Headache Medicine, v.11, n.1, 2020

EDITORIAL

Migraine surgery

Cirurgia para Enxaqueca

Él

cio Juliato Piovesan .............................................................................................................................................................................1-2

VIEWS AND REVIEWS

Headache in patients infected with the novel coronavirus (Covid-19): An integrative literature review

Cefaleia em pacientes infectados pelo novo coronavírus (Covid-19): uma revisão integrativa da

literatura

Sarah

Nilkece Mesquita Araújo Nogueira Bastos; Diego Afonso Cardoso Macedo de Sousa; Simone

Santos e Silva Melo; Bárbara Louise Freire Barbosa; Larisse Giselle Barbosa Cruz; Raimundo Pereira

Silva-Néto.................................................................................................................................................................................3-6

ORIGINAL ARTICLES

The

Migraine Tree: a shared tool for migraine information

A Árvore da Enxaqueca: uma ferramenta compartilhada para informação sobre enxaqueca

izabeth Leroux ...........................................................................................................................................................................................7-9

Migraine aura: results from an art contest

Aura da enxaqueca: resultados de um concurso de arte

Bruna de Freitas Dias; Arao Belitardo de Oliveira; Juliane Prieto Peres Mercante; Michele Viana; Luiz Paulo

Queiroz; Mario Fernando Prieto Peres..................................................................................................................................10-13

Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per

protocol analysis

Atividade da ECA após treinamento físico aeróbio é correlacionada com sono em pacientes com migrânea:

uma análise secundária por protocolo

Arã

o Belitardo Oliveira; Bruna Visniauskas; Jair Ribeiro Chagas; Mario Peres.......................................................14-21

Sociodemographic characteristics of patients with chronic headache

Características sociodemográﬁcas dos pacientes portadores de cefaleia crônica

Patrick Giordanni Gomes Sampaio; Hiago Diniz Maracajá; Sara Raquel Nóbrega Figueiredo; Virgínia

abriela Nóbrega Figueiredo; Túlio Carneiro Monteiro Temoteo; Nátalia Meg Adijuto de Melo.................22-24

THESIS

Peripheral projections of

the trigeminovascular system as antimigraine target

Projeções periféricas do sistema trigeminovascular como alvo anti-enxaqueca

Alejandro Labastida-Ramírez; Antoinette Maassen Van Den Brink................................................................................25-26

Headache Medicine

Scientic Publication of the Brazilian Headache Society

ISSN 2178-7468, e-ISSN 2763-6178

VOLUME 11

∙ NUMBER 1 ∙ 2020

CONTE

NTS

Headache Medicine, v.11, n.1, 2020

Headache Medicine

Scientic Publication of the Brazilian Headache Society

Editores-chefes

Marcelo Moraes Valença

Universidade Federal de Pernambuco, Recife, PE, Brasil.

Mario Fernando Prieto Peres

Hospital Israelita Albert Einstein, IPq – HCFMUSP, São Paulo, SP, Brasil.

Editor Cientíco

Raimundo Pereira Silva-Néto

Universidade Federal do Delta do Parnaíba, Parnaíba, PI, Brasil.

Editor Emeritus

Wilson Luiz Sanvito

FCM Santa Casa de São Paulo, São Paulo, SP, Brasil.

Pesquisa Básica e Procedimentos

Élcio Juliato Piovesan

Universidade Federal do Paraná, Curitiba, PR, Brasil.

Ensino, alunos e residentes

Yara Dadalti Fragoso – Santos, SP, Brasil.

Cefaleia na Mulher

Eliane Meire Melhado

Universidade de Catanduva, Catanduva, SP, Brasil.

Multiprossional

Juliane Prieto Peres Mercante

IPq – HCFMUSP, São Paulo, SP, Brasil.

Arão Belitardo de Oliveira

ABRACES – Associação Brasileira cefaleia em Salvas e

Enxaqueca, São Paulo, SP, Brasil.

Debora Bevilacqua Grossi

FMUSP – Rebeirão Preto, SP, Brasil.

Cefaleias Secundárias

Pedro Augusto Sampaio Rocha

Universidade Federal de Pernambuco, Recife, PE, Brasil.

Hipertensão e Hipotensão Liquórica

Ida Fortini HC FMUSP, São Paulo, SP, Brasil.

Sandro Matas

UNIFESP, São Paulo, SP, Brasil

Cefaleias Trigêmino-Autonômicas

Maria Eduarda Nobre

Rio de Janeiro, RJ, Brasil

Cefaleia na Infância

Marco Antônio Arruda

Universidade Federal de São Paulo, SP, Brasil.

Dor orofacial

Eduardo Grossmann – Porto Alegre, RS, Brasil.

Controvérsias e Expert Opinion

Joao José Freitas de Carvalho – Fortaleza, CE, Brasil.

Clinical Trials

Fabiola Dach

FMUSP, Ribeirão Preto, SP, Brasil.

Teses

Fernando Kowacs, Porto Alegre, RS, Brasil.

Imagens e Vídeos

Paulo Sergio Faro Santos

INC, Curitiba, PR, Brasil.

Advocacy

Elena Ruiz de La Torre

WHAM (World Headache Association for Migraine)

Madri, Espanha.

A revista Headache Medicine é uma publicação de propriedade da Sociedade Brasileira de Cefaleia, indexada no Latindex e no Index Scholar, publicada

pela Sociedade Brasileira de Cefaleia, www.sbcefaleia.com.br. Os manuscritos aceitos para publicação passam a pertencer à Sociedade Brasileira de

Cefaleia e não podem ser reproduzidos ou publicados, mesmo em parte, sem autorização da HM & SBCe. Os artigos e correspondências deverão ser

encaminhados para a HM através de submissão on-line, acesso pela página www.headachemedicine.com.br - Distribuição gratuita para os membros

associados, bibliotecas regionais de Medicina e faculdades de Medicina do Brasil, e sociedades congêneres

Editores Associados

CONSELHO EDITORIAL

SSN 2178-7468, e-ISSN 2763-6178

iii

Headache Medicine, v.11, n.1, 2020

Headache Medicine

Scientic Publication of the Brazilian Headache Society

CONSELHO EDITORIAL

Rodrigo Noseda

Harvard Medical School, Boston, MA, EUA

Marlind Alan Stiles

Jefferson Universtty, Philadelphia, PA, EUA

Charles Siow, Singapore

Maurice Borges Vincent, Indianapolis, IN, EUA

Michele Viana, Novara, Itália

Margarita Sanchez Del Rio, Madri, Espanha

Sait Ashina,

Harvard Medical School, Boston, MA, EUA

Todd D Rozen,

Mayo Clinic, Jacksonville, FL, EUA

Elena Ruiz de la Torre, Espanha

Marco Lisicky, Cordoba, Argentina

Maria Teresa Goycochea, Buenos Aires, Argentina

Alex Espinoza Giacomozzi, Santiago, Chile

Joe Munoz Ceron, Bogotá, Colômbia

Faisal Amin, Copenhague, Dinamarca

Uwe Reuter, Berlim, Alemanha

Abouch Valenty Krymchantowski, Rio de Janeiro, RJ

Alan Chester Feitosa Jesus, Aracaju, SE

Ana Luisa Antonniazzi, Ribeirão Preto, SP

Carla da Cunha Jevoux, Rio de Janeiro, RJ

Carlos Alberto Bordini, Batatais, SP

Daniella de Araújo Oliveira, Recife, PE

Djacir D. P. Macedo, Natal, RN

Elder Machado Sarmento, Barra Mansa, RJ

Eliana Meire Melhado, Catanduva, SP

Fabíola Dach, Ribeirão Preto, SP

Fernando Kowacs, Porto Alegre, RS

Henrique Carneiro de Campos, Belo Horizonte, MG

Jano Alves de Sousa, Rio de Janeiro, RJ

João José de Freitas Carvalho, Fortaleza, CE

Luis Paulo Queiróz, Florianópolis, SC

Marcelo C. Ciciarelli, Ribeirão Preto, SP

José Geraldo Speziali, Ribeirão Preto, SP

Marcelo Rodrigues Masruha, Vitória, ES

Pedro Ferreira Moreira Filho, Rio de Janeiro, RJ

Pedro André Kowacs, Curitiba, PR

Mauro Eduardo Jurno, Barbacena, MG

Paulo Sergio Faro Santos, Curitiba, PR

Pedro Augusto Sampaio Rocha Filho, Recife, PE

Renata Silva Melo Fernandes, Recife, PE

Thais Rodrigues Villa, São Paulo, SP

Renan Domingues, Vitória, ES

Conselho Editorial Internacional

Conselho Editorial Nacional

A revista Headache Medicine é uma publicação de propriedade da Sociedade Brasileira de Cefaleia, indexada no Latindex e no Index Scholar, publicada

pela Sociedade Brasileira de Cefaleia, www.sbcefaleia.com.br. Os manuscritos aceitos para publicação passam a pertencer à Sociedade Brasileira de

Cefaleia e não podem ser reproduzidos ou publicados, mesmo em parte, sem autorização da HM & SBCe. Os artigos e correspondências deverão ser

encaminhados para a HM através de submissão on-line, acesso pela página www.headachemedicine.com.br - Distribuição gratuita para os membros

associados, bibliotecas regionais de Medicina e faculdades de Medicina do Brasil, e sociedades congêneres

