions include the following: JPG, GIF, PNG, PSD, or TIF. The Publication Management System accepts only high definition images with the following features: ● Width up to 1000 px and DPI equal to or higher than 300; ● The image formats should be preferentially TIF or JPG; ● The maximum image size should be 8 MB; ● If figures have multiple parts (e.g., A, B, C, D), each part must be counted as a separate image in the total number allowed.

Authorship Authorship credit should be based on criteria established by the International Committee of Medical Journal Editors: (1) substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; (2) drafting the article or revising it critically for important intellectual content; and (3) final approval of the version to be published. References Authors are responsible for the completeness, accuracy, and format of their references. References should be numbered consecutively using Arabic numbers in the text. All authors shall be listed in full up to the total number of six; for seven or more authors, list the first three authors followed by “et al.” There should be no more than 90 references for original articles and no more than 120 for systematic reviews or update articles. Refer to the List of Journals Indexed in Index Medicus for abbreviations of journal names, or access the list at http://www.nlm.nih.gov/tsd/serials/lji.html. Sample references are given below. For more information, please check: http://www.ncbi.nlm.nih.gov/books/NBK7256/.

Tables and Graphs Tables should be numbered in Arabic numbers consecutively as they appear in the text, with a concise but self-explicative title, without underlined elements or lines inside it. When tables have too many data, prefer to present graphics (in black and white). If there are abbreviations, an explicative text should be provided on the lower margin of the table or graph. Appendices Appendices will only be published online, not in the print journal, and may include additional figures or tables that enhance the value of the manuscript. Appendices must be submitted online with the rest of the manuscript and labeled as such. Questionnaires will be considered as Appendices.

Examples

Online Manuscript Submission

● Journals: Author | Article Title | Journal Title | Date of Publication | Volume Number | Issue Number | Pagination. Huttenhower C, Gevers D, Knight R, et al. Structure, function and diversity of the healthy human microbiome. Nature 2012;486(7402):207-214 ● Dissertations and Theses: Author | Title | Content Type | Place of Publication | Publisher | Date of Publication | Pagination. Baldwin KB. An exploratory method of data retrieval from the electronic medical record for the evaluation of quality in healthcare [dissertation]. Chicago: University of Illinois at Chicago, Health Sciences Center; 2004:116

All manuscripts should be submitted free of charge at http:// mc.manuscriptcentral.com/iaorl, which gives access to the ScholarOne Manuscripts submission system where the submission of the article is done by the authors and the evaluation process is done by the reviewers of our editorial board in a blinded process where the names of the authors are not displayed in any instance. The system will ask for your user ID and password if you have already registered. If you have not registered, click on the link “Create Account” and make your registration. In case you have forgotten your password, click on the appropriate link and the system will generate an automatic e-mail with the information.

A-2


A-3

Instructions to Authors The author(s) should keep a copy of all submitted material for publication because the editor cannot be held responsible for any lost material. After submission, the system offers the option of saving a copy of your manuscript in PDF format for your control. The journal strongly recommends that the authors submit their electronic manuscripts written in Microsoft Word. In the “Preparing Manuscript” step a screen that simulates the word processor will be displayed, where it is possible to “copy and paste”, including tables.

Deadlines

Ethics and Financial Disclosure: The manuscript will be assigned to an Editor for solicitation of peer review and editorial evaluation ONLY after this form has been submitted by the corresponding author.

Submissions not in compliance with the following instructions will be returned to the author by the editorial office and a corrected version must be resubmitted within 30 days. Papers not resubmitted within that time will be withdrawn from consideration. Revised manuscripts must follow the same instructions and should be submitted within 30 days of the revision letter date. Accepted manuscripts sent to the publisher will be typeset and proofs will then be sent by e-mail to the corresponding author. If proofs are not approved and received within 2 business days, the article will not be published. The reviewers should send their comments within 20 days.

Patient Confidentiality

English Language Assistance

For manuscripts containing photographs of a person, submit a written release from the person or guardian, or submit a photograph that will not reveal the person’s identity (eye covers are inadequate to protect patient identity).

Appropriate use of the English language is a requirement for publication in IAORL. Authors who wish to improve the grammar and spelling in their articles may wish to consult a professional service. Many companies provide substantive editing via the web. A few examples are: www.journalexperts.com www.editage.com Please note that IAORL has no affiliation with these companies and use of the service does not guarantee your manuscript will be accepted.

