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ISSN 0004-282X

1-12

Celebrating 70 years of publication

Vol . 70, N o 1, January 2012

SĂŁo Paulo, SP, Brazil

Volume 70, Number 1, January, 2012, SĂŁo Paulo, SP, Brazil

QUANTO ANTES MELHOR

Tratamento de 1ª linha para Esclerose Múltipla13,14 s COPAXONEŽ reduz em 50% a taxa anual de surtos jå no primeiro ano15 s COPAXONE preserva a vigilância imunológica do paciente Ž

16,17

, diferentemente de algumas drogas com

perfil imunossupressor que podem comprometer esta vigilância18-23 s COPAXONEŽ possui estudo prospectivo de longo prazo com observação de 22 anos de doença17

COPAXONEÂŽ (acetato de glatirâmer) - solução injetĂĄvel - uso subcutâneo 20mg/mL - USO ADULTO - Indicaçþes: Reduzir a freqßência de recidivas nos pacientes com esclerose mĂşltipla remissiva recidivante (EMRR). Ainda nĂŁo existem estudos comprovando o benefĂ­cio do COPAXONEÂŽ em outras formas de Esclerose MĂşltipla. TambĂŠm ĂŠ indicado no tratamento de pacientes que tiveram um primeiro episĂłdio clĂ­nico bem definido e que apresentem alto risco de desenvolver a esclerose mĂşltipla clinicamente definida (EMCD). Contra-indicaçþes: O produto estĂĄ contra-indicado para pacientes com hipersensibilidade conhecida ao acetato de glatirâmer ou manitol. AdvertĂŞncias e Precauçþes: A administração deve ser feita exclusivamente por via subcutânea. NĂŁo deve ser administrado por via intravenosa; os pacientes devem ser instruĂ­dos sobre tĂŠcnicas de auto-administração da injeção de COPAXONEÂŽ para garantir a segurança da administração. Baseado nos dados atuais, nĂŁo ĂŠ necessĂĄrio nenhuma precaução especial para pacientes envolvidos em atividades que requerem alerta mental, como dirigir veĂ­culos ou operar mĂĄquinas. Como o acetato de glatirâmer pode modificar a resposta imunolĂłgica, deve-se considerar a possibilidade de que ele possa interferir com a função imunolĂłgica. Gravidez e lactação: Categoria B de risco na gravidez. Interaçþes medicamentosas: Interaçþes entre o COPAXONEÂŽ e outros fĂĄrmacos nĂŁo foram completamente avaliadas. Reaçþes Adversas: Reaçþes adversas mais comumente observadas: reaçþes no local de aplicação, vasodilatação, dor no peito, astenia, infecção, dor, nĂĄusea, artralgia, ansiedade e hipertonia. Posologia: a dose recomendada para adultos para o tratamento de esclerose mĂşltipla remissiva recidivante ĂŠ de 20 mg/dia injetada subcutaneamente. VENDA SOB PRESCRIĂ‡ĂƒO MÉDICA. Reg. MS 1.5573.0001. Farm. Resp.: MĂ´nica Riyoko Nekozuka – CRF-SP n° 16.970. Teva FarmacĂŞutica Ltda. A persistirem os sintomas, o mĂŠdico deve ser consultado. Documentação CientĂ­fica e informaçþes adicionais estĂŁo Ă  disposição da classe mĂŠdica, mediante solicitação.*CIS: SĂ­ndrome ClĂ­nica Isolada. Copaxone possui indicação em bula.

Contra-indicaçþes: o produto estĂĄ contra-indicado para pacientes com hipersensibilidade conhecida ao acetato de glatirâmer ou manitol. Interaçþes medicamentosas: interaçþes entre o COPAXONEÂŽ (acetato de glatirâmer) e outras drogas nĂŁo foram completamente avaliadas. 3FGFSĂ?ODJBT$PNJ(FUBM -BODFU  t.JMMFS+3+.BOBH$BSF1IBSN  4VQQM# 44t.JLPM%%FUBM -BODFU/FVSPM0DU  t4PSNBOJ.1FUBM/FVSPMPHZ   t'JMJQQJ.FUBM /FVSPMPHZ  t+PIOTPO,15IFS$MJO3JTL.BOBHFt'PSE$FUBM.VMU4DMFSt.FU[-.FUBM +/FVSPM/FVSPTVSH1TZDIJBUSZ t;JFNTTFO5FUBM)FBMUI2VBM-JGF0VUDPNFTt$BOGBWSFVY$ FUBM+3$PMM1IZTJDJBOT&EJOCt$BOGBWSFVY$ FU"-#SBJOt+PVSOBMPGUIF/FVSPMPHJDBM4DJFODFT GFCSVBSZWPM 4VQQMt'PSE$$ FUBM.VMU4DMFSt+PIOTPO,1 BM/FVSPMPHZt)BBT+'JS[MBGG.  &VSPQFBO+PVSOBMPG/FVSPMPHZt8FCFS.4 FUBM /FVSPUIFSBQFVUJDT  t"IBSPOJ3 FUBM1SPD/BUM"DBE4DJ64"  t.VOEFM5'5:@""/.BZ t$IVO+ FUBM$MJO/FVSPQIBSN  t-PQF[%JFHP34 FUBM/BU 3FW%SVH%JTDPWFSZ  t6OEFSTUBOEJOHDBODFSBOESFMBUFEUPQJDT/BUJPOBM$BODFS*OTUJUVUF8FCTJUFt,BQQPT- FUBM/&OHM+.FE  t$PIFO+" FUBM/&OHM+.FE  

Arquivos de Neuro-Psiquiatria

2,3

EDITORIALS

VIEWS AND REVIEWS

01

The 70 years of Arquivos de Neuro-Psiquiatria

59

02

How much radiologically isolated syndrome suggestive of multiple sclerosis is multiple sclerosis?

LETTERS

Treatment of neuromyelitis optica: an evidence based review

ARTICLES

67

A rare cause of recurrent peripheral facial palsy

05

Incidental demyelinating inflammatory lesions in asymptomatic patients: a Brazilian cohort with radiologically isolated syndrome and a critical review of current literature

69

Multiple subcortical strokes caused by mucormycosis in a patient with lymphoma

71

12

Clinical predictors of response to immunomodulators for multiple sclerosis

Cervical myelopathy caused by ligamentum flavum ossification

73

17

Accuracy of prospective memory tests in mild Alzheimer’s disease

Facial somatosensorial evaluation in idiopathic trigeminal neuralgia

75

22

Translation, cultural adaptation and psychometric evaluation of the LeganĂŠs cognitive test in a low educated elderly Brazilian population

Meningioma after immunomodulation for multiple sclerosis

IMAGES IN NEUROLOGY

28

Autism spectrum disorder and celiac disease: no evidence for a link

34

The impact of EEG in the diagnosis and management of patients with acute impairment of consciousness

40

Devising and validating a headache diary in a series of patients with chronic daily headache from Colombia

45

Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis

52

Cyclosporin safety in a simplified rat brain tumor implantation model

77

Magnetic resonance appearance of recurrent ophtalmoplegic migraine

78

“Black turbinate sing�: a potential predictor of mucormycosis in cavernous sinus thrombophlebitis

THESES 79

Peripheral biomarkers in bipolar disorder: a population-based study in young adults

79

Severity and functional ability scale for amyotrophic lateral sclerosis patients

Opinion 81

Spontaneus spinal epidural hematoma during pregnancy

82

NOTICES AND COMMENTS


A nova geração no tratamento do TDAH2

Manhã

Tarde

Início da Noite

Eficácia consistente ao longo do dia, mesmo até 13 horas após a dose.1 Importante contraindicação: histórico de abuso de drogas. Importante interação medicamentosa: uso concomitante com IMAO devido à potencialização de efeitos. VENVANSE* (dimesilato de lisdexanfetamina). Apresentação: cápsulas de uso oral de 30 mg, 50 mg e 70 mg de dimesilato de lisdexanfetamina; frascos com 28 cápsulas. Indicação: para o tratamento do Transtorno Déficit de Atenção/Hiperatividade (THDA) em crianças de 6 a 12 anos de idade. Contraindicações: arterioesclerose avançada, doença cardiovascular sintomática, hipertensão moderada a grave, hipertireoidismo, sensibilidade conhecida ou reação de idiossincrasia a aminas simpatomiméticas, glaucoma, estados de agitação, histórico de abuso de drogas, durante ou até 14 dias após o uso de inibidores da monoaminoxidase. Advertências e Precauções: as anfetaminas têm alto potencial de abuso e de dependência, especialmente em doses maiores que as terapêuticas e em uso prolongado, podendo nestas condições causar morte súbita e eventos cardiovasculares graves. Deve ser usado com cautela em casos de anormalidades estruturais cardíacas ou outros problemas graves do coração, hipertensão e outras condições cardiovasculares, transtorno psicótico pré-existente, tiques motores e fônicos e síndrome de Tourette, uso de outros fármacos simpatomiméticos. Deve ser descontinuado na presença de convulsões. Pode ser necessário interrompê-lo se ganho de peso e crescimento abaixo do esperado. Pode causar doping. Categoria C de gravidez: só deve ser usado se os potenciais benefícios justificarem o potencial risco para o feto. A amamentação deve ser suspensa durante seu uso. Interações Medicamentosas: agentes acidificantes e alcalinizantes da urina, antidepressivos IMAO, bloqueadores adrenérgicos, anti-histamínicos, anti-hipertensivos, alcalóides de veratrum, etosuximida, antidepressivos tricíclicos, agentes simpatomiméticos, meperidina, fenobarbital, fenitoína, clorpromazina, haloperidol, carbonato de lítio, norepinefrina, propoxifeno. Reações Adversas: dor no abdômen superior, vômito, náusea, boca seca, diarreia, pirexia, nervosismo, apetite diminuído, anorexia, vertigem, cefaleia, convulsão, discinesia, inquietação, tremor, insônia, insônia inicial, irritabilidade, labilidade afetiva, tique, agitação, agressão, hiperatividade psicomotora, depressão, disforia, logorreia, episódios psicóticos, episódios maníacos, alucinação, ansiedade, euforia, erupção cutânea, síndrome de Stevens-Johnson, angioedema, urticária, hiperidrose, hipersensibilidade, reação anafilática, visão borrada, midríase, taquicardia, palpitações, dispneia, perda de peso, aumento da pressão arterial, hepatite eosinofílica, fadiga, sonolência. Posologia: Dose inicial recomendada: 30 mg, uma vez ao dia, pela manhã. Dose máxima recomendada: 70 mg/dia. Para maiores informações: vide bula - VENDA SOB PRESCRIÇÃO MÉDICA. Reg. MS - 1.6979.0004 *Marca depositada. Referência Bibliográfica: 1. Wigal SB et al. A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder. Child and Adolescent Psychiatry and Mental Health 2009;3(17):115. At: http://www.capmh.com/content/3/1/17; on 23/Feb/2011. 2. Goodman DW. Lisdexamfetamine Dimesylate (Vyvanse), A Prodrug Stimulant for Attention-Deficit/Hyperactivity Disorder. P&T May 2010;35(5):273-87.

Venvanse* é um medicamento. Durante seu uso não dirija veículos ou opere máquinas, pois sua agilidade e atenção podem estar prejudicadas. www.shire.com.br Shire Farmacêutica Brasil Ltda. - Edifício Rochaverá Towers Av. das Nações Unidas, 14.171, Torre Ebony - 5º andar - 04794-000 - São Paulo - SP - Brasil Material destinado exclusivamente à classe médica. ANC VYV JUN/2011


Celebrating 70 years of publication

Volume 70, Number 1, January, 2012, São Paulo, SP, Brazil

THE OFFICIAL JOURNAL OF THE ACADEMIA BRASILEIRA DE NEUROLOGIA

Vision: Arquivos de Neuro-Psiquiatria will be the main Latin America peer-reviewed journal in neurosciences Mission: Arquivos de Neuro-Psiquiatria will provide clinical neurologists and other neurocientists with sigfnificant peer-reviewed articles, editorials, reviews and clinical reports to improve neurological practice, education, clinical research, professional improvement and brazilian neurology international visibility

Editors José Antonio Livramento Luís dos Ramos Machado Associated Editors Acary Souza Bulle Oliveira Alberto Alain Gabbai Carlos Alberto Mantovani Guerreiro Paulo Caramelli Founding Editor Oswaldo Lange Emeritus Editor Antonio Spina-França Netto Arquivos de Neuro-Psiquiatria Dr. Oswaldo Lange Association Luís dos Ramos Machado, SP, President José Antonio Livramento, SP, Vice-President Carlos Alberto Mantovani Guerreiro, SP, Secretary Acary Souza Bulle Oliveira, SP, Treasure Carlos Augusto Takeuchi, SP José Píndaro Pereira Plese, SP Luiz Alberto Bacheschi, SP Maria Fernanda Mendes, SP Paulo Caramelli, MG Alberto Alain Gabbai, SP Márcia Maiumi Fukujima, SP Executive Office Adriana Spina França Machado, SP, manager Rua Vergueiro 1421 cj 804 – Torre Sul 04101-000 – São Paulo – SP – Brasil Fone (5511)3884-2042; Fax (5511)2369-9721 e-mail: anprev@globo.com Apoio:

Publishers Arquivos de Neuro-Psiquiatria Dr. O. Lange Association Zeppelini Editorial Ltda, São Paulo www.zeppelini.com.br Marketing EPM - Editora de Projetos Médicos phone/fax: (5511)5084-3576 / (5511)5575-3450 epm@plugnet.com.br Academia Brasileira de Neurologia Elza Dias Tosta, DF, President Rubens José Gagliardi, SP, Vice-President Gilmar Fernandes do Prado, SP, Secretary Mônica Santoro Haddad, SP, Treasurer Francisco Eduardo Costa Cardoso, MG, Delegate to WFN www.abneuro.org academia@abneuro.org Cataloguing ISSN 0004-282 - paper publication ISSN 1678-4227 – online publication NLL (National Lending Library of Sciences and Technology, Boston, UK, 1947) WHO/UNESCO (Word Medical Periodicals, 1949) EMBASE - Excerpta Medica (Elsevier, Amsterdam, 1960) MEDLINE (National Library of Medicine, Bethesda USA, 1966) ISI (Institute for Scientific Information, Philadelphia USA, 1969)/JCR, 2003 LILACS (BIREME, São Paulo, 1982) SCOPUS (Elsevier, 1998) SciELO (1999) QUALIS/CAPES (B2, 2009) Circulation Monthly, 2500 copies


Editorial Advisory Board Abelardo de Queiroz Campos Araújo, Rio de Janeiro RJ (FIOCRUZ) Alberto Alain Gabbai, São Paulo SP (UNIFESP) Amauri Batista da Silva (Brasília DF) Amilton Antunes Barreira, Ribeirão Preto SP (USP-RP) Andrew J Lees (London, UK) Aroldo Luiz da Silva Bacellar (Salvador BA) Christina Marra (Seattle, USA) Ehrenfried Othmar Wittig (Curitiba PR) Elza Dias Tosta da Silva (Brasília DF) Fernando Cendes, Campinas SP (UNICAMP) Fernando Coroneti, Botucatu SP (UNESP) Fernando Kok, São Paulo SP (FMUSP) Fernando Otávio Quaresma Cavalcante (Belém, PA) Francisco Eduardo Costa Cardoso, Belo Horizonte MG (UFMG) Fulvio Alexandre Scorza, São Paulo SP (UNIFESP) Gérard Saïd (Paris, France) Gilberto Belisario Campos (Belo Horizonte MG) Gilson Edmar Gonçalves e Silva (Recife PE) Hélio Afonso Ghizzoni Teive, Curitiba PR (UFPR) James F Toole (Winston-Salem, USA) Joaquim Pereira Brasil Neto, Brasília DF (UnB) José Luiz Dias Gherpelli, São Paulo SP (FMUSP) José Geraldo Camargo Lima (São Paulo SP) José Pindaro Pereira Plese, São Paulo SP (FMUSP)

Jun Kimura (Kyoto, Japan) Lineu César Werneck (Curitiba PR) Luís Ataíde (Recife PE) Luiz Alberto Bacheschi (São Paulo SP) Marco Aurélio Lana Peixoto, Belo Horizonte MG (UFMG) Marcos Raimundo Gomes de Freitas, Niterói RJ (UFF) Maria José Sá (Porto, Portugal) Maria Lúcia Brito Ferreira, Recife PE (HR-SSEPE) Maria Lúcia Vellutini Pimentel, Rio de Janeiro RJ (Sta Casa RJ) Marilisa Mantovani Guerreiro, Campinas SP (UNICAMP) Milberto Scaff (São Paulo SP) Newra Tellechea Rotta (Porto Alegre RS) Osvaldo Massaiti Takayanagui, Ribeirão Preto SP (USP-RP) Paulo Norberto Discher de Sá (Florianópolis SC) Pedro L Ponce (Caracas, Venezuela) Ricardo Nitrini, São Paulo SP (FMUSP) Roberto E P Sica (Buenos Aires, Argentina) Rubens José Gagliardi, São Paulo SP (FCM-Sta Casa SP) Sebastião Eurico de Melo Souza (Goiânia GO) Sérgio Augusto Pereira Novis (Rio de Janeiro RJ) Sérgio Roberto Haussen (Porto Alegre RS) Umbertina Conti Reed, São Paulo SP (FMUSP Vicente de Paulo Leitão de Carvalho (Fortaleza CE) Vladimir Hachinski (London, Canada)

Editorial area Supervisors Cerebrovascular disorders Adriana Bastos Conforto, São Paulo SP (FMUSP) Ayrton Roberto Massaro, São Paulo SP Fábio Iuji Yamamoto, São Paulo SP (FMUSP) Clinical neurophysiology Carlos Otto Heise, São Paulo SP (FMUSP) Francisco José Carchedi Luccas, São Paulo, SP João Aris Kouyoumdjian, SJR Preto SP (Famerp) Lineu Correa da Fonseca, Campinas SP (PUC) Cognitive disorders Jerson Laks, Rio de Janeiro RJ (UFRJ) Paulo Caramelli, Belo Horizonte MG (UFMG) Epilepsy Carlos Alberto Mantovani Guerreiro, Campinas SP (UNICAMP) Eliana Garzon, São Paulo SP (FMUSP) Luiz Ataíde Jr., Recife PE (FMUFP) Experimental neurology Fulvio A. Scorza, São Paulo SP (EPM-UNIFESP) Gerson Chadi, São Paulo SP (FMUSP) Headache and pain Getúlio Daré Rabelo, São Paulo SP (FMUSP) José Geraldo Speciali, Ribeirão Preto SP (FMUSP-RP) Maurice Vincent, Rio de Janeiro RJ (UFRJ) History of Neurology Péricles Maranhão Filho, Rio de Janeiro RJ (UFRJ) Rubens Reimão, São Paulo SP (FMUSP) Infectious diseases of the nervous system Abelardo Queiroz Campos Araújo, Rio de Janeiro RJ (FIOCRUZ) Osvaldo Massaiti Takayanagui, Ribeirão Preto SP (FMUSP-RP) Paulo Pereira Christo, Belo Horizonte MG (UFMG) Ronald Salamano, Montevideu (Uruguai) Ronaldo Abraham, Taubaté SP (UNITAU)

Interventionist neuroradiology Paulo Puglia Jr., São Paulo SP (FMUSP) Letters Alberto Alain Gabbai, São Paulo SP (UNIFESP) Andrew J. Lees, London UK (UCL Institute of Neurology) Eduardo Genaro Mutarelli, São Paulo SP (FMUSP) Laura Moriyama, London UK (UCL Institute of Neurology) Lineu César Werneck, Curitiba PR (UFPR) Newra Tellechea Rotta, Porto Alegre RS (UFRS) Sergio Augusto Pereira Novis, Rio de Janeiro RJ (Sta Casa RJ) Sérgio Roberto Haussen, Porto Alegre RS (FFFCMPA) Motor neuron disease Acary Souza Bulle Oliveira, São Paulo SP (EPM-UNIFESP) Dagoberto Callegaro, São Paulo SP (FMUSP) Movement disorders Egberto Reis Barbosa, São Paulo SP (FMUSP) Francisco Cardoso, Belo Horizonte MG (UFMG) Helio Afonso Ghizoni Teive, Curitiba PR (UFPR) Henrique Ballalai Ferraz, São Paulo SP (EPM-UNIFESP) Myopathy Anamarli Nucci, Campinas SP (UNICAMP) Lineu César Werneck, Curitiba PR (UFPR) Suely Kazue Nagahashi Marie, São Paulo SP (FMUSP) Neurogenetics Fernando Kok, São Paulo SP (FMUSP) Iscia Lopes Cendes, Campinas SP (UNICAMP) Neuroimaging Antonio José da Rocha, São Paulo SP (Sta Casa SP) Claudia Costa Leite, São Paulo SP (FMUSP) Emerson Gasparetto, Rio de Janeiro RJ (UFRJ) Leandro Lucato, São Paulo SP (FMUSP)


Neuroimmunology Angelina Martins Lino, São Paulo SP (FMUSP) Carlos Oehninger, Montevideu (Uruguai) Maria José Sá, Porto (Portugal) Maria Lúcia Brito Ferreira, Recife PE (HR-SSEPE) Maria Lúcia Vellutini Pimentel, Rio de Janeiro RJ (Sta Casa RJ) Neurological critical care José Manuel Rocha Fernandes, São Paulo SP (FMUSP) Neuro-oncology Suely Kazue Nagahashi Marie, São Paulo SP (FMUSP) Suzana Maria Fleury Malheiros, São Paulo SP (EPM-UNIFESP) Neuropathology Carmen Lúcia Lancelotti, São Paulo SP (Sta Casa SP) Leila Chimelli, Rio de Janeiro RJ (UFRJ) Sérgio Rosemberg, São Paulo SP (FMUSP) Neuropsychology Eliane Miotto, São Paulo SP (FMUSP) Alessandra Gotuzo Seabra, São Paulo SP (Univ Mackenzie) Neurosurgery José Píndaro Pereira Plese, São Paulo SP (FMUSP) Mario Augusto Taricco, São Paulo SP (FMUSP) Roberto Sérgio Martins, São Paulo SP (FMUSP)

Pediatric neurology Alexandra Pruffer Queiroz Campos Araújo, Rio de Janeiro RJ (UFRJ) José Luiz Dias Gherpelli, São Paulo SP (FMUSP) Marilisa Mantovani Guerreiro, Campinas SP (UNICAMP) Umbertina Conti Reed, São Paulo SP (FMUSP) Peripheral neuropathy Angelina Martins Lino, São Paulo SP (FMUSP) Wilson Marques Jr., Ribeirão Preto SP (FMUSP-RP) Psychiatry Antonio Egídio Nardi, Rio de Janeiro RJ (UFRJ) Cássio Bottino, São Paulo SP (FMUSP) Quirino Cordeiro, São Paulo SP (FMUSP) Physiotherapy / speech therapy Letícia Lessa Mansur, São Paulo SP (FMUSP) Lúcia Iracema Zanotto Mendonça, São Paulo SP (FMUSP) Márcia Radanovic, São Paulo SP (FMUSP) Rehabilitation in neurology Paulo Nicolau Borsoi Salum, São Paulo SP (FMUSP) Sleep disorders Rosana Cardoso Alves, São Paulo SP (FMUSP) Stella Tavares, São Paulo SP (EPM-UNIFESP)

Otoneurology Cristiana Borges Pereira, São Paulo SP (FMUSP)

Arquivos de Neuro-Psiquiatria is a periodic registered in the Departamento de Imprensa e Propaganda (11795), Departamento Nacional de Propriedade Industrial (97414) and 1º Ofício de Títulos e Documentos de São Paulo, Brasil. Its owner and publisher is the Arquivos de Neuro-Psiquiatria Dr. Oswaldo Lange Association, a gainless society registered in the 6º Ofício de Registro de Pessoas Jurídicas de São Paulo (12770), in the Ministério da Fazenda (CNPJ 57394579/0001-31) and in the Secretaria de Finanças do Município de São Paulo (CCM 9416334-0). It is the Official Journal of the Academia Brasileira de Neurologia / Brazilian Academy of Neurology since 1970. It is published monthly since 2012, with absolute regularity over these 70 years since its foundation in 1943. Permission to photocopy articles: This publication is protected by copyright. Permission to reproduce copies of articles for noncommercial use may be obtained from the Copyright Clearing Center: www.copyright.com . Annual subscription rates: Brazil – R$ 320,00 (until 03/10/12, R$ 300,00); other countries $180.00. Subscription prices outside Brazil must be prepaid. Prices subjected to change without notice. Information: anprev@globo.com; phone (5511) 3884-2042, (5511)3149-6605; fax (5511) 2369-9721. Manuscripts submission: www.scielo.br/anp

The announcer is entirely responsible for the advertisements included in this issue. The authors are fully responsible for the opinions and concepts expressed in the manuscripts published in this issue, which do not necessarily reflect the opinion of the editors.


ACADEMIA BRASILEIRA DE NEUROLOGIA CONDIÇÕES PARA INGRESSO

A

Academia Brasileira de Neurologia (ABN) Ê a sociedade que congrega os neurologistas e os especialistas em neurociências aplicadas em nosso país. É a única sociedade dessas åreas com representatividade. Ela Ê reconhecida pela Associação MÊdica Brasileira (AMB) e pela World Federation of Neurology (WFN). Para poder ingressar na ABN em qualquer categoria o colega deverå estar em dia com o Conselho Regional de Medicina (CRM) e ser associado e estar em dia com a Associação MÊdica Brasileira (AMB) atravÊs de sua Federada Regional (Associação MÊdica local). Os Membros da ABN são admitidos em uma das seguintes categoria: Titular, Efetivo, Aspirante, Associado e Discente. – Titular: É necessårio preencher uma das seguintes condiçþes: possuir Título de Professor Titular de Neurologia, de Docente Livre de Neurologia, ou Professor Adjunto em Neurologia obtido por concurso público de provas e títulos em Faculdade de Medicina do País; possuir grau de Mestre ou Doutor em Neurologia obtido ou reconhecido por Faculdade de Medicina do País; possuir Título de Especialista em Neurologia fornecido pela ABN ou ter completado 100 (cem) crÊditos, de acordo com regulamentação em vigor (consultar a Secretaria-Tesouraria Geral). – Efetivo: É necessårio preencher uma das seguintes condiçþes: possuir Título de Especialista conferido por lei federal e homologado por autoridade competente após ter concluído cursos de Residência MÊdica em Neurologia Clínica; estar exercendo atividade em Neurologia Clínica hå, no mínimo, três anos ou completar 60 (sessenta) crÊditos, de acordo com regulamentação específica deste Estatuto e no Regimento Geral. – Aspirante: Estar cursando Residência em Neurologia em Instituição reconhecida pela ABN. – Associado: Exercer atividade afim à Neurologia (não Ê necessårio ser mÊdico). Preenchidas as condiçþes para a categoria desejada, o interessado deverå enviar à Secretaria-Tesouraria Geral:

s s s s s s

CARTASOLICITANDOADMISSĂŽO CARTADEAPRESENTA ÎODE-EMBROS4ITULARES CURRICULUMVITAERESUMIDO COMPROVANTESDEESTAREMDIACOMO#2-ECOMA&EDERADADA!-" CĂ˜PIADODIPLOMADEGRADUA ÎO DOCUMENTOCOMPROVANDOSUASCREDENCIAISPARAINGRESSARNACATEGORIAĂŒQUALSECANDIDATA

– Discente: É necessårio ser Estudante de Medicina e que faça parte de Liga Acadêmica ligada à neurologia e neurociências, devidamente reconhecida pela Faculdade ou Universidade de origem. A Liga Acadêmica serå responsåvel em enviar todos os anos uma lista com os dados dos acadêmicos interessados, com nome, endereço, telefones de contato, ano de início e tÊrmino do curso, e-mail e número da matrícula, CPF e RG. Maiores informaçþes Rua Vergueiro 1353 - sala 1404 - 14º andar - Torre Norte Top Towers Office - 04101-000 São Paulo / SP Fones: (11) 5084-9463 / 5083-3876 - E-mail: academia@abneuro.org ou visitando: www.abneuro.org


Oi, que bom te ver de novo.

A vida como era antes. Agora.

(1,2)

Rapidez de ação e segurança no tratamento da depressão e depressão associada à ansiedade.(3,4)

RECONTER - OXALATO DE ESCITALOPRAM - 10 MG OU 20 MG COM 10 OU 30 COMPRIMIDOS REVESTIDOS USO ORAL USO ADULTO - INDICAĂ&#x2021;Ă&#x2022;ES tratamento da depressĂŁo, do transtorno do pânico, com ou sem agorafobia; transtorno de ansiedade generalizada (TAG); transtorno de ansiedade social (fobia social). CONTRAINDICAĂ&#x2021;Ă&#x2022;ES: pacientes com hipersensibilidade ao escitalopram ou a qualquer componente da fĂłrmula; e em crianças. Uso concomitante com IMAOS e pimozida. PRECAUĂ&#x2021;Ă&#x2022;ES E ADVERTĂ&#x160;NCIAS: pacientes podem apresentar piora clĂ­nica da depressĂŁo no inĂ­cio do tratamento ou surgimento de pensamento/comportamento suicida; A famĂ­lia dos pacientes em uso de antidepressivos deve ser alertada da necessidade de monitoração do paciente quanto ao aparecimento de agitação, irritabilidade, mudanças no comportamento e outros sintomas, bem como o aparecimento de ideação suicida. Pacientes com depressĂŁo maior, em tratamento com um antidepressivo isolado, podem ter aumentada a probabilidade de precipitação de um episĂłdio manĂ­aco/misto em pacientes de risco para o transtorno bipolar, RECONTER nĂŁo estĂĄ aprovado para uso no tratamento de depressĂŁo bipolar. Reaçþes reportadas quando da interação com um IMAO: OPWLY[LYTPH YPNPKLa TPVJSVU\Z PUZ[HIPSPKHKL H\[VUTPJH JVT WVZZPIPSPKHKL KL Ă&#x2026;\[\Hs LZ YmWPKHZ KVZ ZPUHPZ ]P[HPZ JVUM\ZqV TLU[HS HNP[HsqV WZPJVTV[VYH JVTH ( ZxUKYVTL serotoninĂŠrgica ĂŠ uma reação adversa, potencialmente fatal, causada pela administração de dois ou mais fĂĄrmacos prĂł-serotoninĂŠrgicos como triptofano, IMAO, anfetamina, lĂ­tio, antidepressivos tricĂ­clicos, venlafaxina, buspirona. O uso de ISRS e ISRSN tem sido associado ao desenvolvimento de acatisia Alguns pacientes com transtorno do pânico podem HWYLZLU[HY ZPU[VTHZ KL HUZPLKHKL PU[LUZPĂ&#x201E;JHKVZ UV PUxJPV KV [YH[HTLU[V JVT HU[PKLWYLZZP]VZ YLJVTLUKHZL \TH KVZL PUPJPHS IHP_H 6 TLKPJHTLU[V KL]L ZLY KLZJVU[PU\HKV UH ocorrĂŞncia de convulsĂľes; deve ser evitado em epilepsia instĂĄvel e monitorado nos pacientes com epilepsia controlada. Em portadores de diabetes, pode ocorrer alteração do controle glicĂŞmico. A experiĂŞncia clĂ­nica no uso combinado de ISRSs e ECT ĂŠ limitada. HĂĄ relatos de sangramentos cutâneos anormais (equimose e pĂşrpura) com o uso dos ISRSs. Hiponatremia foi relatada como reação adversa rara com o uso de ISRS; deve-se ter cautela em pacientes de risco como idosos, cirrĂłticos ou em uso concomitante de medicamentos que sabidamente podem causar hiponatremia. Os ISRSs devem ser utilizados com orientação mĂŠdica em pacientes com histĂłrico de mania/hipomania; e devem ser descontinuados em qualquer paciente que entre em fase manĂ­aca. Interrupção do tratamento: deve ser gradual durante 1-2 semanas. Durante o tratamento o paciente nĂŁo deve dirigir veĂ­culos ou operar mĂĄquinas, pois sua habilidade e atenção podem estar prejudicadas. GRAVIDEZ E LACTAĂ&#x2021;Ă&#x192;O: categoria de risco na gravidez: C. Este medicamento nĂŁo deve ser utilizado por mulheres grĂĄvidas sem orientação mĂŠdica ou do cirurgiĂŁo-dentista. O escitalopram ĂŠ excretado no leite materno. O uso do escitalopram durante o terceiro trimestre de gravidez poderĂĄ resultar em distĂşrbios neurolĂłgicos e comportamentais no recĂŠm-nascido. BebĂŞs expostos a ISRS durante a gravidez podem ter risco aumentado de hipertensĂŁo pulmonar persistente (HPP) do recĂŠmnascido. [Chambers et al. (2006)]. INTERAĂ&#x2021;Ă&#x2022;ES COM MEDICAMENTOS, ALIMENTOS E Ă LCOOL: coadministraçþes contraindicadas: IMAOs (tranilcipromina, moclobemida, ou RIMA04(6YL]LYZx]LS"WPTVaPKH"VTLWYHaVS"JPTL[PKPUH"PUPIPKVYLZKH*@7* Ă&#x2026;\V_L[PUHSHUaVWYHaVS[PJSVWPKPUH:xUKYVTLZLYV[VUPUtYNPJH!ZLYV[VUPUtYNPJVZJVTV[YHTHKVSLZ\TH[YPW[HUH Aumento dos nĂ­veis plasmĂĄticos dos fĂĄrmacos: erva-de-sĂŁo-joĂŁo (reaçþes adversas); desipramina; metoprolol. Alteração da função plaquetĂĄria (tendĂŞncias hemorrĂĄgicas): antipsicĂłticos atĂ­picos e fenotiazidas; antidepressivos tricĂ­clicos (maioria); ĂĄcido acetilsalicĂ­lico; AINEs. REAĂ&#x2021;Ă&#x2022;ES ADVERSAS: muito comum: nĂĄuseas. Comuns: diminuição do apetite; ansiedade, inquietude, sonhos anormais, diminuição da libido em homens e mulheres, anorgasmia (feminino); insĂ´nia, sonolĂŞncia, tonturas, parestesias, tremores; sinusite, bocejo; diarreia, constipação intestinal, vĂ´mitos, boca seca; aumento da sudorese; problemas de ejaculação, impotĂŞncia masculina; fadiga, pirexia; artralgia, mialgia; ganho de peso. Incomuns: bruxismo, agitação, irritabilidade, ataques do pânico, estado confusional; alteraçþes do paladar e no sono, sĂ­ncope; epistaxe; hemorragia intestinal; edema; urticĂĄria, alopecia, eritema, prurido (rash); midrĂ­ase, distĂşrbios visuais, tinitus; taquicardia; perda de peso. Raros: agressividade, despersonalização, alucinaçþes, eventos relacionados Ă  ideação suicida; sĂ­ndrome ZLYV[VUPUtYNPJH"YLHsqVHUHĂ&#x201E;Sm[PJH"IYHKPJHYKPH+LZJVUOLJPKVZ!ZLJYLsqVPUHKLX\HKHKVOVYTUPVHU[PKP\Yt[PJVOPWVUH[YLTPH"THUPH"KPZJPULZPHKLZVYKLUZKVTV]PTLU[VJVU]\SZ LZ" priapismo, galactorreia em homens; trombocitopenia; hepatite; equimoses, angioedemas; hipotensĂŁo ortostĂĄtica; retenção urinĂĄria; alteraçþes nos testes de função hepĂĄtica. AplicĂĄveis nJSHZZL[LYHWv\[PJHKVZ0:9:Z!PUX\PL[\KLWZPJVTV[VYHHJH[PZPH7}ZJVTLYJPHSPaHsqV!HULTPHOLTVSx[PJHSL\JVWLUPH[YVTIVJP[VWLUPH-PIYPSHsqVH[YPHSPUZ\Ă&#x201E;JPvUJPHJHYKxHJHPUMHY[V do miocĂĄrdio, torsade de pointes, arritmia ventricular, taquicardia ventricular. Diabetes mellitus, hiperprolactinemia, SIADH. Diplopia, glaucoma. Hemorragia gastrintestinal, pancreatite, OLTVYYHNPH YL[HS /LWH[P[L M\STPUHU[L PUZ\Ă&#x201E;JPvUJPH OLWm[PJH ULJYVZL OLWm[PJH OLWH[P[L 9LHsqV HStYNPJH 7YVSVUNHTLU[V KV PU[LY]HSV 8; WYLKVTPUHU[L LT WHJPLU[LZ JVT KVLUsH cardĂ­aca preexistente, protrombina diminuĂ­da. Hipoglicemia, hipocalemia. RabdomiĂłlise. Acatisia, distĂşrbios extrapiramidais, convulsĂľes, hipoestesia, mioclonus, sĂ­ndrome neurolĂŠptica maligna, nistagmo, crise epilĂŠptica, sĂ­ndrome serotoninĂŠrgica, discinesia tardia. Aborto espontâneo. Psicose aguda, agressĂŁo, raiva, delĂ­rio, pesadelo, paranoia, alucinaçþes visuais. 0UZ\Ă&#x201E;JPvUJPHYLUHSHN\KH7YPHWPZTV,TIVSPZTVW\STVUHY(UNPVLKLTHLX\PTVZLLYP[LTHT\S[PMVYTLYLHsqVKLMV[VZZLUZPIPSPKHKLZxUKYVTLKL:[L]LUZ1VOUZVUULJY}SPZLLWPKtYTPJH [}_PJH\Y[PJmYPH;YVTIVZL]LUVZHWYVM\UKHOPWV[LUZqVOPWV[LUZqVVY[VZ[m[PJHĂ&#x2026;LIP[L[YVTIVZLPOSOLOGIA: administração diĂĄria, em dose Ăşnica, com ou sem alimentos. Tratamento da depressĂŁo e prevenção de recaĂ­das: dose usual: 10 mg/d. Dose mĂĄxima: 20 mg/d. Geralmente, sĂŁo necessĂĄrias 2-4 semanas para obtenção de uma resposta antidepressiva. Tratamento do transtorno do pânico com ou sem agorafobia: dose inicial: 5 mg/d na 1ÂŞ semana do tratamento, antes do aumento da dose para 10 mg/d. Dose mĂĄxima: 20 mg/d.. Tratamento do TAG: dose inicial: 10 mg/d. Dose mĂĄxima: 20 mg/d, apĂłs no mĂ­nimo uma semana de tratamento.. Tratamento do transtorno de ansiedade social (fobia social): dose usual: 10 mg/d; dose pode ser reduzida [atĂŠ 5 mg/d] ou aumentada [ atĂŠ 20 mg/d], dependendo da necessidade. Pacientes idosos (> 65 anos de idade): dose inicial: metade da dose YLJVTLUKHKH L \TH KVZL Tm_PTH THPZ IHP_H *YPHUsHZ L HKVSLZJLU[LZ #  HUVZ KL PKHKL! UqV t YLJVTLUKHKV V \ZV" Z\H ZLN\YHUsH L LĂ&#x201E;JmJPH UqV MVYHT LZ[HILSLJPKHZ ULZ[H WVW\SHsqV0UZ\Ă&#x201E;JPvUJPHYLUHS!UqVtULJLZZmYPVHQ\Z[LKLKVZLLTWHJPLU[LZJVTKPZM\UsqVYLUHSSL]LV\TVKLYHKH5qVL_PZ[LTLZ[\KVZYLHSPaHKVZJVTWHJPLU[LZJVTM\UsqVYLUHS NYH]LTLU[LYLK\aPKH0UZ\Ă&#x201E;JPvUJPHOLWm[PJHWHJPLU[LZJVTWYVISLTHZUHTL[HIVSPaHsqVWLSH*@7* !KVZLPUPJPHS!TNKK\YHU[LHZWYPTLPYHZZLTHUHZKV[YH[HTLU[VWVKLUKV ser aumentada atĂŠ 10 mg/d. DESCONTINUAĂ&#x2021;Ă&#x192;O: redução da dose deve ser gradual durante 1-2 semanas, para evitar possĂ­veis sintomas de descontinuação. Reg. MS 1.0033.0156/ -HYT9LZW!*PU[PH+LSWOPUVKL(UKYHKL*9-:7U¢30)):-(94(*Ă&#x152;<;0*(3;+(*5719\H(SILY[V*VYYLPH-YHUJMVY[,TI\:70UKÂ&#x201A;Z[YPHIYHZPSLPYH RECONTER-MB01-11/Serviço de Atendimento LIBBS: 08000-135044. VENDA SOB PRESCRIĂ&#x2021;Ă&#x192;O MĂ&#x2030;DICA. SĂ&#x201C; PODE SER VENDIDO COM RETENĂ&#x2021;Ă&#x192;O DA RECEITA. RECONTER ĂŠ um medicamento. Durante seu uso, nĂŁo dirija veĂ­culos ou opere mĂĄquinas, pois sua agilidade e atenção podem estar prejudicadas. A persistirem os sintomas, o mĂŠdico deve ser consultado. +VJ\TLU[HsqVJPLU[xĂ&#x201E;JHLPUMVYTHs LZHKPJPVUHPZLZ[qVnKPZWVZPsqVKHJSHZZLTtKPJHTLKPHU[LZVSPJP[HsqV

CONTRAINDICAĂ&#x2021;Ă&#x192;O: Uso concomitante com IMAOs. 05;,9(h²64,+0*(4,5;6:(!*VTPUPIPKVYLZKH*@7* JVTVĂ&#x2026;\V_L[PUHL[PJSVWPKPUH

/(21$5'%7$</25'(VFLWDORSUDPWUDQVODWLQJPROHFXODUSURSHUWLHVLQWRFOLQLFDOEHQHĂ&#x20AC;WUHYLHZLQJWKHHYLGHQFHLQPDMRUGHSUHVVLRQ-3V\FKRSKDUPDFROYQS*$512&.-21(6.3 0F&250$&.3/(VFLWDORSUDPDUHYLHZRILWVXVHLQWKHPDQDJHPHQWRIPDMRUGHSUHVVLYHGLVRUGHULQDGXOWV&16'UXJVYQS5$217KH&OLQLFDO3KDUPDFRNLQHWLFVRI(VFLWDORSUDP&OLQ 3KDUPDFRNLQHWYQS5(&217(5Â&#x160; HVFLWDORSUDP 6mR3DXOR/LEEV)DUPDFrXWLFD/WGD%XODGH0HGLFDPHQWR


Apoio Ă  PrĂĄtica da Medicina desde 1929. Com muito entusiasmo continuamos a produzir o que hĂĄ de melhor em lĂ­quor no Brasil, desde a coleta atĂŠ o mais refinado dos exames. E o fazemos com disciplina, com modĂŠstia e com paixĂŁo. Buscamos o diagnĂłstico tĂŁo preciso quanto necessĂĄrio, dentro dos mais sadios princĂ­pios da medicina.

AlĂŠm do exame clĂĄssico o LaboratĂłrio de LĂ­quor Spina França tambĂŠm oferece: s )SOELETROFOCALIZAĂ&#x20AC;âOCOM)MUNOBLOTTING E)MUNOFIXAĂ&#x20AC;âOEMSOROEL¤QUOR s 0ESQUISADEANTICORPOSPARAPARASITAS BACTÂŁRIAS FUNGOSEV¤RUS s $IAGNÂ&#x2DC;STICOIMUNOLÂ&#x2DC;GICODENEUROBORRELIOSEDOENĂ&#x20AC;ADE,9-% S¤MILE S¤NDROME DE"AGGIO 9OSHINARI  s 0#2PARA"ORRELIA "RUCELLA 6¤RUSDA#ORIOMENINGITE ,INFOCITĂ&#x2013;RIA %NTEROV¤RUS (ERPESV¤RUS (36 (36 6:6 #-6 %"6 ((6 ((6 ((6 ()6 CARGA VIRAL *# V¤RUS ,EPTOSPIRA ,ISTERIA -ICOBACTERIAS .EISSERIA 0NEUMO E OUTROSAGENTES s 0ROTE¤NA#REUTZFELDT *AKOB 

Parceiros ,IM &-530 ,IM &-530 ,IM &-530 ,IM &-530 ,ABORATÂ&#x2DC;RIO&LEURY ,ABORATÂ&#x2DC;RIO(#OR #ENTRODE'ENOMAS

s -ARCADORES DE $EMäNCIA ` !MILÂ&#x2DC;IDE 0ROTE¤NASo e P-o s )MUNOFENOTIPAGEME#ITOMETRIADE&LUXO

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LOGO EPÉZ - QUADRICROMIA

Registro M.S. Número: 1.0525.0040

É UM PRIVILÉGIO ESCREVER A PRÓPRIA HISTÓRIA DO COMEÇO AO FIM.

Uma nova leitura na história do paciente com Alzheimer.

www.torrentonline.com.br www.torrentonline.com.br www.torrentonline.com.br

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(7)

font acciden presidency

Único IAChE aprovado para todas as fases da DA.(1,2,3) Menor incidência de eventos adversos quando comparado aos outros IChE.(4) www.torrentonline.com.br www.torrentonline.com.br www.torrentonline.com.br Melhora a qualidade de vida do paciente e de seus cuidadores.(5)

Menor custo do mercado

(6)

Apresentação

Caixa com 30 comprimidos; o equivalente a 1 mês de tratamento.

Opção de adquirir o medicamento mais rapidamente, sem a burocracia dos tratamentos de alto custo.

Contraindicação: pacientes com hipersensibilidade ao cloridrato de donepezila. Interação Medicamentosa: fenitoína e carbamazepina.

Epéz é um medicamento. Durante o seu uso, não dirija veículos ou opere máquinas, pois sua agilidade e atenção podem estar prejudicadas.

EPÉZ (cloridrato de donepezila). Registro MS nº 1.0525.0040. USO ADULTO. Composição, forma farmacêutica e apresentações: EPÉZ 5 mg: cada comprimido contém 5 mg de cloridrato de donezepila; embalagens contendo 10 ou 30 comprimidos revestidos. EPÉZ 10 mg: cada comprimido contém 10 mg de cloridrato de donezepila; embalagens contendo 30 comprimidos revestidos. Indicações: Doença de Alzheimer de intensidade leve, moderadamente grave e grave. Contraindicações: em pacientes com hipersensibilidade à donepezila, a derivados de piperidina ou a qualquer componente da formulação. Precauções e advertências: pode exacerbar o relaxamento muscular durante anestesia. Pode causar bradicardia, podendo ser particularmente importante em pacientes com alteração do nó sinoatrial ou outras de condução cardíaca supraventricular. Pacientes com maior risco de desenvolver úlceras devem ser cuidadosamente monitorados quanto a sintomas de sangramento gastrintestinal ativo ou oculto. Pode causar obstrução do fluxo vesical e convulsões generalizadas, embora a última situação pode ser também uma manifestação da Doença de Alzheimer. Deve-se ter cuidado em pacientes com história de asma ou doença pulmonar obstrutiva. Gravidez: somente deve ser usado durante a gravidez se o benefício em potencial da medicação justificar o risco potencial para o feto. Categoria de risco à gravidez: C - Este medicamento não deve ser utilizado por mulheres grávidas sem orientação médica ou do cirurgião-dentista. Lactação: não está indicado. Pediatria: não há dados para documentar a sua segurança e a eficácia em crianças. Idosos: as concentrações sanguíneas médias de donepezila são comparáveis àquelas observadas em jovens voluntários saudáveis. Interações medicamentosas: não há informações sobre o efeito da donepezila na depuração de drogas metabolizadas pela CYP3A4 (cisaprida e terfenadina) ou pela CYP2D6 (imipramina). O cetoconazol e a quinidina inibem o metabolismo da donepezila in vitro. Não se sabe se esses inibidores possuem um efeito clínico. A fenitoína, carbamazepina, dexametasona, rifamicina e o fenobarbital podem aumentar a taxa de eliminação da donepezila. O produto pode interferir com a atividade de medicamentos anticolinérgicos. Pode-se esperar um efeito sinérgico quando a donepezila for administrada concomitantemente com succinilcolina, agentes bloqueadores neuromusculares semelhantes ou agonistas colinérgicos, tais como o betanecol. Reações adversas: as mais comuns que determinaram a interrupção do tratamento foram: náusea, diarreia e vômitos. Outras possíveis: cefaleia, dores generalizadas, fadiga, síncope, anorexia, equimose, perda de peso, artrite, cãibras musculares, insônia, tontura, depressão, sonolência, sonhos anormais, micção frequente, dor no peito, dor de dente, hipertensão, vasodilatação, fibrilação atrial, fogachos, hipotensão, incontinência fecal, sangramento gastrintestinal, distensão abdominal, dor epigástrica, desidratação, delírios, tremor, irritabilidade, parestesia, agressividade, vertigem, ataxia, aumento de libido, choro anormal, nervosismo, afasia, dispneia, prurido, urticária, catarata, irritação ocular, visão turva, incontinência urinária, noctúria, agitação, colecistite, confusão, convulsões, alucinações, pancreatite e “rash”. Posologia: Adultos/Idosos: o cloridrato de donepezila deve ser tomado por via oral, uma vez por dia. As doses clinicamente eficazes são 5 mg e 10 mg nos pacientes com doença leve a moderadamente grave. A dose de 10 mg é a dose clinicamente eficaz nos pacientes com doença grave. A dose inicial é de 5 mg e pode ser aumentada para 10 mg após 4 a 6 semanas. O dose diária máxima recomendada é de 10 mg. Doses maiores que 10 mg/dia ainda não foram estudadas em estudos clínicos de grande escala. Com a descontinuação do tratamento, observa-se diminuição gradativa dos efeitos benéficos do cloridrato de donepezila. Não há evidências de efeito rebote ou de abstinência após a descontinuação repentina da terapia. Tratamento de Manutenção: pode ser mantido enquanto houver benefício terapêutico para o paciente. Comprometimento Renal e Hepático: os pacientes com insuficiência hepática leve a moderada ou renal podem seguir um esquema posológico semelhante porque a depuração do cloridrato de donepezila não é significativamente alterada por essas condições. Crianças: não existem estudos adequados e bem-controlados para documentar a segurança e a eficácia do cloridrato de donepezila emwww.torrentonline.com.br qualquer tipo de doença que ocorra em crianças. EPÉZ deve ser tomado à noite, antes de deitar. Poderá ser tomado com ou sem alimentos. A dose www.torrentonline.com.br www.torrentonline.com.br não deve ser duplicada caso o paciente esqueça uma dose. (Jul 10). VENDA SOB PRESCRIÇÃO MÉDICA. SÓ PODE SER VENDIDO COM RETENÇÃO DE RECEITA. AO PERSISTIREM OS SINTOMAS, O MÉDICO DEVERÁ SER CONSULTADO”.