SSN 2178-7468, e-ISSN 2763-6178

Headache Medicine, v.11, n.1, 2020

Sociedade Brasileira de Cefaleia – SBCe

liada à International Headache Society – IHS

Av. Tenente José Eduardo n° 453, sala 203

27323-240 Barra Mansa - RJ - Brasil

Fone:+55 (24) 9 8847-9980 www.sbcefaleia.com.br

secretaria@sbcefaleia.com.br

Josiane Moreira da Silva - Secretária Executiva SBCe

DIRETORIA 2018/2021

DELEGADOS

Academia Brasileira de Neurologia (ABN)

Fernando Kowacs

José Geraldo Speziali

American Headache Society (AHS)

Marcelo Cedrinho Ciciarelli

Associación Latinoamericana de Cefaleias (ASOLAC)

Carlos Alberto Bordini

European Headache Federation (EHF)

Marco Antônio Arruda

International Headache Society (IHS)

Pedro André Kowacs

Sociedade Brasileira para o Estudo da Dor (SBED)

Eduardo Grossman - José G Speziali

Responsável pelo Site

Paulo Sérgio Faro Santos

Responsável pelas Mídias Sociais

Arão Belitardo Oliveira

Comissão de Ética

Elcio Juliato Piovesan - Jano Alves de Souza

José Geraldo Speziali - Mauro Eduardo Jurno

Registro de Cefaleia no Brasil

Fernando Kowacs - Mauro Eduardo Jurno

Vanise Grassi - Élder Machado Sarmento

Liselotte Menke Barea - Luis Paulo Queiroz

Marcelo Cedrinho Ciciarelli - Mario FP Peres

Pedro Augusto Sampaio Rocha-Filho

Políticas Públicas, Institucionais e Advocacy

Patricia Machado Peixoto

COMISSÕES

Prêmios

Carlos A Bordini - Djacir Dantas de Macedo

Jano Alves de Souza - Mauro Eduardo Jurno

Pedro F Moreira Filho - Raimundo P Silva-Néto

Atividades Físicas e Fisioterapia

Cláudia Baptista Tavares - Daniela A Oliveira

Debora Bevilaqua-Grossi

Cefaleia na Infância

Marco Antonio Arruda - Thais Rodrigues Villa

Cefaleia na mulher

Eliana Meire Melhado

Dor Orofacial

Ricardo Tanus Valle

Leigos

Celia A P Roesler - Henrique Carneiro de

Campos - João José Freitas de Carvalho

Paulo Sérgio Faro Santos

Alunos Residentes

Yara Dadalti Fragoso - Diego Belandrino Swerts

Izadora Karina da Silva - Marcos Ravi Cerqueira

Ferreira Figueiredo - Caroline Folchini

Saulo Emanuel Gomes Silva - Walkyria Will-

Patrick Emanuell - Eduardo Nogueira

Psicologia

Juliane Prieto Peres Mercante - Rebeca V. A.

Vieira - Rosemeire Rocha Fukue

Procedimentos Invasivos

Cláudio Manoel Brito

Élcio Juliato Piovesan

Presidente Elder Machado Sarmento

Secretário Mario Fernando Prieto Peres

Tesoureiro Pedro Augusto Sampaio Rocha Filho

Headache Medicine 2020, 11(1):1-2 ISSN 2178-7468, e-ISSN 2763-6178

ASAA

DOI: 10.48208/HeadacheMed.2020.1

Headache Medicine

Editorial

Migraine surgery

Élcio Juliato Piovesan

Neurologist responsible for the Committee on Invasive Procedures of the Brazilian Headache Society.

The Brazilian Headache Society hereby states its position regarding migraine surgery, a

procedure created by American plastic surgeon Bahman Guyuron and that has been re-

ported over the past months in the Brazilian media. The premise of Guyuron’s technique is

that there are four trigger sites for headaches in patients with Chronic Migraines, namely:

frontal, temporal, occipital and rhinogenic sites

. Guyuron suggests that there is a muscle

component and a vascular component in these regions. The vascular component (vasodilation)

compresses the nerve and causes pain (in the vein-artery-nerve complex), while the muscle

component is contracted especially in the sites where nerves go through muscles, also known

as X foramens, and promotes pain.

There are numerous scientic studies on the subject, many with decient methodology and

other with more appealing methodology. Professor Rami Burstein (world renowned referen-

ce in the eld of physiopathology of headaches), in an article evaluating a series of seven

patients, showed that some individuals had improvements in post-traumatic headaches and

persistent daily headaches since the beginning, while others were non-responsive (chronic

migraine). The Professor himself questions if the procedure works or not, suggesting that it

should be applied to experimental studies.

A task force from the American Headache Society stated their concern on the subject as

such: “Don’t recommend surgical deactivation of migraine trigger points outside of a clinical

trial. The value of this form of “migraine surgery” is still a research question. Observational

studies and a small controlled trial suggest possible benet. However, large multicenter, ran-

domized controlled trials with long-term follow-up are needed to provide accurate estimates

of the effectiveness and harms of surgery. Long term side effects are unknown but potentially

a concern.”

3-7

The members believed that this term would make it easier for doctors and patients to recognize

the procedures at hand. The idea of a surgical “solution” is inherently attractive to patients.

Interest in surgical approaches to headaches has been motivated by the accidental improve-

ment in headaches observed among patients that have undergone several “forehead rejuve-

nation” surgical procedures. These procedures are based on the premise that the contraction

of facial and other muscles collides with branches of the trigeminal nerve.

The procedures are frequently referred to collectively as “headache deactivation surgery”,

though multiple locations and surgical procedures are involved. These include corrugator

supercilii resection with fat grafting, “temporal liberation” procedures, involving dissection

of the glabelar region, transection of the zygomaticotemporal branch of the trigeminal ner-

ve and resection of the semispinalis capitis muscle with fat grafting to reduce pressure on

the occipital nerve. Finally, some surgeons also conduct nasal septoplasty or try to address

possible intranasal trigger sites.

Élcio Juliato Piovesan

piovesan1@hotmail.com

Received: February 12, 2020.

Accepted: March 16, 2020.

Edited by

Mario Fernando Prieto Peres

ASAA

Piovesan EJ

Migraine surgery

However, there is limited evidence to support that such sur-

geries are effective or safe. Several randomized studies have

been conducted, but there are methodological deciencies.

Moreover, most studies in the literature were conducted by

the same group of surgeons proposing the procedure and

published in a single subspecialty journal.

4-7

Despite the lack of good quality evidence to balance the pros

and cons of surgical treatments for headaches, these proce-

dures are becoming more common. Recent research from the

Plastic Surgery Society found that 18% of interviewees had

conducted a headache surgery. Sixty percent of those that

did not conduct the surgery said they were “interested if the

patient was referred to them by a neurologist.”

The American Headache Society emitted a statement urging

“patients, healthcare professionals and migraine treatment

specialists themselves, to exercise caution in recommending or

seeking such therapy”. The statement continued declaring that

“In our view, surgery for migraine is a last-resort option and

is probably not appropriate for most sufferers. To date, there

are no convincing or denitive data that show its long-term

value. Besides replacing the use of more appropriate treat-

ments, surgical intervention also may produce side effects

that are not reversible and carry the risks associated with any

surgery. It also can be extremely expensive and may not be

covered by insurance.”

Given that the value of a headache

migraine is still uncertain, the AHS and Choose Wisely Task

Force believe that patients should only undergo this treatment

in the context of procedures within clinical trials that seek to

develop good quality evidence on the harms and benets

of treatment.

References

1. Guyuron B. Is migraine surgery ready for prime time? Thesurgi-

cal team’s view. Headache 2015; 55:1464-1473.

2. Blake P, Nir R-R, Perry CJ, Burstein R. Tracking patients with

chronic occipital headache after occipital nerve decompression

surgery: A case series. Cephalalgia. 2019; 39: 556-563.

3. Gaul C, Holle D, Sandor PS, et al. The value of “migraine sur-

gery.” Overview of the pathophysiological concept and current

evidence. Nervenarzt. 2010;81:463-470.

4. Guyuron B, Reed D, Kriegler JS, Davis J, Pashmini N, Amini S.

A placebo-controlled surgical trial of the treatment of migraine

headaches. Plast Reconstr Surg. 2009;124:461-468.

5. Kung TA, Pannucci CJ, Chamberlain JL, Cederna PS. Migraine

surgery practice patterns and attitudes. Plast Reconstr Surg.

2012;129:623-628.

6. American Headache Society urges caution in using any surgical

intervention in migraine Treatment. Position Statement of the

American Headache Society. http://www.americanheada-

chesociety.org/american_headache_society_urges caution in

using any surgical intervention in migraine treatment/ Accessed

January 11, 2013.

7. Guyuron B, Kriegler JS, Davis J, Amini SB. Comprehensive

surgical treatment of migraine headaches. Plast Reconstr Surg.

2005; 115:1-9.

