ISSN 0004-282X
Arquivos de Volume 79, Number 6, June 2021 Neuro -psiquiatriA
Level of knowledge and misconceptions about brain concussion in Brazilian adults What can be expected to be seen in a Neurology ward? Eleven-year experience in a Brazilian university hospital Evaluation of structural changes in orbitofrontal cortex in relation to medication overuse in migraine patients: a diffusion tensor imaging study Determinants of disability development in patients with multiple sclerosis Epidemiological and clinical aspects of Guillain-Barré syndrome and its variants Primary central nervous system tumors in Sergipe, Brazil: descriptive epidemiology between 2010 and 2018 Effects of resistance training on postural control in Parkinson’s disease: a randomized controlled trial High prevalence of psychiatric comorbidities in children and adolescents at a tertiary epilepsy center
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REALIZAÇÃO: GERENCIAMENTO: Arquivos de Volume 79, Number 6, June 2021 Neuro -psiquiatriA THE OFFICIAL JOURNAL OF THE ACADEMIA BRASILEIRA DE NEUROLOGIA (BRAZILIAN ACADEMY OF NEUROLOGY)
Academia Brasileira de Neurologia Indexing Carlos Roberto M. Rieder (Porto Alegre, Brazil) - President Web of Science (1969) - Science Citation Index Expanded and JCR (2003) Delson José da Silva (Goiânia, Brazil) - Vice-President Scopus (from 1945 to 1965, from 1971 to Present) and Scimago Gisele Sampaio (São Paulo, Brazil) - General Secretary (1947-1965, 1971-ongoing) Jerusa Smid (São Paulo, Brazil) - 1st Secretary MEDLINE/PubMed (1965-) Edmar Zanoteli (São Paulo, Brazil) - General Treasurer SciELO (1999) José Luiz Pedroso (São Paulo, Brazil) - 1st Treasurer LILACS (BIREME/OPAS/OMS, 1982) Fernando Cendes, (Campinas, Brazil) - Delegate to World DOAJ Federation of Neurology EMBASE - Excerpta Medica (Elsevier, Amsterdam, 1960) Carlos Alberto Mantovani Guerreiro, (Campinas, Brazil) - Deputy LATINDEX Delegate to the World Federation of Neurology NLL (National Lending Library of Sciences and Technology, Boston, www.abneuro.org.br | [email protected] UK, 1947) WHO/UNESCO (Word Medical Periodicals, 1949) Marketing Knowedge hub Editora Omni Farma Ltda. phone: (5511)5180-6169 Circulation e-mail: [email protected] Monthly, 2600 copies
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Vorkapic C, Leal S, Alves H, Douglas M, Britto A, Dantas EHM. Born to move: a review on the impact of physical exercise on brain health and the evidence from human controlled trials. Arq Neuropsiquiatr. 2021;79(6):536-60. https://doi.org/10.1590/0004-282X-ANP-2020-0166. Page: 538. Figure 2.
Apoio: Editors-in-Chief Founding Editor (in memoriam) Hélio Afonso Ghizoni Teive (Curitiba, Brazil) Oswaldo Lange Paulo Caramelli (Belo Horizonte, Brazil) Emeritus Editor (in memoriam) Past Editors-in-Chief Antonio Spina-França Netto José Antonio Livramento (São Paulo, Brazil) Luís dos Ramos Machado (São Paulo, Brazil)
ASSOCIATE EDITORS
Cerebrovascular Disorders, Interventional Neuroradiology and Marzia Puccioni-Sohler (Rio de Janeiro, Brazil) Neurointensive Care Paulo Pereira Christo (Belo Horizonte, Brazil) Ayrton Roberto Massaro (São Paulo, Brazil) Sérgio Monteiro de Almeida (Curitiba, Brazil) Gabriel Rodriguez de Freitas (Rio de Janeiro, Brazil) Jamary Oliveira Filho (Salvador, Brazil) Movement Disorders Marcos Christiano Lange (Curitiba, Brazil) José Luiz Pedroso (São Paulo, Brazil) Octávio Marques Pontes Neto (Ribeirão Preto, Brazil) Laura Silveira Moriyama (Campinas, Brazil) Sheila Cristina Ouriques Martins (Porto Alegre, Brazil) Renato Puppi Munhoz (Toronto, Canada) Vitor Tumas (Ribeirão Preto, Brazil) Child Neurology Ana Carolina Coan (Campinas, Brazil) Neuromuscular Disorders and Peripheral Neuropathy Alexandra Pruffer Queiroz Campos Araújo (Rio de Janeiro, Brazil) Edmar Zanoteli (São Paulo, Brazil) Juliana Gurgel-Giannetti (Belo Horizonte, Brazil) Francisco de Assis Aquino Gondim (Fortaleza, Brazil) Marcondes Cavalcante França Jr. (Campinhas, Brazil) Clinical Neurophysiology Wilson Marques Jr. (Ribeirão Preto, Brazil) Carlos Otto Heise (São Paulo, Brazil) Luciano De Paola (Curitiba, Brazil) Luís Otávio Sales Ferreira Caboclo (São Paulo, Brazil) Neurogenetics Iscia Teresinha Lopes Cendes (Campinas, Brazil) Paulo José Lorenzoni (Curitiba, Brazil) Sarah Teixeira Camargos (Belo Horizonte, Brazil) Rosana Hermínia Scola (Curitiba, Brazil)
Cognitive Neurology and Neuropsychology Neuroimaging Leonardo Cruz de Souza (Belo Horizonte, Brazil) Antonio José da Rocha (São Paulo, Brazil) Michael Hornberger (Norwich, United Kingdom) Carolina de Medeiros Rimkus (Campinas, Brazil) Mônica Sanchez Yassuda (São Paulo, Brazil) Celi dos Santos Andrade (São Paulo, Brazil) Sonia Maria Dozzi Brucki (São Paulo, Brazil) Leandro Tavares Lucato (São Paulo, Brazil)
Epilepsy Neuroimmunology Clarissa Lin Yasuda (Campinas, Brazil) Maria Fernanda Mendes (São Paulo, Brazil) Fábio A. Nascimento (Boston, USA) Tarso Adoni (São Paulo, Brazil) Lécio Figueira Pinto (São Paulo, Brazil) Yara Dadalti Fragoso (Santos, Brazil)
Experimental Neurology and Neuroscience Neurological Rehabilitation Grace Schenatto Pereira Moraes (Belo Horizonte, Brazil) Adriana Bastos Conforto (São Paulo, Brazil) Karina Braga Gomes (Belo Horizonte, Brazil) Chien Hsin Fen (São Paulo, Brazil) Luciene Covolan (São Paulo, Brazil) Vivaldo Moura Neto (Rio de Janeiro, Brazil) Neuro-oncology Suzana Maria Fleury Malheiros (São Paulo, Brazil) General Neurology Eduardo Genaro Mutarelli (São Paulo, Brazil) Neuropathology Orlando Graziani Povoas Barsottini (São Paulo, Brazil) Lea Tenenholz Grinberg (San Francisco, USA) Péricles Maranhão-Filho (Rio de Janeiro, Brazil) Sérgio Rosemberg (São Paulo, Brazil) Headache Neuropsychiatry Mário Fernando Prieto Peres (São Paulo, Brazil) Antonio Lucio Teixeira (Houston, USA) Pedro André Kowacs (Curitiba, Brazil) Analuiza Camozzato (Porto Alegre, Brazil) Pedro Sampaio (Recife, Brazil)
History of Neurology Pain Carlos Henrique Ferreira Camargo (Curitiba, Brazil) Daniel Ciampi de Andrade (São Paulo, Brazil) Ethel Mizrahy Cuperschmid (Belo Horizonte, Brazil) Fabíola Dach Eckeli (Ribeirão Preto, Brazil) Ylmar Correa Neto (Florianópolis, Brazil) Sleep Disorders Images in Clinical Neurophysiology Dalva Poyares (São Paulo, Brazil) Fábio A. Nascimento (Harvard Medical School, Massachusetts General Rosana Cardoso Alves (São Paulo, Brazil) Hospital, Clinical Neurophysiology and Epilepsy Fellow - Boston, MA, USA) Karen Nunez-Wallace (Baylor College of Medicine - Houston, Texas, USA) Social Media and Visual Abstract Adriana Moro (Curitiba, Brazil) Infectious Diseases of the Nervous System and Cerebrospinal Fluid Studies Elisa de Paula França Resende (Belo Horizonte, Brazil) Cristiane Nascimento Soares (Rio de Janeiro, Brazil) Fernando Tensini (Curitiba, Brazil)
EDITORIAL BOARD
Acary de Souza Bulle Oliveira (São Paulo, Brazil) Andrew J. Lees (London, United Kingdom) Alberto J. Espay (Cincinatti, USA) Bruce L. Miller (San Francisco, USA) Alexis Brice (Paris, France) Bruce Ovbiagele (Charleston, USA) Andrea Slachevsky (Santiago, Chile) Carlos Alberto Mantovani Guerreiro (Campinas, Brazil) Américo Ceiki Sakamoto (Ribeirão Preto, Brazil) Carlos Roberto de Mello Rieder (Porto Alegre, Brazil) Christina Marra (Seattle, USA) Maria Lúcia Brito Ferreira (Recife, Brazil) Didier Leys (Lille, France) Marilisa Mantovani Guerreiro (Campinas, Brazil) Fernando Cendes (Campinas, Brazil) Mônica Levy Andersen (São Paulo, Brazil) Fernando Kok (São Paulo, Brazil) Oscar Del Brutto (Guayaquil, Ecuador) Francisco Cardoso (Belo Horizonte, Brazil) Oscar Gershanik (Buenos Aires, Argentina) Giancarlo Comi (Milan, Italy) Osvaldo José Moreira do Nascimento (Rio de Janeiro, Brazil) Gilmar Fernandes do Prado (São Paulo, Brazil) Osvaldo Massaiti Takayanagui (Ribeirão Preto, Brazil) Henrique Ballalai Ferraz (São Paulo, Brazil) Pedro Chaná-Cuevas (Santiago, Chile) Hugh J. Willison (Glasgow, United Kingdom) Raimundo Pereira da Silva Neto (Teresina, Brazil) Jaderson Costa da Costa, (Porto Alegre, Brazil) Regina Maria Papais-Alvarenga (Rio de Janeiro, Brazil) João José Freitas de Carvalho (Fortaleza, Brazil) Ricardo Allegri (Buenos Aires, Argentina) Joaquim Ferreira (Lisbon, Portugal) Ricardo Nitrini (São Paulo, Brazil) Joaquim Pereira Brasil Neto (Brasília, Brazil) Roger Walz (Florianópolis, Brazil) José Manuel Ferro (Lisbon, Portugal) Rubens José Gagliardi (São Paulo, Brazil) Lineu César Werneck (Curitiba, Brazil) Sérgio Teixeira Ferreira (Rio de Janeiro, Brazil) Luiz Henrique Martins Castro (São Paulo, Brazil) Stefan Schwab (Erlangen, Germany) Márcia Lorena Fagundes Chaves (Porto Alegre, Brazil) Ugo Nocentini (Roma, Italy) Marco Aurélio Lana-Peixoto (Belo Horizonte, Brazil) Umbertina Conti Reed (São Paulo, Brazil) Marcos Raimundo Gomes de Freitas (Rio de Janeiro, Brazil) Vladimir Hachinski (London, Canada) Maria José Sá (Porto, Portugal) Walter A. Rocca (Rochester, USA)
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 Academia Brasileira de Neurologia, no provide society registered in the 1° Oficial de Registro de Títulos e Documentos e Civil de Pessoa Jurídica, in the Ministério da Fazenda (CNPJ 43.185.230/0001-85) and in the Secretaria de Finanças do Município de São Paulo (CCM 9.129.811-3). 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.
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Arquivos de Neuro -psiquiatriA Volume 79, Number 6, June 2021, São Paulo, SP, Brazil
EDITORIAL 467 Images in Clinical Neurophysiology: a new subsection Imagens em Neurofisiologia Clínica: uma nova subseção Fábio Augusto NASCIMENTO, Karen NUNEZ-WALLACE
ARTICLE 469 Level of knowledge and misconceptions about brain concussion in Brazilian adults Nível de conhecimento e de equívocos sobre concussão cerebral em adultos brasileiros Amanda Vitória Lacerda DE ARAÚJO, Renata AREZA-FEGYVERES, Carla Cristina GUARIGLIA, Jéssica Natuline IANOF, Regina Maria BARATHO, José Luiz Carlos DEMARIO, Rafael Gustavo Sato WATANABE, Renato ANGHINAH 478 What can be expected to be seen in a Neurology ward? Eleven-year experience in a Brazilian university hospital O que se espera encontrar em uma enfermaria de Neurologia? A experiência de 11 anos em um hospital universitário brasileiro Daniel Gabay MOREIRA, Enedina Maria Lobato de OLIVEIRA, Fernando Morgadinho dos Santos COELHO, Henrique Ballalai FERRAZ, Silvio FRANCISCO, Vanderci BORGES, Denis Bernardi BICHUETTI 483 Evaluation of structural changes in orbitofrontal cortex in relation to medication overuse in migraine patients: a diffusion tensor imaging study Avaliação das mudanças estruturais no córtex orbitofrontal em relação ao uso excessivo de medicamentos em pacientes com migrânea: um estudo de imagem por tensor de difusão Aygul TANTIK PAK, Sebahat NACAR DOGAN, Yildizhan SENGUL 489 Determinants of disability development in patients with multiple sclerosis Determinantes do desenvolvimento de deficiência em pacientes com esclerose múltipla Fatma KARA, Mehmet Fatih GÖL, Cavit BOZ 497 Epidemiological and clinical aspects of Guillain-Barré syndrome and its variants Aspectos epidemiológicos e clínicos da síndrome de Guillain-Barré e suas variantes Dayanne Rodrigues da Cunha Alves Bento OLIVEIRA, Rubens Nelson Morato FERNANDEZ, Talyta Cortez GRIPPE, Fabiano Silva BAIÃO, Rafael Lourenco DUARTE, Diego Jose FERNANDEZ 504 Primary central nervous system tumors in Sergipe, Brazil: descriptive epidemiology between 2010 and 2018 Tumores primários do sistema nervoso central em Sergipe, Brasil: epidemiologia descritiva entre 2010 e 2018 Bárbara Loiola SANTOS, Arthur Maynart Pereira OLIVEIRA, Hélio Araújo OLIVEIRA, Robson Luis Oliveira de AMORIM 511 Effects of resistance training on postural control in Parkinson’s disease: a randomized controlled trial Efeitos de um treinamento de resistência muscular no controle postural em indivíduos com doença de Parkinson: um estudo aleatorizado controlado Janini CHEN, Hsin Fen CHIEN, Debora Cristina Valente FRANCATO, Alessandra Ferreira BARBOSA, Carolina de Oliveira SOUZA, Mariana Callil VOOS, Julia Maria D’Andréa GREVE, Egberto Reis BARBOSA 521 High prevalence of psychiatric comorbidities in children and adolescents at a tertiary epilepsy center Alta prevalência de comorbidades psiquiátricas em crianças e adolescentes de um centro terciário de epilepsia Maria Antonia SERRA-PINHEIRO, Isabella D’ANDREA-MEIRA, Abraão Iuri Medeiros ANGELIM, Fernanda Alves FONSECA, Nicolle ZIMMERMANN
VIEW AND REVIEW 527 Music-based therapy in rehabilitation of people with multiple sclerosis: a systematic review of clinical trials Terapia baseada na música na reabilitação de indivíduos com esclerose múltipla: revisão sistemática de ensaios clínicos Josiane LOPES, Ivo Ilvan KEPPERS 536 Born to move: a review on the impact of physical exercise on brain health and the evidence from human controlled trials Nascidos para o movimento: uma revisão sobre o impacto do exercício físico na saúde do cérebro e as evidências de estudos controlados em humanos Camila VORKAPIC, Silvânia LEAL, Heloisa ALVES, Michael DOUGLAS, André BRITTO, Estélio Henrique Martin DANTAS TABLE OF CONTENTS
HISTORICAL NOTES 551 “Estrutura da Celula Nervoza”, by Bruno Lobo and Gaspar Vianna (1908): a pioneering work on Brazilian Neuroscience “Estrutura da Celula Nervoza”, de Bruno Lobo e Gaspar Vianna (1908): uma obra pioneira na Neurociência brasileira Bruno Lopes SANTOS-LOBATO, José Eymard Homem PITTELLA 554 Probable first report of a motor deafferentation syndrome in the Paraguayan War Provável primeiro relato de uma síndrome de desaferentação motora na Guerra do Paraguai Marleide da Mota GOMES, Marcos Raimundo Gomes de FREITAS
IMAGES IN NEUROLOGY 557 Sentinel inflammatory demyelinating lesions preceding primary CNS lymphoma Lesões inflamatórias desmielinizantes sentinelas precedendo linfoma primário do SNC Danielle Mesquita TORRES, Milena Sales PITOMBEIRA, Igor Bessa SANTIAGO, Gabriela Joca MARTINS, Kellen Paiva FERMON, Daniel Gurgel Fernandes TAVORA, Fernanda Martins Maia CARVALHO 559 Value of 3D-TOF MR angiography and 4D-dynamic contrast-enhanced MRI in the assessment of spontaneous posterior cavernous sinus dural arteriovenous fistula Valor da angiografia por ressonância magnética 3D-TOF e RM 4D-dinâmica pós- contraste na avaliação de fístula arteriovenosa espontânea do seio cavernoso Francisco Bermal CAPARROZ NETO, Lucas Giansante ABUD, Rafael Gouveia Gomes de OLIVEIRA, Daniel Giansante ABUD, Soraia Ramos Cabete FABIO
LETTERS 561 Comment on “YouTube as a source of information for restless leg syndrome” Comentário sobre “YouTube como fonte de informação a respeito da síndrome das pernas inquietas” Alisha DUGGAL, Taghreed ALWAN, Shan ALI, Tomasz SZMUDA, Paweł SŁONIEWSKI
ERRATUM 562 Erratum https://doi.org/10.1590/0004-282X-ANP-2021-e006 EDITORIAL
Images in Clinical Neurophysiology: a new subsection Imagens em Neurofisiologia Clínica: uma nova subseção Fábio Augusto NASCIMENTO1, Karen NUNEZ-WALLACE2
he subspecialty of Clinical Neurophysiology involves the assessment of function of the central, peripheral, and autonomic nervous systems as well as skeletal muscle 1Massachusetts General Hospital, Department of Neurology, Boston, using both clinical evaluation and electrophysiologic testing. The latter includes MA, USA. electroencephalography (EEG), magnetoencephalography (MEG), electromyogra- 2Optum Care Medical Group, Huntington Beach, CA, USA. Tphy (EMG), nerve conduction studies (NCS), polysomnography (PSG), evoked potentials, and Fábio Augusto NASCIMENTO autonomic testing. Practicing in clinical neurophysiology requires a sound understanding of https://orcid.org/0000-0002- clinical neurology, normal neurophysiology, and the wide array of abnormal neurophysiologic 7161-6385; Karen NUNEZ-WALLACE https://orcid.org/0000-0003- findings that may be associated with different neurologic disorders. 2114-4735 It is often challenging for neurology trainees to acquire optimal knowledge in neurophysiol- Correspondence: Fábio Augusto Nascimento e Silva; E-mail: ogy during residency given its high clinical demand coupled with the multitude of subspecialties [email protected]; within neurology. Similarly, trainees may not have the opportunity to be exposed to all facets of [email protected]. Conflict of interest: There is no clinical neurophysiology thereby narrowing their experience as budding neurologists. In light conflict of interest to declare. of these system-based constraints, the Arquivos de Neuro-Psiquiatria recognizes the need for a Authors’ contribution: FAN: new journal subsection exclusively focused on the field of clinical neurophysiology. We hope this drafting manuscript; KNW: drafting manuscript. subsection will expand trainees’ learning experience and ultimately improve patient care as well Received on May 27, 2021; Accepted as potentially encourage some trainees to pursue further training in neurophysiology. on May 27, 2021. Images in Clinical Neurophysiology welcomes manuscripts with highly educational value related to the subspecialty of neurophysiology. Neurophysiologic content (educational images and/or videos of EEG, EMG, NCS, PSG, and evoked potentials) should be previously unpub- lished, interesting material highlighting clear examples of established observations curated for a trainee readership. Authors should also submit three multiple-choice questions along with answers related to the respective manuscript. Authors may consider selecting cases of uncommon presentations of common neuro- physiologic disorders or common presentations of uncommon neurophysiologic disorders. Additionally, describing artifacts that may be mistakenly interpreted as abnormal also has great educational value. Within the realm of EEG and epilepsy, authors may consider the fol- lowing examples as reference: • A case of typical notched delta pattern on EEG in a patient with Angelman syndrome1. • A report of the “texting rhythm” on EEG associated with cortical processing related to the use of personal electronic devices2. • A description of snoring-related artifact, which was previously thought to arise from the cortex overlying the amygdala (“limbic spindles”)3.
Within the realm of electrodiagnostic testing in neuromuscular medicine, the following examples may serve as excellent teaching tools in highlighting the technical aspects of testing as well as the importance of a keen clinical correlation: • The presence of ‘pseudo-conduction block’ without other demyelinating features in vascu- litic mononeuritis multiplex, where a conduction block is manifested by focal infarction and axonal loss rather than the typical demyelinating mechanism4. • The lack of temporal dispersion and conduction block with a predominance of prolonged distal latencies in anti-MAG demyelinating neuropathy, which provides a distinguishing feature from CIDP (chronic inflammatory demyelinating polyradiculopathy)5.
467 • The evaluation of anatomical variants, such an acces- across the globe. We are truly grateful to the Arquivos de sory deep peroneal nerve, in case of peroneal neurop- Neuro-Psiquiatria for creating this new subsection in the jour- athy resulting in foot drop with preservation of toe nal. We hope Images in Clinical Neurophysiology will become extension6. a unique educational resource and serve to (i) supplement neurophysiology education on an international level and (ii) We hope to attract outstanding and highly educational inspire neurology trainees to embrace the fascinating field of neurophysiology manuscripts ideally led by trainees from neurophysiology.
References
1. Nascimento FA, Thiele EA, Thibert RL. Teaching neuroimages: 4. McCluskey L, Feinberg D, Cantor C, Bird S. “Pseudo-conduction notched delta and angelman Syndrome. Neurology. 2021 block” in vasculitic neuropathy. Muscle Nerve. 1999 Oct;22(10):1361- May;10.1212/WNL.0000000000012201. https://doi.org/10.1212/ 6. https://doi.org/10.1002/(sici)1097-4598(199910)22:10<1361::aid- WNL.0000000000012201 mus4>3.0.co;2-1 2. Hanrahan B, Tatum 4th WO. Teaching NeuroImages: Texting 5. Gondim F, De Sousa EA, Latov N, Sander HW, Chin RL, Brannagan TH. rhythm: A common EEG finding in the era of smartphone use. Anti-MAG/SGPG associated neuropathy does not commonly cause Neurology. 2020 Dec;95(24):e3454-55. https://doi.org/10.1212/ distal nerve temporal dispersion. J Neurol Neurosurg Psychiatry. WNL.0000000000010757 2007 Aug;78(8):902-4. https://doi.org/10.1136/jnnp.2006.111930 3. Sheikh Z. Snoring-related artifact: scalp EEG correlate of historical 6. Kayal R, Katirji B. Atypical deep peroneal neuropathy in the “limbic spindles”. Epileptic Disord. 2021 Feb;23(1):201-2. https://doi. setting of an accessory deep peroneal nerve. Muscle Nerve. 2009 org/10.1684/epd.2021.1241 Aug;40(2):313-5. https://doi.org/10.1002/mus.21324
468 Arq Neuropsiquiatr 2021;79(6):467-468 https://doi.org/10.1590/0004-282X-ANP-2019-0436 ARTICLE
Level of knowledge and misconceptions about brain concussion in Brazilian adults Nível de conhecimento e de equívocos sobre concussão cerebral em adultos brasileiros Amanda Vitória Lacerda DE ARAÚJO1, Renata AREZA-FEGYVERES1, Carla Cristina GUARIGLIA1, Jéssica Natuline IANOF1, Regina Maria BARATHO2, José Luiz Carlos DEMARIO2, Rafael Gustavo Sato WATANABE1, Renato ANGHINAH1
ABSTRACT Background: Brain concussion (BC) is seen as a public health priority due to its high incidence and morbidity rate, among thousands of people around the world. There are needs for fast identification, accurate diagnosis and correct management in order to reduce the short and long-term problems relating to BC. Proper knowledge of BC in the population and among clinicians is a critical factor in achieving this. Objectives: To evaluate the level of self-reported BC knowledge and gaps/misconceptions, and to identify variables correlated with this level. Methods: A cross-sectional descriptive survey was performed. A Brain Concussion Knowledge Questionnaire (BCKQ) that had been created to capture data was widely distributed. Total scores, domain partial scores and percentages of correct and incorrect answers were calculated to ascertain the level of knowledge relating to BC. Results: The sample was formed by 1,247 Brazilian adults (age: 41.7±11.8 years). Partial scores of the BCKQ revealed the existence of poor knowledge and misconceptions in all domains of the questionnaire, especially regarding questions about recovery from and management of BC. Moderate correlations between BCKQ scores and professions (p=0.312; P=0.00) or previous brain concussion knowledge (p=0.489; P=0.00) were observed. In a multiple linear regression model, age, profession and sports practice were predictors of BC knowledge. Conclusion: This first study to analyze the level of BC knowledge in a sample of Brazilian adults suggests that poor knowledge and misconceptions are present. Thus, meaningful and useful information was provided by this study for developing health education programs about BC for the population in order to improve fast diagnosis and correct BC management. Keywords: Brain Concussion; Cerebral Concussion; Health Care; Questionnaires.
RESUMO Introdução: A concussão cerebral (CC) é considerada prioridade em saúde pública devido à sua alta incidência e taxa de morbidade. Há necessidade de identificação rápida, diagnóstico acurado e manejo correto após essas lesões, com objetivo de reduzir problemas de curto e longo prazo. O conhecimento apropriado da população, atletas e de clínicos é primordial para que isto seja alcançado. Objetivos: Avaliar o nível de conhecimento autorrelatado sobre CC, descrever lacunas/equívocos e identificar variáveis correlacionadas com este nível. Métodos: Foi realizada uma pesquisa descritiva transversal. O Questionário de Conhecimento sobre Concussão Cerebral (QCCC) criado foi amplamente distribuído. Pontuações totais e parciais em domínios e porcentagens de respostas corretas e incorretas foram calculadas para obter o nível de conhecimento sobre CC. Resultados: A amostra foi formada por 1.247 brasileiros adultos (41,7±11,8 anos). Pontuações parciais do QCCC revelaram baixo nível de conhecimento, principalmente em questões sobre recuperação e manejo. Observou‑se correlações moderadas entre a pontuação no QCCC e a profissão dos participantes (p=0,312, P=0,00) ou conhecimento prévio sobre CC (p=0,489, P=0,00). A regressão linear múltipla mostrou que a idade, profissão e prática de esportes podem ser preditoras do conhecimento sobre CC. Conclusão: Esse primeiro estudo a analisar o nível de conhecimento sobre CC em uma amostra de adultos brasileiros sugere baixo conhecimento e equívocos sobre esta condição. Assim, informações úteis e significantes foram fornecidas para o desenvolvimento de programas de educação em saúde sobre CC para o público, com objetivo de melhorar a identificação rápida e o manejo correto de concussões. Palavras-chave: Concussão Encefálica; Concussão Cerebral; Atenção à Saúde; Questionários.
1Universidade de São Paulo, Ambulatório de Reabilitação Cognitiva Pós-Trauma Cranioencefálico, São Paulo, SP, Brazil. 2Universidade de São Paulo, Centro Dr. Jair Minoto Abe, São Paulo SP, Brazil. Amanda Vitória Lacerda DE ARAÚJO https://orcid.org/0000-0003-2681-4240; Renata AREZA-FEGYVERES https://orcid.org/0000-0003-2913-7089; Carla Cristina GUARIGLIA https://orcid.org/0000-0003-2979-9330; Jéssica Natuline IANOF https://orcid.org/0000-0002-8720-6137; Regina Maria BARATHO https://orcid.org/0000-0001-8743-1740; José Luiz Carlos DEMARIO https://orcid.org/0000-0002-6090-7478; Rafael Gustavo Sato WATANABE https://orcid.org/0000-0003-1684-573X; Renato ANGHINAH https://orcid.org/0000-0001-8414-8536 Correspondence: Amanda Vitória Lacerda de Araújo; E-mail: [email protected]. Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: AVLA, RAF, CCG, and RW were responsible for designing the study and constructing the questionnaire. AVLA, RA, and RAF wrote the study and critically assessed the methodological quality. JNI interpreted the results, updated reference lists and created tables and figures. RMB and JLCD were responsible for statistical analysis. Received on December 17, 2019; Received in its final form on July 22, 2020; Accepted on August 04, 2020.
469 INTRODUCTION The lack of evidence about BC knowledge among Brazilians makes it difficult to develop health education programs and, Brain concussion (BC) is a type of mild traumatic brain consequently, to prevent BC. Thus, the current study has an injury (TBI)1. It is a complex injury that increasingly is receiv- important role, consisting of identifying whether there is a ing the attention of researchers. BC is seen as a public health lack of knowledge or misconceptions about BC. Furthermore, priority2 due to its high incidence among contact sports play- these data should serve as a basis in the literature for devel- ers3,4 and the large numbers of cases in the general popu- oping future studies that aim to carry out health education lation5,6, which leads to morbidity in thousands of people programs to alert about the dangers of BC. worldwide. The United States Centers for Disease Control Moreover, the present study on BC knowledge levels has estimated that the annual incidence of TBI ranges from should highlight problems relating to access to health infor- 1.6 to 3.8 million cases, including sports-related concussion7. mation and prevention of BC in a population in Brazil, an In Brazil, Junge et al.8 showed that TBI was the second most emerging country. This is particularly important because pre- prevalent injury in football (soccer) during the World Cup vious Brazilian studies showed that the estimated incidence in Brazil in 2014. Thus, brain concussions are seen as a pub- of TBI was low18, compared with what has been reported lic health priority2 particularly in countries where contact in studies conducted in other countries. Moreover, previ- sports are very common, such as football in Brazil. ous Brazilian studies found low rates of brain concussion A non-penetrating blunt head trauma resulting in func- reported (38–53%) among TBI cases notified21, in compari- tional transient brain disturbance may involve altered mental son with the BC rates of 80–90% identified10,18 in other stud- status, loss of consciousness and post-concussive symptoms, ies. Lower incidence and notification rates could be related such as headache, dizziness, memory deficits, poor attention to poor BC knowledge in the population and, therefore, prob- or irritability9,10. Therefore, BC is of concern because of the lems with case identification, thus leading to unreported hos- spectrum of potential complications relating to it. pital notifications. Thus, based on previous data10,22, preven- Potential complications involve persistence of post-con- tion of potentially serious short and long-term consequences cussive symptoms for prolonged periods of time (>3 months), relating to BC could be impaired by poor knowledge. and are seen in 10–15% of concussed individuals11,12,13. Hence, there is a critical need to develop research eval- Prolonged post-concussive symptoms are related to impair- uating the Brazilian population’s BC knowledge in order to ments of quality of life14 and may lead to contact sports play- identify problems or misconceptions about BC and provide ers’ retirement5,14. Furthermore, repeated brain concussions the basis for developing health education programs aimed at have been associated with chronic traumatic encephalopa- prevent the consequences of these shortcomings. The cur- thy in contact sports players14. This progressive tauopathy rent cross-sectional study was performed (1) to evaluate the leads to deleterious effects on long-term brain functioning12. level of self-reported BC knowledge in a sample of Brazilian Moreover, a second impact syndrome leading to catastrophic adults; (2) to describe gaps or misconceptions; and (3) to cerebral edema and death may occur if people suffer a sec- identify variables correlated with BC knowledge levels. ond impact before the first BC has been resolved15,16. Because of the potential harm caused by BC, and its inci- dence, there are needs for fast identification, accurate diag- METHODS nosis and correct management, to reduce the short and long-term problems. Identification of BC depends on symp- In order to assess the level of BC knowledge in a sample toms detected through clinical observations and patient of Brazilian adults, a cross-sectional descriptive survey was self-reporting, or observations by witnesses5,10. Thus, proper conducted. An online questionnaire was distributed between knowledge of BC in the population and among sports play- January and August 2018. Ethical approval was obtained ers and clinicians is a critical factor for improving the iden- from the University of São Paulo Human Research Ethics tification, reporting and correct management of BC as well Committee; all participants provided online informed con- as reducing post-concussive sequelae, severe long-term brain sent prior to study enrolment; and data were stored and pro- function consequences, and death16,17. cessed anonymously. Knowledge regarding BC in the general population has been investigated in a range of studies around the world. Participants However, the results have suggested that knowledge or mis- Participants were selected through an open sampling conceptions about BC is poor among sports players clini- procedure by means of clusters. Self-administered online cians, and general population18,19,20. Thus, there is a need for surveys were distributed to potential participants randomly. BC health education programs around the world, and efforts Participants belonging to sports clubs, athletic associa- to implement such programs are currently underway it18,19,20. tions, universities and schools located in São Paulo, Brazil, On the other hand, to the best of our knowledge, there are no were recruited. Participants were considered eligible if they Brazilian studies on the level of knowledge about BC in Brazil. were males or females living in Brazil, aged over 18 years and
470 Arq Neuropsiquiatr 2021;79(6):469-477 native Portuguese speakers. Invitations to complete the sur- score of six points is possible. In the domains of functional vey were disseminated via e-mail and social media, consist- and neurological consequences of BC and recovery and man- ing of an information form that explained the details of the agement, nine points are possible. The 18-item checklist study and invited participation. was scored with one point for each correct sign or symptom (ranging from 0 to 18). Survey design Based on a detailed review of the literature, previous sur- Statistical analysis veys3,23 and feedback from two experts in the field of BC The data were entered into a Microsoft Excel spread- (RAF and RA), a pilot version of the structured 31-item Brain sheet (v. 2010, Microsoft®). Descriptive statistics were cal- Concussion Knowledge Questionnaire (BCKQ) was gener- culated to summarize demographics, total BCKQ score, par- ated and screened for mistakes. The pilot version was cor- tial scores, percentage of correct and incorrect answers and rected and subsequently applied to a representative sample adherence rate. Normally-distributed data were described of Brazilians. Additional adjustments were made to produce as the mean and standard deviation (SD) and non-normal the final version of the BCKQ. data as the median and percentile. Frequency and percen- Statements for the BCKQ were context-adapted from tile were used to describe categorical variables. Our pri- the previous studies3,23. Additional statements were included mary outcomes were the total score found through the with a view to deepening the evaluation of concussion BCKQ survey, partial scores for each domain and percent- knowledge. The BCKQ was developed on an online platform age of correct answers. The data were then entered into, and (Google Forms®). all analyses were performed in, the SPSS software, version An online-link survey method was used to improve the 21. Pearson’s correlation coefficient (r) was used to exam- applicability of the BCKQ because this allows recruitment ine correlations between the total BCKQ score and age. of a larger sample and makes it possible for individuals who Correlations between the total BCKQ score and the vari- would be unable to attend a face-to-face meeting, to respond ables of sex, degree of schooling, type of profession, prac- to the survey from their homes24. Moreover, instant electronic ticing of sports, previous concussion knowledge and his- data archiving makes the data collection more flexible25. tory of concussion were analyzed by means of Spearman’s The BCKQ contained written instructions, an online informed rho (p). All analyses were conducted with the significance consent form and 31 items designed for self-administration. level set at p<0.05. Missing data were reported in the Results The BCKQ was structured into three parts: a demographic section and were used to calculate the adherence rate of section (sex, age, schooling and profession), an experience- the BCKQ. A multiple linear regression model was used to related section (sports practice, BC history and previous con- determine factors influencing the level of knowledge about cussion education) and a brain concussion knowledge sec- BC. The independent variables included in the regression tion (31 items). These 31 items were divided into four specific model were age, sex, degree of schooling, type of profession domains: identification and causes of BC (six items); func- and practicing of sports and its frequency. tional and neurological consequences of BC (nine items); recovery and management after BC (nine items); and sports- related BC (six items). Each item presents BC facts or miscon- RESULTS ceptions, in which the participant is able to choose between true or false alternatives. Additionally, the BCKQ has a check- The BCKQ survey was completed by 1247 Brazilian adults list containing the fourteen most frequent BC signs or symp- (mean age 41.7±11.8 years), living in São Paulo. The demo- toms26,27 plus four distractor symptoms. The participants graphics of the participants are listed in Table 1. were informed that they should mark all signs/symptoms Table 2 summarizes the data on previous BC knowledge that they thought were related to BC. No definition of BC was and history of BC. A total of 56% of the participants (n=700) provided for the participants, so that this would not influ- reported having previous knowledge about BC. However, ence the participants’ responses. a high number of people reported the alternative “I do not All 31 BCKQ items were tabulated to create a total BC know or I’m not sure what brain concussion is” (44%; n=547). knowledge score. Each item of the specific domains was These data highlight the absence of knowledge about BC in a marked as either correct or incorrect. A score of one point high percentage of the sample and should be considered con- was given for the correct answer. Total BC knowledge was cerning. Participants who checked the option “I do not know calculated by summing the number of correct answers. or I’m not sure what brain concussion is” did not proceed to The total possible BCKQ score is 48 points: this score rep- the next section of the questionnaire. Thus, the BCKQ total resenting 100% correct answers and, therefore, high or and partial scores are presented based on a sample of 700 improved knowledge of BC. The total score is formed by the participants. sum of the partial scores from the domains. In the domains Knowledge gaps and misconceptions were identified of identification and causes of BC and sports-related BC, a through the BCKQ total score. The mean total BCKQ score
Araújo AVL et al. Brain concussion knowledge in Brazil 471 Table 1. Demographic characteristics of the study sample Table 2. Information on previous knowledge of concussion or (n=1,247). history of concussion (n=1,247). Demographic characteristics Frequency (%) Frequency Questions and alternatives (%) Sex (n=1,247) Have you heard of concussion? (n=1,247) Female 1048 (84) Yes 701 (56) Male 199 (16) No 546 (44) Age in years (n=1,247) What is your source of knowledge about concussion? (n=1,014) <20 9 (0.7) Healthcare professional 268 (38) 20–29 165 (13.2) Television, newspaper or magazine 272 (39) 30–39 435 (34.9) Internet 189 (27) 40–49 313 (25) Coach or team coach 25 (4) 50–59 210 (16.8) Congress, conference or scientific meeting 51 (7) 60–69 103 (8.3) Others 209 (30) >70 12 (1) Have you ever had concussion or do you live with someone who Education level (n=1,247) has had concussion? (n=1,365*) Elementary school 6 (4.8) I have never had concussion 635 (51) High school graduate 121 (9.8) Yes, I have already had concussion 62 (5) Bachelor’s degree or higher 1120 (89.8) Yes, I have a family member or friend who had 126 (10) Profession concussion Fields of healthcare or sports 284 (23) I do not know or am not sure what concussion is 542 (44) Other areas 963 (77) Not available 7 (1) Type of sports (n=1,214) *Question with multiple possible answers. Contact sports 61 (5) Non-contact sports 704 (58) None 449 (37) Level of sports practice (n=1,239) Professional 21 (1.8) Semi-professional 49 (4) Recreational 703 (56.7) None 466 (37.6) Sports frequency None 449 (36) Once every 15 days 78 (6.3) Once or twice a week 288 (23.1) Three or four times a week 313 (25.1) Five or six times a week 69 (5.5) Figure 1. Percentages of correct and incorrect answers in each specific domain of the Brain Concussion Knowledge Daily 50 (4) Questionnaire, among the sample of Brazilian adults (n=700).
was 24±10.3 points, corresponding to a correct-answer rate rates of 58 and 55%, respectively. The domain of sports- of 50%. Thus, poor BC knowledge was observed. Based on related BC had a mean score of 4±1.4 points and a correct- the partial scores for each domain, specific larger gaps answer rate of 66%. or misconceptions could be seen in the domain of recov- In the question about the main signs or symptoms of ery and management after BC, with the lowest mean BC, the participants’ mean score for the 18-item checklist score (3.5±1.8 points) and lowest rate of correct answers was 7±3.3 points, corresponding to a correct-answer rate of (38%) (Figure 1). However, all the domains had low scores. 38%. Figure 2 shows the percentage of correct and incorrect The mean score in the domains of identification and causes answers. Anxiety (13%), depression (15%), noise intolerance of BC (3.5±1.5 points) and functional and neurological con- (21%), light intolerance (26%) and sleep disturbance (34%) sequences of BC (5±2 points) represented correct-answer had the lowest rates of correct answers (Figure 2).
472 Arq Neuropsiquiatr 2021;79(6):469-477 Data were based on a sample of 700 individuals. Figure 2. Percentages of signs and symptoms most commonly correlated with brain concussion, according to the responses among the sample of Brazilians adults, in the Brain Concussion Knowledge Questionnaire (n=700).
Table 3 show detailed information about the percent- schooling (p=0.106; P=0.00). No correlations were observed ages of the answers to each BCKQ statement. Alarming gaps for the other variables analyzed. and misconceptions were observed. There was a high rate of Multiple linear regression was performed on the data relat- incorrect answers (87%) to the statement “the only way to be ing to 700 participants (Table 4). This showed that age was sure that a person has suffered brain damage from a concus- significantly related to the level of BC knowledge. Thus, for sion is by cranial tomography or magnetic resonance imag- every one-year increase in age, the participants tended to ing of the skull”. Sixty-five percent believed that “emotional have a BCKQ score that was 0.15 points lower. Type of pro- problems after brain concussion are usually not related to fession, which was categorized as healthcare-related, sports- brain damage”. Similarly, 60% chose an incorrect answer related or unrelated to either of the preceding categories, was when asked if “a brain concussion can make a person feel also a predictor. Thus, participants in healthcare-related pro- depressed, hopeless and sad”. High rates of incorrect answers fessions tended to have higher BCKQ scores. Participants in were also observed regarding the statements “it is easy to tell sports-related professions had BCKQ scores that were 7.03 if a person has had brain damage from a concussion because points lower. This was an alarming result because sports pro- of the way a person behaves” (56%) and “most people who fessionals are close to individuals who are more likely to suf- suffer a brain concussion do not realize the effect of the injury fer a BC. Furthermore, participants who practiced sports had on their behavior and reasoning” (55%). Also, most of the par- BCKQ scores that were 1.82 points lower than those of par- ticipants (69%) did not know that “a person may die if a sec- ticipants who did not. Curiously, regression analysis showed ond brain concussion occurs before recovery from an earlier that participants who practiced sports daily had BCKQ concussion”. Impairment of the capacity to learn new things scores that were 4.01 points lower (Table 4). Since the indi- was also a knowledge gap for 358 of the participants (52%). viduals who played sports daily in our sample were athletes, Fifty-two percent of the participants (n=362) believed this is a worrying result. No interaction occurred between the that “recovery from a brain concussion does not occur”. Most other variables included in the model. of the participants (91%) also did not know that the symp- toms of a brain concussion pass after 10 days. Equally, 74% of the sample (n=517) presented incorrect answers when asked DISCUSSION if “sports players who had a brain concussion would be more likely to have another”. Fifty-five percent (n=385) thought that To the best of our knowledge, this is the first study to a sports player who had suffered a BC could continue playing examine the level of BC knowledge among Brazilian adults. if he or she felt good. Likewise, 57% of the sample believed The results from this cross-sectional descriptive survey pro- that a “soccer player who had suffered a brain concussion vide evidence of poor BC knowledge and a moderate rate of could return to the next ball practice if he or she felt well”. misconceptions in a sample of Brazilians with a high level The BCKQ adherence rate remained high for most ques- of schooling. Our findings showed that a high proportion of tions, with a rate of missing answers<1%. Moderate posi- the sample did not know what BC is (44%). These data high- tive correlations between BCKQ total scores and professions light the absence of knowledge about BC in a high percentage linked to the fields of healthcare or sports were observed of the sample and should be considered concerning. (p=0.312; P=0.00). Similarly, the BCKQ total score also showed Moreover, there was poor knowledge in all BCKQ domains, a moderate positive correlation with previous BC knowledge i.e., the participants had impaired knowledge of how to iden- (p=0.489; P=0.00). Only poor correlations were found in rela- tify a BC and what causes it, the functional and neurological tion to sex (p=0.096; P=0.00), age (r=0.2; p=0.00) and degree of consequences of BC, the recovery and correct management
Araújo AVL et al. Brain concussion knowledge in Brazil 473 Table 3. Knowledge gaps identified for each statement in specific domains of the Brain Concussion Knowledge Questionnaire, according to the answers of the Brazilian sample (n=700).