LOGO EPÉZ - PB

REFERÊNCIAS BIBLIOGRÁFICAS: 1) Bula Epéz. 2) Bula Excelon. 3) Bula Reminyl. 4) Hansen RA et al. “Efficacy and safety of donepezil, galantamine and rivastigmine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis.” Clin Interv Aging 2008;3(2):211-25. 5) Wimo A et al. “Impact of donepezil treatment for Alzheimer’s disease on caregiver time.” Curr Med Res Opin 2004; 20(8): 1221-5. 6) Revista ABCFARMA, dezembro de 2011. 7) “An Open Label, Randomised, 2-Period, 2-Treatment, 2-Sequence, Crossover, Single-Dose Bioequivalence Study of Donepezil Hydrochloride 10 mg tablet (Test formulation;Torrent Pharmaceuticals Ltd., India) versus Eranz® 10 mg tablet (Reference formulation; Wyeth-Whitehall Ltda., Brazil) in Healthy Human Volunteers under Fasting Conditions. May 2008 (Study Code: PK-07-103).

www.torrentonline.com.br www.torrentonline.com.br www.torrentonline.com.br


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ALOIS® – cloridrato de memantina – FORMA FARMACÊUTICA, VIA DE ADMINISTRAÇÃO E APRESENTAÇÃO: Uso oral. Comprimidos revestidos de 10 mg. Caixas com 30 e 60 comprimidos. USO ADULTO. INDICAÇÕES DO MEDICAMENTO: ALOIS® é indicado na Doença de Alzheimer moderadamente grave a grave e em outras demências caracterizadas por distúrbios da função cerebral, com os seguintes sintomas principais: distúrbios da concentração e memória, perda de interesse e distúrbios das funções motoras necessárias para efetuar atividades diárias e humor deprimido (síndrome demencial), condições que requerem aumento do cuidado e da vigilância. É indicado também no tratamento da espasticidade cerebral e espinhal, como por exemplo, resultante de disfunção cerebral em crianças, traumatismos cranianos, esclerose múltipla, paraplegia, acidentes vasculares encefálicos, Doença de Parkinson e síndromes parkinsonianas. CONTRAINDICAÇÕES: ALOIS (cloridrato de memantina) é contraindicado em pacientes com hipersensibilidade à memantina, à amantadina ou aos componentes da formulação do produto. PRECAUÇÕES E ADVERTÊNCIAS: Durante o tratamento o paciente não deve dirigir veículos ou operar máquinas, pois sua habilidade e atenção podem estar prejudicadas. Deve-se ter precaução nos pacientes em estados graves de confusão mental e em pacientes em tratamento com outros medicamentos que atuam no Sistema Nervoso Central. A memantina deve ser utilizada com cuidado em pacientes com disfunção renal e hepática e epilepsia. Gravidez: Não há estudos adequados e bem controlados sobre a segurança do uso de memantina em mulheres grávidas. Os estudos em animais não demonstraram efeitos lesivos em relação à embriotoxicidade e teratogenicidade. Lactação: É provável que a memantina seja excretada no leite materno, com isso, cuidados especiais devem ser tomados quando o produto for prescrito a mulheres que estejam amamentando. INTERAÇÕES MEDICAMENTOSAS: O uso de bebidas alcoólicas pode interferir na ação do ALOIS (cloridrato de memantina) podendo causar efeitos desagradáveis. O efeito dos seguintes medicamentos pode ser alterado pela memantina e suas doses devem ser ajustadas pelo médico:- amantadina, cetamina, dextrometorfano;dantroleno, baclofeno;- cimetidina, ranitidina, procainamida, quinidina, quinina, nicotina; - hidroclortiazida; - agonista dopaminérgico, como a L-dopa, bromocriptina. - anticolinérgicos, anticonvulsivantes, barbituratos e neurolépticos e inibidores da MAO. O uso de bebidas alcoólicas pode interferir na ação do ALOIS® (cloridrato de memantina) podendo causar efeitos desagradáveis. REAÇÕES ADVERSAS: Nos testes clínicos sobre demências moderadamente graves a graves, a incidência geral de efeitos adversos não foi diferente das do tratamento com o placebo, e os efeitos adversos foram geralmente de gravidade leve ou moderada. A seguinte tabela fornece uma análise geral dos eventos adversos

mais frequentes, independentes da relação causal (> 4% para a memantina), que foram observados em pacientes com demência moderadamente grave a grave. Termo preferido Memantina Placebo (WHO ART) n=299 n=288 Agitação 27 (9,0%) 50 (17,4%) Aparecimento de lesões 20 (6,7%) 20 (6,9%) Incontinência urinária 17 (5,7%) 21 (7,3%) Diarreia 16 (5,4%) 14 (4,9%) Insônia 16 (5,4%) 14 (4,9%) Tontura 15 (5,0%) 8 (2,8%)

Termo preferido (WHO ART) Dor de cabeça Alucinações Queda Constipação Tosse

Memantina n=299 15 (5,0%) 15 (5,0%) 14 (4,7%) 12 (4,0%) 12 (4,0%)

Placebo n=288 9 (3,1%) 6 (2,1%) 14 (4,9%) 13 (4,5%) 17 (5,9%)

Os efeitos colaterais são leves a moderados. As reações adversas mais comuns são alucinações, confusão, tontura, cefaleia e cansaço. As reações adversas menos frequentes são ansiedade, hipertonia (aumento do tônus muscular), vômito, cistite e aumento da libido. Em pacientes que já apresentaram ataque epilético, existe a possibilidade da memantina aumentar a chance de um novo ataque. POSOLOGIA: A dose recomendada de ALOIS® (cloridrato de memantina) para pacientes idosos e adultos é 20 mg (2 x 1 comprimido) diariamente. Para reduzir o risco de efeitos colaterais esta dose é gradualmente alcançada pelo seguinte esquema de tratamento diário: Manhã 1ª. Semana 2ª. Semana

Tarde ½ compr ½ compr

Nenhum ½ compr

Manhã Tarde 3ª. Semana 1 compr ½ compr 4ª. Semana e demais semanas 1 compr 1 compr

A dose inicial usual, na primeira semana é de meio comprimido uma vez ao dia (1 x 5 mg). Na segunda semana, a dose é aumentada para meio comprimido duas vezes ao dia (2 x 5 mg) e para 1 comprimido (1 x 10 mg) e meio comprimido (1 x 5 mg) diariamente, administrados separadamente, na terceira semana. A partir da quarta semana, a dose usual é de um comprimido duas vezes ao dia (2 x 10 mg). Os comprimidos devem ser ingeridos com um pouco de água, junto das refeições ou lanches. Em pacientes com disfunção renal, a dose deve ser ajustada, baseada na eficácia clínica terapêutica bem como na função renal do paciente, sendo que a mesma deve ser monitorada frequentemente. VENDA SOB PRESCRIÇÃO MÉDICA. SÓ PODE SER VENDIDO COM RETENÇÃO DA RECEITA. Reg. MS nº 1.0118.0592.

Contraindicações: ALOIS (cloridrato de memantina) é contraindicado em pacientes com hipersensibilidade à memantina, à amantadina ou aos componentes da formulação do produto. Interações medicamentosas: O uso de bebidas alcoólicas pode interferir na ação do ALOIS (cloridrato de memantina) podendo causar efeitos desagradáveis.

ALOIS® (cloridrato de memantina) é um medicamento. Durante seu uso, não dirija veículos ou opere máquinas, pois sua agilidade e atenção podem estar prejudicadas. Referências Bibliográficas: 1. Reisberg B, Doody R, Stoffler A, et al. Memantine in moderate-to-severe Alzheimer’s Disease N Engl J Med 2003; 348:1333-41. 2. Thomas SJ, Grossberg GT Memantine: a review of studies into its safety and efficacy in treating Alzheimer’s Disease and other dementias Clinical Interventions in Aging 2009 4: 367-77. 3. Bula do produto.


Table of Contents

Volume 70, Number 1, January, 2012, São Paulo, SP, Brazil

EDITORIALS 1 The 70 years of Arquivos de Neuro-Psiquiatria Os 70 anos de Arquivos de Neuro-Psiquiatria LR Machado, JA Livramento

2

How much radiologically isolated syndrome suggestive of multiple sclerosis is multiple sclerosis? O quanto a síndrome radiológica isolada sugestiva de esclerose múltipla é realmente esclerose múltipla?

MA Lana-Peixoto

ARTICLES 5 Incidental demyelinating inflammatory lesions in asymptomatic patients: a Brazilian cohort with radiologically isolated syndrome and a critical review of current literature Desmielinização inflamatória incidental em indivíduos assintomáticos: uma coorte brasileira com síndrome radiológica isolada e uma revisão crítica da literatura atual ACM Maia Jr., AJ Rocha, BR Barros, CP Tilbery

12

Clinical predictors of response to immunomodulators for multiple sclerosis Preditores clínicos de resposta aos imunomoduladores em esclerose múltipla

GS Olival, LCP Lima, GPS Lima, CP Tilbery

17

Accuracy of prospective memory tests in mild Alzheimer’s disease Acurácia dos testes de memória prospectiva na doença de Alzheimer leve

SP Martins, BP Damasceno

22 Translation, cultural adaptation and psychometric evaluation of the Leganés cognitive test in a low educated elderly Brazilian population Tradução, adaptação cultural e avaliação psicométrica da prova cognitiva de Leganés em uma população idosa brasileira com baixo nível educacional VVA Caldas, MV Zunzunegui, ANF Freire, RO Guerra

28

Autism spectrum disorder and celiac disease: no evidence for a link Transtorno autístico e doença celíaca: sem evidências de associação

IC Batista, L Gandolfi, YKM Nobrega, RC Almeida, LM Almeida, D Campos Jr., R Pratesi

34 The impact of EEG in the diagnosis and management of patients with acute impairment of consciousness Impacto do EEG no diagnóstico e conduta dos pacientes com alteração aguda do estado da consciência JAG Ricardo, MC França Jr., FO Lima, CL Yassuda, F Cendes

40

Devising and validating a headache diary in a series of patients with chronic daily headache from Colombia Diseño y validación de un diario de cefalea en pacientes con cefalea crónica diaria en Colombia

GF Torres, MI Otálvaro, FO Lima, JC Vargas, Y Castellanos, J Xiomara-García, JD Triana, CA Forero, CD Guevara, R Pardo

45

Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis Alteraciones morfológicas en las mitocondrias en la piel de enfermos con esclerosis lateral amiotrófica esporádica

GE Rodríguez, DMC González, GMG Monachelli, JJL Costa, AF de Nicola, REP Sica

52

Cyclosporin safety in a simplified rat brain tumor implantation model Segurança do tratamento com ciclosporina em um modelo pré-clínico de tumor cerebral experimental em ratos

FHC Felix, JB Fontenele, MG Teles, Neto JE Bezerra, MHAM Santiago, RL Picanço Filho, DB Menezes, GSB Viana, MO Moraes


Table of Contents VIEWS AND REVIEWS 59 Treatment of neuromyelitis optica: an evidence based review Tratamento da neuromielite óptica: uma revisão baseada em evidências

D Sato, D Callegaro, MA Lana-Peixoto, K Fujihara, on behalf of Brazilian Committee for Treatment and Research in Multiple Sclerosis (BCTRIMS)

LETTERS 67

A rare cause of recurrent peripheral facial palsy Uma causa rara de paralisia facial periférica recorrente

J Pinho, S Rocha, Á Machado, E Lourenço

69

Multiple subcortical strokes caused by mucormycosis in a patient with lymphoma Múltiplos infartos subcorticais causados por mucormicose em paciente com linfoma

PEJ Caballero, AMF García, JCP Cuenca, IC Naranjo

71

Cervical myelopathy caused by ligamentum flavum ossification Mielopatia cervical por ossificação do ligamento amarelo

WS Paiva, MS Soares, LS Bernardo, RS Brock, MJ Teixeira

73

Facial somatosensorial evaluation in idiopathic trigeminal neuralgia Avaliação somatosensitiva facial em neuralgia idiopática do trigêmeo

LA da Silva, SRDT de Siqueira, JTT de Siqueira, MJ Teixeira

75

Meningioma after immunomodulation for multiple sclerosis Meningioma após imunomodulação em esclerose múltipla

Vieira RGK, Vale TC, Rocha CF, Araújo CR, Lana-Peixoto MA, on behalf of the Brazilian Committee for Treatment and Research in Multiple Sclerosis (BCTRIMS)

IMAGES IN NEUROLOGY 77

Magnetic resonance appearance of recurrent ophthalmoplegic migraine Aspectos de ressonância magnética na enxaqueca oftalmoplégica recorrente

AJ da Rocha, P Breinis, MLR Monteiro

78

“Black turbinate sign”: a potential predictor of mucormycosis in cavernous sinus thrombophlebitis “Sinal da concha preta”: um potencial preditor de mucormicose nas tromboflebites do seio cavernoso

DM Nunes, AJ Rocha, M Rosa Jr. , CJ Silva

THESES 79

Peripheral biomarkers in bipolar disorder: a population-based study in young adults Biomarcadores periféricos no transtorno bipolar: um estudo de base populacional em adultos jovens

PV Silva

79 Severity and functional ability scale for amyotrophic lateral sclerosis patients Escala de gravidade e habilidade funcional em pacientes com esclerose lateral amiotrófica MA Orsini

Opinion 81 Spontaneous spinal epidural hematoma during pregnancy Hematoma extradural espinhal espontâneo durante a gravidez S Matsubara

82 NOTICES AND COMMENTS


Editorial

The 70 years of Arquivos de Neuro-Psiquiatria Os 70 anos de Arquivos de Neuro-Psiquiatria Luís dos Ramos Machado, José Antonio Livramento

Editors

T

he journal Arquivos de Neuro-Psiquiatria will reach its 70th anniversary in 2012. It came into being Oswaldo Lange’s idealism and, with firm support from Tolosa and Longo, the first issue of Arquivos de Neuro-Psiquiatria was published in June, 1943. Since then, it has maintained absolute regularity of publication, without any delays, despite the immense difficulties faced by its editors, especially in the early years. Certain milestones are emblematic of its progress: the international indexations, starting with the National Lending Library of Medicine (NLL) in 1947, and including Medline (1966), ISI (1969), Scopus (1998), and SciELO (1999); the outstanding performance of Antonio Spina França Netto as the editor in chief starting in 1986, when the form and content of the journal were renewed and modernized; the adoption of the peer review system, starting in 1988; the entry into SciELO and the open-access system, starting in 1999; the adoption of the English language for all studies, starting in 2009; and the professionalization of the journal, starting in 2010. The problems that surround the editing process of Arquivos de Neuro-Psiquiatria in the current editorial world are neither small nor easy to resolve. There is a universal trend for large publishers to absorb small journals; shortage of resources; difficulties in achieving improvements in the impact factor; resistance among many Brazilian researchers against publishing their studies with use, despite the enormous visibility that the journal provides for authors and their manuscripts; obstinate refusal of many Brazilian authors to cite studies published in Arquivos de Neuro-Psiquiatria; sparse institutional support from funding bodies; official policies for stimulating scientific production that end up penalizing Brazilian journals; and many operational difficulties, which are often unexpected. Nonetheless, we can also count on some major support: researchers who continue to publish with us despite having other opportunities abroad; our Area Supervisors; our Reviewers; our Editorial Board; our International Consultative Board; our Editorial Advisers; the Brazilian Academy of Neurology (Academia Brasileira de Neurologia); SciELO; CNPq/CAPES; our Subscribers; and our Advertisers. Through everyone’s dedicated participation, for which we give our hearty thanks, we have gained the nourishment and resources that allow us to continue our endeavors and, especially, to dream of a Brazilian journal with greater international projection. How should we commemorate the 70th anniversary of this journal? It is very simple: by following the example of the Editors who preceded us, or in other words, by always working harder. In this regard, the following innovations will be implemented. Arquivos de Neuro-Psiquiatria is going to start to be published every month, starting in 2012. Thus, there will be 12 issues instead of the present 6 ones. We believe that in this manner, the editorial process will gain in quality and speed. We will also adopt the Ahead of Print publication system, thereby ensuring that authors have full visibility for their studies online, as soon as the editorial process has been completed, without the need to wait for formal publication. We are going to insert Arquivos de Neuro-Psiquiatria into iPad; and we will create closer ties with the Brazilian Academy of Neurology through a broader and more encompassing partnership. We have been able to count on exceptional collaboration, already at the ready and highly qualified, to work hard with us, especially over the last two years, when we started a wide-ranging policy of opening up to lists of new direct collaborators. We would like very much to hear any criticisms and suggestions from our readers, authors, reviewers, and neuroscience researchers, no matter whether these in relation to modifications to the journal’s format, changes to its content, or even changes to strategic aspects of the journal. We hope that we can continue to reliably count on everyone’s participation and support. Arquivos de Neuro-Psiquiatria will certainly be the journal for all Brazilian neurologists and neuroscientists. Larger, visually more attractive, more representative, more modern, and also increasingly cited.

1


Editorial

How much radiologically isolated syndrome suggestive of multiple sclerosis is multiple sclerosis? O quanto a síndrome radiológica isolada sugestiva de esclerose múltipla é realmente esclerose múltipla? Marco Aurélio Lana-Peixoto

MD, PhD CIEM MS Research Center, Medical School of the Federal University of Minas Gerais, Belo Horizonte MG, Brazil. Correspondence: Marco A. Lana-Peixoto Rua Padre Rolim, 769 – Sala 1.301; 30130-090 – Belo Horizonte MG-Brasil E-mail: marco.lanapeixoto@gmail.com Conflict of interest: There is no conflict of interest to declare. Received 07 October 2011 Received in final form 14 October 2011

2

I

n spite of the progress in Neuroimmunology, a specific biomarker for the diagnosis of multiple sclerosis (MS) remains to be defined. Meanwhile, as growing enthusiasm has been associated with the development of new therapeutic options and the recent evidence that the disease-modifying agents may be more beneficial for MS patients if initiated as early as possible following disease onset1, investigators and clinicians alike continuously search for early signs of the disease. The incorporation of specific magnetic resonance imaging (MRI) features for dissemination in space and in time2,3 into the diagnostic criteria for MS by the International Panel4 and their revisions in 20055 and 20106 have allowed the earlier diagnosis of MS in patients, who still lack complete clinical evidence of dissemination in both space and time. However, the occurrence of symptoms consistent with neurologic dysfunction of the central nervous system still lingers as a basic requirement for its diagnosis. Additionally, as long as a specific biomarker is not introduced into clinical practice, alternative diagnoses must be excluded. The diagnosis of MS is particularly challenging in a group of patients who present no history of symptoms consistent with MS or objective signs of neurologic dysfunction, whose brain MRI shows abnormal signals with spatial dissemination, which is highly suggestive of demyelinating disease. Such findings have been described in first-degree relatives of patients with MS who are at particular risk7, in some subjects with history of psychiatric disorders8, and surprisingly in other patients who undergo MRI scans for reasons that were not related to the MS investigation. The term radiologically isolated syndrome (RIS) was recently introduced to describe these individuals9. In this Issue of Arquivos de Neuro-Psiquiatria, Maia Júnior et al.10 report their observations on the clinical and imaging features of 12 Brazilian patients with RIS during a median follow-up period of 49 months. Reasons for acquisition of brain MRI in their cohort as in other published series varied widely. The most frequent reasons for the first MRI scan in RIS patients in the reported series included migraine and other types of headache; trauma and radiculalgia; depression; epilepsy; endocrinopathies; and cognitive dysfunction. One half of the patients in the Brazilian cohort showed temporospatial dissemination of the MRI lesions on a second MRI scan during the follow-up period, whereas two subjects developed symptoms of neurologic dysfunction, as a clinically isolated syndrome (CIS), or recurring symptoms compatible with the diagnosis of clinically definite MS (CDMS). Similar features of the Brazilian series had already been demonstrated in a French cohort in the initial description of RIS, in 200811, and in subsequent published series9,12,13. In the published cohorts, during the follow-up period, many patients not only developed an increased number of T2-lesions on MRI, an evidence of temporospatial dissemination – and therefore MS by MRI criteria, but they also exhibited clinical manifestations of central nervous system dysfunction. This clinical eloquence could either take the form of CIS or CDMS. Additionally, patients with RIS, CIS or CDMS have a number of common epidemiological and imaging features, which differ from healthy controls.


The more the RIS patients have paraclinical abnormalities, such as gadolinium enhancement in brain MRI and presence of oligoclonal bands or increased IgG index on the cerebrospinal fluid (CSF), the earlier the first neurological symptom occurs9,12,13. Patients who also develop increased number of MRI lesions during the follow-up period are also at higher risk of developing CDMS9,12,13. In a study of 70 RIS subjects during a mean follow-up period of 5.2 years, it was observed that 91% of them developed new MRI lesions, 37% of which with gadolinium enhancement12. A clinical event occurred in 33% of the individuals, with the same clinical expression as classically described in CIS14 in a mean time of 2.3 years. Eight patients showed progression to CDMS, but no one had progressive MS12. Like unanticipated brain spatial dissemination of MRI lesions in the absence of clinical symptoms consistent with MS, MRI abnormal signals in the spinal cord in asymptomatic individuals are occasionally found, either following the finding of unanticipated brain MRI, or during orthopedic or medical workup. In a recent paper, Okuda et al.15 reported their findings on 71 RIS patients who had cervical spine MRI scans acquired prior to the development of the first clinical event. Cervical spinal cord abnormal signals highly suggestive of MS were disclosed in 25 patients (35%), whereas clinical progression to CIS or primary progressive MS was observed in 21 (84%) of the 25 subjects over a median time of 1.6 years. Only three patients out of 46, who did not have spinal cord lesions, developed a clinical event. The diagnostic predictive value of an asymptomatic spinal cord lesion in subjects with RIS for development of CIS or PPMS had a sensitivity of 87.5%, specificity of 91.5% and positive predictive value of 84%. These observations support the view that asymptomatic subjects who possess MRI abnormal signals in both brain and cervical spinal cord, in comparison with the brain alone, are at high risk for developing clinical MS15. Many authors consider RIS as a form of “pre-clinical MS”9,11-13. Notwithstanding, most RIS subjects develop new MRI lesions in the course of time – dissemination in space and time. Some subjects still remain free from neurological symptoms to have their brain lesions only uncovered at the autopsy16. However, if one takes into account cognitive function appropriately assessed by a neuropsychological battery, the proportion of RIS subjects with silent lesions may be much lower. Cognitive impairment has been found in up to 70% in MS, it is present in patients in early stages of disease, it is only mildly associated with functional status as measured by the expanded disability status scale, and may be even identified in patients with CIS17. It affects several aspects of the higher cortical functioning including attention, information processing efficiency, executive functioning, processing speed, and longterm memory, although processing speed and visual learning and memory are most frequently impaired17. In this line of evidence, a recent paper18 showed that out of 26 RIS subjects

who underwent neuropsychological evaluation none had a strictly normal cognitive function. When compared with healthy controls, the speed of information processing, executive functions and short-term memory were the most consistently cognitive functions impaired in RIS and MS patients. Differences between RIS and MS patients were seen only in the difficulty of performing executive tasks and in the shortterm memory. No correlation was found between sites and number of MRI lesions using Barkhof–Tintore criteria and cognitive dysfunction18. Other investigators have found that T1 hypointense and T2 hyperintense lesion volumes in MS patients are predictive factors for impaired performance in at least one cognitive test19. As a result of the cognition impairment, RIS subjects may present fewer social and vocational activities, higher rate of unemployment, and greater difficulties in performing routine household tasks, being still more vulnerable to psychiatric illness than individuals with a purely physical disability20. Likewise, as cognition impairment has a direct impact on the quality of life (QoL), which is decreased in MS patients21, it is expected that future studies will demonstrate decreased QoL in subjects with RIS. However, neuropsychological assessment may depict high frequency of cognitive impairment with deficit of attention and concentration, impairment of executive functions, decreased speed of information processing, and involvement of short-term memory22. These cognitive changes are similar to those found in MS patients, but RIS subjects are usually less severely affected than MS ones18. This finding is in agreement with the early occurrence of cognitive impairment in MS and even its observation in CIS patients23,24. Although RIS and MS patients have striking similarities on their conventional MRI features, the use of quantitative MR indices has provided evidences of their differences, as well as an explanation for the lack of clinical expression in RIS subjects25. Whereas other MRI metrics have shown that RIS and RRMS patients have values of global and tissue-specific volumes, which are similarly lower than those found in healthy controls, magnetization transfer ratio (MTr) imaging that provides information on tissue integrity at the cellular level, is much milder in RIS than in RRMS. MTr values in the normal-appearing brain were similar in RIS subjects and in healthy controls, but they were much higher than those in RRMS patients. Interestingly enough it was found that the areas with lower MTr in EMRR subjects as compared with RIS were the very eloquent ones, as they are usually deeply involved in pathological substrate of the disease. It is probable that RIS subjects may have a milder degree of demyelination or a better repair response to insult25. By using MRI metrics, the authors25 demonstrated the probability of 13/19 (70%) RIS patients of being RRMS. Interestingly predictive factors included abnormal CSF (10/10 subjects), dissemination in time in a new MRI

Lana-Peixoto MA. How much RIS is MS?

3


scan (9/10 subjects) and a positive cervical spine MRI (6/7 subjects). As Maia Junior et al.10 emphasize in their analysis of the Brazilian series, “all patients with RIS should be considered to have high risk of developing MS”. However, neurologists must take into consideration all predictive factors of conversion of

RIS in clinical MS, as well as the information provided by appropriate imaging techniques to grade this risk. Certainly in the near future, the introduction of both, more sharpened imaging techniques, and more efficacious and safer drugs will allow neurologists to make better judgments on starting therapy much earlier on these patients.

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Comi G. Shifting the paradigm toward the earlier treatment of multiple sclerosis with interferon beta. Clin Ther 2009;31:1142-1157.

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Barkhof F, Filippi M, Miller DH, et al. Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 1997;120:2059-2069.

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Maia Junior AC, Rocha JA, Barros BR, Tilbery CP. Incidental demyelinating inflammatory lesions in asymptomatic patients: a Brazilian cohort with radiologically isolated syndrome and a critical review of current literature. Arq Neuropsiquiatr 2012;70:5-11.

Cutajar R, Ferriani E, Scandellari C, et al. Cognitive function and quality of life in multiple sclerosis patients. J Neurovirol 2000;6 (Suppl): S186-S190.

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Hakiki B, Goretti B, Portaccio E, Zipoli V, Amato MP. Subclinical MS: follow-up of four cases. Eur J Neurol 2008;15:858-861.

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Schulz D, Kopp B, Kunkel A, Faiss JH. Cognition in the early stage of multiple sclerosis. J Neurol 2006;253:1002-1010.

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Zipoli V, Goretti B, Hakiki B, et al. Cognitive impairment predicts conversion to multiple sclerosis in clinically isolated syndrome. Mult Scler 2010;16:62-67.

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De Stefano N, Stromillo ML, Rossi F, et al. Improving the characterization of radiologically isolated syndrome suggestive of multiple sclerosis. PLoS ONE 2011;6:e19452. doi:10.1371/journal.pone.0019452.

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Tintore M, Rovira A, Martinez MJ, et al. Isolated demyelinating syndrome: comparison of different MRI criteria to predict conversion to clinically definite multiple sclerosis. Am J Neuroradiol 2000; 21:702-706.

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Lebrun C, Bensa C, Debouverie M, et al. Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging, clinical conversion profile. J Neurol Neurosurg Psychiatry 2008;79:195-198. Lebrun C, Bensa C, Debouverie M, et al. for CFSEP. Club Francophone de la Sclérose en Plaques. Radiologically isolated syndrome and magnetic resonance imaging, cerebrospinal fluid, and visual evoked potential: follow-up of 70 patients. Arch Neurol 2009;66:841-846.

Arq Neuropsiquiatr 2012;70(1):2-4


Article

Incidental demyelinating inflammatory lesions in asymptomatic patients: a Brazilian cohort with radiologically isolated syndrome and a critical review of current literature Desmielinização inflamatória incidental em indivíduos assintomáticos: uma coorte brasileira com síndrome radiológica isolada e uma revisão crítica da literatura atual Antonio Carlos Martins Maia Jr.1, Antonio José da Rocha1, Bernardo Rodi Barros2, Charles Peter Tilbery3

ABSTRACT Despite the definition of specific diagnostic criteria to identify radiologically isolated syndrome (RIS) suggestive of multiple sclerosis, its natural history remains incompletely understood. We retrospectively analyzed a Brazilian cohort of 12 patients to clarify their features and to emphasize the role of imaging predictors in clinical conversion. We demonstrated that, although some individuals did not exhibit progression over a lengthy follow-up period (16.7%), most patients will progress clinically or radiologically in the initial years of the follow-up (83.3%). Infratentorial and spinal cord involvement, as well as the total number of lesions, were more relevant predictors of progression than gadolinium enhancement. Further studies remain necessary to define the risk of conversion in males and to clarify the cognitive abilities of RIS patients. This study may provide an improved understanding of the natural course and evolution of incidental magnetic resonance imaging lesions, and further assists with the management of RIS in clinical practice.

Key words: multiple sclerosis, radiologically isolated syndrome, incidental demyelination, magnetic resonance. RESUMO Apesar da definição dos critérios diagnósticos específicos para identificar a síndrome radiológica isolada (SRI) sugestiva de esclerose múltipla, sua história natural ainda não foi completamente entendida. Analisamos retrospectivamente uma coorte brasileira de 12 pacientes visando a esclarecer suas características e enfatizar o papel da imagem em predizer conversão clínica. Embora alguns indivíduos não apresentem progressão em longo período de acompanhamento (16,7%), a maioria dos pacientes com SRI progrediu clínica ou radiologicamente nos primeiros anos do seguimento (83,3%). O comprometimento infratentorial e da medula espinhal, bem como o número total de lesões, foram mais relevantes em predizer a progressão que a presença de impregnação pelo gadolínio. Estudos futuros são necessários para definir o risco de conversão em homens e para esclarecer a repercussão cognitiva da SRI. Este estudo pode ampliar o entendimento da história natural e da evolução das lesões incidentais à imagem de ressonância magnética contribuindo para a adequada condução clínica da SRI.

Palavras-Chave: esclerose múltipla, síndrome radiológica isolada, desmielinização incidental, ressonância magnética.

The term radiologically isolated syndrome (RIS) was recently introduced to describe patients who have incidental brain magnetic resonance imaging (MRI) abnormalities suggestive of multiple sclerosis (MS), but without any signs or symptoms attributable to the disease1. The proposed diagnostic criteria include brain MRI to establish anatomic dissemination in space (DIS) in the absence of a better explanation or a clinical history of inflammatory demyelinating disease of

the central nervous system (CNS). RIS is well known in clinical practice; however, the natural history of this condition remains incompletely understood2. The current literature has demonstrated that RIS patients may develop clinical symptoms, converting to either relapsingremitting or primary progressive MS3. Alternatively, patients may show progression in the MRI lesions without any objective clinical symptoms (radiologic progression); patients may even show

MD, PhD Division of Neuroradiology, Fleury Medicina e Saúde, São Paulo SP, Brazil; Division of Neuroradiology, Santa Casa de Misericórdia de São Paulo, São Paulo SP, Brazil;

1

2

MD, Division of Neuroradiology, Santa Casa de Misericórdia de São Paulo, São Paulo SP, Brazil;

3

MD, PhD Division of Neurology, Santa Casa de Misericórdia de São Paulo, São Paulo SP,Brazil.

Correspondence: Antonio José da Rocha; Rua Dr. Cesário Motta Junior 112; 01221-020 São Paulo SP - Brasil; E-mail: a.rocha@uol.com.br Conflict of interest: There is no conflict of interest to declare. Received 26 May 2011; Received in final form 01 September 2011; Accepted 08 September 2011

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stabilized brain abnormalities in subsequent imaging examinations1-6. The aim of this report is to describe retrospectively the clinical-radiological features and evolution of the first Brazilian series of patients with RIS. Clinical and imaging predictors were analyzed. Our data were also compared with previous findings.

METHODS The protocol was approved by the Institutional Committee of Human Research, and informed consent was obtained from all patients. This is a retrospective analysis of clinicalradiological data from a series of patients diagnosed with RIS in Santa Casa de Misericórdia de São Paulo and Fleury Medicina e Saúde from January 2002 to March 2011. The diagnoses were defined in accordance with recently proposed criteria1. Patients who underwent a clinical follow-up and at least two imaging examinations were included in this study. To confirm the diagnosis of RIS, we performed comprehensive neurological evaluations and detailed clinical histories, including an active search for symptoms attributable to MS. Differential diagnosis for multifocal T2 abnormalities was actively conducted according to current criteria7. We selected patients that underwent comparable MRI protocols, including Axial FLAIR (TR/TE/TI 11000/140/2600 ms), T2-weighted spin echo (SE) (5000/101 ms) and T1-weighted SE with and without magnetization transfer pulse (TR/TE, 510/12; MT pulse) sequences. We also examined T1 sequences (SE and SE/MT) after intravenous gadolinium (Gd) administration. Spinal cord studies included T1- and T2-weighted SE sequences. T1 SE sequences with fat saturation after intravenous Gd administration were also analyzed. According to established neurological criteria, clinical symptoms were considered in the appropriate clinical settings as clinically isolated syndrome (CIS) related to MS or as clinically definite MS (CDMS)8. In the absence of any objective clinical symptoms, radiologic progression was defined as the presence of a new T2 focal abnormality, Gd enhancement or enlargement of pre-existing lesions in longitudinal follow-up scans. Imaging stability of the abnormalities was considered in subsequent examinations when neither clinical symptoms nor radiologic progression were documented. MRI abnormalities and follow-up assessments were analyzed collaboratively by the authors. Tests for interaction were performed for age, gender, the presence of oligoclonal bands in cerebrospinal fluid (CSF), the number of lesions and the presence of Gd enhancement, infratentorial lesions or spinal cord lesions in the baseline MRI. These potential predictors of conversion to MS or of the development of new brain lesions were analyzed using the Cox regression model, generating hazard ratios (HR) with 95% confidential intervals and p values <0.05. The duration of the followup period was also confronted to each patient’s outcomes.

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RESULTS Sixteen patients (14 females, 2 males) were diagnosed with RIS during the study period. According to our defined criteria, 4 patients (all female) were excluded from this study due to the availability of only one imaging examination. Table 1 summarizes the demographic, clinical, laboratory and imaging data from our series of the remaining 12 patients, as well as the evolution of these parameters. Patient ages ranged from 17 to 54 years, with a median age of 38.7 years (standard deviation of 9.5 years). The median follow-up period for these patients was 49.2 months (range 11–109 months). All patients had a normal neurological examination at the first MRI scan, without any familial history of MS. Symptoms that led to the first MRI scan included primary headache (7/12–58.3%) and depression unrelated to a typical inflammatory-demyelinating CNS syndrome (2/12–16.7%). One patient reported hyperprolactinemia, while another patient had a pineal cyst previously observed on a computed tomography scan. One patient was being investigated for a long-lasting horizontal nystagmus (Table 2). Brain MRI scans were available from all 12 patients; spinal cord studies (cervical segment at least) were only available for 5 of the patients. The baseline brain MRI scans exhibited DIS according to the Barkhof criteria9. We documented more than nine T2 hyperintensities (11/12–91.6%), three or more periventricular T2-weighted lesions (11/12–91.6%), infratentorial lesions (6/12–50%), juxtacortical lesions (12/12– 100%) and Gd enhancement (4/12– 33.3%). Radiologic progression was documented in 50% of patients (6/12), while MRI stability without the development of any objective clinical symptoms was documented in 16.7% of patients from our series (Fig 1). Four patients (4/12–33.3%) exhibited paresthesia attributable to a demyelinating event. Two of those patients (2/12–16.7%) were diagnosed with CIS (mean follow-up period – 12 months), while the 2 remaining patients (2/12–16.7%) had recurrent symptoms compatible with CDMS (mean follow-up period of 57.5 months). In each patient, the total lesion number varied from 5 to 36 lesions (median=14; SD 9.4), with a periventricular distribution predominating. A statistically significant correlation was found between the total number of lesions in the first examination and subsequent clinical conversion (p=0.017). Patients in the subgroup that developed clinical manifestations during the follow-up period exhibited, on average, 26 focal lesions in the first MRI scan (Fig 2). In contrast, patients in the subgroup without symptoms exhibited only, on average, 12.3 lesions in the first scan. There was no statistically significant difference in the number of lesions predicting CIS or CDMS (p=0.65). Furthermore, 50% (6/12) of our patients exhibited infratentorial lesions in the first examination. This parameter was also significant to predict clinical conversion (p=0.017).


Maia Júnior ACM et al. Demyelinating lesions: asymptomatic patients

7

F

F

F

F

F

F

2

8

6

5

7

1

F

32

41

34

50

35

47

41

38

54 38 17 37

Age

No

No

No

No

No

No

No

No

Yes No Yes No

CSF

10

5

16

14

9

11

12

22

14 32 22 36

Number of lesions

None

1

None

None

None

None

None

1

Gadolinium enhanced lesions None 1 2 None

None

None

None

None

1

None

None

1

Infratentorial lesions 1 1 4 9

5

1

7

11

5

4

5

16

Periventricular lesions 6 15 14 12

M

F F

M

F F

F F F F F F

4

3 9

12

2 8

6 5 7 1 11 10

Primary headache Migraine Microadenoma follow-up Pineal cyst follow-up Primary headache Primary headache

Migraine Depression

Primary headache

Depression Physiological nystagmus

Primary headache

Clinical features

CSF: cerebrospinal fluid; MRI: magnetic ressonance imaging.

Gender

Patient

38 47 26 109 14 22

107 25

11

97 23

Clinical follow-up (months) 71

5

3

9

3

3

7

7

4

Cortical lesions 4 12 3 7

Not avaliable Not avaliable Not avaliable Not avaliable Not avaliable Not avaliable

Not avaliable Not avaliable

Not avaliable

3 5

CSF analysis positive for presence of oligoclonal bands or an increased IgG index (months) Not avaliable

Table 2. Age, gender, reason for obtaining baseline MRI scan, CSF status and follow-up period.

CSF: cerebrospinal fluid; MRI: magnetic ressonance imaging; CDMS: clinically definite multiple sclerosis; CIS: clinically isolated syndrome.

10

F

M F F M

4 3 9 12

11

Gender

Patient

Table 1. List of patients with demographic data, CSF analysis and MRI findings.

-

-

71

20 48

 

22

14

109

26

47

38

25

107

Clinical Follow-up (months) 71 97 23 11

 

Median follow up (months): 35,5 (range 14 - 109)

Median follow up (months): 34,8 (range 11 - 97) Median time to first clinical episode (months): 34,7 (range 7 - 71)

CDMS CDMS CIS CIS Radiological progression Radiological progression Radiological progression Radiological progression Radiological progression Radiological progression Radiological stability Radiological stability

Follow-up

Time of the first clinical event (months) 7

Not avaliable

1

Not avaliable

Not avaliable

Not avaliable

Not avaliable

Not avaliable

Not avaliable

Spinal cord lesions 3 3 1 3


!

Fig 1. Radiologic stability (patient #10). Axial FLAIR images at baseline (Jan-2009) (A-D) and follow-up (May-2010) (E-F). Note the presence of unchanged lesions in the periventricular white matter and at the juxtacortical region (total=10 lesions).

!

Fig 2. Radiologic progression and subsequent clinical conversion during the follow-up period (patient #3). Baseline MRI (2003) - Axial FLAIR images (A-C) and axial T1 SE MT image after intravenous Gd administration. Note juxtacortical, periventricular and cerebellar lesions (total=32 lesions) with no evidence of blood-brain barrier disruption. Comparative images in 2007 (D-G) exhibited radiologic progression of lesions. Note the appearance of new lesions in FLAIR images not previously seen in the baseline study (arrows). Also note focal Gd enhancement, denoting acute inflammatory activity. At the time that these images were acquired, there were no clinical symptoms. A new comparative study was obtained in 2010 (H-K), exhibiting new lesions in FLAIR images and new foci of Gd enhancement. Clinical symptoms emerged during the last examination; this patient was considered clinically definite multiple sclerosis.

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Spinal cord lesions compatible with focal demyelination were demonstrated in all examined patients from our series ( five patients). Clinical symptoms were documented in the follow-up of four patients from this subgroup. Focal inflammatory activity, characterized by Gd enhancement, was observed in the first examination in four patients from this cohort (4/12–33.3%). No statistical correlation between Gd enhancement and clinical conversion was found (p=0.43). Focal brain hypointensities on T1 sequences (i.e., black holes) consistent with irreversible damage were documented in two patients (2/12–16.7%) in the first MRI scan. Clinically definite MS was confirmed in one of these patients. Two different patients (2/12–16.7%) developed this pattern during the follow-up period. One patient from this subgroup converted to CDMS, and the other patient converted to radiologic progression.

DISCUSSION Incidental demonstration of demyelinating lesions has been reported in autopsies and in familial and twin studies10-13. However, the advent of MRI has increased the possibility of demonstrating multifocal brain and spinal cord lesions compatible with MS, even in unsuspected scenarios1-6,14. Postmortem studies from the pre-MRI era have revealed typical pathologic findings of MS in patients who were apparently asymptomatic during their lifetimes11; these studies have also reported unexpected lesions in some patients15. With the extensive availability of brain and spinal cord MRI at present, imaging studies performed for indications other than suspicion of demyelinating disease may reveal lesions in patients that are highly suggestive of MS (i.e., with ovoid, well-circumscribed, homogeneous and periventricular distribution). In 2009, Okuda et al.1 proposed the concept of radiologically isolated syndrome to describe this scenario based on Barkhof ’s criteria9 to confirm DIS. Structural neuroimaging studies of patients with an initial clinical event suggestive of MS usually reveal other brain or spinal lesions. Most of these CNS lesions present at the time of MS diagnosis were asymptomatic, suggesting the existence of a presymptomatic period of unknown duration. New asymptomatic lesions also often appeared during the course of established MS, confirming the subclinical activity of the disease4,16,17. Currently, there is neither a single clinical feature nor a sole diagnostic test that can confirm the diagnosis of MS. A recent revision of the International Panel Criteria confirmed MRI as the most effective paraclinical tool to define DIS dissemination in time (DIT) for the diagnosis of MS in patients with at least one clinical event consistent with a demyelinating disease after exclusion of alternative possibilities18. These criteria have been successful in defining the diagnosis of MS in the first clinical manifestation without compromising

specificity and accuracy19-21. Using only a single MRI analysis, all patients in our study exhibited DIS, and 33.3% of the patients exhibited DIT according to these new criteria19,21. Furthermore, clinical conversion was only documented in 33.3% of all cases (2/12 of CIS; 2/12 of CDMS). Our data suggest that all MRI criteria in RIS cases should be used parsimoniously as long as MS remains an exclusionary diagnosis. Unless patients develop a clinical symptom typical of a demyelinating episode, MRI analysis alone is not enough to confirm the diagnosis of MS1,2,22. In our series of patients, there was no difference in median ages between both groups (36.75 and 39.75 years old with and without clinical symptoms, respectively). In our cohort, patients who presented CIS were younger on average (median 27.0 years old) than patients in the entire cohort (median 46 years old). In our study, patients with CDMS were not as young as those with CIS. In our review of the current literature, we found that all previously described studies reported the predominant occurrence of RIS in women1-6. Although RIS was more prevalent in women, we determined that in these previous studies the rate of conversion to CDMS was higher in males as compared to that of females1-4,6,23. Both men in our series converted to CDMS during the follow-up period. However, this tendency should be further confirmed in larger studies. In this small cohort of patients with RIS, only two patients exhibited stabilized brain abnormalities and did not develop clinical symptoms consistent with MS during the follow-up period (mean duration of 18 months). Although the follow-up  period in this study was relatively short, we emphasize that the number of lesions on the baseline MRI scans was smaller than that noted in remaining patients. It is important to note that a long-term follow-up period is mandatory to correctly define stabilized brain abnormalities. Radiologic progression in our series of patients was in line with previous reports1-6,14. Radiologic progression occurred in 50% (6/12) of our patients, with a mean follow-up time of 2.8 years. Okuda et al.1 found a radiologic progression rate of 59%, with a median follow-up time of 2.7 years. Our results showed a tendency toward earlier radiologic progression and clinical conversion to MS in proportion to the total basal number of lesions. This observation appears to be supported by the same arguments explaining the high risk of conversion following CIS with brain and spinal cord asymptomatic lesions14,17,24,25. Radiologic progression in RIS is in line with a recent observation in CIS cohorts that confirmed the occurrence of a long-term radiologic progression, albeit less commonly than in CDMS26. There is much evidence supporting the importance of the preclinical phase of MS14. RIS is likely to be a heterogeneous syndrome rather than simply presymptomatic MS27. Patients may have a presymptomatic stage of MS with an expected clinical evolution to symptomatic MS; alternatively, patients may

Maia Júnior ACM et al. Demyelinating lesions: asymptomatic patients

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remain with only subclinical activity and no evolution to MS (i.e., radiologic progression). The impact of RIS on subsequent neurologic outcomes remains unclear, although it has been examined in the current literature2,27,28. Lebrun et al.23 recently suggested that RIS patients have similar cognitive profiles to MS patients. It could be suggested that RIS patients are MS patients with an undiagnosed, isolated symptom presenting as cognitive dysfunction. It is possible that there exists a destructive process that remains below the clinical threshold of detection (i.e., subclinical MS). Therefore, new MR techniques, including MT, spectroscopy or diffusion tensor imaging might clarify the relevance of preclinical lesions and thus improve our understanding of unexpected manifestations in further analyses. In contrast with previous studies, Gd enhancement was not confirmed as a predictor of either radiologic or clinical progression1,3. It is possible that our results were influenced by the low incidence of this finding (4/12â&#x20AC;&#x201C;33%) in our series. Gadolinium enhancement in brain lesions reflects disturbances of the blood-brain barrier (BBB) with high sensitivity. Disruption of the BBB is an early event in the development of inflammatory lesions in MS and a robust predictor of the occurrence of relapses29. Lebrun et al.5 demonstrated that patients whose baseline MRI scans exhibited Gd enhanced lesions had a substantially increased risk of developing new lesions. However, the authors emphasized that the risk of developing clinical symptoms was not defined. Four of 12 (33.3%) patients (2 males) developed an objective clinical symptom consistent with CNS inflammatorydemyelinating syndrome and fulfilled the criteria for either CIS or CDMS. The time taken for the development of clinical symptoms in our series ranged from 7 to 71 months (median time 2.9 years). Okuda et al.6 found a conversion rate of 22% (10/44) with a median time to clinical symptoms of 5.4 years, while Lebrun et al.5 found a conversion rate of 33% (23/70) with a median time to CIS of 2.3 years. Both studies confirm that longer follow-up periods are crucial to defining MS conversion in many patients, but clinical conversion following RIS most commonly occurs during the initial years5,6. In our series, all patients who converted to CDMS presented spinal cord and/or infratentorial lesions at the baseline MRI scan, and only one patient had a Gd enhanced lesion. A recent report regarding a large series of RIS patients confirmed that the presence of an affected spinal cord predicted the subsequent development of CIS or CDMS6. Bot et al.30 showed that spinal cord abnormalities are prevalent in early-stage MS, even in the absence of clinical manifestations. The authors confirmed that spinal cord lesions are useful to demonstrate DIS at the time of diagnosis30. Our study is in agreement with these previous reports; current data support

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Arq Neuropsiquiatr 2012;70(1):5-11

the contention that spinal MRI should be performed in any patient with incidental demyelinating lesions in order to provide prognosis counseling27,30,31. The concept of preclinical MS now challenges experts with several unanswered questions27. Standard neurologic evaluations often fail to detect cognitive impairments in MS patients, and some patients with RIS might also be cognitively impaired. Cognitive impairment was recently described to occur with similar frequency in early stage MS patients and RIS patients23. Brex et al.32 postulated that the extent of inflammation and demyelination early in the course of MS may influence the extent of axonal loss later in the disease. The occurrence of a considerable number of lesions in RIS patients and the presence of black holes both allow us to identify RIS patients at risk of cognitive impairment, even from an initial examination. We propose that further clinical studies should address the role of the total number of lesions and black holes in the evolution of RIS in the cognitive performance of patients, even in the absence of symptoms. We recognize several limitations of this study, mainly due to the number of patients and to the absence of neuropsychological testing. In our practice, very few patients without symptoms undergo spinal cord MRI evaluations, CSF analyses and visual evoked potential studies, thereby limiting a full analysis of this patient series. Similar studies have highlighted the importance of demonstrating DIS and DIT during the preclinical phase of lesions that are suggestive of demyelinating disease. Additional prospective studies are needed to determine the frequency of conversion of RIS to CDMS and to build strategies to manage RIS patients. In conclusion, this Brazilian RIS cohort confirmed the predominance of female patients presenting with RIS. Most of the patients exhibited clinical or radiological progression in a short follow-up period. We propose that further studies are necessary to better define the risk of conversion in males and to clarify the role of the total number of brain lesions and black holes on cognitive function of RIS patients. Our results provide evidence that infratentorial lesions, spinal cord involvement and the total number of lesions are more relevant than Gd enhancement in the prediction of both clinical and radiological progression. Although some individuals did not exhibit progression during a long follow-up period, we believe that all patients with RIS should be considered as having a high risk of developing MS. Infratentorial and spinal cord lesions are the best predictors for the inference of prognosis. We propose that a larger series of patients could shed more light on the natural course and evolution of incidental MRI lesions, and further assist in the management of patients in clinical practice.