Headache Medicine 2020, 11(1):3-6 ISSN 2178-7468, e-ISSN 2763-6178

ASAA

DOI: 10.48208/HeadacheMed.2020.2

Headache Medicine

Views and Reviews

Headache in patients infected with the novel coronavirus (Covid-19):

An integrative literature review

Cefaleia em pacientes infectados pelo novo coronavírus (Covid-19): uma revisão integrativa da literatura

Sarah Nilkece Mesquita Araújo Nogueira Bastos

Diego Afonso Cardoso Macedo

Simone Santos

e Silva Melo

Bárbara Louise Freire Barbosa

Larisse Giselle Barbosa Cruz

Raimundo Pereira

Silva-Néto

Doctorate in Nursing and Medical Student, Federal University of Delta of Parnaíba.

Master in Nursing and Medical Student, Federal University of

Delta of Parnaíba.

Medical Student, Federal University of Delta of Parnaíba.

Doctorate in Neurology and Adjunct Professor of Neurology, Federal

University of Delta of Parnaíba, Piauí, Brazil.'

Abstract

Introduction

The disease caused by the new coronavirus was named by the acronym Covid-19 which means “CO-

rona VIrus Disease”, while “19” refers to the year 2019, when the rst cases in Wuhan, China, were

identied.

Objective

Our objective was to identify the prevalence of headache and to know its clinical characteristics in

COVID-19 patients, available in the literature.

Methods

Based on a literature search in the major medical databases and using the descriptors “headache and co-

ronavirus”, “headache and 2019-nCoV”, “headache and SARS- CoV-2”, “headache and coronavirus and

2019-nCoV” and “headache and coronavirus and SARS-CoV-2” we include articles published between Ja-

nuary 2019 and April 2020. We found 94 articles, but only 13 met the inclusion criteria.

Results

In 13 articles analyzed in this review, a total of 3,105 Chinese patients (51.6% men and 48.4% women)

had laboratory diagnoses of COVID-19. In 240 (7.7%) patients, headache was an associated symptom

of COVID-19, but in only 52 (21.7%) of them there was some information about the characteristics of

this headache.

Conclusions

COVID-19 patients have several clinical manifestations, including headache that is nonspecic with a

prevalence of 7.7%.

Resumo

Introdução

A doença causada pelo novo vírus Corona foi batizada com o acrônimo COVID-19, que signica

“Doença de Corona VIrus”, enquanto “19” refere-se ao ano de 2019, quando foram identicados os

primeiros casos em Wuhan, na China.

Objetivo

Nosso objetivo é identicar a prevalência da cefaleia e conhecer suas características clínicas em paciente

com COVID-19, disponíveis na literatura.

Método

Com base em uma pesquisa bibliográca nas principais bases de dados médicos e utilizando os

descritores “headache and coronavirus”, “headache and 2019- nCoV”, “headache and SARS-CoV-2”,

“headache and coronavirus and 2019-nCoV” and “headache and coronavirus and SARS-CoV-2” incluímos

artigos publicados entre janeiro de 2019 e abril de 2020. Foram encontrados 94 artigos, mas apenas

13 preencheram os critérios de inclusão.

Resultados

Em 13 artigos analisados nesta revisão, um total de 3.105 pacientes chineses (51,6% homens e 48,4%

mulheres) tiveram diagnóstico laboratorial de COVID-19. Em 240 (7,7%) pacientes, a cefaleia foi um

sintoma associado ao COVID-19, mas em apenas 52 (21,7%) deles havia alguma informação sobre as

características dessa cefaleia.

Conclusão

Os pacientes com COVID-19 apresentam várias manifestações clínicas, inclusive cefaleia que é inespe-

cíca e com uma prevalência de 7,7%.

Sarah Nilkece Mesquita Araújo

Nogueira Bastos.

Federal University of Delta of Parna-

íba, Avenida São Sebastião, 2819,

Fátima, Parnaíba, PI 64001-020,

Brazil. Fone: +55 8699470-0770.

sarahnilkece@hotmail.com.

Received: April 11, 2020.

Accepted: April 12, 2020.

Edited by

Mario Fernando Prieto Peres

Keywords:

Headache

Coronavirus

Covid-19

2019-nCoV

SARS-CoV-2

Palavras-chave:

Cefaleia

Coronavirus

Covid-19

2019-nCoV

SARS-CoV-2

Bastos SNMAN, Sousa DACM, Melo SSS, Barbosa BLF, Cruz LGB, Silva-Néto RP.

Headache in patients infected with the novel coronavirus (Covid-19): An integrative literature review

Introduction

he disease caused by the novel coronavirus (2019-nCoV) was

named by the acronym COVID-19 which means “COrona VIrus

Disease”, while “19” refers to the year 2019, when the rst cases in

Wuhan, China, were identied. The virus that causes this disease, a

beta coronavirus, is called SARS-CoV-2 (severe acute respiratory syn-

drome coronavirus 2) and it is the same virus that causes Severe Acute

Respiratory Syndrome (SARS), identied in 2002, and Middle East

Respiratory Syndrome (MERS), identied in 2012. Transmission of

2019-nCoV from humans to humans has been conrmed in China

and the USA and occurs mainly with the contact of respiratory dro-

plets from infected patients

In December 2019, in China, a novel coronavirus was identied

as the cause of a severe acute respiratory syndrome and received

worldwide attention. It is a new emerging zoonotic agent that results

in a severe syndrome that, in some patients, leads to the need for

intensive respiratory treatment with specialized management in

intensive care units

In January 2020, the World Health Organization (WHO) declared

the outbreak in China as a public health emergency of international

interest. In March 2020, with the spread of the virus in different

countries, the infection caused by SARS-CoV-2 was considered a

pandemic and called COVID-19. In early April, WHO recorded

more than 1 million cases of patients infected with SARS-CoV-2

worldwide and more than 65,000 deaths caused by the pandemic

worldwide. In Brazil, at the time of writing this manuscript, there are

more than 18,000 cases of infection and more than 1,000 deaths

According to a Chinese study, the main clinical symptoms of patients

with COVID-19 are fever (88.7%), cough (67.8%), fatigue (38.1%),

sputum production (33.4%), dyspnoea (18.6%), sore throat (13.9%)

and headache (13.6%). Gastrointestinal symptoms, such as diarrhea

(3.8%) and vomiting (5.0%) are less frequent

. Elderly and people

with underlying diseases are susceptible to infection and more pre-

disposed to severe outcomes, which may be associated with acute

respiratory distress syndrome (ARDS) and the cytokine storm

5,6

Although headache is one of the clinical manifestations of CO-

VID-19, this symptom is still poorly characterized. In this context, our

objective was to identify the prevalence of headache and to know

its clinical characteristics in a patient with COVID-19, available in

the literature.

Methods

This study was an integrative and retrospective review of the articles

on headache as a symptom of COVID-19 published in the last 16

months. The research was performed in the online databases Litera-

tura Latino-Americana e do Caribe em Ciências da Saúde (LiLacs),

Scientic Electronic Library Online (SciELO), Chinese National

Knowledge Infrastructure (CNKI) and Medical Literature and Retrivial

System onLine (MEDLINE/PubMed®), from January 2019 to April

2020, given the current status of the pandemic by SARSCov-19. We

have used the descriptors “headache and coronavirus”, “headache

and 2019-nCoV”, “headache and SARS-CoV-2”, “headache and

coronavirus and 2019-nCoV” and “headache and coronavirus

and SARSCoV-2”.

Articles written in all languages were included. Editorials, comments,

letters to the editor, review articles, articles that were not fully availa-

ble or those that did not have accurate information were excluded.

To ensure the validity of these articles, the selected studies were

analyzed in detail, by all authors, for the presence of headache in

patients with COVID-19.

In our search, we found a total of 94 articles, but with the elimination

of repeated articles, only 49 remained.

After reading the abstracts, we excluded articles that did not des-

cribe headache with associated symptom (36 articles). Only 13

articles describing case series were included and made up this

review, totaling 3,105 patients (Figure 1).

Figure 1. Flowchart of search and selection of studies

Data were analyzed based on demographic and clinical characte-

ristics and are presented as percentages. The percentage is always

related to the total number of patients whose information was avai-

lable for the specic issue.

Results

In 13 articles analyzed in this review, a total of 3,105 Chinese pa-

tients (51.6% men and 48.4% women) had laboratory diagnoses of

COVID-19. In 7.7% (240/3,105) patients, headache was an associa-

ted symptom of COVID-19, but in only 21.7% (52/240) of them there

was some information about the characteristics of this headache,

as shown in Table 1.

Discussion

Coronaviruses are a large class of viruses that exist widely in nature

and the newly discovered 2019-nCoV is the seventh coronavirus

currently known to infect humans and also responsible for the current

Bastos SNMAN, Sousa DACM, Melo SSS, Barbosa BLF, Cruz LGB, Silva-Néto RP.

Headache in patients infected with the novel coronavirus (Covid-19): An integrative literature review

pandemic that started in China

To the best of our knowledge, this is the rst study to assess he-

adache characteristics in patients with COVID-19. We found that

headache was an initial symptom of the disease in 3,105 pacients

with this disease. Its prevalence has been reported in most studies,

but its semiological characteristics have rarely been addressed.

According to the International Classication of Headache Disor-

ders, 3rd edition (ICHD- 3)

, headache attributed to systemic viral

infection is characterized by its temporal relation to onset of viral

infection and signicant improvement or resolution in parallel with

the improvement or resolution of systemic viral infection. Headache

is usually diffuse and of moderate to severe intensity (Table 2).