Mandatory Author Forms

Using Previously Published Material and Illustrations For manuscripts containing illustrations and/or material reproduced from another source, permission from the copyright holder, medical illustrator, or original publication source must be obtained and submitted to the editorial office. IRB Policy and Animal Studies For all manuscripts reporting data from studies involving human participants, formal review and approval, or formal review and waiver (exemption), by an appropriate institutional review board (IRB) or ethics committee is required and should be described in the Methods section with the full name of the reviewing entity. All clinical research requires formal review, including case reports, case series, medical record reviews, and other observational studies. For experiments involving animals, state the animalhandling protocol in the Methods section, including approval by an institutional board. Duplicate or Redundant Submission Manuscripts are considered with the understanding that they have not been published previously and are not under consideration by another publication. If the author explicitly wishes the journal to consider duplicate publication, he or she must submit the request, in writing, to the Editor with appropriate justification.

The International Archives of Otorhinolaryngology Scientific Merit Journal Prize The IAORL Scientific Merit Journal Prize is awarded every year for up to three best systematic review (meta-analysis) papers published each year in the journal. The 2016 manuscript awards will be selected from articles published in issues 1-4 of volume 20, based on novelty, impact, data quality, and number of online downloads by the journal readers. The adjudication committee consists of the editorial board, assisted by comments received through the peer review process. The judgment of the papers will be published after issue number 4 of volume 20. The result will be communicated to the winners and officially published in volume 21 of IAORL. All authors and co-authors will receive certificates of Scientific Merit.


calendario 2017_inglês_revista_arquivos.pdf 1 19/09/2016 15:52:27

PRELIMINARY SCHEDULE OF COURSES | 2017* MARCH

TH

113 TEMPORAL BONE DISSECTION COURSE XX THEORETICAL AND PRACTICAL COURSE ON ENT ENDOSCOPY - MODULES I AND II XI COURSE OF BASIC NEUROTOLOGY - PRINCIPLES AND PRATICE XX THEORETICAL AND PRACTICAL (HANDS-ON) COURSE ON PHONOMICROSURGERY WITH DISSECTION OF EXCISED LARYNGES

APRIL

3RD MEETING OF SWALLOWING DISORDERS: DIAGNOSTIC AND THERAPEUTIC ASPECTS V COURSE OF RHINOPLASTY FOR BEGINNERS - HANDS ON

MAY

TH

114 TEMPORAL BONE DISSECTION COURSE 99TH ENDOSCOPIC SINUS SURGERY COURSE - HANDS ON - BAHIA XII AUDIOLOGY EVOKED POTENTIALS COURSES: THEORY AND PRATIC (HANDS ON) IV COURSE OF REJUVENATION OF THE UPPER THIRD OF THE FACE (EYEBROW LIFT ANF BLEFAROPLASTY) - HANDS ON II COURSE FACIAL REJUVENATION: RHITIDECTOMY - HANDS ON

JUNE

XVII COURSE MULTICENTER OF COCHLEAR IMPLANT AND BONE CONDUCTION HEARING AIDS - MODULE I - BASIC OTOPLASTY COURSE II STAPES SURGERY COURSE

AUGUST C

M

Y

CM

CY

CMY

K

PLACE

20, 21, 22 15, 16, 17 27, 28 29, 30, 31

SP SP SP SP

DATE

PLACE

28, 29 26, 27, 28

RS SP

DATE

PLACE

08, 09, 10 18, 19, 20 29, 30 22, 23 24, 25, 26

SP BA SP SP SP

DATE

PLACE

07, 08, 09, 10 24 30

SP SP SP

DATE

PLACE

FROM AUG/07/2017 ONLINE TO MAR/12/2018 03, 04, 05 BA 18, 19 SP 21, 22, 23 SP

OTOMASTER 100TH ENDOSCOPIC SINUS SURGERY COURSE - HANDS ON - BAHIA 15TH COURSE ON STOMATOLOGY (ORAL MEDICINE) XI PRATICAL COURSE OF ELECTRONISTAGMOGRAPHY - PRINCIPLES AND PRATICE

SEPTEMBER

MY

DATE

VIII WORKSHOP REHABILITATION COCHLEAR IMPLANT PATIENTS - HCFMUSP VI NOSE - LIVE ENDOSCOPIC ENDONASAL SURGERIES 19TH COURSE ON SNORING AND OBSTRUCTIVE SLEEP APNEA - THEORY, LIVE CLINIC AND LIVE SURGERY