BCKQ (n=700) Frequency (%) Statements (correct answer) True False NA Domain of identification and causes of brain concussion 1. Brain concussion can cause brain damage even if the person has not fainted (T) 580 (82) 120 (18) 0 2. A person needs to have passed out to be diagnosed with brain concussion (F) 154 (23) 544 (77) 2 3. The only way to tell whether someone has suffered brain damage from concussion is by mean of 608 (87)* 91 (13) 1 cranial tomography or magnetic resonance imaging (F) 4. Brain concussion can only occur if there is a direct hit to the head (F) 233 (34) 465 (66) 2 5. An impact on the body that causes rapid acceleration and deceleration of the head can cause brain 528 (75) 172 (25) 0 damage even if there is no direct blow to the head (T) 6. It is easy to tell whether a person has brain damage from concussion from the way the person looks 391 (56)* 309 (44) 0 or behaves (F) Domain of functional and neurological consequences of brain concussion 7. Brain concussion is harmless and never results in long-term problems or brain damage (F) 196 (28) 504 (72) 0 8. A little brain damage does not matter, as people only use a small part of their brains anyway (F) 92 (13) 607 (87) 1 9. Most people who suffer brain concussion do not realize the effect of concussion on their behavior 310 (45) 388 (55)* 2 and reasoning (T) 10. A person may die if a second brain concussion occurs before recovery from a previous one (T) 223 (41) 473 (69)* 4 11. Brain concussion can make a person feel depressed, hopeless and sad (T) 278 (40) 422 (60)* 0 12. Emotional problems after brain concussion are usually not related to brain damage (F) 453 (65)* 245 (35) 2 13. A person who has suffered brain concussion may have trouble recalling facts before the 547 (78) 151 (22) 2 concussion (T) 14. Multiple concussions over the course of life can give rise to brain problems (T) 518 (74) 180 (26) 2 15. A person who has suffered brain concussion may have trouble learning new things (T) 330 (48) 368 (52)* 2 Domain of recovery and management of brain concussion 16. Sometimes a second blow to the head can help a person remember things that were forgotten (F) 273 (40) 425 (60) 2 17. Once a recovering person feels normal, the recovery process is complete (F) 197 (29) 501 (71) 2 18. Complete recovery from brain concussion is not possible, no matter how badly the person wants to 362 (52)* 337 (48) 1 recover (F) 19. How quickly a person recovers from brain concussion depends mainly on how hard they work 374 (54)* 324 (46) 2 on recovery (F) 20. It is recommended to rest and remain inactive during recovery from brain concussion (F) 521 (76)* 178 (24) 1 21. After 10 days the symptoms of brain concussion are usually completely gone (T) 65 (8) 634 (91)* 1 22. A person who has not recovered from brain concussion is less able to withstand a second blow to 297 (42) 402 (58)* 1 the head (T) 23. The most appropriate way to evaluate the progress of recovery after brain concussion is by asking 101 (14) 596 (86)* 3 the person who was concussed how they feel (T) 24. Most people wake up quickly and undamaged after being knocked unconscious by a blow to 165 (24) 531 (76)* 4 the head (T) Domain of sports-related brain concussion 25. In sports, brain concussion rarely happens (F) 70 (10) 628 (90) 2 26. Athletes who have had one brain concussion are more susceptible to having another (T) 178 (26) 517 (74)* 5 27. Athletes who practice contact sports are at greater risk of brain concussion (T) 560 (80) 137 (20) 3 28. A soccer player who has suffered brain concussion may continue to play as long as they feels 385 (55)* 313 (45) 2 good (F) 29. A soccer player who has suffered brain concussion during a workout can return to the next ball 401 (57)* 295 (43) 4 practice as long as they feel good (F) 30. A soccer player who felt dizzy after suffering brain concussion and returned to dizziness when 173 (25) 523 (75) 4 training should continue training until the dizziness improves (F) BCKQ: Brain Concussion Knowledge Questionnaire; F: false; T: true.
474 Arq Neuropsiquiatr 2021;79(6):469-477 Table 4. Multiple linear regression model to predict variables Similarly, a high number of incorrect answers were observed relating to brain concussion knowledge (n=700). regarding common signs or symptoms of BC. In our study, peo- Variables Estimate SE p-value ple had higher knowledge of post-concussive symptoms such Age (years) -0.15 0.03 <0.001* as confusion, headache, impaired consciousness, dizziness, Sex (female) 1.20 0.93 0.195 blurred vision and amnesia. However, there were very low num- Profession bers of correct answers in relation to behavioral symptoms, light or noise intolerance and sleep disturbance. Previous stud- Healthcare (reference category) 1.00 -- ies also showed limited knowledge regarding post-concussive Sports-related -7.03 2.37 0.003* symptoms in the general population29,30. Light or noise intoler- Not related to healthcare -7.32 0.84 <0.001* ance was also poorly identified in a study by Knollman-Potter or sports et al.31. Data from Waltzman et al.32 showed that a small por- Degree of schooling tion of their participants correctly chose sleep disturbance as Elementary school 1.00 -- a common post-concussive symptom. In agreement with our (reference category) findings, studies have demonstrated that people tend to be High school graduate 6.19 6.95 0.373 familiar with certain BC symptoms, such as headache, dizzi- Bachelor’s degree or higher 6.59 6.85 0.336 ness and impaired consciousness33,34. Behavioral symptoms are Sport practice (yes) 1.82 0.78 0.021* less correlated to a BC by the general population31. Sports frequency Overall, previous studies identified poor levels of BC None (reference category) 1.00 -- knowledge in various aspects such as post-concussive Once every 15 days -1.58 1.55 0.309 symptoms, identification, recovery and management after the BC3,17,19,20,34,35. For example, McKinlay et al.21 reported Once or twice a week -1.84 0.97 0.058 that there was significant uncertainty in the general popu- Three or four times a week -1.70 0.98 0.084 lation about what a BC is and how it should be managed. Five or six times a week -1.00 1.68 0.551 Other studies also reported these findings29,32. Our results Daily -4.01 1.92 0.037* were generally consistent with these previous studies. SE: standard error; *p<0.05. Interestingly, the first international study36 about BC knowledge showed that a significant proportion of their sam- ple believed that a second blow to the head could help mem- after BC and the recovery after sports-related BC. These find- ory recover, which also was shown in our study. A recent study ings are supported by the fact that many of the participants showed that the proportion of people who considered this stated that they did not know what a BC is. On the other hand, statement correct was only 10%3. Our results in this regard are a proportion of the participants stated that they had previous only concordant with those of a study conducted in 1988. Thus, BC knowledge from healthcare professionals, the internet or there is concern about this information, and it highlights the television, newspapers or magazines. Thus, our findings show significant breadth of misconceptions found in our study. that when the participants had previous BC information, the Other specific findings from previous studies are concor- transfer of knowledge may have been impaired, thus resulting dant with our results. One study3 showed that a high number in gaps or misconceptions. Furthermore, an additional con- of participants rejected the statement regarding the increased cern was noted through multiple linear regression, consider- likelihood of a second blow to the head in sports. The percent- ing that playing sports daily and having sports-related profes- age of incorrect answers to this statement was also high in sions were predictive variables for lower scores in the BCKQ. our study. Similarly, these authors3 indicated that a substan- tial number of participants considered that the most appro- Brain concussion knowledge priate way to evaluate the recovery would be to ask individu- The BC knowledge scores varied depending on the BCKQ als who had become concussed how they felt. The same was domain. For instance, there was a higher number of incorrect observed in our sample. In comparing our findings with those answers in relation to statements about recovery and manage- of the study by Weber and Edwards3, on which our question- ment after BC. This finding is worrying because a lack of ade- naire was based, the level of BC knowledge in our sample was quate management and recovery may expose people to more significantly lower. Thus, our data support the data in the serious consequences, such as post-concussion syndrome9,10, current literature and show that Brazilian adults with high chronic traumatic encephalopathy15 or second impact syn- schooling levels had poor knowledge about BC. These find- drome16. To prevent the range of potential consequences ings highlight the urgency of health education regarding BC in of a BC, the Brazilian population needs to become familiar Brazil. Studies have indicated that implementation of health with the various aspects of BC management and recovery. education programs for the general population have led to Previous studies also found that there was limited knowledge gains in knowledge regarding the symptoms of BC, identifica- regarding the recovery and management of people with BC3,28. tion of this condition and correct recovery from it18,37,38.
Araújo AVL et al. Brain concussion knowledge in Brazil 475 Improvements of knowledge about BC in the general pop- BC education programs are established, studies should be ulation may increase the frequency of symptom reporting conducted to ascertain the most effective means of dissemi- and demands for treatment39, as well as helping to prevent nating information to the general population. a range of complications and sequelae18 relating to BC. In the light of the results from these previous studies, an increasing Study limitations and future research number of health education programs aimed at various sec- There are several limitations to this study. First, despite the tors of the population have emerged in other countries18,37,38,39. authors’ attempt to obtain a diversified sample of Brazilian Unfortunately, this scenario has not been observed in Brazil. adults, the final sample was composed of a higher number of Hence, the current study highlights the need for an females, people with high schooling levels and non-athletes. approach to health education for the general population This sample composition may limit the ability to generalize regarding prevention of BC, which would reduce the poten- the results from our study. Second, use of an online survey to tially serious short and long-term consequences of this reach a wider range of participants may introduce the inabil- injury. The results highlight evidence of poor knowledge and ity to verify whether participants answered the questions misconceptions about BC, which may be related to impaired without help from other sources of knowledge. prevention plus a high rate of unreported BC at healthcare For future research, the aim should be to have a proba- services in Brazil10,18. Furthermore, our results serve as a basis bilistic sample that is also homogeneous, i.e., with a balance for developing future studies that aim to develop health edu- of factors such as sex, age, profession, socioeconomic status, cation programs for the general population or to investigate education level and exercise practice level. Moreover, studies specific aspects of the poor knowledge and misconceptions using interviews, comprehensive methodologies, qualitative found in this study. research or open-ended questions may help to understand Regarding health education programs aimed at the general patterns of responses, difficulties in interpretation or mis- population, previous studies have shown that as more infor- conceptions of understanding of the survey. Larger studies mation about the etiology, management and sequelae of BC aiming to ascertain the variables that influence knowledge of has emerged, awareness about the importance of safe concus- concussion should be conducted. In addition, future studies sion management has improved17,18,31,37,38,39. This has been dem- investigating the effectiveness of using health education pro- onstrated through improvements in some concussion-related grams about BC are strongly recommended. knowledge over time38. Thus, understanding the knowledge In conclusion, in this first study to examine the level of gaps and misconceptions contributes to formulating strate- BC knowledge among Brazilian adults, the findings showed gies that are needed to specifically address these problems29. that BC knowledge was poor. This mirrors previous studies. Education programs should ideally promote active Our study provided very useful information about BC knowl- engagement of patients and improve the ability to apply pre- edge among Brazilian adults and demonstrated the need vious healthcare knowledge in situations of everyday life31. for health education programs about BC. Health education The approaches used need to include multiple parts of soci- programs can improve the knowledge of the population and ety, such as the general community, parents, caregivers, ath- should help to increase rapid identification and correct man- letes and healthcare professionals39. Furthermore, dissemi- agement of BC. Larger-scale research is needed to investi- nation of information should include government resources, gate the BC knowledge among groups of Brazilians such as campaigns and structured programs within public health- healthcare and sports professionals. Variables that influence care services31. To educate the general population about BC knowledge should be investigated in larger samples in BC, the educational methods and materials used should be order to understand what the main focus of health educa- focused on websites, flyers or lectures17,31,39. However, before tional programs should be.
References
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Araújo AVL et al. Brain concussion knowledge in Brazil 477 https://doi.org/10.1590/0004-282X-ANP-2020-0310 ARTICLE
What can be expected to be seen in a Neurology ward? Eleven-year experience in a Brazilian university hospital O que se espera encontrar em uma enfermaria de Neurologia? A experiência de 11 anos em um hospital universitário brasileiro Daniel Gabay MOREIRA1, Enedina Maria Lobato de OLIVEIRA1, Fernando Morgadinho dos Santos COELHO1, Henrique Ballalai FERRAZ1, Silvio FRANCISCO1, Vanderci BORGES1, Denis Bernardi BICHUETTI1
ABSTRACT Background: Neurological disorders are significant causes of morbidity and mortality worldwide. However, data about general neurological inpatient admissions in Brazil is limited. Objective: To investigate the prevalence of neurological disorders according to disease group and lesion site among patients admitted to a general Neurology ward. Methods: This was an observational and descriptive study. The hospital discharge database for the Neurology ward was surveyed in accordance with the International Classification of Diseases, 10th edition (ICD-10), from September 2008 to October 2019. The final diagnosis was classified into neurological disorder groups and site.Results: Overall, 2,606 clinical neurological patient files were included, with mean length of hospitalization of 16.7 days and a total of 325 readmissions (12.5%). The overall mortality rate in the ward was 3.8% (100 patients). Among all the diagnoses, cerebrovascular disease was the most prevalent (45.8%), followed by inflammatory disorders (22.2%). The brain was the most common lesion site (66.0%), followed by peripheral nerves (10.0%) and meninges and cerebrospinal fluid (7.7%).Conclusions: The disease pattern upon admission showed that a majority of the cases consisted of cerebrovascular disorders and that the brain was the most frequently affected structure, although we observed that a wide variety of cases were admitted, encompassing all neurological disorders. Keywords: Neurology; Patients’ Rooms; Prevalence; Disease.
RESUMO Introdução: As doenças neurológicas representam importante causa de morbidade e mortalidade globalmente, mas informações acerca de internações hospitalares em neurologia no Brasil são limitadas. Objetivo: Investigar a prevalência de admissões neurológicas por grupo de doenças e pela topografia atendidas em uma enfermaria de neurologia geral.Métodos: Estudo observacional e descritivo. Avaliados diagnósticos de saída de acordo com o Código Internacional de Doenças-10 (CID-10) no período de setembro de 2008 a outubro de 2019. Os diagnósticos foram classificados em grupos de doença e por topografia.Resultados: Foram incluídos 2,606 pacientes, com tempo médio de internação de 16,7 dias e um total de 325 (12,5%) readmissões. A mortalidade geral na enfermaria foi de 100 (3,8%) pacientes. A doença cerebrovascular foi mais prevalente (45,8%), seguida das doenças inflamatórias (22,2%). A topografia encefálica foi a mais comum (66,0%), seguida de nervos periféricos (10,0%), meninges e líquido cefalorraquidiano (7,7%). Conclusões: O perfil de doenças observado neste estudo demonstrou maior prevalência das doenças cerebrovasculares e da topografia encefálica, embora uma grande variedade de doenças tenha sido admitida dentro do espectro de doenças neurológicas. Palavras-chave: Neurologia; Enfermaria; Prevalência; Doença.
1Universidade Federal de São Paulo, Escola Paulista de Medicina, Disciplina de Neurologia, São Paulo SP, Brazil. Daniel Gabay MOREIRA https://orcid.org/0000-0002-5918-185X; Enedina Maria Lobato de OLIVEIRA https://orcid.org/0000-0002-4939-7200; Fernando Morgadinho dos Santos COELHO https://orcid.org/0000-0002-8482-3754; Henrique Ballalai FERRAZ https://orcid.org/0000-0002-3821-1407; Silvio FRANCISCO https://orcid.org/0000-0001-9179-8764; Vanderci BORGES https://orcid.org/0000-0002-8723-2757; Denis Bernardi BICHUETTI https://orcid.org/0000-0002-4011-3734 Correspondence: Denis Bernardi Bichuetti; Email: [email protected]. Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: DBB: contributed to study conception and design, acquisition of data, analysis and interpretation and critical review of the manuscript for important intellectual content. DGM: contributed to study conception and design, acquisition of data, analysis and interpretation and critical review of the manuscript for important intellectual content. EMLO, FMSC, VB, SF and HBF contributed to critical review of the manuscript for important intellectual content. Statistical analysis was performed by DGM and DBB. Received on June 28, 2020; Received in its final form on September 16, 2020; Accepted on September 20, 2020.
478 INTRODUCTION We reviewed all 6,717 entries from patients admitted from 2008 to 2019. The patients were assembled in a data- Neurological disorders account for nearly 12% of total base of diagnoses that was created in accordance with the deaths globally and are the main cause of overall disease International Classification of Diseases, 10th edition (ICD-10), burden, which is represented by the number of years of upon medical discharge. Since the hospital system combines healthy life lost as the result of disability. The World Health clinical and surgical patients, we excluded from the analysis Organization (WHO) has estimated that morbidity due to all non-clinical neurological patients, i.e. cases of nervous neurological diseases has overtaken diseases consequent system tumors, traumatic brain and spine injury, Parkinson to HIV/AIDS and malignant neoplasm1. In the United disease admitted for implantation of deep brain stimulation, Kingdom National Health Service, one in every six people central vascular malformations (such as intracranial aneu- has a neurological condition and deaths due to neurologi- rysm and arteriovenous malformation) and, hydrocepha- cal causes increased by 39% between 2001 and 2014, while lus. Also, any records with incomplete data were excluded. all other causes of death decreased by 6% over the same Only patients older than 12 years were included, since this is period2. It has been is estimated that this impact is even an adult-only ward. greater in developing countries than in higher-income The following variables were collected: age, sex, length nations3. In Brazil, data relating to the distribution of neu- of stay, readmission, clinical outcome (death or discharge) rological disorders is scant. Most of the studies investigat- and ICD-10 diagnosis. We subsequently classified the ICD-10 ing this have drawn a profile of these diseases in outpatient diagnoses into neurological disease groups and lesion care settings4,5,6. sites, in order to understand whether residents and stu- Hospital São Paulo is a major tertiary care hospital dents were encountering different diseases, with an oppor- located in the southern district of São Paulo, a megalopolis tunity to evaluate patients within the entire spectrum of with a population greater than 21 million inhabitants7. It is neurological symptoms, thus fulfilling the academic pur- the major teaching hospital for Escola Paulista de Medicina, pose of the unit. The neurological diseases were grouped the medical school of the Universidade Federal de São Paulo. as degenerative, metabolic, seizures, infectious, inflam- The Neurology ward of Hospital São Paulo is responsible for matory, cerebrovascular and unclassified. The lesion site medical assistance for all neurological admissions from the groups were the brain (comprising brain, midbrain and Neurology and Neurosurgery Department, one of most tra- cerebellar lesions), cerebrospinal fluid, spine, peripheral ditional centers for Neurology training across the country. nerves, neuromuscular junction or muscle, multiple site This unit has 18 beds: eight dedicated to clinical Neurology and unclassified. and ten to Neurosurgery. A multidisciplinary team that The analysis was performed using Microsoft Excel® and includes residents from Neurology, Nursing, Physiotherapy, Epi-InfoTM 7. Quantitative variables were presented as means Psychology and Speech and Language Pathology, all of them and standard deviations, while qualitative variables were supervised by skilled tutors, is responsible for the medical presented as absolute numbers and percentages. assistance8. To better understand the prevalence of major inpatient neurological disorders that are being cared for in the scenario RESULTS of the 21st century, we designed a retrospective study with prospectively acquired data on all admissions to the general Overall, 2,606 patients with clinical neurological diag- Neurology ward over a period of 11 continuous years. noses were included for analysis. Table 1 describes the demographic and general characteristics of the admis- sions included during the study period. The largest group METHODS was of cerebrovascular diseases (45.8%), followed by inflammatory (22.2%) and unclassified (13.8%) (Figure 1) This was a retrospective, descriptive and observational (Table 2). The group with unclassified diagnoses encom- study that used prospectively acquired data. It evaluated passed patients discharged due to headache and single all patients admitted to the Neurology ward of Hospital nerve impairments. The rest of the groups had each a per- São Paulo, which is part of the public healthcare system centage incidence inferior to 10%. of Brazil, over the period from September 2008 to October The most common lesion site was the brain (66.00%), fol- 2019. The study was approved by the ethics committee of lowed by peripheral nerves (10.0%), meninges and cerebro- the Federal University of São Paulo. The patients’ medical spinal fluid (7.7%) and spinal cord (6.6%) (Figure 2) (Table 2). records were obtained from the hospital system database, The other anatomical lesion sites each had proportions which collects information at the time of patient discharge. smaller than 5%. It is important to note that the multiple Thus, the study was exempted from obtaining individual site group only included diagnoses of encephalomyelitis. consent through a statement. The unclassified group represented general ICD-10 codes, for
Moreira DG et al. Neurology ward in a Brazilian university hospital 479 Table 1. Demographics of the 2,606 admissions over an 11- situations in which it was not possible to be certain of the year period. correct lesion site, such as when the discharge diagnosis was n % filled out as “unspecified demyelinating disease of the central Age (n=2,606) nervous system” or “other degenerative specified diseases of Mean±SD 48.8±18.0 - the nervous system”. 12–20 136 5.2 21–30 361 13.8
31–40 431 16.5 Table 2. Groups according to neurological disorders and lesion 41–50 393 15.1 site admitted to the neurology ward. 51–60 521 20.0 n % 61–70 438 16.8 Neurological disorders (n=2,606) 71–80 241 9.3 Cerebrovascular 1192 45.7 81–90 75 2.9 Inflammatory 579 22.2 91–99 10 0.4 Seizures 201 7.7 Sex (n=2,606) Infectious 183 7. 0 Female 1,361 52.2 Degenerative/metabolic 91 3.5 Male 1,245 47.8 Unclassified 360 13.8 Length of stay (days) Lesion site (n=2,606) Mean 16.6 - Brain 1720 66.0 Admissions (n=2,606) Peripheral nerve 261 10.0 1st admission 2,281 87.5 Meninges and cerebrospinal fluid 200 7.7 Readmission 325 12.5 Spine 163 6.3 Clinical outcome (n=2,606) Muscle 126 4.8 Discharge 2,506 96.2 Multiple sites 63 2.4 Death 100 3.8 Unclassified 73 2.8 Total 2,606 100.0 Total 2,606 100.0
Figure 1. Groups of neurological disorders admitted to the Neurology ward (n=2,606).
480 Arq Neuropsiquiatr 2021;79(6):478-482 Figure 2. Groups according to lesion sites, admitted to the Neurology ward (n=2,606).
DISCUSSION headache, seizures, cerebrovascular diseases and demen- tia syndrome4,5. We categorized headache diagnoses in the Inpatient care is clinically challenging, demands multi- unclassified group, as they most likely represent a symptom disciplinary coordinated care and is potentially high-priced, of inpatients’ final diagnoses, rather than a separate disease. especially in academic hospitals9. Comprehending a unit’s Nonetheless, headache was included in the third most preva- profile of patient admissions and disease prevalence is a first lent group among neurological admissions. step towards organizing this care and shaping educational The diagnostic process varies among diseases and dis- programs in university hospitals. tinct specialties. There are three major spectra: clinical-dom- Cerebrovascular diseases are the largest cause of neuro- inant, laboratory-dominant and neuroimaging-dominant15. logical admissions worldwide, with frequencies ranging from The role of neuroanatomy in understanding and determin- 47.5 to 62%. Infectious diseases and seizures alternate in the ing possible lesion sites has long been established within the second and third position, ranging from 3.9 to 21.8% and 4.8 approached to neurological disorders. This is vital for guiding to 9.8%, respectively10,11,12,13. In one of the few Brazilian inpa- investigation and neurological rationale, especially in aca- tient series available, the cerebrovascular group was the most demic centers16. In our series, the brain was the site predom- prevalent, with a frequency of 51%14. In our ward too, cerebro- inantly affected, which was not surprising considering that vascular diseases were the most prevalent group, followed by nearly half of our admissions were due to cerebrovascular dis- inflammatory diseases, mainly composed of multiple sclero- ease, followed by inflammatory diseases mainly encompass- sis, neuromyelitis optica, myasthenia gravis, Guillain-Barré ing relapses of multiple sclerosis and central nervous system syndrome and optic neuritis alone. This might be explained demyelinating and inflammatory diseases. Nevertheless, we by the fact that Hospital São Paulo has specialized Neurology found that all areas of Neurology and neurological clinical outpatient clinics that care for demyelinating and neuromus- sites were being seen, which was in keeping with the purpose cular disease. Besides being the hospital’s main provider of of an academic unit. acute care, our emergency unit is also an open walk-in clinic, This study was not intended to be a complete review so many patients with inflammatory diseases without diag- of clinical admissions or treatment results, which would noses come to our hospital seeking care. require a complete chart review of all admitted patients. The outpatient scenario in Brazil differs from the hospi- The fact that we excluded all possible surgical patients might talization profile, given that the most common complaints have reduced the number of patients cared for by clini- or diseases seen in neurological consultation offices are cal Neurology residents that we evaluated, given that some
Moreira DG et al. Neurology ward in a Brazilian university hospital 481 neurosurgical patients might first have been admitted to admitted to the ward. This biases the inpatient population clinical care and investigation, and were then moved to surgi- towards those with more complex diseases and longer stays. cal care. Moreover, this study embraces a common limitation In conclusion, in this Brazilian general Neurology ward, of database studies, i.e. situations of incomplete or incorrect lesions to the brain and cerebrovascular diseases accounted input of data. To surmount this, a complete review of all med- for the major causes of neurological admissions. The present ical records would need to be conducted, which was beyond findings contribute to a better understanding of hospital- the objectives of this report. Furthermore, it is worth men- ized neurological patients and can help in future planning of tioning that patients seeking care in Hospital São Paulo are allocation of effort and medical assistance priorities, as well first assisted in the neurological emergency service and many as guiding academic centers in organizing their rotations to receive their complete medical treatment there and are not cover the full spectrum of neurological care.
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482 Arq Neuropsiquiatr 2021;79(6):478-482 https://doi.org/10.1590/0004-282X-ANP-2020-0360 ARTICLE
Evaluation of structural changes in orbitofrontal cortex in relation to medication overuse in migraine patients: a diffusion tensor imaging study Avaliação das mudanças estruturais no córtex orbitofrontal em relação ao uso excessivo de medicamentos em pacientes com migrânea: um estudo de imagem por tensor de difusão Aygul TANTIK PAK1, Sebahat NACAR DOGAN2, Yildizhan SENGUL1
ABSTRACT Background: Migraine is a prevalent neurological disease that leads to severe headaches. Moreover, it is the commonest among the primary headaches that cause medication overuse headache (MOH). The orbitofrontal cortex (OFC) is one of the structures most associated with medication overuse. Objective: To determine microstructural changes in the OFC among migraine patients who developed MOH, through the diffusion tensor imaging (DTI) technique. Methods: Fifty-eight patients who had been diagnosed with migraine based on the Classification of Headache Disorders (ICHD-III-B) were included in the study. Patients were sub-classified into two groups, with and without MOH, based on the MOH criteria of ICHD-III-B. DTI was applied to each patient. The OFC fractional anisotropy (FA), and apparent diffusion coefficient (ADC) values of the two groups were compared. Results: The mean age of all the patients was 35.98±7.92 years (range: 18-65), and 84.5% (n=49) of them were female. The two groups, with MOH (n=25) and without (n=33), were alike in terms of age, gender, family history, migraine with or without aura and duration of illness. It was found that there was a significant difference in FA values of the left OFC between the two groups (0.32±0.01 versus 0.29±0.01; p=0.04). Conclusions: An association was found between MOH and changes to OFC microstructure. Determination of neuropathology and factors associated with medication overuse among migraine patients is crucial in terms of identifying the at-risk patient population and improving proper treatment strategies specific to these patients. Keywords: Migraine Disorders; Medication Overuse Headache; Orbitofrontal Cortex; Diffusion Tensor Imaging.
RESUMO Introdução: A migrânea é uma doença neurológica prevalente que causa fortes dores de cabeça. Além disso, é a mais comum entre as cefaleias primárias que causam cefaleia por uso excessivo de medicamentos (CUEM). O córtex orbitofrontal (OF) é uma das estruturas mais associadas ao uso excessivo de medicamentos. Objetivo: Determinar alterações microestruturais no córtex OF em pacientes com migrânea que desenvolveram CUEM, por meio da técnica de imagem por tensor de difusão (ITD). Métodos: Cinquenta e oito pacientes com diagnóstico de migrânea, com base na Classificação das Cefaleias (ICHD-III-B), foram incluídos no estudo. Os pacientes foram subclassificados em dois grupos, com e sem CUEM, com base nos critérios de CUEM da ICHD-III-B. A ITD foi aplicada a cada paciente. Os valores de anisotropia fracionada OFC (AF) e coeficiente de difusão aparente (CDA) dos dois grupos foram comparados.Resultados: A média de idade de todos os pacientes foi de 35,98±7,92 anos (variação: 18–65), sendo 84,5% (n=49) do sexo feminino. Os dois grupos, com CUEM (n=25) e sem (n=33), são semelhantes em termos de idade, sexo, história familiar, migrânea com ou sem aura e duração da doença. Verificou-se que houve diferença significativa nos valores de AF do córtex OF esquerdo entre os dois grupos (0,32±0,01 versus 0,29±0,01; p=0,04). Conclusões: Foi encontrada associação entre o CUEM e as alterações na microestrutura do córtex OF. A determinação da neuropatologia e dos fatores associados ao uso excessivo de medicamentos entre pacientes com migrânea é crucial para identificar a população de pacientes em risco e melhorar as estratégias de tratamento adequadas específicas para esses pacientes. Palavras-chave: Transtornos de Enxaqueca; Cefaleia por Uso Excessivo de Medicamentos; Córtex Pré-Frontal; Imagem por Tensor de Difusão.
1Gaziosmanpasa Training and Research Hospital, Department of Neurology, Istanbul, Turkey. 2Gaziosmanpasa Training and Research Hospital, Department of Radiology, Istanbul, Turkey. Aygul TANTIK PAK https://orcid.org/0000-0002-7414-3800; Sebahat NACAR DOGAN https://orcid.org/0000-0003-1512-5060; Yildizhan SENGUL https://orcid.org/0000-0002-5087-9944 Correspondence: Aygul Tantik Pak; E-mail: [email protected]. Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: ATP: made a substantial contribution to the acquisition of data. ATP, YS and SND: made substantial contributions to the conception or design of the study and the acquisition/interpretation of data. ATP, YS and SND: made substantial contributions to the conception or design of the study. All authors made substantial contributions to manuscript development, gave final approval of the manuscript for submission and agree to be accountable for all aspects of the work. ATP, YS and SND: are the guarantors for the overall content of the manuscript. Received on August 10, 2020; Received in its final form on September 27, 2020; Accepted on December 08, 2020.
483 INTRODUCTION patients who developed MOH, and there10,12,13 is no study that has assessed the OFC through DTI. Migraine is the most common primary headache impact- In our research, we aimed to compare the OFC of patients ing the population of patients who are at a younger and more with and without MOH, through the method of region of productive age1. Comorbid conditions that occur with severe interest (ROI) based on DTI. debilitating headaches lead to serious social and economic burdens. Neuropsychiatric symptoms such as anxiety (par- ticularly panic and phobia), depression, bipolar disorder, METHODS obsessive-compulsive disorder and nicotine dependence, along with psychiatric disorders such as substance abuse2,3, Study procedure frequently accompany migraine3. Our research was designed as a prospective, observational Medication overuse headache (MOH) occurs mostly cross-sectional study. The study was performed in accordance among patients who have chronic migraines. It has been with the ethical guidelines that were stated in the “Helsinki observed that MOH develops in 8.2% of the migraine Declaration” and was approved by the Gaziosmanpasa patients living in Brazil4. MOH recurs in nearly 30% of the Training and Research Hospital Ethics Committee. Written patients within one year following discontinuation of pain informed consent was obtained from the participants after medication and adjustment of the treatment5. Given this they had been given precise explanations about the scope of knowledge and studies that have assessed the association the procedures. between migraine and substance abuse, it is considered that there is a predisposition link between migraine and Participants substance abuse3. Eighty-two patients who had been admitted to the neu- The basic features of substance abuse, such as com- rology outpatient clinic and diagnosed with migraine were pulsive drug use and drug-induced recurrence, have been included in the study. The inclusion criteria were that the found to be partially caused by changes in the functioning participants needed to be between the ages of 18–65 and of the orbitofrontal cortex (OFC)6,7. Through hypofunction- to be diagnosed with migraine based on the International ing of the OFC, the inhibition mechanism is impaired8, and Classification of Headache Disorders (ICHD-III-B). This clas- this induces an increase in impulsivity and deterioration in sification states that migraine is a unilateral throbbing severe reward and decision-making mechanisms6,9. This is observed headache that lasts for 4 to 72 hours; it is described as a pri- among substance abusers and contributes to development mary headache that arises due to physical activity and co- of MOH in migraine patients. In a PET study, glucose metab- occurs with nausea, vomiting, phonophobia and photo- olism was measured before and after drug withdrawal in phobia14. Our exclusion criteria comprised presence of the chronic migraine and MOH cases, and several regions of the following: additional headaches (apart from migraine and brain that are associated with pain were found to be hypo- MOH), neurodegenerative diseases, history of neurosurgery metabolic. However, they were rapidly reactivated upon with- procedure, head trauma, history of stroke, previously known drawal of analgesics. On the contrary, it has been observed psychiatric disorders, withdrawal from the study, use of a that hypometabolism in the OFC remained despite drug prosthesis that was incompatible with MRI, use of metal withdrawal, and it has been put forward that this might be appendages (metal kneecaps and pacemakers), claustropho- associated with relapses among MOH patients10. Given this bia and cerebral lesions that hindered examination of cranial information, we established the hypothesis of our research MR imaging of the patient (including lacunar infarctions and on the premise that MOH could develop as a result of behav- leukoaraiosis, detection of vascular lesions in cranial MRI ioral pathologies induced by structural impairments in the or poor quality of MRI). As a result, 24 patients excluded. OFC of migraine patients. Thirteen patients with migraine declined to participate or Diffusion tensor imaging (DTI) is a magnetic resonance did not go to their MRI appointment. After the MRI, 11 addi- imaging (MRI) technique that is used to map and charac- tional patients were excluded due to leukoencephalopathy. terize the three-dimensional diffusion of water as a func- Fifty-eight patients completed the study protocol and these tion of spatial location. Several DTI parameters are used to formed our sample for analysis. assess diffusion and, indirectly, fiber tract microstructure. The sociodemographic characteristics of the patients, DTI shows where neuronal/axonal loss occurs as a result of family history, duration of illness, presence of aura, frequency neurodegeneration and inflammation. Fractional anisotropy of monthly episodes and the names and quantities of anal- (FA) measures the anisotropic diffusion of water molecules gesics that were being administered to the patients every and the average diffusion coefficient (ADC) describes the month were recorded. To measure the severity of pain, a user- magnitude of the average molecular displacement through friendly visual analogue scale (VAS)15 was used, in which the diffusion11. In the literature, only a limited number of neu- “0” point represented the absence of any pain, while the “10” roimaging studies have been conducted among migraine point represented the most severe pain in the patient’s life.
484 Arq Neuropsiquiatr 2021;79(6):483-488 The patients were subdivided into two groups: those who had MOH and those who did not. In accordance with the International Classification of Headache Diseases (ICHD- III-B), MOH was defined as a situation in which a patient who has had primary headache on more than 15 days/month for more than three months has drug intake on more than 10 days a month over a period of at least 3 months in the case of ergotamine, triptans, opioids and combinations of analgesics in particular; while for simple analgesics this situation was considered to consist of regular intake of drugs on more than 15 days a month over a period of at least 3 months14. All of our participants were using simple analgesics at the time of the interview.
Magnetic resonance imaging protocol MRI was performed using 1.5 T-MRI units (GE Signa Explorer; GE, Milwaukee, WI, USA). 3D T1W volumetric sequences (TR/TE/TI, 8.7/3.2/450 ms) without contrast were applied using fast gradient brain volume imaging (BRAVO) with an isotropic voxel resolution of 1 mm. Generalized par- allel imaging was applied by using auto-calibrating recon- struction for cartesian (ARC) with an acceleration factor of two for phase-encoding direction. The DTI included a sin- Figure 1. Placement of the regions of interest in the gle-shot, spin-echo, echo-planar sequence with TR: 4950 orbitofrontal region. ms TE: 102 ms; matrix: 128 × 128 field of view: 230 mm and slice thickness 5.5 mm; and 24 diffusion-encoding direc- tions were used with the values of b=0 s/mm2 and b=1000 groups (with and without MOH). The OFC DTI metrics of s/mm2. Parallel imaging was performed through ARC with the two groups were compared. To assess the association an acceleration factor of two. The Advantage Workstation between OFC and MOH (dependent variable: DTI value of (AW) scanner console (software version 4.6; GE Healthcare) OFC; independent variables: age, gender, duration of illness, was used for fractional anisotropy (FA) apparent diffusion frequency of the episodes, pain severity and presence of coefficient (ADC) map reconstruction. The 3D T1W images MOH), multivariate regression analysis was used. Statistical were used as anatomical references for placement and trac- significance was considered as p<0.05 in all tests. ing of ROIs. These images were coupled with the correspond- ing region of FA-ADC maps at the same section level. All the ROIs were drawn manually in circular shapes with constant RESULTS size. The adaptation of the sizes and placement of the ROIs in the OFC (Figure 1) were achieved through simultaneous The mean age of all the patients was 35.98±7.92 years assessment by experienced radiologists (SND). The radiolo- (range: 18-65), and 84.5% (n=49) of them were female, while gist was blinded to neurological symptoms during the imag- 15.5% (n=9) of them were male. Among all the patients, ing analysis. 67.24% (n=39) had a family history of migraine; and 39.7% (n=23) had migraine with aura, while 60.3% (n=35) had Statistical analysis migraine without aura. The mean duration of the disease was The IBM SPSS statistics software, version 20.0, was used 7.36±7.26 years, while the incidence of migraines per month for the statistical analysis of the data. Categorical measure- was 8.13±4.90, and the mean VAS value was 8.87±1.20. It was ments were evaluated as numbers and percentages, while determined that the mean OFC FA values of all patients were numerical measurements were evaluated as the mean and 0.29±0.05 × 10-3 mm2/s on the right side and 0.30±0.05 × 10-3 standard deviation (or median and minimum-maximum), mm2/s on the left side; while the mean values of OFC ADC and descriptive statistical methods were used. The distri- was 8.27±0.61 × 10-3 mm2/s on the right side and 8.14±0.54 × bution of the data was evaluated based on the Shapiro-Wilk 10-3 mm2/s on the left side. The amount of analgesic, which test. In cross-group comparisons, the independent-sample t was administered in all patients, was 11.50±10.27 per month test was used for data with normal distribution, whereas the and 43.1% (n=25) of the patients had MOH (Table 1). Mann-Whitney U test was used for data that did not have The patients were divided into two groups: those with normal distribution. The patients were subdivided into two MOH (group I) and those without MOH (group II). The two
Pak AT et al. Structural changes of medication overuse in migraine patients 485 Table 1. Sociodemographic, clinical and diffusion tensor imaging Table 2. Comparison of sociodemographic, clinical and data of all the patients. diffusion tensor imaging data of the groups. Age (mean±SD) 35.98±7.92 years MOH (+) MOH (-) p-value (n=25) (n=33) (min-max values) (18–51) Age (mean±SD) 36.80±1.60 35.36±1.37 0.50* Gender % (n) (min-max) (18–51) (18–49) Female 84.5% (n=49) Gender % (n) Male 15.5% (n=9) Female 88.00% (n=22) 81.82% (n=27) Family history % (n) Male 12.00% (n=3) 18.18% (n=6) 0.71** Yes 67.24% (n=39) Family history No 42.86% (n=19) % (n) Aura % (n) Yes 68.00% (n=17) 66.67% (n=22) Yes 39.7% (n=23) No 32.00% (n=8) 33.33% (n=11) 0.97** No 60.3% (n=35) Aura % (n) Duration of diagnosis of migraine 7.36±7.26 years Yes 40.00% (n=10) 39.39% (n=13) (mean±SD) No 60.00% (n=15) 60.61% (n=20) 0.74** Monthly incidence of migraine 8.13±4.90 (mean±SD) Duration of diagnosis VAS score (mean±SD) 8.87±1.20 6.68±1.07 7.87±1.47 0.51* of migraine OFC FA (mean±SD) (mean±SD) Right 0.29±0.05 × 10-3 mm2/s Monthly incidence of migraine 11.48±0.88 5.60±0.62 <0.001* Left 0.30±0.05 × 10-3 mm2/s (mean±SD) OFC ADC (mean±SD) Amount of Right 8.27 0.61 × 10-3 mm2/s painkiller ± 19.60±2.14 5.36±0.61 <0.001* administered per 3 2 Left 8.14±0.54 × 10 mm /s month (pcs/month) Medication overuse headache % (n) VAS score 9.20±0 .17 8.63±0.24 0.06* Yes 43.1% (n=25) (mean±SD) No 56.9% (n=33) OFC FA (mean±SD) x 10-3 mm2/s SD: standard deviation; VAS: visual analog scale; OFC: orbitofrontal cortex; FA: fractional anisotropy; ADC: apparent diffusion coefficient. Right 0.30±0.01 0.29±0.01 0.71* Left 0.32±0.01 0.29±0.01 0.04* OFC ADC (mean±SD) x 10-3 mm2/s Right 8.30±0.61 8.23±0.60 0.69* groups were similar in terms of age, gender, family history, migraine with aura/without aura and duration of diagnosis Left 8.20±0.55 8.05±0.52 0.29* of migraine (p>0.05). It was found that there was a significant MOH: medication overuse headache; SD: standard deviation; *independent- sample t test; **Pearson’s chi-square; OFC: orbitofrontal cortex; FA: fractional difference in FA values of the left-side OFC between the two anisotropy; ADC: apparent diffusion coefficient. groups (0.32±0.01 versus 0.29±0.01; p=0.04) (Table 2). The multivariate regression analysis, which was per- formed to assess the relationship between the presence medication overuse behavior might be a consequence of a of MOH and left OFC FA value, independent of age, gen- susceptibility to substance abuse due to OFC impairment. der, duration of illness, incidence of the attack and sever- However, it should be kept in mind that medication overuse ity of pain, detected that there was a significant correla- may also cause OFC impairment. This is a bidirectional rela- tion between the MOH and the FA value of the left OFC tionship. The OFC plays a vital role in generating and using (ß=0.43; p=0.01). outcome predictions. In a study evaluating chronic migraine patients (n=42) with medication overuse, using neuropsychiatric tests, DISCUSSION these patients manifested significant deterioration in orbi- tofrontal task performance, compared with patients with In our study, we found a significant relationship between episodic migraine (n=42) and a control group without occurrence of MOH and changes to the OFC in patients headache (n=41)16. In another study evaluating medication who had been diagnosed with migraine, which was also overuse among migraine patients through neuropsychologi- compatible with our hypothesis. Our findings suggest that cal tests, Iowa gambling task scores for OFC function were
486 Arq Neuropsiquiatr 2021;79(6):483-488 assessed. It was found that there was a significant deterio- was assessed through DTI MRI, and this was done using a ration in decision-making tests and Iowa gambling task novel design, compared with the previous functional MRI scores among migraine patients with addictive-like behav- and PET studies. ior, whose decision-making and outcome perception was Our research and other studies in the literature relating impaired despite the adverse impacts of medication over- to the OFC demonstrated that impairment of the patients’ use17. Taking into consideration these findings, we aimed management of behaviors occurs. These outcomes can be to evaluate the microstructure of the OFC by means of the foreseen, as conclusions drawn from the functional, struc- DTI MRI technique, among migraine patients who devel- tural and volume changes in the OFC. It could be considered oped MOH. Consequently, microstructural impairment, that migraine patients’ pathological drug use behavior devel- which we detected in the OFC, accounts for the finding that ops in MOH as a result of an impairment in the OFCs of these our migraine patients in whom MOH developed displayed patients. Indeed, the fact that changes to the OFC were found behavior of continuing to take medication even though they to be significantly associated with FA values based on the were aware of the potential detrimental impacts of medica- DTI findings from patients with MOH verifies this argument. tion overuse. It has been revealed in studies evaluating MOH patients Limitations through the voxel-based morphometry MRI technique Only the OFC was assessed in our study, and the linkages that the OFC volume was smaller in non-responding MOH of the OFC, limbic and paralimbic regions were not assessed. patients18,19. In a study by Riederer et al., the gray matter vol- Following cessation of these patients’ medications, their umes of patients with MOH were measured by using voxel- MRIs were not repeated. Moreover, no psychiatric interviews based morphometry MRI. Whereas increases in the vol- or neuropsychological tests on OFC function (objection alter- umes of the thalamus bilaterally and the ventral striatum nation and object reversal learning tasks, gambling tasks, go/ were observed, there were decreases in the volumes of the no-go tasks, olfactory recognition, theory of mind and social OFC, anterior cingulate cortex, insula and precuneus20. In processing measures, and self-rating or family-rating scales a study on MOH through functional MRI, it was revealed on the patient’s behavior)24 were conducted on our patients that the functioning of the primary somatosensory cortex, to determine their behavioral pathologies. inferior parietal lobule, supramarginal gyrus and regions of In conclusion, the OFC is a cortical structure that enables the lateral pathway of the pain matrix returned to normal individuals to adjust and control their behaviors and to ben- six months after discontinuation of the painkillers that the efit from the consequences, through conclusions that they patients had been receiving. Based on this finding, it was have drawn from the events that they experienced previously, suggested that MOH did not cause irreversible damage21. for the new circumstances that they encounter. However, the regions that were examined through MRI in Our research gives rise to the notion that frequent medi- that study were merely the regions that play a role in the pain cation overuse among migraine patients could be associated mechanism. It was also reported in another study, in which with dysfunction of this region. This result is crucial since positron emission tomography was used, that recovery from it indicates that the OFC could be a marker for response to hypometabolism occurred in these regions following discon- treatment or could be a manifestation of adverse outcomes. tinuation of the medication. Nonetheless, the hypometabo- Furthermore, from our review of the literature, we deter- lism that had been detected in the OFCs remained after ces- mined that there were no studies analogous to ours, in terms sation of the medication and MOH relapse was linked to the of study design. We believe that, thanks to this finding, we OFC damage10. This finding is also compatible with those have made a remarkable contribution to identification of the of previous studies, in which it was suggested that changes pathophysiology of MOH. However, in future studies, it might to the OFC were associated with impaired decision-mak- be pertinent to identify whether the process is reversible, ing ability and behavior of drug and substance abuse22,23. through repeating patients’ MRIs and investigating whether Similarly, in our study, the microstructural changes to the there would be a continuation of impact on the OFC, after OFC in migraine patients were found to be compatible with regulation of these patients’ prophylactic treatments and MOH. However, in our study, the microstructure of the OFC cessation of their analgesics.