Possibly, the neuroinvasive predisposition characteristic of corono-

viruses is an explanation for patients with COVID-19 to develop

headache. Genomic analysis shows that SARS-CoV-2 shares a highly

homologous sequence with SARS-CoV-1 and MERSCoV, in addition to

a similarity of receptors in human cells. This can affect the respiratory

tract and also the central nervous system, especially the thalamus

and brain stem

Headache was observed in patients of all age groups, both in

adults

7-13

, as in children

. It is important to note that headache is a

characteristic symptom of pneumonia caused by coronavirus and

not exclusive to COVID-19, and does not behave as a differential

symptom between these viral infections

Table 1. Clinical characteristics of headache in 3,105 patients with coronavirus disease 2019 (Covid-19) in the period from January 2019 to April 2020

in China.

Published studies Number of patients

Age (years)

Sex

Headache preva-

lence

Headache prevalence

Average Variation n %

Tian et al., 2020

262 47. 5 1–94 M=127; F=135 17 6.5

Mild to moderate intensity in 93.5%

of patients and it appeared at the

beginning of the disease

Xu et al., 2020

62 41.0 19-65 M=35; F=27 21 34.0

71.4% of patients and it appeared at

the beginning of the disease

Huang et al., 2020

41 49.0 18-65 M=30; F=11 3 7. 3 NR

Liu et al., 2020

30 35.038 21-59 M=10; F=20 16 53.3

It appeared at the beginning of the

disease

Cheng et al., 2020

1,078 46.0 0.25-94 M=573; F=505 22 2.0 NR

Wang et al., 2020

31 7. 1 0.5-17 M=15; F=16 3 9.7 NR

Li et al., 2020

54 51.5 25-82 M=22; F=32 ? Rare NR

Chen et al., 2020

99 55.5313.1 21-82 M=67; F=32 8 8.0 NR

Liu et al., 2020

137 55.0316.0 20-82 M=61; F=76 13 9.5 NR

Mi et al., 2020

10 68.4318.5 34 -87 M=2; F=8 1 10.0 NR

Jin et al., 2020

651 NR NR M=331; F=320 67 10.3

It was more frequent in patients with

gastrointestinal symptoms (21.6%

versus 8.8%)

Ding et al., 2020

5 50.239.8 39-66 M=2; F=3 2 40.0 NR

Zhang et al., 2020

645 NR NR M=328; F=317 67 10.4

It was more frequent in patients with

abnormal pulmonary imaging ndings

(11.3% versus 2.8%)

Legend: M – male; F – female; NR – not reported.

Table 2 . Diagnostic criteria of ICHD-3 for headache attributed to systemic viral infection.

A. Headache of any duration fullling criterion C

B. Both of the following:

1. systemic viral infection has been diagnosed

2. no evidence of meningitic or encephalitic involvement

C. Evidence of causation demonstrated by at least two of the following:

1. headache has developed in temporal relation to onset of the systemic viral infection

2. headache has signicantly worsened in parallel with worsening of the systemic viral infection

3. headache has signicantly improved or resolved in parallel with improvement in or resolution of the systemic viral infection

4. headache has either or both of the following characteristics:

a. diffuse pain

b. moderate or severe intensity

D. Not better accounted for by another ICHD-3 diagnosis

Bastos SNMAN, Sousa DACM, Melo SSS, Barbosa BLF, Cruz LGB, Silva-Néto RP.

Headache in patients infected with the novel coronavirus (Covid-19): An integrative literature review

In the studied cases of COVID-19, headache was usually associated

with other typical symptoms of the disease, such as gastrointestinal

symptoms. When the patient experienced nausea, vomiting and

diarrhea, headache was more frequent, probably due to the higher

fever and hydroelectrolytic imbalance

We found in the 13 studies a prevalence of headache equal to 7.7%

(240 out of 3,105 patients), ranging from 2.0% to 53.3%. A factor

that may determine a higher prevalence of headache in COVID-19

patients is pneumonia, considered a predictive factor for severe

subtypes of the disease. We observed that in patients with changes

in pulmonary radiological images there was a higher prevalence of

headache when compared to patients with normal exams

The symptoms of COVID-19 are nonspecic, making the initial clinical

presentation indistinguishable from other viral respiratory diseases.

Initially, there is a predominance of systemic manifestations, such

as fever, fatigue, myalgia and asthenia

. However, the headache

that can also appear at the beginning of the disease should not be

neglected, but contribute to the diagnosis, especially in those patients

with a positive epidemiological history.

This review had some limitations. All patients were from China,

so some articles found were written in Chinese and needed to

be translated

10 -13

. In addition, as it is pandemic, new studies were

published almost daily and described the headache incompletely.

However, we believe that these ndings are consistent with the

clinical manifestations of this disease.

Conclusion

COVID-19 patients have several clinical manifestations, including

headache that is nonspecic with a prevalence of 7.7%.

Funding: This research received no specic grant from any funding

agency in the public, commercial, or not-forprot sectors.

Conflict of Interest: There is no conict of interest.

References

1. Guo YR, Cao QD, Hong ZS, Tan YY, Chen SD, Jin HJ, et al.

The origin, transmission and clinical therapies on coronavirus

disease 2019 (COVID-19) outbreak - an update on the status.

Mil Med Res 2020 Mar;7(1):11.

2. Rodriguez-Morales AJ, Cardona-Ospina JA, Gutiérrez- Ocam-

po E, Villamizar-Peña R, Holguin-Rivera Y, Escalera-Antezana

JP, et al. Clinical, laboratory and imaging features of CO-

VID-19: A systematic review and meta-analysis. Travel Med

Infect Dis 2020;13:101623.

3. World Health Organization (WHO). Coronavirus disease

(COVID-2019) situation reports. Available in: <https://www.

who.int/emergencies/diseases/novel-coronavirus-2019/situa-

tion- reports/> Accessed on: April 10, 2020.

4. Guan W, Ni Z, Hu Y, Liang W, Ou C, He J et al. Clinical

characteristics of Coronavirus disease 2019 in China. N Engl

J Med 2020;28.

5. BRASIL. Ministério da Saúde. Protocolo de manejo clínico do

coronavírus (covid-19) na atenção primária à saúde. Secretaria

de Atenção Primária à Saúde. Brasília. Março, 2020.

6. Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, et al. Clinical

characteristics of 138 hospitalized patients with 2019 novel

Coronavirus-infected pneumonia in Wuhan, China. JAMA.

2020;323(11):1061-1069.

7. Tian S, Hu N, Lou J, Chen K, Kang X, Xiang Z et.al. Characte-

ristics of COVID-19 infection in Beijing. J Infect 2020;80(4):401-

406.

8. Xu WX, Wu XX, Jiang XG, Xu KJ, Ying LJ,Ma CL et.al. Clinical

ndings in a group of patients infected with the 2019 novel Co-

ronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective

case series. BMJ 2020;368:m606.

9. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y et.al. Clinical

features of patients infected with 2019 novel coronavirus in

Wuhan, China. Lancet 2020;395(10223):497-506.

10. Liu M, He P, Liu HG, Wang XJ, Li FJ, Chen S, et. al. Clini-

cal characteristics of 30 medical workers infected with new

coronovirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi

2020;43(3):209-214.

11. Cheng JL, Huang C, Zhang GJ, Liu DW, Li P, Lucy CY, et al. Epi-

demiological characteristics of novel coronavirus pneumonia in

Henan. Zhonghua Jie He He Hu Xi Za Zhi 2020;43(4):327-331.

12. Wang D, Ju XL, Xie F, Lu Y, Li F, Huang H, et al. Clinical analysis

of 31 cases of 2019 novel coronavirus infection in children from

six provinces (autonomous region) of northern China. Zhonghua

Er Ke Za Zhi 2020;58(4):E011.

13. Li YY, Wang WN, Lei Y, Zhang B, Yang J, Hu JW, et al. Com-

parison of the clinical characteristics between RNA positive

and negative patients clinically diagnosed with 2019 novel

coronavirus pneumonia. Zhonghua Jie He He Hu Xi Za Zhi

2020;43(5):427-430.

14. Chen N, Zhou M, Dong X, Qu J, Gong F, Han Y, et al. Epi-

demiological and clinical characteristics of 99 cases of 2019

novel coronavirus pneumonia in Wuhan, China: a descriptive

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characteristics of novel coronavirus cases in tertiary hospitals in

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Disorders, 3rd edition. Cephalalgia 2018;38(1):1- 211.

Headache Medicine 2020, 11(1):7-9 ISSN 2178-7468, e-ISSN 2763-6178

ASAA

DOI: 10.48208/HeadacheMed.2020.3

Headache Medicine

Original

The Migraine Tree: a shared tool for migraine information

A Árvore da Migrânea: uma ferramenta compartilhada para informação sobre migrânea

Elizabeth Leroux

Brunswick Medical Center, Montreal, Canada.

Abstract

Migraine awareness is a critical step in minimizing the disease burden. The Migraine Tree is

a web structure designed by a Canadian team to inform people living with migraine and give

them the knowledge they need to understand their disease and make daily decisions. This

article summarizes the reasons for the creation of the Migraine Tree, its design and underlying

principles and proposes future collaborations for translation in other languages.