OCTOBER

DATE

PLACE

15, 16 21, 22 28, 29

SP SP SP

DATE

PLACE

04, 05, 06 16, 17, 18 17, 18

SP SP SP

18, 19, 20

SP

24, 25, 26 26, 27 19, 20

SP SP SE

NOVEMBER

DATE

PLACE

DECEMBER

DATE

PLACE

04, 05, 06 07, 08, 09

SP BA

XXI THEORETICAL AND PRACTICAL COURSE ON ENT ENDOSCOPY - MODULES I AND II 28TH BIG EAR - THE MOST IMPORTANT OTOLOGY LIVE SURGERY COURSE 4RD ADVANCED COURSE OF DISSECTION IN OTORHINOLARYNGOLOGY - MODULE I - NASSOSINUSAL ADVANCED SURGERY 4RD ADVANCED COURSE OF DISSECTION IN OTORHINOLARYNGOLOGY - MODULE II - OTOLOGIC AND NEUROTOLOGIC SURGERY FOCUS ENDOSCOPIC SURGERY OF THE EAR 4RD ADVANCED COURSE OF DISSECTION IN OTORHINOLARYNGOLOGY - MODULE III - FACIAL PLASTIC SURGERY 4RD ADVANCED COURSE OF DISSECTION IN OTORHINOLARYNGOLOGY - MODULE IV - SURGERY SNORING AND APNEA COURSE LARYNGOLOGY - FORL IN SERGIPE

XXI THEORETICAL AND PRACTICAL (HANDS-ON) COURSE ON PHONOMICROSURGERY WITH DISSECTION OF EXCISED LARYNGES 08, 09, 10 SP XVIII COURSE MULTICENTER OF COCHLEAR IMPLANT AND BONE CONDUCTION HEARING AIDS - MODULE II - ADVANCED 22, 23, 24, 25 SP VII BROADCASTED COURSE IN RADIOLOGY IN OTORHINOLARYNGOLOGY 13,14,16 E 17 ONLINE 4RD MEETING (PRACTICAL) OF SWALLOWING DISORDERS: FUNCTIONAL ENDOSCOPIC EVALUATION OF SWALLOWING (FESS) AND DIGESTIVE 24, 25 RS ENDOSCOPY DIAGNOSIS & MANAGEMENT OF THE TINNITUS - EXPERTISE OF THE TINNITUS RESEARCH GROUP - CLINICAL HOSPITAL UNIVERSITY OF SÃO PAULO 30/NOV. E 01/DEZ. SP TH

101 ENDOSCOPIC SINUS SURGERY COURSE - HANDS ON - BAHIA 115TH TEMPORAL BONE DISSECTION COURSE *SCHEDULE SUBJECT TO CHANGE

INFORMATIONS AND REGISTRATION: SITE: WWW.FORL.ORG.BR | E-MAIL: CURSOSFORL@FORL.ORG.BR | TEL: 55 (11) 3068-9855

|

FACEBOOK:

/FUNDACAO.OTORRINOLARINGOLOGIA


hearing_save_the_date A4 ingles_pb.pdf 1 19/09/2016 16:23:26

C

M

Y

CM

MY

CY

CMY

K


Continuation from outside back cover

344 “Positive to Negative” Dix-Hallpike test and Benign Paroxysmal Positional Vertigo recurrence in elderly undergoing Canalith Repositioning Maneuver and Vestibular Rehabilitation Karyna M. O. B. de Figueiredo Ribeiro, Lidiane Maria de Brito Macedo Ferreira, Raysa Vanessa de Medeiros Freitas, Camila Nicácio da Silva, Nandini Deshpande, and Ricardo Oliveira Guerra 353 Residual Hearing Preservation with the Evo® Cochlear Implant Electrode Array: Preliminary Results Ricardo Ferreira Bento, Fabiana Danieli, Ana Tereza deMatosMagalhães, Dan Gnansia, and Michel Hoen 359 Early and Delayed Effect of Functional Endoscopic Sinus Surgery on Intraocular Pressure Mohammad Waheed El-Anwar, Mohammad Abdelhady, Hazem Saeed Amer, and Manar A. Ghali 364 Granulocyte-Macrophage Colony-Stimulating Factor Production and Tissue Eosinophilia in Chronic Rhinitis Aleksandar Peric, Cveta Spadijer-Mirkovic, Svjetlana Matkovic-Jozin, Ljiljana Jovancevic, and Danilo Vojvodic 370 Curcumin Reduces the Noise-Exposed Cochlear Fibroblasts Apoptosis Tengku Siti Hajar Haryuna, Wibi Riawan, Ardyansyah Nasution, Suprapto Ma’at, Juliandi Harahap, and Indri Adriztina 377 Evaluation of the Effects of Bismuth Subgallate on Wound Healing in Rats. Histological Findings Rafaela Mabile Ferreira dos Santos, Claudia Paraguaçu Pupo Sampaio, Daniela Pache de Moraes, and Rubianne Ligório de Lima