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Neurol Sci. 2012 May;33 Suppl 1:S151-5. https:// brain damage: the role of the right ventromedial prefrontal doi.org/10.1007/s10072-012-1071-4 cortex. J Cogn Neurosci. 2003 Apr;15(3):324-37. https://doi. org/10.1162/089892903321593063 18. Lai T-H, Chou K-H, Fuh J-L, Lee P-L, Kung Y-C, Lin C-P, et al. Gray matter changes related to medication overuse in patients with 8. Crews FT, Boettiger CA. Impulsivity, frontal lobes and risk for chronic migraine. Cephalalgia. 2016 Dec;36(14):1324-33. https://doi. addiction. Pharmacol Biochem Behav. 2009 Sep;93(3):237-47. org/10.1177/0333102416630593 https://doi.org/10.1016/j.pbb.2009.04.018. 19. Riederer F, Gantenbein AR, Marti M, Luechinger R, Kollias S, Sándor 9. Hornak J, O’Doherty J, Bramham J, Rolls ET, Morris RG, Bullock PS. Decrease of gray matter volume in the midbrain is associated PR, et al. Reward-related reversal learning after surgical with treatment response in medication-overuse headache: possible excisions in orbito-frontal or dorsolateral prefrontal cortex in influence of orbitofrontal cortex. J Neurosci. 2013 Sep;33(39):1543-9. humans. J Cogn Neurosci. 2004 Apr;16(3):463-78. https://doi. https://doi.org/10.1523/JNEUROSCI.3804-12.2013 org/10.1162/089892904322926791 20. Riederer F, Marti M, Luechinger R, Lanzenberger R, Meyenburg J 10. Fumal A, Laureys S, Di Clemente L, Boly M, Bohotin V, Vandenheede von, Gantenbein AR, et al. Grey matter changes associated with M, et al. Orbitofrontal cortex involvement in chronic analgesic- medication-overuse headache: correlations with disease related overuse headache evolving from episodic migraine. Brain. 2006 disability and anxiety. World J Biol Psychiatry. 2012 Oct;13(7):517-25. Feb;129(Pt 2):543-50. https://doi.org/10.1093/brain/awh691 https://doi.org/10.3109/15622975.2012.665175 11. Mori S, Zhang J. Principles of diffusion tensor imaging and its 21. Ferraro S, Grazzi L, Mandelli ML, Aquino D, Di Fiore D, Usai S, et al. applications to basic neuroscience research. Neuron. 2006 Pain Processing in medication overuse headache: a functional Sep;51(5):527-39. https://doi.org/10.1016/j.neuron.2006.08.012 magnetic resonance imaging (fMRI) study. Pain Med. 2012 12. Shibata Y, Ishiyama S, Matsushita A. White matter diffusion Feb;13(2):255-62. https://doi.org/10.1111/j.1526-4637.2011.01183.x abnormalities in migraine and medication overuse headache: A 1.5-T 22. London ED, Ernst M, Grant S, Bonson K, Weinstein A. Orbitofrontal tract-based spatial statistics study. Clin Neurol Neurosurg. 2018 cortex and human drug abuse: functional imaging. Cereb Cortex. Nov;174:167-173. https://doi.org/10.1016/j.clineuro.2018.09.022 2000 Mar;10(3):334-42. https://doi.org/10.1093/cercor/10.3.334 13. Zheng Z, Xiao Z, Shi X, Ding M, Di W, Qi W, et al. White matter lesions 23. Volkow ND, Fowler JS, Wang G-J. The addicted human brain viewed in in chronic migraine with medication overuse headache: a cross- the light of imaging studies: brain circuits and treatment strategies. sectional MRI study. J Neurol. 2014 Apr;261(4):784-90. https://doi. Neuropharmacology. 2004;47 Suppl 1:3-13. https://doi.org/10.1016/j. org/10.1007/s00415-014-7267-1 neuropharm.2004.07.019 14. The International Classification of Headache Disorders, 3rd edition 24. Zald D, Rauch S. The Orbitofrontal Cortex [Internet]. New York: Oxford (beta version). Cephalalgia. 2013 Jul;33(9):629-808. https://doi. University Press; 2006 [cited 2020 Jun 26]. Available at: http://gen.lib. org/10.1177/0333102413485658 rus.ec/book/index.php?md5=dcb9be87057bc080822cad45d88bf743
488 Arq Neuropsiquiatr 2021;79(6):483-488 https://doi.org/10.1590/0004-282X-ANP-2020-0338 ARTICLE
Determinants of disability development in patients with multiple sclerosis Determinantes do desenvolvimento de deficiência em pacientes com esclerose múltipla Fatma KARA1, Mehmet Fatih GÖL1, Cavit BOZ1
ABSTRACT Background: Multiple sclerosis (MS) is one of the most common chronic neurological diseases affecting the central nervous system in young adults. Objective: To investigate demographic and clinical factors that are effective in the development of irreversible disability from the onset of MS, and to identify factors that affect the transformation from the relapse-remitting MS (RRMS) phase to the progressive MS (PMS) phase. Methods: Retrospective study on 741 patients who were diagnosed with RRMS and PMS according to the McDonald criteria, and were enrolled into the Turkish MS database of the Department of Neurology MS Polyclinic, at the Faculty of Medicine, Karadeniz Technical University, in Trabzon, Turkey. Kaplan-Meier analysis was used to evaluate the time taken to reach EDSS 4 and EDSS 6 from the onset of disease, and the time taken between EDSS 4 and EDSS 6. Results: Age of onset >40 years; having polysymptomatic-type onset, pyramidal or bladder-intestinal system-related first episode;≥ 7 episodes in the first 5 years; and <2 years between the first two episodes were found to be effective for MS patients to reach EDSS 4 and EDSS 6. The demographic and clinical parameters that were effective for progression from EDSS 4 to EDSS 6 were: pyramidal or bladder-intestinal system-related first episode; 4–6 episodes in the first 5 years; >2 years until start of first treatment; and smoking.Conclusions: Our findings reveal important characteristics of MS patients in our region. However, the associations between these parameters and MS pathophysiology remain to be elucidated. Keywords: Multiple Sclerosis; Epidemiology; Therapy.
RESUMO Introdução: A esclerose múltipla (EM), uma das doenças neurológicas crônicas mais comuns, afeta o sistema nervoso central em jovens adultos. Objetivo: Investigar fatores demográficos e clínicos que são efetivos no desenvolvimento de deficiência irreversível, desde o início da EM, e identificar fatores que afetam a transformação da fase de EM recorrente-remitente (EMRR) para a fase de EM secundária progressiva (EMSP). Métodos: Estudo retrospectivo de 741 pacientes que foram diagnosticados com EMRR e EMSP, de acordo com os critérios de McDonald, e inscritos no banco de dados turco MSBase, do Departamento de Neurologia da MS Polyclinic, da Universidade Técnica de Karadeniz, Turquia. Análise de Kaplan-Meier foi usada para avaliar o tempo para alcançar EDSS 4 e EDSS 6, desde o início da doença e o tempo entre EDSS 4 e EDSS 6. Resultados: Idade de início>40 anos, início do tipo polissintomático, primeiro ataque relacionado ao sistema piramidal ou bexiga-intestinal, ≥7 recaídas nos primeiros 5 anos e <2 anos entre os dois primeiros ataques foram considerados eficazes em pacientes com EM que atingiram EDSS 4 e EDSS 6. Parâmetros demográficos e clínicos que foram efetivos no progresso de EDSS 4 para EDSS 6: primeiro ataque relacionado ao sistema piramidal ou bexiga-intestinal, 4–6 recaídas nos primeiros 5 anos, >2 anos até o início do primeiro tratamento e tabagismo. Conclusão: Estudo revelou características importantes dos pacientes com EM em nossa região. No entanto, as associações entre esses parâmetros e a fisiopatologia da EM ainda precisam ser elucidadas. Palavras-chave: Esclerose Múltipla; Epidemiologia; Terapia.
INTRODUCTION unpredictable functional disabilities that are associated with the CNS region(s) affected2,3. It was reported in 2013 that Multiple sclerosis (MS) is one of the most common around 2.3 million people suffer from MS on a global scale4. chronic neurological diseases affecting the central nervous There are three types of MS. The first and the most com- system (CNS) in young adults. Its frequency is higher among mon type is relapsing-remitting multiple sclerosis (RRMS), females1. MS progresses with inflammatory demyelination which is characterised by relapses of new or increasing neu- and subsequent axonal loss, which causes a wide range of rological symptoms that are followed by periods of partial
1Karadeniz Technical University, Faculty of Medicine, Department of Neurology, Trabzon, Turkey. Fatma KARA https://orcid.org/0000-0002-4675-0689; Mehmet Fatih GÖL https://orcid.org/0000-0001-7773-641X; Cavit BOZ https://orcid.org/0000-0003-0956-3304 Correspondence: Mehmet Fatih Göl; E-mail: [email protected]. Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: FK: performed data collection. MFG, FK: data analysis and interpretation. FK: primary author. CB: conceived the ideas. MFG, FK and CB: provided revisions to scientific consent of manuscript. MFG, FK and CB: principal investigators. Received on July 15, 2020; Received in its final form on August 22, 2020; Accepted on September 07, 2020.
489 or complete recovery. The secondary progressive (SPMS) Exclusion criteria course develops in RRMS patients around 15–20 years after • Diagnoses of PPMS and progressive relapsing MS (PRMS) onset. The third type is primary progressive multiple sclerosis (those with progressive-type onset). (PPMS), which shows steady progression from the onset for • Diagnoses of any other neurological or psychological at least 6 months or more without attacks5. disease. Clinical variability during the onset of MS may provide • Not signing the consent form. important prognostic clues about the progression of the dis- ease to the progressive stage. Factors associated with a good Study design prognosis in MS include early onset, female sex, initial symp- Forms prepared by the researchers were used to deter- toms consisting of sensory symptoms or optic neuritis, cases in mine the clinical features of the disease and the sociode- which the initial symptom affects only one CNS region, having mographic characteristics of the patients. The follow- less disability at 5 years after onset, better recovery after the first ing were recorded on the patient preliminary information episode, longer duration between first and second episode, low form: patient’s name and sex, disease history, family history, number of episodes during the first five years and a long time patient’s complaints on admission, date of disease onset, until the Expanded Disability Status Scale (EDSS) score exceeds number of episodes, date and time of episodes, history of 3 points. On the other hand, the following factors are considered episodes, episode treatments, medications used in MS treat- to suggest poor prognosis: male sex, advanced age, onset with ment, treatment duration, other physical diseases and med- motor-cerebellar-spinal cord or bladder-intestinal tract symp- ications used, EDSS score, diagnostic tools and history of toms, incomplete recovery after the first episode, high relapse drug and substance use. These forms were filled out when rate in the first two years, severe disability at 5 years after onset, the patient first sought care, and the forms were also updated a short time until EDSS score exceeds 3 points and a short time at the times of patient follow-ups. between the first and second episodes6,7. Because the disease is The following parameters were evaluated for associa- unpredictable in nature and the factors affecting prognosis vary tions with disease progression: age at onset, sex, type of onset from region to region8,9,10, determining the characteristics of dis- (determined as monosymptomatic or polysymptomatic),type ease progression and factors that contribute to disabilities are of first episode, number of episodes in the first five years after of high importance for clinical management. the onset of the disease, length of time between the first In this study, we aimed to determine the demographic and second episodes, time of starting immunomodulator or and clinical factors that are effective for development of irre- immunosuppressive treatments that affect disease progres- versible disability from the onset of disease, and to identify sion, smoking (and number of cigarettes smoked per day), factors that affect the transformation from the RRMS phase presence of EDSS 4 (limitation of walking without restric- to the secondary progressive MS (SPMS) phase. tion) and EDSS 6 (walking with one-sided support), and the time taken to reach specific degrees of disability, such as pro- gression from EDSS 4 to EDSS 6. METHODS In this study, the patients were classified according to the first attack types, into five categories: sensory, visual, pyrami- Patients dal, brainstem-cerebellar and bladder-intestinal. They were This was a retrospective study on 741 patients who classified based on their age at onset of the disease, into the were diagnosed with RRMS and PMS in accordance with following three categories: <18, 18–40 or >40 years. They were the McDonald criteria11. This study analyzed a cohort of classified based on the number of relapses in the first five Turkish people: demographic and clinical data were col- years, into the following three groups: 1–3, 4–6 and ≥7 relapses. lected from the medical records of the Turkish MS Registry The patients were divided into three groups according to the at Farabi Hospital, Faculty of Medicine, Karadeniz Technical time interval between the first two attacks (<2, 2–5 and >5 University, in Trabzon, Turkey. The patients were followed up years) and they were also divided into two groups according on a regular basis, with at least one visit every 3-4 months, to the starting time of treatment (≤2 years and >2 years). and the patients were also examined when they came back to In MS, an episode (a period of worsening) is defined as the hospital during periods of active complaints. Approval for a period wherein new symptoms develop or existing symp- the study was obtained from Karadeniz Technical University toms are exacerbated, or a period in which new neurological Faculty of Medicine Ethics Council. findings lasting for at least 24 hours (often ending with par- tial or complete recovery) are observed. Symptoms occurring Inclusion criteria within one month are considered as part of the same episode. • Patients diagnosed with RRMS and SPMS in accordance The progressive phase is defined as continuous worsening with the McDonald 2010 criteria. of symptoms and indications for at least 6 months, with or • Signing the consent form and agreeing to participate and without the occurrence of episodes, that causes an irrevers- continue in the study. ible increase of at least 1.0 point in EDSS score when it was
490 Arq Neuropsiquiatr 2021;79(6):489-496 previously ≤5.5 or 0.5 point when it was >5.5 (increases in Table 1. Demographic and clinical features of multiple EDSS score in the period related to relapses and independent sclerosis patients. from corticosteroid treatment response were ruled out)4,6. Mean±SD or n/%) RRMS (n=645) PMS (n=96) p-value Sex Male 224 (34.7%) 31 (32.3%) Statistical analysis 0.639 The data obtained from the study were transferred to Female 421 (65.3%) 65 (67.7%) electronic media and analyzed using the SPSS 20.0 statistical Educational level software package. In addition to descriptive statistical meth- Illiterate 12 (2%) 5 (5.7%) Primary school 256 (41.6%) 60 (69.0%) ods (mean, standard deviation, median, frequency, ratio, <0.001* minimum and maximum), quantitative data were analyzed High school 161 (26.2%) 14 (16.1%) by means of statistical tests. Chi-square analysis was used to University 186 (30.2%) 8 (9.2%) Marital status evaluate whether there was any difference between two or Single 162 (26.2%) 6 (68%) more groups, whether there was any correlation between the Married 451 (72.9%) 79 (89.8%) <0.001* two variables and the degree of homogeneity between groups. Divorced 6 (1%) 3 (3.4%) In the chi-square analysis used in our study, the endpoints Age (years) 39.34 (±10.67) 50.04 (±8.64) <0.001* were defined as reaching EDSS 4, reaching EDSS 6, progres- Age at onset (years) 30.03 (±10.11) 31.56 (±10.31) 0.168 sion from EDSS 4 to EDSS 6, and reaching the secondary pro- Duration of disease 7.65 (±7) 8.32 (±6.11) 0.073 gressive phase of the disease. Kaplan-Meier analysis was also (years) used to evaluate the times taken to reach EDSS 4 and EDSS Disease onset 6 from the onset of disease, and the length of time between Monosymptomatic 591 (91.6%) 70 (72.9%) <0.001* EDSS 4 and EDSS 6. The statistical significance level was Polysymptomatic 54 (8.4%) 26 (27.1%) determined as p<0.05 in all analyses. First attack type Visual 160 (24.8%) 13 (13.5%) Sensory 147 (22.8%) 4 (4.2%) Pyramidal 176 (27.3%) 56 (58.3%) RESULTS <0.001* Brainstem- 155 (24%) 21 (21.9%) Demographic and clinical characteristics of cerebellar multiple sclerosis patients Bladder-intestinal 7 (1.1%) 2 (2.1%) Number of attacks in 2.79 (±1.52) 5.18 (±1.77) <0.001* Out of the 926 MS patients registered in the Turkish MS 5 years database, 741 patients were included in this study and 185 Time between first 33 (±45) 25.5 (±38.7) 0.046* MS patients were excluded. These were excluded because two attacks (months) of their progressive onset, missing EDSS scores or irregular Treatment start time 46.2 (±64.8) 94.4 (±89) <0.001* follow-up. There were 235 patients with follow-ups shorter (months) than 5 years, 450 MS patients with follow-ups shorter than Smoking Yes 172 (90.1%) 19 (9.9%) 10 years and 291 MS patients with follow ups of more than 0.991 10 years. The demographic and clinical characteristics of the No 314 (90.5%) 33 (9.5%) MS patients are shown in Table 1. Number of cigarettes per day 1–10 44 (32.6%) 6 (50%) Among the 741 MS patients who met the inclusion crite- 0.340 ria, 65.6% (n=486) were female and 34.4% (n=255) were male. ≥10 91 (67.4%) 6 (50%) Types of disease-modifying treatment The female/male ratio was 1.9. Among these patients, 87% First-line therapies (n=645) had a diagnosis of RRMS and 13% (n=96) had a diag- Interferon beta-1a 261 (40.5%) 40 (41.7%) nosis of PMS (Table 1). Interferon beta-1b 120 (18.6%) 21 (21.9%) Evaluation of the descriptive statistics on the demo- Glatiramer acetate 129 (20%) 20 (20.8%) graphic and clinical characteristics of the patients with Second-line therapies RRMS and PMS showed that low education level (p<0.001), Azathioprine 3 (0.4%) 10 (10.4%) >0.05 being single (p<0.001), higher age (p<0.001), polysymptom- Fingolimod 34 (5.3%) - atic onset (p<0.001), having an initial episode with pyramidal Teriflunomide 23 (3.6%) - or bladder-intestinal symptoms (p<0.001), higher number of Methotrexate - 2 (2.1%) episodes in first 5 years (p<0.001), short time period between Mitoxantrone - 2 (2.1%) the first two episodes (p=0.046) and longer time period until Natalizumab - 1 (1%) the start of the first treatment (p<0.001) were associated with Cyclophosphamide worse clinical progress. The results from the chi-square anal- Not receiving any 74 (11.5%) - ysis on the demographic and clinical characteristics of MS treatment patients are shown in Table 2. RRMS: relapse-remitting multiple sclerosis.
Kara F et al. Multiple sclerosis and disability development 491 Table 2. Distribution of progression among multiple sclerosis patients. Progressive Total EDSS 4 p-value EDSS 6 p-value p-value EDSS 4-6 p-value phase Sex Male 486 143 (29.4%) 83 (17.1%) 65 (13.4%) 77 (53.8%) 0.273 0.554 0.639 0.968 Female 255 85 (33.3%) 48 (18.8%) 31 (12.2%) 46 (54.1%) Age at onset <18 59 21 (35.6%) 8 (13.6%) 6 (10.2%) 7 (33.3%) 18–40 560 160 (28.6%) 0.069 97 (17.3%) 0.398 69 (12.3%) 0.277 92 (57.5%) 0.102 >40 122 47 (38.5%) 26 (21.3%) 21 (17.2%) 24 (51.1%) Disease onset Monosymptomatic 661 186 (28.1%) 101 (15.3%) 70 (10.6%) 95 (51.1%) <0.001* <0.001* <0.001* 0.097 Polysymptomatic 80 42 (52.5%) 30 (37.5%) 26 (32.5%) 28 (66.7%) First attack type Visual 173 43 (24.9%) 22 (12.7%) 13 (7.5%) 18 (41.9%) Brainstem-cerebellar 176 48 (27.3%) 26 (14.8%) 21 (11.9%) 26 (54.2%) Pyramidal 232 112 (48.3%) <0.001* 74 (31.9%) <0.001* 56 (24.1%) <0.001* 70 (62.5%) 0.005* Sensory 151 22 (14.6%) 6 (4%) 4 (2.6%) 6 (27.3%) Bladder-intestinal 9 3 (33.3%) 3 (33.3%) 2 (22.2%) 3 (100%) Number of attacks in 5 years 1-3 519 115 (22.2%) 44 (8.5%) 18(%3.5) 39 (33.9%) 4-6 174 84 (48.3%) <0.001* 63 (36.2%) <0.001* 55(%31.6) <0.001* 60 (71.4%) <0.001* ≥7 48 29 (60.4%) 24 (50%) 23(%47.9) 24 (82.8) Time between first two attacks <2 years 428 136 (31.8%) 86 (20.1%) 69 (16.1) 81 (59.6%) 2–5 years 197 47 (23.9%) 0.007* 23 (11.7%) 0.029* 18 (8.5%) 0.017* 20 (42.6%) 0.108 >5 years 107 44 (41.1%) 22 (20.6%) 9 (9.8%) 22 (50%) Time of treatment after diagnosis ≤2 years 320 66 (20.6%) 29 (9.1%) 19 (5.9%) 27 (40.9%) <0.001* <0.001* <0.001* 0.009* >2 years 340 150 (44.1%) 96 (28.2%) 69 (20.3%) 90 (60%) Smoking Yes 191 56 (29.3%) 34 (17.8%) 19 (9.9%) 32 (57.1%) 0.902 0.446 0.991 0.294 No 347 100 (28.8%) 53 (15.3%) 33 (9.5%) 47 (47%) Number of cigarettes per day 1–10 50 13 (26%) 8 (16%) 6 (12%) 7 (53.8%) 1.000 0.723 0.340 0.904 ≥10 97 24 (24.7%) 12 (12.4%) 6 (6.2%) 11 (45.8%) EDSS: Expanded Disability Status Scale.
The results from Kaplan-Meier analysis on demographic the progress from EDSS 4 to EDSS 6 were: pyramidal or blad- and clinical parameters affecting the progression and develop- der-intestinal system-related first attack; >3 relapses in the first ment of MS patients are shown in Table 3. It was observed that 5 years; >2 years until initiation of first treatment; and smoking. the demographic and clinical parameters that were effective regarding the time taken to reach EDSS 4 and EDSS 6 were sim- ilar. These parameters were as follows: age at onset >40 years; DISCUSSION having polysymptomatic-type onset, pyramidal or bladder- intestinal system-related first attack; ≥7 relapses in the first MS is the most common of the diseases that develop 5 years; and <2 years between the first two attacks. The demo- due to inflammatory demyelinating events in the CNS. It is graphic and clinical parameters that were effective regarding a chronic disease that progresses with neuroinflammation
492 Arq Neuropsiquiatr 2021;79(6):489-496 Table 3. Demographic and clinical features affecting progression among multiple sclerosis patients. Time taken to Time taken to Time taken to go from Total reach EDSS 4 reach EDSS 6 EDSS 4 to EDSS 6 Median 95%Cl p-value Median 95%Cl p-value Median 95%Cl p-value General 741 15.4 12.9–17.9 21.9 18.8-25.0 3.0 2.5–3.5 Sex Female 486 15.4 12.9–17.9 20.2 15.8–24.6 3.0 2.4–3.7 0.370 0.595 0.713 Male 255 14.2 8.6–19.9 23.5 15.8–31.1 2.8 1.9–3.7 Age at onset <18 59 17.8 8.2–27.5 25.9 5.6 0–11.9 18–40 560 16.3 12.9–19.7 <0.001* 20.2 16.3–24.1 0.003* 2.8 2.0–3.5 0.110 >40 122 10.3 8.7–11.8 15.6 10.5–20.6 3.3 2.6–3.9 Disease onset Monosymptomatic 661 15.8 13.3–18.4 23.5 19.0–27.9 3.0 2.4–3.7 0.002* 0.001* 0.285 Polysymptomatic 80 9.1 7.0–11.2 13.0 10.9–15.1 2.9 1.7–4.0 First attack type Visual 173 19.7 17.8–21.6 24.3 21.2–27.4 3.0 1.5–4.6 Brainstem-cerebellar 176 13.5 7.9–19.2 23.1 13.4–32.8 2.2 1.3–3.1 Pyramidal 232 10.2 8.3–12.0 <0.001* 16.4 13–19.8 <0.001* 3.4 2.4–4.4 0.013* Sensory 151 42.2 Bladder-intestinal 9 8.2 0–18.5 10.3 2.7–17.8 2.0 1.8–2.2 Number of attacks in 5 years 1–3 519 19.7 16.6–22.9 28.7 23.9–33.5 5.3 3.2–7.3 4–6 174 10.8 8.2–13.4 <0.001* 15.9 12.4–19.5 <0.001* 2.8 2.5–3.1 0.001* ≥7 48 5.9 1.2–10.7 11.4 9.1–13.6 3.2 1.8–2.5 Time between first two attacks <2 years 428 11.3 9.3–13.2 16.5 12.9–20.1 2.9 2.3–3.5 2–5 years 197 1 7.1 11.9–22.3 <0.001* 20.2 18.4–22.0 <0.001* 3.0 1.0–5.3 0.453 >5 years 107 20.7 16.8–24.7 28.7 25.4–32.0 3.5 1.0–6.1 Time of treatment after diagnosis ≤2 years 320 14.2 6.2–22.2 5.0 2.9–7.0 0.210 0.753 0.015* >2 years 340 15.4 12.7–18.1 21.1 17.7–24.5 2.7 2.2–3.2 Smoking Yes 191 14.2 7.4–21.0 21.1 13.5–28.7 2.6 1.8–3.3 0.846 0.243 0.018* No 347 15.5 12.8–18.2 20 .1 15.2–28.5 4.2 2.3–6.1 Number of cigarettes per day 1–10 50 19.0 3.1–34.9 2.7 1.0–4.8 0.583 0.200 0.470 ≥10 97 15.8 8.4–23.3 21.1 2.8 0–5.6 EDSS: Expanded Disability Status Scale; 95%CI: 95% confidence interval.
and neurodegeneration in the CNS and is considered to the general impression was that the disease had worse be of autoimmune origin. It involves the cortex and deep prognosis in male patients than in female patients12,13,14,15. gray matter, but white matter is usually affected to a higher However, in yet other published studies, male sex was not degree. Demyelination and axonal degeneration associated found to be a factor associated with poor prognosis, as with MS lesions cause different degrees of disability develop- in our study16,17,18. In our study, the reason why the male ment in patients. patient group was not associated with a poor prognosis In the current study, it was found that sex was not an was thought to be the similar prevalence of the disease in effective factor for disability development. In other studies, males and females, and the exclusion of PPMS and PRMS
Kara F et al. Multiple sclerosis and disability development 493 patients with a progressive-type onset, which may have concluded that the number of episodes was an effective fac- obscured the results. tor for disability development1,12,16,22,27. In the study by Tremlett Compared with other types of episodes, having an initial et al., it was found that the number of episodes in the first five episode with bladder-intestinal system symptoms was found years had a significant effect on disease progression, but that to be associated with shorter time to reach EDSS 4 and 6, the number of episodes over the longer term was less impor- and faster progression from EDSS 4 to EDSS 6. Furthermore, tant28. Consistent with the literature, we found that a high we observed that the type of first episode had a significant number of episodes in the first five years was associated with effect on disability development. In the literature, four differ- disability development. ent studies showed results similar to our study, concluding It was found that patients with <2 years between the first that patients with a first episode related to the bladder-intes- two episodes reached EDSS 4 and EDSS 6 faster, and there tinal system were at increased risk of disability development, was a statistically significant difference, compared with the whereas only one study reported that sphincter symptoms other two groups. Consistent with our study, other stud- had no independent effect on disability development19,20. ies have also shown that a short time interval between the However, different results have been obtained in other stud- first two episodes is indicative of worse disease progres- ies, and some have associated various other symptoms with sion16,17,27,29,30. Almost all studies in the literature suggest MS prognosis (for better or for worse)17,21. Although these results similar to ours. studies show that there are contradictory results in the lit- There was no statistically significant difference in the erature, our results were similar to those of the majority of time taken to reach EDSS 4 and EDSS 6 between the two studies, and we found that having a first episode related to groups, according to the time when treatment was started, the bladder-intestinal system was an effective factor in the but it was observed that starting the treatment after two development of irreversible disability. years shortened the progression from EDSS 4 to EDSS 6, and In our study, MS patients were divided into three age this difference was significant. There are studies in the liter- groups according to disease onset (<18, 18–40, and over ature showing that starting treatment early was not related 40 years of age). From evaluating these groups, we concluded to progression of the disease29,31,32. Similarly, in another study, that being over 40 years old at diagnosis was a factor asso- receiving treatment at any time of the disease was not asso- ciated with increased disability development. Similar to our ciated with poor prognosis18 In three different studies, it study, other studies have also found that late onset of dis- was shown that disease progression measured by the time ease was associated with poor prognosis12,17,22,23,24. There are taken to reach EDSS milestones was slower with IFN β treat- a few studies that reported different findings. For instance, ment30,33,34,35. In another study, it was found that treatments in a study by Trojano et al. published in 1995, it was found that were effective against the course of the disease that that late onset was associated with good prognosis; however, were started during the clinical isolated syndrome stage pre- the limit for advanced age was identified as 25 years in that vented disability development36. These results suggest that study25. Similarly, in another published study, the age at onset treatments that are effective against the course of the dis- of the disease was not found to be associated with poor prog- ease may have partially positive effects on disability develop- nosis18. Consistent with many other studies in the literature, ment. However, in our patient group, there were 235 patients we determined that late onset of disease was an indicator of with follow-ups shorter than 5 years, 450 MS patients with worse clinical progress. This may be attributed to the age- follow-ups shorter than 10 years and 291 MS patients with related deterioration of repair mechanisms. follow-ups of more than 10 years. The fact that the time when Comparison of onset type showed that MS patients with treatment started was not directly related to disability devel- polysymptomatic-type onset reached EDSS 4 and EDSS 6 sig- opment can be explained by the different treatment options nificantly faster than patients with monosymptomatic-type used by the patients, and by insufficient follow-up duration onset. In the literature, two different studies reported results for many of our patients, which would limit the evaluation of similar to ours22,26. On the other hand, polysymptomatic-type long-term outcomes from treatments. onset was found to have no effect on the prognosis of MS in In our study, smoking was found to have no effect on several studies27. Our findings can be explained by the fact reaching the EDSS 4 and EDSS 6 milestones, but it was found that the involvement of multiple neurological systems at the that it shortened the progression from EDSS 4 to 6, and this same time may be a clinical indicator of the involvement of difference was statistically significant. Many studies investi- more than one region in the CNS. Therefore, a relationship gating the relationship between smoking and MS progression between the number of lesions and disability development have suggest that smoking causes disease progression37,38,39,40. may exist. The reason why the results from our study were partially con- We found that patients with ≥7 episodes in the first five sistent with the literature was thought to be related to the years reached EDSS 4 and EDSS 6 in shorter times, and that lack of smoking data in most patient records included in this their progress from EDSS 4 to EDSS 6 was faster than was study and the possibility that patients provided incomplete seen among other patients. Similarly, in other studies, it was or incorrect information about smoking.
494 Arq Neuropsiquiatr 2021;79(6):489-496 In conclusion, in this study, some factors that cause first-episode type related to the bladder-intestinal system; worse disease progression in MS patients were identi- ≥7 episodes in the first 5 years; <2 years between the first two fied. To summarize, these factors were: age at onset (being episodes; time until the start of treatment greater 2 years; older than 40 years); polysymptomatic-type onset; having a and smoking.
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496 Arq Neuropsiquiatr 2021;79(6):489-496 https://doi.org/10.1590/0004-282X-ANP-2020-0314 ARTICLE
Epidemiological and clinical aspects of Guillain-Barré syndrome and its variants Aspectos epidemiológicos e clínicos da síndrome de Guillain-Barré e suas variantes Dayanne Rodrigues da Cunha Alves Bento OLIVEIRA1, Rubens Nelson Morato FERNANDEZ1, Talyta Cortez GRIPPE1,2, Fabiano Silva BAIÃO3, Rafael Lourenco DUARTE4,5, Diego Jose FERNANDEZ6
ABSTRACT Background: Guillain-Barré syndrome (GBS), an acute polyradiculoneuropathy that occurs because of an abnormal inflammatory response in the peripheral nervous system, is clinically characterized by acute flaccid paresis and areflexia with or without sensory symptoms. This syndrome can lead to disabling or even life-threatening sequelae. Objective: This study aimed to present the clinical and epidemiological aspects of GBS in patients admitted to a tertiary-level hospital in the Federal District between January 2013 and June 2019. Methods: In this observational, cross-sectional and retrospective study, medical records of patients diagnosed with acute inflammatory demyelinating polyradiculoneuropathy, acute motor axonal neuropathy or acute axonal motor-sensitive neuropathy based on electromyographic findings were included, and clinical data were collected retrospectively. Results: A total of 100 patients (63 males and 37 females; ratio, 1.7:1) aged 2–86 years (mean, 36.4 years) were included. The mean annual incidence rate of GBS was 0.54 cases/100,000 inhabitants, with 52 and 49% of the cases occurring between October and March (rainy season) and between April and September (dry season), respectively. The proportions of patients showing each GBS variant were as follows: demyelinating forms, 57%; axonal forms, 39%; and undetermined, 4%. The mean duration of hospitalization was 8–15 days for most patients (38%). During hospitalization, 14% of the patients required mechanical ventilation and 20% experienced infectious complications. Conclusion: The findings indicate that there was an increase in the incidence of GBS during the rainy season. Moreover, we did not observe the typical bimodal distribution regarding age at onset. Keywords: Guillain-Barré Syndrome; Electromyography; Neurophysiology; Epidemiology.
RESUMO Introdução: Síndrome de Guillain-Barré (SGB), uma polirradiculoneuropatia aguda que ocorre devido a uma resposta inflamatória anormal no sistema nervoso periférico, é caracterizada clinicamente por paralisia flácida aguda e arreflexia, com ou sem sintomas sensitivos. Essa síndrome pode deixar sequelas incapacitantes ou até ameaçar a vida. Objetivo: Apresentar os aspectos clínicos e epidemiológicos da SGB em pacientes internados em um hospital terciário do Distrito Federal, no período de janeiro/2013 a junho/2019. Métodos: Estudo observacional, transversal e retrospectivo, no qual pacientes com diagnóstico de polirradiculoneuropatia desmielinizante inflamatória aguda, neuropatia axonal motora aguda ou neuropatia axonal sensitivo motora aguda a partir dos achados eletroneuromiográficos foram selecionados e seus dados clínicos coletados retrospectivamente em seus prontuários.Resultados: Um total de 100 pacientes (63 homens e 37 mulheres; proporção de 1,7:1), com idades entre 2–86 anos (média, 36,4 anos), foram incluídos. A taxa média anual de incidência de SGB foi de 0,54 casos/100.000 habitantes, com 52 e 49% dos casos ocorrendo entre outubro e março (período chuvoso) e entre abril e setembro (período seco), respectivamente. A proporção de pacientes que apresentaram cada variante de SGB foi a seguinte: formas desmielinizantes, 57%; formas axonais, 39%; e indeterminado, 4%. A duração média da hospitalização foi de 8–15 dias para a maioria dos pacientes (38%). Durante a hospitalização, 14% dos pacientes necessitaram de ventilação mecânica e 20% apresentaram complicações infecciosas. Conclusão: Os resultados indicam aumento na incidência de GBS durante a estação chuvosa. Além disso, não observamos a distribuição bimodal típica em relação à idade de início. Palavras-chave: Síndrome de Guillain-Barré; Eletromiografia; Neurofisiologia; Epidemiologia.
1Hospital de Base do Distrito Federal, Instituto de Gestão Estratégica em Saúde do Distrito Federal, Departamento de Neurofisiologia Clínica, Brasília DF, Brazil. 2Centro Universitário de Brasília, Faculdade de Medicina, Brasília DF, Brazil. 3Hospital da Força Aérea de Brasília, Brasília DF, Brazil. 4Secretaria Municipal de Saúde de Anápolis, Anápolis GO, Brazil. 5Centro de Diagnóstico por Imagem de Goiânia, Goiânia GO, Brazil. 6Instituto de Neurologia de Goiânia, Goiânia GO, Brazil. Dayanne Rodrigues da Cunha Alves Bento OLIVEIRA https://orcid.org/0000-0002-4035-2217; Rubens Nelson Morato FERNANDEZ https://orcid.org/0000-0003-2978-0269; Talyta Cortez GRIPPE https://orcid.org/0000-0003-3126-8002; Fabiano Silva BAIÃO https://orcid.org/0000-0002-0289-1754; Rafael Lourenco DUARTE https://orcid.org/0000-0001-7924-1496; Diego Jose FERNANDEZ https://orcid.org/0000-0002-9373-4200 Correspondence: Dayanne Rodrigues da Cunha Alves Bento Oliveira; E-mail: [email protected]. Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: DRCABO and RNMF: conceived the presented idea. DRCABO, FSB, RLD and DJF: designed the study and collected the data. TCG: performed the statistical analysis. DRCABO: wrote the first draft. All authors discussed the results and contributed to the final manuscript. TCG and RNMF: made the final revision. Received on June 30, 2020; Received in its final form on September 14, 2020; Accepted on September 19, 2020.
497 INTRODUCTION METHODS
Guillain-Barré syndrome (GBS) is an acute immune- In this observational, cross-sectional and retrospective mediated polyneuropathy characterized by flaccid and rap- study, the medical records of patients diagnosed with AIDP, idly progressive paresis that is symmetrical, ascending and AMAN or AMSAN, based on the findings from electroneuro- areflexic1. In two-thirds of the patients, upper respiratory myography (ENMG) performed between January 2013 and tract infection (URTI) or diarrheal disease (usually caused June 2019, in the neurophysiology sector of a tertiary-level by Campylobacter jejuni) occurs 1–4 weeks before the onset hospital in the Federal District, the only public hospital in of neuropathy2. Cases of GBS have also been reported soon the Federal District that performs this examination, were after administration of the rabies vaccine, as well as with cer- included. The study was approved by the local ethics com- tain vaccines against the influenza A virus. Similarly, pos- mittee under number 29193019.2.0000.8153. sible associations with acute arbovirus infections, includ- The median, ulnar, superficial and deep fibular, sural and ing Zika and chikungunya, have been extensively studied in tibial nerves of all four limbs were analyzed. Regarding motor recent years3. conduction, distal latency, amplitude (baseline to negative GBS is mediated by humoral and cellular responses peak), conduction speed and duration (first negative deflec- that directly destroy the myelin sheath of axons of periph- tion to the baseline of the last negative deflection) of the eral nerves4. Although GBS variants share immunomediated compound muscle action potential, along with minimum pathogenesis, they differ in their pathophysiology, clinical F-wave latency, were analyzed. Regarding sensory conduc- presentations and endpoints, and are classified into differ- tion, amplitude (baseline to negative peak), onset latency ent subtypes. For example, immune reactions against epi- and conduction velocity of the sensitive action potential topes of Schwann cell surface membranes or myelin result were analyzed. in demyelinating neuropathy, while those directed against The ENMG findings and medical records of 100 patients axonal membrane antigens cause the acute axonal form of with a clinical history and findings of physical and cerebro- the syndrome5. spinal fluid examination compatible with GBS were reviewed However, over recent years, microstructural changes in in accordance with the Asbury and Cornblath criteria12. the nodal region have been discussed as the key to under- Patients diagnosed with acute demyelinating or axonal polyra- standing the pathophysiology of neuropathies associated diculoneuropathy due to paraneoplastic conditions, systemic with ganglioside antibodies, and a new category of nodo- diseases, acquired immunodeficiency syndromes or polyneu- paranodopathies has been proposed, in order to better ropathies that were later diagnosed as chronic demyelinating characterize these disorders. The concept of nodo-parano- inflammatory polyneuropathy (CIDP) were excluded. dopathies seems appropriate for several acute and chronic The following variables were analyzed: age, sex, predis- neuropathies associated with antibodies against gangliosides posing factors, form of the disease, electrophysiological char- and paranodal axo-glial proteins, as this concept focuses on acteristics, complications, need for ventilatory support, dura- the site of the primary nerve injury while considering the tion of hospitalization, seasonality and mortality. specific pathophysiological mechanisms, reconciling mor- As the Federal District is located in a tropical climate phological contrasts and electrophysiological findings, and region where the seasons are poorly defined, the seasonal avoiding wrong diagnoses6. distribution of GBS incidence was evaluated in two periods: In North America and Europe, the demyelinating form, dry (April to September) and rainy (October to March)13. i.e. acute inflammatory demyelinating polyradiculoneuropa- thy (AIDP), is predominant. The less common axonal forms are found in only 5% of patients and include acute motor RESULTS axonal neuropathy (AMAN). Patients with axonal forms of GBS reach the nadir of symptoms earlier than those with Epidemiological data the demyelinating form, although the recovery rates for the Data on epidemiological characteristics, the form of the two forms are comparable7. Motor-sensory axonal neuropa- disease, predisposing factors and duration of hospitalization thy (AMSAN) is considered to be the most severe form of the are presented in Table 1. Among the 100 patients included GBS phenotype and typically exhibits rapid progression to in this study (mean age, 36.4 years; range, 2–86 years), the tetraplegia8. In Asia and Central and South America, axonal number of male patients was predominantly high (male-to- forms constitute 30–47% of cases1. female ratio, 1.7:1.0). The patients were subdivided into four Few studies have evaluated the epidemiology of this syn- age groups. In the <14 years group, the prevalence of GBS was drome in Brazil9,10,11. The objective of this study was to dem- similar between the sexes; however, in the remaining groups, onstrate the clinical and epidemiological aspects of GBS in a the number of male patients was predominantly high. series of patients admitted to a tertiary-level hospital in the The most frequently observed variant of the dis- Federal District. ease was the demyelinating form, followed by axonal
498 Arq Neuropsiquiatr 2021;79(6):497-503 Table 1 Clinical characteristics. Clinical characteristics (n=100) Demographic characteristics % Age 0–14 years 12 15–34 years 35 35–59 years 43 Over 60 years 10 Sex Male 63 Female 37 Form of disease (%) AIDP 57
AMAN 24 Figure 1. Incidence rate of Guillain-Barré syndrome. AMSAN 15 Undefined 4 Previous factors (%) URTI 23 distribution. Student’s t-test was chosen because the sample distribution was normal. AGEC 26 The mean frequencies of occurrence of GBS were 5±3.98 Arboviruses 11 and 9.3±3.23 in the dry and rainy seasons, respectively. Other (vaccination and pregnancy) 4 During both these seasons, the demyelinating forms were Unknown 36 observed predominantly (50% in the rainy season and 64.5% Duration of hospitalization in the dry season). With regard to the annual incidence rate 0 days 2 of GBS, a larger proportion of GBS cases were observed dur- 1–7 days 27 ing the rainy seasons of all years except 2013 and 2016; during these two years, 52.1 and 53.8% of the cases, respectively, 8–15 days 38 occurred in the dry season (Figure 2). 16–30 days 23 ≥30 days 10 Predisposing factors AIDP: acute demyelinating inflammatory polyneuropathy; AMAN: motor Among the predisposing factors for GBS identified in the axonal neuropathy; AMSAN: motor-sensory axonal neuropathy; URTI: upper respiratory tract infections; AGEC: acute gastroenterocolitis 30-day period before the onset of neurological symptoms, his- tories of upper respiratory tract infections (URTI) and acute gastroenterocolitis (AGEC) showed the highest frequencies. Patients with a history of arbovirus infections (13%) were neuropathy (AMAN and AMSAN). Definition of the patho- also observed, with 18 and 19% showing symptoms sugges- physiological mechanism underlying 4% of the cases was tive of Zika and chikungunya, respectively, and 63% showing not possible because ENMG was performed at an early stage. serological positivity for dengue fever. Attempts made to contact these patients for further exami- We registered two GBS cases of women with ongoing nation were unsuccessful. pregnancies; one was diagnosed with AIDP and the other The annual case frequency was 8–23 cases/year; the high- with AMAN. Additionally, we registered one case of AIDP est incidence rate was observed in 2013 (23 cases), followed relating to a woman in the late puerperium. A history of influ- by 2018 (18 cases). The incidence rates remained constant enza vaccination in the 60 days before the onset of neurologi- between 2014 and 2016 (13 cases/year) and decreased in cal symptoms was identified in one patient. Higher incidence 2017 (8 cases). In the first half of 2019, 12 cases were recorded. rates of URTI (59%), AGEC (73%), and arbovirus infections The average annual frequency of occurrence of GBS was (55%) were observed in the rainy season. 14.28 cases/year. The average annual incidence rate was 0.54 cases/100,000 inhabitants in the Federal District. Complications Evaluation of the GBS frequency distribution between Fourteen percent of all the patients required mechanical the seasons using Student’s t-test revealed a significant dif- ventilation at some point during the course of the disease. ference in GBS distribution according to the season (p=0.05; Among them, 64.3 and 35.7% had demyelinating and axonal Figure 1). Thus, the season was a relevant factor for case forms of the disease. About 20% of all the patients presented
Oliveira DRCAB et al. Guillain-Barré syndrome: epidemiology and clinical aspects 499 Table 2. Duration of hospitalization and form of the disease. Form of disease Hospitalization period Demyelinating Axonal Undefined (n=55) (n=39) (n=4) 1–7 days 19 (34.5%) 8 (20.5%) 0 8–15 days 19 (34.5%) 16 (41%) 3 (75%) 16–30 days 12 (22%) 10 (25.6%) 1 (25%) >30 days 5 (9%) 5 (12.9%) 0
GBS: Guillain-Barré syndrome. Figure 2. Annual Guillain-Barré syndromeincidence coefficient and Guillain-Barré syndromeincidence in the rainy and dry Time between symptom onset and periods from 2013 to 2019 (June). electroneuromyography recording Most patients (n=38) underwent ENMG 8–15 days after the onset of symptoms. Furthermore, 27, 24 and 6 patients underwent the examination 16–30 days, 7 days, and 30–60 days after symptom onset, respectively. While most patients with infectious complications during hospitalization, in underwent ENMG once, 22 patients underwent a second which the lungs were the most prevalent focus of infection ENMG. Among these 22 patients, 12 patients underwent the (85%). Among the 57 patients with a demyelinating form of second exam within 60 days; in 41% of the patients in this the disease, 24.5% recovered from this complication, com- subgroup, definition of the form of the disease was possible pared with 12.8% of the 39 patients with an axonal form. only after performing the second examination.