Resumo

A conscientização sobre a migrânea é uma etapa crítica para minimizar a carga da doença.

A Árvore da Migrânea é uma estrutura online projetada por uma equipe canadense para

informar as pessoas que vivem com migrânea e fornecer o conhecimento necessário para

entender sua doença e tomar decisões diárias. Este artigo resume os motivos da criação

da árvore da migrânea, seu design e princípios subjacentes e propõe futuras colaborações

para tradução em outros idiomas.

Elizabeth Leroux

Medical Center, Montreal, Canada

leroux.mail@gmail.com

Received: March 26, 2020.

Accepted: March 28, 2020.

Edited by

Mario Fernando Prieto Peres

Keywords:

Migraine

Awareness

Education

Palavras-chave:

Migrânea

Conscientização

Educação

ASAA

Leroux E

The Migraine Tree: a shared tool for migraine information

Introduction

he Migraine Tree is a web structure designed by a Canadian

team to inform people living with migraine and give them the

knowledge they need to understand their disease and make daily

decisions. This article summarizes the reasons for the creation of the

Migraine Tree, its design and underlying principles and proposes

future collaborations for translation in other languages.

A need for therapeutic education tools

Therapeutic education has been recommended to manage chronic

diseases

. A World Health Organization report in 1998 summari-

zed its principles and benets. People living with migraine make

numerous decisions every day related to their condition and need

the knowledge to make choices that will allow them to function and

avoid negative consequences. A systematic review of therapeutic

education for migraine found positive outcomes on quality of life,

headache related disability, depression and headache frequency

The amount of information on migraine that has to be explained to

patients is overwhelming. It cannot be synthetized in a busy clinic visit.

Physicians may not have the time or communication skills to effectively

counsel patients

. Education sessions have been found to be effective

to improve outcomes and limit visit to the emergency department,

but organizing and funding such sessions is not always possible

. The

amount of misleading information available online is signicant.

People looking for reliable information can be bewildered by the

numerous promises of cures and quick xes. On the other side,

scientic websites and blogs sometimes have too much unclassied

information, making it difcult to nd the topic needed. Every person

with migraine has different needs. Attacks, symptoms, triggers and

response to therapy vary. Having access to relevant, easy to unders-

tand information is crucial for migraine management. Some resources

are also written in a language for health care providers and do not

necessarily address people’s needs and concerns.

The Migraine Tree structure and design

The Migraine Tree is an original idea of Dr Elizabeth Leroux, a

headache neurologist from Canada. After years of involvement in

headache care and counselling, and previous web experiences with

Migraine Quebec, she realized that a structure could help patients

and health care providers to nd what they need, contribute to a

better understanding of the global approach and also have an

educational value for health care providers not familiar with mi-

graine management.

It was very important to choose a positive symbol for the structure.

The Tree was chosen as a symbol of growth. Every culture, every

country is familiar with trees. Trees assemble in forests, communities.

They are resilient, they can lose their leaves and then grow new

ones. They can bear owers and fruits. Every person with migraine

is part of a forest and can grow as new skills are learned.

The Migraine Tree uses a structure linking the network of the roots

to the trunk and then to another network of branches. The structure

was presented to patients during a focus group for feedback and the

structure was found to be easy to use and understand. One interes-

ting points the patients provided was that the the word «alternative

therapies» was not used. This was a mindful decision, as opposing

alternative and traditional medicine was not thought to be benecial

to patients. For example, some supplements have been shown to be

effective for migraine prevention and acupuncture is also supported

by evidence.

For some options at the Leaf level, two pages exist on a single topic:

the WHY focuses on the rationale and proof of effectiveness. The

HOW presents practical tips to use the treatment.

The Migraine Tree visual design was accomplished through a gra-

phic design contest led by 3aLogic, a company based in Quebec.

The nal design was chosen for its simplicity and colored in green

and blue, in order to offer a soothing image. Images accompanying

the texts were acquired in majority from the 123RF database and

paid for by Migraine Canada. The team valued positivity, diversity

and even humor to give an encouraging vibe to the readers. In the

team’s experience, people with migraine do not like to see images

of pain and suffering repeatedly, as is unfortunately the case in

the media.

Figure 1. The Migraine Tree.

ASAA

Leroux E

The Migraine Tree: a shared tool for migraine information

is the excess of distracting ads that may bother people with migraine

who are photosensitive. It can be used in the clinic for teaching, the

health care provider familiar with the pages being able to point out

which topics are of interest from a particular patients.

The writing of the content

Topics were chosen and structured by Dr Leroux. Due to the large

numbers of pages needed (close to 140), a team of Canadian

writers was assembled. All writers were volunteers and agreed to

decline authorship on the texts they provided. The guidelines of

the Sick Kids Hospital from Toronto were used to determine format

(PDF). The format chosen for most pages is a Question and Answer,

that makes browsing for specic information easier. Questions were

inspired from the clinical work of the health care providers who

contributed. A checklist format has also been used, especially for the

HOW pages. The pages have been limited to 600 to 900 words to

avoid reading fatigue. The tone, format and style of pilot pages

were reviewed by volunteer patient editors to provide guidance

to the writers. Writers were instructed to write in an accessible

and friendly way. They were encouraged to describe the typical

challenges met by patients and choose words to empower them as

much as possible. Some articles are more complex and may not

be accessible to all readers but could benet readers with higher

literacy or scientic background.

In order to optimize search engine optimization (SEO), internal

and external links were included in the pages. Key words and tags

were selected. Scientic references were imported from Pubmed,

prioritizing recent review articles.

A branch of the tree (Social Life) is still to be written by patients. This

branch focuses on social impact of migraine and how to deal with

relationships, school, and the workplace. Input from patients will be

solicited through Migraine Canada in 2020. Engaging the patient

community is extremely important.

Building a Migraine Tree community, sharing with

other countries

The Migraine Tree was created in a spirit of sharing. The need for

patient information of migraine is universal. Migraine is a common

disease in all countries. Numerous resources are available in the

English language, with the United Kingdom and the United States

leading the way with well-organized and nancially sustainable

associations. For other languages though, resources are scarce.

Headache associations don’t always have the resources necessary

to build elaborate educational tools. Reinventing the website wheel

for each country, each association, would be time consuming for

busy health care providers and volunteers alike. One of the goals of

the team was to save time to other patient associations. In order to

facilitate sharing, all the pages of the Migraine Tree are archived in

a DropBox. Folders and pages all have an ID number. This archive

is easy to share for translation.

Another important aspect of the Migraine Tree is its sustainability.

As it is based on a hierarchical ensemble of numerated articles, it

can be maintained relatively easily as knowledge progresses. Each

article could be improved by requesting feedback from patients. As

long as there is no duplication, new leaves can be added or even

replace a similar leaf with a better version that can then be trans-

lated in other languages, a bit like the articles of the Wikipedia

encyclopedia. Pages containing country-specic data would need

to be adapted (lists of medications, coverage comments).

In order to improve the Migraine Tree, feedback from users should be

gathered in the future, both from health care providers and patients.

Concl usion

The Migraine Tree is a new online structure offering people with

migraine a wealth of reliable information in a format that is easy to

browse. Future collaborations could be developed with other coun-

tries to make this information accessible to more people.

References

1. Ofman JJ, Badamgarav E, Henning JM, Knight K, Gano AD,

Jr., Levan RK, et al. Does disease management improve clinical

and economic outcomes in patients with chronic diseases? A

systematic review. Am J Med. 2004;117(3):182-92.

2. Kindelan-Calvo P, Gil-Martinez A, Paris-Alemany A, PardoMon-

tero J, Munoz-Garcia D, Angulo-Diaz-Parreno S, et al. Effective-

ness of therapeutic patient education for adults with migraine. A

systematic review and meta-analysis of randomized controlled

trials. Pain medicine (Malden, Mass). 2014;15(9):1619-36.

3. Fortin AHt. Communication skills to improve patient satisfaction

and quality of care. Ethn Dis. 2002;12(4):S3-58-61.

4. Lagman-Bartolome AM, Lawler V, Lay C. Headache Education

Active-Waiting Directive: A Program to Enhance Well-Being Du-

ring Long Referral Wait Times. Headache. 2018;58(1):109-17.

Table 1. The different levels of the Migraine Tree.

Level Denition Examples

Roots The medical background and diversity of people with migraine. Medical and psychological comorbidities

Hormonal factors

Other headaches

Trunk information that is relevant for most people with migraine at the beginning of

their journey to improvement

Causes of migraine

Use of a diary

Research and placebo response

Branches Treatment approaches are presented on an equal level. Behavioral approaches, acute and preventive

medications, neuromodulation

Leaves Details on approaches, skills and treatments. Individual medications, devices, skills

Headache Medicine 2020, 11(1):10-13 ISSN 2178-7468, e-ISSN 2763-6178

ASAA

DOI: 10.48208/HeadacheMed.2020.4

Headache Medicine

Original

Migraine aura: results from an art contest

Aura da enxaqueca: resultados de um concurso de arte

Bruna de Freitas Dias

Arao Belitardo de Oliveira

Juliane Prieto Peres Mercante

Michele Viana

6,7

Luiz Paulo de Queiroz

Mario Fernando Prieto Peres

2,3,4

Faculdade Israelita de Ciências e Saúde Albert Einstein (FICSAE) .