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Maia Júnior ACM et al. Demyelinating lesions: asymptomatic patients

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Article

Clinical predictors of response to immunomodulators for multiple sclerosis Preditores clínicos de resposta aos imunomoduladores em esclerose múltipla Guilherme Sciascia do Olival1, Leonardo Ciciarelli Pereira Lima2, Gabriel Paiva Silva Lima1,Charles Peter Tilbery3

ABSTRACT Objectives: To determine, based on clinical criteria, the proportion of multiple sclerosis (MS) patients responsive to immunomodulators (RI) and nonresponsive to immunomodulators (NRI), and to ascertain whether clinical and epidemiological data differs between RI and NRI patient groups. Methods: Patients were assessed on rate of exarcerbations per year, for the period before and after commencement of treatment. The RI and NRI groups were compared for several clinical and epidemiological characteristics. Discussion and conclusion: A total of 31.4% of the patients were nonresponders to the immunomodulatory treatment. The main predictors of immunomodulatory response were early diagnostic and commencement of therapy and high rate of annual exacerbations prior to treatment. Given the arsenal of medication options available for MS management, screening potential candidates for different therapeutic approaches are critical to optimize evolution of patients with the disease.

Key words: multiple sclerosis, immunomodulators, predictors. RESUMO Objetivos: Avaliar por meio de critérios clínicos, a proporção de pacientes com esclerose múltipla (EM) responsivos aos imunomoduladores (RI) e não responsivos aos imunomoduladores (NRI) e avaliar se dados clínicos e epidemiológicos são distintos nesses dois grupos. Métodos: Os pacientes foram avaliados quanto à taxa de surtos por ano no período antes e após o início do tratamento. Diversas características clínicas e epidemiológicas foram comparadas entre os pacientes RI e NRI. Discussão e conclusão: Em nossa população, 31,4% dos pacientes não responderam ao tratamento com os imunomoduladores. Os principais preditores de resposta aos imunomoduladores foram: diagnóstico e início precoce da terapia e elevada taxa de surtos anual antes do tratamento. Como existem várias opções medicamentosas disponíveis para o tratamento da EM, a identificação de candidatos potenciais para abordagens terapêuticas diferentes representa o ponto crucial para otimizar a evolução dos pacientes com essa doença.

Palavras-Chave: esclerose múltipla, imunomoduladores, preditores.

Multiple sclerosis (MS) is an autoimmune disease characterized by demyelinating inflammatory activity of the central nervous system. It is most prevalent in young adults between 20 and 40 years of age and constitutes a frequent cause of neurological dysfunction in this age group1. Immunomodulatory therapy had been proven to be effective in modifying the natural course of the disease in patients with MS. Interferon beta (IFNb) and glatiramer acetate (GA) comprise the first line of therapy for MS and have seemed to reduce the rate of demyelination exacerbations compared to placebo in clinical trials2-5. However, not all patients are responsive to this treatment6.

The absence of biomarkers and the unpredictability of MS evolution leads to difficulty in distinguishing between response to therapy and disease activity7, requiring the use of clinical and imagiologic criteria to define the efficacy of therapies. The presence of differences in clinical and epidemiological characteristics between responders (RI) and nonresponders (NRI) to immunomodulators has yet to be determined. The investigation of these clinical and epidemiologic characteristics is of primary importance, since the definition of clinical predictors of response to immunomodulators will allow the early identification of patients that should switch therapies.

1

Neurologists of the Irmandade da Santa Casa de Misericórdia de São Paulo, São Paulo SP, Brazil;

2

Graduate Student of the Santa Casa de São Paulo, Faculty of Medical Sciences, São Paulo SP, Brazil;

3

MD, PhD, Full Professor of the Santa Casa de São Paulo, Faculty of Medical Sciences, São Paulo SP, Brazil.

Correspondence: Guilherme Sciascia do Olival; Rua Piauí, 305 – Apto. 51; 01241-001 São Paulo SP – Brasil; E-mail: guilhermesolival@gmail.com / guiolival@yahoo.com.br Conflict of interest: There is no conflict of interest to declare. Charles Peter Tilbery is member of Advisory Board of Biogen Idec and Merck Serono, participate in clinical trials for Bayer Schering, Merck Serono and Genzyme and has received honoraria for speaking at symposia from Bayer Schering, Merck Serono, Biogen Idec and Teva Neuroscience. Received 10 May 2011; Received in final form 17 August 2011; Accepted 24 August 2011

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The aims of this study were: • to determine, based on clinical criteria, the proportion of RI and NRI patients with MS seen at the Care Center for Multiple Sclerosis Treatment (CATEM) of the Neurology Discipline of the Department of Medical Sciences at Santa Casa de São Paulo Hospital; • to ascertain whether clinical and epidemiological data, such as gender, age at MS onset, disease duration, and clinical evolution, differ between RI and NRI patient groups and identify which of them could be used as clinical predictors.

METHODS The present study was previously approved by the Research Ethics Committee of Santa Casa de São Paulo Hospital. Inclusion criteria Patients diagnosed with relapsing-remitting MS between 1998 and 2008 were retrospectively selected for inclusion in the study, according to the following criteria: Poser’s from 1998 to 20018; McDonald’s from 2001 to 20059; and revised McDonald’s criteria from 2005 to 200810. During such period, those patients were treated at the CATEM of the Neurology Discipline of the Department of Medical Sciences of Santa Casa de São Paulo Hospital. Exclusion criteria All patients with irregular use of immunomodulators, treatment time of less than two years, poor anamnesis for the period prior to treatment, harboring the primary progressive form of MS, conversion to the secondary progressive form in less than two years, or use of medications other than IFNb or GA during the study period, were excluded from the study. Follow-up The decision to start treatment was made after the clinically defined diagnosis, meaning the second exacerbation. After commencement of treatment, patients were seen every three months and checked for the presence of symptoms and changes in the physical examination, consistent with exacerbation, and instructed to seek treatment at the service in the event of new symptoms. The expanded disability status scale (EDSS) was applied at each consultation. Patients were administered with the following immunomodulators: intramuscular IFNb 1a 30 mcg once per week11, subcutaneous IFNb 1b 300 mcg on alternate days12, subcutaneous IFNb 1a 22 or 44 mcg three times per week13, and daily subcutaneous GA 20 mg14. Medications were switched in the event of treatment failure or intolerable adverse reactions. The changes were made from IFNb lower dose to higher dose and, then, GA and vice versa.

Criteria for clinical response to treatment Patients were assessed based on rate of relapses per year between disease onset and commencement of treatment, and rate of exacerbations after the beginning of treatment. Patients were classified as RI if a 25% or greater reduction in exacerbation was evident after start of the treatment, given that this had been the response to placebo in the larger randomized trials2-5. Remaining patients were classified as NRI. Clinical parameters of response analyzed Patients were divided into RI and NRI groups and compared for the following clinical and epidemiological characteristics: age at disease onset; age at diagnostic and treatment commencement; time between disease onset and diagnostic/start of treatment; gender; interval between first and second relapses; relationship between rate of exacerbation per year in the period before and after treatment; and EDSS at the start and after two years of treatment. Statistical analysis Statistical analyses were performed using the SPSS® Statistics software package, version 19.0.0 (SPSS, Chicago, USA), on an IBM® personal computer. The association among categorical variables was assessed by the chi-square and Fisher tests. For continuous nonparametric and parametric variables, the Mann-Whitney and ANOVA tests were used, respectively, in comparisons between RI and NRI. A 95% confidence interval was used and a p-value <0.05 was considered statistically significant.

RESULTS Of 430 patients registered between 1998 and 2008 at CATEM, 145 used immunomodulators for more than two years. Patients were excluded from this subgroup for the following reasons: four due to irregular immunomodulator use; ten with poor prior anamnesis data for a period prior to the study; two with primary progressive form of MS; and eight subjects that converted to the secondary progressive form. This gave a total study sample of 121 patients. The distribution of immunomodulators in the initial course of treatment was: 22 patients in intramuscular IFNb 1a 30 mcg once per week; 38 in subcutaneous IFNb 1b 300  mcg on alternate days; 39 in subcutaneous IFNb 1a 22 or 44 mcg three times per week; and 22, subcutaneous GA 20 mg daily. From among these patients, 51 switched treatment over to another immunomodulator during treatment, with 23 of these cases being due to adverse effects and 28 for clinically-defined treatment failure. The main collateral effects reported were influenza symptoms and skin reactions at injection sites. None of these patients received any other

Olival GS et al. MS: immunomodulators response

13


disease-modifying therapy, such as azathioprine, methotrexate, or natalizumab. Response to immunomodulators The proportion of RI was 83 patients (68.6%) and the NRI was 38 (31.4%), based on the clinical criteria of a 25% or greater reduction in exacerbation. Table contains the clinical parameters of response to the immunomodulators evaluated. Clinical characteristics in relation to response to immunomodulators Comparing the RI and NRI patient groups, no difference for age at disease onset (p=0.54) or age at diagnostic and treatment onset (p=0.96) was found. However, longer time between disease onset and diagnostic/therapy beginning commencement was found in the NRI Group (6.1 years, on average) compared to the RI Group (3.5 years, on average), with p<0.001. No differences were found between men and women (p=0.89). The interval between the first and second exacerbations was not associated with response to medications. The annual rate of relapses prior to treatment was 1.1 in RI greater than 0.5 in NRI, and the annual rate of exacerbations after treatment was 0.3 in RI lower than 0.9 in NRI (p<0.001). Both groups had the same rating on the EDSS at treatment commencement and showed increased ratings during the study period (p=0.39). The EDSS rating in the NRI Group rose from 1.6 to 3.1 after two years of treatment, whereas the RI Group rating increased from 1.4 to 1.7 over the same period.

DISCUSSION In the present study, response to therapy was based on the clinical criteria of the rate of relapses per year before and

after treatment. Patients exhibiting a 25% or greater reduction in exacerbations after therapy commencement were considered responsive to treatment, a figure based on the response to placebo described in previous trials2-5. Functional assessment by the EDSS can be employed, but it has several limitations. First, the scale is nonlinear with a bimodal distribution. Second, the scale places greater emphasis on gait disabilities and is less sensitive for assessing other neurologic sequelae. Lastly, the scale tends to have a high inter-rater variability. The neurological damage caused by MS is erratic and unpredictable, where in some cases minor lesions can lead to severe functional impairment, yet in other cases large lesions have minimal functional impact. Thus, rating response to therapy by quantifying dysfunction does not provide a realistic picture in that the aim of immunomodulators is not to cure, but to control the disease. Based on this rationale, we proposed that response to immunomodulators be assessed by rate of relapses per year or by time interval between exacerbations in the same individual. The aim of this study was not to compare efficacy of the medications, because head-to-head studies have previously confirmed, only the negligible difference among the drugs used15-17. In this study, 31.4% of the patients had an unsatisfactory reduction in annual rate of relapses, a finding comparable with rates reported in the literature6,18-20. Waubant et al.18, in a study of similar design, comparing reduction in rate of exacerbations after immunomodulator therapy, found a proportion of 31% NRI. Villoslada et al.19 conducted a study in Pamplona, Spain, and found that patients responsive to therapy were older and had longer intervals between disease onset and start of therapy, and they suggested that these data represent a patient group with a milder form of the disease from the outset.

Table. Clinical characteristics of multiple sclerosis patients in use of immunomodulators for at least two years. Characteristic Age at disease onset (years) Age at diagnostic/treatment commencement (years) Time between disease onset and diagnostic/ treatment (years) Number of men (%) Number of women (%) Interval between 1st and 2nd exacerbation (years) Annual rate of exacerbations between disease onset and treatment (exacerbations/year) Annual rate of exacerbation after treatment commencement (exacerbations/year) EDSS at treatment commencement EDSS after two years of treatment

All patients n=121 28.0±8.7 32.9±8.8

Responsive n=83 (31.4%) 28.4±8.9 32.6±8.1

Nonresponsive n=38 (68.6%) 27.8±8.3 33.7±10.4

4.3±3.8

3.5±3.4

6.1±4.2

<0.001

23 (19.0%) 98 (81.0%) 2.4±2.5

15 (65.2%) 68 (69.4%) 2.1±2.0

8 (34.8%) 30 (30.3%) 3.5±3.5

0.89 0.89 0.06

0.9±0.6

1.1±0.7

0.5±0.3

<0.001

0.2±0.2

0.3±0.3

0.9±0.5

<0.001

1.5±1.2 2.1±1.7

1.4±1.1 1.7±1.4

1.7±1.5 3.1±2.2

0.39 0.001

Values expressed as mean±standard deviation unless specified otherwise. MS: multiple sclerosis; EDSS: expanded disability status scale.

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p-value 0.54 0.96


In the present study, patient ages at disease onset and start of therapy were found not to differ between groups, although the assessment of delay to diagnostic and therapy onset reached statistical significance, with the NRI patients experiencing longer delays before diagnostic and start of the treatment. This disparity with the literature may be explained by the difference in our study population and healthcare resources. Access to public health services in Brazil is limited. MS is less incident, and diagnosis can sometimes be delayed. Moreover, CATEM was the first MS center in the country and drew patients from regions throughout S達o Paulo state and even individuals from other states, who had harbored the disease for some time without treatment. Therefore, we believe that in our milieu, patients with late diagnoses did not present milder forms of the disease, but delayed undergoing diagnosis due to difficulties in accessing reference centers in neurology. EDSS studied in this casuistic revealed that RI and NRI started out with similar neurological compromise yet evolved differently. The group of patients delaying diagnostic/treatment could represent individuals at a more treatment-resistant phase of MS, raising questions on the impact of long-term immunomodulatory therapy on the natural course of the disease. Studies assessing the impact of long-term immunomodulatory therapy use are lacking. The rate of relapses also reached statistical difference, proving to be higher in RI patients prior to treatment. These data may reflect the fact that patients that benefit most from therapy are those with greater disease-related inflammatory activity. It is likely that the group of RI was differently than NRI since the beginning of the disease with a more inflammatory physiopathology and, therefore, more responsive to immunomodulatory treatment. In MS patients that had two or more relapses prior to treatment, it is possible to calculate a rate of exacerbation per year, which is likely to be the natural history of disease. We propose that therapy can be considered effective or not based on this rate, instead of an absolute number of relapses. However, we should note that while some patients have a milder form of the disease, groups with more aggressive forms must receive the earliest diagnosis and treatment possible and, in some cases, it may require a more potent therapy, since the response to the immunomodulators may not be sufficiently effective. Likewise, increased attention is necessary to readily change therapy, if so required, in the group at higher risk for poor response to therapy, such as those whose diagnostic/ therapy commencement was delayed after the first exacerbation and with lower rate of annual exacerbations prior to treatment.

Some limitations apply to this study with reduced impact to the main findings. Potential bias in our data stem from the adoption of rate of exacerbation as a measure of response, given that the severity of exacerbations depends on the region with demyelination, while incomplete recovery after relapses could reflect the individual pathological pattern of the disease activity. Nevertheless, patients, who had converted to the secondary progressive form in less than two years, were excluded because their group had a low relapse rate per year and could be mistakenly regarded as RI. This strategy overestimated the proportion of RI up to 7%. Other bias would be the different diagnosis criteria, which has changed during the assessed period. Also, these results are derived from a single center and there is no control group. Consequently, these results need to be reproduced in other cohorts. In view of the erratic progression of MS and that the inflammatory phase can result in irreversible axonal loss, identification of patients who respond poorly to immunomodulators is pivotal in reconsidering other therapeutic approaches and consequent switches in first-line treatments or in indicating second-line therapies. Although MS has long been suspected as constituting a primary autoimmune disease affecting the central nervous system (CNS), no single physiopathology has yet been established for the different mechanisms of damage. Differences in pathologies among patients suggest that clinically diagnosed MS may in fact comprise several different entities, all of which damage the CNS. Thus, this raises the possibility that perhaps a substantial number of patients are not responsive to current therapy because their individual pathology is not responsive. It can therefore be surmised that, at present, MS therapy is partially effective and has common inherent collateral effects, which limit its application. This situation is in part due to the absence of biomarkers of response to therapy. Biomarkers of response to therapy would allow the identification of the best RI, increasing the efficacy of drugs and preventing unnecessary treatment of NRI with these drugs, thereby reducing both costs and collateral effects. This scenario is set to become more complex with the emergence of novel drugs at phase 3 of clinical trials (e.g., laquinimod, rituximabe, daclizumabe) plus the development of combination therapy20,21. In conclusion, in the population studied, 31.4% of the patients were NRI to the immunomodulatory treatment. The main predictors of immunomodulatory response were early diagnostic/commencement of therapy after the first exacerbation, and high rate of annual exacerbations prior to treatment. Given the various medication options available for MS management, screening potential candidates for different therapeutic approaches are critical to optimize evolution of patients with the disease.

Olival GS et al. MS: immunomodulators response

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Moreira M, Lana-Peixoto MA, Callegaro D, et al. Consenso expandido do BCTRIMS (Comitê Brasileiro de Tratamento e Pesquisa em Esclerose Múltipla) para o tratamento da esclerose múltipla: II. As evidências para o uso de glicocorticóides e imunomoduladores. Arq Neuropsiquiatr 2002;60:875-880.

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Article

Accuracy of prospective memory tests in mild Alzheimer’s disease Acurácia dos testes de memória prospectiva na doença de Alzheimer leve Sergilaine Pereira Martins1, Benito Pereira Damasceno2

ABSTRACT Objectives: To verify the accuracy of prospective memory (ProM) tests in Alzheimer’s disease (AD). Methods: Twenty mild AD patients (CDR 1), and 20 controls underwent Digit Span (DS), Trail Making (TM) A and B, visual perception, Rey Auditory-Verbal Learning tests, and Cornell Scale for Depression. AD diagnosis was based on DSM-IV and NINCDS-ADRDA criteria. ProM was assessed with the appointment and belonging subtests of Rivermead Behavioral Memory Test (RBMT); and with two new tests (the clock and animal tests). Results: AD patients had a worse performance than controls on the majority of tests, except DS forward and TM-A. There was no correlation between RBMT and the new ProM tests. As for accuracy, the only significant difference concerned the higher sensitivity of our animal test versus the RBMT belonging test. Conclusions: The clock and the animal tests showed similar specificity, but higher sensitivity than the RBMT subtests.

Key words: prospective memory, Alzheimer’s disease, neuropsychological tests, dementia, aging. RESUMO Objetivos: Verificar a acurácia dos testes de memória prospectiva (MP) na doença de Alzheimer (DA). Métodos: Foram avaliados 20 pacientes com DA leve (CDR 1; diagnóstico baseado no DSM-IV e NINCDS-ADRDA) e 20 controles passaram pelos testes de dígitos, das trilhas A e B, de percepção visual, do aprendizado verbal de Rey e da Escala Cornell para Depressão. MP foi avaliada com os subtestes de compromisso e pertence do Teste de Memória Comportamental da Rivermead e dois novos testes (do relógio e dos animais). Resultados: Os pacientes com doença de Alzheimer tiveram um desempenho inferior aos controles na maioria dos testes, exceto nos dígitos diretos e na trilha A. Não houve correlação entre os subtestes de Memória Comportamental da Rivermead e os novos testes de memória prospectiva. A única diferença quanto à acurácia foi que o teste dos animais teve maior sensibilidade que o do pertence da Rivermead. Conclusões: Os testes do relógio e dos animais mostraram similar especificidade, porém maior sensibilidade do que os subtestes da Rivermead.

Palavras-Chave: memória prospectiva, doença de Alzheimer, testes neuropsicológicos, demência, envelhecimento.

Alzheimer’s disease (AD) is characterized by progressive loss of cognitive functions with impairment of daily life activities of the affected elderly people. Loss of memory is, in general, the first and most important symptom1. Impaired ability to learn new information or to recall previously learned information (i.e., retrospective episodic memory) is required for the operational diagnosis of the disease. However, memory is a complex functional system, and other types of memory than the retrospective episodic (e.g., semantic, prospective) may be early impaired in AD. As conceived of by Tulving2, the episodic retrospective memory (RetM) represents events in his personal biographic history. It involves conscious recollection of these episodes ( for example, when one was getting married), and it is typically evaluated by means of learning a list of words or a series of figures.

In the AD, RetM deficit, particularly the free and delayed recall of series of words, sentences, or objects, occurs earlier than the medial temporal atrophy shown by magnetic resonance imaging, and it is considered the most reliable predictor of the disease in its preclinical stage3. Impairment of prospective memory (ProM), though a common initial complaint of AD patients, has been neglected in cognitive studies of the disease. While RetM is the memory of the past, ProM is the memory of the future4. ProM consists in remembering to carry out intended actions at an appropriate point in the future, such as to keep appointments, pay bills, take medicine, carry out domestic chores, and give one person the message that someone else has called. To perform a ProM task, one must remember there was an intention (the prospective component) and the contents of the

1

Postgraduate Neurologist, State University of Campinas (UNICAMP), Campinas SP, Brazil;

2

MD, PhD, Professor, Department of Neurology, Medical School, State University of Campinas (UNICAMP), Campinas SP, Brazil.

Correspondence: Benito Pereira Damasceno; Department of Neurology, Medical School, State University of Campinas; Rua Tessália Vieira de Camargo, 126 – Caixa Postal: 6111; 13083-970 Campinas SP – Brasil; E-mail: damascen@unicamp.br Conflict of interest: There is no conflict of interest to declare. Received 06 December 2010; Received in final form 26 August 2011; Accepted 02 September 2011

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intention, “what to do” (the retrospective component). This retrospective component is highly dependent on the medial temporal lobe structures, it is what makes ProM (to memorize or learn a list of things to do in the future) to be similar to RetM (to remember a list of events from the past), and constitutes one of the reasons why ProM and RetM are usually impaired in the early stages of the AD5,6. The prospective component is what characterizes ProM as unique, different from learning, in that it is the memory of an intention, essential for goal-directed behaviors. As highlighted by Karantzoulis et al.7, even such prospective component is a complex process, which involves at least four stages: intention formation, to plan the future activity, i.e., what and when to do it; intention retention, to hold the intention in memory while other activities are occurring, i.e., during the ongoing task; intention initiation, the point at which the appropriate cue (e.g., an event) triggers an effortful and controlled search of memory for the intention; and intention execution, when the retrieval context actually occurs and the action of the intended action is executed. In tests for assessment of RetM, the recovery of information requires an active and conscious process. This pattern does not apply for ProM. The tests, which have been applied to assess ProM, involve the presentation of information to which the patient will be asked to recognize or recall later on in response to a signal provided by the examiner8. Einstein and McDaniel9 classify ProM tasks according to a factor that triggers action: it may be a particular event (ProM based on an event) or a determined time (ProM based on time). Since until recently the research on memory had tended to neglect ProM, it is not surprising that the traditional memory test batteries ( for example, Wechsler’s battery)10 do not include tests for assessment of ProM. One of the first attempts to include ProM tasks in clinical assessment was the Rivermead Behavioral Memory Test battery (RBMT)11, which consists of two event-based ProM tasks: the appointment and belonging tests. These tests are event-based and require that the subject remembers to perform a simple action later on during the assessment session. The aim of this study was to investigate the performance of patients with mild AD as compared to healthy control subjects on two new ProM tests, which were developed by the authors (the clock test, based on time; and the animal one, based on an event), and to compare the accuracy of these two tests with that of the appointment and the belonging tasks of the RBMT12. This study was approved by the Medical School Ethics Committee. All the patients and controls signed the informed consent form.

METHODS We studied 20 patients with mild AD followed-up in the Neuropsychology Unit of the State University of Campinas

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Arq Neuropsiquiatr 2012;70(1):17-21

(UNICAMP) Hospital, and 20 normal matched controls. Routine laboratory examinations for dementia assessment (including B12 and folic acid dosage, serology for syphilis, thyroid hormones) and brain computed tomography were carried out in all patients. The diagnosis of probable AD was based on DSM-IV1 and NINCDS-ADRDA criteria13, and its severity, on the Clinical Dementia Rating (CDR)14. We included only patients with Mini-Mental State Examination (MMSE)15 scores between 16 and 24, and CDR score of 1. Exclusion criteria were: history of other neurological or psychiatric diseases, drug or alcohol addiction, and prior exposition to neurotoxic substances. Control subjects were matched to the patients for age (±5 years) and education (±2 years), with CDR 0, and without previous history of neurological or psychiatric disease, or memory complaints. A detailed interview and a battery of neuropsychological tests were applied to all of them. The neuropsychological assessment comprised the following tests, for which all subjects repeated the instruction for the proposed tasks in order to verify their understanding. The ProM was assessed using two tests of the RBMT (Brazilian version validated by Yassuda et al., 2010)12: the appointment and the belonging test; and two other tests developed by the authors: the clock and the animal ones. Appointment test The subjects are required to ask for their next appointment when they hear the ringing of the alarm clock, which is set to go off 15 minutes after the instruction has been given. Scoring system: one point if the correct response was given following a prompt (“What were you going to do when the alarm rang?”) and two if it was given without a prompt (maximum score=2). Belonging test At the beginning of the session, the examiner borrows from the subject a personal belonging, which the examiner hides, letting the subject know where it is hidden (e.g., into a drawer) with an instruction that the subject asks for it to be returned at the end of the session. Then, at the end of the session, the examiner says: “That is the end of the session”. If the subject does not spontaneously request the belonging, the examiner gives a prompt: “Was there something you were going to ask me for?” Scoring: one point if the subject recalled the item, another one if he/she recalled the location and additional points for each response which was given without a prompt (maximum score=4). Animal test Subjects are told that they are going to see 20 photographs of animals, one at a time (during five seconds), and that his/her task is to name each animal (naming task) and, in case he/she sees some object or food in the mouth of the animal,


to inform to the examiner (this is a ProM task embedded in a naming task). For the ProM task, there are two photographs: one in the 5th and another in the 19th position. Scoring: one point for each correct response (maximum score=2). Clock test At the beginning of the session, the subject is asked to remind the examiner of an appointment five minutes afterwards, with the instruction: “In five minutes I have to tell to the nurse about a medication. Could you please remind me to go to talk to her on five minutes?” This time is spent with other tests or activities. There must be a clock visible in the periphery of the subject visual field. Scoring: two points if the subject reminds the examiner after five minutes with an error of (±) 30 seconds; one for errors higher than this (and none if there is no reminding); (maximum score=2). As regards to the last two ProM tests (the animal and the clock ones), they were developed by the authors in an experimental attempt to improve the accuracy of ProM tests, so they have no previous psychometric validation. Their construction followed the criteria proposed by McDaniel and Einstein16 for creating typically prospective tasks: • the execution of the intended action must not be immediate: not be executed immediately after the intention, but delayed or postponed to some point in the future; • the ProM task must be embedded in another ongoing activity; • the time frame for response must be limited: to have constrained time frame of opportunities in which forgetting or recalling of the task is required for initiating the intended action; • to have limited time frame for accomplishing the action, it cannot be a task that requires long time to be carried out (e.g., reading a book or going on a trip) and in case of tasks in laboratory, it must be carried out in seconds or in a few minutes; • there must be an intention – this is a critical factor that characterizes the ProM task: to be based on an consciously formed intention or plan; and • the formed intention should not be maintained in working memory, in the focus of consciousness, but temporarily forgotten by performing other activities, otherwise it would constitute a vigilance task, not a ProM one. The subjects have also been tested for other cognitive functions whose deficits could interfere with the performance of ProM tasks (counterproofs): attention/concentration – digit span subtest of WMS-R10; executive function – trail making A and B17; depression and anxiety – Cornell Scale for Depression in Dementia (CSDD)18; visual perception – abstract figures (modified from Jones-Gotman et al.)19; and RetM – Rey Auditory-Verbal Learning Test (RAVLT)17.

The statistical analysis was carried out using SAS System for Windows20, version 9.1.3. We used Student’s t-test to compare patients and controls as for age and education; and Wilcoxon signed rank test for matched pairs to compare their performance on the neuropsychological tests. McNemar’s exact test was used to compare the ProM subtests with each other as regards the performance of AD patients on these tests. We also used the average weighted Kappa coefficient for correlation and measurements of accuracy, assessing the sensitivity and specificity for each of the ProM tests. Statistical significance considered was p<0.05.

RESULTS There were 9 men and 11 women in each group. Dementia patients had similar age (mean 75.6±standard deviation 7.8 versus 73.8±6.5 years; p=0.447) and educational level as controls (5.6±4.5 versus 5.8±4.4 years; p=0.915). They also performed as controls on digit span forward (p=0.324) and trail making A (p=1.000), but worse on MMSE (22.6±1.9 versus 29.0±1.3; p=0.0001), digit span backwards (3.3±0.7 versus 4.0±0.9; p=0.0005), trail making B (12.3±5.7 versus 21.0± 6.0; p=0.0001), visual perception (8.1±1.3 versus 9.0±0.9; p=0.015), RAVLT delayed recall (1.1±1.6 versus 6.65±2.6; p<0.0001). Dementia patients ProM total scores were inferior to those of controls (4.1±2.5 versus 8.8±1.2; p<0.0001). Their performance was particularly worst on the clock (p=0.0004), the belonginglocation (p=0.0003), the animals (p<0.0001), and the appointment (p<0.0001) subtests. Only two ProM tests were correlated with RAVLT mean score of five immediate recall trials: the animals (r=5372, p<0.05) and the appointment (r=4706, p<0.05), but without significant correlation with RAVLT delayed recall (r=0.3288 and r=0.2233, respectively). Cornell Scale for Depression in Dementia (CSDD) showed no signs of depression in the Dementia Group. In this scale, nine dementia patients scored 0, and 11 scored 1 or 2. In the dementia subgroup with scores 1 (eight subjects) or 2 (three subjects), the analysis of correlation between CSDD and ProM scores showed a statistically significant relationship only with the animals’ test (r=0.606, p<0.05, two-tailed), but this correlation was positive, which means that CSDD scores did not influence negatively the performance on ProM tasks. In order to compare the performance of the groups on the ProM tests of the RBMT with the clock and animal tests, the correlation between the memory subtests was measured using the average weighted Kappa coefficient. For the interpretation of the magnitude of this coefficient, values ≥0.75 indicate excellent correlation, values between 0.75 and 0.40 point to good correlation and values ≤0.40 indicate no correlation. All our values were below 0.40, thus indicating no correlation between RBMT and our tests, and suggesting they are not equivalent (Table 1).

Martins SP et al. Alzheimer’s disease memory tests

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The performance of the groups on RBMT ProM tests (appointment, belonging-item and belonging-location tests) and on the clock and the animal tests was analyzed by assessing their accuracy (sensitivity and specificity), as seen in Table 2. Statistical analysis with the Cochran test showed significant difference for sensitivity only in the comparison of the belonging-item test versus the animal one (p=0.0469). No significant difference was found for specificity.

DISCUSSION All subjects could understand what was expected of them in the tasks proposed. Even those who failed in ProM tests could, at the end of the testing session, remember the instructions that had been given to them. AD patients showed significantly inferior performance on all ProM tasks: animals, appointment, clock, and belonginglocation tests. This inferior performance cannot be related to age, for the small difference of age between the two groups was not statistically significant. Furthermore, the age effect on cognitive performance is usually secondary to the effect of education level15,21, which was similar in both groups. The difficulties experienced by AD patients can neither be explained by deficit of attention, visual perception or executive function, for there was not a correlation between ProM and the control tests for these cognitive functions. The impairment of ProM in the present patients was expected, since AD affects multiple cognitive domains, first and foremost memory, and its different subtypes22. We found that only two ProM tests (the animals and the

appointment) were correlated to RAVLT immediate recall, but not with RAVLT delayed one. This finding indicates that the ProM tests are related to intention formation and working memory operations involved in the immediate recall of the word list, but not to the specifically RetM component required for delayed recall. Thus, these ProM tests do not evaluate the same memory component (retrospective, episodic) assessed by RAVLT. Moreover, other studies5,6,23-25 have shown that ProM is primarily and early affected in AD, independently of the concurrent deficit of RetM. There are indications that ProM and RetM depend on different cognitive processes and different brain regions. Performance on ProM tests is more reliant on intention formation, strategic planning, self-initiated retrieval, and interruption or inhibition of ongoing actions, which are cognitive processes highly dependent on the frontal lobes, but not on the hippocampal system. Positron emission tomography (PET) studies of young adults performing ProM tasks have found several localized brain activations, particularly in the right dorsolateral and ventrolateral prefrontal cortices, anterior cingulate gyrus, left parahippocampal gyrus, and midline medial frontal lobe5. The authors of this article related these localized activations to specific cognitive operations involved in ProM, such as: holding an intention toward future behavior, checking target items within presented stimuli, and dividing attention between the planned ProM action and the routine activity in which it was embedded. Contrary to our expectations, we found no correlation between the RBMT and our ProM (the animals and the clock tests), indicating that they do not evaluate ProM in the same

Table 1. Correlation between the prospective memory tests (Kappa index coefficients). Test Animal Clock

Belonging test – item AD 0.1707 CO -0.1538 AD -0.0837 CO -0.2857

Belonging test – location AD 0.1626 CO 0.1475 AD 0.1045 CO 0.1667

Appointment test AD 0.3617 CO -0.1905 AD 0.1139 CO 0.1111

AD: Alzheimer’s disease Group; CO: Control Group.

Table 2. Accuracy of ProM tests for diagnosis of Alzheimer’s disease. ProM tests Clock test Appointment test Belonging test - item Belonging test - location Animal test

Impaired Normal Impaired Normal Impaired Normal Impaired Normal Impaired Normal

AD

CO

15 5 18 12 11 9 13 7 17 3

5 15 3 17 7 13 2 18 5 15

ProM: prospective memory; AD: Alzheimer’s disease Group; CO: Control Group.

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Arq Neuropsiquiatr 2012;70(1):17-21

Accuracy Sensitivity (%) 75

Specificity (%) 75

90

85

55

65

65

90

85

75


way. Thus, we cannot conclude whether any of them is more suitable for studying this subtype of memory. On the other hand, we also evaluated the accuracy of these tests in distinguishing AD from normal aging by comparing the patients’ sensitivity and specificity. All four ProM tests showed similar accuracy, except that the animals’ test was more sensitive than the belonging-item one. Although several authors have found that ProM is early affected in AD, few studies have yielded effective tests for assessing this type of memory. The guidelines proposed by McDaniel and Einstein16 for creating informative ProM tasks have contributed to the elaboration of new instruments to

assess a more comprehensive cognitive profile of AD, already in the initial stages of the disease. This study presents some limitations. The sample is small and the scoring system has a limited variation of scores (0, 1 and 2); thus, rendering difficult the statistical analysis. In spite of these limitations, we can conclude that the clock and the animals’ tests – used for the first time in this study – have similar or even higher sensitivity than the ProM tests of RBMT battery; there were no differences in performance between the ProM tests based on time and those based on event; and both ProM and RetM are significantly impaired in the mild phase of AD.

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Article

Translation, cultural adaptation and psychometric evaluation of the Leganés cognitive test in a low educated elderly Brazilian population Tradução, adaptação cultural e avaliação psicométrica da prova cognitiva de Leganés em uma população idosa brasileira com baixo nível educacional Vescia Vieira de Alencar Caldas1, Maria Victoria Zunzunegui2, Aline do Nascimento Falcão Freire3, Ricardo Oliveira Guerra4

Abstract Objective: To validate the Leganés cognitive test (LCT) for cognitive screening in low educated elderly Brazilians. Methods: The study sample was composed of 59 elderly residents from the city of Santa Cruz, in Brazil, with low schooling levels. Reliability was analyzed with a two-day interval between assessments, and concurrent validity was assessed using the Mini Mental State Examination (MMSE). Results: According to the LCT, the prevalence of dementia was 11.8%. The scale items showed a moderate to strong correlation between domains (p<0.01), and inter-rater reliability exhibited ICC=0.81, 95%CI=0.72–0.88. The factor analysis resulted in two factors: memory and orientation. Interscale agreement was considered poor (k=-0.02), supporting the hypothesis of an educational impact on final MMSE scores. Conclusion: The results suggest that LCT has acceptable levels of reliability for use in low-educated Brazilian elderly.

Key words: cognition, dementia, elderly, education. Resumo Objetivo: Validar a prova cognitiva de Leganés (PCL) para rastreio cognitivo em população idosa brasileira com baixa escolaridade. Métodos: A amostra foi composta por 59 idosos residentes no município de Santa Cruz, no Rio Grande do Norte. A confiabilidade foi analisada com intervalo de dois dias entre as avaliações; a validade concorrente foi feita utilizando o Mini-Exame do Estado Mental (MEEM). Resultados: De acordo com a PCL, a prevalência de demência foi de 11,8%. Os itens da escala mostraram correlações de moderada à forte entre os domínios (p<0,01). A confiabilidade intraexaminador foi considerada boa, com ICC=0,81, CI95%=0,72–0,88. A análise fatorial mostrou dois domínios distintos: memória e orientação. A concordância entre a PCL e o MEEM foi considerada ruim (k=-0,02), reforçando a hipótese da influência educacional no escore do MEEM. Conclusão: A PCL apresenta boa confiabilidade para uso em população idosa brasileira com baixo nível de escolaridade.

Palavras-Chave: cognição, demência, idoso, escolaridade.

The increased prevalence of dementia around the world has been highlighted as one of the consequences of population aging. Estimates suggest a worldwide population of about 24 million elderly people with dementia, approximately 60% of whom are living in developing countries1.

Many screening tools have been developed to identify the presence of cognitive impairment in the elderly, but their results are partially influenced by age, education, race, language, sensory limitations, and other systemic processes2,3. In addition, most of these tools have been developed in countries

1

Master in Physical Therapy by the Federal University of Rio Grande do Norte (UFRN), Natal RN, Brazil;

2

PhD in Epidemiology, Professor at the Preventive Medicine Department of the University of Montreal, Canada;

3

Master in Physical Therapy by the UFRN, Natal RN, Brazil;

4

PhD in Physical Activity and Health Sciences, University of Granada, Spain; Professor at the Physical Therapy Department of the UFRN, Natal RN, Brazil.

Correspondence: Vescia Vieira de Alencar Caldas; Departamento de Fisioterapia; Avenida Senador Salgado Filho, 3.000 – Campus Universitário; 59078-970 Natal RN, Brasil – E-mail: vesciacaldas@yahoo.com.br Conflict of interest: There is no conflict of interest to declare. Received11 May 2011; Received in final form 11 August 2011; Accepted 18 August 2011

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where education levels are high, which may produce falsepositive results when used in low-educated populations4,5. In order to minimize such problems, several studies have been conducted to adjust cut-off values of existing instruments according to education levels, or to design new tools with a lower education impact in their total scores6-9. Cut-offs have been proposed in Brazil for some of the main cognitive screening instruments used in elderly10-13. The Leganés cognitive test (LCT) was originally developed by Spanish researchers in the longitudinal study Envejecer em Leganés (Aging in Leganés) as a cognitive screening scale adapted to low-educated populations14. The LCT assesses basic cognitive ability functions and it shows strong reliability and validity in the studied populations5. Using a cognitive assessment scale, which is both easy to administer and not influenced by education in the Brazilian population, may represent an alternative in preventing the educational biases of existing cognitive assessment scales. Thus, this study aims to culturally adapt the LCT order to use it in low educated elderly Brazilians, and to evaluate its psychometric properties by examining its reliability and validity.

METHODS Population and sample The sample comprised subjects from a study conducted in Brazil and in Canada to culturally adapt and evaluate physical and mental health assessment instruments for later use in a longitudinal study on aging and mobility in Canada, Brazil, and Colombia. This longitudinal study, funded by the Canadian Institutes of Health, seeks to provide greater knowledge on the development of functional disability in elderly with different epidemiological profiles, as well as to explain sex-related differences in mobility, to guide future community-based prevention strategies. To that end, a pilot study was conducted from October to December, 2009 in the city of Santa Cruz, with a population of 32,000 inhabitants, located 150 km from Natal, the capital of the State of Rio Grande do Norte, in Brazil. Sample calculation The sample for this study was calculated to estimate a Cohen’s Kappa of 0.80, with 80% power for a null hypothesis of 0.45, for dichotomous measures of cognitive impairment. A sample of 64 subjects was considered enough to estimate an intraclass correlation coefficient close to 0.80 in a 95% confidence interval. Inclusion criteria Subjects were required to be from 65 to 74 years-old and they should not exhibit any  severe disabilities. Disability was considered severe when the individual was incapable of

performing the following activities unassisted: bathing, getting out of bed, eating, and using the toilet. Those who reported difficulties, but managed to perform these activities, were included in the study. Sampling strategy A random sample of elderly residents of the community was used. They were  stratified according to the functional ability into two groups: full and reduced mobility. This criterion was established based on two questions in the questionnaire: difficulty of walking 1.5 km and climbing stairs. The ones who reported severe difficulty in at least one of the questions were considered as having reduced mobility. In addition, participants were equally divided according to sex, with 32 men and 32 women stratified into two age groups: 65–69 years old and 70–74 years old. Interviewer training Six interviewers were trained using the same training pattern based on videotapes, protocol instructions, and data forms. Cognitive assessment instruments LCT The LCT is a cognitive screening test developed in 2000 by Zunzunegui et al.14. It was designed to be easy to administer and to have no impact of schooling on its final scores. Test completion does not depend on the ability to write, calculate, draw, or conduct abstract thinking, allowing for an adequate cognitive screening in low-educated populations. It consists on the following areas: • temporal orientation – date, day of week, time (0–3); • spatial orientation: place and address (0–2); • personal information: age, date of birth (day/month/ year), mother’s maiden name (0–3); • naming test: ability to name common objects presented in six drawings (0–6); • immediate memory – remembering six objects shown in the drawings. The test starts with the following sentence: “Please tell me the names of the objects you saw in the drawings, and try to remember them because I will ask you again later”. (0–6); • late memory – five minutes after the naming test, the elderly were asked to recall the objects that were shown (0–6); • logical memory – immediate memory of a short story with six ideas (0–6). The total score ranges from 0 to 32, and can reach 0 to 8 in the orientation domain and 0 to 24 in the memory one. Higher scores are associated with better performance and the cognitive impairment cut-off is 22 points. The LCT has not been validated for the Brazilian population, but it was

Caldas VVA et al. Leganés cognitive test: validation

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designed and administered in a population with a similar sociodemographic profile, particularly regarding education levels15-17.  MMSE Two  screening instruments for  dementia and cognitive impairment were used in the cognitive assessment of subjects: the MMSE and the LCT. The MMSE is a screening test widely used around the world to detect dementia and other cognitive disorders. The scale was validated for the Brazilian population by Bertolucci  et al., in 1994, and differentiated cut-off adjustments have been proposed according to education levels. In the present study, the cut-off adapted to the elderly was used, which classifies individuals with scores below 23/24 as cognitively impaired11-13. Procedures Translation and cross-cultural adaptation of the LCT Once authorized by the author, we obtained the original Spanish version of the scale. Back-translation and the bilingual method were used for translation and transcultural adaptation. Initially, two Spanish translators, aware of the research objectives, translated the instrument proposed by Zunzunegui et al.14, seeking content that was both semantically and conceptually equivalent to the original version. Later, both translators worked together and reached a consensus between their translations. A copy was made of the consensual translation, generating the first Portuguese version of the original instrument. Then, the Portuguese version was sent to another translator (Spanish/Portuguese), who had no prior knowledge of the material to be back-translated. When this new Spanish version of the instrument was completed, the translators participating in the study’s first phase carried out a comparative analysis between this and the original version in Spanish, and the translation of this consensus into Portuguese resulted in the second Portuguese version of the instrument. The translation of the original text was proofread by researchers of the Brazilian version, who were proficient in Spanish and familiar with the contents in its source language, an essential condition for adequate translation.  Data collection Data were collected in two home visits, where the researcher initially informed the elderly on the collection process. Those who agreed to participate in the study signed a free and informed consent form. The first collection day consisted of applying the multidimensional questionnaire proposed in the pilot study, assessing both direct and self-reported physical health measurements through physical performance tests. The cognitive assessment scales (MMSE and LCT) were also administered

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Arq Neuropsiquiatr 2012;70(1):22-27

on the first day. After a two-day interval, the elderly were reevaluated using the same tests applied in the first collection, with some simplifications. Cognitive performance and depression assessments were once again administered on the second collection day, without any changes to the previous procedure. For each subject both collections were made by a same researcher from the trained team, in order to determine intra-observer reliability. The study was approved by the Research Ethics Committee of the Federal University of Rio Grande do Norte (UFRN), and all participants signed an informed consent before the evaluation. Data analysis Descriptive analysis It was performed using measures of central tendency and dispersion (mean and standard deviation) for continuous variables, and absolute and relative frequency distributions were analyzed for categorical variables. Reliability and validity The Intraclass Correlation Coefficient was used to determine reliability levels. Internal consistency was verified by using Pearson’s correlation for LCT items, and the factor analysis for the major domains that make up the scale. In order to analyze instrument validity, Pearson’s correlation was used to evaluate MMSE and LCT scores, while the Student’s t-test was used to compare the means. Agreement between both cognitive scales regarding dementia screening was assessed using the kappa coefficient. All data were analyzed with PASW 17.0, considering a significance level of p<0.05.

RESULTS The translation/back-translation processes occurred without any conflicts between the Portuguese and Spanish LCT items. With regards to cultural adaptation, no comprehension problems with the final Portuguese version of the instrument were observed among the studied subjects. Therefore, we consider the process of translation and cultural adaptation of the Brazilian version of LCT to be satisfactory. The study sample was initially composed of 64 elderly, 5 of whom were excluded after the end of data collection due to incomplete questionnaires, resulting in a final sample of 59 subjects: 30 men and 29 women. Mean age was 69.5±2.9 years-old. Sociodemographic data for the sample are given in Table 1. The mean and standard deviation of the cognitive scores obtained for each LCT domain are shown in Table 2. Mean total score on the LCT was 26.3±4.1; this value is above the cut-off proposed for the screening of dementia for this


Table 1. Clinical and sociodemographic characteristics of the sample. Variable

Categories 65–69 years 70–74 years Male Female Illiterate Literate <510 510–1.530 1.531–2.250 >2.251 Yes No

n 26 32 30 29 24 35 5 46 4 4 30 29

% 44.1 54.2 50.8 49.2 40.7 59.3 8.5 78.0 6.8 6.8 49.2 50.8

Independent

48

81.4

Dependent

11

18.6

Independent

41

69.5

Dependent Yes No Yes No No impairment Impaired

18 39 20 19 40 52 7

30.5 66.1 33.9 32.2 67.8 88.1 11.8

No impairment

37

62.7

Impaired

22

37.2

Age Sex Education Income (In Brazilian Reais)

Depression Basic activities of daily living Instrumental activities of daily living Chronic conditions Falls last year Leganés Cognitive Test Mini Mental State Examination  

Source: Data collected by the researchers. Note: 1 US$ ≈ BR$1.65.

instrument (22 points). Mean total score on the MMSE was 23.4±3.6, oscillating between the case/no case classification proposed by Almeida, in 1998. Descriptive analysis of the MMSE scores is shown in Table 3. Reliability Internal consistency analysis using Pearson’s correlation is depicted in Table 4. Significant correlations were found between memory and orientation domains (p<0.01). Correlations between immediate and late memory are strong, suggesting learning effect. Reliability analysis showed strong inter-rater reliability, with an ICC=0.81 (95%CI=0.72–0.88). Concurrent validity Agreement between both cognitive scales regarding  dementia screening was considered poor, as evidenced by the low kappa coefficient (k=-0.02), with no significant difference. Construct validity The LCT factor analysis resulted in two factors: memory and orientation, which explain slightly more than half (57%) of the variance in the resulting score (Table 5). The first domain, considered as the Memory Domain, was composed of the following items: naming, immediate memory, late memory and logical memory. The second domain, consisting of the resulting scores in spatial orientation, temporal orientation and personal information, refers to what we consider the Orientation Domain.

Table 2. Scores of Leganés cognitive test (LCT). LCT domains Naming test Immediate memory Late memory Logical memory Spatial orientation Temporal orientation Personal information Total score

Mean±standard Deviation 5.55±0.98 5.01±1.18 5.20±1.09 3.40±1.93 1.93±0.38 2.64±0.58 2.52±0.56 26.67 ± 3.30

Min–Max 0–6 0–6 0–6 0–6 0–2 0–3 0–3 0 – 32

Source: Data collected by the researchers.

Table 3. Mini Mental State Examination (MMSE) scores. MMSE domains Temporal orientation Spatial orientation Immediate memory Calculation and attention Late memory Visual constructive ability Language Total score

n 59 59 59 59 59 59 59 59

Source: Data collected by the researchers.

Mean±standard deviation 4.49±0.85 4.67±0.50 2.83±0.46 2.57±1.82 1.49±1.04 0.52±0.50 6.81±1.33 23.44±3.63

Min–Max 0–5 0–5 0–3 0–5 0–3 0–1 0–8 0 – 30

DISCUSSION Most cognitive scales are influenced by individual education level, making it difficult to screen true positives for dementia18. Some authors have indicated a strong education impact on the total scores of important screening scales, such as the MMSE, even after cut-off adjustments according to education levels19. The impact of sociocultural aspects, such as education level and environmental contexts, compromises the reliability and validity levels of current cognitive assessment tools for research in elderly populations. Moreover, the use of cognitive assessment tools adapted to the Brazilian reality is extremely important in the clinical field, since early detection of dementia in the elderly allows for preventive and therapeutic decision-making. The possibility of conducting this study with an elderly population in a city in Northeast Brazil, whose socioeconomic and cultural characteristics are so peculiar, provided the necessary conditions to study validity and reliability for the Brazilian context. The successful translation and cultural adaptation of the LCT advances the use of such instruments,

Caldas VVA et al. Leganés cognitive test: validation

25


Table 4. Pearson correlation among Leganés cognitive test (LCT) items. LCT domains Naming test Immediate memory Late memory Logical memory Spatial orientation Temporal orientation Personal information

2 0.46*

3 0.51* 0.78*

 

 

Correlations 4 5 0.24 -0.1 0.24 0.11 0.33* 0.16 0.21

 

 

6 -0.12 -0.01 0.14 0.2 0.40*

7 0.51 0.01 0.07 0.1 0.2 0.1

 

Source: Data collected by the researchers. *p<0.01.