Treatment Among the 100 patients evaluated, 98 received hospital DISCUSSION treatment. The treatment of choice was immunoglobulin- based in 88 patients; however, six patients had to undergo Previously, a meta-analysis estimated the overall annual more than one cycle of treatment because of the refractori- incidence rate of GBS to be 0.8–2 cases/100,000 individu- ness of the condition. None of the patients had complications als14. In Latin America, high incidence rates have been relating to infusion of the drug. In addition, eight patients reported in Chile (2.12 cases/100,000)15 and Argentina (2.06 underwent plasmapheresis, and only one of them presented cases/100,000)16, while a relatively low annual incidence rate with hemodynamic instability during the treatment. In that has been reported in Brazil (0.4 cases/100,000)9. The esti- case, the treatment had to be suspended. No specific treat- mated annual average incidence rate in the Federal District ment (immunoglobulin-based or plasmapheresis) was indi- is 0.5 cases/100,000, which is similar to that of Brazil. cated for two patients because they showed mild clinical The incidence rates differed over the years, with peaks symptoms and good recovery. observed in 2013 (0.89 cases/100,000) and 2018 (0.46 cases/100,000) (Figure 1). Most patients with acute parapare- Duration of hospitalization time and form of the sis are evaluated in our hospital. However, there might have disease been a few evaluated in private hospitals, and the data of As detailed in Table 1, the duration of hospitalization was these patients were not included while calculating the inci- 8–15 days for most patients. Among those hospitalized for dence rates. more than 31 days, 70% suffered respiratory failure and con- The proportions of AIDP and axonal forms of GBS may sequently required mechanical ventilation during the initial vary in different countries depending on the climatic con- period of hospitalization. In these patients, respiratory fail- ditions, basic sanitation and geographical region of origin ure progressed to infectious complications. Table 2 shows of the patient. In North America and Europe, demyelinat- the relationship between the duration of hospitalization and ing forms are predominant (69–90%), while axonal forms are the form of the disease: the duration of hospitalization was more common in Asia and South America17. higher for axonal forms (22 days) than for demyelinating In Brazil, a study on GBS conducted in Rio Grande do forms (14 days). Norte between 1994 and 2007 showed that demyelinating forms predominated (81.8%) and that motor axonal (AMAN, Mortality 14.7%) and motor-sensitive forms (AMSAN, 3.3%) were pres- In our data, no mortality was observed during the follow- ent11. Another study revealed that the highest incidence rate up period (2013–2019). was shown by demyelinating forms (57%), followed by AMAN
500 Arq Neuropsiquiatr 2021;79(6):497-503 (24%) and AMSA (15%), in the Federal District13. A previous Recently, a nationwide increase in the incidence of GBS study14 reported that men are more susceptible to GBS than following the Zika virus epidemic in 2015 was reported28. women; this finding is in line with that of the current study However, this was not supported by maintenance of annual (male-to-female ratio, 1.7:1). incidence during this period, in our study (Figure 2). According to the International Study on GBS17, the disease Reports on the incidence of GBS associated with preg- is prevalent in all age categories. The incidence rate increases nancy, surgery or trauma are rare18. We identified two cases in with age, from 0.6 cases/100,000 people/year for individuals pregnant women and one case in a woman in the late puerpe- aged <2 years to 2.7 cases/100,000 people/year for those aged rium; however, no other predisposing factors were identified. >80 years14, and shows bimodal distribution with peaks for Incidence of GBS shortly after administration of rabies young (15–34 years) and older (>60 years) adults18. On the con- vaccine and various types of influenza vaccines has also trary, we found a higher incidence rate (43%) among individu- been reported. One study reported that the incidence of GBS als aged 35–59 years than among those aged >60 years (10%). increased by 1.6 cases/1,000,000 people vaccinated against Previous studies have failed to identify a clear relation- influenza A virus subtype H1N1 and other seasonal influenza ship between the incidence of GBS and seasons, and such a viruses3. On the other hand, a recent retrospective evalua- relationship is variable across countries17. However, the asso- tion of 3,523 cases of GBS in France showed that there was ciation between the occurrence of UPTI before GBS and win- no association between seasonal influenza vaccination and ter is clear9. GBS29. In our study, only one patient with a history of influ- Overall, we found that the incidence rate of GBS was enza vaccination within 60 days before the onset of GBS higher in the rainy season (52%) than in the dry season symptoms was noted; this individual had a demyelinating (48%). Demyelinating forms were found to be predominant form of the disease. in the dry period (64.5%) while demyelinating and axonal GBS is a potentially fatal disease that requires intensive forms showed similar incidence rates (50%) in the rainy sea- medical care, monitoring of vital signs, management of auto- son. Although in most years the incidence rates of GBS were nomic dysfunctions and administration of immune treat- higher in the rainy season than in the dry season, the oppo- ment. Several randomized clinical trials have evaluated the site was true in 2013 and 2016 (dry season, 52.1 and 53.8%, effects of immunotherapy on GBS over recent decades, and respectively). In 2017, the two seasons showed similar rates intravenous immunoglobulin therapy and plasmapheresis of GBS incidence (Figure 1). have been proven to be equally effective30. In our study, 98% Other studies have also reported seasonal distribution of of the patients were hospitalized, and 89.7 and 8.1% of them incidence rates of GBS. This variability is thought to reflect underwent immunoglobulin therapy and plasmapheresis, the variability of predisposing factors, such as infections of respectively. The medical records did not indicate the treat- the gastrointestinal and respiratory tracts. In our study, this ments that the remaining patients underwent. possibility was corroborated by high rates of infections, as Respiratory failure is the most serious short-term com- predisposing factors during the rainy season19,20,21,22,23,24. plication of GBS. About 20–30% of patients may need inva- GBS is typically a post-infection disease characterized by sive mechanical ventilation, which increases the risk of rapid monophasic progression of the disease after infection development of complications. Among intubated patients, (interval of <1 month), usually without relapse. Identification 60% develop complications such as pneumonia, sepsis, gas- of the predisposing factor is important, as it could be corre- trointestinal bleeding and pulmonary embolism31. The lon- lated with the clinical phenotype and prognosis. The agent ger the progression time of AIDP is, the stronger the signs of most commonly associated with GBS is Campylobacter jejuni severity and the indication for intensive monitoring will be25. (specifically serotype O: 19), which causes axonal injury and The progression pattern and speed differ between AMAN and Wallerian degeneration and is characterized by the presence AIDP. AMAN shows faster progression and an earlier peak. of GM1 and GD1 antiganglioside antibodies, with a poor The current study presented similar findings (requirement prognosis25. In the present study, similar observations were for mechanical ventilation, 14%; development of infectious made, i.e. 65.3% of cases with a recent history of AGEC pro- complications, 20%; and pulmonary focus of infection, 85%). gressed to an axonal form of the disease. The recovery patterns of patients with AMAN also differ Reports on associations between GBS and infections from those with AIDP32. The recovery speed of patients with such as dengue, chikungunya, and Zika viruses are now avail- AIDP is relatively uniform, while two patterns of recovery have able26,27. In our series of cases, there was a clinical suspicion been observed in patients with AMAN: recovery within a few of involvement of arboviruses in 11% of cases, with predomi- days and slow and partial recovery. Rapid recovery is caused nance in the dry season (63.6%). Among the corresponding by resolution of the driving block, and poor recovery is associ- patients, 63% tested serologically positive for dengue virus ated with extensive axonal degeneration of nerve roots33. infection, 18% presented with symptoms suggestive of Zika, In our study, the number of patients with prolonged dura- and 19% were suspected of chikungunya; however, no spe- tion of hospitalization (>30 days) was similar to that observed cific tests were performed for confirmation. in previous studies (axonal forms, 12%; and demyelinating
Oliveira DRCAB et al. Guillain-Barré syndrome: epidemiology and clinical aspects 501 form, 9%). A high proportion of the patients with demyelin- In our study, defining the disease type of five patients was ating forms of the disease had infectious complications and possible only after performing the second ENMG, while this required mechanical ventilation. was not possible in the cases of another four patients because ENMG plays a key role in the evaluation of patients with of the lack of a control examination. GBS. The criteria defined for AMAN and AMSAN by Ho and Moreover, although we tried to eliminate all the non-GBS Hadden were based on the initial assumption that these polyneuropathies through the ENMG-based inclusion crite- subtypes were pathologically characterized by simple axo- ria, these criteria carry a lack of sensitivity. Thus, some cases nal degeneration. However, some patients with AMAN show of GBS might be excluded because not all of them fulfil the transient conduction block or deceleration in the intermedi- criteria in all evaluations. It is also important to acknowl- ate and distal nerve segments, which mimics demyelination edge that we did not divide the cases according to the clini- but without the development of abnormal temporal disper- cal variants because there was a registration bias in some of sion and is referred to as reversible conduction failure (RCF), the medical reports (undisclosed information). at the onset of the condition34. In conclusion, we have presented updated data on the The lack of distinction between RCF and demyelinating epidemiology, seasonality and electrophysiology of GBS from conduction block leads to erroneous classification of AMAN a representative region of our country. We did not observe and RCF as AIDP34. Therefore, serial electrophysiological stud- the typical bimodal distribution regarding the age at onset. ies are mandatory for diagnosing GBS subtypes, identifying There is a possible association between the incidence of GBS pathophysiological mechanisms and making the prognosis. and the rainy season.
References
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Oliveira DRCAB et al. Guillain-Barré syndrome: epidemiology and clinical aspects 503 https://doi.org/10.1590/0004-282X-ANP-2020-0151 ARTICLE
Primary central nervous system tumors in Sergipe, Brazil: descriptive epidemiology between 2010 and 2018 Tumores primários do sistema nervoso central em Sergipe, Brasil: epidemiologia descritiva entre 2010 e 2018 Bárbara Loiola SANTOS1, Arthur Maynart Pereira OLIVEIRA2,3, Hélio Araújo OLIVEIRA2, Robson Luis Oliveira de AMORIM4
ABSTRACT Background: Central nervous system (CNS) tumors are a heterogeneous group with high morbidity and mortality. Objectives: To describe the epidemiology of primary CNS tumors diagnosed in the state of Sergipe from 2010 to 2018. Methods: We evaluated histopathological and immunohistochemical reports on primary CNS tumors diagnosed in Sergipe, Brazil, between 2010 and 2018 and collected data regarding age, sex, location, World Health Organization (WHO) classification and histology.Results: Altogether, 861 primary CNS tumors were found. Tumors in brain locations occurred most frequently (50.8%; n=437). The neoplasms observed were most prevalent in the age range 45–54 years (20.4%; n=176). Grade I tumors occurred most frequently, corresponding to 38.8% of the cases (n=38) in the age group of 0–14 years, and 44.6% (n=340) in the population ≥15 years old. Between 0 and 14 years of age, other astrocytic tumors were the most prevalent (29.6%; n=29). In the age group between 15 and 34, gliomas were the most frequent (32.7%; n=54). Meningiomas predominated in the age group of 35 years and above, comprising 47.5% of cases (n=206) in the 35–74 age group; and 61.2% (n=30) among patients over 75 years old. Conclusion: The epidemiology of primary CNS tumors in Sergipe between 2010 and 2018 is consistent with data in other current studies on the subject. Studies on the epidemiological evolution of these entities in Sergipe are needed. Keywords: Brain Neoplasms; Epidemiology; Prevalence.
RESUMO Introdução: Os tumores do sistema nervoso central (SNC) são um grupo heterogêneo de entidades que apresenta significativa morbimortalidade. Objetivos: O presente estudo visa à descrição epidemiológica dos tumores primários do SNC com diagnóstico histopatológico no estado de Sergipe, Brasil, entre 2010 e 2018. Métodos: Foram avaliados laudos histopatológicos e imuno-histoquímicos de tumores primários do SNC, diagnosticados entre 2010 e 2018, no estado de Sergipe. Os dados coletados foram descritos de acordo com as variáveis de idade, sexo, localização, classificação da Organização Mundial da Saúde (OMS) e tipo histológico.Resultados: Foram encontrados 861 tumores primários do SNC. A localização cerebral foi a mais frequente (50,8%; n=437). As neoplasias observadas prevaleceram na faixa etária de 45 a 54 anos (20,4%; n=176). Os tumores grau I foram os mais frequentes, correspondendo a 38,8% dos casos (n=38) na faixa etária de 0–14 anos e 44,6% (n=340) na população a partir de 15 anos de idade. Na faixa etária entre 0–14 anos, o grupo histológico dos outros tumores astrocíticos foi o mais prevalente (29,6%; n=29). Na população entre 15–34 anos, os gliomas foram os mais frequentes (32,7%; n=54). Os meningiomas predominaram nas faixas etárias a partir de 35 anos, com 47,5% dos casos (n=206) entre 35–74 anos; e 61,2% (n=30) nos pacientes acima de 75 anos de idade. Conclusão: A descrição epidemiológica dos tumores primários do SNC em Sergipe, entre 2010 e 2018, é condizente com outros trabalhos atuais sobre o tema. Estudos voltados à evolução epidemiológica dessas entidades em Sergipe são necessários. Palavras-chave: Neoplasias Encefálicas; Epidemiologia; Prevalência.
1Universidade Federal de Sergipe, Departamento de Medicina de Lagarto, Lagarto SE, Brazil. 2Universidade Federal de Sergipe, Departamento de Medicina, Aracaju SE, Brazil. 3Fundação de Beneficência Hospital de Cirurgia, Serviço de Neurocirurgia, Aracaju SE, Brazil. 4Universidade Federal do Amazonas, Programa de Pós-Graduação em Ciências da Saúde, Manaus AM, Brazil. Bárbara Loiola SANTOS https://orcid.org/0000-0002-1188-2788; Arthur Maynart Pereira OLIVEIRA https://orcid.org/0000-0003-4413-592X; Hélio Araújo OLIVEIRA https://orcid.org/0000-0002-3004-240X; Robson Luis Oliveira de AMORIM https://orcid.org/0000-0003-2391-7519 Correspondence: Bárbara Loiola Santos; E-mail: [email protected]. Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: HAO and AMPO: study conception and design. BLS and HAO: acquisition of data. BLS and AMPO: analysis and interpretation of data. BLS, AMPO and RLOA: writing of the manuscript. BLS and RLOA: critical review. Received on April 08, 2020; Received in its final form on October 19, 2020; Accepted on October 21, 2020.
504 INTRODUCTION METHODS
Disordered proliferation of brain cells originates Study design tumors, which may be malignant or non-malignant1,2,3. This was an observational and descriptive retrospective In Brazil, it has been estimated that 11,090 new cases longitudinal study in which histopathological reports on of malignant central nervous system (CNS) tumors will patients who underwent removal of primary CNS tumors occur in 2020. Except for non-melanoma skin cancer, in the state of Sergipe, Brazil between January 2010 and CNS neoplasms correspond to the tenth most prevalent December 2018 were analyzed. The reports were collected type of cancer among women in Brazil, and are the ninth from the database laboratories in Sergipe that agreed to par- most frequent among men and women in the northeast- ticipate in the study. ern region of Brazil4. Because of the location, unpleasant neurological deterioration may be seen in cases of both Inclusion criteria malignant and non-malignant CNS tumors. Moreover, All patients who underwent surgery to treat primary CNS these neoplasms are responsible for significant mortality tumors in the state of Sergipe, between January 2010 and in the population4,5,6,7. December 2018, and whose histopathological material was The World Health Organization (WHO) published a new analyzed, were included in this study. Patients were enrolled update on the classification of tumors of the central ner- regardless of their place of residence since their addresses vous system in 2016. In this, their classification came to were not available from the laboratories that attended to incorporate molecular characteristics, in addition to the these cases. histological aspects of tumor entities. The new perspective has an impact on diagnosing tumor types since it enhances Exclusion criteria discrimination between subtypes resembling histopatho- We excluded patients whose histopathological reports logical categories and therefore optimizes the accuracy of were inconclusive, along with cases of metastasis. Among the diagnosis8,9,10. histopathological reports, 52 c ases were found to be incon- Because of the heterogeneity of these tumors and the dif- clusive or contained incomplete information, and were ferent methods used in studies, their precise epidemiologi- therefore excluded from this study. cal description is complex11,12,13. Moreover, many sites do not have a non-malignant tumor registration system. This limits Data collection technique and instruments the analysis on the distribution and characterization of these The data-gathering period was between November 2018 entities in the population14. and February 2019. After the methodology of the current proj- Comparative studies have shown increasing incidence ect had been presented to the Research Ethics Committee of CNS tumors over the years15,16,17. This may be occur- of the Federal University of Sergipe and approval had been ring through increased exposure to possible risk factors granted, data collection at the laboratories that agreed to such as high-dose irradiation or genetic syndromes, or participate started. through improved access to screening imaging tests18,19,20. Five anatomopathological laboratories located in Aracaju, Furthermore, it has been suggested in some studies that the Sergipe, are registered in the National Register of Healthcare increasing use of wireless devices and cordless phones are Establishments (CNES). Four out of these five were respon- risk factors for the development of CNS tumors21,22. sible for all of the anatomopathological reports on brain sur- In Sergipe, a state in northeastern Brazil, few stud- geries in Sergipe, and all of them agreed to participate in this ies have evaluated the epidemiology of CNS tumors. This current research. state does not have a notification system for benign CNS The data analysis followed the 2016 WHO classification tumors, which highlights the importance of epidemio- for stratification of CNS tumors, in which the tumors are logical studies based on the histopathological diagnosis divided into four groups, according to increasing degrees of of these entities. In Aracaju, a city located in Sergipe, the severity, ranging from grade I to IV. In 2016, an updated clas- population-based cancer registry (RCBP) possesses a high- sification was published, incorporating molecular charac- quality database, that supports national ratings for the teristics to define tumor entities10. We used this updated incidence of primary malignant CNS tumors. This formed classification for CNS tumors, but no molecular analy- a reference point for parallels with the findings of the pres- sis had been performed in most cases. Therefore, given ent study. the small number of cases with molecular analysis, it was The objective of this study was to characterize the decided not to describe molecular data in this current CNS primary tumors in Sergipe between 2010 and 2018. study. After data collection, we analyzed the prevalence of Through these data, we described the current panorama of tumors and their epidemiological characteristics accord- distribution of these entities, with the aim of contributing to ing to the variables of age, sex and location, in accordance knowledge of the epidemiology of these tumors. with the categories of the International Classification of
Santos BL et al. Primary central nervous system tumors 505 Diseases, 10th edition (ICD-10), WHO grade and histologi- most frequently, comprising 64.2% (n=278) of these entities cal tumor type. and 32.3% (n=278) of the entire sample. Glioblastoma was the most common type of glioma, corresponding to 63.7% Ethical considerations (n=177) of the glioma cases. Meningiomas were the second This study was approved by the Research Ethics most prevalent tumor, present in 29.6% (n=255) of the sam- Committee of the Health Campus of the Federal University of ple. The meningothelial and transitional histological types of Sergipe (UFS). No consent form was applied because no per- meningiomas accounted for 40.3% (n=103) and 25.4% (n=65) sonal identification of the patients was used. Nor was there of the cases, respectively (Table 1). Meningiomas were the any analysis of medical records or contact with any patient. most common tumors in females, whereas among males, gli- Confidentiality of information regarding healthcare service omas occurred most frequently (Table 1). user identification and anonymity in future publication of The histological groups were also evaluated according to results will remain assured. age groups. In the population from 0 to 14 years of age, 98 tumors were found. The group of “other astrocytic tumors” Statistical data analysis was the most prevalent, comprising 29.6% (n=29) of these The data were systematized, analyzed and statistically entities. This group was followed by medulloblastomas and tested using the Statistical Package for the Social Sciences ependymal tumors, with 27.6% (n=27) and 14.3% (n=14) of (SPSS) software version 20.0 and the R software version 3.5.0. the cases for this age group, respectively (Table 2). The variables were described through absolute and relative In the population between 15 and 34 years old, 165 cases frequencies, medians, arithmetic means and standard devia- were found, which represented 19.2% of the study population. tions. After descriptive analysis, it was investigated whether Gliomas occurred most frequently, in 32.7% (n=54) of the cases. the data followed normal distribution of probability, using In the 35 to 74 age group, which represented 50.4% (n=434) of the Kolmogorov-Smirnov test. The results of interest were the population, meningiomas were the most common neo- tested using the nonparametric Mann-Whitney test. plasms, affecting 47.5% (n=206). The same trend was observed in the sample aged 75 years or over, in which meningiomas were responsible for 61.2% (n=30) of these cases (Table 2). RESULTS The locations of the tumors were stratified according to the ICD-10 classification. The following locations were Epidemiology of primary CNS tumors in found: brain (C70.0, C71.0 to C71.4, C71.8, C71.9), brain- the state of Sergipe between 2010 and 2018 stem (C71.7), cerebellum (C71.6), ventricles (C71.5) spi- Altogether, 861 primary CNS tumors were found in Sergipe nal cord (C70.1, C72.0, C72.1), pineal gland (C75.3, D35.4, between 2010 and 2018, after applying the study exclusion D44.5), sella (C75.1, C75.2, D 35.2, D44.3) and unspecified criteria. Out of the total, 56.9% (n=490) were in females and (C70.9, C72.9). Other locations were classified under codes 43.1% (n=371) were in males. Overall, neuroepithelial tumors C72.2 to C72.5. The brain was the most common site, fol- accounted for 50.2% (n=433) of the cases. Gliomas occurred lowed by the cerebellum (Figure 1). Among the gliomas and
Table 1. Distribution of primary central nervous system tumors according to histological groups, Sergipe, Brazil, 2010–2018. Males Females Total Histological groups n % n % n % Gliomas 144 51.8 134 48.2 278 32.3 Meningiomas 73 28.6 182 71.3 255 29.6 Medulloblastomas 31 51.7 29 48.3 60 7. 0 Ependymal tumors 21 50.0 21 50.0 42 4.9 Other astrocytic tumors 24 48.9 25 51.0 49 5.7 Schwannomas and neurofibromas 45 52.9 40 4 7.1 85 9.9 Tumors of the pineal region 2 50.0 2 50.0 4 0.5 Hemangiomas and hemangioblastomas 8 44.4 10 55.6 18 2.1 Craniopharyngiomas 2 33.4 4 66.6 6 0.7 Pituitary adenomas 14 31.8 30 68.2 44 5.1 Neuronal and mixed neuronal-glial gliomas 6 31.6 13 68.4 19 2.2 Germ cell tumors 2 100 - - 2 0.2
506 Arq Neuropsiquiatr 2021;79(6):504-510 Table 2. Distribution of primary central nervous system tumors according to histological group and age range, Sergipe, Brazil, 2010–2018. Histological groups % (n) Age group Gliomas Meningiomas Medulloblastomas Ependymal tumors Other astrocytic tumors Pituitary tumors 0–14 5.4% (15) - 45.5% (30) 37.5% (15) 61.2% (30) - 15–19 4.7% (13) 1.17% (3) 1.5% (1) 7.5% (3) 4.1% (2) 2.2% (1) 20–44 25.9% (72) 22.3% (57) 37.9% (25) 42.5% (17) 32.7% (16) 51.1% (23) 45–54 21.9% (61) 31.0% (79) 9.1% (6) 12.5% (5) 2.0% (1) 17.8% (8) 55–74 35.9% (100) 34.5% (88) 6.1% (4) - - 26.7% (12) >75 6.1% (17) 11% (28) - - - 2.2% (1)
Figure 1. Distribution of primary central nervous system tumors according to the originating site, Sergipe, Brazil, 2010–2018.
meningiomas, the brain was affected in 79.5% (n=221) and craniopharyngiomas. The pineal gland was the site of 100% 70.6% (n=180) of the cases, respectively. Evaluation of sex (n=2) of germ cell tumors. and location in relation to meningiomas showed a ratio of Regarding the WHO grade, the largest proportion of the 2.4 women for each man, for spinal tumors. Among cerebral tumors were classified as grade I, which represented 43.9% tumors, a ratio of 2.3 women for each man with meningi- (n=378) of the cases, followed by grade IV tumors, corre- oma was found. sponding to 27.9% (n=240) of the sample. The entities clas- In the groups of medulloblastomas and other astro- sified as grade II and grade III represented 14.1% (n=121 and cytic tumors, the cerebellum was the most frequent loca- 6% (n=52) of the cases, respectively (Tables 3 and 4). tion, which corresponded to 43.3% (n=26) and 28.6% (n=14) From the second decade of life onwards, increasing num- of the cases, respectively. For ependymal tumors, the intra- bers of cases were observed. Moreover, there was a peak ventricular site was the most affected, accounting for 26.2% between the fourth and sixth decades of life, with subsequent (n=11) of these neoplasms. The sella site was the location reduction. From 2010 to 2018, the average number of tumors of 100% (n=44) of pituitary adenomas and 50% (n=3) of per year was 86.1 (±97.5).
Santos BL et al. Primary central nervous system tumors 507 Table 3. Distribution of primary central nervous system tumors according to histology and World Health Organization grade in children (age 0–14 years), Sergipe, Brazil, 2010–2018. Grade I Grade II Grade III Grade IV Unspecified Histological group n % n % n % n % n % Medulloblastomas ------26 96.2 1 3.7 Gliomas - - 3 20.0 1 6.7 11 73.3 - - Other astrocytic tumors 29 100 ------Ependymal tumors - - 11 78.5 3 21.4 - - - - Schwannomas and neurofibromas 3 100 ------Neuronal and mixed neuronal-glial gliomas 6 85.7 ------1 14.3 Craniopharyngiomas - - 1 100 ------Tumors of the pineal region ------2 100
Table 4. Distribution of primary central nervous system tumors according to histology and World Health Organization graduation in adolescents and adults (age ≥15 years), Sergipe, Brazil, 2010–2018. Grade I Grade II Grade III Grade IV Unspecified Histological group n % n % n % n % n % Gliomas - - 56 21.4 37 14.1 168 64.1 2 0.76 Meningiomas 218 85.8 29 11.4 5 1.96 - - 3 1.17 Medulloblastomas ------32 96.7 1 3.03 Other astrocytic tumors 17 85.0 1 5.0 - - - - 2 10.0 Ependymal tumors 4 14.3 17 60.7 6 21.4 1 3.6 - - Schwannomas and neurofibromas 82 100 ------Neuronal and mixed neuronal-glial gliomas 1 8.3 3 25.0 - - - - 8 66.7 Craniopharyngiomas 5 100 ------Tumors of the pineal region ------2 100 Hemangioma and hemangioblastomas 13 72.2 ------5 27.8 Pituitary adenomas ------44 100 Germ cell tumors ------1 100
DISCUSSION cases of CNS tumors diagnosed in the United States between 2010 and 2014, while men accounted for 42.1%14. The present study describes the epidemiological aspects of In Aracaju, Sergipe, a population-based cancer registry primary CNS tumors diagnosed in Sergipe between 2010 and (RCBP) collects high-quality epidemiological data from this 2018. The patients’ ages ranged from 6 to 92 years, with a mean state. These data are taken to the National Cancer Institute of 44.6 years. Patients aged between 45 and 54 years predomi- (INCA) to aggregate with the national estimates for cancer nated, representing 20.4% (n=176) of the cases. Regarding the in Brazil. According to INCA data, which are based on what epidemiological characterization, predominance of female is collected by each state’s RCBP, the estimate for the num- cases was observed, which corresponded to 56.7% of all the ber of new cases of primary malignant neoplasms of the CNS cases. Males accounted for 43.1% of the sample. Although these in Brazil, in 2020, was 11,090 cases. Out of this total, 5,870 data from 2010 to 2018 diverged from findings over the previ- were estimated to be among males and 5,220 among females. ous decade in Sergipe23, they were in line with results from other In Sergipe, 90 new cases were expected in 2020: 40 in males studies24,25. In a previous study in which 2,131 primary CNS and 50 in females4. These estimates are compatible with the tumors were evaluated, 53.7% of the sample was represented data obtained in the present study. However, both benign and by females, while 46.2% were male patients26. Similar data were malignant tumors were evaluated, which can be explained by described in the Central Brain Tumor Registry of the United the fact that a significant percentage of CNS tumors are not States (CBTRUS). In that series, women comprised 57.9% of all diagnosed through histopathology in Sergipe27.
508 Arq Neuropsiquiatr 2021;79(6):504-510 Meningiomas were more prevalent in females than in 1994 and 2013 was described, consisting of greater num- males, with a ratio of 2.3:1, respectively. This finding is con- bers of non-malignant tumors26. This divergence can possi- sistent with data from previous studies, which reported that bly be explained in terms of the great heterogeneity of enti- meningeal tumors were approximately three times more fre- ties among CNS tumors. Moreover, the methodologies and quent among females than among males19,25,28. classifications used to study these neoplasms have differed Neuroepithelial tumors comprised approximately half of between many of the studies conducted. all the neoplasms observed (50.2%). Among the different his- In the present study, a progressive increase in the num- tological groups, gliomas had the highest prevalence (32.3%) ber of tumors diagnosed was found between 2010 and 2018. in the entire sample, followed by meningiomas (29.6%). These Other studies have sought to investigate risk factors for pos- findings are consistent with data from other studies in the sible increased incidence of these tumors22,34,35,36. However, current literature26,29. increased life expectancy, greater access to diagnostic tests Regarding age groups, a mean age at the time of diag- for the population and population growth may influence nosis of 44.64 years was observed. This was lower than these findings18. what was found in another similar study30. The peak preva- The main limitation of the present study was the signif- lence was observed between 45 and 54 years of age, with a icant number of cases that fulfilled the exclusion criteria. subsequent reduction in the number of tumors, especially These cases were excluded because, in some databases, it after the sixth decade of life. These findings are similar to was not possible to access immunohistochemical reports to those described in other studies23,31. Higher prevalence of confirm inconclusive histopathological diagnoses. In addi- other astrocytic tumors in the age group of 0–14 years was tion, disparate approaches to the reports between laborato- described in previous studies12,14. Increasing numbers of ries visited adversely affected the number of examinations meningioma cases in older age groups were also described available for this study. Studies focusing on the incidence of in other studies14,32. these tumors are essential in order to determine the evolu- A similar study conducted previously described the epi- tion of CNS tumors over time. demiology of CNS tumors in the state of Sergipe between the Nevertheless, our epidemiological description of CNS years 2000 and 201023. In that study, 775 primary CNS tumors tumors in the state of Sergipe between 2010 and 2018 is con- were found. Male sex was more prevalent, corresponding to sistent with the data from other recent studies. This char- 50.8% (n=429) of the cases. Meningiomas and glioblastomas acterization also shows similarities with a study conducted were the predominant histological types, which represented on the population of Sergipe between 2000 and 2010 regard- 21% (n=177) and 18.7% (n=158) of the cases, respectively23. ing age groups, locations, and most prevalent histological There was an absolute increase in the number of tumors types25. The annual average numbers of benign and malig- from the previous cohort to the current one, although with- nant tumors found were similar, in absolute numbers, to out statistical significance (p=0.762). We emphasize that the incidence of malignant CNS tumors estimated for 2020 some bias exists in this comparison since we cannot con- through the RCBP of Aracaju, Sergipe. This may be related to firm that the populations compared were homogeneous or the low rate of histopathological diagnosis of these tumors in that the methods used in the previous study were similar to the state of Sergipe27. In Brazil, CNS tumor registries do not those used in the present study. The growth in the number of present the necessary standardization for more reliable data CNS neoplasms that we observed is a trend corroborated by analysis37. Therefore, more studies on pathological reports are other studies; however, the evidence is conflicting. In a meta- essential for evaluating the epidemiological evolution of CNS analysis on 38 articles that was performed in 2014, there were tumors in Sergipe. Studies on the incidence of these tumors no statistically significant changes in CNS tumor incidence and possible associated risk factors are relevant approaches. rates33. However, in a study based on the Girona cancer regis- Knowledge of the evolution profile is vital for optimization of try, an increase in the incidence of CNS neoplasms between approaches used among the patients affected.
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510 Arq Neuropsiquiatr 2021;79(6):504-510 https://doi.org/10.1590/0004-282X-ANP-2020-0285 ARTICLE
Effects of resistance training on postural control in Parkinson’s disease: a randomized controlled trial Efeitos de um treinamento de resistência muscular no controle postural em indivíduos com doença de Parkinson: um estudo aleatorizado controlado Janini CHEN1,2,3, Hsin Fen CHIEN1,2,3, Debora Cristina Valente FRANCATO1,2, Alessandra Ferreira BARBOSA2,4, Carolina de Oliveira SOUZA1,2, Mariana Callil VOOS2,4, Julia Maria D’Andréa GREVE5, Egberto Reis BARBOSA1
ABSTRACT Background: Postural instability affects Parkinson’s disease (PD) patients’ postural control right from the early stages of the disease. The benefits of resistance training (RT) for balance and functional capacity have been described in the literature, but few studies have been conducted showing its effects on PD patients’ postural control. Objective: To investigate the effects of a three-month RT intervention on static posturography (SP) measurements and clinical functional balance assessment among PD patients. Methods: Seventy-four patients were randomly assigned to a three-month RT intervention consisting of using weightlifting machines at a gym (gym group) or RT consisting of using free weights and elastic bands (freew group), or to a control group. The participants were evaluated at baseline, three months and six months. We evaluated changes of SP measurements under eyes-open, eyes-closed and dual-task conditions (primary endpoint), along with motor performance and balance effects by means of clinical scales, dynamic posturography and perceptions of quality of life (secondary endpoints). Results: There were no significant interactions in SP measurements among the groups. Unified Parkinson Disease Rating Scale (UPDRS-III) motor scores decreased in both RT groups (p<0.05). Better perceived quality of life for the mobility domain was reported in the gym group while functional balance scores improved in the freew group, which were maintained at the six-month follow-up (p<0.05). Conclusions: This study was not able to detect changes in SP measurements following a three-month RT intervention. Both RT groups of PD patients showed improved motor performance, with positive balance effects in the freew group and better perceived quality of life in the gym group. Keywords: Resistance Training; Parkinson Disease; Postural Balance; Rehabilitation; Quality of Life.
RESUMO Introdução: A instabilidade postural afeta o controle postural desde os estágios iniciais da doença de Parkinson (DP). A literatura descreve benefícios do programa de fortalecimento muscular no equilíbrio, na capacidade funcional, porém poucos estudos investigaram seus efeitos no controle postural na DP. Objetivo: Investigar os efeitos de um programa de três meses de fortalecimento nas medidas da posturografia estática (PE) e nos testes clínicos na DP.Métodos: Participaram do ensaio aleatório controlado 74 pacientes, designados em um dos seguintes grupos: fortalecimento utilizando aparelhos de musculação (gmusc); fortalecimento com pesos livres e elásticos (gpeso); e grupo controle. As avaliações ocorreram antes da intervenção, 3 e 6 meses após intervenção. Foram avaliados alterações nas medidas
1Universidade de São Paulo, Hospital das Clínicas, Faculdade de Medicina, Departamento de Neurologia, Clínica de Distúrbios do Movimento, São Paulo SP, Brazil. 2Grupo de Pesquisa em Reabilitação em Distúrbios do Movimento, São Paulo SP, Brazil. 3Universidade de São Paulo, Hospital das Clínicas, Faculdade de Medicina, Departamento de Ortopedia e Traumatologia, São Paulo SP, Brazil. 4Universidade de São Paulo, Departamento de Fisioterapia, Terapia Ocupacional e Fonoaudiologia, São Paulo SP, Brazil. 5Universidade de São Paulo, Hospital das Clínicas, Faculdade de Medicina, Instituto de Ortopedia e Traumatologia, Laboratório de Estudo do Movimento, São Paulo SP, Brazil. Janini CHEN https://orcid.org/0000-0003-3591-1472; Hsin Fen CHIEN https://orcid.org/0000-0002-2490-6021; Debora Cristina Valente FRANCATO https://orcid.org/0000-0003-1008-5012; Alessandra Ferreira BARBOSA https://orcid.org/0000-0002-8215-7858; Carolina de Oliveira SOUZA https://orcid.org/0000-0002-4177-5262; Mariana Callil VOOS https://orcid.org/0000-0001-6252-7287; Julia Maria D’Andréa GREVE https://orcid.org/0000-0003-1778-0448; Egberto Reis BARBOSA https://orcid.org/0000-0002-6996-9130 Correspondence: Janini Chen; E-mail: [email protected] Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: JC: conception/data collection/data analysis and interpretation/drafting the article/critical revision of the article/final approval of the version to be published. HFC: conception/data analysis and interpretation/drafting the article/critical revision of the article/final approval of the version to be published. DCVF and AFB: data collection/drafting the article/critical revision of the article/final approval of the version to be published. COS and MCV: drafting the article/critical revision of the article/final approval of the version to be published. JMDG: critical revision of the article/final approval of the version to be published. ERB: conception/drafting the article/critical revision of the article/final approval of the version to be published. Received on June 17, 2020; Received in its final form on August 23, 2020; Accepted on September 17, 2020.
511 da PE nas condições de olhos abertos, olhos fechados e dupla tarefa (desfecho primário), efeitos sobre sintomas motores, equilíbrio por meio de escalas clínicas, posturografia dinâmica e percepção da qualidade de vida (desfechos secundários).Resultados: Não houve interações significativas nas medidas da PE entre os grupos. As pontuações motoras da Escala Unificada de Avaliação da Doença de Parkinson (UPDRS-III) diminuíram em ambos os grupos de fortalecimento (p<0,05). Houve melhora da percepção da qualidade de vida para o domínio mobilidade no gmusc, assim como ganhos nas pontuações dos testes funcionais no gpeso, mantido no seguimento após seis meses (p<0,05). Conclusões: O programa de fortalecimento não altera o controle postural medida pela PE. Apesar disso, ambos os grupos de fortalecimento apresentaram melhor desempenho motor, efeitos positivos a médio prazo no equilíbrio no gpeso e melhor desempenho na qualidade de vida no gmusc. Palavras-chave: Treinamento de Resistência; Doença de Parkinson; Equilíbrio Postural; Reabilitação; Qualidade de Vida.