Associação Brasileira de Cefaleia em Salvas e Enxaqueca (ABRACES).

Instituto

de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (IPQ-HCFMUSP).

Instituto Israelita de Pesquisa

Albert Einstein Hospital Israelita Albert Einstein (HIAE).

Universidade Federal de Santa Catarina

Headache Group, Department of Basic and Clini-

cal Neurosciences, King’s College London, London, UK.

Headache Center, Neurocenter of Southern Switzerland (NSI), Regional Hospital Lugano.

Abstract

Introduction

Migraine is a common primary headache and a major cause of disability. In at least a third of migraine attacks, the hea-

dache is preceded or accompanied by aura, and the visual manifestation is the most frequent phenotype. Migraine with

aura is underdiagnosed and undertreated. So, a detailed aura iconography is important for better recognition, prevention,

and treatment of migraine with aura.

Objective

A visual aura art contest was performed by ABRACES (Brazilian Association of Cluster Headaches and Migraines) in order

to provide new images for raising awareness among the population and professionals and decreasing the gap between

diagnosis and treatment.

Methods

The contest involved a free subscription of drawings, paintings, and digital art that expressed realistic results of a visual aura

of migraine and answering a questionnaire. The awards were separated into two categories (painting/drawing and digital

art/photography) and amounted up to R$5,000.

Results

There were 139 participants (76% women). The most common visual aura’s characteristic was colorful points, and the

less frequently was golden. The duration of visual aura was 110.6±450.5 min (1- 3,600 min). 36.7% of the subscribers

have only one kind of visual aura, and 33.8% answered that have more than one kind. 46.5% said that their visual aura

almost never occurs without pain after or while aura, and 19% reported that their visual aura always occurs without a

headache.

Conclusion

Art contests are useful tools for disease awareness. Further actions in disseminating aura images may help migraine aura

underdiagnosis and undertreatment.

Resumo

Introdução

A enxaqueca é uma cefaleia primária comum e uma das principais causas de incapacidade. Em pelo menos um terço dos ata-

ques de enxaqueca, a cefaleia é precedida e/ou acompanhada por aura e a manifestação visual é o fenótipo mais frequente.

Enxaqueca com aura, um subtipo de enxaqueca, é subdiagnosticada e subtratada. Portanto, uma iconograa detalhada

da aura é importante para um melhor reconhecimento, prevenção e tratamento da enxaqueca com aura.

Objetivo

Um concurso de arte de aura visuais foi realizado pela ABRACES (Associação Brasileira de Dores de Cabeça e Enxaqueca),

para que mais imagens possam ser usadas para aumentar a conscientização da população e dos prossionais, otimizando

o diagnóstico e o tratamento.

Métodos

O concurso envolveu inscrição gratuita de desenhos, pinturas, e arte digital e fotograa que expressavam resultados realistas

de uma aura visual de enxaqueca e preenchimento de um questionário. Os prêmios foram separados em duas categorias

(pintura/desenho e arte digital/fotograa), numa quantia até R$ 5.000.

Resultados

Foram 139 participantes, 24% homens e 76% mulheres. A mais prevalente característica da aura visual foi a presença de

pontos coloridos e menos frequentemente dourados. A duração média foi de 110,6 minutos (450,5 de desvio padrão),

mediana de 20 minutos, mínimo de 1 minuto e máximo de 3600 minutos. 36,7% dos participantes possuem apenas um tipo

de aura visual e 33,8% responderam que possuem mais de um tipo. 46,5% disseram que sua aura visual quase nunca ocorre

sem dor após ou durante a aura e 19% relataram que sua aura visual sempre ocorre sem dor de cabeça.

Conclusão

Concursos de arte são ferramentas úteis para a conscientização de doenças. Outras ações na disseminação de imagens

da aura podem ajudar no subdiagnóstico e subtratamento da aura da enxaqueca.

Mario F P Peres

mariop3r3s@gmail.com

Received: January 15, 2020.

Accepted: January 22, 2020.

Edited by

Marcelo M. Valença

Keywords:

Migraine

Aura

Contest

Palavras-chave:

Enxaqueca

Aura

Concurso

Dias BF, et al.

Migraine aura: results from an art contest

Introduction

igraine is a common primary headache and a major cause

of disability

. It is characterized by recurrent episodes of

headache often associated with nausea, vomiting, photophobia

and phonophobia. The annual prevalence in general population

is an average of 12%, and it is more frequent in 25 to 55 years old

individuals and women population

. Patients have episodic attacks

separated by interictal phases. The attack is an interplay between

genetic

and environmental factors, possibly resulting in a dysfunc-

tional state and structure alteration of the brain

4,5

In at least a third of migraine attacks, the headache is preceded

and/or accompanied by reversible neurologic symptoms, named

aura. This condition is classied as migraine with aura, a subtype of

migraine disorder. In early descriptions, aura is linked to migraine

since 1870, when Elliott showed the idea of migraine as a disorder

characterized by aura, and associated with creativity, intellect, and

visual disturbance.

According to Headache Classication Committee of the Interna-

tional Headache Society (IHS)

, aura is described as one or more

of visual, sensitive, speech, motor, brainstem or retinal symptoms.

Positive and/or negative visual manifestation is the most frequent

phenotype, present in 98% of the patients

. Prevalent symptoms are

ashes of bright light, foggy/blurred vision, zigzag or jagged lines,

scotoma and phosphenes; and less frequent are more complex

perception, such as misperception of distance, fractured vision,

dysmorphopsias, tunnel vision, hemianopsia, curved or circular

lines, among others

. Since visual auras varies in form, severity

and duration both among patients and within each patient

, the

anatomical location, extent and probably nature of the underlying

occipital dysfunction must vary.

Migraine with aura are underdiagnosed and undertreated, partially

because of misdiagnosis

. The consequences are chronic migraine,

decreased quality of life and work productivity

11–13

. A detailed aura

iconography is important for better recognition, prevention and

treatment of migraine with aura.

An aura art contest was performed by ABRACES (Brazilian Asso-

ciation of Cluster Headaches and Migraines), so more images can

be used for raising awareness of population and professionals,

decreasing the gap between diagnosis and treatment.

Methods

The Art Contest Migraine Visual Aura by ABRACES involved free

subscription of drawings, paintings, digital art and photography

that expressed realistic results of a visual aura of migraine. The

applications were open to September 22

until October 6

, 2019.

The awards were separated in two categories (painting/drawing

and digital art/photography) and were equivalent to up to R$ 5.000.

The participants were people that have migraine with visual aura or

people with artistic skills that asked somebody who has.

Visual aura was characterized as a disturbance of visual perception

that occurs before the start of a migraine (or during), in a gradual

way, lasting ve minutes to one hour and completely reversible.

Some questions were ascertained, such as: “how did you hear about

the contest?”, “are you submitting this work to someone else?”, “how

long does your aura take on average (in minutes)?”, “do you have

more than one type of aura?”, “does your visual aura occur without a

headache?” and “what are the characteristics of your visual aura?”.

Double data and data not properly lled were excluded to analy-

zing the results.

Statistical analysis

Categorical variables are presented as percentages and absolute

number and continuous variables are presented as means with

standard deviation, median, maximum and minimum data.

Results

There were 139 participants in the contest. It was composed by

24% men and 76% women.

Most of participants heard about the contest by social medias:

Instagram (38%) and Facebook (38%), 9% from google, 9% from

ABRACES website, 5% from other vehicle of information and

1% from interview. The great majority submitted their own art

expressing their visual aura.

Figure 1 detailed the prevalence of the characteristics of the visual

aura. The most common was presence of points and colorful and

the less common was golden. 20% of the participants answered

that their visual aura has others features not mentioned.

Figure 1. Percentage of visual disturbances reported by contest participants

Type of color

The mean duration of visual aura was 110.6 minutes (450.5 of standard

Dias BF, et al.

Migraine aura: results from an art contest

deviation), median of 20 minutes, minimum of 1 minute and maximum of

3600 minutes.

About the predominance of the pattern of visual aura, 36.7% of the sub-

scribers have only one kind of visual aura and 33.8% answered that have

more than one kind. Besides visual aura, 6% of the participants also present

loss of strength in one half of the body, 9% have difculty of speaking and

14.4% show tingling of in a half of face or body (Figures 2 and 3).

About the relation with headache, 8 participants did not ll the eld. From

131 of the participants that answered, 46.5% said that their visual aura

almost never occurs without pain after or while aura and 19% reported that

their visual aura always occurs without a headache (Figures 4, 5 and 6).

Figure 2. Percentage of visual aura types.

Figure 3. Percentage of visual auras, non-visual auras, with one type of

visual auras or more than one visual aura.

Figure 4. Visual aura occurring with or without headache.

Figure 5. Winners of the contest for the category digital art

Figure 6. Winners of the contest for the category painting

Discussion

The visual aura contest attracted a signicant number of participants who

contributed with representations of migraine auras. This helped us in gen-

erating new iconography of migraine aura and therefore will be of help in

increasing awareness of this underdiagnosed condition. Art contests are

a useful tool for awareness campaigns. The images uploaded were from

a great variety of visual auras.