Table 5. Factor Analysis of Leganés cognitive test (LCT) domains. LCT domains Naming test Immediate memory Late memory Logical memory Spatial orientation Temporal orientation Personal information

Factor 1 0.66 0.83 0.9 0.55 -0.29 0.2 0.17

Factor 2 -0.43 -0.23 -0.1 0.26 0.74 0.75 0.38

Source: Data collected by the researchers.

since it eliminates the cultural bias present in most cognitive assessments. No comprehension problems were observed among the subjects, allowing the instrument to be administered in a clear and reliable way. In the present study, we used a sample of young-elderly with no history of falls and independent as to activities of daily living (ADLs). This population was chosen according to the criteria of a longitudinal study jointly conducted by researchers from three countries. Using a sample of healthy elderly made it difficult to detect cases of dementia, since cognitive decline is directly associated with increased age, disability and institutionalization20. However, even in a situation where dementia was not significantly observed, the results of the study on LCT reliability and validity ​​indicated satisfactory psychometrics, especially regarding reproducibility of the values obtained. Sociocultural and environmental factors did not alter reliability, showing similar results to those of the original ones that first developed and validated the scale. With regard to LCT composition, we observed a moderate to strong correlation between items related to memory and orientation domains. Therefore, LCT produces reliable results because it is a simple and direct measure for evaluating cognitive performance in the elderly5,14. According to Herrera et al., the prevalence of dementia among the elderly in Brazil is 7.1%, and may reach 12% for illiterate elderly21. The use of LCT and MMSE as screening tools in our study revealed dementia rates of 11.8 and 37.2%, respectively, calculated according to an education-based classification.

26

Arq Neuropsiquiatr 2012;70(1):22-27

Comparing PLC and MMSE cognitive screening results, we found a poor agreement rate (kappa close to zero). Moreover, significant differences between means were observed, suggesting discrepancies in classifying individuals with suspected dementia, and over-estimation of dementia when administering MMSE to a low-educated population, as found in other studies22. The poorer performance in MMSE domains related to attention, calculation and language mastery reinforces the hypothesis of an education impact on total scores. The LCT, which is based on the construction of its assessment items, is an instrument capable of assessing cognitive function in the elderly with no interference from education levels. Using factor analysis for the Brazilian version of LCT, we observed that domains related to memory and orientation clustered, forming two factors, as proposed in the study where the scale was originally developed. By including both of these important cognitive function domains, LCT can be easily administered and its validity ensured, since these items are amongst the most sensitive in the early detection of dementia and among the most specific in functional decline associations8. Evaluating aspects related to memory and orientation appears to be most adequate for populations with low formal education levels23. Memory impairments derive from the process of cognitive aging, and complaints related to this ability are among the most common in the elderly24. Temporal orientation, however, is an early and highly specific marker of cognitive problems, besides being less dependent on education than other tasks, such as attention, calculation, spatial orientation, language, and drawing. Temporal orientation is a modifiable mortality risk predictor that may help in clinical practice; it could also help promoting health actions for the elderly population, aimed at reducing mortality by allocating the resources required to maintain and rehabilitate cognitive capacity24. Based on these results, we believe that the Brazilian version of the LCT has acceptable levels of reliability for use in low-educated elderly individuals, given that it minimizes the education bias present in most cognitive assessment scales. Finally, we consider that developing screening tools adapted to the Brazilian reality may be a viable alternative to minimize or even prevent the education bias observed in the results of cognitive scales validated for Brazil.


References 1.

Scazufca M, Menezes PR, Araya R, et al. Risk factors across the life course and dementia in a Brazilian population: results from the Sao Paulo Ageing & Health Study (SPAH). Int J Epidemiol 2008;37: 879-890.

2.

Nasreddine ZS, Phillips NA, Bédirian V, et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695-699.

3.

Folstein MF, Folstein SE, McHugh PR. Mini-Mental State. A pratical method for grading the cognitive status of patients for the clinical. J Psychiatric Res 1975;12:189-198.

4.

Salmon DP, Lange KL. Cognitive screening and neuropsychological assessment in early Alzheimer’s disease. Clin Geriatr Med 2001;17:229-254.

5.

de Yebenes MJG, Otero A, Zunzunegui MV, Rodrıguez-Laso A, Sanchez-Sanchez F, Del Ser T. Validation of a short cognitive tool for the screening of dementia in elderly people with low educational level. Int J Geriatr Psychiatry 2003;18:925-936.

6.

7.

8.

13.

Brucki SMD, Nitrini R, Caramelli P, Bertolucci PHF, Okamoto IH. Sugestões para o uso do Mini-Exame do Estado Mental no Brasil. Arq Neuropsiquiatr 2003;61:777-781.

14.

Zunzunegui MV, Gutiérrez Cuadra P, Béland F, Del Ser T, Wolfson C. Development of simple cognitive function measures in a community dwelling population of elderly in Spain. Int J Geriatr Psychiatry 2000;15:130-140.

15.

Béland F, Zunzunegui MV. El perfil de las incapacidades funcionales en las personas mayores. Rev Gerontol 1995;5:232-234.

16.

Zunzunegui MV, Béland F, Llacer A, Leon V. Gender diferences in depressive symptoms among Spanish elderly. Soc Psychiatry Psychiatr Epidemiol 1998;33:195-205.

17.

Béland F, Zunzunegui MV. Predictors of functional status in a population of community- dwelling elderly in Spain. Age Ageing 1999;28:153-159.

18.

Liu HC, Chou P, Lin KN, et al. Assessing cognitive abilities and dementia in a predominantly illiterate population of older individuals in Kinmen. Psychol Med 1994;24:763-770.

Yancik, R, Ershler W, Satariano W, Hazzard W,  Cohen HJ,  Ferrucci L. Report of the National Institute on Aging Task Force on Comorbidity. J Gerontol A Biol Sci Med Sci 2007;62:275-280.

19.

Fillenbaum GG, Chandra V, Ganguli M, et al. Development of an activities of daily living scale to screen for dementia in an illiterate rural older population in India. Age Ageing 1999;28:161-168.

Alvarado BE, Zunzunegui MV, Dek Ser T, Béland FD. Cognitive decline is related to education and occupation in a Spanish elderly cohort. Aging (Milano) 2002;14:132-142.

20.

Senanarong V, Assavisaraporn S, Sivasiriyanonds N, et al. The IQCODE: an alternative screening test for dementia for low educated Thai elderly. J Med Assoc Thai 2001; 84:648-655.

Oliveira DLC, Goretti LC, Pereira LSM. O desempenho de idosos institucionalizados com alterações cognitivas em atividades de vida diária e mobilidade: estudo piloto. Rev Bras Fisioter 2006;10:91-96.

21.

Herrera EJR, Caramelli P, Silveira AS, Nitrini R. Epidemiologic survey of dementia in a community-dwelling Brazilian population. Alzheimer Dis Assoc Disord 2002;16:103-108.

22.

Scazufca M, Almeida OP, Vallada HP, Tasse WA, Menezes PR. Limitations of the Mini-Mental State Examination for screening dementia in a community with low socioeconomic status. Eur Arch Psychiatry Clin Neurosci 2009;259:8–15.

9.

Damasceno A, Delicio AM, Mazo DF, et al. Validation of the Brazilian version of mini-test casi-s. Arq Neuropsiquiatr 2005;63:416-421.

10.

Atalaia-Silva KS, Lourenço RA. Translation, adaptation and construct validation of the Clock Test Among elderly in Brazil. Rev Saúde Pub 2008;42:2-7.

11.

Almeida OP. Mini exame do estado mental e o diagnóstico de demência no Brasil. Arq Neuropsiquiatr 1998;56:605-612.

23.

Dickstein DL, Kabaso D, Rocher AB. Changes in the structural complexity of the aged brain. Aging Cell 2007;6:275–284.

12.

Bertolucci PHF, Brucki SMD, Campacci S, Juliano Y. O Mini-Exame do Estado Mental em uma populacao geral. Impacto da escolaridade. Arq Neuropsiquiatr 1994;52:1-7.

24.

Gong G, Rosa-Neto P, Carbonell F, Chen ZJ, He Y, Evans AC. Age- and gender-related differences in the cortical anatomical network. Neuroscience 2009;29:15684-15693.

Caldas VVA et al. Leganés cognitive test: validation

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Article

Autism spectrum disorder and celiac disease: no evidence for a link Transtorno autístico e doença celíaca: sem evidências de associação Icaro Camargo Batista1, Lenora Gandolfi2, Yanna Karla Medeiros Nobrega3, Rodrigo Coutinho Almeida4, Lucas Malta Almeida5, Dioclécio Campos Junior1, Riccardo Pratesi2

Abstract

Objective: To evaluate the possible association between celiac disease (CD) and/or gluten sensitivity (GS) and autism spectrum disorder (ASD). Methods: Occurrences of CD were determined in a group of children and adolescents affected by ASD and, conversely, occurrences of ASD were assessed in a group of biopsy-proven celiac patients. To detect the possible existence of GS, the levels of antigliadin antibodies in ASD patients were assessed and compared with the levels in a group of non-celiac children. Results: The prevalence of CD or GS in ASD patients was not greater than in groups originating from the same geographical area. Similarly the prevalence of ASD was not greater than in a group of biopsy-proven CD patients. Conclusion: No statistically demonstrable association was found between CD or GS and ASD. Consequently, routine screening for CD or GS in all patients with ASD is, at this moment, neither justified nor cost-effective. Key words: autistic spectrum disorder, celiac disease, prevalence, mass screening. Resumo

Objetivo: Avaliar a possível associação entre doença celíaca (DC) e/ou sensibilidade ao glúten (SG) e transtorno do espectro autista (TEA). Métodos: Ocorrências de DC foram determinadas em um grupo de crianças e adolescentes afetados pelo TEA e a ocorrência d TEA foi avaliada em um grupo de pacientes com DC comprovada por biópsia. Para detectar a possível existência de SG, foram determinados níveis de anticorpos antigliadina em pacientes com TEA e comparados ao grupo de crianças sem a doença celíaca. Resultados: A prevalência de DC ou SG não foi maior no grupo de pacientes com TEA quando comparada a grupos de indivíduos originários da mesma região geográfica. De modo similar, a prevalência do TEA não foi maior ao ser comparada ao grupo de pacientes com DC. Conclusão: Não houve associação estatisticamente demonstrável entre DC ou SG e TEA. Consequentemente, não são justificáveis, no momento, exames de rotina para detecção de DC ou SG em pacientes com TEA.

Palavras-Chave: transtorno autístico, doença celíaca, prevalência, programa de rastreamento.

Autism is a disorder of neural development characterized by impaired social interaction and communication, and by restricted and repetitive behavior. It is one of the three recognized autism spectrum disorders (ASDs); the other two are Asperger’s syndrome, which lacks delays in cognitive development and language, and pervasive developmental disorder – not otherwise specified (commonly abbreviated as PDD-NOS), which is diagnosed when the full set of criteria for autism or Asperger’s syndrome is not met1. Children with ASD frequently display tendencies toward self-harm, 1

irritability, hyperactivity, erratic and aggressive behavior. One of the most confounding aspects of ASDs is their wide phenotypic heterogeneity, which suggests that ASDs may possibly encompass several different and specific disorders with different etiologies sharing a common behavioral clinical picture. Although the cause of ASDs and their associated symptoms remain unclear, it is likely that their complex etiology arises from the combined effects of multiple susceptibility alleles in concert with environmental or other non-genetic factors. Evidence from twin and family studies clearly

Graduate Program in Health Sciences, School of Health Sciences, University of Brasília, Brasília DF, Brazil;

Graduate Program in Health Sciences; Department of Pediatrics; Celiac Disease Research Center, School of Medicine, University of Brasília, Brasília DF, Brazil.

2

3

Celiac Disease Research Center; Department of Pharmaceutical Sciences, School of Health Sciences, University of Brasília, Brasília DF, Brazil.

Graduate Program in Health Sciences, School of Health Sciences; Celiac Disease Research Center, School of Medicine, University of Brasília, Brasília DF, Brazil. 4

5

Celiac Disease Research Center, School of Medicine, University of Brasília, Brasília DF, Brazil.

Correspondence: Riccardo Pratesi; SQN 212/Bloco F/Apt. 605; 70864-060 Brasília DF - Brasil; E-mail: pratesir@unb.br Conflict of interest: There is no conflict of interest to declare. Received 27 June 2011; Received in final form 09 August 2011; Accepted 16 August 2011

28


establishes the importance of genetic factors in the development of ASDs2. ASDs were considered to be rare until a few decades ago, but their prevalence has increased more than tenfold over the past 20 years. Their estimated prevalence is 0.9% in the United States3, although data from a recent review of 47 studies conducted in 17 different countries since 1966 found that the prevalence ranged from 0.6 to 0.7%, or one child in about 150 children4. In spite of the controversy regarding whether this is a real rise in the number of cases or the result of increased publicity and better diagnostic criteria, it remains clear that ASDs are disorders that produce major challenges for the families and society. No reliable studies focusing on the prevalence of ASDs have been conducted in Brazil. Although celiac disease (CD) is classically defined as an immune-mediated chronic small-intestinal enteropathy, which is triggered by the ingestion of gluten from wheat, barley and rye in genetically predisposed individuals, CD could be more appropriately described as a multisystem disorder, often showing extra-intestinal symptoms and potentially affecting any organ or body system, including the nervous system5. The diagnosis of CD is traditionally based on positive serological tests and on a biopsy of the upper small intestine revealing varying degrees of villous atrophy, crypt hyperplasia, and intraepithelial lymphocytes. The serological tests commonly used are the IgA-endomysial antibody (IgA-EMA), which possesses specificity approaching 100%, and the IgAanti-transglutaminase antibody (IgA-tTG), which does not have the same specificity but, since it is an enzyme-linked immunosorbent immunoassay (ELISA), it is less expensive and less observer-dependent6. The association between CD and central nervous system dysfunction was initially suggested several decades ago by Cooke and Thomas-Smith7, and their initial review was followed by numerous articles and case reports on patients with established CD and different neurological manifestations, including neuropathy, ataxia, migraines and epilepsy8,9. Some authors have raised the hypothesis that gluten sensitivity may exist in patients with normal jejunal mucosa and negative anti-transglutaminase (IgA-tTG) and IgA-EMA tests. IgA-EMA and IgA-tTG detections are specific for the presence of enteropathy and are excellent indicators of CD. However, these markers are often not detectable in patients with neurological manifestations, particularly in the absence of enteropathy. Although there is not always a diagnostic for gluten sensitivity, the presence of positive antigliadin antibody (IgA-AGA) tests in these patients would raise a high degree of suspicion and could be considered as an indicator for further testing and follow-up10. Screening studies performed over the last decade in Brazil have shown uneven prevalence rates for CD in different regions of Brazil, ranging from 1:52 to 1:417 in the general population11,12 and from 1:214 to 1:681 in presumably healthy

blood donors13,14. Among children younger than 15 years-old, originating from the same geographical region and pertaining to a similar socioeconomic stratum in which the present study was performed, a prevalence of 1:185 (0.54%) was found12. Consequently, it seems that CD prevalence in Brazil is similar to what was found in European countries and in the USA, where an overall prevalence ranging from 1:150 to 1:250 is generally accepted15. Increased presence of gastrointestinal disorders in ASD patients is a recurring theme, both in the medical literature and among the parents and caregivers of autistic children. Several studies have reported that gluten-free and caseinfree diets ameliorated autistic symptoms, although sound evidence that this association really exists and complete agreement among authors regarding this topic is still lacking16-19. Similarly, over the past decade, several authors have suggested that links may exist between CD and ASDs20 and between CD or gluten sensitivity and psychiatric disorders21,22, but these indications have been contradicted by other reports23. The aims of the present study were to evaluate the existence of a possible relationship between CD or gluten sensitivity and ASD, to determine occurrences of CD and/or increased levels of IgA-AGA among a group of children and adolescents affected by ASD and, conversely, to assess occurrences of ASD among a group of biopsy-proven celiac patients.

METHODS The relationship between ASD and CD or ASD and gluten sensitivity was assessed by evaluating a group of 147 patients with ASD for simultaneous occurrences of CD and/or increased levels of IgA-AGA. Conversely, occurrences of ASD were assessed in a group of 211 celiac patients followed-up at the Walk-in CD Clinic of the Hospital from the University of Brasília, Brasília, Federal District, in Brazil. The Hospital from the University of Brasília is a general hospital attending mainly the low-income population originating from the outskirts and suburban regions of the city of Brasília. Racially, this is a predominantly mixed-blood population in which a considerable contribution of European ancestry can be detected in association with variable proportions of other races, mainly Black African and, to a lesser extent, Amerindian. This study received approval from the Ethics Committee of the School of Health Sciences from the University of Brasília, and informed consent for participation in the study and for publication of the results was obtained from all the eligible adult patients or, in the case of children or adolescents, from their parents or guardians. Among the 211 biopsy-proven celiac patients who were included in this study, there were 66 males and 145 females (age range: 1 to 48 years-old; mean age: 15.7 years-old). These

Batista IC et al. Autism and celiac disease

29


patients had been diagnosed as presenting CD, in accordance with the revised criteria of the European Society of Pediatric Gastroenterology and Nutrition (ESPGAN)24. All the celiac patients were evaluated, and members of their families agreed to answer questions, as indicated in the DSM-IV, concerning the possible existence of behavioral abnormalities suggestive of ASD. A small proportion of the patients with ASD was identified through two local societies of parents of autistic children. A larger proportion was found among students in special education classes organized by the Federal District Department of Education. The socioeconomic strata and racial characteristics of the ASD patients were comparable with those of the study group of celiac patients. Among the 147 ASD patients who were enrolled in the study, there were 127 males and 20 females (age range: 1 to 35 years-old; mean age, 8 years-old). All the patients were diagnosed by accredited medical professionals and fulfilled the diagnostic criteria of the DSM-IV for ASD. None of the patients was on a gluten-free diet (GFD). Blood samples were centrifuged, and the resulting sera were stored at -20° C until their use. To exclude individuals with a possible IgA deficiency, IgA levels were measured by turbidimetric immunoquantification (COBAS MIRA, Roche Diagnostic Systems). IgA and IgG antigliadin antibodies (IgAAGA and IgG-AGA) and IgA anti-transglutaminase antibodies (IgA-tTG) were assessed by means of the standard ELISA (Quanta LiteTM IgA and IgG gliadin and human IgA-tTG, INOVA Diagnostic, Inc. CA, USA). According to the manufacturer’s instructions, the upper limit of the normal range was established as 20 arbitrary units. All patients who displayed values above the upper limit in the antigliadin or anti-transglutaminase tests underwent further testing for the presence of anti-endomysium-specific antibodies (IgA-EMA). The IgA-EMA assay was performed using indirect immunofluorescence with cryosections of distal monkey esophagus (Binding Site, Birmingham, UK). Two independent observers examined all the slides, and the presence of brilliant green reticulin-like staining of smooth muscle under the fluorescence microscope was considered a positive result. In the present study, the IgA-tTG test (more sensitive but less specific) was used as a preliminary screening test, while the IgA-EMA one was considered a confirmatory test.

Statistical analysis The prevalence of CD and ASD and the increased level of IgA-AGA were estimated together with their exact binomial 95% confidence intervals (95%CI). To compare the prevalence between groups, the exact p-value for the χ2 statistic was calculated (based on binomial distribution).

RESULTS Among the 147 ASD patients, five displayed abnormal results in the IgA-AGA test, and one showed a weakly positive result in the IgA-tTG test. These six patients were subsequently tested for the presence of IgA-EMA with negative results. The test results and clinical data on these patients can be seen in Table 1. Among the 211 biopsy-proven CD patients followed at the Walk-in CD Clinic of the Hospital from University of Brasília, two cases of ASDs were identified: an 11-year-old boy who fulfilled all of the DSM-IV criteria for an autistic disorder and a seven -year-old boy with Asperger’s syndrome. Both patients had been referred by their attending physicians due to the presence of gastrointestinal symptoms, mainly composed of frequent abdominal cramps and diarrheic episodes. A GFD was strictly followed only by one of the two patients, who showed progressive improvement in gastrointestinal symptoms, although no behavioral improvement could be detected. Since no data on the prevalence of ASDs in Brazil are available as a reference for the prevalence of ASDs in the general population, we used the prevalence found by the latest surveillance summaries of Center of Disease Control (CDC) autism and development disabilities monitoring network, United States, which was conducted in a population of 307,790 eight-year-old children3. The prevalence of ASDs in patients with CD was 0.95% (95%CI=0.11–3.82) and it was not statistically different from the prevalence of 0.9% found in the general US population (p=1.00), as seen in Table 2. No cases of CD were found among the 147 patients with ASD. The reference group, regarding the prevalence of CD in our area, was composed of 2,034 children younger than 15 years-old (age range: 1 to 14 years-old; mean age: 8 years-old),

Table 1. Clinical and laboratory data on the six ASD patients with abnormal results from serological tests. Patients 1 2 3 4 5 6

Sex M M M M M

Age (y) 14 15 6 4 5

IgG-AGA 45.1 3.0 3.4 12.7 5.1

IgA-AGA 9.9 38.8 15.3 50.6 44.1

IgA-tTG 10.9 8.9 29.3 12.6 6.3

IgA-EMA Negative Negative Negative Negative Negative

F

12

6.8

45.4

8.8

Negative

ASD: autism spectrum disorder; M: masculine; F: feminine.

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Arq Neuropsiquiatr 2012;70(1):28-33

Symptoms No gastrointestinal symptoms No gastrointestinal symptoms Constipation and occasional diarrhea No gastrointestinal symptoms Anemia, constipation, bloating, abdominal cramps, mouth ulcers, and chronic fatigue Constipation and occasional abdominal cramps


Table 2. Prevalence of ASDs found among our 211 biopsy-proven celiac disease patients, and estimated prevalence of ASDs found in a population of 307,790 eight-year-old children in the USA3. Groups Prevalence of ASDs among our celiac patients Prevalence of ASDs in the USA population (307,790)

n 211

Prevalence of ASDs 0.95 0.90

95%CI* (0.11–3.82)

p-value (between groups)† 1.00

*Based on binomial distribution; †Exact test; Post-hoc power analysis=1.000; ASD: autism spectrum disorder.

Table 3. Prevalence of CD among our 147 ASD patients and in a group of 2,034 children and adolescents originating from the same geographical region and from a similar low-income stratum. Groups Prevalence of CD among ASD patients Prevalence of CD among subjects without ASDs

n

CD prevalence

95%CI*

147 2034

0.00 0.54

(0.00–2.48)

p-value (between groups)† 0.63

*Based on binomial distribution; †Exact test; Post-hoc power analysis=0.999993; ASD: autism spectrum disorder; CD: celiac disease.

Table 4. Prevalence of IgA-AGA in ASD patients and in 132 non-celiac children originating from the same geographical region and from a similar low-income stratum. Groups Prevalence of IgA-AGA in patients with ASDs Prevalence of IgA-AGA in non-celiac patients without ASDs

n 147 131

IgA-AGA Prevalence 3.4 9.3

95%CI* (1.11–7.76)

p-value (between groups)† 0.08

*Based on binomial distribution; †Exact test; Post-hoc power analysis=0.978618; ASD: autism spectrum disease.

who were part of a previous CD prevalence screening study that we conducted, originating from the same geographical region and pertaining to a low-income population similar to the celiac group of this study. The prevalence of CD in this group was 0.54% and no cases of ASD were found among such children. Consequently, the prevalence of CD in patients with ASD was 0.00% (95%CI=0.00–2.48) and it was not statistically different from the prevalence found in children in the same region (Table 3). To evaluate the possible existence of gluten sensitivity in ASD patients, we used a reference group consisting of 132 children who displayed varying degrees of gastrointestinal symptoms (age range: 1 to 12 years-old; mean age: 5.8 years-old), and who were part of an ongoing study on the prevalence of IgA-AGA in non-celiac (IgA-EMA and IgA-tTG negative) children. The prevalence of IgA-AGA among these children, originating from the same geographical region and socioeconomic stratum, was 9.3%, while the prevalence of IgA-AGA in patients with ASD was 3.4% (95%CI=1.11–7.76), with p=0.08 (Table 4).

DISCUSSION As previously stated, the wide phenotypic heterogeneity suggests that ASDs may possibly encompass several different specific disorders with different etiologies sharing a common behavioral clinical picture. The presently available data point towards probable involvement of multiple interacting

genes and environmental modifiers in the pathogenesis of autism25. The suggestion that CD might be involved in the pathogenesis of autism has mostly been based on the leaky-gut hypothesis, i.e., abnormal intestinal mucosa would permit excessive absorption of short-chain peptides produced from incomplete digestion of dietary gluten in the lumen of the small intestine, through defective action of peptidases. These short peptides, structurally similar to endorphin, could provoke an immune reaction or act as exorphins, thereby directly affecting the nervous system. However, a recent consensus report concluded that the evidence for abnormal gastrointestinal permeability in individuals with ASDs is presently limited and additional properly powered prospective studies with appropriate controls are needed in order to determine the role of abnormal permeability in neuropsychiatric manifestations of ASDs16. Several authors have reported that children with ASDs may experience more constipation, loose stools, recurrent abdominal pain, bloating, and excessive flatulence than presented by non-affected children18,26. Although gastrointestinal problems in individuals with ASDs may go undiagnosed because of atypical symptoms and/or difficulties in communicating with nonverbal patients, it is difficult to establish whether their prevalence is higher than is seen in the general population, due mainly to the lack of prospective well-controlled studies. The presumed association between an excess of gastrointestinal symptoms in children with autism and worsening of their behavior often results in implementation of restrictive diets, mainly targeting

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casein and gluten in the hope of improving their symptoms. Several studies and reviews have addressed the topic of the existence of a possible gut-to-brain connection and the effects of dietary intervention in autism, with varying results17. In a recent extensive literature review on this topic, Millward et al.27 concluded that the current body of evidence to suggest that dietary therapy approaches are effective is still poor, and that large-scale, good-quality randomized controlled trials are needed. The assumption that gastrointestinal symptoms are excessively frequent in autistic children has raised the hypothesis that greater prevalence of CD could also exist among patients with autism, given that one possible point in common between these two very different diseases would be the increased intestinal permeability, which is present in both disorders. However, the results from the few studies on the possible association between CD and autism have not shown consistent results20-23. Additionally, as appropriately noted by Lionetti et al.28, it is important to remember that autism is a neurological disorder of early brain development and therefore it is difficult to establish a temporal correlation between the presence of abnormalities of the central nervous system and the gluten intake, which usually begins after the first six months of age. In the majority of children with diagnosis of autism, careful analysis on their histories will reveal that the symptoms began before they reached 18 months of age. This early onset only provides a limited period of time for the infant to have begun to consume gluten-containing foods. Our results showed that the prevalence of CD in patients with autism was not greater than the prevalence found in a group of 2,034 healthy children originating from the same geographical area. We also found that the prevalence of autism was not significantly greater among our group of 211 biopsy-confirmed CD patients. The possibility of higher gluten sensitivity in ASD children, which would be substantiated by increased presence of IgA-AGA, was also ruled out since there was no significant difference in the prevalence of these antibodies in comparison with the prevalence found in a sample of 131 non-celiac children of similar socioeconomic level originating from the same city.

In conclusion, although the profusion of studies reporting clinical and, especially, behavioral improvement with gluten-exclusion diets in patients with autism cannot be simply ignored, it is at present difficult to statistically demonstrate that there is an association between ASD and CD or between ASD and gluten sensitivity. The reported deleterious effects on brain function, the behavior of children with ASD, consequent to gluten intake, and the frequently reported clinical improvement with restriction diets, if present, are possibly due to other and not completely clarified mechanisms. In the case of gluten sensitivity, in the absence of reliable biomarkers, the diagnosis is still dependent on establishing an exclusion diet in patients who experience distress when eating gluten-containing products29. With the present data, we are forced to agree with the previous work by Pavone et al.23, who concluded that concomitant occurrences of autism and CD in the same individuals are most likely due to pure coincidence. Although we feel that performing routine screening for CD in all patients with ASD is neither justified nor cost-effective, one should also consider that CD is a disease with reliable serological and genetic markers, whereas the ASD diagnosis is based on clinical grounds probably encompassing different disorders with a common clinical expression. It is possible that different results would have been obtained if a specific subset of ASD patients had been selected (e.g., only children with regressive autism). The main limitation of the present paper is that even though both disorders are lifelong conditions, the age of onset of the CD is variable and some of the ASD patients could still develop this disease in the future. Another limitation is that although the source of all patients with ASDs were regional societies of parents of autistic children and all diagnoses had been made by accredited medical professionals, we were only able to perform a complete evaluation in person on a subset of these patients. It is possible that other clinical entities (e.g. fragile X syndrome) could have been included in the group of ASD patients. Additionally, due to the complete lack of data regarding the prevalence of ASDs in Brazil, we used the prevalence of ASD in the USA based on the latest CDC report3, as a reference point for statistical analysis.

References 1.

Johnson CP, Myers SM, and the Council on Children with Disabilities. Identification and evaluation of children with autism spectrum disorders. Pediatrics 2007;120:1183-1215.

2.

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Batista IC et al. Autism and celiac disease

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Article

The impact of EEG in the diagnosis and management of patients with acute impairment of consciousness Impacto do EEG no diagnóstico e conduta dos pacientes com alteração aguda do estado da consciência João A. G. Ricardo, Marcondes C. França Jr., Fabrício O. Lima, Clarissa L. Yassuda, Fernando Cendes

ABSTRACT Objectives: To assess the frequency of electroencephalogram (EEG) requests in the emergency room (ER) and intensive care unit (ICU) for patients with impairment of consciousness (IC) and its impact in the diagnosis and management. Methods: We followed patients who underwent routine EEG from ER and ICU with IC until discharge or death. Results: During the study, 1679 EEGs were performed, with 149 (8.9%) from ER and ICU. We included 65 patients and 94 EEGs to analyze. Epileptiform activity was present in 42 (44.7%). EEG results changed clinical management in 72.2% of patients. The main reason for EEG requisition was unexplained IC, representing 36.3% of all EEGs analyzed. Eleven (33%) of these had epileptiform activity. Conclusion: EEG is underused in the acute setting. The frequency of epileptiform activity was high in patients with unexplained IC. EEG was helpful in confirming or ruling out the suspected initial diagnosis and changing medical management in 72% of patients.

Key words: emergency EEG, impaired of consciousness, emergency room, intensive care unit. RESUMO Objetivo: Avaliar a frequência de exames de eletroencefalograma (EEG) solicitados no pronto-socorro (PS) e na unidade de terapia intensiva (UTI) em pacientes com rebaixamento do nível de consciência, bem como seu impacto no diagnóstico e na conduta. Métodos: Acompanhamos pacientes submetidos ao EEG do PS e da UTI com rebaixamento do nível de consciência até a alta ou óbito. Resultados: Realizamos 1679 EEGs no período de estudo; destes, 149 (8,9%) foram solicitados no PS e na UTI. Incluímos 65 pacientes e 94 EEGs para análise; destes, 42 (44,7%) apresentavam atividade epileptiforme. O EEG mudou a conduta em 72% dos pacientes. A razão principal para solicitação do EEG foi rebaixamento do nível de consciência de origem inexplicável (36,3% dos EEGs). Destes, 33% tinham atividade epileptiforme. Conclusão: Embora o EEG seja pouco usado em condições agudas, a frequência de atividade epileptiforme foi alta nos pacientes com rebaixamento do nível de consciência de origem inexplicável. O EEG foi decisivo para o esclarecimento diagnóstico e implicou mudança da conduta em 72% dos pacientes.

Palavras-Chave: EEG de emergência, rebaixamento de consciência, pronto-socorro, unidade de terapia intensiva.

With the advent of neuroimaging techniques, such as high resolution MRI, PET and SPECT, the importance of the electroencephalogram (EEG) in cerebral disease studies had decreased. However, nowadays, it has received high attention as an important source of information, especially in situations such as unexplained impairment of consciousness1-3, since it may offer valuable real time information about brain activity, which can be decisive in some life-threatening situations, as convulsive status epilepticus (CSE) and nonconvulsive status epilepticus (NCSE), in which early recognition and

immediately treatment may not only prevent death, but also offer better outcomes1-8. It might also give important clues in the diagnosis of certain conditions, such as encephalitis, hypoxic–anoxic brain injury, metabolic disturbances, intoxication and structural lesions2,3,9-12. In the present study, we aimed to assess the frequency of emergent EEG (eEEG) requests and its impact for both diagnosis and patients’ management in order to investigate the necessity of 24-hours EEG service for both emergency room (ER) and intensive care unit (ICU) in a tertiary hospital.

Department of Neurology, Medical School, State University of Campinas (UNICAMP), Campinas SP, Brazil. Correspondence: Fernando Cendes; Department of Neurology; FCM/UNICAMP; Cidade Universitária; 13083-970 Campinas SP - Brasil; E-mail: fcendes@unicamp.br Support: Dr. JAGR received a scholarship from CAPES. Conflict of interest: There is no conflict of interest to declare. Received 09 August 2011; Received in final form 20 August 2011; Accepted 29 August 2011

34


METHODS Subjects selection We included all patients with impairment of consciousness (drowsiness, confusional states or coma) from ER and general ICU for whom an eEEG was requested. Patients were enrolled between May 2008 and June 2009 and followed during hospitalization at UNICAMP university hospital. Exclusion criteria were age under 18 years old, patients in hospital wards and patients with poor quality EEG. The study was approved by the local ethics committee. Clinical and epidemiological data Information was collected through personal interview and/or review of the medical chart. The analyzed variables were age, gender, Glasgow Coma Scale (GSC), presence of focal neurological signs on admission, as well as prior history of seizures, epilepsy and stroke. We also recorded the etiology of the acute neurological condition that prompted admission and patient management after eEEG. During hospitalization, we followed the clinical course and outcomes until discharge or death. EEG analysis eEEG was defined as any EEG performed on an emergency basis13, as well as requested for immediate performance or during non business hour7. Each eEEG was performed on an analogical Nihon Khoden Acquisition System using a 16 channel and scalp electrodes placed according to the International 10–20 System of Herbert Jasper14. The EEG recording lasted from thirty minutes to two hours. We used 5 montages according American Clinical Neurophysiology Society (ACNS) guidelines15, as followed: longitudinal bipolar (double banana); transverse bipolar (coronal); longitudinal-transverse bipolar and two referential montages (including Average and Vertex Cz). Epileptiform activity was defined as spike or sharp waves with asymmetrical transient having a fast rising phase and a slower descending phase followed or not by a slow wave2. Patients underwent manual opening and closure of the eyes, as well as auditive and painful stimulation. Each EEG was evaluated by board certified neurophysiologists and later reviewed by both authors (JAGR and FC) in order to standardize criteria (Table 1).

For each patient, we recorded initial diagnostic hypothesis and final diagnosis. We compared these data and identified those individuals whose eEEG findings motivated changes in medical management, such as adjustment of antiepileptic drug dosage (AED) and indication for sequential EEG. Statistical analysis We used chi-squared or Fisher`s exact tests to compare categorical variables among subgroups of patients. Statistical significance was considered at α of 5%. Statistical analysis was performed using SYSTAT software (Systat Software, version 12.0, Chicago, IL, USA).

RESULTS During the study period, a total of 1679 EEGs were performed by our EEG laboratory, including routine, hospital wards, emergency room and ICU. Of these, 149 (8.9%) were performed as emergent EEG and 20 (13.4%) performed by other services (they were not from ER or ICU), which were not included. Ninety four EEGs from the ER and ICU were analyzed (Fig 1). Those 94 emergent EEGs were performed on 38 (58.5%) men and 27 (41.5%) women. Age ranged from 18 to 91 years (mean 55.7; ±17.9). Nearly 25% had focal signs and 16.7% had a previous history of epilepsy. The average of GCS was 8.8 (±3.6), with most of the patients (50.8%) with a GCS under 8. The most common diagnoses in our cohort were cerebrovascular diseases (ischemic and hemorrhagic stroke, aneurism and sinus venus thrombosis) in 17 (26.2%) patients, brain trauma injury (BTI) in 8 (12.3%) and central nervous system (CNS) tumor in 5 (7.7%). Overall, half of the patients presented seizures on admission. Those early seizures were more frequent among patients with cerebrovascular diseases (Table 2). Presenting characteristics of EEG The number of EEGs performed for each patient ranged from 1 to 6; most of these (53.3%) were performed after 24 hours of admission. In 89 EEGs, activation methods were performed. Manual opening and closure of the eyes did not reveal any reactivity in 39 (43.8%), painful stimulus did not reveal any EEG reactivity in 33/87 (37.9%), and auditive stimulus did

Table 1. Operational definitions for EEG findings. Epileptiform activity Focal epileptiform activity Generalized epileptiform activity Triphasic waves PLED/BiPLED Diffuse slowing Focal slowing Low voltage Burst–suppression Electrocerebral inactivity

Presence of sharp wave, spikes, with or not preceded by slow wave Epileptiform activity well localized in a hemisphere or lobe Epileptiform activity generalized, symmetric and synchronous Delta waves, positive wave preceded and followed by negative waves Periodic lateralized epileptiform discharge and bilateral independent PLED Delta or theta waves diffusely distributed Delta or theta waves localized in a hemisphere or lobe Slow waves with amplitude less than 20 microvolts Paroxysmal activity alternating with periods of suppression of EEG Isoelectric EEG recording

Ricardo JAG et al. Impairment of consciosness: EEG

35


not reveal any reactivity in 44/87 (50.6%). The main EEG abnormalities found in this cohort are shown in Fig 2. The main reason underlying indication of the eEEG was not clear in 3 medical requests. Most of the remaining EEGs were requested to investigate impairment of consciousness or status epilepticus (convulsive or non-convulsive). Other reasons for medical request were herpetic encephalitis, myoclonus evaluation and management of AED. Among the 33 EEGs that were indicated due to unexplained impaired of consciousness, 11 (33.3%) had epileptiform activity (Table 3). Comparison of the initial diagnostic and final diagnosis hypothesis showed that the EEG confirmed the hypothesis in 36 (39.6%), the EEG ruled out the diagnosis in 30 (32.9%) and was not helpful in 25 (27.5%). After EEG acquisition, patient management changed in 66 (72.5%), for example, as showed in Fig 3 and 4. Outcomes predictors Twenty six (40%) patients died in our cohort. Fatal outcome was more frequent among patients who developed hemodynamic complications (57.1%), electrolytic (63.5%) disturbance, sepsis (39.7%) or renal failure (68.3%) (Table 4).

1679 EEG (baseline)

ER (87 (58.4%)

Emergency 149 (8.9%)

Routine 1530 (91.1%)

ICU 42 (28.2%)

Ohers 20 (13.4%)

60 (69.0% Included

34 (80.9%) Included

27 (31.0%) Not included*

8 (19.1%) Not included*

*Number of exams was not included in the study due to technical reasons.

Fig 1. Flowchart showing the number of EEGs performed in electroencephalography service.

Table 2. Initial diagnosis, history of seizures and EEG epileptiform abnormalities on admission and outcomes. Initial diagnosis Aneurysm Alcohol withdrawal Hemorrhagic stroke Ischemic stroke Stomach cancer Convulsive seizure Encephalitis Anoxic Encephalopathy Epilepsy Schizophrenia Chronic liver disease AMI CHF CNS infection Exogenous intoxication CJD SLE NHL Ataxia telangiectasia Dementia Sepsis Superior vena cava occlusion AIDS BTI Cerebral sinus thrombosis CNS tumor Liver transplantation Mielodysplasic syndrome

No of patients (percentage) 3/65 (4.62) 2/65 (3.08) 3/65 (4.62) 8/65 (12.31) 1/65 (1.54) 1/65 (1.54) 3/65 (4.62) 4/65 (6.15) 4/65 (6.15) 1/65 (1.54) 2/65 (3.08) 1/65 (1.54) 1/65 (1.54) 2/65 (3.08) 2/65 (3.08) 1/65 (1.54) 1/65 (1.54) 1/65 (1.54) 1/65 (1.54) 2/65 (3.08) 1/65 (1.54) 1/65 (1.54) 1/65 (1.54) 8/65 (12.31) 3/65 (4.62) 5/65 (7.69) 1/65 (1.54) 1/65 (1.54)

Seizures on admission

Epileptiform activity

2/3 (66.70) 1/2 (50.00) 1/3 (33.30) 6/8 (75.00) 0/1 (0.00) 1/1 (100.00) 2/3 (66.67) 1/4 (25.00) 4/4 (100.00) 0/1 (0.00) 0/2 (0.00) 0/1 (0.00) 0/1 (0.00) 0/2 (0.00) 0/2 (0.00) 0/1 (0.00) 1/1 (100.00) 0/1 (0.00) 1/1 (100.00) 0/2 (0.00) 0/1 (0.00) 1/1 (100.00) 1/1 (100.00) 4/8 (50.00) 3/3 (100.00) 3/5 (60.00) 0/1 (0.00) 1/1 (100.00)

1/3 (33.3) 1/2 (50.0) 2/3 (66.7) 3/8 (37.5) 0/1 (0.0) 0/1 (0.0) 1/2 (50.0) 1/4 (25.0) 2/4 (50.0) 0/1 (0.0) 0/2 (0.0) 0/1 (0.0) 0/1 (0.0) 2/2 (100.0) 1/2 (50.0) 1/1 (100.0) 1/1 (100.0) 0/1 (0.0) 0/1 (0.0) 2/2 (100.0) 0/1 (0.0) 0/1 (0.0) 1/1 (100.0) 3/8 (37.5) 0/3 (0.0) 2/5 (40.0) 1/1 (100.0) 0/1 (0.0)

Outcomes (death) 0/3 (0.00) 0/2 (0.00) 1/3 (33.33) 5/8 (62.50) 1/1 (100.00) 0/1 (0.00) 1/3 (33.33) 2/4 (50.00) 2/4 (50.00) 0/1 (0.00) 1/1 (100.00) 1/1 (100.00) 1/1 (100.00) 1/2 (50.00) 0/2 (0.00) 1/1 (100.00) 1/1 (100.00) 1/1 (100.00) 1/1 (100.00) 0/2 (0.00) 1/1 (100.00) 1/1 (100.00) 0/1 (0.00) 3/8 (37.50) 1/3 (33.33) 0/5 (0.00) 0/1 (0.00) 0/1 (0.00)

AMI: acute myocardial infarction; CJD: Creutzfeldt-Jakob disease; SLE: systemic lupus eritemathous; NHL: non-Hodgkinâ&#x20AC;&#x2122;s lymphoma; BTI: brain traumatic injury; CNS: central nervous system; CHF: congestive heart failure; AIDS: acquired immune deficiency syndrome.

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Epileptiform activity

44.7

Triphasics waves

7.5 72.3

Diffuse slowing Low voltage

31.9

Burst-suppression

4.3

Electrocerebral inactivity

2.1

PLED/BIPLED

5.3 0

10

20

30

40

50

60

70

80

Fig 2. EEG findings in percentage of patients. F7 - T3 T3 - T5 T5 - 01 Fp1 - F3 F3 - C3 C3 - P3 P3 - 01 Fp2 - F4 F4 - C4 C4 - P4 P4 - 02 F8 - T4 T4 - T6 T6 - 02

DISCUSSION

100Âľ V 1 seg

Fig 3. An EEG of a 67 years old male, one month of history characterized by alteration of behavior, little contact with environment, rigidity. EEG showing periodic complexes with short intervals. The presence of this pattern conducted an investigation of Creutzfeldt-Jakob disease which was confirmed after necropsy. T3 - T5 T5 - 01 Fp1 - F3 F3 - C3 C3 - P3 P3 - 01 Fp2 - F4 F4 - C4 C4 - P4 P4 - 02 F8 - T4 T4 - T6

100Âľ V 1 seg

Fig 4. An EEG of a 66 years old male, obtained from a patient after surgery for basocellular carcinoma of face. EEG showing continuous focal sharp and polyspike activity in right hemisphere alternating with suppression periods (burstsuppression). Clinically, patient presented in coma and oral automatisms, without sedation, for four days. Table 3. Reasons of medical requests for emergent EEG and frequency of epileptiform activity. Indication of EEG Unexplained impairment of consciousness Herpetic encephalitis Status epilepticus Myoclonic NCSE Management of AED

Reaction during manual eyes opening and closure was significantly more common in patients who survived (OR 5.3 p<0.05) (Table 4). The GCS on admission was not associated with the outcome of patients (p>0.05). Age, localization of the disease in the CNS, focal signs, non reactivity to auditive and painful stimulus were not associated with poor outcome (death) (Table 4).

Epileptiform activity No Yes n (%) n (%)

Total n (%)

22 (66.7)

11 (33.3)

33 (100)

2 (66.7) 14 (46.7) 0 (0.0) 11 (52.4) 2 (66.7)

1 (33.3) 15 (53.3) 2 (100.0) 10 (47.6) 1 (33.3)

3 (100) 29 (100) 2 (100) 21 (100) 3 (100)

Although EEG is not an expensive exam and it changes medical management as shown by several studies, its use is not available in most tertiary hospitals. We analyzed 94 EEGs ordered on emergency basis from patients with impairment of consciousness. Our study showed that a high proportion (44.7%) of EEGs performed in patients with impairment of consciousness had epileptiform activity. The EEG changed management in 72.2% of the patients. By contrast, the proportion of EEGs ordered by ER and ICU was very low (8.9%) relative to the number of exams performed in the EEG laboratory during the study period. The same pattern of underutilization of eEEG was reported in previous studies3,7,16. In developing countries, costs and the small number of specialized professionals (technicians and eletroencephalographers) are key issues13. In the other hand, many physicians do not believe that EEG will help or change the medical intervention, especially when neuroimaging is available. In our series, most EEGs were performed after 24 hours of admission (53.3%), in contrast to a previous Indian study that reported that 84.3% of the EEGs were performed in less than 24 hours13. This difficulty to have EEG on time often bring as consequence inappropriate treatment, in particular when there is a possibility of NCSE. We found epileptiform abnormalities in almost half of our patients, comparable to another study17, but we think this is an underestimate for at least two reasons. First, most of the patients were taking sedatives, which are known to interfere with EEG recordings. Second, EEGs were performed on an analogical system that precluded the change of montages, sensibility and time scale that improves the chances of finding abnormal patterns18. The significance of epileptiform abnormalities in patients without history of epilepsy is unclear and may occur in up to 6.6% in some studies. However, the risk of seizure occurrence is two folds higher in the presence of interictal epileptiform discharges19. In the last three decades, EEG had lost importance in the investigation of cerebral diseases, but several studies have shown the utility of EEG in conditions other than epilepsy, including evaluation of prognosis in coma. In our study, the EEG confirmed the diagnosis in 39.6% of the cohort and ruled out in 32.3%, being comparable with earlier studies3,13,16,17.

AED: antiepileptic drug; NCSE: nonconvulsive status epilepticus.

Ricardo JAG et al. Impairment of consciosness: EEG

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Table 4. Predicting factors of prognosis. Variables More 50 years old Focal signs Hemodynamic disturb. Electrolytic disturb. Renal failure Sepsis CNS disease Epileptiform activity Nonreactivity by passive eye opening Nonreactivity by auditive stimulus Nonreactivity by dolorous stimulus

Outcomes Death (%) 76.9 (20/26) 40 (10/25) 76.9 (20/26) 88.5 (23/26) 61.5 (16/26) 92.3 (24/26) 65.4 (17/26) 23.1 (6/26) 57.7 (15/26) 53.9 (14/26) 46.2 (12/26)

Alive (%) 53.8 (21/39) 38.5 (15/39) 41.7 (15/36) 33.3 (12/36) 22.2 (8/36) 41.7 (15/36) 79.5 (31/39) 46.2 (18/39) 22.2 (8/36) 35.3 (12/34) 32.4 (11/34)

Chi-Square p value 0.063 0.902 0.007 0.0001 0.002 0.0001 0.176 0.063 0.004 0.116 0.226

CNS: central nervous system.

In our cohort, the most common reason for EEG requisition was to investigate unexplained altered level of consciousness (36.3%), to evaluate convulsive status epilepticus (31.9%) and nonconvulsive status epilepticus (23.1%). In the last two conditions, EEG is the gold standard for diagnosis3,16,20. We encountered a higher proportion (33.3%) of epileptiform activity in patients with unexplained altered level of consciousness. In an early study, status epilepticus was encountered in 37% of 198 patients with altered level of consciousness without clinical seizures21. Another study using continuous EEG observed status epilepticus in 8% of 236 comatose patients5. This last group of patients in our cohort did not have signs of subclinical status epilepticus or previous history of epilepsy. Despite of the absence of minor clinical signs of seizures, EEG showed abnormalities and permitted the correct diagnosis and treatment. Although we had a small number of patients with stroke in this series, they had a high frequency of epileptiform activity on EEG (6/8; 75%). Previous studies have shown an association between acute stroke and epilepsy22-25. In a review24, the prevalence of post-ischemic stroke seizures ranged from 2 to 33%, with 50 to 78% of first seizures occurring within 24 hours. Another study6 found a high proportion of nonconvulsive and convulsive seizures in intracerebral hemorrhage (27.8%) compared with ischemic stroke (6%), and over half of traumatic brain injured patients had nonconvulsive seizures

detected by continuous EEG monitoring, reinforcing literature data about the necessity of available EEG service at 24 hours for stroke and other ER and ICU patients especially in the acute phase. The GCS were not different between groups of outcome, confirming that GCS has limited value except for impairment of consciousness related to head trauma26, 27. The main limitation of our study was the nature of data collection from medical charts to complete our database and the possibility of over or underestimating the data from charts and medical EEG request. In conclusion, although eEEG is an underutilized diagnostic tool, the frequency of EEGs presenting epileptiform activity was high in patients with unexplained altered level of consciousness. In most cases, EEG proved to be useful, either confirming or ruling out the suspected initial diagnosis. The EEG makes the difference especially when available within 24 hours after admission. Therefore, we believe that ER and ICU physicians should be aware of the usefulness of EEG and request it more often in appropriate circumstances.

ACKNOWLEDGMENTS We thank the medical staff and EEG technicians from the EEG service at University Hospital of UNICAMP.

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Cohn HR, Mulder DW, Neumann MH. Cerebral vascular lesions: electroencephalographic and neuropathologic correlations. Arch Neurol 1948;60:163-181.

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Camilo O, Goldstein LB. Seizures and epilepsy after ischemic stroke. Stroke 2004;35:1769-1775.

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Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C. Epileptic seizures after a first stroke: the Oxfordshire Community Stroke Project. BMJ 1997;315:1582-1587.

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Sternbach GL. The Glasgow coma scale. J Emerg Med 2000;19:67-71.

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Segatore M, Way C. The Glasgow Coma Scale: time for change. Heart Lung 1992;21:548-557.