INTRODUCTION Eligibility criteria The study inclusion criteria were: idiopathic PD diagno- Parkinson’s disease (PD) patients show lack of pos- sis based on the United Kingdom Parkinson’s Disease Society tural stability and motor coordination1 and impaired ability Brain Bank diagnostic criteria18; age 50–75 years; Hoehn to keep the center of mass over the base of support during and Yahr (HY) stage scores of 2–3; antiparkinsonian drug movement. Maintaining upright stance involves muscle acti- treatment consisting of stable daily doses for at least three vation and joint integrity as well as neural responses to exter- months before inclusion; ability to walk independently with- nal disturbances2,3,4. out assistance devices; and Mini-Mental State Examination Assessing postural control is challenging, but static (MMSE) score of 24 or more. The exclusion criteria were: posturography (SP) provides quantitative information on orthopedic conditions; severe pain; unstable cardiovascu- postural control. SP measures shifts in the vertical forces lar and/or metabolic disease; vestibular dysfunction; prior on a force platform that are exerted by body sway during stroke; and attending a physical rehabilitation program at upright stance and these measurements make it possible to least six months before inclusion. infer the center of pressure (COP). PD patients have larger This study was approved by the local ethics committee COP displacement variability than healthy older adults5,6,7. and was registered at ClinicalTrials.gov (NCT: 02674724). Moreover, studies have suggested that there may be an asso- ciation between mediolateral sway, increased COP velocity, Randomization and blinding poor postural control and risk of falls in this population8,9. The participants were randomly assigned to one of three It has been reported in the literature that muscle groups: RT by using weightlifting machines at a gym (gym strength10, mobility11 and balance12 may improve with resis- group); RT by using free weights and elastic bands (freew tance exercise training (RT), with a positive impact on func- group); and a control group. We used a computer ran- tional capacity and reduction of the risk of falls in PD13. dom number generator to create 13 blocks of six-number However, only a few well-designed controlled studies14,15,16,17 sequences (expecting a study dropout proportion of 20% have qualitatively assessed SP in relation to RT programs, RT or more). Randomly generated number sequences were modalities and postural control, among PD patients. placed in sealed opaque envelopes and randomly assigned Therefore, the aim of this study was primarily to deter- to patients after enrollment. A physiotherapist, blinded to mine the effects of a three-month RT intervention on SP mea- intervention assignment, examined all participants before surements among PD patients. The secondary objective was and after the intervention in their best clinical condition (ON to evaluate the impact of this exercise intervention on motor state). The flow chart shows group allocation (Figure 1). performance, functional balance scores, dynamic posturog- raphy measurements and perceptions of quality of life (QoL). Study intervention The conceptual framework of our intervention was based on the American College of Sports Medicine guidelines19. It is METHODS recommended that free-weight multiple machines and single- joint exercises should be used. For older patients, the lifting Study design and participants velocity should be slow to moderate, with one to three sets per We conducted a three-arm, single-blind randomized exercise, at 60–80% of a one-repetition maximum (1-RM) for controlled trial. Patients were recruited from the outpa- 8–12 repetitions with 1–3 min of rest between sets19. tient clinic of the Movement Disorders Clinic, Hospital das A group of up to four patients participated in each RT Clinicas HCFMUSP, Department of Neurology, Faculdade de session, consisting of 50 minutes of training, twice a week Medicina, Universidade de São Paulo, and from the Brazil for 3 months. The aim of both RT groups was to activate all Parkinson Association, São Paulo, between September 2013 postural muscles, especially trunk muscles, that play a role and February 2016. in maintaining balance during motor performance and in
512 Arq Neuropsiquiatr 2021;79(6):511-520 Consolidated Standards of Reporting Trials: patients recruitment and follow-up. Randomized, single-blinded clinical trial with three groups: Gym: resistance training with gym equipment group; FreeW: resistance training with free weights group; Control: control group. Figure 1. The CONSORT flow diagram.
reducing the risk of falls20,21. Lower-limb muscles were also (1-RM) and then they were encouraged to perform three sets recruited for stability in performing the exercises. of 8 to 12 repetitions with 60-second rests between sets19. Each RT session started with a five-minute warm-up, in which The workload was progressively increased by 5 to 10% if the the participants were asked to side-tilt and rotate the trunk with patient did not feel muscle fatigue after the previous train- their arms abducted, and to raise and lower their arms without ing19. The weightlifting exercises included lateral pulldown, moving the trunk. They were then instructed to perform hip flex- back extension, seated row, seated chest press, abdominal ion, extension and abduction with 10 repetitions of each exercise. crunch and leg press (Figure 2). At the end of each session, there was a cool-down period that included upright stretching of quadriceps, hamstring, triceps bra- RT by using free weights chii and pectoris muscles for 15 seconds each22. and elastic bands (freew group) We chose to perform two different RT protocols due The RT program targeted the same muscle groups as in to lack of evidence regarding what the most effective type the gym group, including abdominal, paraspinal, middle tra- of exercise might be, for improving postural control in PD. pezius, latissimus dorsi, rhomboid, quadriceps femoris and All three groups were instructed to perform stretching exer- gluteal muscles. The workload was progressively increased, cises at home. using dumbbells, elastic bands and ankle weights if the patient did not feel muscle fatigue after the previous train- RT by using weightlifting ing19 (Figure 2). machines at a gym (gym group) The participants performed RT using weightlifting Control group machines at a gym (Biodelta®, São Paulo, Brazil). The initial Each participant received a booklet describing sets of workload was defined as 60% of a one-repetition maximum stretching exercises to be performed twice a week during
Chen J et al. Resistance training on postural control 513 Participants in the gym group performed resistance exercises using machines, which included lateral pulldown, back extension, seated row, seated chest press, abdominal crunch and leg press. The main objective was to recruit postural muscles, especially extensor trunk muscles with lower-limb stabilization to perform each exercise. Workloads were progressively increased by 5 to 10%. Participants in the freew group performed exercises aimed at recruiting the same muscle groups as in the gym group, which were: abdominals, paraspinal, middle trapezius, latissimus dorsi, rhomboid, quadriceps femoris, gluteal muscles and lower limbs. The training workload was increased through use of dumbbells, elastic bands and ankle weights. All participants were instructed not to perform the Valsalva maneuver during the movement phase, but to activate abdominal muscles during expiration. Figure 2. Resistance training program.
the study period. They were instructed to perform a vari- Clinic® software. They were instructed to maintain a com- ety of seated and standing 15-second stretches involving fortable standing position and look fixedly at a spot one trunk, hamstring, pectoral, brachial triceps and quadri- meter away and not to move or speak during the test (unless ceps muscles23. Their practice frequency was monitored when performing the dual-task condition). A baseline sup- through phone calls. This exercise protocol is customar- port base was drawn on a sheet of paper, for use in subse- ily used in rehabilitation programs and has no equivalent quent assessments. The mean measurements for three workloads in RT. 60-second trials were recorded for each condition tested: eyes-open (EO), eyes-closed (EC) and dual-task (DT). For the Primary endpoint measurements latter, the participants were asked to say as many words The study was conducted at the Laboratory of Movement beginning with the letter F as possible, during the whole test Study, Instituto de Ortopedia e Traumatologia, Hospital das period, and then to name as many animals and fruits as they Clínicas, Faculdade de Medicina, Universidade de São Paulo, could. The primary outcome measurements included the fol- Brazil. lowing COP displacement variables assessed in SP after the For SP, the participants were placed in a quiet upright RT intervention: stance on the force platform (AccuSway Plus, Advanced • Mediolateral displacement (ML), representing the stan- Mechanical Technology Inc., AMTI, Massachusetts, United dard deviation of the COP on the mediolateral axis, States). Postural sway data was analyzed using the Balance expressed in centimeters (cm).
514 Arq Neuropsiquiatr 2021;79(6):511-520 • Anteroposterior displacement (AP), representing the United States) and Excel Office 2010. An α level of signifi- standard deviation of the COP on the anteroposterior cance was set at p<0.05 and all tests were two-sided. axis, expressed in cm. • Velocity, as the mean velocity of COP displacement in all directions, measured in centimeters per second (cm/s). RESULTS • Area of the ellipsis that covers 95% of the COP trajectory, expressed in square centimeters (cm2). Out of 316 patients screened for eligibility, 74 met the inclusion criteria and were enrolled in the study. Six patients Secondary endpoint measurements did not complete the training protocol (Figure 1). The secondary outcome measurements of the study included: Unified Parkinson’s Disease Rating Scale, Part III Baseline characteristics (motor examination) (UPDRS-III); Berg Balance Scale (BBS); Table 1 shows the demographic and clinical character- Mini-Balance Evaluation Systems Test (Mini-Best); Timed istics of the participants. There were no significant differ- Up and Go (TUG) test to assess functional balance; 39-item ences among the groups at baseline with regard to MMSE, Parkinson’s Disease Questionnaire (PDQ-39) to assess how UPDRS‑III, Mini-Best and BBS, TUG, PDQ-39 domains scores often people affected by Parkinson’s disease experience dif- or posturography variables (p>0.05). ficulties across eight dimensions of daily living: mobility, impact on activities of daily living, bodily discomfort, emo- Effects of intervention tional wellbeing, stigma, social support, cognition and com- ANOVA did not show any significant group versus time munication domains; and dynamic posturography (Balance interactions in SP measurements (primary outcome), in ® Master platform, NeuroCom International Inc., Oregon, relation to the eyes-open condition for ML (F4,142=2.232;
United States) to assess the following tasks: a) stepping up p=0.068), AP (F4,142=2.125; p=0.080), velocity (F4,142=0.615; and over an obstacle: first stepping with the left leg then p=0.666) or area (F4,142=2.021; p=0.094). Similarly, there swinging the opposite leg onto a 10-cm-high box and then was no significant main effect regarding group in SP mea- landing the left leg on the force plate. The leg lift-up index surements, in relation to the eyes-closed condition for quantifies the maximal lifting force exerted by the leading ML (F4,142=0.747; p=0.561), AP (F4,142=1.582; p=0.182), veloc- leg and is expressed as a percentage of the individual’s body ity (F4,142=0.386; p=0.817) or area (F4,142=0.758; p=0.553). weight; b) movement time (MovTime) quantifies the number There was also no significant effect regarding the dual-task of seconds required to complete the task of stepping up and condition for ML (F4,142=1.652; p=0.164), AP (F4,142=0.640; over an obstacle; and c) tandem speed is the velocity at which p=0.634), velocity (F4,142=0.192; p=0.941) or area (F4,142=0.755; tandem walking is performed, expressed as cm/s. The score p=0.556) (Figure 3). recorded was the mean value of three trials for each task. ANOVA showed that there was a group-versus-time
All measurements were collected at baseline, at one week interaction for UPDRS-III scores (F4,142=3.396; p=0.010). after completing the intervention period (at three months) Tukey’s post-hoc tests showed a reduction in UPDRS-III and at the six-month follow-up. score at the three-month follow-up, compared with base- line (26.46 vs. 29.58; p=0.028), in the freew group and at the Statistical analysis three‑month follow-up, compared with baseline (25.61 vs. The sample size was calculated after a pilot study. 29.13; p=0.014), in the gym group (Table 2). The number of participants required to detect a change of at For Mini-Best scores, a significant group-versus- least one standard deviation in SP measurements was 21 for time interaction was observed (F4,142=3.231; p=0.014). each group (power=0.8; alpha=0.05). Tukey’s post-hoc tests showed improved scores at the three- Differences in baseline characteristics among groups month (25.35 vs. 23.69; p=0.015) and six-month follow-ups, were assessed by means of univariate analysis of variance compared with baseline (25.69 vs. 23.69; p=0.001), in the (ANOVA) for age, MMSE scores and disease duration. We freew group only. also tested for the equality-of-proportion hypothesis, for HY Similarly, a significant group-versus-time interaction was stage, gender and race/ethnic group. observed for BBS scores (F4,142=2.529; p=0.043). Tukey’s post- To determine the effect of treatment, two-way ANOVA hoc tests showed score improvements at the three-month (group versus time) was used to compare posturography (52.62 vs. 51.00; p=0.020) and six-month follow-ups, com- measurements and functional balance scores. Whenever an pared with baseline (52.96 vs. 51.00; p=0.001), in the freew interaction was noted, Tukey’s multiple-comparison post- group. hoc test was used to compare each pair of groups for each For PDQ-39 domains, group-versus-time interaction outcome. was seen for the mobility domain (F4,142=3.021; p=0.019). All analyses were conducted on an intention-to-treat Tukey’s post-hoc test showed score improvement at the three- basis using the Statistica software package v. 13.3 (TIBCO, month follow-up, compared with baseline (21.46 vs. 34.72;
Chen J et al. Resistance training on postural control 515 Table 1. Demographic and clinical characteristics of the participants. Gym group Gym group vs. Gym group Freew group Control Freew group vs. vs. control Freew group p-value (n=23) (n=26) (n=25) control p-value p-value p-value Gender, n (%) Male 17 (73.9) 18 (69.2) 18 (72) 0.882ª 0.828ª 0.717ª _ Female 6 (26.1) 8 (30.8) 7 (28) Race/ethnic group, n (%) White 16 (69.6) 17 (65.4) 13 (52) 0.214ª 0.332ª 0.755ª Black 1 (4.3) 0 2 (8) 0.602ª 0.141ª 0.283ª _ Mixed 5 (21.7) 7 (26.9) 8 (32) 0.424ª 0.691ª 0.674ª Asian 1 (4.3) 2 (7.7) 2 (8) 0.602ª 0.967ª 0.626ª HY stage, n (%) 2 6 (26.1) 3 (11.5) 6 (24) 0.868ª 0.243ª 0.189ª _ 2.5 14 (60.9) 20 (76.9) 16 (64) 0.823ª 0.311ª 0.224ª 3 3 (13) 3 (11.5) 3 (12) 0.913ª 0.959ª 0.873ª Education level, years Mean (SD) 7.3 (5.1) 9.4 (4.4) 8.5 (3.8) _ _ _ 0.255b Range 2–19 2–16 3–15 BMI Mean (SD) 25.6 (3.1) 25.9 (3.6) 25.7 (4.3) _ _ _ 0.972b Range 18.5–33.6 19.4–32.5 18.3–36.5 Age, years Mean (SD) 63.4 (6.9) 63.2 (6.4) 63.6 (7) _ _ _ 0.977b Range 50–75 50–74 52–75 Disease duration, years Mean (SD) 7.6 (6) 8.4 (5.9) 9.6 (4.8) _ _ _ 0.462b Range 2–30 2–25 2–18 MMSE scores _ Mean (SD) 27.4 (1.9) 26.9 (2.4) 27.5 (2.1) _ _ 0.527b Range 24–30 24–30 24–30 Data presented as mean (standard deviation, SD) or (%). %: percentage; N: number; HY stage: Hoehn and Yahr stage; BMI: body mass index; MMSE: Mini-Mental State Examination; ª: test for equality of proportions, b: ANOVA.
p=0.001) in the gym group. Interactions were not signifi- lift-up index starting with the left leg (F4,142=1.351; p=0.253)
cant for other domains: activities of daily living (F4,142=1.368; or the right leg (F4,142=0.798; p=0.528). Likewise, no interac-
p=0.247); bodily discomfort (F4,142=2.144; p=0.078); emo- tion for movement time was seen for the left leg (F4,142=1.414;
tional well-being (F4,142=1.220; p=0.304); stigma (F4,142=0.637; p=0.232) or the right leg (F4,142=0.670; p=0.613) (Table 2).
p=0.636); social support (F4,142=1.070; p=0.373); cognition There were no serious adverse events in our study.
(F4,142=0.346; p=0.997); and communication (F4,142=0.166; The events reported during training sessions for the freew p=0.954) (Table 2). group included a fall episode (one participant), mild tran- For TUG, no group-versus-time interaction was seen in sient joint pain (three participants) and orthostatic hypoten-
any group (F4,142=0.273; p=0.894) (Table 2). sion (three participants), with no serious injury. For the gym For dynamic posturography, no significant group-versus- group, there were reports of an outdoor fall (one participant), time interaction was seen for tandem walking speed task mild transient muscle pain (three participants) and ortho-
(F4,142=1.800; p=0.132). Similarly, for the task of stepping up static hypotension (two participants). For the control group, and over an obstacle, there was no significant interaction for only one participant reported joint pain.
516 Arq Neuropsiquiatr 2021;79(6):511-520 Figure 3. Static posturography measurements under eyes-open, eyes-closed and dual-task conditions
Chen J et al. Resistance training on postural control 517 Table 2. Functional clinical tests, dynamic posturography and quality of life. Gym group Freew group Control group P value Baseline 3 months 6 months Baseline 3 months 6 months Baseline 3 months 6 months 29.13 25.61 27.65 29.58 26.46 28.38 26.44 27.48 27.60 UPDRS-III (0-108) 0.010* (10.06) (10.03) (9.92) (12.06) (11.17) (10.05) (9.95) (7.99) (8.12) 8.70 8.04 7.91 7.88 7.96 8.56 8.20 8.12 TUG (sec) 8.5 (2.10) 0.894 (3.39) (3.27) (2.89) (1.88) (1.93) (1.73) (1.87) (1.88) 52.09 53.17 52.96 51.00 52.62 52.96 52.28 52.28 52.24 BBS (0-56) 0.043* (4.5) (3.17) (2.93) (4.74) (3.02) (2.82) (2.79) (3.41) (3.07) 24.48 25.87 25.70 23.69 25.35 25.69 24.92 24.52 25.04 Mini-Best (0-32) 0.014* (4.24) (4.97) (4.24) (4.71) (4.04) (3.92) (4.14) (3.97) (3.66) Stepping up 16.65 19.74 19.04 16.35 19.00 18.65 19.48 19.08 20.84 Lift-up index left (%) 0.253 (5.25) (5.75) (3.96) (5.59) (6.89) (7.53) (8.28) (6.32) (6.84) 18.48 20.48 20.17 16.69 19.77 18.88 18.00 19.04 20.76 Lift-up index right (%) 0.583 (7.48) (7.48) (6.04) (7.00) (8.65) (8.38) (6.81) (7.04) (7.22) 2.02 1.81 1.69 2.09 1.92 1.96 1.82 1.82 1.70 MovTime left (sec) 0.232 (0.71) (0.65) (0.55) (0.73) (0.78) (0.73) (0.40) (0.38) (0.30) 1.93 1.69 1.76 1.95 1.80 1.85 1.71 1.68 1.63 MovTime right (sec) 0.613 (0.70) (0.64) (0.77) (0.07) (0.68) (0.77) (0.39) (0.30) (0.35) 19.40 20.93 22.58 19.80 22.65 22.00 19.38 19.25 19.82 Tandem speed (cm/s) 0.132 (11.4) (10.37) (11.63) (5.96) (7.16) (7.91) (5.73) (6.20) (5.54) PDQ-39 34.72 21.46 25.80 30.52 23.94 24.63 23.12 24.94 23.52 Mobility 0.019* (24.10) (21.04) (25.16) (22.02) (19.34) (20.63) (19.51) (17.64) (17.97) 37.58 25.21 29.21 36.53 28.21 29.02 24.24 24.03 20.18 Daily living 0.247 (23.70) (19.53) (19.61) (25.99) (21.14) (22.18) (21.44) (16.41) (16.55) 30.79 21.04 22.45 28.54 22.61 27.43 22.36 22.68 23.70 Emotional wellbeing 0.304 (22.68) (16.54) (17.73) (23.44) (15.08) (16.35) (16.65) (15.42) (17.41) 20.90 19.03 14.10 25.03 19.73 18.78 12.78 13.49 11.52 Stigma 0.749 (21.62) (22.65) (17.21) (18.38) (18.17) (16.79) (15.89) (18.46) (15.71) 15.78 9.06 10.14 15.88 11.54 11.22 8.19 9.33 12.14 Social Support 0.373 (16.84) (13.68) (15.26) (22.87) (22.74) (19.14) (13.95) (15.07) (18.85) 26.50 25.30 24.25 27.44 27.39 26.46 19.52 18.78 17.00 Cognition 0.997 (20.87) (17.55) (19.03) (20.36) (19.60) (20.23) (19.30) (15.62) (18.84) 26.19 22.49 21.69 26.28 23.65 20.86 27.49 23.97 25.02 Communication 0.954 (20.64) (19.56) (18.11) (26.22) (19.49) (15.54) (17.99) (16.36) (21.37) 42.43 26.78 32.16 25.96 25.47 25.92 34.97 32.32 32.35 Bodily discomfort 0.078 (24.66) (22.02) (20.35) (26.01) (14.05) (20.19) (21.89) (20.87) (17.70) Data presented as mean (standard deviation), sec: seconds; %: percentage; cm/s: centimeters per second; UPDRS-III: Unified Parkinson’s Disease Rating Scale, part III; TUG: timed up & go; MovTime: movement time; PDQ-39: quality of life perception; BBS: Berg balance scale; Mini-Best: Mini-Balance Evaluation Systems Test; lift-up index: maximal lifting force; Tandem speed: tandem walk speed; *: difference among groups (p<0.05).
DISCUSSION increase in COP velocity26. According to those authors, larger posterior COP sway could increase arm movement by shifting Our study found that there were no statistically signifi- the center of gravity forward and helping gait initiation, which cant changes in SP measurements following a three-month suggests that lower-limb training may interfere with antici- RT intervention among PD patients. However, there is no patory postural adjustments26. However, the sample size was consensus on SP measurements and how they correlate with small and these findings should be interpreted with caution. postural control in PD patients. In contrast, another three-month RT protocol including trunk Some authors have suggested that larger COP displace- and lower limb exercises did not show any changes in COP ment is likely to be a predictor of postural instability8,24, sway, in comparison with balance exercises27. Although this but few have investigated SP measurement after RT in PD. balance program gave rise to improvements in clinical balance Santos et al.25 assessed the effects of two months of RT using tests, these were insufficient to show on SP measurements27. gym weightlifting equipment, starting at a workload of 40% of Although the dual-task condition has been shown to influ- 1-RM. In addition to improved gait speed, they found only a ence postural control in PD5, we did not see this effect in our reduction in COP sway path length measurements after the patients. Despite methodological differences between the RT training25. Similarly, a ten-week high-intensity RT intervention intervention evaluated in our study and those of the other studies resulted in a 29% increase in the posterior COP sway and 11% mentioned above, it is important to point out that the question
518 Arq Neuropsiquiatr 2021;79(6):511-520 remains whether one or two COP variable changes after a RT pro- movements against different external loads and, even though gram can be inferred to represent a functional gain in PD patients. they trained at a lower workload than the gym group, this prac- SP is considered to be the gold standard for the evaluation of pos- tice may have been more demanding in terms of motor control tural control, but postural instability is multifactorial in PD and and may have resulted in better postural control. muscle strengthening alone may be insufficient to improve pos- In our study, we found better perceived QoL for the mobil- tural adjustments so as to maintain an upright stance. ity domain (PDQ-39) in the gym group after RT intervention. Our RT protocol did not have any impact on dynamic Our findings are in accordance with those of other studies posturography measurements and the same question can be reporting better perceived QoL following a two-month high- raised as in relation to SP. Although the PD patients were 25% intensity training program25 and a six-month program13. weaker and slower in lifting their leg over a box, compared Our study had some limitations. We cannot rule out the with healthy controls28, studies have found no improvement existence of a placebo effect since the control group could in postural parameters after three29 or six-month RT inter- have expected to participate in RT intervention; the isokinetic ventions23, and the intervention was insufficient to optimize machine for muscle strengthening was not available for our strategies for gains in functional independence12. study; the participants in our sample were not stratified for In our study, significant improvement in motor symp- the presence of dyskinesia, and involuntary movements may toms was seen in both RT groups, with reductions in UPDRS- have influenced posturographic measurements and may have III scores (–3.52 for the gym group; –3.12 for the freew group). had a confounding effect or produced outliers; and our train- In contrast, these scores increased in the control group ing protocol did not include exercises for plantar flexion and (+1.04). Previous studies showed that a score reduction of 2.3 dorsiflexion or for hip abduction or adduction, which may to 2.7 is clinically relevant30. One study reported that a reduc- have influenced our balance measurements, especially static tion in UPDRS-III score was maintained up to a 24-month balance. However, the strengths of this study were the single- follow-up13 and another demonstrated a score reduction of blind randomized design with a supervised training protocol 5.07 after a six-month RT intervention23. However, there was and the three-month follow-up after the intervention. no change in UPDRS scores after a two-month RT interven- Although SP allows quantitative measurements of body tion; its short duration and/or training design were insuffi- sway, our findings suggest that it was not an appropriate tool cient to promote neuromuscular adaptations25. for discriminating postural control changes after RT interven- The impact of RT on functional mobility is not yet clear. TUG tion and it may have limited value in assessing patients in clin- time was reduced after three-month31 and six-month RT pro- ical practice. SP is considered to be the golden standard assess- grams23. In contrast, our findings concur with the results from a ment for postural control measurements, but in our study the meta-analysis that reported that RT was not superior to other functional scales provided better assessments on the func- training interventions regarding TUG time32. Likewise, another tional capacity of our sample of patients. Therefore, further three-month RT intervention increased muscle strength, but studies with more comprehensive assessments of the impact was insufficient to increase TUG time10. None of the studies of RT and posturography measurements are needed. mentioned above reported any reduction close to 3.5 seconds, The study intervention helped to improve motor ability and which is considered to be the minimal clinically significant dif- perceived QoL in the gym group. It helped to improve motor and ference33. It is noteworthy that the three groups in our study balance scores with moderately positive effects in the freew group, showed good time performance at baseline (less than 9 sec- possibly because training with free weights required greater pos- onds), so it is possible that a ceiling effect may have occurred. tural motor control. Both protocols were well accepted and The freew group performed better in the BBS and Mini-Best could easily be implemented in centers for physical activities. tests. Although BBS is a widely used scale, ceiling effects are Overall, there was good adherence to training among the par- likely to occur. Thus the Mini-Best scale is more sensitive for ticipants and they showed no serious adverse events during the detecting postural instability than BBS34. Bearing in mind that exercise sessions, which suggests that this training was safe. a three-month high-intensity RT intervention had a positive In conclusion, after this three-month training intervention, impact on BBS scores35 and another three-month RT protocol there were no changes in SP measurements. However, both inter- did not improve on BESTest scores27, we chose to use both scales vention groups showed improved motor performance (UPDRS‑III in order to broaden our functional assessment. The freew group motor scores) with better perceived QoL in the gym group and was asked to perform more coordinated specific sequences of moderate effects on functional balance in the freew group.
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520 Arq Neuropsiquiatr 2021;79(6):511-520 https://doi.org/10.1590/0004-282X-ANP-2020-0202 ARTICLE
High prevalence of psychiatric comorbidities in children and adolescents at a tertiary epilepsy center Alta prevalência de comorbidades psiquiátricas em crianças e adolescentes de um centro terciário de epilepsia Maria Antonia SERRA-PINHEIRO1, Isabella D’ANDREA-MEIRA1,2, Abraão Iuri Medeiros ANGELIM1, Fernanda Alves FONSECA1, Nicolle ZIMMERMANN1
ABSTRACT Background: Epilepsy is highly comorbid with psychiatric disorders and a significant amount of the morbidity related to epilepsy is in fact a result of psychiatric comorbidities. Objective: To investigate the frequency of different psychiatric comorbidities in children with refractory epilepsy. Methods: We present preliminary observational data from a series of patients (n=82) examined in the psychiatric branch of a tertiary epilepsy center in Rio de Janeiro, Brazil. Patients were classified as presenting autism spectrum disorders, mood disorders, anxiety disorders, disruptive disorders, attention deficit hyperactivity disorder (ADHD), intellectual development disorder, psychotic episode, dissociative/conversive disorders or others. We determined the frequency of each disorder, along with demographic data, medications prescribed, electroencephalogram findings and additional medical examinations and consultations.Results: The most common comorbidities in our sample were autism spectrum disorders and ADHD. Antipsychotics and selective serotonin uptake inhibitors were the most commonly prescribed psychiatric medications. Conclusions: Knowledge about the prevalence of such comorbidities may provide more targeted interventions in Psychiatry and Psychology services linked to epilepsy centers. Keywords: Epilepsy; Comorbidity; Children.
RESUMO Introdução: Epilepsia é altamente comórbida, com transtornos psiquiátricos, e uma parte significativa da morbidade da epilepsia se associa com os transtornos psiquiátricos comórbidos. Objetivo: Investigar a frequência de diferentes comorbidades psiquiátricas em crianças com epilepsia refratária. Métodos: Apresentamos dados observacionais preliminares de uma amostra de pacientes (n=82) avaliados no setor de Psiquiatria de um centro terciário de tratamento de epilepsia no Rio de Janeiro, Brasil. Pacientes foram classificados como apresentando transtorno do espectro autista, transtorno do humor, transtorno de ansiedade, transtornos disruptivos, transtorno do déficit de atenção de hiperatividade (TDAH), transtorno do desenvolvimento intelectual, episódio psicótico, transtornos dissociativos/ conversivos e outros. Foram determinados frequência de cada transtorno, bem como dados demográficos, medicações prescritas e achados de eletroencefalograma. Resultados: As comorbidades mais comuns na nossa amostra foram transtornos do espectro autista e TDAH; antipsicóticos e inibidores seletivos da recaptura de serotonina (ISRS) foram as medicações psiquiátricas mais comumente prescritas. Conclusões: Conhecimento acerca da prevalência dessas comorbidades pode facilitar a instituição de intervenções mais precisas em serviços de Psiquiatria e Psicologia vinculados a centros de tratamento de epilepsia. Palavras-chave: Epilepsia; Comorbidade; Crianças.
INTRODUCTION the estimates for the incidence of epilepsy vary widely, rang- ing from 41 to 187/100,000/year. A very significant subset of Epilepsy is a common condition worldwide that gives epileptic patients does not achieve remission with the treat- rise to a significant burden for patients. Among children, ments available. Rosati et al.1 estimated that 20% of epileptic
1Instituto Estadual do Cérebro Paulo Niemeyer, Rio de Janeiro RJ, Brazil. 2Universidade Federal Fluminense, Niterói RJ, Brazil. Maria Antonia SERRA-PINHEIRO https://orcid.org/0000-0002-4590-878X; Isabella D’ANDREA-MEIRA https://orcid.org/0000-0001-9507-6849; Abraão Iuri Medeiros ANGELIM https://orcid.org/0000-0003-2664-9062; Fernanda Alves FONSECA https://orcid.org/0000-0002-9476-2449; Nicolle ZIMMERMANN https://orcid.org/0000-0003-4771-4070 Correspondence: Maria Antonia Serra-Pinheiro; E-mail: [email protected]. Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: MASP: writing, research design and patient’s assessment. IDM, AIMA: writing and exams analyses. FAF: data collection and writing. NZ: writing, research design and data analyses. Received on July 17, 2020; Received in its final form on September 04, 2020; Accepted on September 20, 2020.
521 children continue to have seizures despite their use of anti- Even though the mechanisms underlying comorbidity epileptic drugs. of epilepsy with psychiatric disorders may be highly com- Epilepsy is a highly comorbid condition. Clinical and psy- plicated, there is significant evidence showing that patients chiatric conditions co-occur with epilepsy at rates far higher with this comorbidity present associations with lower qual- than in the general population. A Norwegian population- ity of life, poorer psychosocial adaptation and difficulty in based study among 0–17-year-olds revealed that 43% of the achieving epilepsy control19. epileptic children had developmental or psychiatric comor- In this paper, we aimed to describe the frequency of dif- bidities. Complicated epilepsies were associated with higher ferent psychiatric comorbidities and the use of psychotropic comorbidity, but uncomplicated cases also had substantial medications in a group of children and adolescents exam- comorbid conditions2. Studies evaluating the presence of psy- ined in a tertiary epilepsy center who were referred for pedi- chiatric comorbidities in children and adolescents with epi- atric psychiatric consultation, including children evaluated lepsy tend to exclude samples indicated for surgery3, which for epilepsy surgery. was not the case of our work here. The mechanisms underlying these comorbidities are multiple and, to a certain degree, unclear. For schematic pur- METHODS poses, comorbidities can be explained by the following: • Shared risk. In this case, there is either a genetic risk for Participants both the epilepsy and the psychiatric disorder and/or The Ethics Committee of Paulo Niemeyer State Brain an underlying neurological injury or pathological condi- Institute approved this retrospective analysis. All medical tion that increases the risk of epilepsy and psychopathol- records of patients who attended at least one consultation at ogy. The increased risk of autism in epilepsy, for instance, the outpatient child psychiatry clinic of the Epilepsy Center of seems at least in part mediated by common genetic risk4. Paulo Niemeyer State Brain Institute in the city of Rio de Janeiro • The effect of the epileptic activity itself. There is evidence (Brazil) from January 2014 to July 2016 were reviewed. A single that seizures can lead to building of inadequate cortical experienced psychiatrist with a PhD who worked exclusively networks5 and that patients with uncontrolled seizures within child and adolescent psychiatry examined the patients. have a faster decrease in frontocentral and limbic corti- To make the diagnosis of psychogenic non-epileptic sei- ces and in thalamic volumes than do patients with good zure (PNES), we only included patients who had already seizure control6. Seizures can also be presented as pheno- undergone a video electroencephalogram (v-EEG). typic copies of psychiatric disorders such as bipolar disor- The records of a total of 82 patients were examined. All of ders7 or panic disorder8. these patients had been referred to the child psychiatrist from • The psychosocial burden of epilepsy. Epilepsy may lead to a neuropediatrician. The patients had to be at most 17 years decreased quality of life, which is associated with occur- old at the time of the first interview with the psychiatrist. rence of depression9. In a study by Novy et al.10, high social burden in epilepsy cases explained the association with Procedures psychiatric comorbidities. The diagnoses first established and medications first • The treatment for epilepsy. Use of antiepileptic drugs and last prescribed were recorded. The patients’ charts is associated with a series of cognitive, behavioral were reviewed and diagnoses were ascribed based on the and emotional symptoms. For example, topiramate Diagnostic and Statistical Manual of Mental Disorders, 5th decreases word fluency11; levetiracetam is associated Edition (DSM-5)20. The child psychiatrist gathered informa- with aggressive behavior12; and benzodiazepines may be tion from a caregiver and/or the patient. associated with uninhibited behavior13,14. Surgical treat- Psychiatric diagnoses were categorized as autism spec- ment of epilepsy can have psychiatric consequences too, trum disorders (ASD), mood disorders, anxiety disorders, with development of de novo syndromes, like mania, for disruptive disorders, attention deficit hyperactivity disorder example15. (ADHD), intellectual developmental disorder (IDD), psycho- • The effect of psychiatric disorders on the seizure thresh- sis or others (less frequent diagnoses in this population: spe- old. Psychiatric disorders are notably associated with cific learning disorders, reactive attachment disorder, encop- stress. Therefore, even though most antidepressants resis, feeding and eating disorders). can lower the seizure threshold, the occurrence of sei- For the purpose of this article, patients were included in zures actually might diminish with the treatment for the IDD category only if they were not diagnosed with any depression16,17,18, possibly because the amelioration of the other psychiatric disorder and had a typical presentation of depression leads to lower stress levels. IDD. The rationale was that we were not endeavoring to exten- • Others. Psychotropics can alter the seizure threshold. sively analyze the cognitive profile of children with epilepsy. Epilepsy can lead to accidents involving head trauma, This has been done elsewhere and, since our sample was not which can increase the risk of psychiatric disorders. extensively evaluated from a neuropsychological point of view,
522 Arq Neuropsiquiatr 2021;79(6):521-526 our data would not contribute to the literature. The idea in cre- performed descriptive statistics (means, standard devia- ating this diagnostic category was to acknowledge that, even tions, frequencies and percentages) and comparative analy- though in patients with IDD we also looked for another psy- ses (chi-square and Mann-Whitney tests) according to sex, chiatric diagnosis that might explain their symptoms, there among the diagnoses presented. was a small subset of patients with behavioral symptoms and IDD who did not have other psychiatric diagnoses that would explain their presentation. These are the patients classified as RESULTS having IDD in this study. Their challenging behavior led to a psychiatric evaluation, but they did not fulfill the criteria for As can be observed in Table 1, sex distribution was simi- a formal psychiatric diagnosis. Our sample did, of course, lar across the sample and the most frequent age range seen have more patients with IDD comorbid with other diagnoses. by the psychiatrist was 10-14 years old. These, however, were not accounted for here as having IDD. Autism (26.8%) and ADHD (26.8%) were the most com- The patients were divided into groups according to the mon diagnoses in this sample, but all the other categories presence or absence of electroencephalogram changes, among (disruptive, mood, anxiety, IDD, dissociative/conversive whom epileptiform activity and slow activity on the tracing and psychosis) were present in the sample at frequencies were highlighted. They were divided according to the location beyond what would be expected from a sample without epi- and laterality of the activity in the interictal period. They were lepsy (Table 1). classified as having EEG abnormalities in the following The medications most commonly prescribed for the regions: temporal, anterior extra-temporal, posterior extra- patients’ psychiatric conditions were antipsychotics (36.6%) temporal, hemispheric, para-sagittal or multifocal; or as those and selective serotonin reuptake inhibitors (25.6%) (Table 2). who did not present alterations in the examinations. The antipsychotics prescribed were, in order of frequency: ris- peridone, aripiprazole, quetiapine, olanzapine and clopixol. Statistical analyses Regarding the type of epilepsy presented, 88.1% of the The Statistical Package for the Social Sciences (SPSS), patients had focal epilepsy, 3.9% had generalized epilepsy version 20 for Windows, was used for the analyses. We and 7.8% had focal and generalized epilepsy, according to
Table 1. Clinical and demographic characterization of the sample (n=82). n Percentage (%) Sex Female 41 50.0 Male 41 50.0 Age range 0–4 years old 2 2.4 5–9 years old 25 30.5 10–14 years old 41 50.0 Demographic data 15–17 years old 14 1 7.1 Mean (standard Age in years 10.88 (3.44) deviation) City Rio de Janeiro 50 61.0 Other cities 32 39.0 Other consultations Psychology service 29 35.4 than neurology and psychiatry Neuropsychology service 17 20.7 Attention deficit/hyperactivity disorder 2 26.8 Autism spectrum disorders 22 26.8 Disruptive disorders 20 24.4 Mood disorders 18 22.0 Psychiatric Anxiety disorders 17 20.7 disorders Intellectual disability 13 15.9 Dissociative/conversive disorders (Psychogenic 6 7. 6 non-epileptic seizures) Other diagnoses 8 9.8 Psychosis 3 3.7
Serra-Pinheiro MA et al. Psychiatric comorbidities in epilepsy 523 Table 2. Medications and examination results of the sample indirectly, through the burden of living with epilepsy and its (n=82). treatments, may have important psychiatric implications. n Percentage (%) This study aimed to ascertain occurrences of psychiatric Antipsychotics 30 36.6 disorders in a pediatric sample at a tertiary care epilepsy Selective serotonin center in Brazil. 21 25.6 reuptake inhibitors The results indicated that both sexes were affected by Medications Mood stabilizer 2 2.4 comorbid psychiatric diagnoses. Disruptive disorders were Stimulant 0 0 significantly more frequent in males, which was not surpris- Other 1 1.2 ing. ADHD (26.8%) and ASD (26.8%) were the most common psychiatric comorbidities; dissociative/conversive disorders No alterations 30 36.6 (psychogenic non-epileptic seizures) occurred in 7.3% of the Anterior extra-temporal 23 28.0 sample. The most commonly prescribed drugs were antipsy- Temporal 15 18.3 chotics and SSRIs. The high frequency of prescription of anti- VEEG or EEG Posterior extra-temporal 3 3.7 location psychotics might be related to the low availability of behav- Hemispheric 3 3.7 ioral therapy in Brazil, since there is evidence that this kind Para-sagittal 3 3.7 of treatment is effective for people with IDD and with ASD. Multiregional 5 6.1 The areas most commonly affected in EEGs relate to the Left 18 36.0 networks involved in psychiatric disorders. Use of an auto- VEEG or EEG mated diagnostic procedure based on a statistical machine Right 11 22.0 lateralization learning methodology using EEGs has been proposed, with Bilateral 21 42.0 promising results21. Newson et al.22 showed a correlation Magnetic Lesion 25 40.3 between frequency bands in EEGs and psychiatric disorders. resonance imaging Normal 37 59.7 However, these characteristics were not assessed in our study. VEEG: video-eletroencephalogram; EEG: electroencephalogram. The diagnoses most associated with epilepsy in our sam- ple were ASD and ADHD. These findings regarding comor- bidities in epilepsy were also found in previous studies on children with epilepsy23,24. The association between autism the 2017 ILAE classification. Most of the patients (51.3%) and epilepsy is well known. Matsuo et al.25 found that 15.2% had undefined etiology, but 13.1% had genetic causes, 10.5% of their sample of children with epilepsy also had a diagnosis had encephalomalacia, 7.8% had a tumor, 6.5% had Lennox- of ASD. On the other hand, autism is also more common in Gastaut syndrome, 2.6% had cortical dysplasia, 2.6% had the families of epileptic patients. It has been suggested that heterotopia, 1.3% had hemimegaloencephaly and 1.3% the relationship between ASD and epilepsy is bidirectional. had juvenile myoclonic epilepsy. Regarding the EEG results, Therefore, it is possible that they share common risk factors no abnormalities were observed in 36.5% of the patients. or heritability26. Abnormalities in the GABA system are pres- Among the changes found, the most common locations were ent both in epilepsy and ASD and in various syndromes in in the frontotemporal (15.3%), temporal (8.2%) and frontal which the prevalence of ASD and epilepsy are increased27. (5.9%) regions (Table 2). Autism is prevalent in patients with epilepsy of many differ- The results from six patients (7.3% of the total sample) ent types, especially when there is co-occurring intellectual with PNES showed that the patients were similarly distrib- disability28. The interaction of epilepsy, autism and intellec- uted across the age groups. Regarding comorbidities among tual disability is further complicated because several charac- the patients with PNES: four patients were diagnosed with a teristics that could serve as signals for the presence of ASD, mood disorder (57.1%); two cases were diagnosed with anxi- such as language development delay, are also frequently pres- ety disorder (28.6%); one patient (14.7%) was diagnosed with ent in patients with intellectual disability. Accordingly, there an IDD; one patient was diagnosed with ASD (14.7%); no case are cases of patients with epilepsy and intellectual disabil- was diagnosed with disruptive disorders; one case was diag- ity that were spuriously diagnosed with ASD29. The second nosed with ADHD (14.7%); and one case was diagnosed with decade of life is a period of increased risk for the develop- psychosis (14.7%). ment of epilepsy in patients with ASD. However, in approxi- mately 50% of the cases, the epilepsy diagnosis predates the diagnosis of ASD. DISCUSSION ADHD was also a frequent diagnosis. The associa- tion between ADHD and epilepsy is more controversial, Epilepsy is a complex disorder that may occur in conse- because some consider that, since epilepsy is frequently quence of various neurologic injuries, known or unknown. associated with cognitive impairments, an additional diag- The cause of the epilepsy and the epilepsy itself, directly and nosis of ADHD should not be granted. A study found that
524 Arq Neuropsiquiatr 2021;79(6):521-526 inattentiveness is more severe in patients with epilepsy and with epilepsy who presents with significant dysfunctional ADHD than in children with only ADHD30. Accordingly, not ADHD symptoms. all patients with epilepsy have attentional deficits that cause As expected, in a center devoted to the treatment of significant impairment. In those who do, appropriate recog- refractory epilepsy, we identified patients diagnosed with nition and treatment of ADHD may be useful. The associa- dissociative/conversive disorders presenting as PNES (24%), tion of stimulants with seizures has hindered the treatment which is expected in adults, according to the previous litera- of ADHD in patients with epilepsy, in several cases. This is ture32. To our surprise, however, in our sample, there were no probably reflected in the low frequency of prescription of patients presenting with both PNES and epilepsy. Previous stimulants in our sample. It was generally accepted that studies investigating PNES in children and adolescents have stimulants could only be used in patients whose epilepsy was also found a notable percentage of individuals with only under strict control. However, recent evidence has suggested PNES without epilepsy33. that even patients with refractory epilepsy and ADHD may Psychiatric comorbidities in patients with epilepsy are benefit from the use of stimulants31. With the available data, significantly more prevalent than in the general population a cautious and individualized approach considering poten- and have a major impact on the quality of life of patients tial risks and benefits is certainly indicated for any patient with epilepsy.
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526 Arq Neuropsiquiatr 2021;79(6):521-526 https://doi.org/10.1590/0004-282X-ANP-2020-0374 VIEW AND REVIEW
Music-based therapy in rehabilitation of people with multiple sclerosis: a systematic review of clinical trials Terapia baseada na música na reabilitação de indivíduos com esclerose múltipla: revisão sistemática de ensaios clínicos Josiane LOPES1, Ivo Ilvan KEPPERS1
ABSTRACT Background: Multiple sclerosis (MS) is a major cause of chronic neurological disability in young adults. An increasing number of controlled studies have assessed the potential rehabilitative effects of new drug-free treatments, complementary to the standard care, including music-based therapy (MBT). Objective: To analyze the evidence for the effectiveness of MBT within the therapeutic approaches to individuals diagnosed with MS. Methods: A systematic review of clinical trials was performed with searches in the following databases: BIOSIS, CINAHL, Cochrane, EBSCO, ERIC, Google Scholar, IBECS, LILACS, LISA (ProQuest), Medline, PEDro, PsycINFO (APA), Psychological & Behavioral, PubMed, SciELO, Scopus, SPORTDiscus and Web of Science. Clinical trials comparing MBT versus conventional therapy/ no intervention were included. Results: From the 282 studies identified, 10 trials were selected. Among these, the total sample consisted of 429 individuals: 253 were allocated to the experimental group (MBT) and 176 to the control group (conventional therapies or no intervention). All the studies presented high methodological quality. Modalities of MBT were clustered into four groups: (1) Rhythmic auditory; (2) Playing musical instruments; (3) Dance strategy; and (4) Neurological music therapy. Overall, the studies consistently showed that MBT was better than conventional therapy or no intervention, with regard to gait parameters (double support time and walking speed), fatigue level, fatigability, coordination, dexterity, balance, walking endurance, lower extremity functional strength, emotional status and pain. Regarding mental fatigability and memory, the data were conflicting and the evidence was unclear. Conclusion: MBT is a safe and effective approach for clinical rehabilitation of MS patients that leads to positive results regarding both motor and non-motor functions. Keywords: Multiple Sclerosis; Music Therapy; Rehabilitation.
RESUMO Introdução: A esclerose múltipla (EM) é a maior causa de incapacidade neurológica crônica em adultos jovens. Um crescente número de estudos controlados avalia a reabilitação por meio de tratamentos não medicamentosos, cuidados complementares incluindo a terapia baseada na música (TBM). Objetivo: Analisar a evidência de efetividade da TBM na abordagem terapêutica de indivíduos diagnosticados com EM. Métodos: Foi realizada uma revisão sistemática de ensaios clínicos com busca nas bases de dados Biosis, Cinahl, Cochrane, Ebsco, Eric, Google Scholar, Ibecs, Lilacs, Lisa (ProQuest), Medline, PEDro, PsycINFO (APA), Psychological & Behavioral, PubMed, SciELO, Scopus, Sportdiscus e Web of Science. Foram incluídos ensaios clínicos comparando TBM versus terapia convencional/sem intervenção. Resultados: Dentre os 282 estudos identificados, 10 ensaios foram selecionados. Desses, a amostra total consistia em 429 indivíduos (253 alocados no grupo experimental (TBM) e 176 no grupo controle (terapias convencionais ou sem intervenção). Todos os estudos apresentaram elevada qualidade metodológica. Modalidades da TBM foram reunidas em quatro grupos: (1) Audição rítmica; (2) Tocar instrumentos musicais; (3) Dança como estratégia; e (4) Terapia neurofuncional baseada na música. A maioria dos estudos identificou que a TBM é melhor que a terapia convencional ou nenhuma intervenção nos parâmetros da marcha (duplo apoio e velocidade), níveis de fadiga, fatigabilidade, coordenação, destreza, equilíbrio, força de membros inferiores, estado emocional e dor. Os dados sobre fatigabilidade mental e memória foram conflitantes e as evidências são incertas. Conclusão: A TBM é uma abordagem segura na reabilitação clínica de indivíduos com EM e propicia resultados positivos nas funções motoras e não motoras. Palavras-chave: Esclerose Múltipla; Musicoterapia; Reabilitação.