Systematic Reviews 382 Clinical Value of High Mobility Group Box 1 and the Receptor for Advanced Glycation End-products in Head and Neck Cancer: A Systematic Review Austin Nguyen, Sheila Bhavsar, Erinn Riley, Gabriel Caponetti, and Devendra Agrawal 390 Supra-auricular versus Sinusectomy Approaches for Preauricular Sinuses Mohammad Waheed El-Anwar, and Ahmed Shaker ElAassar 394 Treatment and Prognosis of Facial Palsy on Ramsay Hunt Syndrome: Results Based on a Review of the Literature Rafael da Costa Monsanto, Aline Gomes Bittencourt, Natal José Bobato Neto, Silvia Carolina Almeida Beilke, Fabio Tadeu Moura Lorenzetti, and Raquel Salomone

A-1 Instructions to Authors

The colored content of this issue is available online at www.thieme.com/iao.

C3.indd 1

20/09/16 4:55 PM


Issue 4

Volume 20

October - November - December 2016

ISSN 1809-9777

INTERNATIONAL ARCHIVES OF

OTORHINOLARYNGOLOGY

Official Publication of the Otorhinolaryngology Foundation and Societas Oto-Rhino-Laryngologia Latina

Editorial

291 Prof. Dr. Aroldo Miniti – A Great Master Ricardo Ferreira Bento

Original Research

294 Influence of Hormonal Changes on Audiologic Examination in Normal Ovarian Cycle Females: An Analytic Study Indri Adriztina, Adlin Adnan, Ichwanul Adenin, Siti Hajar Haryuna, and Sorimuda Sarumpaet 300 Newborn Hearing Screening in a Public Maternity Ward in Curitiba, Brazil: Determining Factors for Not Retesting Idalina Luz, Angela Ribas, Lorena Kozlowski, Mariluci Willig, and Ana Paula Berberian 305 Comparison of Pre-Attentive Auditory Discrimination at Gross and Fine Difference between Auditory Stimuli Himanshu Kumar Sanju, and Prawin Kumar 310 Temporal Resolution and Active Auditory Discrimination Skill in Vocal Musicians Prawin Kumar, Himanshu Kumar Sanju, and J. Nikhil 315 Relationship between Speech Perception and Level of Satisfaction of Hearing Aid Users Erika Barioni Mantello, Carla Dias da Silva, Eduardo Tanaka Massuda, Miguel Angelo Hyppolito, and Ana Cláudia Mirândola Barbosa dos Reis 321 Pitch and Loudness Tinnitus in Individuals with Presbycusis Bruna Macangnin Seimetz, Adriane Ribeiro Teixeira, Leticia Petersen Schmidt Rosito, Leticia Sousa Flores, Carlos Henrique Pappen, and Celso Dall’igna 327 Auditory Temporal Resolution in Individuals with Diabetes Mellitus Type 2 Rajkishor Mishra, Himanshu Kumar Sanju, and Prawin Kumar 331 Workplace Activity in Health Professionals Exposed to Chemotherapy Drugs: An Otoneurological Perspective Natália Martinez Fernandes, Isadora Gonçalves Pelissari, Licia Assunção Cogo, and Valdete Alves Valentins dos Santos Filha 339 The Influence of Tinnitus on the Audiometric Threshold of Sufferers Onyinye Ukaegbe, Basil Ezeanolue, and Foster Orji

Rio de Janeiro • New York • Stuttgart Thieme Publicações Ltda, Av. Nilo Peçanha, 50, sala 2508, Rio de Janeiro 20020-906, Brazil www.thieme-connect.com/products


International Archives of Otorhinolaryngology