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Varelas PN, Spanaki MV, Hacein-Bey L, Hether T, Terranova B. Emergent EEG: indications and diagnostic yield. Neurology 2003;61:702-704.

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Kilbride RD, Costello DJ, Chiappa KH. How seizure detection by continuous electroencephalographic monitoring affects the prescribing of antiepileptic medications. Arch Neurol 2009;66:723-728.

Ricardo JAG et al. Impairment of consciosness: EEG

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Article

Devising and validating a headache diary in a series of patients with chronic daily headache from Colombia Diseño y validación de un diario de cefalea en pacientes con cefalea crónica diaria en Colombia Gabriel F. Torres1, Martha I. Otálvaro1, Juan C. Vargas2, Yulexi Castellanos3, Jeimy Xiomara García3, Javier D. Triana3, Cesar A. Forero3, Carlos D. Guevara4, Rodrigo Pardo5

Abstract

Objective: To devise and test the reliability and validity of a brief headache diary in a series of Colombian patients with chronic daily headache. Methods: The study was designed in five stages: selection of domains (group of patients and experts); initial devising of the items (writing group); identification of non-understandable items (n=20); assessment of internal consistency (n=100); assessment of validity and assessment of sensitivity to change during seven consecutive days (n=25, 175 observations). Results: Five domains were selected: headache presence, severity and length of pain, analgesics intake, and missing workdays. The headache diary is internally consistent (≈75% of rotated variance), correlates with the medical interview (Spearman’s rho and Kendall’s tau over 0.8 for each domain) and it has an adequate and stable sensitivity and specificity (82 to 96%). Conclusions: This headache diary is a reliable and valid instrument and represents the most important features affecting Colombian patients with chronic daily headache. Key words: Colombia, diagnosis, headache disorders, medical records, reproducibility of results, validation studies. Resumen

Objetivo: Diseñar y testar la validez y reproducibilidad de un diario de cefalea en una serie de pacientes Colombianos con cefalea crónica diaria. Métodos: El estudio fue diseñado en cinco fases: selección de los dominios (grupo de pacientes y expertos); diseño inicial de los ítems (grupo redactor); identificación de ítems no comprensibles (n=20); determinación de la consistencia interna (n=100); determinación de la validez y la sensibilidad al cambio durante siete días consecutivos (n=25, 175 observaciones). Resultados: Fueron seleccionados cinco dominios: presencia, severidad y duración del dolor, ingesta de analgésicos y días laborales perdidos. El diario tiene una adecuada consistencia interna (≈75% de la varianza), se correlaciona con la entrevista médica (rho de Spearman y tau de Kendall >0.8 para cada dominio) y tiene sensibilidad y especificidad estables y satisfactorias (82 a 96%). Conclusiones: Este diario de cefalea es un instrumento confiable y registra las principales características de las cefaleas en pacientes con cefalea crónica diaria.

Palabras-Clave: Colombia, diagnóstico, cefalea, registros médicos, reproducibilidad de resultados, estudios de validación.

The chronic daily headache (CDH) affects from 4 to 7% of general population worldwide and it is a common cause of consultation in outpatient clinics1-4. Patients with CDH score worse in physical functioning and general health perceptions of quality of life scales than those with migraine and healthy

controls5,6. Several factors might affect the internal validity of studies in CDH patients, among them the lack of reliable measurement instruments. Lipton et al. defined CDH as headaches that occur for ≥4 hours a day on ≥15 days a month over three months7. In the next decade,

1

Neurologist at Hospital Santa Clara E.S.E., Bogotá, Colombia;

2

Neurologist at Hospital El Tunal, E.S.E. and Clinica Carlos Lleras Restrepo, Bogotá, Colombia;

3

Resident of Clinical Neurology at the Universidad Nacional de Colombia, Bogotá, Colombia;

4

Neurologist at Clinica Carlos Lleras Restrepo, Bogotá, Colombia;

Neurologist at Clinica Carlos Lleras Restrepo; Assistant Professor at the Unit of Clinical Neurology and Centre for Epidemiological Research at Universidad Nacional de Colombia, Bogotá, Colombia.

5

Correspondence: Gabriel F. Torres; Departamento de Medicina Interna. E.S.E. Hospital Santa Clara; Carrera 15 No. 1 – 59 Sur, Bogotá – Colombia; E-mail: gftorresa@unal.edu.co Support: This study was partially funded by the Colombian Association of Neurology (Asociación Colombiana de Neurología). Conflict of interest: There is no conflict of interest to declare. Received 06 July 2011; Received in final form 16 August 2011; Accepted 24 August 2011

40


20% of the patients with episodic headaches will develop CDH8. CDH at baseline, coexisting migraine, not being married and sleeping problems increase the risk of worst prognosis. Several instruments have been developed to evaluate the burden of headaches in patients with migraine9-13. However, an adequately validated instrument to assess the headache frequency in Colombian patients with CDH has not been determined yet. To assess the main characteristics of headache episodes and their impact on work activities, we devised and tested the reliability and validity of a brief headache diary (HD) in a series of Colombian patients with CDH.

METHODS Patients aged 18 years or older that fulfilled the International Headache Society (IHS) criteria for migraine or tension type headache with CDH were recruited for this study14. Patients with history of cognitive deficit, severe visual impairment and inability to telephone contact were excluded. The protocol was approved by the Ethics Committee from Hospital Santa Clara, Universidad Nacional de Colombia and Hospital El Tunal, in Bogotá, Colombia. Devising the items Selection of domains Fifteen patients with CDH were individually interviewed on the most important issues that a HD should include (group of patients). Likewise, a group of 12 people composed by neurologists and general practitioners, with experience in headache treatment and diagnosis, were individually contacted and interviewed about the most important issues in a HD (group of experts). The proposed domains were gathered and a group of eight people (writing group) performed the initial drafting, including at least three items for each domain. Detection of ambiguous or non-understandable items Ten patients answered the initial draft and explained with their own words the meaning of each item. No other instruction was given. Items that were not understood by each patient were rewritten by the writing group. This second draft was applied to a new series of ten patients until each one of the items was completely understood. Internal consistency Since this instrument has been designed as a multiple domains instrument, the internal consistency was determined through a factor analysis15. To this end, the items devised in the previous section were applied to a different set of 100 patients16. Analysis of the main components with a Varimax rotation was applied to this set of data. The factors were selected keeping at least one for each domain. The items with

loadings ≥0.8 (or otherwise selected as providing information about quantitative pain characteristics) on each factor were kept in the final version of the HD. Validity Two types of validity were tested: criterion (using the neurologist’s interview as a golden standard) and construct (using logic construct of intensity, length of pain and analgesic intake). Sensitivity to change was tested assuming that every patient was initiated on prophylactic drugs or at least the dose of previous medication was adjusted. We formally tested the change in severity and length through the follow-up. Test-retest reliability was not tested because of the high variability of the symptoms across time. To test the criterion validity, a group of 28 patients answered the HD during seven consecutive days. By the end of this period, a phone or a personal contact was made by a neurologist. During this interview, presence, length of pain, severity, analgesics intake, and missing workdays were determined for the previous seven days. To test the construct validity, the relationship between severity of symptoms and analgesics intake and length of pain were formally tested. These analyses were repeated for each of the seven days to evaluate consistency through multiple observations. Statistical analysis To determine the relationship between the data in the HD and the golden standard, Spearman’s rank correlation coefficient (Spearman’s rho) was used for binary variables and Kendall’s rank correlation coefficient (Kendall’s tau) was used for the ordinal ones. Confidence intervals were calculated according to Altman and Siegel for Spearman and Kendall correlations, respectively17,18. The severity of pain was divided into quartiles. The other variables were dichotomized to improve the power of their correlations. To obtain an overall estimate of sensitivity and specificity, which takes into account the variability between each day of fulfilling the HD, an approach based on Generalized Estimating Equations (GEE) was used. To this end, the proportion of positive answers were determined through them along the positive answers in the golden standard (sensitivity). Likewise, the proportion of negative answers was determined with the negative answers in the golden standard (specificity)19. We explored the effect of the day of fulfilling the HD, age, abuse of analgesics, headache subtype, and site of recruitment over the estimates of sensitivity and specificity. Modifications over 20% of the univariate estimates were considered significant. To determine the construct validity, multiple binomial logistic regressions were calculated using analgesic intake as a dependent variable and severity and length of pain individually as explanatory variables. To determine sensitivity to change, ANOVA repeated measures were used with severity and length of pain as dependent variables and time as an independent one15. A p-value <0.05 was considered significant for all tests. Calculations were performed using Stata, version 8.0.

Torres GF et al. Chronic daily headache

41


RESULTS Devising the items Domains selection The groups of patients and experts determined that a HD, which includes the presence, length and severity of pain, analgesics intake and missing workdays, would assess the main characteristics of headache episodes and their impact on work activities in patients with CDH. The proposed items to assess pain intensity were devised to be expressed on a fivepoint visual analogue scale, once the patient has accepted to have a headache. Therefore, the four-point scale proposed by the International Classification of Headache (including 0 as no pain) was not used14. Detection of ambiguous or non-understandable items During the first interview (n=10), two items related to length of pain were identified as non-understandable by two patients: “At what time did the headache begin? At what time did it end?” and “the pain lasted: half morning, the entire morning, half afternoon, the entire afternoon, all day?”. The writing group did not find an alternative way of rephrasing these questions, so they were excluded from the internal consistency analysis. A second set of questions was applied to a new group of patients (n=10). All patients understood these items. Internal consistency The five factors identified by the factor analysis explained 75% of rotated variance. The first factor explained 27% of variance and had high loading on “How many hours did you have the headache today?” (number of hours with headache) (0.9). The second factor accounted for 17% of variance with a high loading on “Did you have a headache today?” (yes/no) (0.8). The third one explained 12% of the variance and had a high loading on “What medications did you have to take today to improve your headache?” (the name of the medication) (0.9). The forth explained 10% of the variance and with high loadings on “Did the headache prevent you from leaving your home?” (yes/no) (0.8) and “How strong was your headache today?” (very mild/ mild/ moderate/ severe/ very severe) (0.4). The last one accounted for 8% of the variance and had a high loading on “Did the headache prevent you from going to work today?” (yes/no) (0.9). Validity Criterion validity Thirty-two patients received the HD and were asked to answer it during seven consecutive days, 25 patients returned the HD and allowed telephone interviews (175 observations). Patients for this phase were mostly women (76%), had chronic migraine

42

Arq Neuropsiquiatr 2012;70(1):40-44

(84%) and had a median age of 44.6 years-old (interquartile range – IQR=25–75%: 28.9–50.6). The median of Spearman’s rho through the seven days of fulfilling the HD for presence was 0.8 (IQR 25–75%: 0.7–0.9), for severity of pain was 0.7 (IQR 25–75%: 0.5–0.7), for analgesics intake was 0.8 (IQR 25–75%: 0.7–0.9). The median of Kendall’s tau for length of pain through the follow-up was 0.8 (IQR 25–75%: 0.7–0.8) (Fig 1). The sensitivity of each item, which is defined as the proportion of positive answers among the positive ones in the golden standard, varied from 82 to 95%. Likewise, the specificity, which is defined as the proportion of negative answers among the negative ones in the golden standard, varied from 86 to 96% (Table 1). After adjusting each of the main covariates (age, gender, day of fulfilling the HD, analgesic abuse, subtype of chronic headache, and recruitment site), modifications over 20% from the original estimates were not found on the bivariate models where convergence was achieved. Construct validity The relationship between severity of pain and analgesics intake was statistically significant for most of the days when the HD was fulfilled (OR=1.7–11). Similarly, the relationship between length of pain and analgesics intake was significant for all the days (OR=2.5–14), as it can be seen in Fig 2. A statistically significant relationship was not found between the items devised to measure headache related missing workdays and the golden standard (data not shown). Sensitivity to change The p-values for the repeated measures ANOVA for time as covariate were <0.001, for length of pain and 0.08, for severity of the headache episodes.

DISCUSSION In this study we have shown that this HD is a valid and reliable instrument in Colombian patients with CDH and it Table 1. Accuracy of each item from the headache dairy. Item

Sensitivity Specificity (95% CI) (95% CI) 95% (90–98) 86% (78–94)

Did you have a headache today? How many hours did you have the 82% (73–91) 91% (86–95) headache today? What medications did you have to 84% (74–93) 91% (87–94) take today to improve your headache? How strong was your headache 82% (64–100) 93% (90–97) today (very mild/ mild/ moderate/ severe/ very severe)? ¶

*Generalized estimating equations of the proportion of positive answers in headache diary among positive answers in the gold standard (sensitivity), and negative answers among negative answers in gold standard (specificity). Unstructured working correlation matrix and identity link functions were used for calculations. ¶An exchangeable correlation matrix was used; CI: confidence interval.


Correlation coefďŹ cient

A

1

1

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

0 0

Correlation coefďŹ cient

C

2

4 Days

6

B

0

8

0

1

1

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

0

2

4 Days

6

8

D

0 0

2

4 Days

6

8

0

2

4 Days

6

8

Fig 1. Correlations between the headache dairy and the clinical interview through the seven days of fulfilling it. A: presence; B: analgesics intake; C: severity of pain; D: length of pain.

100

100

80

80

60

60

% patients requiring analgesics 40

40

20

20

0

0 0

1

2

3

Length of Pain Quartile

4

5

0

1

2

3

4

5

Severity of Pain Quartile

Fig 2. Relationship between length and severity of pain and analgesics intake through the seven days of fulfilling the headache diary.

Torres GF et al. Chronic daily headache

43


records the main characteristics of headache episodes for patients and treating physicians. The domains have been selected by a representative sample of patients and by physicians with experience in diagnosis and treatment of primary headaches (content validity). The selected items were understood by each patient. Validity has been tested through the application of the HD during seven consecutive days and the accuracy estimates have proved to be independent of age, gender, day of fulfilling and recruitment site (Fig 1 and 2). Importantly, we believe that testing the performance of the HD longitudinally might provide more accurate estimators of accuracy and adherence (≈80% in this sample). To this end, we used an approach based on the binomial family of GEE. Previous authors have proposed GEE as a valid method to determine proportions of dichotomous variables of correlated data19. Even thought, to the best of our knowledge, GEE has not been previously used as a method to determine accuracy estimates for single studies, since these are proportions, they provide the rationale for the use of GEE (Table 1). Likewise, a regression model based on GEE might provide a method to evaluate the effect of covariates over such estimates. Sensitivity to change was tested using a multiple measures approach15. Despite the short time of follow-up, a change in the headache severity and a trend to a decreased length of pain were observed in this study after the beginning of therapy or modification of previous treatment. This change, on a week to week basis, has been observed by other authors20.

There are two important issues about the validity of this HD. First, although the expert group selected impacts on work activities as a domain that should be included in the HD, devised items did not correlate with the golden standard (data not shown). We believe that this domain is a complex construct and a single question might not account for it ( from low performance to total absence). Nevertheless, we kept the item: “Did the headache prevent you from going to work today” in the final version of this HD, because of internal consistency and because it provides valuable information for research and statistical purposes. Second, the highly variable nature of this symptom on a day to day basis prevented us to evaluate the stability of the data provided by the HD (test-retest reliability). However, the stability of the correlations through the follow-up as well as the adequate internal consistency of this instrument might account for a high reliability of the HD. In summary, we have shown a brief HD that assesses the main characteristics of headaches. This diary includes the main domains identified by patients and treating physicians, it also has a high internal consistence and is a valid instrument in Colombian patients with CDH. We believe that this instrument might help patients with adequate feedback of headache progress, allow treating physicians a better assessment of a goal-directed therapy and allowing them to improve the reliability of results from future researches in Colombian patients with CDH.

References 1.

Scher AI, Stewart WF, Liberman J, Lipton RB. Prevalence of frequent headache in a population sample. Headache 1998;38:497-506.

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Bigal ME, Sheftell FD, Rapoport AM, Lipton RB, Tepper SJ. Chronic daily headache in a tertiary care population: correlation between the International Headache Society diagnostic criteria and proposed revisions of criteria for chronic daily headache. Cephalalgia 2002;22:432-438.

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Cramer JA, Silberstein SD, Winner P. Development and validation of the Headache Needs Assessment (HANA) survey. Headache 2001;41: 402-409.

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Kosinski M, Bayliss MS, Bjorner JB, et al. A six-item short-form survey for measuring headache impact: the HIT-6. Qual Life Res 2003;12: 963-974.

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Wagner TH, Patrick DL, Galer BS, Berzon RA. A new instrument to assess the long-term quality of life effects from migraine: development and psychometric testing of the MSQOL. Headache 1996;36:484-492.

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The International Classification of Headache Disorders: 2nd edition. Cephalalgia 2004;24(Suppl 1):S9-S160.

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Monzon MJ, Lainez MJ. Quality of life in migraine and chronic daily headache patients. Cephalalgia 1998;18:638-643.

Streiner DL, Norman GR. Health measurement scales: a practical guide to their development and use. 2nd ed. Oxford; New York: Oxford University Press; 1995.

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Lipton RB, Bigal ME, Steiner TJ, et al. Classification of primary headaches. Neurology 2004;63:427-435.

Norman GR, Streiner DL. Biostatistics: the bare essentials. St. Louis: Mosby; 1994.

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Lyngberg AC, Rasmussen BK, Jorgensen T, Jensen R. Prognosis of migraine and tension-type headache: a population-based follow-up study. Neurology 2005;65:580-585.

Altman DG, Gardner MJ. Statistics in Medicine: Calculating confidence intervals for regression and correlation. BMJ 1988;296:1238-1242.

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Siegel S, Castellan NJ. Nonparametric statistics for the behavioral sciences. 2nd ed. New York: McGraw-Hill; 1988.

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Queiroz LP, Peres MF, Kowacs F, et al. Chronic daily headache in Brazil: a nationwide population-based study. Cephalalgia 2008;28:1264-1269.

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Queiroz LP, Peres MF, Piovesan EJ, et al. A nationwide population-based study of tension-type headache in Brazil. Headache 2009;49:71-78.

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Guitera V, Muñoz P, Castillo J, Pascual J. Quality of life in chronic daily headache: a study in a general population. Neurology 2002;58: 1062-1065.

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Stewart WF, Lipton RB, Simon D, Von Korlf M, Liberman J. Reliability of an illness severity measure for headache in a population sample of migraine sufferers. Cephalalgia 1998;18:44-51.

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Hanley JA, Negassa A, Edwardes MD, Forrester JE. Statistical analysis of correlated data using generalized estimating equations: an orientation. Am J Epidemiol 2003;157:364-375.

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Martin BC, Pathak DS, Sharfman MI, et al. Validity and reliability of the migraine-specific quality of life questionnaire (MSQ Version 2.1). Headache 2000;40:204-215.

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Jackson JL, Shimeall W, Sessums L, et al. Tricyclic antidepressants and headaches: systematic review and meta-analysis. BMJ 2010;341:c5222.

Arq Neuropsiquiatr 2012;70(1):40-44


Article

Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis Alteraciones morfológicas en las mitocondrias en la piel de enfermos con esclerosis lateral amiotrófica esporádica Gabriel E. Rodríguez1,2, Deniselle M. Claudia González3,4, Gisella M. Gargiulo Monachelli1,4, Juan J. López Costa5, Alejandro F. de Nicola3,4, Roberto E. P. Sica2

ABSTRACT Objectives: Mitochondrial dysfunction has been reported in the central nervous system, hepatocytes and peripheral blood lymphocytes from patients with sporadic amyotrophic lateral sclerosis (SALS). However, the status of skin mitochondria has not been reported, in spite of the fact that SALS patients present skin abnormalities. The objective of the present study was to compare mitochondrial ultrastructural parameters in keratinocytes from patients with SALS and healthy controls. Methods: Our study was based on the analysis of 112 skin mitochondria from 5 SALS patients and 99 organelles from 4 control subjects by electron microscopy. Results: Computerized image analysis showed that mitochondrial major axis length, area and perimeter of the organelle were significantly smaller in SALS respect of healthy control subjects. Morphologically, SALS mitochondria presented cristolysis and breakage of the outer membrane. Conclusions: Mitochondrial dysfunction in the skin may possibly reflect changes occurring in mitochondria of the central nervous system. The analysis of mitochondrial morphology in this tissue may be of value to follow disease progression and, eventually, the effectiveness of current therapies for SALS.

Key words: amyotrophic lateral sclerosis, electron microscopy, keratinocytes, mitochondria. Resumen Objetivos: Existen alteraciones en la función mitocondrial en el sistema nervioso central, en hepatocitos y en linfocitos de sangre periférica en SALS. Aunque, no se ha estudiado si existen cambios estructurales en las mitocondrias de la piel. Nuestro objetivo fue comparar la ultraestructura de mitocondrias en queratinocitos de enfermos con SALS con la de controles sanos. Método: Fueron analizadas en el microscopio electrónico 112 mitocondrias dérmicas de 5 pacientes y 99 provenientes de 4 controles. Resultados: EL análisis computarizado mostró que el eje mayor mitocondrial, el área y el perímetro de las organelas fueran significativamente menor que en controles. Morfológicamente, las mitocondrias de SALS presentaron cristólisis y ruptura de la membrana externa. Conclusión: La alteración mitocondrial en la piel posiblemente refleje cambios que también ocurran en las mitocondrias neuronales. Este análisis morfológico de las mitocondrias podría tener valor en el seguimiento de la enfermedad y eventualmente en la evaluación de la efectividad de futuras terapias.

Palabras-Clave: esclerosis amiotrófica lateral, microscopía electrónica, queratinocitos, mitocondria.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that compromises motor neurons of the spinal cord and brainstem. About 10 to 20% of ALS cases belong to the familial form (FALS); 2 to 5% of them present a mutation in the superoxide dismutase type I (SOD1) gene. The largest majority of patients belong to the sporadic form

(SALS) of unknown etiology. Multiple factors have been held responsible for motor neuron degeneration, including glutamate excitotoxicity, increased generation of reactive oxygen species (ROS), abnormal mitochondrial function, altered calcium homeostasis, deposits of cytoplasmic clusters of protein aggregates, proteasomal disability, impaired

Neurology Department, Hospital Ramos Mejía, Buenos Aires, Argentina;

1

Department of Science and Technology, School of Medicine, University of Buenos Aires (UBA), Buenos Aires, Argentina;

2 3

Department of Human Biochemistry, School of Medicine, UBA, Buenos Aires, Argentina,

Laboratory of Neuroendocrine Biochemistry, Institute of Medicine and Experimental Biology – CONICET, Buenos Aires, Argentina;

4 5

Institute of Cell Biology and Neuroscience “Prof. E. de Robertis”, School of Medicine, UBA, Buenos Aires, Argentina.

Correspondence: Gabriel E. Rodríguez; Neurology Department; Hospital Ramos JM Ramos Mejía; Urquiza 609; CP: 1221 Buenos Aires - Argentina; Email: gerodrig@intramed.net Support: The University of Buenos Aires (UBACyT M029), Fiorini Foundation and the National Research Council of Argentina (CONICET, PIP). Conflict of interest: There is no conflict of interest to declare. Received 09 February 2011; Received in final form 18 August 2011; Accepted 25 August 2011

45


axoplasmic transport, changes of cytoskeletal architecture and inflammation1. Participation of oxidative stress in SALS is supported by the increased content of oxidative markers in biological fluids2-4. Pathological overproduction of ROS could arise from either increased production or decreased activity of antioxidant scavengers. In pathological situations, mitochondria have been implicated in generation of ROS, calcium-mediated excitotoxicity and intrinsic apoptotic pathways5. There is substantial evidence for mitochondrial dysfunction in SALS, supported by morphological, molecular and functional observations in human patients, transgenic mice overexpressing mutant SOD1 and the Wobbler mouse mutant. Afifi and colleagues6 first reported abnormal mitochondrial morphology in the atrophic muscles of SALS patients and, subsequently, mitochondrial abnormalities have been reported in the central nervous system7-10, liver cells11 and peripheral blood lymphocytes12 of SALS patients. Muscle biopsies in SALS have shown increased mitochondrial volume associated to increased calcium levels13; also, reduced activity of mitochondrial respiratory chain complex I and complex IV in skeletal muscle and the spinal cord have been reported14,15. Along this line, electron microscopy of motor neurons from animal models of ALS, including SOD1 transgenic and Wobbler mice, revealed prominent mitochondrial abnormalities, such as vacuolation, crystolysis, edema and rupture of outer membranes16-18. Recent findings have greatly expanded our understanding of the mitochondria role in the pathogenesis of neurodegenerative diseases. Indeed, mitochondrial dysfunction and oxidative stress occur early in all major neurodegenerative diseases, and there is strong evidence that mitochondrial impairment aggravates disease outcome19. In spite of the fact that SALS has been considered a disease of motor neurons, it might also compromise other organs, such as the skin. In this respect, SALS patients are resistant to the development of pressure sores (decubitus ulcers). The skin of these patients feels supple, like tanned leather, and loses elasticity. Fullmer and colleagues20 have found extensive alterations within the connective tissues of the dermis in a high percentage of SALS patients. The reported skin changes include elastosis, increased mucopolysaccharides, local areas of regenerated connective tissue and altered collagen21,22. Deposits of amorphous material consisting of hyaluronic acid have been found in skin biopsies from SALS patients, but not from controls and, interestingly, the amount of this mucopolysaccharide acid correlates with disease length23-25. Therefore, it is likely that mitochondrial abnormalities are not restricted to the central nervous system (CNS) and may appear in tissues yet unexplored. Taking into consideration this possibility, the objective of our study was to compare mitochondrial ultrastructural parameters in keratinocytes from the skin of SALS patients and healthy controls.

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Arq Neuropsiquiatr 2012;70(1):45-51

methodS We analyzed 112 mitochondria from 5 patients with the diagnosis of definite SALS, based on El Escorial (Arlie House modified) criteria26,27 and 99 from 4 healthy controls without any signs of neurological disease. We performed a skin biopsy with a punch device number 3 after local anesthesia with 3% lidocaine. Keratinocytes measured in the study were those near the basement membrane. The latter was identified morphologically by electron microscopy. The research protocol was approved by the Ethics Committee of the Ramos Mejía Hospital and informed consent was obtained in writing from each individual tested. Electron microscopy The biopsies were taken from the skin of the shoulder and small blocks of tissue were obtained by cutting longitudinal sections of 3–5 mm maximum thickness. Blocks were immersed immediately for 2 h in phosphate buffered 2.5% glutaraldehyde. After overnight washing in 0.1 M sodium phosphate buffer, tissue blocks containing the epidermal region were postfixed in 1% OsO4 in 0.1 M phosphate buffer pH 7.4 for 1 h and stained with 1% uranyl acetate. Afterwards, tissue blocks were dehydrated and flat-embedded in Durcupan (Fluka Chemic AG, Sweden). Semithin sections (0.8–1µm) were stained with toluidine blue for light microscopy (LM) observations. For electron microscopy (EM), ultrathin sections (60–70 nm) were obtained with a Reichert ultramicrotome (Vienna, Austria) from keratinocytes. Sections were stained with lead citrate, examined at 20000 and 40000 X magnifications and photographed using a Zeiss 109 electron microscope. Morphological parameters of skin mitochondria were analyzed using a computerized image analyzer (OPTIMAS 6.02)18. Thus, quantitative analysis comprised determination of mitochondrial axis length, area, perimeter, size and the presence or absence of crystolysis, edema and membrane integrity. Statistical analysis Data are expressed as means ±2 SEM. Comparisons between groups were calculated by Student´s t-test for independent samples, and p<0.05 was considered statistically significant. All statistics were carried out using SPSS software version 15.0 (SPSS, Inc. Chicago).

Results Clinical data of the studied population are shown in Table. The average age in ALS group was 43.8 (±11.71) and 46.25 (±13.25) years in the control group (p:ns). Observations of mitochondrial morphology in keratynocytes from SALS


Discussion The present investigation demonstrated pronounced morphological abnormalities in skin keratinocytes of SALS patients. Low power microscopy of skin biopsies in our series of patients showed mitochondria of small size, along with reductions in area and perimeter. In addition, high power microscopy evidenced damage to cristae, edema and altered membrane continuity. These findings are in consonance with mitochondrial abnormalities reported in the central nervous system of SALS patients and animal models of motor neuron degeneration8,10. Our present investigation suggests that changes taking place in skin mitochondria may reflect to some extent the mitochondrial abnormalities of the degenerating nervous system.

Major axis lenght of mitochondria in keratinocytes (μm)

A

***

0.45 0.425 0.40 0.375

B

0.35 Healthy

Area of mitochondria in keratinocytes (μm2)

0.12

SALS

***

0.11 0.10 0.09 0.08 0.07 Healthy

C

Perimeter of mitochondria in keratinocytes (μm)

patients revealed important differences with healthy controls. Thus, the mitochondrial major axis length was significantly lower in SALS patients in comparison to the organelles from control keratynocytes (SALS: 0.358±0.150 μm; controls: 0.440±0.166  μm; mean±2 SEM; p<0.001) (Fig 1A). Fig 1B shows the comparison of mitochondrial area in the two groups obtained by image analysis. Mitochondrial area was also significantly reduced in SALS vs. control mitochondria (SALS: 0.076±0.061 μm2; controls 0.105±0.072 μm2; p<0.001). The same trend was found for the mitochondrial perimeter, which was decreased in SALS keratynocytes (1.106±0.445 μm) compared with controls (1.349±0.481 μm; p<0.0001) (Fig 1C). Typical microphotographs obtained by electron microscopy of keratynocyte ultrastructure are shown in Fig 2. Upper and lower microphotographs on the left hand side confirmed the decreased size of SALS mitochondria (asterisk, Fig 2A, C) as opposed to the organelles of control keratynocytes (Fig 2B, D). Whereas most mitochondria from controls showed the expected size, occasionally some smaller mitochondria were observed as well (Fig 2B; arrowhead). Higher magnification photomicrographs (40000 X) allowed a further comparison of intramitochondrial ultrastructure (Fig 3). In this case, several mitochondria from SALS patients showed increased signs of crystolysis, which were totally absent in controls (arrow, Fig 3B). In addition, 4.46% of the total number of mitochondria obtained from the skin of SALS patients presented a disorganized ultrastructure, including disrupted cristae and loss of membrane integrity near the poles (Fig 4A, arrowhead). This abnormality was not observed in healthy controls (Fig 4B). In summary, electron microscopy observations of SALS skin mitochondria revealed that severe pathological changes, including decreased size, edematous matrix and damage of mitochondrial membranes, were specifically associated with the neurodegenerative condition.

1.40

SALS ***

1.30 1.20 1.10 1.00 Healthy

SALS

Fig 1. (A) Quantitation of the mitochondrial major axis length (mean±2 SEM) in keratinocytes from healthy subjects (Healthy) and sporadic amyotrophic lateral sclerosis (SALS) patients. Statistical analysis demonstrated significant lower values in the mitochondrial major axis length in keratinocytes from SALS patients (***p<0.001 vs. healthy controls). (B) Computarized analysis of the mitochondrial area (mean±2 SEM) in keratinocytes from healthy subjects (Healthy) and SALS patients. A significant decrease in this parameter was demonstrated in keratinocytes from SALS patients (***p<0.001 vs. healthy controls). (C) Computerized image analysis of the mitochondrial perimeter. Mitochondrial perimeter was significantly decreased (SALS) respect of healthy subjects (***p<0.0001). Table. Demographic and clinical characteristics of sporadic amyotrophic lateral sclerosis patients and controls. ALS Patients 1 2 3 4 5 Controls 6 7 8 9

Sex

Age

Male Male Male Fem. Male

41 46 26 58 48

Male Fem. Male Fem.

37 38 45 65

ALS type Spinal Spinal Bulbar Spinal Spinal

Time onset to diagnosis (months) 14 7 48 7 35

ALS: amyotrophic lateral sclerosis.

Rodríguez GE et al. ALS: mitochondria of the skin

47


A

B

C

D

Fig 2. Electron microscope microphotographs in keratinocytes from control subjects and sporadic amyotrophic lateral sclerosis (SALS) patients. (A and C) SALS keratinocyte showing mitochondria of lower size (asterisk) than those found in healthy controls (B and D). Magnification: 20000 X.

Abnormal mitochondria is an important source of ROS, but also become damaged when handling of ROS is unbalanced5. The involvement of increased oxidative stress involving mitochondria is a likely explanation, albeit probable incomplete, of SALS neurodegeneration. In this respect, increased mitochondrial volume in motor nerve terminals of SALS patients was first described by Siklós et al in 199613. Other reports also found morphologic abnormalities of mitochondria in SALS patients, either in liver biopsy specimens11 or in axons, which show accumulation of mitochondria as well13. Interestingly, conglomerates of dark mitochondria at the presynaptic terminals of anterior spinal motor neurons were described by Sasaki and colleagues28, suggesting mitochondrial involvement in disabled synaptic contacts between lower motor neurons and their inputs. In addition, functional abnormalities of the mitochondria were described in the CNS, liver and muscle of SALS patients10,11,14. These changes suggest that the neurochemical basis for the observed morphological changes are widespread among different tissues and may consist in impaired mitochondrial bioenergetics,

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Arq Neuropsiquiatr 2012;70(1):45-51

loss of membrane potential, reduced calcium buffering capacity and disrupted calcium homeostasis29. In our investigations, we resorted to explore skin mitochondria, because the skin may be, as well, a target for the SALS disease´s putative causes. Clinical signs of skin pathology described in the Introduction are accompanied by changes of the transactivation-responsive DNA-binding protein-43 (TDP-43), one of the major component of the ubiquitin-positive inclusions in SALS30. However, to date, no abnormalities had been described in the mitochondria of keratinocytes of these patients. Considering that mitochondria of liver, muscle and other tissues are affected, it became rational to assume that changes would also be seen in the mitochondria of keratinocytes, reinforcing the concept advanced by Siklós et al.13, that changes of mitochondrial area might be a marker of dysfunction. Although mitochondrial function was not evaluated in our study, rupture of the mitochondrial membranes was one of the findings in the skin of SALS patients. It is known that the intrinsic apoptotic pathway originating in mitochondria is activated by ROS improperly handled by the cell´s anti-


A

B

C

D

Fig 3. High-power electron microscopy photomicrographs showing smaller mitochondria in sporadic amyotrophic lateral sclerosis (A, C) than in healthy controls (B, D). Magnification: 40000 X.

A

B

Fig 4. Electron microscopy microphotographs from keratinocytes obtained from sporadic amyotrophic lateral sclerosis (SALS) and healthy subjects. The arrow marks an abnormal mitochondrion in a keratinocyte obtained from a SALS patient, showing cristolysis and complete rupture of the outer membrane (A). Mitochondria from control subject (B). Magnification: 40000 X.

oxidant enzymatic machinery31. One of the typical morphological aspects of apoptosis is the breakdown of the external membrane, which causes the release of cytochrome c. The latter combines with the APAF molecule and caspase-9 to form the apoptosome, leading to programmed cell death32. From this point of view, the morphological changes of skin mitochondria demonstrated in this investigation may be the

systemic expression of mitochondrial malfunction yielded by excessive ROS. It is presently unknown in tissues different from the CNS if local factors are responsible for higher levels of ROS or if they depend on an indiscriminate general state of oxidative stress33. Thus, there might be a systemic imbalance of ROS associated to this neurodegenerative disease that could explain ultrastructural lesions of skin mitochondria. In

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relation to this subject, increased serum levels of thiobarbituric acid reactive substances (TBARS) in SALS patients have been preliminary demonstrated in our laboratory (unpublished results). In the present study, morphological changes found in SALS skin were restricted to mitochondrial size, area and membrane integrity. The altered parameters could result from the action of an environmental stressor whose intensity might produce a swift cell division in association to the breakdown of the mitochondrial membrane. Thus, we suggest that mitochondrial damage may be a more widespread phenomenon than previously thought in

SALS, despite the fact that the CNS seems to be the main structure that clinically express the various semiological features characterizing the illness.

Acknowledgements The laboratory assistance of Mariana López Ravasio (Instituto de Biología Celular y Neurociencias “Prof. E. de Robertis”, School of Medicine, Buenos Aires University) is gratefully acknowledged. The authors would also like to thank the volunteers for their participation.

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Brooks BR. El Escorial World Federation of Neurology Criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial “Clinical limits of amyotrophic lateral sclerosis” workshop contributors. J Neurol Sci 1994;124(Suppl): S96-S107.

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Brooks B, Miller G, Swash M, Munsat TL. World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord 2000;1:293-299.

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Wiedemann FR, Manfredi G, Mawrin C, Beal MF, Schon EA. Mitochondrial DNA and respiratory chain function in spinal cords al ALS patients. J Neurochem 2002;80:616-625.

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Nakano Y, Hirayama K, Terao K. Hepatic ultrastructural changes and liver dysfunction in amyotrophic lateral sclerosis. Arch Neurol 1987;44:103-104.

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Curti D, Malaspina A, Facchetti G, et al. Amyotrophic lateral sclerosis: oxidative energy metabolism and calcium homeostasis in peripheral blood lymphocytes. Neurology 1996;47:1060-1064.

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Siklós L, Engelhardt J, Harati Y, Smith RG, Joó F, Appel SH. Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis. Ann Neurol 1996;39:203-216.

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Emerit J,  Edeas M,  Bricaire F. Neurodegenerative diseases and oxidative stress. Biomed Pharmacother 2004;58:39-46.

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Article

Cyclosporin safety in a simplified rat brain tumor implantation model Segurança do tratamento com ciclosporina em um modelo pré-clínico de tumor cerebral experimental em ratos Francisco H. C. Felix1, Juvenia B. Fontenele2, Milena G. Teles3, João E. Bezerra Neto3, Márcia H. A. M. Santiago3, Roberto L. Picanço Filho3, Dalgimar B. de Menezes4, Glauce S. B. Viana5, Manoel O. de Moraes5

ABSTRACT Brain cancer is the second neurological cause of death. A simplified animal brain tumor model using W256 (carcinoma 256, Walker) cell line was developed to permit the testing of novel treatment modalities. Wistar rats had a cell tumor solution inoculated stereotactically in the basal ganglia (right subfrontal caudate). This model yielded tumor growth in 95% of the animals, and showed absence of extracranial metastasis and systemic infection. Survival median was 10 days. Estimated tumor volume was 17.08±6.7 mm3 on the 7th day and 67.25±19.8 mm3 on 9 th day post-inoculation. Doubling time was 24.25 h. Tumor growth induced cachexia, but no hematological or biochemical alterations. This model behaved as an undifferentiated tumor and can be promising for studying tumor cell migration in the central nervous system. Dexamethasone 3.0 mg/kg/day diminished significantly survival in this model. Cyclosporine 10 mg/kg/day administration was safely tolerated.

Key words: brain neoplasms, neoplasms, experimental, carcinoma 256, Walker, cachexia, cell movement, immunosuppressive agents. RESUMO Neoplasias encefálicas constituem a segunda causa neurológica de morte. Foi desenvolvido um modelo animal simplificado de tumor cerebral em ratos utilizando a linhagem celular W256 (carcinoma 256 de Walker) para permitir teste de novos tratamentos. Ratos Wistar foram inoculados nos gânglios da base (caudato subfrontal direito) com uma solução celular tumoral, por via estereotáxica. Este modelo demonstrou crescimento tumoral em 95% dos animais inoculados com sucesso, além de mostrar ausência de metástases extracranianas e infecção sistêmica. A mediana de sobrevida dos animais foi de 10 dias. O volume tumoral estimado foi de 17,08±6,7 mm3 no sétimo dia e de 67,25±19,8 mm3 no nono dia após a inoculação. O tempo de duplicação foi estimado em 24,25 h. O crescimento tumoral induziu a caquexia, mas não houve alterações bioquímicas ou hematológicas. Esse modelo permite fácil reprodução e comporta-se como um tumor indiferenciado, mostrando potencial para estudar migração celular tumoral no sistema nervoso central. Dexametasona 3,0 mg/kg/dia reduziu significantemente a sobrevida dos animais inoculados com tumor nesse modelo. Ciclosporina 10 mg/kg/dia não teve efeito na sobrevida, sendo sua administração bem tolerada.

Palavras-Chave: neoplasias encefálicas, neoplasias experimentais, carcinoma 256 de Walker, caquexia, movimento celular, imunossupressores.

There is a continuing need for experimental neuro-oncology for animal models that can be used to assess the efficacy of innovative approaches for the treatment of brain tumors. The rat has been one of the most widely used of all experimental animals, and rat brain tumor models have been used extensively

since the mid 1970s. Rat tumor models have a series of advantages when compared to mouse models despite the recent and frequent use of knockout genetic mice models. It was first reported in the early 1970s that central nervous system (CNS) tumors could be reproducibly and

Laboratory of Experimental Oncology, Physiology and Pharmacology Department, Universidade Federal do Ceará, Fortaleza CE, Brazil. 1

Pediatric hemato-oncologist, Hospital Infantil Albert Sabin, Fortaleza CE, Brazil;

Professor of Pharmacy, Department of Pharmacy, Faculdade de Farmácia, Odontologia e Enfermagem, Universidade Federal do Ceará (UFC), Fortaleza CE, Brazil;

2

3

UFC, Fortaleza CE, Brazil;

4

Professor of Pathology, Pathology and Forensics Department, Faculdade de Medicina, UFC, Fortaleza CE, Brazil;

5

Professor of Pharmacology, Physiology and Pharmacology Department, Faculdade de Medicina, UFC, Fortaleza CE, Brazil.

Correspondence: Francisco H. C. Felix; Hospital Infantil Albert Sabin; Rua Tertuliano Sales 544; 60410-790 Fortaleza CE - Brasil; E-mail: helderfelix@hias. ce.gov.br Conflict of interest: There is no conflict of interest to declare. Received 01 November 2010; Received in final form 05 August 2011; Accepted 12 August 2011

52


selectively induced in adult rats after treatment with chemical carcinogens. These studies led to the development of a number of implanted rat brain tumor models that were highly reproducible1,2. W256 tumor has been used in a number of brain tumor animal models or CNS heterotopic tumor growth models3,4. Morreale et al.5 developed an improved technique to transplant tumors to the CNS of rats, resulting in more efficient tumor growth in brain parenchyma, less invasion of adjacent structures (meninges, skull bone, subcutaneous tissue and skin) and less distant dissemination. We had modified the model of Morreale, manually inoculating cellular suspensions obtained from in vivo solid tumors (in contrast to the in vitro cell source usually used), aiming at the simplicity and easiness of reproduction of the brain tumor model. We, then, treated animals bearing brain tumors with dexamethasone, an immunosuppressant widely used to treat tumor-related brain edema, and with cyclosporine (CS), a candidate drug for chemotherapy multidrug resistance reversal.

METHODS wWalker carcinosarcoma tumor was maintained in vivo by intramuscular inoculation of 1.0x106 tumor cells, obtained from previous generation of tumor bearing animals in the hind limb of 150–200 g Wistar rats (Rattus norvegicus), every 9 days. Drugs Drugs used were of analytical grade or commercially available. Dexamethasone phosphate 4 mg/mL (Prodome, Brazil) and cyclosporine 100 mg/mL (Biosintetica, Brazil) were used for treatment. Cyclosporine was extemporaneously manipulated for i.p. use as published elsewhere6. Timeline of experiments Animals were operated to implant an apparatus comprised of a cannula for tumor inoculation, stereotactically positioned. After this, animals received saline (SHAM) or a tumor cell suspension and the indwelling cannula was occluded. Treated animals received drugs and their survival was annotated as outlined in next sections. Animals were euthanized after a predefined time for tumor volume estimation. Animals and inoculation Male Wistar rats (200–250 g) had a cannula stereotactically implanted in the target point of the CNS (anteriorposterior=1.5  mm; lateral=3.0 mm; dorsoventral=4.0 mm; in relation to bregma). Cannulas were crafted as previously described and were occluded with a needle so that its tip went 2.0 mm below the cannula tip6. This procedure created

a pocket where, after 5-15 days (mean 8), a cell suspension with 6.0–7.0x104 viable W256 tumor cells in 1x10-6 L volume was manually inoculated using a 25 μL syringe (model 702 80400, Hamilton Co., Reno-Nevada-USA). After inoculation, we waited 5 minutes to permit diffusion of cell suspension into the interstitial fluid. Cell suspension was prepared from solid W256 tumors, using a method previously described7. Cell viability was tested in the cell suspension by Trypan blue staining7. Animal handling and all the procedures followed the requirements of the Institutional Ethics Board on the Use of Animals in Experimentation. Ether handling and using is not prohibited in our Institution and followed strict safety rules. Experimental groups Experiments were carried out with groups of six animals each, in triplicate (n=18 per treatment). Only dexamethasone treated animals were different: 12 animals received 0.3  mg/kg/day and 6 animals received 3.0 mg/kg/day. A SHAM-operated group received a cell-free isotonic saline inoculated after cannula implantation. Tumor inoculated animals were treated with vehicle (saline or CS diluent, control group), dexamethasone 0.3 or 3.0 mg/kg/day or CS 10 mg/kg/day in daily i.p. injections beginning 7 days before tumor inoculation (dexamethasone treatment has begun 4 days after inoculation). Tumor volume estimation (TVE) was performed in 2 animal groups inoculated with tumor cell suspension that developed brain tumors, but were killed seven or nine days after inoculation (n=16). Animal examination and sample handling Animals from SHAM, control and CS treated groups had routine laboratorial exams performed (10 animals each group). Blood samples were collected from retroocular plexus of rats with capillary tubes seven days after tumor cell inoculation and used to blood cell counting and creatine dosage. Automated total white blood cells count was done (C-6, Beckman Coulter, CA – USA). Neutrophil and lymphocyte count was done manually in May-Grümwald-Giemsa stained slides. Values obtained were classified according to reference values8. The main goal of these exams was testing cyclosporine safety, not dexamethasone, so the animals treated with the latter drug were not tested. Animals from all groups (seven per group) were weighed throughout the experiment: before apparatus implantation, on the 5th day post-inoculation (5d) and on the day of death or euthanasia. Organs were inspected macro- and microscopically for evidence of dissemination and weighed just after euthanasia (except for dexamethasone treated animals, as the main purpose was detect metastasis facilitation by CS). Animals were checked twice daily for their status. When an animal was found dead, its survival (expressed in days from the tumor inoculation procedure) was registered.

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When an animal showed signs of imminent death, it suffered euthanasia by ether inhalation9 and its survival was registered. Animals used for TVE suffered euthanasia by intracardiac fixative perfusion9, after deep anesthesia by ether inhalation. SHAM animals suffered euthanasia by ether inhalation. Organs were fixed by immersion in 20 times their volumes of neutral buffered 10% formalin fixative. Two independent pathologists revised the sections and described brain (tumor cell appearance, organization, normal tissue infiltration, meningeal tumor growth, inflammatory infiltrates, hemorrhage and necrosis), lungs and liver (search for metastatic foci), kidneys (looking for interstitial or parenchymatous changes). TVE group brain slides were used for calculation of tumor volume (TV) and doubling time (DT). Sections previously compared with stereotactic atlas pictures for proper localization were observed with an ocular micrometer (20 times magnification). The tumor diameters were measured in millimeters in each section. TV was calculated assuming that inoculation point was roughly in the center of the tumor, using a modified ellipsoid volume calculation formula, as previously described10. Measures taken from animals that suffered euthanasia 7 or 9 days after inoculation were used to calculate the DT, expressed as the time length in hours necessary to duplicate tumor volume. DT was calculated as previously described10. Statistical analysis of data Data were electronically registered and summarized using Microsoft Excel (Microsoft Corporation, USA). All statistical tests were performed with R 2.X (R Development Core Team, 2009). Hematological, biochemical, weight and tumor volume results were showed as mean and standard deviation of mean (mean±SD). Univariate comparison between groups was performed with student’s t-test or one-way ANOVA (Tukey as post-hoc test). Multivariate comparison was performed with mixed effects model ANOVA (Bonferroni test as post-hoc), linear regression, binomial logistic regression and multinomial logistic regression. Survival of animals was presented as median and compared with log-rank test and Cox proportional hazards regression. Alpha-type error level for significance was 0.05.

RESULTS Only animals that had an uneventful experimental procedure were included in the study. Ninety-five per cent of the animals successfully inoculated developed brain tumors (data not shown). Only animals that developed brain tumors were used in this study. Three animals were excluded because of wound infection. The median of survival time for control group was 10 days. No dissemination was identified in lungs

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Arq Neuropsiquiatr 2012;70(1):52-58

and liver. Fourteen of the control animals were examined for tumor growth outside the inoculation point. Tumor growth related to the inoculation site was seen in bony skull in four animals. The animals that suffered euthanasia for TVE measurements showed no tumor growth outside the inoculation point. Brain tumor and TVE Brain tumors were formed by small and medium-sized round cells with regular cell shape, nucleus with reticular chromatin and prominent nucleoli. Cells were undifferentiated and highly mitotic (30 mitosis by high power magnification field). Tumors formed nodules centered at the inoculation point with necrotic foci and many satellite nodules. They were not encapsulated, and tumor cells infiltrated deeply into normal brain, perivascular spaces and white matter tracts, like corpus callosum (Fig 1). There were tumor necrosis and hemorrhagic areas (41.7% of tumors), as well as deposits of a fibrinoid proteinaceous material and vascular neoformation. There were tumor cell infiltrations in the meninges of 97.5% of the analyzed animals. Some tumors showed intense infiltration by neutrophils (33.3%). Estimated TV at day 7 (n=12) was 17.08±6.7 mm3, and at day 9 was 67.25±19.8 mm3 (n=4). We assumed that tumor growth was log linear between days 7 and 9 in order to estimate DT. Calculated value was 24.25 h. The measure of largest tumor diameter, but not estimated volume, was correlated significantly with neutrophil infiltration, but not with other histological features observed (linear regression, p<0.05, R2=0.6, F value=3.2). Hematological and biochemical results Comparison of hematological values between groups by multinomial logistic regression disclosed no statistically significant difference (Table 1). Mean serum creatine levels were not significantly different between groups (ANOVA). Weight of animals and organs Control animals showed a statistically significant weight loss in the second week after implantation (mean reduction 10%), suggesting tumor-induced cachexia (Mixed model ANOVA, Bonferroni test, p<0.01, DF=8, F value=9.7) (Table 2). SHAM animals showed a normal behavior of gaining weight with time. All tumor-bearing animals showed a significant difference from SHAM animals in the last measure (second week), irrespective of treatment. Cyclosporine treated animals showed a statistically significant weight loss beginning in the first week after implantation, suggesting accelerated cachexia induction (Mixed model ANOVA, Bonferroni test, p<0.05, DF=8, F value=9.7). Mean brain weight was significantly higher in control and CS groups than in SHAM group (p<0.05, ANOVA). The same did not occur with mean lung or liver weight (Table 3).