Aura features reported by the participants were like the ones described

in previous papers

8,14

Further spread of the images is planned, a book with aura images is under

development and hopefully will published soon. The same images could be

uploaded and disseminated via social media and website / search engine

such as Google. Indeed Health information is one of the most frequently

searched topics on the Internet

Availability of aura images to the general public may increase aura diagno-

sis, improving the access to migraine or other headache sufferers because

recognition of visual patterns by patients is likely to occur.

Conclusion

Art contests are useful tools for disease awareness. Further actions in

disseminating aura images may help migraine aura underdiagnosis and

undertreatment.

Dias BF, et al.

Migraine aura: results from an art contest

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Insight Rep 2003; May.

Headache Medicine 2020, 11(1):14-21 ISSN 2178-7468, e-ISSN 2763-6178

ASAA

DOI: 10.48208/HeadacheMed.2020.5

Headache Medicine

Original

Plasma ACE activity after aerobic exercise training is related to

sleep in migraine patients: A secondary, per protocol analysis

Atividade da ECA após treinamento físico aeróbio é correlacionada com sono em pacientes com migrânea:

uma análise secundária por protocolo

Arão Belitardo Oliveira

1,2

Bruna Visniauskas

Jair Ribeiro Chagas

Mario Peres

2,5

Universidade Federal de São Paulo, Neurologia e Neurocirurgia, São Paulo, São Paulo, Brazil.

Hospital Israelita Alber Einstein, Instituto do Cerebro,

São Paulo, São Paulo, Brazil.

Tulane University School of Medicine, Department of Physiology, New Orleans, Louisiana, Estados Unidos.

Universi-

dade Federal de São Paulo, Biologia Molecular, São Paulo, São Paulo, Brazil.

Universidade de São Paulo, Instituto de Psiquiatria, São Paulo, São

Paulo, Brazil.

Abstract

Angiotensin converting enzyme-1 (ACE) has been implicated in sleep regulation and nociception. In a

secondary, per-protocol analysis, we investigated the effect of a 12-week aerobic exercise program on

plasma ACE activity (primary outcome variable), migraine clinical outcomes, and psychometric scores be-

tween migraine and control, non-headache participants. Fifty-nine participants (migraine: n=31 and control:

n=28) gave signed consent form and were per-protocol analyzed. At baseline, there were no differences

between groups for ACE activity. After the intervention period, the ACE activity increased in the migraine

exercise group compared to control waitlist group [mean difference (95% CI) = 33.8 nM.min

–1

.mg

–1

(1.0,

66.5), p = 0.02]. Among patients, the migraine exercise group showed greater numeric reduction in the

number of sleep deprivation-triggered attacks compared to migraine waitlist group (-21 vs -8, respectively),

and lower insomnia scores [mean difference (95% CI) = -0.625 (-996, -254), p = 0.001]. There was an

inverse correlation between BECK-II insomnia domain scores and ACE activity (r = -0.53, p = 0.035). This

study suggests that aerobic exercise training increases plasma ACE activity with possible implication on

sleep regulation in migraine patients.

Resumo

A enzima conversora de angiotensina-1 (ECA) está implicada na regulação do sono e nocicepção. Em uma

análise secundária por protocolo, objetivamos investigar o efeito de um programa de exercícios aeróbicos

de 12 semanas na atividade da ECA plasmática (variável de resposta primária), variáveis clínicas e escores

psicométricos entre participantes com migrânea e controle sem nenhum tipo de cefaleia. Cinquenta e nove

participantes (enxaqueca: n = 31 e controle: n = 28) assinaram o termo de consentimento e foram anali-

sados por protocolo. No período basal, não houve diferenças entre os grupos para a atividade da ECA.

Após o período de intervenção, a atividade da ECA aumentou no grupo de exercícios com migrânea em

comparação ao grupo de lista de espera de controle [diferença média (IC95%) = 33,8 nM.min – 1.mg – 1

(1,0, 66,5), p = 0,02]. Entre os pacientes, o grupo exercício mostrou maior redução numérica no número

de ataques desencadeados por privação do sono em comparação com o grupo controle (-21 vs -8, respec-

tivamente) e menores escores médios do domínio de insônia BECK-II [diferença média (95% CI) = -0,625

(-996, -254), p = 0,001]. Houve uma correlação inversa entre os escores de insônia e a atividade da ECA

(r = -0,53, p = 0,035). Este estudo sugere que o exercício aeróbico regular aumenta a atividade da ECA

no plasma com possível implicação na regulação do sono em pacientes com migrânea.

Arão Belitardo Oliveira

araoliva@gmail.com

Received: March 12, 2020.

Accepted: March 23, 2020.

Edited by:

Marcelo Moraes Valença

Keywords:

Physical Activity

Exercise Therapy

Angiotensin-Converting Enzyme

Chronic Pain

Headaches Disorders

Migraine

Sleep

Palavras-chave:

Atividade Física

Terapia por Exercício

Enzima conversora da angiotensina

Dor crônica

Cefaleias

Migrânea

Sono

Oliveira AB et al.

Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis

Introduction

erobic exercise training exerts prophylactic effects on migrai-

1,2

, and also promotes anxiolytic effects

in this population.

In spite of ample theoretical explanations for the preventive effects

of exercise for migraine, the mechanisms underlying the therapeutic

effects of aerobic exercise are still elusive.

Angiotensin-I-converting enzyme (ACE), a key protease of the renin

angiotensin system (RAS), has been implicated in migraine patho-

physiology by mechanisms still not understood

3–5

. ACE cleavages

angiotensin-I into angiotensin-II (AngII), a potent vasoconstrictor

which also orchestrates several physiological adjustments and

adaptations in response to acute and chronic physical exercise

6,7

The RAS is operative in stress sensitivity

and sleep regulation

which are associated with migraine triggers

, and pain perception

Thus, it is plausible to hypothesize the participation of this signaling

system in the clinical response to regular aerobic exercise and the

mechanisms related to common migraine triggers such as stress

and sleep deprivation.

Considering the participation of ACE in other pathological states

such as hypertension, heart failure, diabetes, and chronic kidney

disease, and the health-related effects of aerobic exercise training

counterpointing an exaggerated RAS tone observed in these con-

ditions

6,7

, we hypothesized that migraine patients would exhibit

higher plasma ACE activity and that aerobic exercise training would

reduce plasma ACE activity in this population. Secondarily, we

hypothesized that there would be correlations between changes in

ACE and clinical outcomes, as well as with migrainerelated triggers

and psychometric variables associated with ACE physiology.

Therefore, we compared plasma ACE activity between patients with

migraine and healthy, nonheadache individuals, and investigate

the inuence of aerobic exercise training on this protease activity.

We further exploited possible correlations between exercise training-

induced changes in ACE activity, psychometric scores (i.e., stress,

sleep, etc.) and clinical outcomes (e.g., days with headaches and

migraine triggers). These data were preliminary presented at the

5th European Headache and Migraine Trust International Congress,

held in Glasgow in September 2016.

Methods

Study Design

This is secondary, per-protocol analysis of a randomized controlled

trial aimed at testing the effect of a 12-week aerobic exercise

program on clinical outcomes

. We analysed the plasma ACE

activities, clinical outcomes and psychometric scores, as well as

tested the correlations between these variables. Participants were

randomly assigned to receive intervention with aerobic exercise

training (exercise groups) or enter a waitlist (waitlist groups). Simple

randomization (1:1) was performed using an online number

generation software.

Study’s protocol was composed by 7 clinical visits scheduled every

4 weeks, including the screening, neurological examination, and

delivery of headache diaries (Visit 0), and revaluations for checking

the headache diagnosis and diaries (visits 1-6). The baseline

period was set as the 4-week period between visits 0 and 1.

Blood sampling and psychometric interview were scheduled in the

samevisit, between visits 1 and 2, and were followed by the 12-

week intervention period. The last 4 weeks of the intervention period

(between visits 5-6) was set as “post-intervention” period for clinical

analyses. Test-retest visits for blood collection and psychometric

interviews were scheduled in the same order. All women were at

the follicular phase of the menstrual cycle at the blood sampling

visit. Retest visits for blood sampling were performed between 2-5

days after the last exercise session, or 48h after the last exercise

session within the same phase of the menstrual cycle as undertaken

at baseline. For all test-retest visits, participants were instructed to

breakfast regularly, but to abstain from coffee. All patients were

within the interictal period during all test-retest measurements.

The study’s protocol complied with the 1964 Helsinki declaration

on human research and was approved by the UNIFESP`s Research

Ethical Committee, registered under #081511, and all participants

gave written informed consent. This study was also registered in

the National Institute of Health (www.ClinicalTrials.gov) under

#NCT01972607.

Participants

We recruited patients from the Headache Unit of Hospital São

Paulo and a headache tertiary clinic, and healthy individuals

from the local community through printed and electronic media

advertisements between March 2012 and March 2015. Participants

were screened and evaluated by a neurologist. In this analysis, we

added 9 participants to the primary analysis sample, 7 chronic

migraine patients and 2 healthy controls.