1Universidade Estadual do Centro-Oeste, Departamento de Fisioterapia, Guarapuava PR, Brazil. Josiane LOPES https://orcid.org/0000-0003-0128-4618; Ivo Ilvan KEPPERS https://orcid.org/0000-0002-5901-4007 Correspondence: Josiane Lopes; E-mail: [email protected]. Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: Both authors did data collection, data analysis and writing and analyses of the final text. Received on July 31, 2020; Received in its final form on September 07, 2020; Accepted on October 01, 2020.
527 INTRODUCTION free gestures or structured rhythmic or dancing sequences), instrumental improvisation and listening to music tracks17. Multiple sclerosis (MS) is an autoimmune and neu- Some studies have highlighted the effectiveness of MBT for rodegenerative disorder characterized by destruction of showing connectivity changes in different brain networks myelin in the central nervous system (CNS), caused by a and enhancing motor recovery in terms of gait (velocity, complex interplay between genetic and environmental cadence and stride length), upper-limb function and pare- factors1,2. MS is mostly diagnosed in young adults, with sis, balance and mood functions14. Cognitive clinical effects disease onset occurring in most cases between the ages of have been observed in the domains of attention, memory, 20 and 40 years3,4,5. There is increasing incidence and prev- concentration and learning21,22, in which affective vocal- alence of MS in both developed and developing countries. izations have been shown to modulate attention via acti- It affects approximately 2.3 million people worldwide (one vation of prefrontal-limbic networks23. Studies have doc- million only in USA)6. However, the underlying cause of umented satisfactory results from programs using MBT MS remains uncertain7. among people diagnosed with stroke, Parkinson’s disease, It is a major cause of chronic neurological disability in chronic aphasia, Alzheimer’s disease, dementia and cere- young adults (aged 18–50 years), associated with complex bral palsy24,25,26,27. On the other hand, the scientific evidence disabilities8. MS can affect any area of the CNS with vari- about MBT has only been systematically explored poorly able clinical manifestations (e.g. visual, motor and sensory among people with MS. deficits, speech disturbances, sphincter disorders, cognitive An understanding of the effects of MBT shown in relation impairment, sexual problems and fatigue)9,10. These disabil- to MS rehabilitation would clarify comprehension and could ities usually lead to progressive limitation of functioning in assist in clinical management and could serve as a basis for daily life, thus requiring longer-term multidisciplinary man- further research. The aim of the current study was to analyze agement. MS has a variable and uncertain prognosis11,12. the evidence for the effectiveness of MBT, within the thera- To date, the aim of the pharmacological treatments available peutic approaches to individuals diagnosed with MS. for MS, and in particular the disease-modifying treatments, is to achieve reduction of the clinical relapse severity and fre- quency, thereby slowing down the disease progression13. METHODS Nevertheless, many of these symptoms can deleteriously impact the occupational profile, social participation, self- A systematic review was conducted in order to provide esteem and quality of life of patients. Over the last 11 years, an an overview of the current state of evidence relating to MBT increasing number of controlled studies conducted on sev- as an intervention for rehabilitation among people with MS. eral neurological disorders have assessed the potential reha- This study was conducted in accordance with the Preferred bilitative effects of new drug-free treatments that would be Reporting Items for Systematic Reviews and Meta-Analyses complementary to the standard care, including music-based (PRISMA) guidelines28. therapy (MBT)3,14,15,16. MBT therapeutic techniques have been This study did not require animal or human participa- described17, such as rhythmic auditory stimulation, thera- tion; therefore, ethics approval was not required. The proto- peutic instrumental music performance, melodic intonation col for this systematic review was registered in PROSPERO, therapy and musical mnemonic training. These techniques an international prospective register of systematic reviews form the core of neurological music therapy14. (available at: http://www.crd.york.ac.uk/PROSPERO/), The effectiveness of interventions in the context of music- under the number: CDR42020143080 (University of York based interventions has been explained in terms of auditory- (UK), Centre for Reviews and Dissemination, National motor entrainment18 and sensorimotor coupling to tempo- Institute for Health Research). rally structured auditory input, along with recruitment of a The systematic review was conducted by searching striatal-thalamocortical system, involving the basal ganglia, all papers registered in the following databases: BIOSIS, thalamus, premotor, supplementary motor and dorsolateral CINAHL, Cochrane, EBSCO, ERIC, Google Scholar, IBECS, prefrontal cortex19. This was found to have important fe fects LILACS, LISA (ProQuest), Medline, PEDro, PsycINFO with regard to connecting upper and lower body segments in (APA), Psychological & Behavioral, PubMed, SciELO, coordinated movements, either symmetrically or asymmetri- Scopus, SPORTDiscus and Web of Science. The subject cally (uni- or bi-manually)20. descriptors proposed in the Medical Subject Headings Over recent years, MBT has been increasingly inves- (MeSH) and in the Health Sciences Descriptors (DeCS) tigated in the context of neurological rehabilitation. were used: “Multiple sclerosis”, “music”, “music therapy”, MBT acts on motor skills and cognitive functions. A wide “acoustic stimulation”, “acoustics”, “dance”, “dance therapy” spectrum of MBT is known, such as writing music, sing- and “rhythm” with crossing-referencing using the Boolean ing songs from the light, classical and popular repertoires, operators “AND” and “AND/OR”. No filter was used in the rhythm-movement association (from physical relaxation to databases. Manual searches were also performed based on
528 Arq Neuropsiquiatr 2021;79(6):527-535 analysis of bibliographic references in previously selected The methodological quality of each study was assessed articles. The search period ranged from the beginning of using the PEDro scale (Physiotherapy Evidence Database), each database until July 2020. based on the Delphi list. This scale is composed of 11 items Only studies that met the following criteria were and scores 10. These items are scored as present (one point) included: (a) sample of individuals diagnosed with MS; (b) or absent (zero point) and the total score is obtained by add- investigation of the effect of MBT as a treatment; (c) assess- ing the item scores, thus, the maximum score of the PEDro ment of outcomes related to motor and/or non-motor fac- scale is 10 points. Clinical trials with a PEDro score ≥6 points tors; and (d) published study. The following characteristics are classified as high quality; and <6 points, as low quality30. of the studies were exclusion criteria: (a) presentation of Studies with low methodological quality were not excluded, samples with other neurological diagnoses associated with given that this was one of the aspects of these studies that MS; (b) presentation of individuals with clinically isolated was analyzed. or radiologically isolated forms; (c) addressing a non-con- servative intervention or pharmacological approach as a control; and (d) article classification as a review (systematic RESULTS review or review of the literature), correspondence, edito- rial, conference abstract, observational study or book chap- Studies included ter. Only studies published in Portuguese and/or English Using the search strategy, 282 citations published between were considered. There was no restriction on the year of the beginning of each database and July 2020 were identified, publication of the study. of which 10 were included in the systematic review (Figure 1). The procedures for selecting studies, extracting data There was 100% agreement between reviewers regarding arti- and assessing methodological quality and risk of bias were cle eligibility. All the studies included are presented in Table 1. independently developed by two reviewers. The results were The outcomes assessed focused on both non-motor factors compared and any disagreement was resolved through dis- (anxiety, depression, quality of life, fatigue, mental fatigabil- cussion. If there was no consensus between the reviewers, ity, pain and cognition) and motor factors (balance, motor the opinion of a third reviewer would become necessary. performance, walking endurance and dexterity). The stud- For management of references, the Mendeley software was ies used different assessment tools to evaluate these factors used, which enabling reference identification and control, mentioned above. especially in relation to the potential for duplication of refer- According to the PEDro scale, all the studies pre- ences in different databases. sented a high quality level (≥6). The majority of the stud- The selection and extraction of the data were done in ies met most of the criteria. None of the studies was line with the Cochrane recommendations29. The titles and blinded both to the subjects and to the therapists: this abstracts of the studies were analyzed. Abstracts that met level of blinding would not have been possible due to the the criteria or those that needed further clarification were nature of the studies. Only three studies were blinded to retained for complete review. Subsequently, the abstracts the examiners (Table 2). were analyzed in conjunction with the full texts of the arti- cles. All outcomes were assessed at the conclusion of the MBT or in the light of its long-term effect. The studies selected were analyzed in full text consider- ing the following matters: 1. Referential characterization of the study; 2. Outline; 3. Sample; 4. Interventions; 5. Outcome measurements related to motor and non-motor factors; 6. Results; and 7. Conclusion. The effectiveness of MBT was analyzed in terms of the improvement of the outcomes that had been proposed in each study as a parameter. The content of the studies selected was discussed based on the following topics: Investigation of the use of music as symptomatic and rehabilitation therapy for motor and non- motor disorders associated with MS; Analysis of the constit- uent characteristics and the mode of administration of the protocols for MBT, for rehabilitation of individuals with MS; Comparison between application of MBT and use of conser- vative noninvasive therapies, in care protocols for individu- als with MS; Assessment of the methodological quality of the studies selected. Figure 1. Flowchart of the systematic review analysis.
Lopes J et al. Music-based therapy in rehabilitation 529 Table 1. Characteristics of the studies included in the systematic review. Author Sample Description Outcomes n=20 EG (n=10): Nordoff-Robbins approach: music-making on 14 females: 6 males instruments or singing. Aldridge 29–47 years old Depression, anxiety and (three blocks of music therapy in single sessions et al.37 Clinical form: PP, SP quality of life. (8–10 per block) over the course of 1 year. EDSS: 2.5±1.5 CG (n=10): no intervention Disease duration: 11 years n=10 Gender: not mentioned EG (n=5): rhythmic auditory stimulation (mp3 playing). Gait performance and Conklyn 50.2±5.45 years old (20 min per day every day for 4 weeks) improvement of walking et al.31 Clinical form: PP, SP, RR CG (n=5): no intervention speed. EDSS: not mentioned Disease duration: 16.6±10.43 years n=19 12 females: 7 males EG (n=9): playing musical keyboard (turned on) Gatti 46±9.6 years old (half an hour per day for 2 weeks) Hand dexterity. et al.34 Clinical form: not mentioned CG (n=10): playing music keyboard (turned off) (half an EDSS: not mentioned hour per day for 2 weeks) Disease duration: not mentioned Fatigue and motor and n=17 mental fatigability, 16 females: 1 male EG (n=7): dance walking endurance and Geel 29–65 years old (twice a week for ten weeks, 90 min per session) walking ability et al.1 Clinical form: RR CG (n=10): art activities (poetry, paintings and photography) speed, balance, lower EDSS≤4.5 (twice a week for ten weeks, 90 min per session) limb strength and Disease duration: 3–21 years manual dexterity. n=30 EG (n=15): NMT techniques, performed 3 times a week Cognitive abilities 11 females: 19 males for 8 weeks. All the participants were subjected to the (attention, orientation, Impellizzeri 51.33±10.1 years old same amount of treatment spatial abilities, et al.2 Clinical form: PP, SP, RR (3 times a week for 8 weeks plus) memory and language), EDSS: 5±1.5 CG (n=15): conventional cognitive rehabilitation quality of life and Disease duration: 9–10 years (6 times a week for 8 weeks) depression. n=38 EG (n=20): Music as mnemonic device using an adapted 30 females: 8 males version of Rey’s Auditory-Verbal Learning Test (AVLT) Moore 53.33±10.07 years old (immediate and after 15 min) Learning and short et al.36 Clinical form: not mentioned CG (n=18): Hearing as mnemonic device using an memory. EDSS: 4.88±1.26 adapted computer program using spoken words Disease duration: not mentioned (immediate and after 20 min) EG (n=34): rhythmic cued motor imagery. n=101 (17 min of motor imagery, six times per week, for 85 females: 16 males 4 weeks, with music) Walking speed, walking Seebacher 4 4.1±12 years old EG (n=34): metronome-cued motor imagery perception, fatigue and et al.33 Clinical form: not mentioned (17 min of motor imagery, six times per week, for quality of life. EDSS: 2.0±1.5 4 weeks, with metronome) Disease duration: not mentioned CG (n=33): conventional physiotherapy (six times per week, for 4 weeks). n=59 EG (n=19): music-cued and verbally cued motor imagery 46 females: 13 males (six times per week, for 4 weeks) Seebacher 44.4±15.4 years old EG (n=20): music-cued MI Fatigue and walking et al.32 Clinical form: not mentioned (six times per week, for 4 weeks) speed. EDSS: 2.5±2.0 CG (n =20): motor imagery Disease duration: not mentioned (six times per week, for 4 weeks) EG (n=27): music-assisted learning: single list of n=54 15 words associated with melody of an originally 38 females: 16 males composed song (sung). Verbal learning and Thaut 53.3±9.3 years old (single session of 10 trials, 20 minutes). short term memory et al.18 Clinical form: RR CG (n=27): music-assisted learning: single list of improvements. EDSS: 4.9±1.3 15 words associated with melody of an originally Disease duration: not mentioned composed song (spoken). (single session of 10 trials, 20 minutes). n=81 EG (n=27): movement to music (multiple movement 42 females: 11 males routines accompanied with music). Mobility, balance, Young 49.67±10.33 years old (three 60-min per week for 12 weeks) walking endurance, et al.35 Clinical form: not mentioned EG (n=26): Yoga fit strength, fatigue and EDSS: not mentioned (three 60-min per week for 12 weeks) pain. Disease duration: not mentioned CG (n=28): no intervention n: number of participants; PP: primarily progressive; SP: secondary progressive; RR: remitting-recurrent; EDSS: expanded disability status scale; EG: experimental group; CG: control group; NMT: neurological music therapy.
530 Arq Neuropsiquiatr 2021;79(6):527-535 Table 2. Methodological quality score for each study (PEDro scale). Item 2-Al- 9-Inter- 10-Vari- 1-Ran- 4-Blinding 5-Blind- 6-Blinding 7-Outcome Reference Eligi- location 3-Similar 8-Intention group ability Score domized of partici- ing of of examin- measure- bility* Conceal- prognosis to treat compari- and pre- Allocation pants therapists ers ment ment sons cision Aldridge 0 1 1 1 0 0 0 1 1 1 1 7/10 et al.37 Conklyn 1 1 1 1 0 0 0 1 0 1 1 6/10 et al.31 Gatti 1 1 1 1 0 0 0 1 1 1 1 7/10 et al.34 Geel 1 1 1 1 0 0 0 1 1 1 1 7/10 et al.1 Impellizzeri 1 1 1 1 0 0 1 1 1 1 1 8/10 et al.2 Moore 1 1 1 1 0 0 0 1 0 1 1 6/10 et al.36 Seebacher 1 1 1 1 0 0 0 1 1 1 1 7/10 et al.33 Seebacher 1 1 1 1 0 0 0 1 1 1 1 7/10 et al.32 Thaut 1 1 0 1 0 0 1 1 0 1 1 6/10 et al.18 Young 1 1 1 1 0 0 1 1 1 1 1 8/10 et al.35 *Item not scored.
Participants’ characteristics The group of participants who were allocated to the CG The total number of participants studied was 429 (332 underwent several strategies such as maintaining their daily females and 97 males), among whom 253 were in the exper- activities (without the intervention itself), developing artis- imental group (EG) and 176 in the control group (CG). tic activities (poetry or painting) that did not involve music The sample sizes for the EG and CG in the different stud- and/or musical elements, cognitive rehabilitation, yoga exer- ies ranged from 5 to 34 individuals. All the participants were cises, conventional physiotherapy, motor imagery or play- diagnosed with MS and were aged between 29 and 70 years ing musical instruments without sound. All of the studies old. The majority of the individuals sampled showed the reported that there were no adverse events. clinical form of relapsing-remitting MS, with mean EDSS of 3.18±1.10 points and average MS duration of 11.82±1.10 years Music-based therapy interventions and outcomes (Table 1). All the studies mentioned that participants were excluded when an exacerbation occurred three months or Rhythmic auditory strategies: less before the onset of the study. gait, fatigue and quality of life Conklyn et al.31 tested a four-week home-based walking Intervention characteristics program with rhythmic auditory stimulation, among 10 MS All the articles selected investigated the effect of MBT in patients. They found that there was a significant improve- relation to the standard physical treatment or no treatment. ment in gait parameters (doubled support time and walking The EG underwent MBT sessions and the CG underwent con- speed) after two weeks of treatments. In a home-based pilot ventional physiotherapy, MBT placebo or no intervention. study, Seebacher et al.32 applying music-cued and verbally The duration of the sessions of EG and CG showed great cued motor imagery in one group and music-cued motor variability between studies. Most sessions lasted between 15 imagery in another, and comparing both of these with a CG in and 90 minutes, often between 2 and 3 times a week, in pro- which only motor imagery was applied. They found improve- tocols lasting for between 2 and 60 weeks. ments relating to fatigue follow-up, compared with baseline, The treatment protocols based on interventions involv- in both treatment groups. In another study, the same authors33 ing music used strategies that included application of activi- applied rhythmic-cued motor imagery techniques to a large ties relating to dance, rhythm, singing, memorization of parts sample of MS patients. They confirmed the improvements of music through spoken or sung speech, mental imaging in walking, fatigue perception and quality of life after a treat- associated with music or playing musical instruments. ment applied six times per week, for 4 weeks (Cohen’s d=0.6).
Lopes J et al. Music-based therapy in rehabilitation 531 Playing musical instruments: dexterity Using the Nordoff-Robbins approach (active role of both Gatti et al.34 evaluated the efficacy of musical keyboard patients and musical therapist regarding vocal improvisation playing on hand function improvement in a group of 19 MS or playing instruments, without any previous musical edu- patients, with training for half an hour per day for 2 weeks. cation), Aldridge et al.37 performed three blocks of MBT in Half of the patients played a turned-on musical keyboard a single session over a one-year period, in a group of 20 MS using finger movements (audio on); the other half used a patients. Despite no significant differences, the authors found turned-off keyboard (audio off). The whole program con- improvements of medium effect size on the scales measuring sisted of 46 exercises applied according to increasing levels of self-esteem (Cohen’s d=0.5), depression (d=0.63) and anxiety difficulty, which were firstly demonstrated by a music thera- (d=0.63), which thus suggested that MBT can influence the pist three times. The results were valuable for improvement behavior and mood aspects of MS patients. in hand dexterity (assessed by means of the nine-hole peg test) and in perceived hand functional use, with a difference Neurological music therapy: between the two groups (Cohen’s d=1.66). cognitive function, emotional status , motivation, mood and quality of life Dance strategy: balance, coordination, Neurological music therapy (NMT) is a new integrative fatigue, mental fatigability, walking, therapeutic approach that was presented in only one article2 strength, cognitive, quality of life and pain in this review. A typical NMT technique is based on an asso- Only two studies1,35 reported on the effect of dance. ciative network theory of mood and memory. This suggests Geel et al.1 assessed this effect in relation to fatigue and men- that when an event or some information is processed, neu- tal fatigability, balance, walking ability, lower limb strength ral connections are established together with other elements and manual dexterity. Comparing EG (dance) and CG (art (emotional status, odors and environmental background) of activities), Geel et al.1 showed that there were significant that event, and are stored as nodes in memory. Later, this improvements in the level of fatigue, cognitive capacity and neural node can be activated that musical stimuli38. coordination for the EG. There was no significant change in Impellizzeri et al.2 conducted a study with a sample mental fatigability and health-related quality of life. composed of 30 MS participants. These were randomly in 2 Young et al.35 assessed the effects of MBT in comparison groups: the CG underwent conventional cognitive rehabilita- with adapted yoga. The primary outcomes were improvement tion (CCR) (6 times a week for 8 weeks); and the EG under- in mobility and balance, walking endurance and lower extremity went CCR plus NMT techniques (3 times a week for 8 weeks). functional strength. The secondary outcomes were reduction of In particular, the EG got better results for cognitive function, fatigue and pain. Young et al.35 showed that significant improve- with regard to selective reminding test long-term storage ments with moderate effect sizes occurred in relation to bal- (p<0.000), long-term retrieval (p=0.007) and delayed recall of ance (Cohen’s d=0.7) and walking time performance (Cohen’s the 10/36 spatial recall test (p=0.001), in comparison with the d=0.6), with a trend towards fatigue reduction, in a group of par- CG. Moreover, the improvement in emotional status, motiva- ticipants who underwent MBT, compared with a CG. tion, mood and quality of life (with regard to the mental com- ponent; p<0.000 was more evident in the EG. Music mnemonics: cognition, mood and behavioral and verbal communication It has been highlighted that musical mnemonic devices DISCUSSION facilitate verbal learning and short-term memory among MS patients. Moore et al.36 used music as a mnemonic device There has been an exponential increase in knowledge to test learning and memory ability among 38 MS patients. about MBT as a therapeutic complementary approach for They were divided in two groups: patients who learned words MS. Its efficacy is continually increasing, which makes MBT through music versus patients who learned words through more reliable and precise. The analysis on this systematic speech. Even though the results did not show any signifi- review revealed that MBT provides strong clinical potential cant differences in memory between the groups, there was for rehabilitation of non-motor and motor factors among a significant correlation between auditory verbal learning people with MS. test results and clinical measurements in the music group, in This review included studies published between 2005 comparison with speech group. and 2020. However, there is a lack of studies about MBT and Thaut et al.18 investigated the neural correlates of brain its efficacy with good methodological standards and with plasticity during verbal memory training, with use of music analysis on specific outcomes relating to MS rehabilitation. mnemonics. Their results showed that speech and order Additionally, it can be hypothesized that the effect relating to memory were better under musical conditions than under degenerative diseases like MS is underestimated, given their spoken conditions, with stronger bilateral frontal alpha progressive nature. However, since the intervention period learning-related synchronization in the first group. reported was relatively short and these studies included a
532 Arq Neuropsiquiatr 2021;79(6):527-535 CG, it is very unlikely that disease progression could have auditory stimulation, more than simple metronome cues, greatly hampered correct interpretation of the results14. has been developed to promote walking speed and distance Although music therapy has been recognized as a profes- among people with motor limitations. sion in the healthcare field in the United States since 195639, Analysis on the intervention “playing musical instru- there is an urgent need in Brazil for music therapy to be rec- ments” showed that this strategy focused on mobility out- ognized and strengthened as a healthcare profession, thereby comes, given that it directly involved an activity. This is an becoming clearly differentiated from musical activities that active musical experience that, through including repeti- relate to relaxation and leisure. Only limited scientific evi- tive movements, involves different cerebral regions across dence supports the use of this clinical intervention among a multisensory stimulation effect (visual, vestibular, tactile MS patients40. The rehabilitative effect of music in relation to and proprioceptive), thus promoting functional recovery of neurological disorders is linked to changes in brain neuro- the hands44. plasticity and neural activation3,24,41, but the specific mecha- Cognitive impairment affects 70% of people with MS45. nism still remains unknown. Some deficits, especially relating to memory, attention and A variety of ways to use MBT in strategies for rehabilita- information processing speed, are present from the early tion of people with MS and to measure the outcomes was stage of the disease. So far, there is a lack of effective drugs or observed. The studies reviewed here evaluated MBT as a tool other treatments that might help to cope with these cogni- for rehabilitative purposes, through active techniques (musi- tive dysfunctions. There is a lack of strategies for improving cal improvisation through playing an instrument or sing- cognition in MS and the ways in which this matter has been ing) and passive techniques (music imagery and listening to approached have shown conflicting results. In this review, music). In both types of technique, the aim was to build up one randomized clinical trial that applied the NMT interven- a musical relationship between patient and therapist, so as tion was seen: this is a new approach that can be included to promote motor and cognitive recovery. This was shown among MBT strategies. by Vinciguerra et al.42 through their exploration of the role of Research promoting music as a mnemonic tool for music therapy in MS. improving neuronal plasticity of the temporal regions and In this current review, to facilitate interpretation of the oscillatory network synchronization in the prefrontal area effects from interventions, and for simplicity of explanation, resulted in better learning and memory performance18,42. the findings from the studies selected were grouped into four However, Moore et al.36 reported that the rhythmic and clusters, according to the content of the music-based strat- melodic phrases within music did not seem to directly egy used: (1) Rhythmic auditory; (2) Playing musical instru- support music as a mnemonic device in facilitating learn- ments; (3) Dance strategy; and (4) Neurological music ther- ing processes and information retrieval. This may have apy. The studies focused more on analyzing the evidence for been because recognition tasks are not the most appro- the effect of music-based therapy on motor outcomes. priate method for measuring the effectiveness of temporal All the studies yielded promising positive results in rela- structures in retrieving learned information. Those authors tion to both the motor and the non-motor outcomes that explained their results through the assumption that the par- were assessed. The music interventions were mostly supe- ticipants did not have enough time to memorize the infor- rior to conventional therapy or no intervention. As such, mation and that the music could also have represented a this review provides support for implementing elements distractor element. Nonetheless, it was also true that in the of music-supported rehabilitation in the field of neurology. same study, the analysis on correlations in the music group However, it should be noted that the outcome measurements showed that less cognitively impaired MS patients gained selected were specific to the outcomes that was targeted for more benefits from music mnemonics, in relation to learn- assessment. Therefore, the results are not generalizable for all ing and memory processes. Music-based interventions can symptoms that give rise to impairment in the MS population. be used as dual-task training, apart from providing simple Regarding the rhythmic auditory strategy, improvement training for motricity or cognition14. of gait and reduced fatigue levels were shown. Impaired walk- To demonstrate the components of the dual task, using ing speed due to gait limitations or fatigue plays a crucial role MBT, the action of physically producing music is performed in reducing the level of ability to perform activities of daily simultaneously with auditory stimulus processing or visual living among people with MS42. Rhythmic auditory stimula- stimulus processing. This is relevant, given that large cogni- tion provides improvement of the intrinsic rhythmic move- tive-motor interferences resulting from dual tasks have been ments of gait and the coordination processes. This may be shown in many neurological conditions and have been corre- related to involvement of different motor brain areas, such as lated with the risk of falls14. the cortex, cerebellum and spinal tract31,43. Vinciguerra et al.42 MBT was also associated with approaches for improv- discussed the way in which music also exploits the relation- ing emotional aspects and quality of life of MS patients. ship between body language and sound, such as interaction The physiological explanation for this phenomenon relates between perception and action. In this context, rhythmic to the effect on neurohormonal circuits such as activation of
Lopes J et al. Music-based therapy in rehabilitation 533 the mesolimbic dopaminergic system (nucleus accumbens, intervention, it deserves to be studied in larger samples of hippocampus and amygdala)23,46. Music is able to activate MS patients, with a wide spectrum of clinical disability and the parasympathetic nervous system, in contrast to the sym- appropriate approaches that are chosen such that they are pathetic system, thereby promoting cytokine secretion and tailored to individual clinical outcomes. changes in catecholamine levels47. Music represents part of Although the clinical effects of music-based interven- our genetic heritage, a kind of universal language focused on tions are promising, as shown in this review, further research the relationship between the language of the body and that is needed in order to better understand the principles of how of sound, which is able to reduce stress and preserve mental music interacts with motricity or cognition. To further inves- health conditions. These data are promising and lead to con- tigate this hypothesis, it is important to apply comparative sideration of the use of MBT as a drug-free treatment for sup- experimental designs and to use neuroimaging techniques to porting individuals’ coping strategies in MS42. investigate the neurophysiological processes of music-based There were important limitations to this study. The stud- interventions. Further research is needed in order to com- ies could have provided more details and could have dem- bine effective rehabilitation approaches with appropriate onstrated all the results in the publications than they did. study designs, outcome measurements, types and intensities For example, some studies did not show basic data like the of modalities and cost effectiveness of these interventions. EDSS score or the clinical form of MS. For this reason, it MBT is a safe and effective approach for clinical rehabil- was not possible to analyze the conditions of the sample itation of MS patients that leads to positive results regard- at the baseline and hence the real dimension of the MBT ing motor function. However, regarding mental fatigabil- effects on this specific population. There is a lack of meta- ity and memory, the data were conflicting and the evidence analysis in relation to MBT, in comparison with other reha- was unclear. Although generalization of these findings may bilitation approaches. This is because of the heterogeneity be restricted by the small sample size, this systematic review of samples, follow-up periods, modalities of music interven- showed that MBT can be indicated for improving motor tion, modes of administration of MBT interventions, more factors, even in a neurodegenerative disease like MS. It is than one experimental group and numbers of participants essential to better define these approaches using elements included in each study. of music that were cited as strategies in this current review. Indeed, MBT effects can be underestimated, given the It is relevant to identify more standardized methods to apply progressive course of MS disease, and the role of this inter- in each clinical context. The role of music needs to be better vention still appears unclear. Blinding of participants or understood and included in a multidisciplinary approach for therapists was not feasible, but may still represent a risk of different MBT settings. This can help to further explain the bias. Although we searched extensively, we may have missed role of music in relation to brain neuroplasticity changes and relevant studies. Because MBT is a simple and low-cost thus confirm the strong relevance of MBT in clinical practice.
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Moher D, Shamseer L, Clarke M, Ghersi D, Liberati A, Petticrew M, Neurol. 2016 Jun;7:106. https://doi.org/10.3389/fneur.2016.00106 et al. Preferred reporting items for systematic review and meta- 45. Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple analyses protocols (PRISMA-P) 2015 statement. Syst Rev. 2015 sclerosis. Lancet Neurol. 2008 Dec;7(12):1139-51. https://doi. Jan;4(1):1. https://doi.org/10.1186/2046-4053-4-1 org/10.1016/S1474-4422 (08)70259-X 29. Green S, Higgins JP, Alderson P, Clarke M, Mulrow COA. Introduction. 46. Salimpoor VN, Benovoy M, Larcher K, Dagher A, Zatorre RJ. In: Higgins JP GS, editor. Cochrane handbook for systematic reviews Anatomically distinct dopamine release during anticipation of inter-ventions. England: Willey-Blackwell; 2008. p.1.1-1.2. https:// and experience of peak emotion to music. Nat Neurosci. 2011 doi.org/10.1002/9780470712184.ch1 Feb;14(2):257-62. https://doi.org/10.1038/nn.2726 30. Morton NA. 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Lopes J et al. Music-based therapy in rehabilitation 535 https://doi.org/10.1590/0004-282X-ANP-2020-0166 VIEW AND REVIEW
Born to move: a review on the impact of physical exercise on brain health and the evidence from human controlled trials Nascidos para o movimento: uma revisão sobre o impacto do exercício físico na saúde do cérebro e as evidências de estudos controlados em humanos Camila VORKAPIC1, Silvânia LEAL2, Heloisa ALVES3, Michael DOUGLAS1, André BRITTO4, Estélio Henrique Martin DANTAS1
ABSTRACT Background: Physical exercise has been found to impact neurophysiological and structural aspects of the human brain. However, most research has used animal models, which yields much confusion regarding the real effects of exercise on the human brain, as well as the underlying mechanisms. Objective: To present an update on the impact of physical exercise on brain health; and to review and analyze the evidence exclusively from human randomized controlled studies from the last six years. Methods: A search of the literature search was conducted using the MEDLINE (via PubMed), EMBASE, Web of Science and PsycINFO databases for all randomized controlled trials published between January 2014 and January 2020. Results: Twenty-four human controlled trials that observed the relationship between exercise and structural or neurochemical changes were reviewed. Conclusions: Even though this review found that physical exercise improves brain plasticity in humans, particularly through changes in brain-derived neurotrophic factor (BDNF), functional connectivity, basal ganglia and the hippocampus, many unanswered questions remain. Given the recent advances on this subject and its therapeutic potential for the general population, it is hoped that this review and future research correlating molecular, psychological and image data may help elucidate the mechanisms through which physical exercise improves brain health. Keywords: Physical Activity; Exercise; Brain; Mental Health; Review.
RESUMO Introdução: Evidências das últimas décadas têm mostrado que o exercício físico impacta de forma significativa aspectos neurofisiológicos e estruturais do cérebro humano. No entanto, a maioria das pesquisas emprega modelos animais, o que gera confusão no que diz respeito aos efeitos reais do exercício no cérebro humano, assim como os mecanismos adjacentes. Objetivo: Apresentar uma atualização sobre o impacto do exercício no cérebro; revisar e analisar sistematicamente as evidências provenientes exclusivamente de estudos randomizados controlados em humanos, dos últimos seis anos. Métodos: Foi conduzida uma busca na literatura usando as bases de dados MEDLINE (via PubMed), EMBASE, Web of Science e PsycINFO, para todos os estudos randomizados e controlados publicados entre janeiro de 2014 e janeiro de 2020. Resultados: Foram revisados 24 estudos randomizados controlados em humanos, que observavam a relação entre exercício físico e alterações neuroquímicas e estruturais no cérebro. Conclusões: Ainda que esta revisão tenha observado que o exercício físico melhora a plasticidade cerebral em humanos, particularmente por meio de alterações no fator neurotrófico derivado do cérebro (BDNF), conectividade funcional, núcleos da base e hipocampo, muitas questões ainda precisam ser respondidas. Dados os avanços recentes nessa temática e seu potencial terapêutico para a população em geral, espera-se que este manuscrito e pesquisas futuras que correlacionem estudos moleculares e variáveis psicológicas e de imagem possam ajudar na elucidação dos mecanismos pelos quais o exercício físico melhora a saúde cerebral. Palavras-chave: Atividade Física; Exercício Físico; Cérebro; Saúde Mental; Revisão.
1Universidade Tiradentes, Departamento de Medicina, Laboratório de Biociências da Cinética Humana, Aracaju SE, Brazil. 2Universidade Federal do Estado do Rio de Janeiro, Laboratório de Biociências da Cinética Humana, Rio de Janeiro RJ, Brazil. 3University of Massachusetts, Department of Psychology, Dartmouth MA, United States. 4Universidade Estácio, Departamento de Psicologia, Aracaju SE, Brazil. Camila VORKAPIC https://orcid.org/0000-0002-0809-3964; Silvânia LEAL https://orcid.org/0000-0003-0473-7205; Heloisa ALVES https://orcid.org/0000-0002-6102-7616; Michael DOUGLAS https://orcid.org/0000-0003-2564-1464; André BRITTO https://orcid.org/0000-0002-0106-7210; Estélio Henrique Martin DANTAS https://orcid.org/0000-0003-0981-8020 Correspondence: Camila Vorkapic; E-mail: [email protected]. Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: CFV: designed and implemented the study, designed the data extraction, carried out data analysis and wrote the manuscript with support from SL, HA and AB. EHMD: helped with data extraction and literature search. EHMD and MD gave support in the interpretation of the data. All authors read and approved the final version. Received on May 06, 2020; Received in its final form on August 26, 2020; Accepted on September 17, 2020.
536 INTRODUCTION shown that exercise increases the synthesis of growth fac- tors such as brain-derived neurotrophic factor (BDNF) and In 2004, Bramble and Lieberman suggested that humans insulin-like growth factor (IGF-1), proteins that play a crucial evolved from monkey-like ancestors, specifically due to their role in neuroplasticity, neuroprotection and neurogenesis4. ability to run long distances. According to these authors1, There is also evidence that neuromodulation and neurotrans- strong selection for running was crucial in shaping the body mission are regulated by physical exercise6,7. Lastly, an emerg- of modern man and was an essential factor in the appear- ing concept suggests that brain health and cognitive func- ance of specific anatomical features. Figure 1 shows typi- tions are modulated by the interrelationship between central cal human anatomical and physiological features that are and peripheral factors8. Systemic inflammatory processes, adaptations to running, according to the endurance running which are present in metabolic diseases such as hyperten- theory from Bramble and Lieberman1. The close connection sion or insulin resistance, increase central nervous system between movement (exercise) and human evolution is shown inflammation and are associated with cognitive decline8. by the fact that inactivity makes people physically and men- Human randomized controlled trials have shown that exer- tally ill2. Studies have shown that movement is so essential cise upregulates neurotransmitters9, boosts neurotrophic fac- for humans that the brain not only benefits from it, but also tor synthesis10,11, increments functional connectivity12,13 and requires it in order to function properly3. increases basal ganglion14 and hippocampus15,16 volume. The basic neurobiological mechanisms associated with Studies have indicated that physical exercise reduces physical exercise can occur at two levels: extracellular, with symptoms associated with different mental disorders, such exercise inducing angiogenesis from pre-existing vessels; and as depression and anxiety9, and neurodegenerative diseases intracellular, through increasing hippocampus neurogene- such as Alzheimer’s and Parkinson’s8. Thus, exercise forms sis4. The functional significance of this effect is still uncertain, an effective neuroprotective strategy against the deleterious but it has been suggested that newly formed neurons can be effects of aging17,18. integrated into the existing neural network and become fully Although the understanding of exercise-related molec- functional5. Exercise also seems to induce the growth of new ular and cellular changes in humans is relatively limited, synapses (synaptogenesis)5. In addition, animal studies have imaging technologies have enabled observation of changes
Figure 1. Human anatomical and physiological features that are adaptations to running, according to the endurance running theory.
Vorkapic C et al. The impact of exercise on brain health 537 in brain structure and function as a result of exercise in the many possible mechanisms through which physical exer- humans. Diamond19, for example, found that fitness training cise yields the abovementioned improvements are the fol- had robust but selective benefits for cognition, among which lowing: downregulation of the HPA axis4; upregulation of dif- the largest benefits related to executive control processes. ferent neurotransmitters and neuromodulators16; increased Other studies found that highly fit or aerobically trained par- neurogenesis11, synaptogenesis5 and neurotrophic factors4,6,7; ticipants showed better behavioral performance and greater and the interrelationship between central and peripheral fac- task-related activity in the prefrontal and parietal cortices, tors8. However, at the cellular level, most of this evidence i.e., in regions consistently implicated in attentional selection comes from animal studies5,6,7,8. Figure 2 summarizes the neu- and resolution of response conflict20,21. rophysiological and neurochemical effects of exercise. Neuroimaging studies have suggested that physical exer- It is relevant to note that since the approach of human cise has a protective role in preventing age-related decline neuroscience is basically noninvasive, it does not allow direct and disorders, especially brain atrophy. Colcombe et al.22 measurement of exercise effects on the brain at the cellular observed significant increases in both gray matter and white and molecular levels. To overcome this limitation, research matter volumes (primarily in prefrontal and temporal areas) uses animal models12. However, as previously stated, this in older adults (60–79 years), as a result of an exercise pro- yields significant confusion regarding the real effects of exer- gram. Erickson et al.23 found that aerobically trained subjects cise on human brain structures and neurochemistry, as well showed preservation of and increased hippocampus volume as regarding the underlying mechanisms involved. In addi- and better spatial memory performance. Erickson et al.23 also tion, many human studies have methodological limitations, observed increased anterior hippocampus volume in older such as the lack of control groups or randomization. For this adults, following a long-term exercise program. Interestingly, reason, it is crucial to elucidate the real impact of physical a 1.4% decline in the control group was also observed. exercise on the human brain by examining the evidence spe- Other studies showed that increases in total physical activity cifically from human randomized controlled trials. were positively related to increases in gray matter volume in Therefore, the aims of the current article were: 1) to pres- the prefrontal and cingulate cortices24, as well as greater white ent an update on the impact of physical exercise on brain matter integrity in the frontal and temporal lobes25. Among health; and 2) to review and analyze evidence exclusively
Figure 2. Summary of neurophysiological and neurochemical effects of physical exercise.