A

B

C

D

E

F

G

H

I

Fig 1. (A) Perivascular cell infiltration and fibrinoid deposits. (X100) (B) Brain tumor angiogenesis. Blood vessels of variable diameters can be observed in the caudate area inoculated with tumor. Usually there’s no blood vessel of this size in this area. (X40) (C) Meningeal tumor infiltration. Tumor focal mass grows without a clear border below cortex (arrow) and shows pial meninx neoplastic infiltration. (X40) (D) Tumor dissemination along white matter tract (callosum). Tumor cells invade a section of corpus callosum (CC) ipsilateral to the tumor inoculation point. (X100) (E) Necrosis. Central tumor necrosis, polymorphonuclear cell infiltration and scattered hemosiderin deposits (arrow). (X40) (F) Intratumoral focal hemorrhage. (X400) (G) Perineuronal infiltration. Detail of normal surrounding brain tissue densely infiltrated by migrating tumor cells. (400X) (H) Satellite nodule. Focal tumor nodule grows at the contralateral brain side. (X100) (I) Tumor cell. W256 tumor cell in imprinting preparation. (X1000, oil immersion). Paraffin embedded, hematoxylin-eosin (HE) stained.

Table 1. Neutrophil and lymphocyte counts in animals with and without brain tumor. WBC

Neutrophils

Table 2. Weigh evolution in animals inoculated with tumor (mean ± SD).

Lymphocytes

nx103

nx103

nx103

SHAM (n=10)

11.1±3.0

1.5±0.4 (15%)

9.2±2.7 (83%)

Control (n=10)

13.2±2.6

2.2±1.3 (17%)

10.6±2.6 (80%)

CS (n=10)

10.7±2.1

2.2±0.8 (21%)

8.1±2.1 (76%)

Automated total WBC count was done (Coulter C-6). Neutrophil and lymphocyte count was done manually in May-Grümwald-Giemsa stained slides. We report mean±SD and relative frequencies to WBC (between brackets). CS: cyclosporine treated. Differences were not statistically significant (multinomial logistic regression). WBC: white blood cell. SHAM: isotonic saline.

Surgery SHAM (n=7) Control (n=7) CS (n=7) Dexa (n=7)

218±23 214±25 216±14 204±9

Weight (g) 5d Death or euthanasia (SHAM: 15d) (SHAM: 21–27d) 224±28

249±31

210±20 (-2%) 185±14 (-25%)†* 231±14 (13%)†

193±32 (-10%)* 181±24 (-26%)†* 204±19 (0%)*

Animals were weighted on surgery day, 5 days after inoculation (5d) and on death or euthanasia day. Variation rates (%) within groups comparing to weigh on surgery day are shown between brackets. Weigh averages were compared between and within groups in each occasion. CS: cyclosporine treated. Dexa: dexamethasone treated. SHAM: isotonic saline. *p<0.05 between groups, comparing to SHAM, Mixed-model ANOVA, Bonferroni. † p<0.05 within groups, comparing to initial weigh, Mixed-model ANOVA, Bonferroni.

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Table 3. Brain and lung weigh in animals inoculated with tumor (control and CS-treated) and SHAM. SHAM (n=7) Control (n=7) CS (n=7)

Body weight (g) 179±28

Brain (g) 1.58±0.1

Lungs (g) 1.3±0.5

Liver (g) 6.8±0.6

Kidneys (g) 1.4±0.2

186±29

1.95±0.2 (24%)** 1.83±0.1 (17%)*

1.7±0.4

7.8±0.9

1.7±0.1

1.5±0.6

7.3±1.7

1.5±0.2

171±26

Animals had their bodies weighted and their organs dissected and weighted after death or ether euthanasia. We report mean±SD. Ratio from control or CS groups to SHAM group (%) between brackets. CS: cyclosporine treated. SHAM: isotonic saline. *p<0.05, ANOVA. **p<0.001, ANOVA.

Pharmacological treatment Dexamethasone and CS treated animals median survival was 9.0 (dexa 3.0), 9.5 (dexa 0.3) and 10 (CS) days. Comparison of survival functions by log rank test disclosed a significant difference to control only for dexamethasone 3.0 mg/kg/day. A Cox proportional hazards regression confirmed that, of all the treatments, only the highest dose of dexamethasone diminished survival of animals in this model (HR=4.2, p<0.01, DF=3, likelihood ratio=7.1). The frequency of histological features did not vary significantly with CS treatment (logistic model). Cyclosporine did not modify significantly mean brain weight comparing to control group (Fig 2).

DISCUSSION We obtained a highly malignant and invasive brain tumor model. Treatment with CS, a specific T lymphocyte inhibitor, was safely tolerated and did not affect survival in this model despite its induction of an accelerated cachexia. Cyclosporine is an immunosuppressant that has been shown to possess intrinsic antitumor activity11 and to inhibit p-glycoprotein, a multidrug resistance protein that is a candidate target for brain tumor chemosensitivity modulation12. We may conclude that further pre-clinical and clinical testing with CS in brain tumors is warranted. The model presented here showed good reproducibility. Meningeal dissemination seems to be a late occurrence in this model, and did not modify survival median time (data not shown). The time between surgery and inoculation procedure permitted blood-brain barrier (BBB) healing and reactive local inflammation resolution. All animals had lesion points localized to the right cerebral hemisphere. Left cortical brain lesions, but not right cortex ones, can induce immune deficits13. The short DT during growth log phase indicated that the tumor was fast growing and highly malignant. The presence of satellite nodules near the main tumor mass indicated tumor cell dissemination through any of these three ways: brain parenchyma, perivascular spaces and white matter tracts. Contralateral hemisphere satellite nodule showed that there had been tumor dissemination by cerebrospinal

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Arq Neuropsiquiatr 2012;70(1):52-58

fluid (CSF) circulation routes. Presence of proteinaceous fibrinoid material deposits could indicate fibrinoid necrosis areas. Increase in brain weight was due to local tumor growth, as well as peritumoral brain edema. Lung weight can be used as a quantitative measure of tumor burden in metastatic lung tumorigenesis models14. There were no evidence of significant lung or liver metastasis, no macroscopic changes, no organ weight differences and no microscopic alterations in control or CS treated animals. This showed that CS did not enhance metastatic potential in this model. Primary malignant brain tumors and some extent metastatic tumors show a layer of brain adjacent to tumor (BAT) consisting of tumor cells infiltrating deeply into normal brain tissue, inducing neovascularization. Capillary permeability and blood perfusion in this region are lower than in tumor layer, and drug penetration is impaired15. The mechanisms of invasion are similar to that of metastatic process of non-neurologic solid tumors, depend on adhesion molecules expression and are related to induction of angiogenesis16,17. In vitro and in vivo laboratory models had been developed aiming the study of CNS tumor invasion. Many transplanted tumors show perivascular invasion, probably related to the presence of the vascular basal layer, rich in extracellular matrix (ECM) structural proteins. Some tumor models show cellular migration along white matter tracts or through CSF circulation routes18. Leptomeningeal carcinomatosis is a complication affecting up to 20% of the patients with some histological types of cancer. Animal models of leptomeningeal metastasis are important to study the physiopathology of meningeal invasion by primary and secondary brain tumors4. It was observed in our model a region probably equivalent to BAT layer. It showed to have intense tumor cell activity, with parenchymatous infiltration, markedly cell tumor migration through white matter tracts (as callosum) and along perivascular spaces. Also, our model showed consistent leptomeningeal metastasis. Intracerebral W256 tumor model developed by Morreale et al.5 did not show important invasion of adjacent brain parenchyma. Tumors formed compact, well delimited, masses in contrast to our tumor model. The fact that tumor cells used in this study were obtained in vivo is probably important. Supposedly, these tumor cells from


1.0

1.0

0.8

0.8

0.6

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Control 0.4

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Control

Dexa 0.3

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CS

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CS Dexa 0.3

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Control

Dexa 3.0

0.0

0.0

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Dexa 3.0

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5

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5

Fig 2. Survival function plots. Survival function was estimated with Kaplan-Meier method and compared with log-rank test. Only treatment with dexamethasone 3.0 mg/kg/day (Dexa 3.0) was statistically different from control. Cox proportional hazards regression confirmed this.

animal tumors are geno and phenotypically different from in vitro cultivated cells, with diverse potential to invasiveness. The present model constitutes, thus, a potential tool for the research of tumor cell migration and invasion in CNS. Neoplastic disease related cachexia is caused by the production of a number of cytokines by tumor and inflammatory cells, the most important of them being IL-6, TNF-Îą and PGE219. W256 tumor implantation in extraneural sites is associated with cachexia and modified dietetic glucose and lipid metabolism in host animals, as well as induced hypercalcemia, bone mineral density loss and osteoporosis20,21. Moreover, W256-induced cachexia is associated with immunosuppression caused by lymphocyte apoptosis.22 These metabolic effects of W256 tumor could have contributed to the cachexia presented by the animals of the control group. As far as we are concerned, this is the first experimental account of intracerebral W256 induced cachexia and one of the first experimental brain tumor animal models to show significant cachexia so far. Because of the intracerebral focal growth of the tumor in basal ganglia in this model, there is

also the possibility that the animals had developed diencephalic syndrome23. The highest dose of dexamethasone (3 mg/kg/day) showed a statistically significant detrimental effect on survival of animals in this model, but treatment with CS or dexamethasone 0.3 mg/kg/day did not affect it. Dexamethasone is widely used to treat brain tumor associated edema and has been one of the mainstays of neuro-oncological management of brain tumors for decades24. However, its exact modes of action are not yet clarified, and a dose-effect association has not been established. Dexamethasone is thought to reduce tumor capillary leak and mean diffusivity inside the tumor and adjacent edematous brain, affecting both transcellular and paracellular endothelial transports and inducing metalloproteinase inhibitors25. Edema from highly malignant tumors, such as brain metastases and glioblastoma, responds to the highest degree, and the impact on other tumor types is less prominent24. Additionally, the benefits of steroids must be carefully balanced with its cumbersome and frequent side effects, sometimes life-threatening. Moreover, despite a

Felix FHC et al. Cyclosporin: rat brain tumor

57


possible direct effect of dexamethasone in glioblastoma cells, it has been suggested that it could protect tumor cells from chemotherapy, hence affecting patient survival26. We could show a direct relationship between polymorphonuclear cell infiltrate and tumor diameter in this model. One can postulate tentatively that possibly the tumor infiltrating inflammatory cells play a role in this tumor model, an event already observed in other tumor types27. Neutrophil infiltration could possibly have had influence in survival modulation by dexamethasone. Unfortunately, we did not prospectively compared histology in all the treatments, so we are unable to answer whether dexamethasone reduced neutrophil infiltration as well. The lack of protection from dexamethasone in this model and, additionally, its detrimental effect in survival deserve further experimental clarification in order to find the mechanisms of action of dexamethasone in this particular model.

In conclusion, rat brain simplified implantation of W256 tumor model showed to be highly reproducible, yielding undifferentiated highly malignant tumor with local invasive characteristics similar to that of primary brain tumors, and should be a potential model to the study of tumor cell migration in CNS. The model could be used as a tool to investigate biological behavior and novel treatment options for both brain parenchymatous tumor growth and leptomeningeal carcinomatosis. Brain tumor growth induced significant cachexia, and this model could potentially be used to study diencephalic syndrome. Its attractive points are in vivo tumor origin, easy manual inoculation technique and high intracerebral tumor growth yielding. Dexamethasone, a drug widely used in brain tumor patients, reduced survival in this model. The same did not happen with CS treatment. Cycloporine treatment did not affect adversely tumor-bearing animals. Cyclosporine could thus be used for further testing against brain tumor models.

References Barth RF, Kaur B. Rat brain tumor models in experimental neuro-oncology: the C6, 9L, T9, RG2, F98, BT4C, RT-2 and CNS-1 gliomas. J Neurooncol 2009;94:299-312.

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Peterson DL, Brown Jr WE. Animal models for brain tumors. In: Black PM, Loeffler JS (Eds). Cancer of the nervous system. USA: Blackwell Science, 1997.

Silva RG, Tavora B, Robinson SD, et al. Endothelial alpha3beta1-integrin represses pathological angiogenesis and sustains endothelial-VEGF. Am J Pathol 2010;177:1534-1548.

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Huang TY, Arita N, Hayakawa T, Ushio Y. ACNU, MTX and 5-FU penetration of rat brain tissue and tumors. J Neurooncol 1999;45:9-17.

Gao CF, Xie Q, Su YL, et al. Proliferation and invasion: plasticity in tumor cells. Proc Natl Acad Sci U S A 2005;102:10528-10533.

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Nakagawa H, Yoshioka K, Miyahara E, Fukushima Y, Tamura M, Itoh K. Intrathecal administration of Y-27632, a specific rho-associated kinase inhibitor, for rat neoplastic meningitis. Mol Cancer Res 2005;3:425-433.

Shelton LM, Mukherjee P, Huysentruyt LC, Urits I, Rosenberg JA, Seyfried TN. A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion. J Neurooncol 2010;99:165-176.

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Morreale VM, Herman BH, Der-Minassian V, et al. A brain-tumor model utilizing stereotatic implantation of a permanent cannula. J Neurosurg 1993;78:959-965.

Rebeca R, Bracht L, Noleto GR, et al. Production of cachexia mediators by Walker 256 cells from ascitic tumors. Cell Biochem Funct 2008;26: 731-738.

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Félix FHC. Modelo de implante de tumor de Walker no cérebro de ratos [dissertação]. Fortaleza: Faculdade de Medicina. Universidade Federal do Ceará; 2001.

Fernandes LC, Machado UF, Nogueira CR, Carpinelli AR, Curi R. Insulin secretion in Walker 256 tumor cachexia. Am J Physiol 1990;258: 1033-1036.

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Waki Y, Miyamoto K, Kasugai S, Ohya K. Osteoporosis-like changes in Walker carcinoma 256-bearing rats, not accompanied with hypercalcemia or parathyroid hormone-related protein production. Jpn J Cancer Res 1995;86:470-476.

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of malignant gliomas and implications for treatment. J Clin Oncol 2003;21:1624-1636.

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Freshney RI. Culture of animal cells. New York: Alan R. Liss, 1987.

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Smith CA, Andrews CM, Collard JK, Hall DE, Walker AK. A color atlas of comparative diagnostic and experimental hematology. Barcelona: Wolfe Publishing, 1994.

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American Veterinary Medical Association Panel on Euthanasia. 2000 Report of the AVMA Panel on Euthanasia. J Am Vet Med Assoc 2001;218:669-696.

Lima TM, Lima MM, Almeida DC, Mendonça JR, Curi R. Cachexia induced by Walker 256 tumor growth causes rat lymphocyte death. Cancer Immunol Immunother 2005;54:179-186.

23.

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Steel GG. Growth Kinetics of Tumours. Oxford: Claredon Press, 1977.

Fleischman A, Brue C, Poussaint TY, et al. Diencephalic syndrome: a cause of failure to thrive and a model of partial growth hormone resistance. Pediatrics 2005;115:742-748.

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Sliwa M, Markovic D, Gabrusiewicz K, et al. The invasion promoting effect of microglia on glioblastoma cells is inhibited by cyclosporin A. Brain 2007;130:476-489.

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Kotsarini C, Griffiths PD, Wilkinson ID, Hoggard N. A systematic review of the literature on the effects of dexamethasone on the brain from in vivo human-based studies: implications for physiological brain imaging of patients with intracranial tumors. Neurosurgery 2010;67:1799-1815.

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Aller SG, Yu J, Ward A, et al. Structure of P-glycoprotein reveals a molecular basis for poly-specific drug binding. Science 2009;323:1718-1722.

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Dunn AJ. Interactions between the nervous system and the immune system. Implications for psychopharmacology. In: Bloom FE, Kupfer DJ (Eds). Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, 1995.

Gu Y, Qin L, Qin X, Xu F. The molecular mechanism of dexamethasonemediated effect on the blood–brain tumor barrier permeability in a rat brain tumor model. Neurosci Letters 2009;452:114-118.

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Qian YH, Xiao Q, Chen H, Xu J. Dexamethasone inhibits camptothecininduced apoptosis in C6-glioma via activation of Stat5/Bcl-xL pathway. Biochim Biophys Acta 2009;1793:764-771.

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Hillen F, Baeten CIM, van de Winkel DC, Van der Schaft DWJ, Winnepenninckx V, Griffioen AW. Leukocyte infiltration and tumor cell plasticity are parameters of aggressiveness in primary cutaneous melanoma. Cancer Immunol Immunother 2008;57:97-106.

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Giese A, Bjerkvig R, Berens ME, Westphal M. Cost of migration: invasion

Arq Neuropsiquiatr 2012;70(1):52-58


VIEWS AND REVIEWS

Treatment of neuromyelitis optica: an evidence based review Tratamento da neuromielite óptica: uma revisão baseada em evidências Douglas Sato1,2, Dagoberto Callegaro2, Marco Aurélio Lana-Peixoto3, Kazuo Fujihara4, on behalf of Brazilian Committee for Treatment and Research in Multiple Sclerosis (BCTRIMS)

ABSTRACT Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system characterized by severe optic neuritis and transverse myelitis, usually with a relapsing course. Aquaporin-4 antibody is positive in a high percentage of NMO patients and it is directed against this water channel richly expressed on foot processes of astrocytes. Due to the severity of NMO attacks and the high risk for disability, treatment should be instituted as soon as the diagnosis is confirmed. There is increasing evidence that NMO patients respond differently from patients with multiple sclerosis (MS), and, therefore, treatments for MS may not be suitable for NMO. Acute NMO attacks usually are treated with high dose intravenous corticosteroid pulse and plasmapheresis. Maintenance therapy is also required to avoid further attacks and it is based on low-dose oral corticosteroids and non-specific immunosuppressant drugs, like azathioprine and mycophenolate mofetil. New therapy strategies using monoclonal antibodies like rituximab have been tested in NMO, with positive results in open label studies. However, there is no controlled randomized trial to confirm the safety and efficacy for the drugs currently used in NMO.

Key words: neuromyelitis optica, therapy, aquaporin 4, plasmapheresis, steroids, azathioprine, mycophenolic acid, monoclonal antibodies, mitoxantrone, cyclophosphamide, interferon-beta. RESUMO Neuromielite óptica (NMO) é uma doença inflamatória do sistema nervoso central caracterizada por grave neurite óptica e mielite transversa, com um curso usualmente recorrente. O anticorpo contra aquaporina-4 é positivo em grande porcentagem dos pacientes com NMO e se liga a este canal de água altamente expresso nos processos pediosos dos astrócitos. Devido à gravidade dos ataques de NMO e ao elevado risco de incapacidade, o tratamento deve ser instituído tão logo o diagnostico seja confirmado. Existem evidências crescentes de que pacientes com NMO respondem de forma diferente dos pacientes com esclerose múltipla (EM) e, portanto, os tratamentos utilizados na EM podem não ser adequados para NMO. Os quadros agudos de NMO são tratados com pulsos de corticosteroides em altas doses e plasmaférese. O tratamento de manutenção também deve ser instituído para evitar ataques subsequentes e é baseado em corticosteroides orais em baixas doses ou imunossupressores, como a azatioprina e o micofenolato mofetil. Novas estratégias de tratamento utilizando anticorpos monoclonais como rituximab têm sido avaliadas para NMO, com resultados positivos em estudos abertos. Entretanto, não existem estudos clínicos controlados, randomizados, para confirmar a segurança e eficácia dos tratamentos atualmente utilizados na NMO.

Palavras-Chave: neuromielite óptica, terapia, aquaporina 4, plasmaferese, esteróides, azatioprina, ácido micofenólico, anticorpos monoclonais, mitoxantrona, ciclofosfamida, interferon-beta.

Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system (CNS) characterized by severe optic neuritis (ON) and transverse myelitis (TM)1. Aquaporin-4 (AQP-4) antibody, also known as NMO-IgG, an autoantibody exclusively detected in the sera of NMO, is directed against AQP-4, a water channel richly expressed on foot processes of astrocytes in the CNS2,3. In most series of

NMO, more than half of cases are positive for AQP-4 antibody. In 2006, Wingerchuk et al.4 proposed the revised diagnostic criteria of NMO that incorporated AQP-4 antibody status. For definite NMO, the criteria require (A) ON, (B) TM and (C) at least two of three supportive criteria: (1) contiguous spinal cord lesion in the magnetic resonance imaging (MRI) extending over three vertebral segments; (2) brain MRI not meeting

1

Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan;

2

Department of Neurology, Faculty of Medicine, University of São Paulo (USP), São Paulo SP, Brazil;

3

CIEM Multiple Sclerosis Research Center, Federal University of Minas Gerais Medical School, Belo Horizonte MG, Brazil;

4

Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan.

Correspondence: Douglas Sato; Department of Neurology; Tohoku University Graduate School of Medicine; 1-1, Seiryomachi, Aobaku; 980-8574 Sendai Miyagi - Japan; E-mail: douglas.sato@med.tohoku.ac.jp conflict of interest: There is no conflict of interest to declare. Received 29 August 2011; Accepted 05 September 2011

59


diagnostic criteria for multiple sclerosis (MS); (3) serum positivity for AQP-4 antibody. NMO treatment has two main objectives: one is to control the inflammatory damage in acute attacks and the other one is a maintenance treatment to avoid relapses. The former is based on high dose intravenous corticosteroids and plasmapheresis5; the latter is based on low-dose corticosteroids and immunossupressants6,7. Additionally, there is evidence that AQP-4 antibody titers are reduced in patients without relapses under immunosuppressant treatment8,9. Although NMO attacks are related to severe disability, there are some evidences that NMO patients remain neurologically stable between them, without evidence of progressive deterioration like in MS1. Therefore, it is crucial that treatment is started as early as possible to avoid new relapses and further disability. For this review, the English-language literature was systematically searched using Pubmed (National Library of Medicine) with the keywords neuromyelitis optica, and treatment was accessed on 20th July 2011, resulting in 394 articles. All articles available had the abstract analyzed and full article review was performed once considered relevant. Additional articles referenced in bibliographies from these articles were also reviewed. Case reports that revealed further insights into NMO, not identified in case series analyzed, were included in this review.

Levels of evidence In this review, we used levels of evidence from the Agency for Health Care Policy and Research (also known as Agency for Healthcare Research and Policy)10 (Table 1) and the recommendation grades published for use in clinical guidelines from the American College of Chest Physicians Task Force (Table 2)11. We have classified the available studies in NMO accordingly and provided the recommendations for each treatment (Table 3).

Corticosteroids Corticosteroids have been the mainstay treatment for NMO in both acute and maintenance phase. Methylprednisolone has been used since 1970 as a potent anti-inflammatory or immunosuppressant agent in the treatment of a variety of diseases including those of hematologic, allergic, inflammatory, neoplastic and autoimmune origin. In addition, it is also widely used in prevention and treatment of graft-versus-host disease following allogeneic bone marrow transplantation and acute spinal cord injury. Corticosteroids exert a wide array of physiologic effects including modulation of carbohydrate, protein and lipid metabolism, and maintenance of fluid and electrolyte homeostasis. Moreover, cardiovascular, immunologic, musculoskeletal, endocrine and neurologic physiologic functions are influenced by corticosteroids. Therefore, not only the positive

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effects can be observed, but also many adverse events can be originated from corticosteroids use. These adverse events can be seen acutely like mood/psychic changes, fluid retention with circulatory overload, hyperglycemia, hypokalemia and increased ocular pressure. Chronic corticosteroid use may promote other side effects like hypertension, hirsutism, Cushing’s syndrome, hyperlipidemia, diabetes mellitus, gastrointestinal hemorrhage, aseptic necrosis and bone fractures. The mechanism of action of corticosteroids is not completely understood, but many of their genomic functions originate from regulation of gene expression subsequent to binding specific intracellular receptors and translocation into the nucleus12. More recently, there have been observed evidences that corticosteroids in high doses, as used in high dose intravenous methylprednisolone (HIMP), have significant non-genomic effects, which may explain the rapid clinical response after infusion. These effects are probably mediated by a direct effect on cellular membranes and mitochondrial function, inducing a reduction of adenosine-5’-triphosphate production and promoting cellular apoptosis. Furthermore, HIMP also reduces the mitogen-induced increase of cytoplasmic calcium concentration and inhibits cation cycling across the plasma membrane with only a minimal effect on intracellular protein synthesis. The genomic and non-genomic effects may explain the positive effects of corticosteroids in NMO, inducing a reduction of inflammation, apoptosis of leukocytes, suppression of migration of polymorphonuclear leukocytes and reversal of increased capillary permeability. Although the clinical efficacy of corticosteroids have been established in meta-analysis evaluating the treatment of neuroimmunological diseases13, only few clinical studies have rigorously investigated the efficacy and safety of corticosteroids in NMO. Consequently, the current practice of corticosteroids use in NMO is mainly based on few open-label studies and personal experience on treating other CNS autoimmune diseases. The first open-label study in NMO evaluated the treatment of seven newly diagnosed NMO patients with long-term prednisone and azathioprine, with a follow-up every two months for at least 18 months6. Patients had no relapses during the observation period, and Expanded Disability Status Scale (EDSS) reduced from a mean of 8.2 at baseline to 4 at 18 months. A subsequent study reviewed related 25 patients with NMO who met the 1999 Wingerchuk’s criteria and identified nine patients with long-term use of corticosteroid monotherapy7. The annual relapse rate was significantly lower under use of corticosteroids than the period without the drug (median 0.49 vs. 1.48). Still more interesting, the authors also observed that the odds ratio for the period with 10 mg/day or less was 8.71 if compared with 10 mg/day or over, suggesting that dose tapering below 10 mg/day for relapse prevention should be prescribed carefully, as it may be less than the required for the majority of patients for relapse prevention.


Another evidence that corticosteroids are useful to preserve normal nerve function in NMO is a retrospective study on NMO patients with optic neuritis relapse, which correlated the number of relapses, early corticosteroids intervention and a loss in retinal nerve fiber layer thickness (RNFLT)14. The overall RNFL was thinner in patients in the NMO group than in the MS (63.84 vs. 84.28 Îźm). The frequency of the ON relapses and the time for beginning the treatment with HIMP significantly affected the preservation of the RNFLT.

Table 1. Classification of evidence levels10. Ia Evidence obtained from meta-analysis of randomized controlled trials Ib Evidence obtained from at least one randomized controlled trial IIa Evidence obtained from at least one well-controlled study without randomization IIb Evidence obtained from at least one other type of welldesigned quasi-experimental study III Evidence obtained from well-designed, non-experimental descriptive studies; such as comparative studies, correlation studies and case control studies

Plasmapheresis Plasmapheresis (PE) has been used as an alternative therapy for autoimmune diseases when HIMP is not effective. PE

IV Evidence obtained from expert committee reports or opinions and/or clinical experience of respected authorities

Table 2. Grading recommendations11. Recommendation Description Methodological quality of supporting evidence Implications Grade 1A Strong recommendation, RCTs without important limitations or Strong recommendation, can high-quality evidence overwhelming evidence from observational studies apply to most patients in most circumstances without reservation Grade 1B Strong recommendation, RCTs with important limitations (inconsistent Strong recommendation, can moderate-quality results, methodological flaws, indirect or apply to most patients in most evidence imprecise) or exceptionally strong evidence from circumstances without reservation observational studies Grade 1C Strong recommendation, Observational studies or case series Strong recommendation, but may change when higher quality low-quality or very lowquality evidence evidence becomes available Grade 2A Weak recommendation, RCTs without important limitations or Weak recommendation, best high-quality evidence overwhelming evidence from observational studies action may differ depending on circumstances or patients or societal values Weak recommendation, best Grade 2B Weak recommendation, RCTs with important limitations (inconsistent action may differ depending on moderate-quality results, methodological flaws, indirect or evidence imprecise) or exceptionally strong evidence from circumstances or patients or observational studies societal values Grade 2C Weak recommendation, Observational studies or case series Weak recommendation, other low-quality or very lowalternatives may be equally quality evidence reasonable RCT: Randomized controlled trial.

Table 3. Summary of treatments and recommendation levels used for neuromyelitis optica. Treatment Dose/Regimen Acute attacks Corticosteroid pulse (HIMP) Methylprednisolone 1g/day for 3 to 5 days Plasmapheresis (PE) Relapse prevention Oral prednisone

2 ~ 4 liters per session, 2 to 3 sessions per week, up to 7 sessions

Recommendation

Evidence level

Grade 1C

III IIb

Grade 1C

5 ~ 20 mg/day

Grade 1C

Azathioprine

2 mg/kg/day

Grade 1C

Mycophenolate mofetil

2 g/day

Grade 1C

Rituximab

Grade 1C

Immunoglobulin (IVIG)

375 mg/m /week for 4 weeks or 1g repeated in 2 weeks; monitoring of CD19+ or CD27+ B cells to indicate retreatment 400 mg/kg for 5 days monthly

Mitoxantrone

12 mg/m2/month, maximum cumulative dose 140 mg/m2

Grade 2C

Cyclophosphamide

1 g/day monthly or immunoablation with 2 g/day for 4 days

Grade 2C

2

Grade 2C

III III III III IV III IV

HIMP: High-dose intravenous methylprednisolone; PE: plasmapheresis; IVIG: intravenous immunoglobulin.

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is an extracorporeal blood purification technique designed to remove antibodies, complement, cytokines and chemokines from the plasma. The quick removal of these substances may reduce further damage and interrupt the advancement of lesions faster than immunosuppressive agents, as autoantibodies can persist for several weeks in the circulation. It has been largely used for the treatment of thrombotic thrombocytopenic purpura, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy, Waldenstrom macroglobulinemia and Guillain-BarrĂŠ syndrome15. MS, NMO, acute disseminated encephalomyelitis, Lambert-Eaton myasthenic syndrome, paraproteinemic polyneuropathy and cryoglobulinemic polyneuropathy are some other neurological conditions sometimes treated with apheresis16. Due to the success in other immune mediate diseases, PE is used in NMO taking into consideration that there is evidence that NMO is an autoantibody-mediated disease with complement activation and PE has the potential to remove humoral immune products from systemic circulation17. PE is often prescribed using at least five plasma exchange sessions to achieve a sufficient antibody removal. The rate of extravascular to intravascular equilibration is approximately one to two percent per hour, then five separate exchanges over seven to ten days are required to remove 90% of the total initial body immunoglobulin levels18. In order to be most effective, PE has to be associated with appropriate immunosuppressant therapy, avoiding new immunoglobulin production. If antibody production is not properly blocked, additional PE sessions may be required. PE is an invasive therapeutic procedure and carries some complications. In NMO, it is usually performed using 5% albumin replacement, so complications from fresh frozen plasma infusion are avoided. Reported adverse effects have been hypotension, dyspnea/pulmonary edema due to fluid overload, citrate induced hypocalcaemia, coagulation abnormalities, infection and catheter related issues. As PE can also promote removal from serum of drugs such as azathioprine and cyclophosphamide; it is advisable that these drugs are administered following apheresis sessions19. There is some evidence from some case series that PE is effective for acute relapse treatment in NMO patients who did not respond satisfactorily to HIMP5,17,20,21. Moreover, clinical response seems to be related to the early initiation of treatment20 and it may be observed quickly once PE sessions are started5. A review from the American Academy of Neurology about PE in neurological diseases indicates that there is Class II evidence that PE is probably effective to treat fulminant CNS diseases, including NMO22. However, the randomized study which provided such evidence included 22 patients with various CNS demyelinating diseases, like MS, ADEM, Marburgâ&#x20AC;&#x2122;s disease, but only four patients with acute myelitis and two patients with NMO23. Other small case series have reported positive results with double membrane filtration

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plasmapheresis (instead of centrifugation technique)24 and PE used as rescue therapy 25. The Guidelines on the use of therapeutic apheresis in clinical practice from the American Society for Apheresis published in 201026 considered that PE for NMO is accepted as second line therapy, as it may be helpful in recovery from acute attacks, although it does not prevent further relapses. For long-term treatment, there is only a small case-series study (n=4) indicating that PE is effective not only for acute management, but also intermittent PE may be worthwhile for selected cases where long-term immunosuppressant treatment have failed21.

Azathioprine Azathioprine is a DNA synthesis inhibitor, as it is converted to a purine analogue, with interference in the purines synthesis (adenine and guanine). It inhibits the proliferation of cells, especially lymphocytes. The clinical effects are usually not seen before three to six months after initiation of therapy. It is a reasonably well-tolerated drug used for autoimmune diseases and organ transplantation either alone or in combination. It has been approved as adjunctive therapy in prevention of rejection of kidney transplants and for the management of active rheumatoid arthritis27. Additionally, many off-label uses have been reported, such as adjunct in prevention of solid organ transplants rejection, steroid-sparing agent for corticosteroiddependent Crohnâ&#x20AC;&#x2122;s disease and ulcerative colitis, dermatomyositis/polymyositis, MS and other autoimmune diseases. Common adverse events reported with azathioprine include: fever, malaise, nausea, vomiting, leukopenia, thrombocytopenia, hepatoxicity, myalgia, and infections. It is reported a slight higher risk of developing cancer27. Therefore, periodic monitoring of patients with hematological (complete blood count with differential and platelets), liver function tests, bilirubin and continuous surveillance for clinical signs of cancer are required. More recently, there is increasing evidence to evaluate thiopurine methyltransferase enzyme activity before initiating azathioprine therapy28. Thiopurine methyltransferase enzyme is involved in the metabolism of azathioprine and may determine the clinical response to thiopurines. Patients with intermediate or low thiopurine methyltransferase activity may be at risk for increased myelosuppression, sometimes life-threatening. Therefore, careful monitoring and dose adjustments may be required for these patients. As previously described, the first study included seven newly diagnosed NMO patients with long-term combination of corticosteroids and azathioprine with positive results6. HIMP was given first for five days, followed by oral prednisone (1 mg/kg/day) for two months daily. At week three, patients started azathioprine (2 mg/kg/day). Two months later,


patients began prednisone tapering very slowly until they have achieved a dose of 10 mg/day and azathioprine doses of 75 to 100 mg/day. Another study observed that suspension of azathioprine was followed by increase in AQP-4 antibody levels and clinical attacks in some patients, together with the interruption of corticosteroid in two patients or the maintenance of low-dose corticosteroid treatment (5 mg/day)9. A retrospective study with 36 Brazilian NMO patients analyzed those who used azathioprine alone or in combination with corticosteroids and provided similar findings of reduction in disability and relapse rates29. These results may indicate that combination therapy may be required in some patients. However, there are no multicenter controlled studies to provide class I efficacy evidence of this therapeutic regimen, and side effects may limit the use in some patients.

Rituximab Rituximab is a chimeric monoclonal antibody against the protein CD20, which is primarily found on the surface of B cells and it has the property to eliminate B cells selectively. Rituximab binds to the antigen on the cell surface, activating complement-dependent B cell cytotoxicity. It also binds to human Fc receptors, mediating cell killing through an antibody-dependent cellular toxicity. Rituximab is used in the treatment of many lymphomas, leukemias, transplant rejection and some autoimmune disorders. Besides the clinical studies with rituximab, another evidence that B cells and AQP-4 antibody are closely related to NMO pathogenesis is a case report of a Japanese NMO patient with hypogammaglobulinemia secondary to carbamazepine who reported no relapses during the lowered IgG levels, but who had no attacks relapsed later when the hypogammaglobulinemia resolved in association with the normalization of CD19+ cells30. The first published open label study included eight patients in the USA, where rituximab was well tolerated, and positive response was observed in all patients with significant relapse reduction (2.6 relapse/patient/year to 0) and recovery of neurologic function measured by EDSS from 7.5 to 5.531. Rituximab was administered in four infusions of 375 mg/m2, administered once per week, and B cells were monitored with CD19 marker by flow cytometry. In the retreatment, the regimen used was 1,000 mg administered two weeks apart. However, one patient who did not receive the repeated course of rituximab when planned had an attack, indicating that treatment requires repeated infusions in order to CD19+ cells remain undetectable. A report of three Japanese NMO cases who received rituximab also observed positive results, with a remarkable reduction in the annualized relapse rate ( from 5.0 in the pre-treatment to 0.6 in the post-treatment), but the decrease in EDSS was not so significant ( from 8.7 in the pre-treatment to 8.0 post-treatment), maybe indicating that, although the drug was effective

to control the inflammatory response, the irreversible damage had already been established32. Another study described two NMO cases treated with rituximab33. It was observed a good clinical response in one patient, but the other one have experienced relapses after the treatment, indicating that not all patients respond so well. A possible explanation for the occurrence of relapses following initiation of rituximab in some NMO patients is the transient increase in AQP-4 antibody titers and of B cell activating factor levels, which is observed for two weeks following the initial infusion34. Posterior reversible encephalopathy syndrome after rituximab infusion in NMO have been reported35, but this syndrome has been reported in NMO patients independent of rituximab36, so this may be a relapse related to rituximab initiation rather than a new treatment complication. Another study retrospectively analyzed 25 NMO patients identified in seven centers from USA and Europe35. It was observed a marked reduction in the attacks and improvement in disability. The study had the two regimen of rituximab used in previous studies analyzed together (four infusions of 375 mg/m2, administered once per week, and 1,000 mg administered two weeks apart). The median follow-up was 19 months, and the mean post-treatment relapse rate dropped from 1.7 to 0. Disability has improved in 80% of patients, but two patients died during the study period, one due to a brainstem relapse and the other due to suspected septicemia. The study indicated a promising treatment option, but, like the traditional chemotherapies, it may expose patients to severe infections. Another retrospective study in the USA has also revealed that rituximab treatment was associated with reduction of relapses and stabilization or improvement of disability36. A study with eight European patients evaluated the clinical response and AQP-4 antibody titers with different treatments, measured by a fluorescence immunoprecipitation assay using an extract from cells transfected with EGFP-tagged human AQP-4 M1 and M23 isoforms9. Four patients received rituximab and the reduction of CD19+ cells was correlated with a reduction of AQP-4 antibody titers and positive clinical response. The study also identified that relapses were preceded or paralleled by reoccurrence of CD19+ cells and an increase up to three-fold in the AQP-4 antibody. Another group has also confirmed clinical efficacy of rituximab in 10 NMO patients in Europe, but there was no correlation with AQP-4 antibody levels37. Recently, the results of an open-label study with Korean NMO patients were reported with positive results38. Induction therapy was basically the same of previous studies, followed by maintenance therapy with repeated rituximab infusions (375 mg/m2, once) when the frequency of CD27+ memory B cells was more than 0.05% in peripheral blood. Interestingly, this approach reduced the number of infusions in the maintenance therapy, with a direct impact on treatment costs. Twenty-eight of 30 patients (93%) showed a marked reduction

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in the mean relapse rate from 2.4 to 0.3 while receiving rituximab over 24 months. Seventy percent of patients became relapse-free over 24 months, and disability either improved or stabilized in great majority of patients. One patient continued to have relapses despite rituximab treatment and was switched to mitoxantrone hydrochloride, and another patient had three relapses during treatment, but two relapses were associated with delayed retreatment. AQP-4 antibody levels declined significantly following treatment with rituximab, consistent with the clinical response and the effect on memory B cells. The most common infusion-related reactions, noted in 40% of patients during the first infusion, were transient hypotension and mild to moderate flu-like symptoms, such as a febrile sense, headache and skin rash. Less than half of patients experienced at least one infection episode during the study period, but there were no serious infection. There was no decline in serum total IgG titers, and no patient became seropositive for the JC virus over the 24 months.

cytostatic effect on T and B lymphocytes. It is an inhibitor of inosine monophosphate dehydrogenase, which inhibits de novo guanosine nucleotide synthesis, required for proliferation of T and B lymphocytes. It has been used for prevention of organ transplants rejection and autoimmune diseases, like myasthenia gravis and systemic lupus erythematosus. In 2006, a case report described a NMO patient successfully treated with mycophenolate mofetil 2 g/day who had no relapses over the following two years associated with clinical improvement41. Another study analyzed retrospectively 24 patients treated with mycophenolate mofetil (median dose of 2 g/day) with median treatment duration of 27 months. Patients had reduction in relapse rates (median annualized rate dropped from 1.28 to 0.09) and 91% of patients had stabilization or improvement of disability. In this study, six patients (25%) reported adverse events, which included headache, constipation, easy bruising, anxiety, hair loss, diarrhea and abdominal pain, and low white blood cell counts that required discontinuation42.

Mitoxantrone Cyclophosphamide Mitoxantrone hydrochloride is an anthracenedione used as an antineoplastic agent for prostate cancer and acute nonlymphocytic leukemia in adults. It has been approved for MS treatment, including secondary progressive MS, based on the evidence that it has reduced progression in MS patients with failure in other treatment regimens. It also reduces the clinical relapse rate and MRI outcomes in relapsing-remitting MS patients, and it is helpful on patients with clinical worsening conditions. However, the potential toxicity of this drug limits its use, and patients should be monitored periodically for cardiac, liver and kidney function39. Considering the successful use in MS, mitoxantrone has been evaluated in NMO patients, but the case series have been very limited. In a study, five NMO patients received monthly intravenous infusions of mitoxantrone hydrochloride, 12 mg/m2, for six months, followed by three additional treatments every three months40. During the two years period of treatment, two patients had a relapse within the initial five months of treatment (one severe and one moderate), and improvement was seen clinically and on magnetic resonance images in four patients. One patient had a reversible decrease in cardiac ejection fraction. In another study, there were three patients who received mitoxantrone9. Unfortunately, the response was variable, from reduction of relapse rate in one patient to increased relapse rate in two patients.

Mycophenolate mofetil Mycophenolate mofetil has been largely used for the treatment of several autoimmune diseases. It has a selective

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Cyclophosphamide is an alkylating agent that prevents cell division by cross-linking DNA strands and decreasing DNA synthesis. It is a cell cycle phase nonspecific agent and has immunosuppressant activity. Cyclophosphamide is a prodrug that must be metabolized to active metabolites in the liver. It has been used in the treatment of many neoplasias and some autoimmune diseases, like severe rheumatoid disorders, Wegenerâ&#x20AC;&#x2122;s granulomatosis, myasthenia gravis, MS, systemic lupus erythematosus, autoimmune hemolytic anemia and idiopathic thrombocytopenic purpura. However, most studies are based on open-label studies or case series. In MS, the largest study from the Canadian Co-operative Multiple Sclerosis Study Group with 168 patients failed to demonstrate clinical efficacy of cyclophosphamide43. Another study has indicated some beneficial effects of cyclophosphamide in young MS patients, excluding those with primary progressive MS. In this study, the responsive patients received repeated cyclophosphamide infusions in a bimonthly basis after the induction phase44. Common adverse events of cyclophosphamide include: alopecia, fertility issues, nausea and vomiting, anorexia, diarrhea, mucositis, acute hemorrhagic cystitis or urinary fibrosis, anemia, leukopenia (dose-related with recovery from seven to ten days after cessation) and thrombocytopenia. In NMO, there is scarce data, based mainly in case reports. The use of cyclophosphamide has been reported as effective in immunoablative doses (2,000 mg/day for 4 days) in a patient with NMO associated with refractory systemic lupus erythematosus after response failure with other treatments, like HIMP, intravenous immunoglobulin (IVIG) and


rituximab45. However, another case report indicated a failure of monthly cyclophosphamide pulse (1,000 mg/m2) for six months, although NMO relapses were controlled with rituximab46.

Interferon beta The therapy using interferon beta has been used in MS treatment in routine practice for over 15 years. However, interferon beta is not currently recommended for NMO patients and there are some evidences that it also may be even harmful, increasing the relapse rates47. Other Japanese studies reported MS patients with good response to interferon beta therapy, compared with NMO patients who experienced increased relapse rate after interferon beta treatment48,49. Similarly, a series of 25 NMO patients from France were reported to experience relapses following treatment with interferon beta50. Additionally, there is a case report of a Caucasian NMO patient from United Kingdom51, suggesting that this deleterious response to interferon beta is probably not influenced by racial differences.

Other therapies and future perspectives Eculizumab is a humanized monoclonal IgG antibody that binds to complement protein C5, preventing cleavage into C5a and C5b. Eculizumab inhibits the subsequent formation of terminal complex C5b-9 or membrane attack complex. It is currently under investigation for NMO in an open-

label phase I clinical trial at a single center with 14 patients52. Eculizumab has already been shown to be effective in paroxysmal nocturnal hemoglobinuria53. Each patient will receive eculizumab at a dose of 600 mg each week for four weeks, then 900 mg at the fifth week, and 900 mg every two weeks for 48 weeks. Anecdotal reports have been published using intravenous immunoglobulin54, glatiramer acetate55, but replication of these findings needs to be validated by other studies in a larger number of patients. Other monoclonal antibodies used in MS treatment have been tried in NMO patients refractory to established treatments, like natalizumab, but NMO patients seem to not respond to these therapies (personal communication with Dr Anu Jacob, The Walton Centre, Liverpool UK, unpublished).  

Final remarks The use of corticosteroids and other immunosuppressant drugs for NMO treatment has been based on case reports or small series of cases rather than in double-blinded randomized studies. This does not mean that these drugs are not effective, but that higher levels of evidence of their effectiveness are still lacking. As NMO is a very severe and incapacitating CNS disorder, its treatment has to be decided on the basis of clinical judgment, physicians’ experience, case series and extrapolation from management of other autoimmune conditions while clinical trials are not yet available to provide physicians with options grounded on stronger scientific support.

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LETTERS

A rare cause of recurrent peripheral facial palsy Uma causa rara de paralisia facial periférica recorrente João Pinho, Sofia Rocha, Álvaro Machado, Esmeralda Lourenço

Recurrent peripheral facial palsy (PFP) is not uncommon and it is reported in 3 to 15% of idiopathic PFPs. Other etiologies include intracranial compressive tumors, parotid gland tumors or inflammation, recurrent otitis media, head trauma, multiple sclerosis, sarcoidosis, tuberculosis, Lyme disease, HIV, and the rare Melkersson-Rosenthal Syndrome (MRS). The MRS is a non-necrotizing granulomatous disease characterized by PFP, lingua plicata and orofacial edema, even though the classic triad is reported in only from 20 to 30% of the patients1. We describe a patient with recurrent alternating PFP with MRS.

CASE REPORT A 31 year-old man presented with a three-day history of left sided retro-auricular dull pain, progressive face asymmetry with sensation of foreign body in the left eye, liquid loss through the left corner of his mouth while drinking, and a change in taste. He remembered having had a similar episode six years earlier. He had been followed-up by dermatologists because of a persistent lip swelling, which developed insidiously during his early 20s. He had been treated with oral metronidazol and topical agents for suspicion of fungal infection, he was submitted to a lip biopsy that was reported as unspecific, and had discontinued his treatment. During both episodes of facial palsy, there was a transient increase in lip swelling. He was otherwise healthy. Family history of facial palsy was negative. Examination revealed an isolated left PFP, edema, scaling and fissuring of the upper lip, and lingua plicata with deep central tongue fissure, radiating fissures and irregular tongue edges (Figure). The patient was treated with a seven-day tapering scheme of oral prednisolone, motor rehabilitation. Within two weeks, he had recovered fully with partial improvement of lip swelling. Four weeks later the patient presented with a right PFP and increased upper lip edema, and no signs of previous left PFP. He was treated again with oral prednisolone and motor rehabilitation, recovering completely after four weeks. Blood testing was normal, including

infectious and immunological screen. Thoracic X-ray was also normal. The brain magnetic resonance image (MRI) was normal. He has been asymptomatic for three years.

DISCUSSION The MRS etiology is unknown but autoimmune, allergic, infectious and genetic factors are proposed. Perivascular lymphocytic inflammatory infiltrates and non-caseating epitheloid granulomas are the main findings in lip biopsies2. Finding of decreased C1 inhibitor function and contact sensitivity to food additives supports the immunological hypothesis3. Familial occurrence of MRS and identification of a de novo t(9;21)(p11;p11) translocation in one patient suggest a role for genetic factors4. The MRS should be suspected in patients with PFP and typical cutaneous, lip and tongue findings. Recognition of the classic triad prevents submitting the patient to unnecessary workup. Lip biopsy is required for definite diagnosis, but typical histological findings may be absent4. Treatment with topic, oral and intravenous steroids, salazosulfapyridine, methotrexate, thalidomide and irradiation has been reported, but results are frequently disappointing and progressive disability may be developed5. The rare cause of recurrent and frequently alternate PFP is highlighted in this report, evidence for the benefit of oral steroids in acute PFP in MRS is provided, and the fact that PFP in MRS may have a rather benign course is reported.

Figure. Left peripheral facial palsy and upper lip edema (A-B); lingua plicata with deep central fissure, radiating tongue fissures and irregular tongue edges (C).

Serviço de Neurologia, Hospital de Braga, Braga, Portugal. Correspondence: João Pinho; Serviço de Neurologia, Hospital de Braga, Sete Fontes, São Victor; 4710-243 Braga - Portugal; E-mail: jdpinho@gmail.com Conflict of interest: There is no conflict of interest to declare. Received 10 July 2011; Received in final form 21 July 2011; Accepted 28 July 2011

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syndrome and acquired C1 inhibitor deficiency. Dermatology 2008;217:114-120.


LETTERS

Multiple subcortical strokes caused by mucormycosis in a patient with lymphoma Múltiplos infartos subcorticais causados por mucormicose em paciente com linfoma Pedro Enrique Jiménez Caballero, Alfonso Miguel Falcón García, Juan Carlos Portilla Cuenca, Ignacio Casado Naranjo

Mucormycosis is caused by a saprophytic fungal infection by non-septate hyphae of the genus Mucor. Five classic forms are recognized: rhinocerebral, pulmonary, gastrointestinal, cutaneous, and disseminated. Rhinocerebral mucormycosis (RCM) frequently occurs in immunosuppressed patients, such as those with uncontrolled diabetes mellitus or haematological malignancy1.