538 Arq Neuropsiquiatr 2021;79(6):536-550 from human randomized controlled studies from the last scrutinized. The search strategy included studies, abstracts, six years. titles and keywords, as follows: 1) ((exercise OR physical activity OR exercise program OR exercise intervention OR physical activity intervention METHODS OR physical activity program) AND (brain OR brain changes OR brain volume OR structural changes) AND (healthy) AND Registration and protocol (adults)) NOT children. This review was registered in the International Prospective 2) ((exercise OR physical activity OR exercise program OR Register of Systematic Reviews (PROSPERO) under the CRD # exercise intervention OR physical activity intervention OR 4202015989. It was carried out in accordance with the Preferred physical activity program) AND (neurochemical changes OR Reporting Items for Systematic Reviews and Meta-Analyses neurophysiological changes OR gray matter OR white mat- (PRISMA), a 27-item checklist that includes the title, abstract, ter OR connectivity OR cerebral blood flow OR hippocampus methods, results, discussion and funding, which is designed to OR cortex OR prefrontal cortex OR cortical activity OR neu- help authors of systematic reviews and meta-analyses. rotransmitters OR neurotrophic factors) AND (healthy) AND (adults)) NOT children. Search strategy The search of the literature was conducted indepen- Study selection criteria dently by two reviewers (CFV and SL) using MEDLINE (via Studies that investigated the relationship between phys- PubMed), EMBASE, Web of Science and PsycINFO databases ical exercise and structural or neurochemical changes were for all randomized control trials published between January included in the systematic review. Studies were considered 2014 and January 2020 (last six years). Studies that examined eligible only if: (1) they were human randomized controlled the relationship between physical exercise, structural, and trials (RCTs); (2) they investigated healthy adults; (3) they neurochemical changes were scrutinized. One strategy was were published or accepted for publication in a peer-reviewed to frame the search in the form of a question, while allowing journal; (4) interventions included an aerobic exercise pro- clarifications needed for selecting relevant results: Does exer- gram; (5) intervention programs included other types of phys- cise or physical activity cause structural, neurochemical and ical activity, such as dance, sports and resistance training; neurophysiological changes in the brain of healthy adults, (6) interventions included acute or chronic exercise; (7) inter- according exclusively to RCTs? ventions included observation of the impact of exercise on Another strategy used for creating a searchable question any brain structure (not function), volume, connectivity and was to put it in the form of a PICO question. PICO only par- blood flow; and (8) interventions included observation of the tially applied to our research question, but the principle of impact of exercise on the brain’s neurochemistry (neurotrans- breaking the question into searchable parts is useful and has mitters, neuromodulators or neurotrophic factors). been applied: Studies were excluded if: (1) they were not randomized • P: Population: healthy adults. controlled trials (RCTs); (2) they investigated individuals suf- • I: Intervention: exercise and physical activity. fering from any diseases; (2) they were conducted on chil- • C: Comparison: control. dren or adolescents; (3) they were cross-sectional, reviews • O: Outcome: structural, neurochemical and neurophysi- or study protocols; (4) they were animal studies; (5) the out- ological changes in the brain. come variable was not the impact of physical exercise on brain structures or neurochemistry; (6) they were published We searched the databases using mainly keywords and in any language other than English; and (7) they were pub- controlled vocabularies. Because of the diverse nature of lished before 2014. the relationship between exercise and the nervous system, different keywords can be applied. So the choice of specific Search data extraction keyword was based on the current literature in the field of Two authors (EHMD and AB) separately screened abstracts, exercise neuroscience. A simple chart was set up in order titles, and texts of the retrieved studies. They removed dupli- to help organize the searching. A column representing each cates and excluded those that did not meet the selection cri- idea and two correlated rows was created: one row for the teria. Subsequently, two other authors (MD and HV) collected controlled vocabulary terms and the other for the synonyms the following data from each article that had been selected: (1) and phrases that express the idea in a keyword search. year of publication; (2) sample; (3) intervention characteristics; The terms within the column were combined with OR, while (4) variables of interest; and (6) outcomes. different columns were combined with AND. Consequently, a using the three most common operators (AND, OR and Risk of bias NOT) was applied. Studies that examined the relationship After the phases of search strategy, selection criteria and between exercise or physical activity and brain changes were data extraction, the author CFV assessed the methodological
Vorkapic C et al. The impact of exercise on brain health 539 risk of bias of the studies through the Quality Assessment The total number of minutes (volume) spent on the inter- Tool for Quantitative Studies (QATQS), which was devel- ventions ranged from 10 to 30 minutes during acute protocols oped by the Effective Public Health Practice Project (EPHPP, (S10, S18 and S24) to approximately 40 to 180 minutes/week 1998). QATQS is a tool that provides a standardized means (S1, S2, S3, S4, S5, S6, S7, S8, S11, S12, S13, S14, S15, S16, S17, to assess study quality and develop recommendations for S19, S20, S21, S22 and S23). The overall frequency ranged from study findings. This quality appraisal tool was developed 1 to 7 times per week. as an important step within the systematic review process. Some studies provided data regarding changes in neu- The final results from using the QATQS gave rise to overall rotransmitters (S10, S17 and S23) or neurotrophic synthe- methodological ratings of strong (no weak ratings), moderate sis (S2, S4, S5, S6, S8, S11, S13, S22 and S23). In these stud- (one weak rating) or weak (two or more weak ratings) in eight ies, positive correlations were observed between exercise sections: 1) selection bias; 2) study design; 3) confounders; and increased neurotrophic factors (S2, S4, S5, S8, S13, S22 4) blinding; 5) data collection methods; 6) withdrawals and and S23) and between exercise and upregulation of neu- dropouts; 7) intervention integrity; and 8) analysis. Any dis- rotransmitters (S10). Four studies found that exercise did not agreements were resolved by a third researcher (RV). Table 1 increase the levels of neurotrophic factors (S6, S11 and S17) or shows the assessment of study quality through the QATQS. neurotransmitters (S17). Studies also observed increases (S18 and S23) or no differences in functional connectivity (S12) or in gray matter volume (S11). One study found that exercise RESULTS increased white matter volume (S19) or reduced white mat- ter atrophy (S1). Brain activity in the hippocampus area was The search yielded a total of 96 potentially eligible articles: found to increase after exercise (S24) or decrease but cor- 52 from Medline, 14 from Embase, 24 from Web of Science relate with better cognition (S16). With regard to structural and 6 from PsycINFO. After removing 6 duplicates, 90 were changes, seven studies investigated the effects of exercise on screened in detail. A total of 66 studies were excluded from basal ganglion volume (S14 and S15) and on hippocampus the review because: a) they were animal studies (8); b) they volume (S7, S9, S20, S21 and S23). One study (S14) found no were reviews, meta-analysis, study protocols or cross-sec- differences between groups regarding basal ganglion volume, tional studies (21); c) they were not randomized or controlled but that individuals with declines in mobility levels had sig- (25); and d) they were conducted on non-healthy or pediat- nificant decreases in left putamen volume. Another study ric populations (12). In the end, a total of 24 studies met the found that motor fitness, but not cardiovascular fitness, was inclusion criteria (S126, S210, S327, S46, S528, S629, S717, S830, S913, positively related to the volume of the putamen and the glo- S109, S1131, S1232, S1333, S1434, S1535, S1636, S1737, S1838, S1939, bus pallidus (S15). All studies that investigated changes in S2040, S2114, S2211, S2312 and S2441). These were assessed for the hippocampus found a positive correlation between exer- eligibility and later included in this review. The study extrac- cise and increased hippocampus volume (S7, S9, S20, S21 and tion flow is demonstrated in the PRISMA diagram (Figure 3). S23). Table 2 summarizes the information in the studies. The studies included were published between 2014 and 2020 and were all randomized controlled trials, with sample sizes ranging from 20 to 155 subjects, aged between 21 and DISCUSSION 65 years. The main interventions used in these studies were aerobic exercise15, resistance training6, coordination exer- The aim in this study was to review data exclusively from cises3 or a combination of coordination and cognitive exer- human randomized controlled studies conducted among cises1, calisthenics1 or a mixed program3. healthy adults. The review systematically examined the liter- The risks of bias of the studies included are displayed in ature from the last six years with regard to the effects of phys- Table 1. The risk of performance bias was high in these stud- ical exercise on brain volume, structures, functional connec- ies because it was difficult to blind participants or exercise tivity and neurochemical factors such as neurotransmitters, coaches, but six studies reported blinding of the outcome BDNF and the HPA axis, control groups or randomization. assessors (S4, S11, S18, S21, S22 and S23). The risk of attri- Among the studies that observed changes in neuro- tion bias was high in most studies (due to unreported data), trophic factors (S2, S4, S5, S6, S8, S11, S13, S22 and S23), all of except for six (S7, S9, S10, S12, S20 and S21) Nine studies used them used exercise programs that lasted more than six weeks an active control group (S1, S2, S4, S5, S9, S14, S15, S16 and (regular exercise). Seven studies found a positive correla- S24), instead of a no-intervention control and four studies tion between exercise and increased plasma or serum BDNF did not inform the type of control used (S8, S19, S21 and S23). (S2, S4, S5, S8, S13, S22 and S23). These results are in agree- The total duration of the interventions ranged from one ment with an extensive meta-analysis conducted by Szuhany session (acute) (S10, S18 and S24) to 6 to 52 weeks (S1, S2, S3, et al.42, which demonstrated the strength of the association S4, S5, S6, S7, S8, S9, S11, S12, S13, S14, S15, S16, S17, S19, S20, between exercise and increased BDNF levels in humans. S21, S22 and S23) and to two years (S19 and S20). The review showed a moderate effect size for increases in
540 Arq Neuropsiquiatr 2021;79(6):536-550 WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK WEAK MODERATE MODERATE MODERATE MODERATE MODERATE Overall rating Overall Strong: no weak ratings, no weak Strong: Moderate: one weak rating, one weak Moderate: Weak: two or more weak ratings weak or more two Weak: 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Analyses 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 integrity Intervention Intervention 3 3 3 3 3 3 3 3 3 3 3 3 3 3 1 1 3 3 3 3 1 1 1 1 Withdrawals Withdrawals and drop-outs 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Data Data methods collection collection 3 3 3 3 3 3 3 3 3 3 3 3 1 1 3 3 1 3 3 1 1 3 3 3 3 3 1 3 2 2 2 2 2 2 2 2 2 2 3 2 3 3 1 2 2 2 2 2 Confounders Blinding 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Study design 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 bias Selection Selection 34 27 13 41 9 35 11 28 33 38 12 39 40 37 31 36 10 32 14 17 30 26 6 29 Study Nagamatsu et al., 2016 et al., Nagamatsu Neimann et al., 2014 Neimann et al., 2015 et al., Best Nocera et al., 2016 et al., Nocera Demiracka et al., 2015 et al., Demiracka 2018 et al., Suwabe Oliveira et al., 2019 et al., Oliveira Church et al., 2016 et al., Church 2017 Hriv et al., Gregoire et al., 2019 et al., Gregoire 2018 J et al., Kim Marston et al., 2019 et al., Marston Vaughan et al., 2014 et al., Vaughan 2015 et al., Forti Magon et al., 2016 et al., Magon 2016 et al., Maddock Matura et al., 2017 et al., Matura Zschucke et al., 2014 et al., Zschucke 2014 et al., Tamura Wagner et al., 2017 et al., Wagner 2015 et al., Varma Rosano et al., 2017 et al., Rosano Kleemeyer et al., 2015 et al., Kleemeyer 2017 et al., Kim L Effective public healthcare practice quality assessment (quality assessment tool for quantitative studies). quantitative for quality assessment (quality tool practice public healthcare Effective 1. Table
Vorkapic C et al. The impact of exercise on brain health 541 Figure 3. PRISMA diagram showing the study extraction flow.
BDNF after acute exercise. In addition, the effect of an exer- types45,46. Rasmussen et al.47 and Tang et al.48 also observed cise session on BDNF levels was intensified by regular exer- effects that indicate that an acute exercise-induced increase cise. These authors explained that each episode of exercise in pBDNF is stable in response to different exercise types and results in a “dose” of BDNF activity and that the magnitude protocols. According to the evidence reviewed here, moder- of this “dose” can be enhanced over time by regular exercise. ate-intensity multimodal exercises are more effective in pro- In the present review, most studies that found a correla- moting increases in peripheral levels of BDNF, although it is tion between physical exercise and increased plasma BDNF still not possible to draw definite conclusions or to estab- (pBDNF), used moderate to high-intensity exercise as part of lish recommendation protocols for the type and intensity of the main intervention. Unfortunately, several other studies exercises in a multimodal program that would be required in did not report the intensity level used. In the literature, other order to produce an increase in BDNF levels. Vedovelli et al.49, studies have also found that exercise-induced BDNF effects observed that a combined intervention for increased muscle in humans follow a dose-dependent relationship with regard strength and aerobic conditioning can increase BDNF lev- to duration and intensity of exercise, such that the best out- els, and that aerobic conditioning is at least partially respon- comes are linked to moderate exercise43. A recent review by sible for that improvement. These authors also stated that Knaepen et al.44 found that high intensities and graded exer- BDNF could be a key component of the beneficial effects cise tests elicited the greatest exercise-induced increases of physical activity on cognitive functioning, since this neu- in pBDNF concentration in healthy participants. In acute rotrophin can modulate neurogenesis, neuroplasticity and protocols, this increase has been shown to last post-exer- neuronal survival. In addition, Vaughan et al.11, observed that cise, to some extent. Another interesting fact is that many human studies had found that motor fitness (balance, flex- of the studies reviewed here not only used aerobic exercise, ibility, co-ordination, agility and reaction time ability) was but also used multimodal protocols, resistance training and associated with brain activation patterns that differed from coordinative exercises (S2, S4, S5 and S22). Accordingly, there those related to cardiovascular fitness. Motor fitness training is evidence that increases in pBDNF concentrations can be entails complexity that requires sustained attention and con- observed in response to a variety of exercise protocols and centration, thereby increasing the cognitive load and evoking
542 Arq Neuropsiquiatr 2021;79(6):536-550 Continue... cantly higher 30 min cantly fi cantly elevated after both high- both after elevated cantly fi Outcomes tivity alterations occurred between the visual between occurred tivity alterations ystemic levels of serum mBDNF and tBDNF were not not were and tBDNF mBDNF serum of levels ystemic rst exercise session and 30 min after the last exercise exercise the last session and 30 min after exercise rst elated changes in hippocampus volume may be may volume in hippocampus changes elated fi ffects persisted at 2-year follow-up, relative to balance- to relative follow-up, 2-year at persisted ffects cantly higher serum irisin and BDNF levels in the exercise exercise the in levels BDNF and irisin serum higher cantly response is signi is response fi correlation was observed between changes in BDNF BDNF in changes between observed was correlation e positive changes in fitness were associated with more with more associated were in fitness changes e positive pocampus volume was significantly increased in the increased significantly was pocampus volume um irisin and BDNF levels were signi were levels um irisin and BDNF y the mixed-low-resistance training program (high number (high program training the mixed-low-resistance y esistance training improves memory, reduces cortical reduces white memory, improves training esistance ll interventions resulted in improved cognitive functions but functions cognitive in improved resulted ll interventions raining to volitional fatigue might be necessary to obtain obtain be necessary to might fatigue volitional to raining Onl T Hip Mor Fitness-r of repetitions at a sufficiently high external resistance) was resistance) external high sufficiently a at repetitions of participants. male in older BDNF circulating increase to able results. optimal group. in the control but decreased group, exercise strength changes positive in tissue density and more changes positive in changes positive with more associated in tissue density were volume. in tissue density. changes about by brought Baseline s training. exercise by affected R These e matter atrophy and increases peak muscle power executive executive power peak muscle and increases atrophy matter with balance-and-toning. compared function, and-toning. after the after BDNF protocols. training and high-volume intensity A BDNF plasma in increase larger a induced intervention GMA the occur without could (cognition improvement concentration in BDNF). changes concomitant detectable No performances. and cognitive concentrations Signi found. were group than in the control group Ser session. cortex and parts of the superior parietal area (BA7). Premotor Premotor (BA7). and partsarea the superior parietal cortex of also affected. gyrus were and cingulate area Significant connec
1. 1. 1. 2. 2. 1. 1. 2. 1. 1. 2. 1. 2. 1. total) volume interest (rs-fMRI) and irisin cognition. mood and Functional Functional volume and volume Variables of of Variables connectivity connectivity (mature and (mature Serum BDNF BDNF Serum Brain volume, volume, Brain and cognition Plasma BDNF Plasma BDNF Plasma BDNF Plasma BDNF Hippocampus Hippocampus Hippocampus microstructure 8 weeks 8 weeks Plasma BDNF Duration 12 weeks Plasma BDNF 24 weeks 12 weeks 12 weeks 52 weeks 13 weeks 6 months min, 60 min 60 min, 60 min, 60 min, 3x/week 3x/week 2x/week 3x/week 4x/week 2x/week 3x/week 1x/week informed informed frequency Approx. 45 Approx. 2-3x/week 50-60 min, 25-55 min, Volume and Volume Duration not not Duration Duration not not Duration n/a Not Not high high high High Low- Low and Low vigorous informed Moderate Moderate Intensity of of Intensity Moderate to to Moderate Moderate to to Moderate intervention No No Not Not (HV) Rest Low- Low- (GMA). aerobic aerobic Control Control training Balance exercise intensity intensity intensity activities activities informed exercises condition Mixed low low Mixed resistance resistance and toning and toning intervention intervention Gross motor motor Gross high-volume high-volume training training training training (UBS-A) exercise exercise program High and exercises exercises Aquarobic Aquarobic strength + strength strength + strength + cognitive + cognitive Resistance Resistance upper body upper Lower body Lower Progressive Progressive (LBS-A) and (LBS-A) Coordination Coordination high-intensity high-intensity High-intensity High-intensity High-intensity power training power low resistance resistance low low-volume (HI) low-volume aerobic training training aerobic training aerobic aerobic exercise aerobic Strength training Strength n=20 n=21 n=56 n=34 n=21 n=26 n=52 n=47 n=155 Sample Intervention 13 10 37 28 29 26 17 30 6 Gregoire et al., et al., Gregoire 2019 (S5) 2018 J et al., Kim (S8) Study Kim L et al., 2017 et al., Kim L (S7) Church et al., et al., Church 2016 (S2) Demirakca et al., et al., Demirakca 2016 (S3) 2017 Hvid et al., (S6) et al., Kleemeyer 2015 (S9) Best et al., 2015 et al., Best (S1) Forti et al., 2015 et al., Forti (S4 Summary of the characteristics of the randomized controlled trials. controlled the randomized of the characteristics 2. Summary of Table
Vorkapic C et al. The impact of exercise on brain health 543 Continue... Outcomes f IFG (inferior frontal gyrus) activity showed gyrus)showed activity frontal (inferior f IFG erbal fluency) was improved in the aerobic exercise exercise in the aerobic was improved erbal fluency) ysis did not reveal morphological or functional or functional morphological reveal did not ysis oad or moderate-load resistance training twice per week twice per week training resistance oad or moderate-load eduction was associated with weight loss and improved and improved loss with weight associated was eduction th groups, no differences were observed in the putamen observed were no differences th groups, esults are consistent with an exercise-induced expansion expansion with an exercise-induced consistent esults are dination training increased caudate and globus pallidus and globus caudate increased training dination ffect of training was seen on cerebral N-acetyl aspartate or aspartate N-acetyl seen on cerebral was training of ffect ebral choline concentrations remained stable in the exercise in the exercise stable remained concentrations choline ebral tor fitness but not cardiovascular fitness was positively was positively fitness cardiovascular fitness but not tor wever, those who declined in mobility levels significantly significantly those who declined in mobility levels wever, wever, subsequent analysis in subjects with improved slackline with improved in subjects subsequent analysis wever, esults showed that glutamate and GABA signals increased signals increased and GABA glutamate that esults showed plasma AEA levels. reduces exercise aerobic moderate egular Cer group. in the control increasing while group, No e in cortical in response GM volume and no changes levels BDNF in the concentrations choline Stable 3. exercise. aerobic to of effect a neuroprotective indicate might group intervention exercise. aerobic High-l for 12 for or factors growth on peripheral has no effect weeks adults. middle-aged late in healthy homocysteine In bo in mobility. change of regardless volume Ho decreased in left putamen volume. in left decreased R In addition, exercise. following in the visual cortex significantly in the exercise following in glutamate an increase was there cortex. cingulate anterior The r and GABA. the cortical glutamate of pools of Cognition (v with controls. compared group, fMRI comparisons o in the the intervention following IFG in the right activity lower with controls. compared group, aerobic R This r anger. reduced in particular, mood, connectivity differences before or after the training between between training the after or before differences connectivity groups. and control the intervention the between connectivity of decrease a showed performance which period, during the training areas brain and other striatum network. striatal of the efficiency means an increased MRI anal Ho Mo pallidus. the putamen and globus of with the volume related Coor volume.
1. 2. 1. 2. 1. 1. 2. 2. 1. 2. 1. 2. 1. 2. 1. (MRI) Brain Brain tasks (MRS) weight growth growth volume volume Plasma Cortical interest and body Peripheral Peripheral Functional Functional factors and factors gray matter matter gray GABA levels levels GABA (AEA), mood (AEA), Variables of of Variables connectivity Mobility and metabolism, metabolism, (GM) volume (GM) volume anandamide Brain activity activity Brain homocysteine and cognition. Basa ganglion basal ganglion glutamate and glutamate during cognitive during cognitive 6 weeks Duration 12 weeks 12 weeks 12 weeks 12 weeks 12 months 12 months 40 min, 30 min, 40 min, 90 min, 2x/week 1x/week 3x/week 3x/week 3x/week 3x/week 3x/week informed frequency 20-45 min, 45-60 min, Volume and Volume Duration not not Duration n/a high vigorous Vigorous 30 min Acute Moderate Moderate Intensity of of Intensity Moderate to to Moderate Moderate to to Moderate intervention No and Rest Toning Toning Control Control Balance Sessions exercises exercises condition relaxation Stretching Stretching Educational intervention training training training training Slackline Slackline High-load High-load resistance resistance resistance training and training moderate-load moderate-load Aerobic exercise exercise Aerobic and coordination and coordination n=38 exercise Aerobic n=53 exercise Aerobic list Waiting Moderate n=28 n=92 n=32 exercise Aerobic n=34 exercise Aerobic list Waiting Moderate n=45 n=101 exercise Aerobic Sample Intervention 9 31 32 33 34 35 36 37 Magon et al., et al., Magon 2016 (S12) Study Nagamatsu et al., et al., Nagamatsu 2016 (S14) Neimann et al., Neimann et al., 2014 (S15) Matura et al., et al., Matura 2017 (S11) et al., Oliveira 2019 (S17) Maddock et al., et al., Maddock 2016 (S10) Marston et al., et al., Marston 2019 (S13) Nocera et al., et al., Nocera 2017 (S16) Table 2. Continuation. Table
544 Arq Neuropsiquiatr 2021;79(6):536-550 tness fi cant preservation of of cant preservation fi cant improvements in cant improvements fi tness improvement and increased and increased tness improvement fi Outcomes e correlation between the degree of of the degree between e correlation bilateral hippocampus activity and lower prefrontal prefrontal lower and activity hippocampus bilateral relationships were specific to hippocampus volume, volume, hippocampus to specific were relationships xercise group showed signi showed group xercise ease in glutamate-glutamine levels was observed in the observed was levels ease in glutamate-glutamine xercise program resulted in neurocognitive and physical and physical in neurocognitive resulted program xercise magnitude of the enhanced functional connectivity connectivity functional enhanced the of magnitude oimaging analysis revealed the signi revealed oimaging analysis ongitudinal changes in attentional shift and memory were shift and memory were in attentional ongitudinal changes eased volume of the left hippocampus, left cornu ammonis left hippocampus, the left of eased volume eases in BDNF levels imply neurogenesis may be a may neurogenesis imply levels eases in BDNF olume decrease of about 2% of the hippocampus was was the hippocampus about 2% of of olume decrease single 10-min bout of exercise increased functional functional increased exercise of bout 10-min single greater amount, duration, and frequency of total daily walking walking daily total of frequency and duration, amount, greater articipants of the aerobic group showed a significantly a significantly showed group articipants the aerobic of connectivity between hippocampus DG/CA3 and cortical DG/CA3 hippocampus between connectivity regions. Incr group. in the intervention hippocampus and right cortex (PFC) activity was observed in the aerobic group. in the aerobic observed was activity (PFC) cortex P inversely was which MIST, the to cortisol response reduced amylase and cortisol exercise-induced the previous to related fluctuations. Higher A The memory improvement. of the extent predicted A volume hippocampus with larger associated each were activity men. but not women, among older These compared to the thalamus, used as a control brain region, region, brain used as a control the thalamus, to compared walking activity, low-intensity for significant and remained and activity vigorous-intensity to moderate independent of exercise self-reported The e plasma of levels and increased improvements performance with controls. compared women, in older BDNF, Incr underpinning the cognitive the mechanism component of with exercise. associated improvements A positiv found. was levels BDNF and increased improvement A v with correlated negatively α TNF- with increased correlated and positively levels; BDNF concentrations. A decr only. group in the exercise hippocampus anterior right The e shift. attentional Neur group. in the exercise volume prefrontal bilateral The l changes. volumetric with the prefrontal correlated positively
2. 1. 1. 2. 1. 1. 2. 2. 1. 1. 2. 3. 1. 2. 3. task volume volume volume, volume, interest cognition BDNF and BDNF Functional Functional aspartate). stress task stress glutamate/ glutamate/ Variables of of Variables connectivity connectivity and amylase (fMRI) during Brain volume volume Brain and cognition hippocampus hippocampus Hippocampus Hippocampus Hippocampus Hippocampus Hippocampus Hippocampus NAA (N-acetyl NAA (N-acetyl (MIST) cortisol (MIST) glutamine and Brain activation activation Brain during cognitive during cognitive Not Not 2 years 2 years 6 weeks Duration informed 16 weeks Not Not week 10 min Acute 10,000 10,000 60 min, 2x/week reported everyday threshold steps/day steps/day frequency 60 min, 3x/ 60 min, 10 min/day, Volume and Volume (pedometer) Not Not Low Low to to Low vigorous reported Moderate Moderate 30 min Acute Moderate Moderate Intensity of of Intensity intervention Not Not Not Not Not Rest Light Light Health Control Control informed informed informed exercises condition education stretching stretching Waiting list Waiting tness) fi exercise exercise program (walking) Multimodal strength and strength motor motor (cardiovascular, (cardiovascular, Aerobic exercise exercise Aerobic n=36 exercise Aerobic n=27 exercise Aerobic n=92 n=34 exercise Aerobic n=49 n=40 exercise Aerobic n=110 Calisthenics Sample Intervention 38 39 40 11 12 41 14 Varma et al 2015 et Varma (S21) Tamura et al., et al., Tamura 2014 (S19) Vaughan et al., et al., Vaughan 2014 (S22) Study Wagner et al., et al., Wagner 2015 (S23) Zschucke et al., et al., Zschucke 2014 (S24) Suwabe et al., et al., Suwabe 2018 (S18) Rosano et al., et al., Rosano 2017 (S20) Table 2. Continuation. Table
Vorkapic C et al. The impact of exercise on brain health 545 positive neuroplasticity. Although promising, a greater num- exercise-induced brain lactate levels in humans is difficult, ber of studies, with larger samples and less methodological these results were also observed in S10. biases, are needed in order to better elucidate the relation- Another study analyzed in this review (S23) provided inter- ship between BDNF and multimodal exercise. esting results: a decrease in glutamate-glutamine levels in the In the present review, one study (S17) observed a nega- right anterior hippocampus in the exercise group that seemed tive correlation between moderate regular exercise and to be correlated with a volume decrease in the hippocampus decreased peripheral anandamide levels (AEA). It was also of about 2%. The authors of that study stated that the observed observed that this reduction was associated with weight loss volume changes were not a consequence of a neuronal loss and improved mood. Other data corroborate these findings. in the right hippocampus, but rather, resulted from potential In a study by Matias et al.50, salivary AEA levels were posi- changes in gliogenesis and/or fiber organization. Astroglia are tively correlated with body mass index, waist circumference actively involved in the uptake, metabolism and recycling of and fasting insulin levels. Preclinical studies have also indi- glutamate, and the glutamate-glutamine cycle between neu- cated that AEA has a negative effect on peripheral metabo- rons and glia is a major metabolic pathway that reflects the lism by impairing insulin signaling and mitochondrial func- synaptic release of glutamate. Therefore, changes in gluta- tion51. Although acute aerobic exercise has been shown to mate metabolism might be linked indirectly to the observed increase circulating AEA50, Gasperi et al.52 found increased structural changes, in particular those of glial morphology59. upregulation and activity of resting fatty acid amide hydro- Further investigations regarding changes in peripheral and lase (FAAH) — a major enzyme responsible for AEA break- central neurotransmitter levels after exercise in humans are down — in the lymphocytes of physically active young men, necessary to better elucidate related mechanisms. compared with sedentary young men. The observed lower Two studies in this review observed increases in func- circulating AEA levels associated with improved mood, how- tional connectivity as a consequence of acute aerobic (S18) ever, seems to contradict the current understanding of the and long-term coordinative exercise (S3). One long-term relationship between exercise-related mood enhancement study found that resistance exercise reduced white mat- and endocannabinoids53,54. Several studies have indicated ter atrophy (S1) and a 12-week study found no differences that endocannabinoids have stress-buffering, anxiolytic and in gray matter volume in the aerobic exercise group, com- antidepressant effects via CB1 receptors55. On the other hand, pared with the control (S11). Most of these results were Antunes et al.56 showed that reduced resting plasma AEA in congruent with other studies in the literature that showed exercise-addicted runners was accompanied by higher nega- alterations in white matter and connectivity as a result of tive mood scores. Such discrepancies might be due to the dis- exercise. Colcombe et al.60 reported an anterior cluster of tinct effects of acute versus chronic exercise, measures used increased white matter after six months of exercise, in a during exercise versus resting conditions and heterogeneity group of elderly adults. Indeed, investigators have been wit- among the samples. Endocannabinoid responses to acute nessing significant advancements in the ability to study the and chronic exercise among healthy people deserve further connectivity between brain areas embodied by white mat- investigation. ter (see Smith et al.61 for review). One recent study62 found In this review, two studies observed the effects of acute a correlation between white matter integrity and changes in
and regular physical exercise on other neurotransmitters. VO2 max scores in frontal and temporal white matter tracts. One study (S10) found that acute exercise increases the levels Interestingly, the change in white matter integrity for the of GABA and glutamate in the anterior cingulate and visual aerobic training group did not significantly differ from that cortices. During acute aerobic exercise, in the process of aer- of a control group that participated in one year of non-aer- obic glycolysis, glucose is broken down to pyruvate, which obic exercise, thus suggesting that aspects other than aero- then further breaks down to lactate or lactic acid. When exer- bic exercise contributed to the observed change. Voss et al.63 cise transitions from an aerobic to an anaerobic nature, the also observed that differences in resting functional connec- “anaerobic threshold” is met. Beyond this point, lactic acido- tivity were associated with fitness level. The S3 study of this sis occurs. Lactate is able to cross the blood-brain barrier, but review specifically observed increased connectivity in brain is independently made by astrocytes in the brain, where it areas associated with the default mode network (DMN), such serves as a precursor of glutamate. Glutamate is then taken as the anterior cingulate cortex and the prefrontal cortex, in up by astrocytes and converted to glutamine in the gluta- the intervention group. These brain regions show a decrease mate-glutamine cycle57. Two recent studies used proton in activity when external processing demands are increased. magnetic resonance spectroscopy (H1MRS) to investigate Voss et al.63 demonstrated that some of the functional con- brain-level changes in lactate, glutamate and glutamine58 nections within the DMN exhibit a positive correlation with
and revealed that lactate, glutamate and glutamine levels VO2 max score and spatial memory. transiently increased by approximately 20% in the human Even though these are promising results, it remains nec- cortex. Acute exercise has been known to increase peripheral essary for future research to test whether there is specificity lactate levels and, even though direct quantification of acute in exercise training-induced plasticity of brain networks.
546 Arq Neuropsiquiatr 2021;79(6):536-550 With regard to structural changes, all the studies found (dorsal putamen) and output structure (globus pallidus) of significant changes in the volume of the basal ganglia and the the basal ganglion nuclei. Coordination training, which con- hippocampus. Three studies found that moderate to vigor- stantly requires adapting to new tasks, can be very similar ous aerobic activity was associated with a greater increase in to the early stages of motor learning, and is consequently hippocampus volume (S9, S20 and S21). These results are in associated with improvements in performance and activa- agreement with those from other studies in the current liter- tion of the striatum71,72. Therefore, it can be assumed that the ature that correlated exercise with structural changes in hip- observed volume increase found in the basal ganglia among pocampus volume and vasculature64. Erikson et al.65 showed subjects who attended the coordination training resulted in 73 that subjects with higher VO2 max scores had larger hip- experience-dependent plasticity . Another study in the lit- pocampus volumes than those with lower VO2 max scores. erature found an association between cardiovascular fitness Erickson et al.66 showed a correlation between the volume of and caudate volume74 but, based on the functions of the basal the hippocampus and cardiovascular fitness in older adults. ganglia, it seems reasonable to assume that the association A follow-up study64 demonstrated that long-term aerobic between motor fitness and basal ganglion volume might be exercise increased the volume of the hippocampus by 2% higher than the one between cardiovascular fitness and basal in elderly adults, while controls who underwent one year of ganglion volume. Much research is still needed in order to stretching exercises exhibited a 1.4% decrease in hippocam- elucidate this association. Different tools for statistical anal- pus volume. Similarly, Pajonk et al.67 reported that there was a yses, basal ganglion volume determinations, numbers of 12–16% increase in hippocampus size in a small group of exer- samples and intervention characteristics need to be taken cising schizophrenic patients, as well as in matched controls. into consideration. Interestingly, one study in this review that used strength In conclusion, studying the effects of physical exercise training also observed greater hippocampus volume (S7). on brain structure and neurochemistry is still recent. While The effects of resistance training on other neuroplastic fac- robust animal research protocols have demonstrated that tors, such as neurogenesis or BDNF level, are not clear yet68,69, aerobic exercise is a powerful modulator of structural brain but these results suggest that the improved communication plasticity, human trials have primarily focused on neuro- between muscle fibers and the brain, as a result of strength imaging and cognitive studies, and have yielded conflicting training, may serve a protective role in slowing down age- results. The lack of methodological accuracy and the use of related declines in hippocampus volume70. However, further different types of exercise, frequency, intensity and duration studies are needed to confirm the mechanism of variations in hinders the meaning of results. Even though this short review hippocampus volume according to the type of exercise. found that exercise improves brain plasticity in humans, par- With regard to basal ganglia, one study (S14) found no ticularly through changes in BDNF, functional connectivity, differences in putamen volume in the intervention group, basal ganglia and the hippocampus, many unanswered ques- after 12 weeks of aerobic exercise. However, the authors of tions remain. Therefore, future studies in humans are needed that study observed that individuals with significant declines in order to demonstrate the full potential of physical exercise in mobility levels also showed decreases in left putamen vol- (or movement in general) among healthy individuals and as a ume. Another study (S15) showed increased caudate and therapeutic strategy to remediate a variety of mental and neu- globus pallidus volume in subjects who underwent a coor- rological diseases or to lessen the burden of cognitive decline dinative training. Indeed, better motor fitness goes together associated with aging. It is hoped that future studies correlat- with more frequent execution of motor-demanding exer- ing basic research with psychological variables and imaging cise, thus resulting in more frequent stimulation of the studies may better elucidate the mechanisms through which corresponding sensorimotor (dorsal) part of the striatum physical exercise improves brain health in humans.
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550 Arq Neuropsiquiatr 2021;79(6):536-550 bhttps://doi.org/10.1590/0004-282X-ANP-2020-0288 HISTORICAL NOTE
“Estrutura da Celula Nervoza”, by Bruno Lobo and Gaspar Vianna (1908): a pioneering work on Brazilian Neuroscience “Estrutura da Celula Nervoza”, de Bruno Lobo e Gaspar Vianna (1908): uma obra pioneira na Neurociência brasileira Bruno Lopes SANTOS-LOBATO1, José Eymard Homem PITTELLA2
ABSTRACT Currently, the scientific production in Neuroscience in Brazil is very rich, but, historically, it has been scarce at first. The aim of this study is to present the work “Estrutura da Celula Nervoza”, by Bruno Lobo and Gaspar Vianna (1908), as a pioneering work for Brazilian science. Keywords: Neurosciences; Brazil; History.
RESUMO Atualmente, a Neurociência brasileira demonstra uma pujante produção científica, porém os relatos das primeiras publicações históricas dessa área do conhecimento no Brasil são escassos. O objetivo deste estudo é apresentar a obra “Estrutura da Celula Nervoza”, de Bruno Lobo e Gaspar Vianna (1908), como uma obra pioneira para a ciência brasileira. Palavras-chave: Neurociências; Brasil; História.
INTRODUCTION
In late 19th century and early 20th century, there were advances in histological techniques for the study of the nervous system. In Europe, many works on histol- ogy and organization of the nervous system were pub- lished, and the monumental work by Santiago Ramon y Cajal, published between 1899 to 1904, is a milestone1. In parallel, a 154-page morphological study on the ner- vous tissue was published in Rio de Janeiro (1908) by the two young physicians born in Pará, Bruno Lobo (1884– 1945) (Figure 1A), director of the Anatomopathological Laboratory of Hospício Nacional de Alienados (and future Figure 1. The authors of “Estrutura da Celula Nervoza” (1908). director of the Brazilian National Museum between (A) Bruno Álvares da Silva Lobo (1884–1945), former director of the Brazilian National Museum, between 1915 and 1923. (B) 1915 and 1923), and Gaspar Vianna (1885–1914) Gaspar de Oliveira Vianna (1885–1914) at Instituto Osvaldo Cruz. (Figure 1B), his laboratory assistant (who would be known afterwards as one of the greatest figures in Medicine and (1873–1933) and Eduardo Chapot Prevost (1864–1907). Science in Brazil due to his contributions to the treatment of Their objective was to enlighten about the structure of ner- leishmaniasis and Chagas’ disease)2,3. Both were directly influ- vous system elements, and the text was focused in present- enced by the works of renowned physicians Juliano Moreira ing state of the art description of the structure of the nervous
1Universidade Federal do Pará, Instituto de Ciências da Saúde, Faculdade de Medicina, Belém PA, Brazil. 2Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Anatomia Patológica e Medicina Legal, Belo Horizonte MG, Brazil. Bruno Lopes SANTOS-LOBATO https://orcid.org/0000-0001-9321-5710; José Eymard Homem PITTELLA https://orcid.org/0000-0002-6244-9781 Correspondence: Bruno Lopes Santos-Lobato; E-mail: [email protected]. Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: Both authors contributed with the conception and organization of the manuscript. Both authors wrote and critically evaluated the first draft of the manuscript. Both authors approved the final version of the manuscript for submission. Received on June 18, 2020; Received in its final form on August 25, 2020; Accepted on November 09, 2020
551 system in Portuguese. Here, we aim to discuss the relevance (“delgadas anastomozes”) to better establish relations and of the work “Estrutura da Celula Nervoza” (Structure of the facilitate their function, which is close to the functional con- nervous cell) (Figure 2) for Neuroscience in Brazil. cept of synapse by Sherrington5. The book was divided in an introduction and five sec- tions: origin and development, generalities, cell body, pro- toplasmic extensions, and axons and their sheats (“Orijem ORIGIN AND DEVELOPMENT e Desenvolvimento”, “Generalidades”, “Corpo Celular”, “Prolongamentos Protoplasmáticos” and “Cilindro-eixo e seus Through the description of neuroblasts in the nervous envolucros”). It is richly illustrated, with original microphoto- system of animals, the authors argued that these were precur- graphs and schematic images from other authors. Many sci- sors of nerve cells in adult animals, reinforcing their support entists who published their research on nervous tissue are on the neuron doctrine. They discussed the development of quoted, but Bruno Lobo and Gaspar Vianna do not list the the nerve cell processes such as the protoplasmic extensions references cited at the end of the book or the years the scien- (dendrites) and the axon (“cilindro-eixo”). They also com- tists cited published their investigations. We describe below mented on the origin of the distal end of the axon: if it origi- the sections of the book. nated from a local neuroblast or from an emigrated neuro- At the beginning of 20th century, there was a heated debate blast and differentiated in a Schwann cell. about the nature of the nervous tissue, whether it would be a single large network (reticular theory) or composed of sev- eral cells communicating with each other (neuron doctrine). GENERALITIES Iconic authors such as Joseph von Gerlach, Camillo Golgi and Franz Nissl defended the reticular theory, and their positions In this session, the authors commented on the morpho- were criticized by Lobo and Vianna, which were in favor of logical classification of the nerve cells as proposed by Cajal. the neuron doctrine proposed by Cajal4. Regarding the pos- They pointed out the great variability of dimensions and sible mechanism of communication between nervous cells, shapes of the cell body and its extensions in comparison to Lobo and Vianna admit the existence of thin anastomoses other cell types of the organism.
CELL BODY
This is the main session of the book. Even being a morpho- logical study, Lobo and Vianna tried to suggest the function of some organelles. For example, the authors speculated that the “microzoma” (actually, mitochondria, not rough endoplas- mic reticulum) of nerve cells would have no important func- tion in cell biology, with a rather secondary function with minor importance (or, in their words, “de função secundaria e de somenos importancia”). They also address the “granulações de Nissl” (known as Nissl substance and corresponding to the rough endoplasmic reticulum at the electron microscopy) as a differentiation of the protoplasm, with functions related to the functional and nutritious energy of the element (“enerjia funcional e nutritiva do elemento”). Currently, we know that the rough endoplasmic reticulum is essential for protein synthe- sis. The authors correctly described the presence of a natural brown pigmentation in some nuclei of the brainstem, includ- ing the substantia nigra, and correctly suggested it was mela- nin, which gradually increases until the individual’s complete development. Also, they commented on the recent and excit- ing discovery of neurofibrils, whose proposed function was to transmit the nervous influx (“transmitir o influxo nervozo”), and how pathological states (such as intoxications and infections) could alter the structure of neurofibrils. It is known, nowadays, Figure 2. Front page of “Estrutura da Celula Nervoza” (1908), that the neurofibrils are actually aggregates of microtubules reproduced from Opera Omnia de Gaspar Vianna, 1962. and neurofilaments responsible for axonal transport.
552 Arq Neuropsiquiatr 2021;79(6):551-553 PROTOPLASMIC EXTENSIONS microscope. It was only later on, between 1919 and 1921, that the Spaniard neuroscientist Pío del Río Hortega (1882–1945) Dendrites were confirmed as extensions of the protoplasm discovered the oligodendrocyte, responsible for the synthesis by the authors. They commented on small extensions originated of myelin in the central nervous system. from dendrites, called by various names at the time, including Unfortunately, the pioneering initiative of Bruno Lobo the term “spine” (“espinho”), without a known function. and Gaspar Vianna to publish a work with the most mod- ern discoveries about the morphology of the nervous system in Portuguese and in books or booklets with low circulation AXONS AND THEIR SHEATHS went unnoticed by the national and international scien- tific community. Furthermore, they were young research- Lobo and Vianna reviewed the current conceptions about ers (both were younger than 30 years old) from a country the axon and the double lipid-protein nature of myelin pro- without tradition in neurological research. At the best of our tein, including a specialized structure called “estrangulamento knowledge, there were no similar works in Brazil before 1908. anular de Ranvier” (currently known as node of Ranvier), and After 1908, “Estrutura da Celula Nervoza” was inserted in a suggested a physical contact between myelin borders. About collection published in 1962, comprising all scientific works Schwann cells, the authors agreed with Ranvier’s opinion by Vianna’s, being the main source for consulting the original that the Schwann cell produces myelin, disagreeing with full document nowadays6. We hope the work and life of Lobo Kölliker and Cajal, who stated that it originated from the and Vianna can be an inspiration for modern generations of axon. They also argued that, in the central nervous system, medical scientists. due to the absence of the Schwann cell, myelin may have a different origin from the myelinated fiber of the peripheral nervous system. At that time, Cajal admitted the existence of ACKNOWLEDGMENTS Schwann cells in the central nervous system, claiming that they were very delicate, requiring the use of elective staining We thank Dr. José Maria de Castro Abreu Júnior for methods and high magnification to identify them under the reviewing the manuscript.
References
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Santos-Lobato BL et al. History of Brazilian neuroscience 553 https://doi.org/10.1590/0004-282X-ANP-2020-0479 HISTORICAL NOTE
Probable first report of a motor deafferentation syndrome in the Paraguayan War Provável primeiro relato de uma síndrome de desaferentação motora na Guerra do Paraguai Marleide da Mota GOMES1,2, Marcos Raimundo Gomes de FREITAS3
ABSTRACT The Paraguayan War ended 150 years ago. Back then, there were outbreaks of combatants’ limb weakness and tingling related to “palustrian cachexia”, not clearly funded at the time on nutritional deficiency, the use of native flora to feed troops, and alcoholism. We report a case of a soldier with ascending paralysis, mental confusion and finally tetraplegia with preserved oculomotricity. This would probably be a case of locked-in syndrome (LIS) due to Gayet-Wernicke’s encephalopathy consequent to thiamine deficiency. The role of thiamine in the peripheral or central nervous system expression was shown decades later to be related to poor diet, or use of foods containing thiaminase or thiamine antagonists, worsened by the fact that the bodily stores of thiamine are restricted, and deficits may grow fast. Keywords: Beriberi; Polyneuropathy; Brain Diseases; Myelinolysis, Central Pontine; Thiamine Deficiency; Locked-in Syndrome.
RESUMO A Guerra do Paraguai terminou há 150 anos. Houve surtos de fraqueza dos membros dos combatentes e parestesias relacionadas à “caquexia palustre”, não claramente fundamentados na época sobre deficiência nutricional, o uso da flora nativa para alimentar as tropas e o alcoolismo. Referimo-nos a um caso de um militar com paralisia ascendente, confusão mental e finalmente tetraplegia com oculomotricidade preservada. Esse relato seria provavelmente devido a um caso de “síndrome do encarceramento” secundário à encefalopatia de Gayet-Wernicke consequente à deficiência de tiamina. O papel da tiamina na expressão periférica ou do SNC foi previsto décadas mais tarde em relação a uma dieta pobre, ou ao uso de alimentos contendo tiamina ou antagonistas da tiamina, agravado pelo fato de que as reservas corporais de tiamina são restritas, e os déficits podem se manifestar rapidamente. Palavras-chave: Beriberi; Polineuropatias; Encefalopatias; Mielinólise Central da Ponte; Deficiência de Tiamina; Síndrome do Encarceramento.
The locked-in syndrome (LIS), also known as motor deaf- ascending paralysis, mental confusion, followed by an appar- ferentation syndrome, is a rare neurological disorder that ent lucidity associated with quadriplegia (Box 1). was first described by Plum and Posner1 in 1966, and which is Before discussing this case, we must remember that the characterized by quadriplegia and anarthria with preserved Paraguayan War ended 150 years ago, and it occurred mostly in consciousness. The syndrome was considered to have many the extreme southwest of Brazil and in Paraguay. Consequently, etiologies (Figure 1). military logistics deficiency led the troops to severe food depri- We emphasize some aspects of a historical vignette vation and related scenarios, as the one here presented. that looks like a LIS description. This is a very pecu- At this wartime, outbreaks of combatants’ limb weakness liar clinical picture described by an academic aristocrat with particular features such as tingling occurred. This was of the Brazilian Army, the author of Memorias2: Alfredo supposedly due to “palustrian causes”. However, there was a Maria Adriano d’Escragnolle Taunay, visconde de Taunay shortage of supply, poor environmental conditions, and diar- (Figure 2). Taunay was also a writer, musician, teacher, mili- rheal diseases, besides reports of native flora being used to feed tary engineer, politician, historian and Brazilian sociologist. troops and alcoholism. There were also accounts on the death He reports the case of a Brazilian soldier who presented an of horses with symptoms similar to that of combatants2,3,4.
1Universidade Federal do Rio de Janeiro, Instituto de Neurologia, Rio de Janeiro RJ, Brazil. 2Universidade Federal do Rio de Janeiro, Instituto de Psiquiatria, Laboratório de História da Psiquiatria, Neurologia e Saúde Mental, Rio de Janeiro RJ, Brazil. 3Universidade Federal Fluminense, Rio de Janeiro RJ, Brazil. Marleide da Mota GOMES https://orcid.org/0000-0001-8889-2573; Marcos Raimundo Gomes de FREITAS https://orcid.org/0000-0001-7747-0287 Correspondence: Marcos Raimundo Gomes de Freitas; E-mail: [email protected] Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: MMG: collected references and worked on the first draft of the paper. MRGF: revised it critically for important intellectual content. The final approval of the version to be published was made by both authors. Received on October 09, 2020; Received in its final form on November 10, 2020; Accepted on November 30, 2020.