CASE REPORT A 56-year-old man was diagnosed with follicular nonHodgkin’s lymphoma. Four months prior to admission, he presented a right headache attributed to rhinosinusitis. Biopsy showed mucormycosis. There was no affectation intracranial in the brain magnetic resonance imaging (MRI), but the patient became blind due to involvement of both central retinal arteries. He underwent debridement of the paranasal sinuses and treatment with liposomal amphotericin B for two months and posaconazole continuously. He was admitted by recurrent episodes of nonfluent aphasia, right sensory disturbance, and motor weakness. In the last episode, the symptoms persisted and the patient had transcortical motor aphasia, right hemiparesis with dominance of the lower limb (manual muscle testing: upper limb 2/5, lower limb 1/5) and right unilateral sensory impairment, which was restricted at his perioral area and homolateral distal hand and foot. Hemogram showed lymphopenia (0,3x109/L) and thrombocytopenia (23x109/L). Blood clotting was normal. Plasma and urine ketone bodies were absent and other laboratory studies were normal. Echocardiogram, cardiac monitoring and Duplex of the supra-aortic trunk were normal. Transcranial duplex showed 70% stenosis at the M1 segment of left middle cerebral artery (MCA) with no other significant changes. MRI brain on T1 sequences with contrast (Fig A) showed an uptake at both cavernous sinus and internal carotid wall, which

determines a 70% arterial lumen stenosis in the left side. On T2 sequences (Fig B), multiple subcortical ischemic lesions in the left MCA territory could be seen. The patient was diagnosed from multiple subcortical strokes in the territory of left MCA secondary to infiltration of its wall caused by mucormycosis. He was again treated with liposomal amphotericin B for two months, with clinical and radiological improvement. In the six-month follow-up, no new cerebrovascular disorders have appeared.

DISCUSSION Mucor is attracted to blood vessels and invasion of their wall (particularly arterial) is the pathological trademark of the infection. The integrity of host defense mechanisms plays a key role. The presence of certain underlying diseases as lymphoma provides a favourable microenvironment for fungal growth. The disease usually spreads to the cavernous sinus, internal carotid artery and subsequently to the brain2. Vascular manifestations of mucormycosis

A

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B

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Fig. Brain magnetic resonance image. (A) Axial T1-weighted image with contrast – uptake at both cavernous sinus and internal carotid wall (arrow) that determine an arterial lumen stenosis in the left side. (B) Axial T2-weighted image shows multiple subcortical ischemic lesions in the left middle cerebral artery territory.

Department of Neurology, San Pedro de Alcántara Hospital, Spain. Correspondence: Pedro Enrique Jiménez Caballero; Calle Dionisio Acedo, 9 – Portal 7, 4-1ª, 10001 Cáceres - Spain; E-mail: pjimenez1010j@yahoo.es Conflict of interest: There is no conflict of interest to declare. Received 19 June 2011; Received in final form 22 July 2011; Accepted 29 July 2011

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include pseudoaneurysms, partial thrombosis, narrowing and arteritic irregularities of intracranial arteries. Their pathologic basis is believed to be a combination of direct endothelial injury and growth of hyphae into the lumen, with resultant distal infarcts and mycotic emboli. Vasculitis usually occurs in the supraclinoid portion of the internal carotid artery. Mycotic pseudoaneurysms, arterial dissection, or venous congestion could lead to intracranial

hemorrhages3. Rapid thickening and enhancement of the carotid artery wall on serial MRI establishes the nature of the arterial involvement by mucormycosis rather than atherosclerosis4. The prognosis is always very poor once the carotid artery is involved. A few successful cases have been reported following extensive sinus debridement and intravenous amphotericin B therapy5.

References 1.

Mathur SC, Friedman HD, Kende AI, Davis RL, Graziano SL. Cryptic mucor infection leading to massive cerebral infarction at initiation of antileukemic chemotherapy. Ann Hematol 1999;78:241-245.

2.

Simmons JH, Zeitter PS, Fenton LZ, Abzug MJ, Fiallo-Scharer RV, Klingensmith GJ. Rhinocerebral mucormycosis complicated by internal carotid artery thrombosis in a pediatric patient with type 1 diabetes mellitus: a case report and review of the literature. Pediatr Diabetes 2005;6:234-238.

3.

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Takahashi S, Horiguchi T, Mikami S, Kitamura Y, Kawase T. Subcortical intracerebral hemorrhage caused by mucormycosis in a patient with

Arq Neuropsiquiatr 2012;70(1):69-70

a history of bone-marrow transplantion. J Stroke Cerebrovasc Dis 2009;18:405-406. 4.

Calli C, Savas R, Parildar M, Pekindil G, Alper H, Yunten N. Isolated pontine infarction due to rhinocerebral mucormycosis. Neuroradiology 1999;41:179-181.

5.

Galetta SL, Wule AE, Goldberg HI, Nichols CW, Glaser JS. Rhinocerebral mucormycosis: management and survival after carotid occlusion. Ann Neurol 1990;28:103-107.


LETTERS

Cervical myelopathy caused by ligamentum flavum ossification Mielopatia cervical por ossificação do ligamento amarelo Wellingson Silva Paiva1, Matheus Schimidt Soares1, Luca Silveira Bernardo1, Roger Schimidt Brock1, Manoel Jacobsen Teixeira2

Ossification of the ligamentum flavum (OLF) is a rare manifestation and when causing myelopathy it affects essentially the thoracic spine1. Only a few cases of symptomatic cervical disease have been reported, with all patients being Japanese2. The first OLF case reported in a Caucasian was performed by Parekh et al., in 19933. Since then, 19 cases have been reported in Caucasian patients and all of them in the thoracic spine2. The authors report the first case with cervical myelopathy caused by OFL in a Caucasian patient surgically treated with a good outcome.

DISCUSSION Since Polgar first reported a case of OLF in 1920 using plain lateral radiographs, most reports of thoracic myelopathy originated from Japan4,5. Cervical spine ossification is rarer, and there have been no cases reported in Caucasians. The histopathological aspects of OLF are similar to ossification posterior to

CASE REPORT A 66-year-old Caucasian woman presented two months of gait disturbance, weakness of the inferior limbs and several episodes of falling down. She noticed progressive sensory loss, which ascended to the mid-thoracic level. Neurological examination of the upper and lower limbs revealed normal tone, bilateral clonus, power in the limbs was 3/5 throughout and equal in all limbs, and hypereflexia in inferior limbs. She had absent sensation below T4 and bilateral ulnar three fingers and ulnar halves. There was no related trauma in her history. A magnetic resonance image (MRI) demonstrated low signal in the region of the ligamentum flavum in T2 images from C2 to C5 (Figure). There was spinal cord compression at C3 to C6 levels, with the most severe being between C3 to C4. A computed tomography (CT) scan confirmed the OLF at levels C2 to C5 (Figure). Decompressive laminectomy with removal of the ligamentum flavum from C3 to C6 was performed. In the twomonth follow-up, post-surgery examination revealed normal tone, absent clonus, return of 4/5 power throughout both her four limbs and normal reflexes.

Figure. Magnetic resonance image with spinal cord hypersignal and compression. Hyposignal in ligamentum flavum indicates ossification. A – sagital slice; B – axial slice; C – sagittal; D – axial cervical spine computed tomography demonstrated hyperdense in ligamentum flavum with narrowing cervical spinal canal.

Division of Neurosurgery, Hospital das Clínicas, Medical School, University of São Paulo (USP), São Paulo SP, Brazil. 1

MD; Staff – Division of Neurosurgery, USP, São Paulo SP, Brazil;

2

MD, PhD; Full Professor of Neurosurgery, USP, São Paulo SP, Brazil.

Correspondence: Wellingson Paiva; Rua Eneas Aguiar 255; 05403-010 São Paulo SP - Brasil; E-mail: wellingsonpaiva@yahoo.com.br Conflict of interest: There is no conflict of interest to declare. Received 12 July 2011; Accepted 04 August 2011

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longitudinal ligament (OPLL)2. OPLL also begins with a degeneration of ligamentous fibers and is followed by endochondral ossification. This process suggests a common etiological factor; these two affections are considered to be a form of ectopic ossification. Ectopic ossifications like OLF can be caused by an increase in the concentration of fibronectin or in the concentration of bone morphogenetic protein4. Both OPLL and OLF are commonly reported in Japanese populations, raising the possibility of a genetic link between the two4. The study reported by Ono et al.5 has preliminarily indicated that abnormalities in

the type XI collagen gene may be involved in spine ossification. Based on the similarities at the molecular level in the calcification process, it may be reasonable to hypothesize that a similar abnormality in a collagen gene may be the cause for OLF. The prognosis after surgery can be good, especially if intramedullary hyperintensities are absent in preoperative MRI2. The partial improvement of the symptoms is probably due to the irreversible spinal damage caused by a long-term cord compression. The OLF presents complex physiopathology and it is rare in non-Asians.

References

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1.

Gondim J, Ramos Jr F. Thoracic spinal cord compression at two levels due to ligamentum flavum calcification: case report. Arq Neuropsiquiatr 1998;56:312-316.

4.

Miyamoto S, Takaoka K, Yonenobu K, Ono K. Ossification of the ligamentum flavum induced by bone morphogenetic protein. An experimental study in mice. J Bone Joint Surg Br 1992;74:279-283.

2.

Ono K, Yonenobu K, Miyamoto S, Okada K. Pathology of ossification of the posterior longitudinal ligament and ligamentum flavum. Clin Orthop Relat Res 1999;359:18-26.

5.

Ono K, Yonenobu K, Miyamoto S, Okada K. Pathology of ossification of the posterior longitudinal ligament and ligamentum flavum. Clin Orthop Relat Res 1999;359:18-26.

3.

Parekh HC, Gurusinghe NT, Perera SS, Prabhu SS. Ossification of the ligamentum flavum in a Caucasian: case report. Br J Neurosurg 1993;7:687-690.

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LETTERS

Facial somatosensorial evaluation in idiopathic trigeminal neuralgia Avaliação somatosensitiva facial em neuralgia idiopática do trigêmeo Luciana Alvarenga da Silva1, Silvia Regina Dowgan Tesseroli de Siqueira2, José Tadeu Tesseroli de Siqueira3, Manoel Jacobsen Teixeira4

Idiopathic trigeminal neuralgia (ITN) is identified by paroxysmal unilateral shock-like pain, distributed in one or more trigeminal branches, with clear diagnostic criteria based on history and clinical exams. Etiology and physiopathology remain obscure. Recently, abnormal expression of voltage-gated sodium channels had been described in these patients, suggesting that ITN could be a channelopathy1. Current diagnostic criteria do not include sensorial deficit; however, recent studies have shown that discrete abnormalities may be present in trigeminal territories2, which could be associated with the chronic evolution of such pain. There are no studies investigating patients nearly onset. A 64-year old, male, was diagnosed with ITN according to the criteria of the International Association for the Study of Pain (IASP)3. He was evaluated with a systematized protocol of facial sensitivity, which included the clinical exam and quantitative sensory testing: gustative thresholds, olfactory thresholds, quantitative salivary and somatosensorial evaluation; all trigeminal branches (front, cheek, and chin) were also evaluated bilaterally: thermal detection, mechanical detection, vibration detection, electric detection, and pain detection threshold. The patient did not have abnormalities in imaging exams (computed tomography or magnetic resonance) or any neurological deficits in the evaluation by the neurologist. Pain had started in the last two weeks. Until the moment of evaluation, the patient had not been prescribed for ITN and was not using any medication. There was a high sweet threshold and absence of identification of the salty taste. Mean salivary flow was 0.2363 g/min. There were differences between the facial sides in somatosensory thresholds: warm, mechanical, vibration, electric and pain (Figure).

These thresholds were higher at the pain side (right), when compared to the left one at the three trigeminal branches, except for the cold threshold, which was lower at the pain than the opposite side. After the evaluation, carbamazepine was prescribed (400 mg/day) and after one week there was complete relieve of symptoms. These data suggest evidence for future studies, which support neuropathic mechanisms in ITN1, and the need to investigate patients in the early onset in order to verify the prevalence of these findings. Besides, there was a reduced gustative detection for some tastes, especially salty, which had already been described for ITN4 and supports central sensitization involved in the physiopathology of this disease since the beginning of onset. There is also in the literature the description of gustative stimuli as triggering factors for ITN in some patients5and the role of that must be understood. 9 8 7 6 5 4 3 2 1 0

Right Left

V1

V2 Trigeminal Branch

V3

Pain threshold *V1: ophthalmic branch; V2: maxillary branch; V3: mandibular branch

Figure. Pain thresholds at the three trigeminal branches: comparison between facial sides.

Neurology Department, Medical School, University of São Paulo (USP), São Paulo SP, Brazil; 1

Gerontologist, Postgraduation student, Neurology Department, Medical School, USP, São Paulo SP, Brazil;

2

PhD, DDS, Assistant Professor of Gerontology, School of Arts, Science and Humanities, USP, São Paulo SP, Brazil;

3

PhD, DDS, Head of the Orofacial Pain Team, Dentistry Division, Hospital das Clínicas, Medical School, USP, São Paulo SP, Brazil;

4

PhD, MD, Full Professor of Neurosurgery, Neurology Division, Medical School, USP, São Paulo SP, Brazil.

Correspondence: Luciana Alvarenga da Silva; Alameda Leningrado, 204; 06437-000Barueri SP – Brasil; E-mail: lucianaa@usp.br Support: This research was supported by the Orofacial Pain Team of the Hospital das Clínicas, Medical School, University of São Paulo, Brazil. Conflict of interest: There is no conflict of interest to declare. Received 21 June 2011; Received in final form 02 August 2011; Accepted 09 August 2011

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In conclusion, this study presented a case of ITN with early onset. Sensory abnormalities were observed at the affected side when compared to the opposite facial one in all

trigeminal branches; this should be investigated in larger samples in order to better understand the physiopathology of this disease, which remains obscure.

References 1.

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Siqueira SR, Alves B, Malpartida HM, Teixeira MJ,  Siqueira JT. Abnormal expression of voltage-gated sodium channels Nav1.7, Nav1.3 and Nav1.8 in trigeminal neuralgia. Neurosciences 2009;164:573-577

2.

Synai VJ, Bonamico LH, Dubrovsky A. Subclinical abnormalities in trigeminal neuralgia. Cephalalgia 2003;23:541-544

3.

Merskey H, Bogduk N. Classification of chronic pain: descriptions

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of chronic pain syndromes and definitions of painterms. Seattle IASP Press; 1994. 4.

Siviero M,  Teixeira MJ,  de Siqueira JT, Siqueira SR. Somesthetic, gustatory, olfactory function and salivary flow in patients with neuropathic trigeminal pain. Oral Dis 2010;16:482-487.

5.

Sharav Y, Benoliel R, Schnarch A, Greenberg L. Idiopathic trigeminal pain associated with gustatory stimuli. Pain 1991;44:171-174.


LETTERS

Meningioma after immunomodulation for multiple sclerosis Meningioma após imunomodulação em esclerose múltipla Rodrigo Gonçalves Kleinpaul Vieira, Thiago Cardoso Vale, Cristiane Franklin Rocha, Carolina Reis Araújo, Marco Aurélio Lana-Peixoto on behalf of the Brazilian Committee for Treatment and Research in Multiple Sclerosis (BCTRIMS)

The coexistence of multiple sclerosis (MS) and central nervous system (CNS) tumors has been reported in more than 30 cases in literature. Meningiomas have been rarely seen in MS patients and their occurrence has been observed during the course of immunomodulatory drugs such as interferon beta1a and beta-1b1-3. We report a case of a frontal meningioma in a patient with relapsing-remitting multiple sclerosis (RRMS) treated with interferon beta-1a for seven years followed by glatiramer acetate for three years.

CASE REPORT A 39-year-old Brazilian black woman had a one-month history of diplopia followed by paresthesia and weakness in the left upper limb eight months later. The patient fully recovered from both episodes, but had additional bouts of vertigo and weakness of the right hand, paraparesis with sphincter impairment and left facial paralysis in monthly intervals. Brain MRI revealed T2-weighted hyperintense lesions in periventricular, deep white matter and subcortical regions. There was no evidence of an intracranial tumor. Spinal cord MRI showed two T2-weighted hyperintense lesions in the lateral portion of C2-C3 and C7 vertebral levels with no gadolinium enhancement. Cerebrospinal fluid examination revealed 9 white blood cells/dL, 24 mg/dL of proteins and an immunoglobulin G index of 0.92. She was diagnosed as having RRMS and interferon beta-1a (22 mg three times a week) was started. After seven years, the patient’s immunomodulatory therapy was changed to glatiramer acetate due to increasing levels of serum liver enzymes. Three years later, a follow-up brain MRI showed a gadolinium-enhanced round lesion in the basal part of the left frontal lobe, with typical appearance of meningioma, in addition to characteristic demyelinating lesions as seen

in MS  (Figure). The patient’s expanded disability status scale score was 1.0 and her Goldmann perimetry was unrevealing.

DISCUSSION There is some controversy in the literature about the incidence of brain tumors in MS patients1-3. Our patient used interferon beta-1a for seven years, when the immunomodulatory treatment was switched to glatiramer acetate. Glatiramer acetate has been found in association with breast cancer and cutaneous lymphoma, but not with a CNS neoplasm4,5. To the best of our knowledge, this is the first report that suggests the association of glatiramer acetate with a CNS tumor. The intracranial meningioma was asymptomatic and casually found in a routine follow-up brain MRI performed three years following the drug switch. Whether any of the immunomodulatory drugs had a role on the meningioma development or the CNS tumor occurred in this MS patient as a sheer coincidence phenomenon, remains to be clarified.

A

B

Figure. (A) Sagittal gadolinium-enhanced T1-weighted brain magnetic resonance imaging showing a homogenous enhanced round lesion in the base of the anterior skull. (B) Sagittal T1-weighted brain magnetic resonance imaging showing hyperintense lesions with typical multiple sclerosis appearance.

CIEM Multiple Sclerosis Research Center, Federal University of Minas Gerais, Belo Horizonte MG, Brazil. Correspondence: Marco Aurélio Lana-Peixoto; Rua Padre Rolim 769/conj. 1301; 30130-090 Belo Horizonte MG - Brasil; E-mail: marco.lanapeixoto@gmail.com Conflict of interest: There is no conflict of interest to declare. Received 11 September 2011; Received in final form 12 September 2011; Accepted 22 September 2011

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References 1.

Handel AE, Ramagopalan SV. Multiple sclerosis and risk of cancer: a meta-analysis. J Neurol Neurosurg Psychiatry 2010;81: 1413-1414.

2.

Drevelegas A, Xinou E, Karacostas D, Parissis D, Karkavelas G, Milonas I. Meningioma growth and interferon beta-1b treated multiple sclerosis: coincidence or relationship? Neuroradiology 2005;47:516-519.

3.

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Gama HPP, Rocha AJ, Silva CJ, et al. Meningioma growth during

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interferon beta-1a treatment for multiple sclerosis. Arq Neuropsiquiatr 2008;66:402-404. 4.

Amaria RN, Corboy JR, Finlayson CA, Robinson WA, Borges VF. Immunomodulatory therapy in multiple sclerosis and breast cancer risk: a case report and literature review. Clin Breast Cancer 2008;8:449-452.

5.

Madray MM, Greene JF Jr, Butler DF. Glatiramer acetate-associated, CD30+, primary, cutaneous, anaplastic large-cell lymphoma. Arch Neurol 2008;65:1378-1379.


Images in neurology

Magnetic resonance appearance of recurrent ophthalmoplegic migraine Aspectos de ressonância magnética na enxaqueca oftalmoplégica recorrente Antônio José da Rocha1, Paulo Breinis2, Mario Luiz R Monteiro3

A

B

C

D

E

F

Figure. T1-weighted post-gadolinium axial and coronal images obtained during the initial episode (A-B) displayed typical focal thickening and enhancement of the proximal cisternal segment of the third right cranial nerve (arrows). (C-D) Comparative images taken 3 years later showed persistent focal thickening without evident enhancement (arrows). (E-F) Images obtained during the recurrence also showed thickening and enhancement (arrows).

A 5-year-old boy presented with severe frontal headache followed by right cranial nerve paresis. His previous medical history, blood tests and CSF analysis were unremarkable, and he made a full recovery after 4 weeks. Nevertheless, a similar episode occurred 5 years later. Magnetic resonance imaging follow-up supported diagnosis of recurrent ophthalmoplegic migraine (Figure).

This rare form of migraine, which mainly affects children1, may present as a triad of symptoms consisting of migraine ophthalmoplegia (nerve palsy) and focal enhancement of an enlarged third cranial nerve at the root exit zone. However, other diagnoses must be ruled out. The controversial pathogenesis of the condition may stem from the reversible breakdown of the blood-brain barrier due to vasospasm during the migraine attack or recurrent demyelinating neuropathy1,2.

References 1.

Miglio L, Feraco P, Tani G, Ambrosetto P. Computed tomography and magnetic resonance imaging findings in ophthalmoplegic migraine. Pediatr Neurol 2010;42:434-436.

2.

Bharucha DX, Campbell TB, Valencia I, Hardison HH, Kothare SV. MRI findings in pediatric ophthalmoplegic migraine: a case report and literature review. Pediatr Neurol 2007;37:59-63.

1

Section of Neuroradiology, Fleury Medicina e Saúde, São Paulo SP, Brazil;

2

Pediatric Neurologist, Faculdade de Medicina do ABC, Santo André SP, Brazil;

3

Division of Ophtalmology and Laboratory of Ophtalmological Investigations (LIM-33), University of São Paulo Medical School, São Paulo SP, Brazil.

Correspondence: Antônio José da Rocha; Rua Cincinato Braga 232; 01333-910 São Paulo SP - Brasil; E-mail: antonio.rocha@fleury.com.br Conflict of interest: There is no conflict to interest to declare. Received 19 August 2011; Received in final form 15 September 2011; Accepted 22 September 2011

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Images in neurology

“Black turbinate sign”: a potential predictor of mucormycosis in cavernous sinus thrombophlebitis “Sinal da concha preta”: um potencial preditor de mucormicose nas tromboflebites do seio cavernoso Douglas Mendes Nunes1, Antônio José da Rocha2, Marcos Rosa Júnior1, Carlos Jorge da Silva2

A

B

C

D

E

F

Figure. Mucormycosis exhibiting “black turbinate sign” that is characterized by low signal intensity (large arrow) of the right inferior nasal turbinate on the coronal T2 image (A) and the absence of enhancement (large arrows) after intravenous gadolinium administration on coronal (B) and axial (C) T1 images; note the typical ipsilateral CST (small arrows). The lack of these features can be observed in the comparative images of bacterial rhinosinusitis associated with bilateral CST (arrows in D-F). Both patients had additional orbital compromise.

Rhinosinusitis has the potential to result in catastrophic intracranial extension in the presence of predisposing conditions, such as diabetes, immunosuppression (fungus) or the incomplete treatment of bacterial infection. It is assumed that cavernous sinus thrombophlebitis (CST) is secondary to retrograde extension due to a valveless system of the vein that communicates paranasal cavities to the cavernous sinus1. The “black turbinate sign” results from dry gangrene in affected

tissues, which presents in early stages paranasal mucormycosis. Conversely, bacterial sinusitis does not promote local necrosis and, therefore, it affects neither mucosal enhancement nor its T2 signal intensity2. A poor prognosis of CST highlights the relevance of correct diagnosis for early treatment. The “black turbinate sign” could represent a potential discriminating feature to distinguish mucormycosis in CST etiology (Figure).

References 1.

Hoxworth JM, Glastonbury CM. Orbital and intracranial complications of acute sinusitis. Neuroimaging Clin North America 2010;20:511-526.

2.

Safder S, Carpenter JS, Roberts TD, Bailey N. The “black turbinate” sign: an early MR imaging finding of nasal mucormycosis. AJNR. Amer J Neuroradiol 2010;31:771-774.

1

Fellow in Neuroradiology, Santa Casa de Misericórdia de São Paulo, São Paulo SP, Brazil;

2

Section of Neuroradiology, Santa Casa de Misericórdia de São Paulo, São Paulo SP, Brazil.

Correspondence: Antônio José da Rocha; Rua Cincinato Braga 232; 01333-910 São Paulo SP - Brasil Conflict of interest: There is no conflict to interest to declare. Received 24 August 2011; Received in final form 15 September 2011; Accepted 23 September 2011

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Theses

Peripheral biomarkers in bipolar disorder: a population-based study in young adults (Abstract) Biomarcadores periféricos no transtorno bipolar: um estudo de base populacional em adultos jovens (Resumo) Pedro Vieira da Silva Programa de Pós-graduação em Ciências Médicas: Psiquiatria na Universidade Federal do Rio Grande do Sul, 2011. Orientador: Flávio Kapczinski. Correspondence: Pedro Vieira da Silva; Laboratório de Psiquiatria Molecular; Hospital de Clínicas de Porto Alegre; Rua Ramiro Barcelos 2350; 90035-903 Porto Alegre RS - Brasil; E-mail: pedromaga@yahoo.com

ABSTRACT Objective: The aim of this study was to confirm, in a sample of young adults from the general population, recent findings regarding the pathophysiology of bipolar disorder. The focus of this investigation was finding group differences in one neurotrophin, two markers of oxidative damage, two proinflammatory cytokines and one anti-inflammatory cytokine in participants with bipolar disorder, major depression and people without any mood episodes. Markers assessed here were brain-derived neurotrophic factor (BDNF), thiobarbituric acid reactive substances (TBARS), protein carbonyl content (PCC), tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-10 (IL-10). Method: Individuals from the general population, previously included in a cross-sectional study (n=1560), with a positive screen for bipolar disorder were recruited, as well as two groups of controls. One had only depressive episodes and the other had no history of mood episodes. This yielded a sample of 231 participants that further underwent diagnostic confirmation with the Structured Clinical Interview for DSM-IV (SCID). All analyses included a check for bivariate associations, as well as an a priori multivariate model with sex, social class, current mood state, use of substances and SCID diagnoses as predictors. Results: The final sample included 55 participants with bipolar disorder, 82 with major depression and 94 healthy controls. Only a minority was using any psychiatric medications (9.6%). Bipolar disorder was associated with higher PCC and TNF-α levels when compared to the control group. Major depression was also associated with higher PCC levels when compared to the control condition. Use of psychiatric medication was associated with lower TNF-α levels. Correlations between the same markers were not as strong as in clinical samples. Conclusions: Two broad conclusions are called for from these results. The first is that early-stage bipolar disorder is already associated with a pro-oxidant, proinflammatory state. The second is that these changes appear more subtle than those observed in typical late-stage, chronic patients, supporting the notion that a form of illness progression takes place. The main caveat is that these data are cross-sectional, not longitudinal, which precludes causal inferences as factors other than the bipolar illness can conceivably induce systemic toxicity.

Key words: bipolar disorder, mood disorders, pathophysiology, neurotrophins, inflammation markers, oxidative stress, general population, case-control.

Severity and functional ability scale for amyotrophic lateral sclerosis patients (Abstract) Escala de gravidade e habilidade funcional em pacientes com esclerose lateral amiotrófica. (Resumo) Marco Antonio Orsini Departamento de Neurologia, Universidade Federal Fluminense (UFF), Rio de Janeiro RJ, Brazil, 2011 Orientador: Prof. Dr. Marcos Raimundo Gomes de Freitas. Co-orientador: Prof. Osvaldo JM Nascimento. Correspondence: Marco Antonio Orsini; Herotides de Oliveira 2/801; 24230-230 Niterói RJ - Brasil; E-mail: orsinimarco@hotmail.com

ABSTRACT Introduction: Amyotrophic lateral sclerosis (ALS) is a progressive, degenerative disease that leads to the motor neurons depletion in the spinal cord anterior horn and pyramidal tract. Several evaluations have been proposed in order to provide a better follow-up and management of secondary complications. However, the biggest difficulty is to select a single instrument to objectively assess the neurological deficit, the

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functional independence level and, above all, one which will include such subjects in specific severity stages. Objective: To present a new tool for clinical and functional evaluation for ALS patients, the Severity and functional ability scale (SFAS), and discuss the clinical and functional profile of 98 patients between March 2007 and December 2009 at Antonio Pedro University Hospital (UFF) and the Deolindo Couto Institute of Neurology (UFRJ). Method: We used the SFAS as clinical and functional indicator. The modified El Escorial criteria were used to establish the diagnosis. The participants underwent a number of five quarterly assessments during the study period of one year. Results and discussion: The average age of the study group was 52.67  years±12.043 years. The average time between the onset of first symptoms and seeking care services was 11.57±12.391 months. The average time between first symptoms and the diagnosis was 20.54±8.413 months. Of the 98 subjects tested, only 24 have completed all phases of the study. Muscle weakness was identified as the initial symptom in most cases. The patients showed progressive impairment of muscle strength, speech, swallowing, breathing and the severity stages. The disease was marked by different forms of initial presentation (speech, limbs, breathing, swallowing), progression speed and diverse clinical characteristics in our population. Conclusion: Knowledge of the clinical and functional ALS peculiarities, obtained by applying the SFAS, serves as a guide for proper monitoring of patients during the development stages and encourages the formulation of a theoreticalconceptual framework, aiming at solving problems in clinical practice.

Key words: amyotrophic lateral sclerosis, motor neuron, epidemiology.

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Opinion

Spontaneous spinal epidural hematoma during pregnancy Hematoma extradural espinhal espontâneo durante a gravidez Shigeki Matsubara

Dear Editor, Braga et al.1 described the conservative treatment of spontaneous spinal extradural hematoma (SSEH). I would like neurologists to pay more attention to SSEH and pregnancy. I have three clarifications. First, pregnancy is a risk factor for SSEH. Recently, we reported a woman with twin pregnancy suffering SSEH at the 16th week of gestation2. To our knowledge, 14 cases of SSEH during pregnancy have been reported2,3: decompression surgeries were performed in all cases. Both veins and arteries can be candidates of origin for SSEH. In the former case, pregnancy increases abdominal pressure, which may lead to a rise in the epidural venous pressure, possibly leading to the rupture of a venous wall. In the latter case, how pregnancy affects it is unclear. Second, short lag time between symptom onset and surgery may not always guarantee recovery, which is important not only medically but also judicially. Surgical decompression within 12 hours of the symptoms’ onset has been generally recommended1. Focusing on the topic to SSEH during pregnancy, of 14, 3 had complete neurological recovery while the remaining 11 did not. Lag time was a median of 24 (range: 8 to 31) and 15 (7 to 36) hours, respectively, showing no difference. In the present case, it was nine hours; however, the patient still could not walk. Braga et al.1 stated: “controversy exists regarding the appropriate time for surgery.” Expectant

management also led to good recovery in cases with mild neurological deficits1. Prognosis may also be influenced by rehabilitation. Third, a rehabilitation program should be established for pregnant women. Rehabilitation after surgery or expectant management may be important for good neurological recovery; however, pregnant patients provide specific concerns. If SSEH occurs in early pregnancy week, “evacuation and continue pregnancy” strategy may be employed, which may require a view toward subsequent rehabilitation. Of 14 SSEH during pregnancy, cesarean section was performed at the time of evacuation in 9, while pregnancy was continued after evacuation in 5 cases, depending on the gestational weeks: SSEH occurred at a median of 37 (range 32 to 41) and 24 (16 to 34) weeks, respectively. Of the latter, four gave term birth, while our patient yielded preterm delivery for whom rehabilitation was started soon after surgery. Although we were cautious about preterm labor and thus closely monitored uterine contractions, she gave birth to a preterm infant at the 29th week; the rehabilitation may be one possible culprit for uterine contractions. An effective rehabilitation program least inducing uterine contractions may benefit pregnant women not only in this specific condition, but also for those requiring rehabilitation, and not sufficiently given it for fear of uterine contractions. Cooperative effort of clinical neurologists and obstetricians may be needed to establish a rehabilitation program for pregnant women.

References 1.

Braga MH, Brandão RA, Carvalho GT, Santos CD, Abreu MS. Conservative treatment of large spontaneous spinal extradural hematoma. Arq Neuropsiquiatr 2010;68:132-134.

2.

Matsubara S, Inoue H, Takamura K, et al. Spontaneous spinal epidural hematoma at the 16 th week of a twin pregnancy. J Obstet Gynaecol Res 2011. doi: 10.1111/j.1447-0756.2010.01522.x. [Epub ahead of print].

3.

Sarubbo S, Garofano F, Maida G, Fainardi E, Granieri E, Cavallo MA. Spontaneous and idiopathic chronic spinal epidural hematoma: two case reports and review of the literature. Eur Spine J 2009;18:10551061.

MD, PhD, Professor, Department of Obstetrics and Gynecology and Perinatal Education Center, Jichi Medical University, Japan. Correspondence: Shigeki Matsubara; Department of Obstetrics and Gynecology and Perinatal Education Center, Jichi Medical University; 3311-1 Shimotsuke, Tochigi, 329-0498 Japan; E-mail: matsushi@jichi.ac.jp Conflict of interest: There is no conflict of interest to declare.

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corrections In the paper: Sato Douglas, Fujihara Kazuo. Atypical presentations of neuromyelitis optica. Arq Neuro-Psiquiatr 2011; 69(5): 824-828, Table 1, the line: “Transient asymptomatic elevation of CK levels; observed few weeks prior to a NMO attack” must be placed in the thirth column, instead of the second column: Table – Summary of clinical and laboratory findings in NMO patients Typical features

Not typical, but commonly reported

Uncommon, observed in few patients

Unilateral or bilateral ON with severe visual impairment

Brain lesions in the hypothalamus, corpus callosum, periventricular area and brainstem. Lesions usually have distinct features of MS lesions

Hypersomnia, associated with bilateral hypothalamic lesions and low CSF hypocretin-1 levels

TM with longitudinally extensive (3 ≥ VS) Intractable hiccups, nausea and Transient asymptomatic elevation of and centrally located lesion vomiting, often lasting for over 48 hours CK levels; observed few weeks prior to a NMO attack AQP-4 antibody positivity in the serum

Painful tonic spasm in the TM recovery period

ON = optic neuritis; TM = transverse myelitis; VS = vertebral segments; AQP-4 = aquaporin-4; CSF = cerebrospinal fluid; CK = creatine phosphokinase.

Notices and comments IV Congresso de Psiquiatria e Medicina Geral e Familiar/IX Encontro de Psicogeriatria 19 a 20 de Janeiro de 2012, em Lisboa, Portugal (Sana Lisboa Park Hotel) Fone: 351 21 842 9710 Email: ana.pais@admedic.pt VII Congresso Nacional da Sociedade Portuguesa de Neuropediatria 20 a 21 de Janeiro de 2012, na Cidade de Porto - Portugal Site: www.neuropediatria.pt Fone: 91 415 6476 Email: secretariado.spnp@gmail.com XIII Pan American Congress of Neurology 5 a 8 Março 2012 La Paz, Bolivia (Radisson Plaza Hotel La Paz) Informações Fone: (+56) 2 946 2633 Fax: (+56) 2 346 8970 Site: www.pcn2012.com E-mail: pcn2012@kenes.com XIII Congresso da SPMFR - Sociedade Portuguesa de Medicina Física e de Reabilitação 8 a 10 de Março 2012 em Cascais, Portugal (Hotel Cascais Miragem) Site: http://www.congressospmfr.org/ Fone: 351 91 5768902 Email: pmfr@spmfr.org 6th World Congress on Controversies in Neurology 8 a 11 de Março 2012 em Viena - Áustria (Hilton Vienna) Site: www.comtecmed.com/cony/2012 Email: info@comtecmed.com Encontro Bienal da Seção Internacional de Epidemiologia e Saúde Pública da Associação Mundial de Psiquiatria 14 a 17 de Março 2012 em São Paulo, SP (Anfiteatro do Instituto de Psiquiatria HC/ FMUSP) Fones: (11) 2046-0314 / 2280-2476 Site: http://wpaepi2012brazil.com E-mail: bleventos@uol.com.br

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XVI Simpósio Internacional de Atualização em Psiquiatria Geriátrica 23 e 24 Março 2012 em São Paulo, SP (Centro de Convenções APAS) Fones: (11) 2046-0314 / 2280-2476 Site: www.blcongressoseventos.com.br E-mail: bleventos@uol.com.br

22nd International Association for Child & Adolescent Psychiatry and Allied Professions 16 a 21 de Junho 2016 no Canadá (Calgary Canadá) Site: http://www.iacapap2016.org/ Fone: 604-984-6455 Email: info@iacapap2016.org

CLAN 2012 - 35º Congresso Latino Americano de Neurocirurgia 31 Março a 5 Abril 2012 no Rio de Janeiro, RJ Site: www.sbn-neurocirurgia.com.br

XXV Congresso Brasileiro de Neurologia 4 a 8 de Agosto de 2012 em Goiânia, GO (Centro de Convenções de Goiânia) Promovida pela ABN, através da Comissão Gestora do Projeto: Dr. Delson José Da Silva (Presidente), Dr. Paulo César Ragazzo (Secretário), Dra. Denise Sisterolli Diniz (Tesoureira). O evento cobrirá todos os aspectos importantes relacionados à neurologia, sobressaindo-se temas como: AVC, Cefaléia, Demências, Distúrbios de Aprendizagem e TDAH, Doença de Parkinson e Outros Distúrbios do Movimento, Doença do Neurônio Motor, Dor Neuropática, Epilepsia, Esclerose Múltipla e Outras Doenças Desmielinizantes, Infecções, Manifestações Neurológicas das Doenças Sistêmicas, Miopatias, Narcolepsia e Outros Distúrbios do Sono, Neuroimagem, Neuroimunologia, Neurologia Infantil, Neuropatia Periférica, Síndrome das Pernas Inquietas, Síndromes Paraneoplásicas e Transtornos Neuropsiquiátricos. Informações Fone: (62) 3241-3939 Site: www.neurogoiania2012.com.br E-mail: eventos.go4@wincentraldeeventos. com.br

Planet Course - Anatomy of the Neurovascular System 1 a 6 Abril 2012 (Session I) / 28 Outubro a 2 Novembro 2012 (Session 2) em São Paulo, SP Site: www.sbn-neurocirurgia.com.br/site/ internacionais.asp 8° Congresso Brasileiro de Cérebro Comportamento e Emoções 2 a 5 de Maio 2012 em São Paulo,SP (Centro de Convenções Frei Caneca) Site: http://www.cbcce.com.br/ Fone: (51) 3028 3878 Fax: (51) 3028 3879 XXIII Congresso Brasileiro de Geriatria e Gerontologia 22 a 25 de Maio 2012 no Rio de Janeiro, RJ (Centro de Convenções Sul América) Site: http://www.cbgg2012.com.br/ Fone: (51) 3028 3878 Fax: (51) 3028 3879 12th International Child Neurology Congress and 11th Asian and Oceanian Child Neurology Congress 27 Maio a 1 Junho 2012 em Brisbane, Australia (Brisbane Convention and Exhibition Centre) Site: www.icnc2012.com

V Simpósio de Estimulação Magnética Transcraniana e III Simpósio da Associação Brasileira de Estimulação Magnética Transcraniana Setembro 2012 em São Paulo, SP (Anfiteatro do Instituto de Psiquiatria HC/FMUSP) Informações Fones: (11) 2046-0314 / 22802476 Site: www.blcongressoseventos.com.br E-mail: bleventos@uol.com.br


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NEUROLOGISTAS NEUROCIRURGIÕES DO DODO ESTADO DE GOIÁS GOIÁS NEUROLOGISTAS NEUROCIRURGIÕES ESTADO DE NEUROLOGISTAS E EENEUROCIRURGIÕES ESTADO DE GOIÁS DR. SEBASTIÃO SEBASTIÃO EURICO EURICO DE DE MELO-SOUZA MELO-SOUZA DR. NEUROLOGIA NEUROLOGIA Instituto de de Neurologia Neurologia de de Goiânia Goiânia Instituto Praça T-18 T-18 -- 140 140 Setor Setor Bueno Bueno -- 74210-250 74210-250 -- Goiânia Goiânia -- GO GO -- Fone/Fax Fone/Fax (62) (62) 3285-2546 3285-2546 Praça E-mail: sebastiaoeurico@terra.com.br E-mail: sebastiaoeurico@terra.com.br

DR. DR. DELSON DELSON JOSE JOSE DA DA SILVA SILVA NEUROLOGIA NEUROLOGIA // TRANSTORNO TRANSTORNO DO DO MOVIMENTO MOVIMENTO Instituto Integrado de Neurociências Instituto Integrado de Neurociências -- IINEURO IINEURO Av. Av. T-15 T-15 -- 106 106 Setor Setor Bueno Bueno (próx. (próx. ao ao Goiânia Goiânia Shopping) Shopping) -- 74230-010 74230-010 -- Goiânia Goiânia -- GO GO Fone (62) 4011-9191 Fone/Fax (62) 3251-9191 E-mail: delson@iineuro.com.br e delsonjsilva@gmail.com Fone (62) 4011-9191 - Fone/Fax (62) 3251-9191 - E-mail: delson@iineuro.com.br e delsonjsilva@gmail.com

NEUROLOGISTAS NEUROCIRURGIÕES ESTADO DO MARANHÃO NEUROLOGISTAS NEUROCIRURGIÕES DO DODO ESTADO DO DO MARANHÃO NEUROLOGISTAS E EENEUROCIRURGIÕES ESTADO MARANHÃO #,Ù.)#!.%52/,Ê')#!%.%52/#)2·2')#! #,Ù.)#!.%52/,Ê')#!%.%52/#)2·2')#! Dr. Dr. Carlos Carlos Eduardo Eduardo Cavalcanti Cavalcanti (CRM-MA (CRM-MA 1557) 1557)

Rua Rua De De Santa Santa Rita, Rita, 514 514 -- Ed. Ed. Catu Catu -- 2º 2º andar andar -- sala sala 204 204 -- 65015-430 65015-430 -- São São Luiz Luiz -- MA MA Fone (98) 3231-5322 Fax (98) 3232-9822 / Fone res (98) 235-2027 Fax res (98) Fone (98) 3231-5322 - Fax (98) 3232-9822 / Fone res (98) 235-2027 - Fax res (98) 235-4471 235-4471 Internet: Internet: http://users.elo.com.br/~neuro/neuro.htm http://users.elo.com.br/~neuro/neuro.htm E-mail: E-mail: neuro@elo.com.br neuro@elo.com.br

NEUROLOGISTAS NEUROCIRURGIÕES ESTADO DO NEUROLOGISTASE EENEUROCIRURGIÕES NEUROCIRURGIÕES DO DODO ESTADO DO PARANÁ PARANÁ NEUROLOGISTAS ESTADO DO PARANÁ

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NEUROLOGISTAS E NEUROCIRURGIÃ&#x2022;ES DO ESTADO DE PERNAMBUCO

4&37*±0%&%*"(/»45*$0/&630-»(*$0%&1&3/".#6$0 4&37*±0%&%*"(/»45*$0/&630-»(*$0%&1&3/".#6$0 TEOQF!IPUNBJMDPNFMDS!TEOQFDPNCS

TEOQF!IPUNBJMDPNFMDS!TEOQFDPNCS

VIII


NEUROLOGISTAS E NEUROCIRURGIĂ&#x2022;ES DOESTADO ESTADO DE JANEIRO NEUROLOGISTAS E NEUROCIRURGIĂ&#x2022;ES DO DODO RIORIO DE JANEIRO Dr. Sergio Pereira Novis Prof. Titular de Neurologia da Fac. Med. UFRJ

Dr. Ricardo Novis Neurologia Rua Ataufo Paiva, 1079 - Grupo 808 - Leblon - 22440-031 - Rio de Janeiro - RJ Fone (21) 2540-8169 - 2540-8158 - E-mail: spnovis@rio.com.br

DR. OSVALDO J.M. NASCIMENTO Prof. Titular de Neurologia da UFF NEUROPATIAS PERIFĂ&#x2030;RICAS - NEUROLOGIA Rua Siqueira Campos, 53 - gr 1204 - Copacabana - 22031-070 - Rio de Janeiro - RJ Fone/Fax (21) 2235-4855 - 2256-9049 - E-mail: ojmnascimento@uol.com.br

#,Ă&#x2122;.)#!.%52/,Ă&#x160;')#! Dr. JosĂŠ Luiz de SĂĄ Cavalcanti Av. Nossa Senhora de Copacabana, 978 - Sala 1009 - Fone/Fax (21) 2521-9942 22060-000 - Rio de Janeiro - RJ

NEUROPATIAS PERIFĂ&#x2030;RICAS - NEUROLOGIA Dr. Marcos R. G. de Freitas Professor Titular da UFF

Rua Miguel de Frias, 77 - Sala 1002 - 24220-100 - NiterĂłi - RJ Fone (21) 2719-0150 - Fax (21) 622-0533

DR. PAULO NIEMEYER FILHO NEUROCIRURGIA Rua JoĂŁo Borges, 204 - 22451-100 - Rio de Janeiro, RJ Fone/Fax (21) 2512-2319

DR. JAMES PITĂ GORAS DE MATTOS Prof. Adjunto de Neurologia da UFRJ #,Ă&#x2122;.)#!.%52/,Ă&#x160;')#! Rua Santa Clara 50 - sala 702 - Fone (21) 2257-2792 22041-010 Rio de Janeiro - RJ

$2!"%,!2$/!2!¡*/ Prof. Associado de Neurologia da UFRJ. Pesq. Titular e Chefe do Laboratório de Pesquisa em Neuroinfecçþes do IPEC-FIOCRUZ NEUROLOGIA E NEUROINFECTOLOGIA

Av. das AmĂŠricas, 700 - Bloco 3 - sala 202 - 22640-100 - Rio de Janeiro - RJ Fone/Fax: (21) 2493-9912 - E-mail: abelardo.araujo@gmail.com IX

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DR. JOSĂ&#x2030; CARLOS LYNCH CLĂ?NICA DE NEUROCIRURGIA R. Jardim Botânico, 600 - sala 605 - Jardim Botânico Fones (21) 2294-1937 e 2274-2593 - E-mail: cneuroamericas@uol.com.br 22461-000 Rio de Janeiro - RJ

Centro NeurolĂłgico da Tijuca Neurologia - Neurocirurgia - Neurofisiologia - BiĂłpsias de Nervos e MĂşsculos

Dr. JosÊ Lourenço Kallås

Dr. Thorkil Diniz Xavier de Brito

Dr. Haroldo Antonio Silva

Dra. Maria Emilia Andraus

Fones: (21) 2568-5311 / 2284-4232 - Fax (21) 2264-0069 - E-mail: centroneurotiju@uol.com.br Rua Camaragibe, 12 - Tijuca - 20520-130 - Rio de Janeiro - RJ Av. Mal. Câmara, 160 / 725 - Castelo - Rio de Janeiro - RJ

Dr. PĂŠricles MaranhĂŁo-Filho (CRM 52.23210.0) NEUROL OG IA

Dra. Eliana Teixeira MaranhĂŁo (CREFITO 4094-F) REAB IL IT AĂ&#x2021; Ă&#x192; O

V EST IB UL AR

Av. das AmĂŠricas, 1155 / sala 1705 - 22631-000 - Rio de Janeiro - RJ Fones: (21) 2429-7523 / (21) 2111-9200 - Fone/Fax: (21) 2495-1251 E-mail: pmaranhaofilho@gmail.com & limaranhĂŁo@gmail.com

#,Ă&#x2122;.)#!.%52/,Ă&#x160;')#!02/&&%2.!.$/0/-0%5 Setor de Neurofisiologia ClĂ­nica

ELETRONEUROMIOGRAFIA, ELETROMIOGRAFIA DE FIBRA Ă&#x161;NICA, POTENCIAIS EVOCADOS (VISUAL, AUDITIVO E SOMATO-SENSITIVO), ELETRENCEFALOGRAFIA, MAPEAMENTO CEREBRAL, POLISSONOGRAFIA, TOXINA BOTULĂ?NICA COM MONITORIZAĂ&#x2021;Ă&#x192;O ELETROMIOGRĂ FICA Centro MĂŠdico Barrashopping Av. das AmĂŠricas, 4666 - Grupo 306 - Barra da Tijuca - Rio de Janeiro - Fone (21) 2430-9229 - Fax (21) 2430-9230 ColĂŠgio Brasileiro de CirurgiĂľes Rua Visconde Silva, 52 - Sala 406 - Botafogo - Rio de Janeiro - Fone (21) 2539-1598 - Fax (21) 2537-8679

DR. JORGE EL-KADUM NOUJAIM NEUROLOGIA Av. Nossa Senhora de Copacabana, 749 - sala 1103 22050-000 - Rio de Janeiro - RJ Fone (21) 2549-4995 - Fax (21) 434-8233 / 2549-4854

CLĂ?NICA MEYER Dr. Julio Cesar Meyer (NeurocirurgiĂŁo)

Dr. Juliano Almeida Coelho (CirurgiĂŁo de Coluna)

Dr. Eduardo Segurasse Faria (NeurocirurgiĂŁo)

Dr. Marcelo Ferreira Santos (Psiquiatra)

Rua 20, nÂş.16 - Vila Santa CecĂ­lia - Volta Redonda, RJ Fone/Fax (24) 3343-6940 - E-mail:clinicameyer@uol.com.br

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NEUROLOGISTAS E NEUROCIRURGIÕES DOESTADO ESTADO GRANDE DO NORTE NEUROLOGISTAS E NEUROCIRURGIÕES DO DODO RIORIO GRANDE DO NORTE Dr. Mário Emílio T. Dourado Júnior NEUROLOGISTAS ENEUROLOGIA NEUROCIRURGIÕES DO ESTADO DO RIO GRANDE DO NORTE - ELETRONEUROMIOGRAFIA DE FIBRA ÚNICA NEUROMED - Clínica Neurológica Ltda Dr. Mário Emílio Dourado Rua Marcílio Furtado, 2042T.- Lagoa Nova -Júnior Natal - RN NEUROLOGIA - ELETRONEUROMIOGRAFIA Fone/Fax (84) 3206-5181 DE FIBRA ÚNICA NEUROMED - Clínica Neurológica Ltda Rua Marcílio Furtado, 2042 - Lagoa Nova - Natal - RN Fone/Fax (84) 3206-5181

NEUROLOGISTAS E NEUROCIRURGIÕES DO ESTADO DO RIO GRANDE DO SUL

CLÍNICA DE NEUROLOGIA INFANTIL NEUROLOGISTAS E NEUROCIRURGIÕES DOESTADO ESTADO GRANDE DO SUL NEUROLOGISTAS E NEUROCIRURGIÕES DO DODO RIORIO GRANDE DO SUL Dra. Newra Tellechea Rotta (CRM 2970) CLÍNICA DE NEUROLOGIA INFANTIL Rua Mariante, 239/202 - 90430-181 - Porto Alegre - RS Dra. Newra Tellechea Rotta (CRM 2970) Fone (51) 3222-1481 Fax (51) 3334-9836 Rua Mariante, 239/202 - 90430-181 - Porto Alegre - RS Fone (51) 3222-1481 Fax (51) 3334-9836 NEUROLOGIA - ELETRENCEFALOGRAFIA

Dr. Frederico A. D. Kliemann - CREMERS 2204 NEUROLOGIA ELETRENCEFALOGRAFIA Av. Independência, 1211 - conj. 301 --Fones (51) 3311-7183 / 3311-5022 - Porto Alegre - RS Dr. Frederico A. D. Kliemann - CREMERS 2204 Av. Independência, 1211 - conj. 301 --Fones (51) 3311-7183 / 3311-5022 - Porto Alegre - RS NEUROLOGIA ELETRENCEFALOGRAFIA Dr. Ronald Franke 2884 NEUROLOGIA -CREMERS ELETRENCEFALOGRAFIA Av. Nilo Peçanha, 666 - Fone/Fax (51) 3331-3101 - 90470-000 - Porto Alegre - RS Dr. Ronald Franke CREMERS 2884 Av. Nilo Peçanha, 666 - Fone/Fax (51) 3331-3101 - 90470-000 - Porto Alegre - RS NEUROLOGIA CLÍNICA

Dra. Maria Cecilia de Vecino - CRMRS 17.114 Rua Mostardeiro, 333 - sala 811 - 90430-001 - Porto Alegre - RS NEUROLOGIA CLÍNICA Fone/Fax (51) 3222-7202 E-mail: mcvecino@uol.com.br - CRMRS 17.114 Dra. Maria Cecilia- de Vecino Rua Mostardeiro, 333 - sala 811 - 90430-001 - Porto Alegre - RS Fone/Fax (51) 3222-7202 - E-mail: mcvecino@uol.com.br #,Ù.)#!.%52/,Ê')#!