554 At that time, Science did not have all the critical clinical literature that sheds light on an underestimated part of the elements to establish the diagnosis of thiamine deficiency history of Neurology in wartime. due to inadequate intake, food with anti-thiamine factors, This soldier, apparently with delirious and rapidly evolv- or alcoholism, besides rare genetic cases5. Regardless of the ing tetraparesis, but with the maintenance of eye move- underlying cause, thiamine deficits may have severe detri- ments, may have had a LIS. This syndrome is linked to several mental effects, with most of the symptoms manifesting at etiologies; it can stem from basilar artery occlusion by stroke, the neurological level5. However, far from the war front, Silva Gayet-Wernicke encephalopathy (GWE) with central pontine Lima was studying beriberi6. He had already identified, then, myelinolysis (CPM) due to thiamine deficiency, a form of dry similarities between cases he assisted and the war cases7. beriberi, and the Guillain-Barré syndrome (GBS). We scrutinized the Brazilian troop neuropathic outbreaks About 82% of patients with GWE present with delir- considering several scenarios in this study, but mainly this ium, as reported by Osiezagha et al.8 based on a case series peculiar case. This would be one of the first reported in the of autopsies. As for the LIS, it is expressed by sustained eye- lid opening, preserved necessary cognitive abilities, severe aphonia or hypophonia, quadriplegia or quadriparesis, and a
Source: digital collection of Fundação Biblioteca Nacional. Figure 1. Motor deafferentation syndrome etiologies9, including the central pontine-myelinolysis and the Gayet- Wernicke encephalopathy caused by thiamine deficiency reported in the Paraguayan War as a hypothesis, and, in Source: Reproduction of original picture by Louis Auguste Moreau (public domain). the backgroung, original photo at the church Tuyu Cué Figure 2. Alfredo d’Escragnolle Taunay, Visconde de Taunay (Neembucu, Paraguai) serving in the Brazilian Infirmary. (1843–1899).
Box 1. Case reported by Alfredo d’Escragnolle Taunay, published posthumously2, and probably one of the first cases of Locked-in syndrome (LIS) in the literature
“You cannot imagine what I am suffering. It is a pain of agony, nor is there any other that is comparable to it. Death is rising! See how cold and immobile feet and legs are”. And, in fact, as he spoke, their limbs were stiffened. “Now, it’s the arms!” And he stood with them straight, as if they were made of stone. […] If you shut up, it was for a short time; the moans and cries started again [...]
At last, he stopped, but when paralysis caught his tongue and lips. And he was stretched out, stiff and immobile, on the death cot […] like a marble statue of those who sleep in the tombs of the Middle Ages. Only his eyes swam in his orbits, still indicating life and horrible anxieties, as tears flowed from them, which wet the pillow. The unfortunate remained for a day and a half until he exhaled his last breath at one o’clock on Jul 26, 1866”.
Gomes MM et al. Deafferentation syndrome 555 primary mode of communication that uses vertical or lateral this discussed case: “Toxic effects were soon noticed in individ- eye movement, or upper eyelid blinking9. uals given large doses for long periods [...] They had troubling Regarding the progressive ascending motor paralysis of neurologic symptoms, such as arm and facial tremors, hypore- the reported case, the GBS should also be considered. This is flexia, weakness, ataxia, and erethism [...]”13. an immune-mediated disease of peripheral nerves and nerve In any case, considering the immobility emphasized by roots that is often activated by infections, which is very com- the writer, and the significant probability of diagnosis related mon in wartime10. The progressive phase of GBS usually lasts to the high prevalence of thiamine deficiency, the most likely from two days to four weeks. Consequently, in patients who diagnosis for the reported case would be GWE with CPM, less reach maximum disability within 24 hours after the onset likely GBS. Coincidently, GBS was first described in the World of the disease, as supposedly occurred in the reported case, War I by Georges Guillain, Jean Alexandre Barré, and André alternative diagnoses should be contemplated. Likewise, Strohl when they witnessed (1916) two similar cases of sol- diagnoses related to altered consciousness may be consid- diers who had partial paralysis with significant impairment ered — except Bickerstaff ’s brain stem encephalitis, a variant of reflexes with spontaneous regression14. However, both of GS with the involvement of cranial nerves. GWE with CPM and GBS have some characteristics of motor Besides, a peripheral disconnection syndrome, which can deafferentation syndrome or LIS that may encompass many occur with GBS and severe post-infection polyneuropathy, etiologies (Figure 2). would include an external ophthalmoplegia, apparently not This case report is similar to that of Alexandre Dumas in present in the reported case9. “The Count of Monte Cristo” (1844), who was “a corpse with In contrast, dry beriberi may mimic the most common living eyes”, and one by Emile Zola, in his novel “Thérèse form of GBS, and polyneuropathy secondary to thiamine Raquin” (1868)9. However, the first case of unmoving physi- deficiency may develop gradually over weeks to months, but cal body, a deafferented patient, in medical literature was also acutely, and consequently may be confused with GBS10. described by Darolles (1875)9. Consequently, the case wit- This polyneuritis can also be associated with GWE by thia- nessed by Taunay in 1866 and only later on published would mine deficiency, as presented by Shible et al.11. be one of the first to recognize the LIS in its initial phase. Regarding the reported manifestations of irritability, rest- This detailed historical research can be useful, as one can lessness, and complaint of intense suffering, with a note about learn from the past. The description by Taunay leads us to stiffness (muscle spasms?), generalized tetanus should also be believe we are addressing LIS or motor deafferentation syn- examined12. Once again, a comment on the report “[...] After all, drome due to thiamine deficiency. It is more likely to happen the doctor reminded him to give him calomel”. In fact, mer- in adverse conditions such as war and in the early phase of cury compounds, like calomel, were used in medicinal prepa- LIS, since its diagnosis is usually only noticed later by atten- rations in the past. However, this toxic cause is less likely for tive caregivers.
References
1. Plum F, Posner JB. The diagnosis of stupor and coma. 4. ed. 9. Laureys S, Pellas F, Van Eeckhout P, Ghorbel S, Schnakers C, Perrin Philadelphia: Oxford University Press; 2007. F, et al. The locked-in syndrome: what is it like to be conscious but 2. Taunay AE. Memórias do Visconde de Taunay. São Paulo: paralyzed and voiceless? Prog Brain Res. 2005;150:495-511. https:// Iluminuras; 2004. doi.org/10.1016/S0079-6123(05)50034-7 3. Taunay AE. La Retraite de Laguna. Paris: Librairie Plon E. Plon, 10. Leonhard SE, Mandarakas MR, Gondim FAA, Bateman K, Ferreira Nourrit et Cie, Imprimeurs-Éditeurs; 1891. MLB, Cornblath DR, et al. Diagnosis and management of Guillain- Barré syndrome in ten steps. Nat Rev Neurol. 2019 Nov;15(11):671- 4. Taunay AE. La Retraite de Laguna. Rio de Janeiro: Tipografia 83. https://doi.org/10.1038/s41582-019-0250-9 Nacional; 1871. 5. Dhir S, Tarasenko M, Napoli E, Giulivi C. Neurological, psychiatric, 11. Shible AA, Ramadurai D, Gergen D, Reynolds PM. Dry beriberi due and biochemical aspects of thiamine deficiency in children and to thiamine deficiency associated with peripheral neuropathy and adults. Front Psychiatry. 2019 Apr;10:207. https://doi.org/10.3389/ wernicke’s encephalopathy mimicking Guillain-Barré syndrome: fpsyt.2019.00207 a case report and review of the literature. Am J Case Rep. 2019 Mar;20:330-4. https://doi.org/10.12659/AJCR.914051 6. Silva Lima JF. Ensaio sobre o beriberi no Brazil. Salvador: Livrarias de JB Martin, Caulina EC e Viuva Lemos; 1872. 12. Sexton DJ, Thwait L. Tetanus. Literature review current through: Sep 2020. UpToDate [accessed on: October 5, 2020]. Available at: https:// 7. Silva Lima JF. Contribuição para a história de uma moléstia www.uptodate.com/contents/tetanus que reina atualmente na Bahia, sob a forma epidêmica e caracterizada por paralisia, edema e fraqueza geral. GMBahia. 13. Davis LE. Unregulated potions still cause mercury poisoning. West J 1866;1:110-3. Med. 2000 Jun;173(1):19. https://doi.org/10.1136/ewjm.173.1.19 8. Osiezagha K, Ali S, Freeman C, Barker NC, Jabeen S, Maitra S, 14. Gomes MM. French school and World War First: neurological et al. Thiamine deficiency and delirium. Innov Clin Neurosci. 2013 consequences of a frightening time. Arq Neuro-Psiquiatr. 2015 Apr;10(4):26-32. May;73(5):463-65. https://doi.org/10.1590/0004-282X20150031
556 Arq Neuropsiquiatr 2021;79(6):554-556 https://doi.org/10.1590/0004-282X-anp-2020-0394 IMAGES IN NEUROLOGY
Sentinel inflammatory demyelinating lesions preceding primary CNS lymphoma Lesões inflamatórias desmielinizantes sentinelas precedendo linfoma primário do SNC Danielle Mesquita TORRES1, Milena Sales PITOMBEIRA1, Igor Bessa SANTIAGO1, Gabriela Joca MARTINS1, Kellen Paiva FERMON1, Daniel Gurgel Fernandes TAVORA1, Fernanda Martins Maia CARVALHO1,2
A 29-year-old man presented with acute seizures and suggested a tumefactive inflammatory pattern (Figures 1D visual impairment. Brain magnetic resonance imaging (MRI) to 1H). New extensive cerebrospinal fluid (CSF) and showed multiple white matter T2-lesions with incomplete blood workup, including aquaporin-4-IgG, was unremark- peripheral enhancement (Figures 1A to 1C). Considering the able. Partial improvement was observed following IVMP. hypothesis of acute disseminated encephalomyelitis, intra- Six months later, after new weakness in the left arm along with venous methylprednisolone (IVMP) was administrated a new periventricular lesion (Figures 1I to 1L), a brain biopsy with full recovery. Two years later, he presented right-sided was performed. Histopathological analysis revealed primary weakness. MRI disclosed a new T2-lesion, and spectroscopy central nervous system (CNS) lymphoma (Figure 2)1,2,3.
Figure 1. Magnetic resonance imaging exams. (A-C): first magnetic resonance imaging performed on March 2016 indicated diffusion restriction on diffusion-weighted image (A), T2 hypersignal (B), and peripheral enhancement on post-contrast T1 sequences (C). D-H: Neuroimaging performed on July 2018 showed a new lesion with peripheral restricted diffusion on diffusion- weighted image (D), T2 hypersignal (E), thick annular enhancement (F), spectroscopy revealed Cho peak increase (G) and minimal relative cerebral blood volume map (rCBV) increase. (H). (I-L): Brain magnetic resonance imaging performed on January 2019 disclosed a new right periventricular lesion with diffusion restriction on diffusion-weighted image (I), mild T2 hyperintensity sequences (J), and homogeneous contrast enhancement (L).
1Hospital Geral de Fortaleza, Serviço de Neurologia, Fortaleza CE, Brazil. 2Universidade de Fortaleza, Programa de Pós Graduação em Ciências Médicas, Fortaleza CE, Brazil. Danielle Mesquita TORRES https://orcid.org/0000-0002-0940-2757; Milena Sales PITOMBEIRA https://orcid.org/0000-0002-3298-0264; Igor Bessa SANTIAGO https://orcid.org/0000-0002-6408-2186; Gabriela Joca MARTINS https://orcid.org/0000-0001-8063-1600; Kellen Paiva FERMON https://orcid.org/0000-0002-4251-6430; Daniel Gurgel Fernandes TAVORA https://orcid.org/0000-0002-0570-9815; Fernanda Martins Maia CARVALHO https://orcid.org/0000-0001-6548-7268 Correspondence: Milena Sales Pitombeira; E-mail: [email protected] Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: DT: literature review, manuscript and imaging preparation, IS: literature review, manuscript preparation; MSP, GJ, KF and FMM: manuscript supervision and revision. Received on September 4, 2020; Accepted on September 25, 2020.
557 Figure 2. Histopathological examination showed atypical lymphoid cell proliferation.
References
1. Mark DK, Deva S, Rudolph J, Castellani RE, Morales SG, Reichs ASK, monitoring. Biomed Res Int. 2018 Jun;2018:3606970. https://doi. Robert KS. Demyelination as a harbinger of lymphoma: a case report org/10.1155/2018/3606970 and review of primary central nervous system lymphoma preceded 3. Jian-Giang Lu, Cian O’Kelly, Safwat G, Derek E, Christopher P, by multifocal sentinel demyelination. BMC Neurol. 2016 May;16-72. Gregg B. Neuroinflammation preceding and accompanying central https://doi.org/10.1186/s12883-016-0596-1 nervous system lymphoma: case study and literature review. World 2. Chiavazza A, Pellerino F, Ferrio A, Cistaro R, Soffietti R, Rudà Neurosurg. 2016 Apr;88:692.e1-692.e8. https://doi.org/10.1016/j. R. Primary CNS lymphomas: challenges in diagnosis and wneu.2015.11.099
558 Arq Neuropsiquiatr 2021;79(6):557-558 https://doi.org/10.1590/0004-282X-ANP-2020-0341 IMAGES IN NEUROLOGY
Value of 3D-TOF MR angiography and 4D-dynamic contrast-enhanced MRI in the assessment of spontaneous posterior cavernous sinus dural arteriovenous fistula Valor da angiografia por ressonância magnética 3D-TOF e RM 4D-dinâmica pós-contraste na avaliação de fístula arteriovenosa espontânea do seio cavernoso Francisco Bermal CAPARROZ NETO1, Lucas Giansante ABUD1,2, Rafael Gouveia Gomes de OLIVEIRA2, Daniel Giansante ABUD3, Soraia Ramos Cabete FABIO4
A 46-year-old female patient presented symptoms of complete right oculomotor nerve palsy without propto- sis. Orbital magnetic resonance (MR) imaging showed no abnormalities (Figure1). 3D time-of-flight MR angiogra- phy revealed high signal intensity in the right cavernous sinus (Figure 2). This isolated finding has a 10–15% rate of false-positive in the diagnosis of dural arteriovenous fistula (DAVF)1. Additional 4D-dynamic contrast-enhanced MR angiography evidenced an early asymmetric enhancement of bilateral cavernous sinus, mainly on the right, draining downward through the inferior petrous sinus (Figure 3)2,3,4,5. Figure 2. 3D time-of-flight MR angiography (A) and the inverted window of this sequence (B) showed a subtle enlargement of the right cavernous sinus and parasellar high signals (arrowhead).
Figure 1. T1-weighted spin-eco (A and B), T2-weighted fat-saturated (A), and post-contrast T1-weighted (B) images from the orbital MR imaging showed no abnormalities. Of note, there are no signs of ocular proptosis or superior ophthalmic vein dilatation.
1Documenta, Hospital São Francisco, Departamento de Radiologia e Diagnóstico por Imagem, Ribeirão Preto SP, Brazil. 2MED Medicina Diagnóstica, Hospital São Lucas, Departamento de Radiologia e Diagnóstico por Imagem, Ribeirão Preto SP, Brazil. 3Universidade de São Paulo, Faculdade de Medicina de Ribeirão Preto, Divisão de Neurorradiologia Intervencionista, Ribeirão Preto SP, Brazil. 4Hospital da Unimed de Ribeirão Preto, Departamento de Neurologia, Ribeirão Preto SP, Brazil. Francisco Bermal CAPARROZ NETO https://orcid.org/0000-0003-0806-3279; Lucas Giansante ABUD https://orcid.org/0000-0002-3777-5753; Rafael Gouveia Gomes de OLIVEIRA https://orcid.org/0000-0002-3255-2710; Daniel Giansante ABUD https://orcid.org/0000-0002-6171-669X; Soraia Ramos Cabete FABIO http://orcid.org/0000-0001-8481-7146 Correspondence: Francisco Bermal Caparroz Neto; E-mail: [email protected] Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: FBCN: conception, organization, writing of the first draft, review and critique; LAG, RGGO, SRCF: review and critique; DGA: execution, review and critique. Received on September 08, 2020; Accepted on September 26, 2020
559 Digital subtraction angiography confirmed a posterior cav- ernous sinus DAVF, and endovascular treatment was pre- scribed (Figure 4).
Figure 3. 4D-dynamic contrast-enhanced MR angiography in early arterial phase (A) disclosed a slight asymmetric enhancement of bilateral cavernous sinus (arrows), mainly on the right (arrows), in the subsequent phases (B). This Figure 4. Digital subtraction angiography revealed a bilateral slow- cavernous sinus dural arteriovenous fistula is draining flow posterior cavernous sinus dural arteriovenous fistula, mainly downward through the inferior petrous sinus (A: arrowhead) on the right (A and B). Cavernous sinus dural arteriovenous fistula and not upward through the superior ophthalmic vein, which was successfully treated by venous approach (C). Post-embolization is present in 9–12% of all cavernous sinus dural arteriovenous of the cavernous sinus was performed through the inferior petrous fistulas. sinus, using coils and liquid embolic agents (Phil®) (D).
References
1. Sakamoto M, Taoka T., Iwasaki S., Nakagawa H., Fukusumi A., signs and symptoms. Ophthalmology. 2002 Sep;109(9):1685-91. Takayama K, et al. Paradoxical parasellar high signals resembling https://doi.org/10.1016/s0161-6420(02)01166-1 shunt diseases on routine 3D time-of-flight MR angiography of the 4. Acierno MD. Painful oculomotor palsy caused by posterior- brain: mechanism for the signals and differential diagnosis from draining dural carotid cavernous fistulas. Arch Ophthalmol. shunt diseases. Magn Reson Imaging. 2004 Nov;22(9):1289-93. 1995 Aug;113(8):1045-9. https://doi.org/10.1001/ https://doi.org/10.1016/j.mri.2004.08.004 archopht.1995.01100080097035 2. Guo H, Yin Q, Liu P, Guan N, Huo X, Li Y. Focus on the target: 5. Thomas AJ, Chua M, Fusco M, Ogilvy CS, Tubbs RS, Harrigan Angiographic features of the fistulous point and prognosis of MR, et al. Proposal of venous drainage–based classification transvenous embolization of cavernous sinus dural arteriovenous system for carotid cavernous fistulae with validity fistula. Interv Neuroradiol. 2018 Apr;24(2):197-205. https://doi. assessment in a multicenter cohort. Neurosurgery. 2015 org/10.1177/1591019917751894 Sep;77(3):380-5;discussion 385. https://doi.org/10.1227/ 3. Stiebel-Kalish H. Cavernous sinus dural arteriovenous NEU.0000000000000829 malformations Patterns of venous drainage are related to clinical
560 Arq Neuropsiquiatr 2021;79(6):559-560 https://doi.org/10.1590/0004-282X-ANP-2020-0544 LETTERS
Comment on “YouTube as a source of information for restless leg syndrome” Comentário sobre “YouTube como fonte de informação a respeito da síndrome das pernas inquietas” Alisha DUGGAL1, Taghreed ALWAN1, Shan ALI1, Tomasz SZMUDA2, Paweł SŁONIEWSKI2
Dear Editor, published by practitioners and the remaining six videos (20%) We read with great interest the study by Arikanoglu et al. by nonmedical specialists. In comparison, the term “restless entitled “YouTube as a source of information for the restless leg syndrome” resulted in 27 medically relevant videos, one less leg syndrome (RLS)”1. The paper shows that much of medical (3%). Uploads by private hospitals, clinics and medical associa- information on YouTube is low-quality or biased. While the tions differed by six more videos (20%). By practitioners and paper offers crucial insight, we believe that the study may nonmedical specialists, there was one video more (4%) and have benefited from including more keywords for its analysis. four videos more (13%), respectively. Thus, as we have shown, In their study, one keyword, “restless leg syndrome”, was used an online study that fails to take into account the extra term to find the videos. We attest that additional terms could have been “restless legs” may be limited in its analysis. used, including “restless legs”. This keyword would have widen the Given the change in nomenclature from restless leg syn- search and capture more individuals searching for information drome to Willis-Ekbom disease in 2013 by the Restless Leg about RLS. In a different online study on RLS, Ingram et al. chose Syndrome Foundation, we also believe that the keywords to use the additional keyword “restless legs”, rather than only “rest- “Willis-Ekbom disease” or “Willis-Ekbom” should have been less leg syndrome”2. On Google Trends, the term “restless legs” has used4. Although the Foundation changed back to the original a 3-times higher average search volume than “restless leg syn- name in 20155, journalistic coverage of the name change may drome”3. This shows that the public searches more often for the have made patients more likely to use the new one. symptom rather than the actual syndrome name. The evaluation of YouTube content on restless leg syn- We used both “restless legs” and “restless leg syndrome” as drome conducted by Arikanoglu et al. provides insight on a search title to analyze the 30 first YouTube videos. The term the reliability of information about this subject on the plat- “restless legs” resulted in 28 medically relevant videos. Eighteen form. Our letter highlights some limitations and encourages of them (60%) were published by private hospitals, clinics researchers to use additional keywords to allow for a more and medical associations, whereas four videos (13%) were robust analysis.
References
1. Arikanoglu A, Demir M, Aluclu MU. Analysis of YouTube as a source 4. New Name. New Look. Same Mission. - Restless Legs Syndrome of information for restless leg syndrome. Arq Neuro-Psiquiatr. 2020 Foundation Blog [accessed on Nov 9, 2020]. Available at: https:// Oct;78(10):611-6. https://doi.org/10.1590/0004-282x20200077 rlsfoundation.blogspot.com/2013/03/new-name-new-look-same- 2. Liguori C, Holzknecht E, Placidi F, Izzi F, Mercuri NB, Högl B, et al. Seasonality mission.html of restless legs syndrome: symptom variability in winter and summer times. 5. Restless Legs Syndrome (RLS) Foundation name change – May 2015 Sleep Med. 2020 Feb;66:10-4. https://doi.org/10.1016/j.sleep.2019.07.026 FAQs - Restless Legs Syndrome Foundation Blog [accessed on Feb 3. Google Inc. Google Trends [accessed on Nov 9, 2020]. Available at: 25, 2021]. Available at: https://rlsfoundation.blogspot.com/2015/05/ https://trends.google.com/trends FAQ-rlsf-namechange.html
1Medical University of Gdansk, Scientific Circle of Neurology and Neurosurgery, Gdansk, Poland. 2Medical University of Gdansk, Neurosurgery Department, Gdansk, Poland. Alisha DUGGAL https://orcid.org/0000-0001-9411-329X; Taghreed ALWAN https://orcid.org/0000-0001-9799-8118; Shan ALI https://orcid.org/https://orcid.org/0000-0002-0005-8830; Tomasz SZMUDA https://orcid.org/0000-0003-1904-6773; Paweł SŁONIEWSKI https://orcid.org/0000-0001-8295-2336 Correspondence: Alisha Duggal; E-mail [email protected] Conflict of interest: There is no conflict of interest to declare. Authors’ contributions: AD: writing — original draft; TA: writing — original draft; SA: writing — original draft; TS: writing — original draft PS: writing — original draft. Received on November 24, 2020; Received in its final form on March 24, 2021; Accepted on April 11, 2021.
561 https://doi.org/10.1590/S0004-282X1993000100002err ERRATUM
In the manuscript “Histopathological and immunohistochemical study of the brain and heart in the chronic cardiac form of Chagas’ disease”, DOI: 10.1590/S0004-282X1993000100002, published in the Arq Neuropsiquiatr 1993;51(1):8-15, on page 4.
Where it reads:
Figure 2 Figure 3
It should read:
Figure 2 Figure 3
562 INFORMATION FOR AUTHORS Most recent revision: May, 2020
EDITORIAL POLICY AND MISSION Arquivos de Neuro-Psiquiatria is the official journal of the Brazilian Academy of Neurology, which publishes, monthly, peer-reviewed arti- cles in the areas of Neur ology and Neurosciences. The journal’s mission is to, the best of our abilities, contribute to improving care for patients with neurological diseases by providing neurologists, health professionals and researchers in Neurology and related fields with open access to original articles (clinical and trans- lational research), editorials, views and reviews, historical papers, neuroimages and letters about published articles. We aim to be the best Neuroscience journal in Latin America within the peer review system. Case reports and articles in the areas of Neurosurgery or Psychiatry are not within the scope of this journal. The journal supports the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals, of the International Committee of Medical Journal Editors (ICMJE), available at: http://www.icmje.org/recommendations/. The journal also supports international standards for the publication of responsible research, developed by COPE - Committee on Publication Ethics (http://publicationethics.org/). Practices that undermine scientific integrity, such as plagiarism and self-plagiarism (redundancy), are considered unethical.Arquivos de Neuro-Psiquiatria adopts the iThenticate System (http://www.ithenticate.com) to identify plagiarism. As of 2020, the journal started accepting the submission of manuscripts previously deposited on preprint servers. For the submission of these manuscripts, it is essential that the authors inform the deposit details in the cover letter.
REVIEW PROCESS Initially, the manuscripts submitted to Arquivos de Neuro-Psiquiatria are evaluated to verify compliance with the scope and formal aspects. In case of non-compliance with the scope, such as case reports and articles in the areas of Neurosurgery or Psychiatry, the manu- scripts will be rejected and the authors will be informed. Manuscripts that do not comply with the standards and formats specified in this document, on the other hand, will be returned for the appropriate adjustments. The manuscripts approved in the evaluation of the scope and formal aspects are sent to the editors-in-chief who carry out a preliminary evaluation of the manuscripts, based on criteria of originality, relevance of the topics covered and methodological quality. In this stage, a second member of the Editorial Board will be called upon, in case of non-compliance with the minimum quality criteria. The manuscripts approved in the preliminary evaluation will be forwarded to the Associate Editors of their respective areas, for indica- tion of the reviewers. In the case the Associate Editor evaluates that the manuscript has merits, it will be sent out for evaluation by two or more external reviewers, in simple blind peer review mode. Currently, approximately 40% of the manuscripts submitted to the Arquivos de Neuro-Psiquiatria are approved for publication.
OFFICIAL LANGUAGE Only clear and concise texts in English will be accepted. It is essential that manuscripts should conform to the international standards of text composition that have been adopted by Arquivos de Neuro-Psiquiatria. When necessary, editors and reviewers may ask authors to perform the revision of the language of the manuscript, by a company certi- fied by the journal. Title, abstract and key words must also be presented in Portuguese or Spanish. The section Brazilian Academy of Neurology may be published in Portuguese and is only included in the printed version.
TYPES AND FORMAT OF CONTRIBUTION The manuscripts submitted should present characteristics that allow them to fit into the following sections: Editorial: an in-depth critical commentary prepared as a response to the Editors’ invitation. • Abstract and Keywords are not required; • The text must not exceed 1,000 words*; • The paper must have up to 10 references.
Original Articles: original clinical or experimental research. • Structured abstract, with up to 250 words; • No more than 7 keywords; • The text should contain with up to 3.000 words*; • Up to 40 references; • With up to 5 tables; • With up to 5 illustrations.
Views and Reviews: reviews, critical analyses or opinion papers on current relevant topics in Clinical Neurology and Neuroscience. • Structured abstract, with up to 250 words; • No more than 7 keywords; • The text should contain with up to 5.000 words*; • Up to 80 references; • With up to 5 tables; • With up to 5 illustrations. Historical Notes: history of Neurology and data on descriptions on neurological signs, diseases or syndromes. • Abstract, not necessarily structured, of no more than 150 words; • No more than 7 keywords; • The text should contain with up to 1.000 words*; • Up to 20 references; • With up to 2 tables; • With up to 2 illustrations. Images in Clinical Neurophysiology: educational images and/or videos in clinical neurophysiology including electroencephalography, electromyography, polysomnography, and evoked potentials. • Abstract and keywords are not required; • The text must not exceed 100 words*; • The manuscript may have up to 3 references; • The manuscript may have up to 2 figures/images/video; • The authors are requested to provide 3 multiple-choice questions with answers related to the manuscript. Images in Neurology: original images that illustrate neurological diseases. • Abstract and Keywords are not required; • The text must not exceed 100 words*; • The paper must have up to 5 references; • With up to 4 illustrations. Letters: Comments on articles previously published in Arquivos de Neuro-Psiquiatria. • Abstract and Keywords are not required; • The text must not exceed 700 words*; • The paper must have up to 5 references; • With up to 4 illustrations.
Brazilian Academy of Neurology: institutional texts on regional issues, consensus, topics related to the activities of the Scientific Departments of the Brazilian Academy of Neurology, annals of scientific meetings and other issues. *The maximum number of words refers only to the study and excludes the abstract, resumo/resumen and the reference list.
STRUCTURE AND PREPARATION OF MANUSCRIPTS Authors must submit their contributions in the Microsoft Word text processing format, using font size 12 (Arial or Times New Roman). The text must contain, in this order:
1) Title and short title Up to 100 characters. Avoid citing the region of place where the work was conducted, except in regional studies; otherwise, the work may cease to have uni- versal interest. Avoid correlating the topic with the methods used: “Neurotuberculosis in the Brazilian prison population”. Preferentially correlate the topic with the conclusion: “Mortality due to neurotuberculosis is higher in the prison population”. The title in Portuguese or Spanish must be placed below the title in English. The short title in English of the manuscript should be indicated.
2) Author(s) Complete given names and surnames. The family names must be stated exactly how they should appear in indexation systems.
3) Complementary information Authors’ affiliations: name of the institution in the native language or in the English version when Latin words are not used, with up to three levels (for example: University, School, Department), City, State or Province, Country. Sectors in which the work was performed should not be stated (clinic, laboratory, outpatient service). Corresponding author, with the respective e-mail. ORCID of all authors of the manuscript. Funding agency(ies). Declaration of conflict of interest. Indication of authors’ contributions.
4) Abstract and Resumo (in Portuguese) or Resumen (in Spanish): For original articles, the abstract should be presented in a structured format: Background; Objective; Methods; Results; Conclusions. Only refer to relevant data, in a clear and concise manner. Avoid abbreviations, unless they are used universally. This is the most important part of the study: if readers do not read the complete text, they should have access through the Abstract/ Resumo/Resumen to the relevant information of the article. The Resumo or Resumen should be placed after the Abstract and Keywords.
5) Keywords and Palavras-chave (in Portuguese) or Palabras-Clave (in Spanish): Only use terms that are include in the Medical Subject Headings – MeSH (http://www.ncbi.nlm.nih.gov/mesh) or Health Science Descriptions – DeCS (http://decs.bvs.br/).
6) Text a) Original articles: Introduction; methods (with explicit reference to compliance with ethical standards, including the name of the Ethics Committee that approved the study and the informed consent declaration made by patients or members of their families); results; dis- cussion; acknowledgments; references. Do not repeat in the text data are expressed in tables and illustrations. b) Views and Reviews: Systematic review or meta-analysis on data from the literature; critical analysis of the present state of knowledge; purely descriptive surveys of data in the literature will not be accepted. c) Historical Notes: Concise presentation of original data of historical interest to neuroscientists; manuscripts with excessively regional interest should be avoided. d) Images in Neurology: Only relevant images should be sent with a summary of the clinical data and comments on the images. e) Letters: Comments on studies published in Arquivos de Neuro-Psiquiatria. *The maximum number of words refers only to the study and excludes the abstract, resumo/resumen and the reference list. 7) Tables In their electronic version, tables must be presented in .doc (Microsoft Word) or .xls (Microsoft Excel) format. Submit tables as complementary files; include sequential number, title and legend.
8) Illustrations All figures must be submitted in JPG, TIFF or PNG format. No identification relating to patients or institutions is permitted. Photos of people who might be recognized on the image need to have been authorized in writing. Each image must be placed in a separate file, with the figure number indicated in the file. Images must be uniform in size and magnification and must not be redundant. The significant find- ings should be properly marked out on the images. Authorization in writing must be provided for use of images that have previously been published and the original citation must appear in the legend. Images need to have the following resolution: a) Artwork in black and white: 1,200 dpi/ppi. b) Half-tones: 300 dpi/ppi. c) Combination of half-tones: 600 dpi/ppi. Legends should be typed with double spacing and figures should be numbered in the order in which they are referred to in the text.
9) Acknowledgments This section should be concise and restricted to acknowledgments that are necessary.
10) References References must be listed at the end of the article and numbered in the order in which they appear in the text.Do not use underlining, boldface or italics. The references must follow the standard of the International Committee of Medical Journal Editors – ICMJE (https://www.nlm.nih.gov/ bsd/uniform_requirements.html). The abbreviation of journal titles should be in accordance with the style presented by Index Medicus: abbreviations of journal titles (http://www2.bg.am.poznan.pl/czasopisma/medicus.php?lang=eng)
Reference format: a) Articles: Author(s). Title of the article. Title of the journal. Year; volume(number): first page-last page of the article; b) Books: If there are up to six authors, list all of them; if more than six, list the first six followed by et al. Author(s). Title of the book. Edition (from the 2nd edition onwards). City: Publishing house; year of publication; c) Chapters of books: When the author of the chapter is the same as the author of the book: Author(s) of the book. Title of the book. Edition (from the 2nd edition onwards). City: Publishing house; year of publication. Title of the chapter; first page-last page of the chapter. Different authorship: Author(s) of the chapter. Title of the chapter. In: author or editor of the book. Title of the book. Edition (from the 2nd edition onwards). City: Publishing house; year of publication. First page-last page of the chapter; d) Books in electronic media: Author(s). Title of the book. Edition (from the 2nd edition onwards). City: Publishing house; year of publication [date of access, using the expression “accessed on”]. Available at: link. e) Studies presented at events: Author(s). Title of the study. In: Annals of the number of the event title of the event; date of the event; city, country where event was held. City of publication: Publishing house; year of publication. First page-last page of the study; f) Dissertations, theses or academic studies: Author. Title of the thesis [degree level]. City of publication: Institution at which it was defended; year of defense of the study.
SUBMISSION OF MANUSCRIPTS Only online submissions will be accepted: https://mc04.manuscriptcentral.com/anp-scielo. The simultaneous submission, in part or in full, to other journals is not allowed. The ANP considers unethical the duplicate or par- tial publication of the same research. Tools for locating text similarity are used by the journal to detect plagiarism. In case plagiarism is detected, the journal follows the Code of Conduct and Best Practice Guidelines for Journal Editors do Committee on Publication Ethics - COPE (http://publicationethics.org/). All authors must associate the ORCID registration number (https://orcid.org/) with their profile in the submission system. Articles submitted to the Editorial Board for publication must include: a) Cover letter, in PDF, signed by all the authors (Download); b) Indication of three to five referees of the authors’ preference, with their e-mail addresses; c) Indication of the authors’ opposed reviewers (optional).
PROCESSING OF THE MANUSCRIPT The journal’s office will verify whether the manuscript is in conformity with the Instructions for Authors and whether it fits within the scope of Arquivos de Neuro-Psiquiatria. In this step, the Editor-in-Chief will be designated (reply within tree days). Manuscripts that do not meet these requirements will be rejected (reply within seven days). The Editor-in-Chief designates an Associate Editor (reply within five days). The Associate Editor evaluates the manuscript and, in the case that the work is judged to have the necessary merits, the Associate Editor indicates the reviewers. The process of seeking, inviting and designating reviewers will be completed within seven days. Reviewers have 15 days to submit their recommendation. The author can follow the processing of the manuscript on the website (http://mc04.manuscriptcentral.com/anp-scielo).
ACCEPTANCE OF THE ARTICLE Manuscripts will be accepted in accordance with the chronological order in which they reach the final format, after fulfilling all stages of the editorial processing.
PUBLICATION FEES Arquivos de Neuro-Psiquiatria does not require fees for publication of accepted manuscripts.
PUBLICATION OF THE ARTICLE The manuscript will be published both in online and in printed form. All published manuscripts are open-access. Original Articles may be published in advance online in the Ahead of Print (AOP) mode and may be cited even if they have not been pub- lished formally. It is established at the outset that the authors will assume the intellectual and legal responsibility for the results described and for the remarks presented. The authors also agree to publish the manuscript exclusively in this journal and to automatically transfer reproduction rights and permissions to the journal’s publisher. ACESSE O SITE ABN•EMC
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DEPOIS FAÇA O LOGIN Sono, Paulo Afonso Mei 2 PARA ACESSAR O PDF Pedro Mota de Albuquerque Cognição e Clélia Maria Ribeiro Franco DO FASCÍCULO Raimundo Nonato Delgado Rodrigues Demência Sandra Cristina Gonçalves Martinez E A PROVA. 1
Patrocínio www.abneuro.org.br ABN EMC Material destinado à classe médica CONDIÇÕES PARA INGRESSO
MEMBRO TITULAR f) Ter completado 100 créditos na área de Neurologia, Para ser Membro Titular, o médico precisa preencher uma de acordo com regulamentação específica prevista das seguintes condições: no Regimento Geral. Ser médico neurologista e: a) Possuir Título de Especialista em Neurologia fornecido MEMBRO ASPIRANTE pela Associação Brasileira de Neurologia – ABN-AMB; ou Será Membro Aspirante o médico que tiver a sua Proposta b) Possuir Título na área de atuação em Neurologia de Admissão aprovada pela Diretoria e obedecer aos Pediátrica fornecido pela Academia Brasileira de requisitos impostos no Estatuto, conforme seguem abaixo: Neurologia – ABN, Associação Médica Brasileira – Preencher no mínimo um dos seguintes requisitos: AMB e Sociedade Brasileira de Pediatria – SBP. a) Estar cursando Residência Médica em Neurologia Clínica em programa aprovado nos termos do Decreto MEMBRO EFETIVO da Presidência da República n° 8.516/15 e Comissão Para ser Membro Efetivo, o médico precisa preencher uma Mista de Especialidade CFM-AMB-CNRM; ou das seguintes condições: b) Estar cursando estágio em Neurologia Clínica com Ser médico neurologista e: carga horária equivalente à Residência Médica em a) Ter concluído Residência Médica em Neurologia programa reconhecido pela ABN; ou Clínica em programa aprovado nos termos do Decreto c) Estar cursando programa de Residência Médica da Presidência da República n° 8.516/15 e Comissão na área de atuação em Neurologia Pediátrica em Mista de Especialidade CFM-AMB-CNRM; ou programa aprovado nos termos do Decreto da b) Ter completado programa de Residência Médica na Presidência da República n° 8.516/15 e Comissão área de atuação em Neurologia Pediátrica em programa Mista de Especialidade CFM-AMB-CNRM; ou aprovado nos termos do Decreto da Presidência da d) Estar cursando estágio em Neurologia Pediátrica com República n° 8.516/15 e Comissão Mista de Especialidade carga horária equivalente à Residência Médica em CFM-AMB-CNRM. programa reconhecido pela ABN.
MEMBRO EFETIVO ASSOCIADO MEMBRO ASPIRANTE ASSOCIADO Para ser Membro Efetivo Associado, o médico precisa Para ser Membro Aspirante Associado, o médico deverá preencher uma das seguintes condições: preencher uma das seguintes condições: Ser médico e: Ser médico e: a) Ter completado Residência Médica em área de a) Estar cursando Residência Médica em área de atuação reconhecida nos termos do Decreto da atuação reconhecida nos termos do Decreto da Presidência da República n° 8.516/15 e Comissão Presidência da República n° 8.516/15 e Comissão Mista de Especialidade CFM-AMB-CNRM; cujo pré- Mista de Especialidade CFM-AMB-CNRM, cujo pré- requisito inclua certificação em Neurologia Clínica, requisito inclua certificação em Neurologia Clínica, que incluem Medicina do Sono, Neurofisiologia incluindo Medicina do Sono, Neurofisiologia Clínica, Clínica, Dor, Terapia Intensiva e demais áreas de Dor, Terapia Intensiva e demais áreas de atuação atuação supervenientemente aprovadas pela AMB; ou supervenientemente aprovadas pela AMB; ou b) Ter completado estágio de Neurologia Clínica ou b) Estar cursando Residência Médica em Neurocirurgia Neurologia Pedi[atrica com carga horária equivalente à em programa aprovado nos termos do Decreto da Residência Médica, reconhecido pela ABN; ou Presidência da República n° 8.516/15 e Comissão Mista c) Ter completado Residência Médica em Neurocirurgia de Especialidade CFM-AMB-CNRM. em programa aprovado nos termos do Decreto da Presidência da República n° 8.516/15 e Comissão Mista MEMBRO ASSOCIADO de Especialidade CFM-AMB-CNRM; ou Será Membro Associado o profissional de nível superior d) Possuir grau de Mestre ou Doutor em Neurologia obtido que, satisfazendo as condições previstas neste Estatuto ou reconhecido por faculdade de Medicina do país; ou e no Regimento Geral, tiver a sua Proposta de Admissão e) Possuir título de professor de Neurologia, de livre-docente aprovada pela Diretoria, além de: em Neurologia, obtido por concurso público de provas e a) Exercer atividade afim à Neurologia (não é necessário títulos em faculdade de Medicina do país; ou ser médico); b) Apresentar carta de recomendação de dois Membros de seus dados cadastrais: nome completo, endereço Titulares ou Titulares Eméritos, atestando as completo, data de nascimento, telefones de contato, qualidades morais e éticas do candidato; CPF, RG e e-mail. c) Submeter Proposta de Admissão com currículo e comprovante dos requisitos acima, assinada por dois MEMBRO TÉCNICO membros, Titulares ou Titulares Eméritos da ABN, à Será Membro Técnico o profissional de nível médio que Secretaria-Tesouraria Geral. exerça atividade técnica relacionada a neurologia e que atenda ao disposto no Regimento Geral. O candidato deve: Cumprindo os requisitos, os candidatos a membros Titular, b) Encaminhar o pedido de admissão dirigido à diretoria Efetivo, Efetivo Associado, Aspirante, Aspirante Associado da ABN e anexar cópia do certificado de conclusão de e Associado deverão enviar à Secretaria-Tesouraria Geral: sua área técnica com seus dados cadastrais: nome a) Carta solicitando admissão; completo, endereço completo, data de nascimento, b) Carta de apresentação escrita por dois membros telefones de contato, CPF, RG e e-mail. Titulares; c) Curriculum vitae resumido; MEMBRO HONORÁRIO d) Comprovantes de estar em dia com o Conselho Regional O título de Membro Honorário será conferido a médicos ou de Medicina – CRM e com a Federada da AMB; pesquisadores que tenham se distinguido no progresso e) Cópia do diploma de graduação; das Neurociências, devendo a proposta ser apresentada f) Documento comprovando suas credenciais para por, no mínimo, três Membros Titulares ou Titulares ingressar na categoria à qual se candidata. Eméritos da ABN e ser aprovada pela Assembleia Geral.
MEMBRO CORRESPONDENTE MEMBRO TITULAR EMÉRITO Será Membro Correspondente o médico estrangeiro que O título de Membro Titular Emérito será concedido ao tiver a sua Proposta de Admissão aprovada pela Diretoria, Membro Titular, médico neurologista com mais de 15 anos comprovando: de filiação à ABN e com mais de 70 anos de idade, mediante a) O exercício da Neurologia ou atividade afim à parecer da Diretoria (com homologação do CD), baseado em Neurologia em seu país; informação anual da Secretaria-Tesouraria Geral. b) Submissão da Proposta de Admissão, assinada por dois membros, Titulares ou Eméritos da ABN, à MEMBRO BENEMÉRITO Secretaria-Tesouraria Geral. O título de Membro Benemérito será conferido a personalidades físicas ou jurídicas que tenham prestado MEMBRO DISCENTE relevantes serviços, ou feito expressivas doações à ABN, Será Membro Discente o estudante de Medicina que tiver devendo a proposta ser apresentada por, no mínimo, três a sua Proposta de Admissão aprovada pela Diretoria. Para Membros Titulares ou Membros Titulares Eméritos e isso, o candidato deve: aprovada pela Assembleia Geral. a) Encaminhar carta do estabelecimento de ensino superior dirigido à Secretaria-Tesouraria que comprove que cursa Medicina, além de seus dados REGULAMENTAÇÃO DOS CRÉDITOS PARA MEMBRO DA ABN cadastrais: nome completo, endereço completo, data A obtenção de créditos será baseada nos seguintes critérios: de nascimento, telefones de contato, CPF, RG e e-mail. a) por atividades promovidas diretamente pela ABN (3 créditos por dia de atividades); MEMBRO ASSOCIADO DISCENTE b) por atividades científicas promovidas pelos Capítulos Será Membro Associado Discente o estudante de ensino Regionais (1 crédito por dia de atividade); superior com interesse em área afim à Neurologia e que c) por atividades copatrocinadas pela ABN (1 crédito tiver a sua Proposta de Admissão aprovada pela Diretoria pela atividade total); da ABN. Para isso, o candidato deve: d) por dissertação aprovada para Mestrado (5 créditos); a) Encaminhar carta do estabelecimento de ensino e) por tese de Doutoramento aprovada (10 créditos); superior dirigido à Secretaria-Tesouraria que comprove f) por trabalho científico publicado em revistas médicas que estuda em curso de área afim à Neurologia, além indexadas (até 10 créditos).