Dr. Sérgio Roberto Haussen

CREMERS 4654 #,Ù.)#!.%52/,Ê')#! Rua Ramiro Barcelos 910/602 - Fones (51) 3311-6273 / 3311-0890 - Porto Alegre - RS shaussen@zaz.com.br Dr. E-mail: Sérgio Roberto Haussen CREMERS 4654 Rua Ramiro Barcelos 910/602 - Fones (51) 3311-6273 / 3311-0890 - Porto Alegre - RS E-mail: shaussen@zaz.com.br

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NEUROLOGISTAS E NEUROCIRURGIÕES DO ESTADO DE SANTA CATARINA NEUROLOGISTAS E NEUROCIRURGIÕES DOESTADO ESTADO SANTA CATARINA NEUROLOGISTAS E NEUROCIRURGIÕES DO DEDE SANTA CATARINA #,Ù.)#!.%52/,Ê')#! Dr. Paulo Cesar Trevisol Bittencourt (CRM-SC 2837) #,Ù.)#!.%52/,Ê')#!

Rua Felipe Schmidt, 73 - sala 706 - Pórtico Centro Comercial - 88010-000 - Florianópolis - SC Dr. Paulo Cesar Trevisol Bittencourt (CRM-SC 2837) Fone (48) 3225-2749 - E-mail: pcb@neurologia.ufsc.br - www.neurologia.ufsc.br Rua Felipe Schmidt, 73 - sala 706 - Pórtico Centro Comercial - 88010-000 - Florianópolis - SC Fone (48) 3225-2749 - E-mail: pcb@neurologia.ufsc.br - www.neurologia.ufsc.br

NEUROLOGIA - NEUROFISIOLOGIA CLÍNICA - EEG 4343) Dr. Nabil Elias Bittar (CRM-SC NEUROLOGIA - NEUROFISIOLOGIA CLÍNICA - EEG Rua Fernando Machado, 359 - 89500-000 - Caçador - SC Dr. Nabil Elias Bittar (CRM-SC 4343) Fone (49) 3563-0472 - E-mail: bittarneurolneurof@msn.com Rua Fernando Machado, 359 - 89500-000 - Caçador - SC Fone (49) 3563-0472 - E-mail: bittarneurolneurof@msn.com

NEUROLOGIA - NEUROFISIOLOGIA CLÍNICA 5603) Dr. Ylmar -Corrêa Neto (CREMESCCLÍNICA NEUROLOGIA NEUROFISIOLOGIA

Rua Menino Deus, 63 - Bloco A - Sala 409 - 88020-210 - Florianópolis - SC Dr. Ylmar Corrêa Neto (CREMESC 5603) Fone (48) 3222-6994 / 3224-1073 - E-mail: dantascorrea@terra.com.br Rua Menino Deus, 63 - Bloco A - Sala 409 - 88020-210 - Florianópolis - SC Fone (48) 3222-6994 / 3224-1073 - E-mail: dantascorrea@terra.com.br

#%.42/$%.%52/$)!'.Ê34)#/ Neurologia - Neurofisiologia Clínica

#%.42/$%.%52/$)!'.Ê34)#/ Dr. André Sobierajski dos Santos (CRM-SC 4371)

Neurologia Neurofisiologia Rua Menino Deus 63, sala 412 - Baia -Sul Medical Center -Clínica 88020-210 - Florianópolis - SC Fone (48) 3222-2223dos - Fax Santos (48) 3224-4984 Dr. André Sobierajski (CRM-SC 4371) Rua Menino Deus 63, sala 412 - Baia Sul Medical Center - 88020-210 - Florianópolis - SC Fone (48) 3222-2223 - Fax (48) 3224-4984

NEUROLOGISTAS E NEUROCIRURGIÕES DOESTADO ESTADO SERGIPE NEUROLOGISTAS E NEUROCIRURGIÕES DO DEDE SERGIPE NEUROLOGISTAS E NEUROCIRURGIÕES DO(CRM-SE ESTADO Dr. Roberto César P. do Prado 1176)DE SERGIPE Professor Adjunto de Neurologia da Universidade Federal de Sergipe (UFS) Dr. Roberto César P. do Prado (CRM-SE 1176) CENTRO DIAGNÓSTICO FUNDAÇÃO SÃO LUCAS Professor Adjunto de Neurologia da Universidade Federal de Sergipe (UFS) Av. Coronel Stanley Silveira, 73 - salas 319 a 321 - Bairro São José - 49015-400 - Aracajú - SE CENTRO DIAGNÓSTICO FUNDAÇÃO SÃO LUCAS Fone (79) 3214-3900 - Fax (79) 3211-3837 - E-mail: rcprado@infonet.com.br Av. Coronel Stanley Silveira, 73 - salas 319 a 321 - Bairro São José - 49015-400 - Aracajú - SE Fone (79) 3214-3900 - Fax (79) 3211-3837 - E-mail: rcprado@infonet.com.br

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INFORMAÇÕES AOS AUTORES - 2012 Revisão mais recente: 20 de outubro de 2011 A missão de Arquivos de Neuro-Psiquiatria é proporcionar aos neurologistas e especialistas de áreas afins acesso aberto a artigos originais, editoriais, artigos de revisão, imagens em neurologia e relatos de caso de interesse clínico. Sua finalidade é contribuir para aprimorar o atendimento aos pacientes com doenças neurológicas, a formação dos neurologistas, a pesquisa clínica, a educação continuada e a orientação prática ao neurologista. Sua visão é ser a melhor revista em neurociências no sistema peer-review na América Latina. Arquivos de Neuro-Psiquiatria é o Jornal Oficial da Academia Brasileira de Neurologia. Publica os consensos e guidelines em neurologia, material didático-científico de seus diferentes Departamentos e também orientações de interesse na atividade profissional dos neurologistas. Arquivos de Neuro-Psiquiatria publica um volume anual e doze números mensais, de janeiro a dezembro, em duas versões: • Arq Neuropsiquiatr - ISSN 1678-4227 (versão online) • Arq Neuropsiquiatr - ISSN 0004-282-X (versão impressa) TIPOS DE CONTRIBUIÇÃO Os textos deverão apresentar características que permitam enquadrá-los nas seguintes seções: • Artigos Originais: pesquisas originais, clínicas ou experimentais. • Artigos de Revisão: análises críticas sobre temas atuais, a convite dos editores. • Notas Históricas: história da neurologia, dados sobre descrição de sinais, doenças ou síndromes neurológicas. • Cartas: comunicação de casos incomuns ou de excepcional interesse clínico. • Imagens em Neurologia: imagens originais ilustrativas de doenças neurológicas. • Resumos de Teses: reprodução do Abstract da Tese ou Dissertação de Mestrado. • Opiniões: comentários sobre artigos publicados. • Análises de livros: análise crítica de publicações em neurociências. • Academia Brasileira de Neurologia:textos sobre questões regionais, consensos, temas relacionados às atividades dos Departamentos Científicos da ABN, anais de reuniões científicas e outros. Os textos devem ser inéditos, claros e concisos, em inglês, tanto para a versão online quanto para a versão impressa. As seções Análises de livros e Academia Brasileira de Neurologia deverão ser publicadas apenas na forma impressa, em português. Forma dos artigos Arquivos de Neuro-Psiquiatria adota as normas editoriais do International Committee of Medical Journal Editors: ICMJE uniform requirements for manuscripts submitted to biomedical journals October 2005 update (www.icmje.org). Os autores devem submeter o original em processador de texto Microsoft Word, fonte 12 (Arial ou Times New-Roman). O texto deve conter, nesta ordem: 1. Apresentação (página de rosto): a. Título sintético e preciso, com até 100 caracteres. O título deve ser sugestivo, chamando a atenção para o conteúdo e não se restringindo a um aspecto estritamente descritivo. A não ser em manuscritos referentes a aspectos particulares de uma região não passíveis de extrapolação para a população geral, deve ser evitada, no título, a descrição da região de procedência do estudo. O título em português deve ser colocado depois do título em inglês.

b. Autor(es): nome e sobrenome, sendo este último na forma desejada para indexação. c. Informações complementares: nome da instituição em que foi feito o estudo, cidade e país; grau e cargo do autor; financiadora; endereço postal e eletrônico para correspondência. 2. Abstract e Resumo: a. artigos, artigos de revisão e notas históricas: até 150 palavras, contendo informação estruturada quanto a: motivo e propósito do estudo, método, resultados, conclusão; b. cartas, imagens em neurologia e opiniões não têm Abstract nem Resumo. 3. Key words e Palavras-Chave: a. artigos, artigos de revisão e notas históricas: após o Abstract e o Resumo, seguindo os Descritores de Ciências da Saúde (http://decs.bvs.br/); b. cartas, imagens em neurologia, opiniões e resumos de teses não têm Key words/Palavras-Chave. 4. Abstract, Key words, Resumo e Palavras-Chave: Devem ser colocadas, nessa ordem, depois do nome dos autores, antes do texto. 5. Texto: a. Artigos Originais: até 3000 palavras, excluindo-se as referências, contendo: introdução e objetivo; método (sujeitos e procedimentos, referência explícita quanto ao cumprimento das normas éticas aplicáveis, incluindo o nome da Comissão de Ética que aprovou o estudo e o Consentimento Informado dos pacientes ou seus familiares); resultados; discussão; agradecimentos; referências. Não repetir no texto dados que constem de tabelas e ilustrações. b. Artigos de Revisão: até 5000 palavras, sem contar as referências, incluindo análise de dados de outros autores ou metanálise, avaliação crítica dos dados da literatura e considerações baseadas em sua experiência pessoal. c. Notas Históricas: até 1000 palavras, excluindo-se as referências; d. Cartas: até 500 palavras, excluindo-se as referências. e. Imagens em Neurologia: até 100 palavras, com resumo dos dados clínicos e comentários sobre as imagens. f. Opiniões: até 400 palavras. g. Teses: até 200 palavras. 6. Tabelas: a. Artigos Originais e Artigos de Revisão: até 5, apresentadas em páginas separadas, incluindo: número de ordem, título e legenda. Não usar barras para separar linhas ou colunas; b. Notas Históricas e Cartas: até 2, com formato semelhante àquele descrito para os artigos. 7. Ilustrações: a. Artigos Originais e Artigos de Revisão: até 3, gráficos ou fotos, de boa qualidade, com legendas em páginas separadas, em preto e branco. Reproduções de ilustrações publicadas: anexar autorização da publicadora e do autor; b. Notas Históricas e Cartas: até 2, com formato semelhante ao descrito para os artigos; c. Imagens em Neurologia: até 4, em uma única página. Obs: Para ilustrações a cores, os custos serão repassados ao(s) autor(es).


8. Referências: a. Artigos Originais: até 30, restritas àquelas essenciais ao conteúdo do artigo; b. Artigos de Revisão: até 60; c. Notas Históricas: até 10; d. Cartas, Opiniões e Imagens em Neurologia: até 5. As referências devem: a. ser numeradas na ordem consecutiva de sua citação ao longo do texto; b. seguir o padrão do Index Medicus; c. incluir todos os autores quando até 6; quando 7 ou mais, listar os 3 primeiros, seguidos de “et al.” Modo de fazer a citação: a. artigos: Autor(es). Título. Periódico; ano; volume: páginas inicial-final (com todos os dígitos); b. livros: Autor(es) ou editor(es). Título. Edição, se não for a primeira. Tradutor(es), se for o caso. Cidade em que foi publicado: publicadora, ano: páginas inicial-final; c. capítulos de livros: Autor(es). Título. Editor(es) do livro e demais dados sobre este, conforme o item anterior; d. resumos: Autor(es). Título, seguido de (Abstr). Periódico ano; volume (Suplemento e seu número, se for o caso): página(s). e. quando não publicado em periódico: Título da publicação. Cidade em que foi publicada: publicadora, ano, página(s); f. livro ou texto online: autor(es). Título. Available at www ... (name of the site). Accessed (month, day, year); g. comunicações pessoais só devem ser mencionadas no texto, entre parênteses. As referências que constam dos artigos publicados neste número servem para orientação. Submissão do manuscrito • Serão aceitas somente submissões online: http://submission. scielo.br • O artigo deve ser submetido à Junta Editorial para publicação incluindo: 1. dois documentos, ambos em PDF e assinados por todos os autores: (a) declaração de anuência para publicação; (b) declaração de conflito de interesses; 2. sugestão de 3 a 5 nomes de especialistas para avaliadores. tramitação do manuscrito A Junta Editorial: a. verifica se o artigo está dentro do formato preconizado nas Instruções para os Autores e se atende ao propósito do periódico, recusando-o quando não satisfizer essas condições; b. após análise preliminar, encaminha os artigos selecionados a um Supervisor de Área específico, o qual emite seu parecer geral em até 48 horas; c. havendo parecer positivo do Supervisor de Área, designa pesquisadores da área para avaliar o trabalho, dentro do sistema de arbitragem por pares (peer-review). Ao final, pelo menos dois especialistas devem avaliar o conteúdo e a forma do texto no prazo máximo de 20 dias. No caso de divergência nas avaliações, o Supervisor de Área pode ser solicitado a emitir seu parecer para dirimir a questão;

d.

recebe e analisa os pareceres dos avaliadores, recusando os artigos julgados insatisfatórios; e. havendo sugestão de correções, dá conhecimento aos autores dos pareceres dos avaliadores e das sugestões destes, juntamente com os comentários editoriais, quanto a conteúdo, estrutura, clareza e redação do texto. Os autores têm até 20 dias para devolver o texto já revisto; f. reencaminha o novo texto aos avaliadores. Estes verificam se a nova versão inclui as correções e sugestões recomendadas, emitindo novo parecer. Este processo pode necessitar de várias rodadas até que o manuscrito seja considerado adequado. O não cumprimento deste processo em pontos considerados essenciais pode implicar na recusa do manuscrito, independentemente de sua aceitação provisória em fases anteriores; g. aceita ou recusa o artigo para publicação; h. se aceito, o(s) autor(es) recebe(m) o artigo no formato final, para anuência; i. após essa anuência, ou após decorrido o prazo de uma semana sem que haja manifestação em contrário, o manuscrito é encaminhado para publicação. O autor pode acompanhar a tramitação do manuscrito pelo mesmo site: http://submission.scielo.br ACEITE DO ARTIGO Os manuscritos serão aceitos pela ordem cronológica em que atingirem o formato final, após cumprimento de todas as etapas da tramitação. Todos os manuscritos serão submetidos a um revisor de língua inglesa com experiência em publicações na área das ciências neurológicas. Os custos financeiros dessa revisão correrão por conta dos autores. PUBLICAÇÃO DO ARTIGO • quando entrar na fase de impressão, já diagramado, o manuscrito não deverá mais ser modificado. Nesta fase, poderá ser publicado online na forma Ahead of Print (AOP), desde que se enquadre na categoria de Artigo Original; • Através do sistema AOP, o manuscrito tem garantido o acesso através da web, podendo ser lido e citado, mesmo que ainda não tenha sido publicado formalmente. À época da publicação formal, será retirado do sistema AOP; • O manuscrito será publicado ao mesmo tempo na forma online e na forma impressa; • Fica estabelecido previamente que os autores concordam: a. com sua publicação exclusiva neste periódico; b. em transferir automaticamente direitos de cópia e permissões à publicadora do periódico c. que assumem a responsabilidade intelectual e legal pelos resultados e pelas considerações apresentados. sede e contatos Administradora: Adriana Spina França Machado. Endereço: Rua Vergueiro 1421 / sala 804 Torre Sul, Ed. Top Towers Offices, 04101-000, São Paulo - SP - Brasil. Telefones: (5511) 3884-2042 e (5511) 3149-6605 Fax: (5511) 2369-9721 E-mail: anprev@globo.com e arq.neuropsiquiatria@terra.com.br


INFORMACIÓN A LOS AUTORES – 2012 Revisión más reciente: 20 de octubre de 2011 La misión de Arquivos de Neuro-Psiquiatría es proporcionar a los neurólogos y especialistas de áreas afines acceso abierto a artículos originales, editoriales, artículos de revisión, imágenes en neurología y relatos de caso de interés clínico. La finalidad es contribuir en la mejoría de la atención a pacientes con enfermedades neurológicas, la formación de los neurólogos, la investigación clínica, la educación continua y la orientación práctica del neurólogo. La visión es ser la mejor revista en neurociencias en el sistema peer-review en América Latina. Arquivos de Neuro-Psiquiatria es una revista Oficial de la Academia Brasileña de Neurología. Publica los consensos y pautas (guidelines) en neurología, material didáctico-científico de los diferentes Departamentos así como orientaciones de interés en la actividad profesional de los neurólogos. Arquivos de Neuro-Psiquiatria publica un volumen anual y doce números mensuales, de enero a diciembre, en dos versiones: • Arq Neuropsiquiatr – ISSN 1678-4227 (versión online) • Arq Neuropsiquiatr – ISSN 0004-282-X (version impresa) TIPOS DE CONTRIBUCIÓN Los textos, en inglés, deberán presentar características que permitan enmarcarlos en las siguientes secciones: • Artículos Originales: investigaciones originales, clínicas o experimentales. • Artículos de Revisión: análisis críticas sobre temas actuales, por invitación de los editores. • Notas Históricas: historia de la neurología, datos sobre descripción de indicios, enfermedades o síndromes neurológicos. • Cartas: comunicación de casos no comunes o de excepcional interés clínico • Imágenes en Neurología: imágenes originales ilustrativas de enfermedades neurológicas. • Resúmenes de Tesis: reproducción del Abstract de la Tesis o Disertación de Maestría. • Opiniones: comentarios sobre artículos publicados. • Análisis de libros: análisis crítico de publicaciones en neurociencias. • Academia Brasileña de Neurología: textos sobre aspectos regionales, consensos, temas relacionados con las actividades de los Departamentos Científicos de la ABN, anuales de reuniones científicas y otros. Los textos deben ser inéditos, claros y concisos, en inglés, tanto para la versión online como para la versión impresa. Las secciones Análisis de libros y Academia Brasileña de Neurología deberán ser publicadas sólo en la forma impresa, en portugués. FORMA DE LOS ARTÍCULOS Arquivos de Nero-Psiquiatria adopta las normas editoriales del International Committee of Medical Journal Editors: ICMJE uniform requirements for manuscripts submitted to biomedical journals October 2005 update (www.icmje.org). Los autores deben enviar el original en procesador de texto Microsoft Word, fuente 12 (Arial o Times New-Roman). El texto debe contener, en este orden: 1. Presentación (página de capa): a. Título sintético y preciso, con máximo 100 caracteres. El título debe ser sugestivo, llamando la atención del contenido y sin restringirse a un aspecto estrictamente descriptivo. A menos que se trate de manuscritos referentes a aspectos particulares de una región, no sujetos a extrapolación en una población general, debe evitarse, en el título, la descripción de la región de procedencia de estudio. El título en

portugués ó en español debe ser colocado posterior al título en inglés, precediendo al nombre de los autores. b. Autor(es): nombre y apellido, siendo éste último en la forma como se desea para indexación; c. Informaciones complementarias: nombre de la institución en que fue realizado el estudio, ciudad y país; grado y cargo del autor; financiador; dirección postal y electrónica para correspondencia. 2. Abstract y Resumen (que pude ser en español): a. Artículos, artículos de revisión y notas históricas: hasta 150 palabras, incluyendo información estructurada con relación a: motivo y propósito de estudio, método, resultados, conclusión; b. cartas, imágenes en neurología y opiniones no tienen Abstract ni Resumen. 3. Key words y Palabras-Clave: a. artículos, artículos de revisión y notas históricas: posterior al Abstract y el Resumen, siguiendo los Descriptores de Ciencias de la Salud (http://decs.bvs.br/); b. cartas, imágenes en neurología, opiniones y resúmenes de tesis no tienen Key words/Palabras-Clave. 4. Abstract, Key words; Resumen, Palabras-Clave: Deben ser colocados, en esta secuencia, posterior al nombre de los autores y antes del texto. 5. Texto: a. Artículos Originales: máximo 3000 palabras, excluyéndose las referencias, incluyendo: introducción y objetivo; método (sujetos y procedimientos, referencia explícita con respecto al cumplimiento de las normas éticas aplicables, incluyendo el nombre de la Comisión de Ética que aprobó el estudio y el Consentimiento Informado de los pacientes o sus familiares; resultados; discusión; agradecimientos; referencias. No repetir en el texto datos que consten en tablas e ilustraciones. b. Artículos de Revisión: máximo 5000 palabras, sin contar las referencias, incluyendo análisis de datos de otros autores o metanálisis, evaluación crítica de los datos de la literatura y consideraciones basadas en su experiencia personal. c. Notas Históricas: máximo 1000 palabras, excluyéndose las referencias. d. Cartas: hasta 500 palabras, excluyéndose las referencias. e. Imágenes en Neurología: máximo 100 palabras, con resumen de datos clínicos y comentarios sobre las imágenes. f. Opiniones: máximo 400 palabras. g. Tesis: máximo 200 palabras. 6. Tablas: a. Artículos Originales y Artículos de Revisión: artículos y artículos de revisión: máximo 5, presentadas en páginas separadas, constando: número de orden, título y legenda; no usar barras para separar líneas o columnas; b. Notas históricas y cartas: máximo 2, con formato semejante al descrito para los artículos. 7. Ilustraciones: a. Artículos Originales y Artículos de Revisión: máximo 3, gráficos o fotos, de buena calidad, con legendas en páginas separadas, en negro y blanco. Reproducciones de ilustraciones publicadas: anexar autorización de la publicadora y del autor; b. Notas históricas y cartas: máximo 2, con formato semejante al descrito para los artículos; c. Imágenes en Neurología: máximo 4, en una única página.


Obs: Para ilustraciones a colores, los costos serán pasados al(los) autor(es). 8. Referencias: a. Artículos Originales: máximo 30, restringidas a las esenciales para el contenido del artículo; b. Artículos de Revisión: máximo 60; c. Notas históricas: máximo 10; d. Cartas, Opiniones e Imágenes en Neurología: máximo 5. Las referencias deben: a. ser enumeradas en el orden consecutivo de su citación a lo largo del texto; b. seguir el patrón del Index Medicus; c. incluir todos los autores hasta 6; cuando sean 7 o más, listar los 3 primeros, seguidos de “et al.” Modo de hacer la citación: a. artículos: Autor(es). Título. Periódico; año; volumen: páginas inicial-final (con todos los dígitos); b. libros: Autor(es) o editor(es). Título. Edición, se no es la primera. Traductor(es), si es el caso. Ciudad en que fue publicado: publicadora, año: páginas inicial-final; c. capítulos de libros: Autor(es). Título. Editor(es) del libro y demás datos sobre este, conforme el ítem anterior; d. resúmenes: Autor(es). Título, seguido de (Abstr). Periódico año; volumen (Suplemento y su número, si es el caso): página(s). e. cuando no es publicado en periódico: Título de la publicación. Ciudad en que fue publicada: publicadora, año, página(s); f. libro o texto online: autor(es). Título. Disponible en www… (nombre del sitio). Accesado (mes, día, año); g. comunicaciones personales sólo deben ser mencionadas en el texto, entre paréntesis. Las referencias que constan en los artículos publicados en este número sirven de orientación. ENVÍO DEL MANUSCRITO • Serán aceptados solamente los envíos online: http://submission.scielo.br • El artículo debe ser enviado a la junta Editorial para publicación incluyendo: 1. dos documentos, ambos en PDF y firmados por todos los autores: (a) declaración de consentimiento para publicación; (b) declaración de conflicto de intereses; 2. sugerencia de 3 a 5 nombres de especialistas para evaluación. TRAMITACIÓN DEL MANUSCRITO La Junta Editorial: a. verifica si el artículo está dentro del formato preconizado en las instrucciones para los Autores y si atiende al propósito del periódico, rechazándolo cuando no satisfaga tales condiciones; b. posterior al análisis preliminar, encamina los artículos seleccionados a un Supervisor de Área específico, el cual emite su parecer general en un máximo de 48 horas; c. resultando positivo el parecer del Supervisor de Área, designa investigadores del área para evaluar el trabajo, dentro del sistema de arbitraje por pares (peer-review). Al final, por lo

d. e.

f.

g. h. i.

menos dos especialistas deben evaluar el contenido y la forma del texto en el plazo máximo de 20 días. En el caso de divergencia en las evaluaciones, el Supervisor de Área puede ser solicitado a emitir su parecer para dirimir la cuestión; recibe y analiza los pareceres de los evaluadores, rechazando los artículos juzgados insatisfactorios; existiendo sugerencia de correcciones, entrega a los autores los pareceres de los evaluadores y de las sugerencias de ellos, junto con los comentarios editoriales, con relación a contenido, estructura, clareza y redacción del texto. Los autores tienen un máximo de 20 días para devolver el texto revisado; reencamina el nuevo texto a los evaluadores. Estos verifican si la nueva versión incluye las correcciones y sugerencias recomendadas, emitiendo nuevo parecer. Este proceso puede necesitar de varias revisiones hasta que el manuscrito sea considerado adecuado. El no cumplimiento de este proceso en puntos considerados esenciales puede implicar en el rechazo del manuscrito, independientemente de su aceptación provisoria en fases anteriores; acepta o rechaza el artículo para publicación; si aceptado, el(los) autor(es) recibe(n) el artículo en el formato final, para consentimiento; posterior al consentimiento, o luego de transcurrido el plazo de una semana sin que exista manifestación contraria, el manuscrito es encaminado para publicación.

El autor puede acompañar la tramitación del manuscrito por el mismo sitio: http://submission.scielo.br ACEPTACIÓN DEL ARTÍCULO Los manuscritos serán aceptados en el orden cronológico en que alcancen el formato final, posterior al cumplimiento de todas las etapas de tramitación. Todos los manuscritos serán enviados al revisor del idioma inglés con experiencia en publicaciones en el área de las ciencias neurológicas. Los costos financieros de esta revisión correrán por cuenta de los autores. PUBLICACIÓN DEL ARTÍCULO • al entrar en la fase de impresión, ya diagramado, el manuscrito no deberá tener más modificaciones. En esta fase, podrá ser publicado online en la forma Ahead of Print (AOP), siempre que se enmarque en la categoría de Artículo Original; • A través del sistema AOP, el manuscrito tiene garantizado el acceso por la página web, pudiendo ser leído y citado, aunque no haya sido publicado formalmente. Para la época de la publicación formal, será retirado del sistema AOP; • El manuscrito será publicado al mismo tiempo en la forma online y en la forma impresa; • Queda establecido previamente que los autores concuerdan: a. con su publicación exclusiva en este periódico; b. en transferir automáticamente derechos de copia y permisos a la publicadora del periódico c. que asumen la responsabilidad intelectual y legal por los resultados y por las consideraciones presentadas. SEDE Y CONTACTOS Dirección: Calle Vergueiro 1421 / sala 804 Torre Sur, Ed. Top Towers Offices, 04101-000, Sao Paulo – SP – Brasil. Teléfonos: (5511) 3884-2042 y (5511) 3149-6605; Fax: (5511) 23699721 E-mail: anprev@globo.com y arq.neuropsiquiatria@terra.com.br


INFORMATION FOR AUTHORS - 2012 Most recent revision: October 20, 2011 The mission of Arquivos de Neuro-Psiquiatria is to provide neurologists and specialists in related fields with open access to original articles, editorials, review articled, images in neurology and case reports of clinical interest. Its purpose is to contribute towards improving attendance for patients with neurological diseases, training for neurologists, clinical research, continuing education and practice guidance for neurologists. Its vision is to be the best neurosciences journal in Latin America within the peer review system. Arquivos de Neuro-Psiquiatria is the official journal of the Brazilian Academy of Neurology. It publishes its consensuses and guidelines on neurology, educational and scientific material from its different departments and also guidance of interest to neurologists’ professional activities. Arquivos de Neuro-Psiquiatria publishes one volume per year, consisting of twelve monthly issues, from January to December, in two versions: • Arq Neuropsiquiatr - ISSN 1678-4227 (online version) • Arq Neuropsiquiatr - ISSN 0004-282-X (printed version) TYPES OF CONTRIBUTION Texts should present characteristics that allow them to fit into the following sections: • Original Articles: original clinical or experimental research. • Review Articles: critical analyses on current topics, by invitation from the editors. • Historical Notes: history of neurology and data on descriptions of signs, diseases or neurological syndromes. • Letters: communication of unusual cases, or cases of exceptional clinical interest. • Images in Neurology: original images that illustrate neurological diseases. • Thesis Abstracts: reproduction of abstracts from theses or master’s dissertations. • Opinions: comments on articles that have been published. • Book Reviews: critical analysis on neuroscience publications. • Brazilian Academy of Neurology: topics relating to the activities of the Academy’s Scientific Departments, annals of scientific meetings and others. The texts should be unpublished, clear and concise, and in English both for the online version and for the printed version. The sections Book Reviews and Brazilian Academy of Neurology will be published only in printed form, in Portuguese. ARTICLE STRUCTURE Arquivos de Neuro-Psiquiatria has adopted the editorial norms of the International Committee of Medical Journal Editors: ICMJE uniform requirements for manuscripts submitted to biomedical journals, October 2005 update (www.icmje.org). Authors must submit the original manuscript using the Microsoft Word text processor, in font size 12 (Arial or Times New Roman). The text must contain the following, in this order: 1. Presentation (cover page): a. Title that precisely summarizes the topic, consisting of up to 100 characters. The title should be suggestive, drawing attention to the content, without being restricted to a strictly descriptive nature. Except in manuscripts referring to particular aspects of a region that cannot be extrapolated to the general population, descriptions of the region from which the study originates should be avoided in the title. The title in Portuguese should be placed after the title in English.

b. Author(s): name and surname, with the latter in the form desired for indexation; c. Complementary information: name of the institution in which the study was produced, with the city and country; authors’ academic degrees and current positions; funding; and postal and electronic addresses for correspondence. 2. Abstract and Resumo: a. Articles, Review Articles and Historical Notes: up to 150 words, containing structured information regarding the reason for and purpose of the study, method, results and conclusion; b. Letters, Images in Neurology and Opinions do not have an Abstract or Resumo. 3. Key words and Palavras-Chave: a. Articles, Review Articles and Historical Notes: after the Abstract and Resumo, in conformity with the Health Science Descriptors (http://decs.bvs.br/); b. Letters, Images in Neurology, Opinions and Thesis Abstracts do not have Key words/Palavras-chave. 4. Abstract, Key words, Resumo, Palavras-chave: Should be placed, in this order, after the name of the authors, before the text. 5. Text: a. Original Articles: up to 3000 words, excluding the references, containing: introduction and objective; method (subjects and procedures, with explicit reference to compliance with the ethical norms applicable, including mention of the name of the ethics committee that approved the study and the informed consent statement for the patients or members of their families); results; discussion; acknowledgements; and references. Data that appear in tables and illustrations should not be repeated in the text. b. Review Articles: up to 5000 words, without counting the references, including analysis on data from other authors or meta-analysis, critical evaluation of data in the literature and remarks based on the author’s personal experience. c. Historical Notes: up to 1000 words, without counting the references; d. Letters: up to 500 words, without counting the references. e. Images in Neurology: up to 100 words, with a summary of the clinical data and comments on the images. f. Opinions: up to 400 words. g. Theses: up to 200 words. 6. Tables: a. Original Articles and Review Articles: up to 5, presented on separate pages, including: order number, title and legend. Do not use bars to separate lines or columns; b. Historical Notes and Letters: up to 2, with a format similar to that described for the articles. 7. Illustrations: a. Original Articles and Review Articles: up to 3 graphs or photos of good quality, in black and white, with legends on separate pages. Reproductions of published illustrations: attach authorization from the publisher and from the author; b. Historical Notes and Letters: up to 2, with format similar to that described for the articles; c. Images in Neurology: up to 4, on a single page. Note: For illustrations in color, the costs will be passed on to the author(s).


8. References: a. Original Articles: up to 30, limited to those that are essential to the content of the article; b. Review Articles: up to 60; c. Historical Notes: up to 10; d. Letters, Opinions and Images in Neurology: up to 5. The references must: a. Be numbered in consecutive order of their citation over the course of the text; b. Follow the pattern of Index Medicus; c. Include all the authors when there are up to 6; when there are 7 or more, list the first 3 and follow them with “et al.” Method for making citations: a. Articles: Author(s). Title. Periodical; year; volume: first-last page (with all the digits); b. Books: Author(s) or Editor(s). Title. Edition, if it was not the first. Translator(s), if this was the case. City in which it was published: publisher, year: first-last page; c. Book chapters: Author(s). Title. Editor(s) of the book and other data on this, as in the preceding item; d. Abstracts: Author(s). Title, followed by (Abstr). Periodical year; volume (Supplement and its number, if this is the case): page(s). e. When it was not published in a periodical: Title of the publication. City in which it was published: publisher, year, page(s); f. Online book or text: Author(s). Title. Available at www ... (name of the site). Accessed (month, day, year); g. Personal communications should only be mentioned in the text, in parentheses. The references that appear in the articles published in this issue serve as a guide. MANUSCRIPT SUBMISSION • Only online submissions will be accepted: http://submission. scielo.br • The article should be submitted to the Editorial Board for publication, together with the following: 1. Two documents, both in PDF and signed by all the authors: (a) declaration of authors’ consent for publication; (b) declaration of conflicts of interest; 2. Suggestion of 3 to 5 names of specialists as reviewers. APPRAISAL PROCEDURES APPLIED TO MANUSCRIPTS The Editorial Board will: a. Verify whether articles are in the format recommended in the Instructions for Authors and whether they meet the purposes of the periodical, and will reject them when these conditions are not satisfied; b. After the preliminary analysis, send the selected articles to a Supervisor for the specific field, who will issue a general opinion report within 48 hours; c. If this report from the Supervisor for the field is positive, designate researchers in the field to assess the study, within the peer-review system. In the end, at least two specialists will have assessed the content and form of the text, within a maximum of 20 days. If the evaluations diverge, the Supervisor for the field may be asked to issue an opinion to settle the issue;

d.

Receive and analyze the opinion reports from the reviewers, and reject articles that are deemed unsatisfactory; e. If corrections have been suggested, make the reviewers’ reports and suggestions known to the authors, together with editorial comments regarding the content, structure, clarity and composition of the text. The authors have a maximum of 20 days to return the text with revisions; f. Forward the new text to the reviewers. These reviewers will check whether the new version includes the corrections and suggestions recommended, and will issue a new opinion report. This process may require several rounds until the manuscript is considered to be acceptable. Noncompliance with this process, in relation to points that are considered essential, may imply that the manuscript will be rejected, regardless of its provisional acceptance at preceding stages; g. Accept or reject the article for publication; h. If accepted, send the article in its final format, to the author(s) for their consent to publication; i. Send the manuscript for publication after this consent has been received, or after a period of one week without any manifestation to the contrary. The author(s) can accompany the appraisal procedures on the manuscript through the same website: http://submission.scielo.br ACCEPTANCE OF THE ARTICLE Manuscripts will be accepted in the chronological order in which they reach the final format, after fulfillment of all the stages of the appraisal procedures. All manuscripts will be submitted to an English-language reviewer with experience in publications in the field of neurological sciences. The financial costs of this review will be borne by the authors. PUBLICATION OF THE ARTICLE • When the manuscript goes into the printing stage, after going through the layout stage, the manuscript can no longer be modified. At this stage, it may be published online in Ahead of Print (AOP) form, provided that it fits within the category of Original Article; • Through the AOP system, access to the manuscript through the internet is guaranteed, and it can be read and cited even though it has not yet been formally published. At the time of formal publication, it will be withdrawn from the AOP system; • The manuscript will be published simultaneously in online form and in printed form; • It is established in advance that the authors agree: a. That their manuscript will be published exclusively in this periodical; b. That the copyright and permissions are transferred automatically to the publisher of the periodical; c. That they assume intellectual and legal responsibility for the results and comments presented. MAIN OFFICE AND CONTACTS Manager: Adriana Spina França Machado. Address: Rua Vergueiro 1421 / sala 804, Torre Sul, Ed. Top Towers Offices, 04101-000, São Paulo – SP, Brazil. Telephones: (5511) 3884-2042 and (5511) 3149-6605 Fax: (5511) 23699721 E-mail: anprev@globo.com and arq.neuropsiquiatria@terra.com.br


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We hope you enjoy reading our Journal We hope you learn something new in Arquivos de Neuro-Psiquiatria We hope you may find here a new diagnostic or therapeutic insight for your patient Our focus is to be a Clinical Journal for Clinical Neurologists


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Eficácia consistente ao longo do dia, mesmo até 13 horas após a dose.1 Importante contraindicação: histórico de abuso de drogas. Importante interação medicamentosa: uso concomitante com IMAO devido à potencialização de efeitos. VENVANSE* (dimesilato de lisdexanfetamina). Apresentação: cápsulas de uso oral de 30 mg, 50 mg e 70 mg de dimesilato de lisdexanfetamina; frascos com 28 cápsulas. Indicação: para o tratamento do Transtorno Déficit de Atenção/Hiperatividade (THDA) em crianças de 6 a 12 anos de idade. Contraindicações: arterioesclerose avançada, doença cardiovascular sintomática, hipertensão moderada a grave, hipertireoidismo, sensibilidade conhecida ou reação de idiossincrasia a aminas simpatomiméticas, glaucoma, estados de agitação, histórico de abuso de drogas, durante ou até 14 dias após o uso de inibidores da monoaminoxidase. Advertências e Precauções: as anfetaminas têm alto potencial de abuso e de dependência, especialmente em doses maiores que as terapêuticas e em uso prolongado, podendo nestas condições causar morte súbita e eventos cardiovasculares graves. Deve ser usado com cautela em casos de anormalidades estruturais cardíacas ou outros problemas graves do coração, hipertensão e outras condições cardiovasculares, transtorno psicótico pré-existente, tiques motores e fônicos e síndrome de Tourette, uso de outros fármacos simpatomiméticos. Deve ser descontinuado na presença de convulsões. Pode ser necessário interrompê-lo se ganho de peso e crescimento abaixo do esperado. Pode causar doping. Categoria C de gravidez: só deve ser usado se os potenciais benefícios justificarem o potencial risco para o feto. A amamentação deve ser suspensa durante seu uso. Interações Medicamentosas: agentes acidificantes e alcalinizantes da urina, antidepressivos IMAO, bloqueadores adrenérgicos, anti-histamínicos, anti-hipertensivos, alcalóides de veratrum, etosuximida, antidepressivos tricíclicos, agentes simpatomiméticos, meperidina, fenobarbital, fenitoína, clorpromazina, haloperidol, carbonato de lítio, norepinefrina, propoxifeno. Reações Adversas: dor no abdômen superior, vômito, náusea, boca seca, diarreia, pirexia, nervosismo, apetite diminuído, anorexia, vertigem, cefaleia, convulsão, discinesia, inquietação, tremor, insônia, insônia inicial, irritabilidade, labilidade afetiva, tique, agitação, agressão, hiperatividade psicomotora, depressão, disforia, logorreia, episódios psicóticos, episódios maníacos, alucinação, ansiedade, euforia, erupção cutânea, síndrome de Stevens-Johnson, angioedema, urticária, hiperidrose, hipersensibilidade, reação anafilática, visão borrada, midríase, taquicardia, palpitações, dispneia, perda de peso, aumento da pressão arterial, hepatite eosinofílica, fadiga, sonolência. Posologia: Dose inicial recomendada: 30 mg, uma vez ao dia, pela manhã. Dose máxima recomendada: 70 mg/dia. Para maiores informações: vide bula - VENDA SOB PRESCRIÇÃO MÉDICA. Reg. MS - 1.6979.0004 *Marca depositada. Referência Bibliográfica: 1. Wigal SB et al. A 13-hour laboratory school study of lisdexamfetamine dimesylate in school-aged children with attention-deficit/hyperactivity disorder. Child and Adolescent Psychiatry and Mental Health 2009;3(17):115. At: http://www.capmh.com/content/3/1/17; on 23/Feb/2011. 2. Goodman DW. Lisdexamfetamine Dimesylate (Vyvanse), A Prodrug Stimulant for Attention-Deficit/Hyperactivity Disorder. P&T May 2010;35(5):273-87.

Venvanse* é um medicamento. Durante seu uso não dirija veículos ou opere máquinas, pois sua agilidade e atenção podem estar prejudicadas. www.shire.com.br Shire Farmacêutica Brasil Ltda. - Edifício Rochaverá Towers Av. das Nações Unidas, 14.171, Torre Ebony - 5º andar - 04794-000 - São Paulo - SP - Brasil Material destinado exclusivamente à classe médica. ANC VYV JUN/2011


O importante no tratamento da EM Ê o equilíbrio entre DHžFiFLDHDVHJXUDQoD

ISSN 0004-282X

1-12

Celebrating 70 years of publication

Vol . 70, N o 1, January 2012

SĂŁo Paulo, SP, Brazil

Volume 70, Number 1, January, 2012, SĂŁo Paulo, SP, Brazil

QUANTO ANTES MELHOR

Tratamento de 1ª linha para Esclerose Múltipla13,14 s COPAXONEŽ reduz em 50% a taxa anual de surtos jå no primeiro ano15 s COPAXONE preserva a vigilância imunológica do paciente Ž

16,17

, diferentemente de algumas drogas com

perfil imunossupressor que podem comprometer esta vigilância18-23 s COPAXONEŽ possui estudo prospectivo de longo prazo com observação de 22 anos de doença17

COPAXONEÂŽ (acetato de glatirâmer) - solução injetĂĄvel - uso subcutâneo 20mg/mL - USO ADULTO - Indicaçþes: Reduzir a freqßência de recidivas nos pacientes com esclerose mĂşltipla remissiva recidivante (EMRR). Ainda nĂŁo existem estudos comprovando o benefĂ­cio do COPAXONEÂŽ em outras formas de Esclerose MĂşltipla. TambĂŠm ĂŠ indicado no tratamento de pacientes que tiveram um primeiro episĂłdio clĂ­nico bem definido e que apresentem alto risco de desenvolver a esclerose mĂşltipla clinicamente definida (EMCD). Contra-indicaçþes: O produto estĂĄ contra-indicado para pacientes com hipersensibilidade conhecida ao acetato de glatirâmer ou manitol. AdvertĂŞncias e Precauçþes: A administração deve ser feita exclusivamente por via subcutânea. NĂŁo deve ser administrado por via intravenosa; os pacientes devem ser instruĂ­dos sobre tĂŠcnicas de auto-administração da injeção de COPAXONEÂŽ para garantir a segurança da administração. Baseado nos dados atuais, nĂŁo ĂŠ necessĂĄrio nenhuma precaução especial para pacientes envolvidos em atividades que requerem alerta mental, como dirigir veĂ­culos ou operar mĂĄquinas. Como o acetato de glatirâmer pode modificar a resposta imunolĂłgica, deve-se considerar a possibilidade de que ele possa interferir com a função imunolĂłgica. Gravidez e lactação: Categoria B de risco na gravidez. Interaçþes medicamentosas: Interaçþes entre o COPAXONEÂŽ e outros fĂĄrmacos nĂŁo foram completamente avaliadas. Reaçþes Adversas: Reaçþes adversas mais comumente observadas: reaçþes no local de aplicação, vasodilatação, dor no peito, astenia, infecção, dor, nĂĄusea, artralgia, ansiedade e hipertonia. Posologia: a dose recomendada para adultos para o tratamento de esclerose mĂşltipla remissiva recidivante ĂŠ de 20 mg/dia injetada subcutaneamente. VENDA SOB PRESCRIĂ&#x2021;Ă&#x192;O MĂ&#x2030;DICA. Reg. MS 1.5573.0001. Farm. Resp.: MĂ´nica Riyoko Nekozuka â&#x20AC;&#x201C; CRF-SP n° 16.970. Teva FarmacĂŞutica Ltda. A persistirem os sintomas, o mĂŠdico deve ser consultado. Documentação CientĂ­fica e informaçþes adicionais estĂŁo Ă  disposição da classe mĂŠdica, mediante solicitação.*CIS: SĂ­ndrome ClĂ­nica Isolada. Copaxone possui indicação em bula.

Contra-indicaçþes: o produto estĂĄ contra-indicado para pacientes com hipersensibilidade conhecida ao acetato de glatirâmer ou manitol. Interaçþes medicamentosas: interaçþes entre o COPAXONEÂŽ (acetato de glatirâmer) e outras drogas nĂŁo foram completamente avaliadas. 3FGFSĂ?ODJBT$PNJ(FUBM -BODFU  t.JMMFS+3+.BOBH$BSF1IBSN  4VQQM# 44t.JLPM%%FUBM -BODFU/FVSPM0DU  t4PSNBOJ.1FUBM/FVSPMPHZ   t'JMJQQJ.FUBM /FVSPMPHZ  t+PIOTPO,15IFS$MJO3JTL.BOBHFt'PSE$FUBM.VMU4DMFSt.FU[-.FUBM +/FVSPM/FVSPTVSH1TZDIJBUSZ t;JFNTTFO5FUBM)FBMUI2VBM-JGF0VUDPNFTt$BOGBWSFVY$ FUBM+3$PMM1IZTJDJBOT&EJOCt$BOGBWSFVY$ FU"-#SBJOt+PVSOBMPGUIF/FVSPMPHJDBM4DJFODFT GFCSVBSZWPM 4VQQMt'PSE$$ FUBM.VMU4DMFSt+PIOTPO,1 BM/FVSPMPHZt)BBT+'JS[MBGG.  &VSPQFBO+PVSOBMPG/FVSPMPHZt8FCFS.4 FUBM /FVSPUIFSBQFVUJDT  t"IBSPOJ3 FUBM1SPD/BUM"DBE4DJ64"  t.VOEFM5'5:@""/.BZ t$IVO+ FUBM$MJO/FVSPQIBSN  t-PQF[%JFHP34 FUBM/BU 3FW%SVH%JTDPWFSZ  t6OEFSTUBOEJOHDBODFSBOESFMBUFEUPQJDT/BUJPOBM$BODFS*OTUJUVUF8FCTJUFt,BQQPT- FUBM/&OHM+.FE  t$PIFO+" FUBM/&OHM+.FE  

Arquivos de Neuro-Psiquiatria

2,3

EDITORIALS

VIEWS AND REVIEWS

01

The 70 years of Arquivos de Neuro-Psiquiatria

59

02

How much radiologically isolated syndrome suggestive of multiple sclerosis is multiple sclerosis?

LETTERS

Treatment of neuromyelitis optica: an evidence based review

ARTICLES

67

A rare cause of recurrent peripheral facial palsy

05

Incidental demyelinating inflammatory lesions in asymptomatic patients: a Brazilian cohort with radiologically isolated syndrome and a critical review of current literature

69

Multiple subcortical strokes caused by mucormycosis in a patient with lymphoma

71

12

Clinical predictors of response to immunomodulators for multiple sclerosis

Cervical myelopathy caused by ligamentum flavum ossification

73

17

Accuracy of prospective memory tests in mild Alzheimerâ&#x20AC;&#x2122;s disease

Facial somatosensorial evaluation in idiopathic trigeminal neuralgia

75

22

Translation, cultural adaptation and psychometric evaluation of the LeganĂŠs cognitive test in a low educated elderly Brazilian population

Meningioma after immunomodulation for multiple sclerosis

IMAGES IN NEUROLOGY

28

Autism spectrum disorder and celiac disease: no evidence for a link

34

The impact of EEG in the diagnosis and management of patients with acute impairment of consciousness

40

Devising and validating a headache diary in a series of patients with chronic daily headache from Colombia

45

Morphological abnormalities in mitochondria of the skin of patients with sporadic amyotrophic lateral sclerosis

52

Cyclosporin safety in a simplified rat brain tumor implantation model

77

Magnetic resonance appearance of recurrent ophtalmoplegic migraine

78

â&#x20AC;&#x153;Black turbinate singâ&#x20AC;?: a potential predictor of mucormycosis in cavernous sinus thrombophlebitis

THESES 79

Peripheral biomarkers in bipolar disorder: a population-based study in young adults

79

Severity and functional ability scale for amyotrophic lateral sclerosis patients

Opinion 81

Spontaneus spinal epidural hematoma during pregnancy

82

NOTICES AND COMMENTS


Arquivos de Neuro-Psiquiatria