Inclusion criteria were: individuals of both sex, aged between 18

and 65 years, non-headache individuals (dened as controls), and

patients with episodic and chronic migraine with/without aura,

according to the 2

version of the International Classication

of Headache Disorders

. Patients should not be under any

prophylactic treatment for migraine (except for using abortive

medication during attacks) or taking any other prescribed drug or

dietary supplement. Participants should be physically inactive (≤1

day/week of leisuretime physical activity the previous 12 months).

Exclusion criteria were: starting any non-pharmacological or

pharmacological treatment during the study period, or presenting

any other disease such as cardiovascular, pulmonary, metabolic,

musculoskeletal, rheumatic, or neurological disorder, including

another primary or secondary headache; smoking, alcohol, or drug

abuse, and disagreement to continue the protocol.

Intervention

All exercise sessions were supervised by experienced exercise

Oliveira AB et al.

Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis

physiologists. The 12- week program of aerobic exercise training

was conducted at the Center for Studies in Psychobiology and

Exercise, São Paulo, Brazil. It comprised 40-minute sessions of

walking or jogging on treadmill, performed 3 times per week

at treadmill speed (m.min

-1

), heart rate, and rate of perceived

effort corresponding to the ventilatory threshold. The ventilatory

threshold was determined during maximal cardiopulmonary

exercise test as described in a previous study

Headache Diary

The headache diary retrieved data on days with migraines,

migraine frequency, number of acute medication used, and

commonly reported migraine attack triggers: stress/irritability,

oversleep, sleep deprivation, alcohol, fasting, odorants and

photic stimuli, foods, menstruation, fatigue, weather, neck/back

pain, or nonidentiable.

Psychometric Questionnaire

Participants lled the psychometric questionnaires at the

Psychobiology Department before the blood collection.

Depression scores were assessed by Beck Depression Inventory-II

(BECK-II). Beck-II questionnaire has been validated and translated

into Brazilian Portuguese.

ACE Activity Assays

Blood samples were collected between 8:00AM and 10:00AM

at the Psychobiology Department after questionnaire lling,

by venepuncture of the antecubital vein in cooled heparinized

vacutainers (BD Vacutainer®, Franking Lakes, NY, USA). Samples

were immediately centrifuged for 10 minutes at a 3,400g at 4°C.

Plasma was separated, aliquoted in 2 mL vials, and stored at

-80°C until analysis. All samples were analysed within 6 months

after blood collection.

ACE activity was determined spectrouorimetrically using

uorescence resonance energy transfer (FRET) peptides. The

FRET peptides Abz-FRK(Dnp)P-OH (Aminotech Pesquisa e

Desenvolvimento, Brazil) was used, as described by Carmona et

al 2006

. Briey, ACE activity assays were performed in a Tris-

HCl 100 mM pH 7.0 buffer containing NaCl 100 mM and ZnCl2

10 mM. Lisinopril (Sigma, USA) was used as ACE inhibitor to

ensure substrate specicity. The reactions were continuously

followed in a Gemini XS uorimeter (Molecular Devices Company,

Sunnyvale, CA, USA) that measured the uorescence at lex =

320nm and lem = 420 nm (Abz group) and lex = 360 nm and

lem =440 nm.

All measurements were performed in duplicate and proteases

activity values were reported as nanomolar of substrate

hydrolyzed per minute per milligram of protein (nM.min

–1

.mg

–1

Outcome Variables

The primary outcome variable was ACE activity. Secondary

outcome variables were changes in days with headaches,

migraine frequency, psychometric scores, and attacks trigger factors.

Statistical Analysis

Between- and within-groups comparisons (4 groups x 2 times) for

ACE activity, anthropometric variables, and psychometric scores

were performed by repeated-measure ANOVA with Bonferroni’s

post hoc corrections for multiple pairwise comparisons. Comparisons

between migraine groups (2 groups x 2 time points) for clinical

variables were performed by repeated-measure ANOVA with

Bonferroni’s adjustments for multiple pairwise comparisons.

Differences between pre-post intervention values (delta values)

for proteases activity were calculated by univariate ANOVA with

Bonferroni’s corrections for pairwise comparisons.

For the trigger factors analyses, we performed descriptive statistics

of the trigger’s prevalence in the patients’ sample. Correlations

were calculated by Pearson’s correlation coefcients or Spearman’s

correlation coefcients, depending on variables distribution features.

The SPSS software (IBM SPSS Statistics for Windows, Version 20.0.

Armonk, NY) was used for statistical analyses. A p < 0.05 was

accepted as statistically signicant.

Results

Fifty-eight participants were randomized, concluded the study,

and were per protocol- analyzed. Participants characteristics’ are

reported in Table 1. For days with migraine and migraine attacks

frequency, there were no statistically signicant differences between

migraine groups at baseline (Table 1). There was a signicant group

vs time interaction [F(1,29) = 8.921, p = 0.006, η2 = 0.56] for

days with migraine. Migraine exercise group showed a signicant

reduction in days with headaches [mean difference (95% CI) = -5.0

(-8.5, -1.4); p = 0.007], without signicant changes observed in the

migraine waitlist group [mean difference (95% CI) = 2.2 (-1.2, 5.7);

p = 0.19)]. No signicant group vs time interaction was observed for

migraine attacks frequency [F(1, 29) =1.389, p = 0.248, η2 = 0.06].

For plasma ACE activity, repeated-measure ANOVA’s pairwise

comparisons showed no differences between groups at baseline

(Figure 1), while there was a group vs time interaction [F(3, 54)

= 3.324, p = 0.026, η2 = 0.42]. Bonferroni-adjusted pairwise

comparisons showed increased ACE activity in migraine exercise

group compared to control waitlist group after the intervention

period [mean difference (95% CI) = 33.8 nM.min

–1

.mg

–1

(1.0, 66.5),

p = 0.02]. One-way ANOVA univariate test using the delta values

expressed as percentage change from baseline showed signicant

between-group effects [F(3, 54) = 3.223, p = 0.03, η2 = 0.41], with

ACE activity in migraine exercise group [mean difference (95% CI) =

47.3 % (21.3 %, 75.5 %)] signicantly higher than the control waitlist

group [mean difference (95% CI) = -9.1% (-41.1 %, 19.3 %)]; p =

0.039] (Figure 1). There were no correlations between ACE activity

and days with migraine, neither at baseline (r = -0.83, p = 0.657)

nor for changes after the intervention period (r = -0.156, p = 0.409).

p < 0.001, η2 = 0.27]. Bonferroni-adjusted pairwise comparisons

Oliveira AB et al.

Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis

Figure 1. Plasma angiotensin-converting enzyme activity at baseline and percentage change after intervention. Data are expressed as mean±SE. *: p <

0.05, compared with control waitlist

Table 1. Participants anthropometric and clinical characteristics. Data are expressed as mean±SD

Groups

Control Waitlist Control Exercise Migraine Waitlist Migraine Exercise

Age (yrs) 35.3±9.5 34.4±11.5 36.2±10.2 39.8±13.5

BMI (kg/cm

) 26.2±3.4 25.6±3.6 26.4±5.4 27.2±4.1

Sex

Female 11 11 12 12

Male 4 4 3 3

Diagnosis

MwoA - - 7 5

MwA - - 4 8

CM - - 4 3

Time with Disease (yrs) - - 15.9±8.9 18.5±11.9

Days with Headaches (/month) - - 9.0±5.9 12.3±8.0

Acute Medication (/month) - - 7.4±6.3 9.4±9.9

SBP (mmHg) 112.5±2.8 114±2.5 110±2.7 115.6±2.5

DBP (mmHg) 74.1±1.7 75±1.5 69.6±1.6 72.6±1.5

2Peak

34.0±7.5 33.0±6.8 31.5±6.7 31.5±6.7

MwoA: Migraine without aura; MwA: Migraine with aura; CM: Chronic migraine; SBP: Sitolic Blood Pressure; DBP: Diatolic Blood Pressure; VO

2Peak

: Peak

Oxygen Uptake (Measure of cardiorespiratory tness).

showed that the migraine waitlist group had higher baseline BECK-

II total score than the control waitlist [mean difference (95% CI) =

11.9 (4.6, 19.1); p < 0.001], control exercise [mean difference (95%

CI) = 12.5 (5.7, 19.3); p < 0.001], and migraine exercise [mean

difference (95% CI) = 7.0 (.56, 13.6); p = 0.027] groups (Figure

2). For the BECK-II insomnia domain, repeated-measure ANOVA

showed a main effect of time [F(1, 58) = 9.444, p = 0.003, η2 =

0.17].

Bonferroni-adjusted pairwise comparisons showed that the migraine

exercise group had higher baseline BECK-II insomnia score than the

control exercise group [mean difference (95% CI) = 0.409 (0.007,

0.901); p < 0.001], and was the only group with signicant changes

after intervention period [mean difference (95% CI) = -0.625 (-996,

-254), p = 0.001] (Figure 2). No signicant main effects of time

or group, neither interaction was observed for BECK-II irritability

domain.

Oliveira AB et al.

Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis

Because triggers prevalence varied both within and between

subjects over the study period, we only conducted a descriptive

analysis of triggers. The most common triggers were stress/

irritability, sleep deprivation, and fasting (Figure 3). The migraine

exercise group showed a greater numeric reduction than migraine

waitlist group for sleep-deprivation (-21 vs -8 attacks, respectively)

and stress/irritability triggers (-20 vs -13, respectively) (Figure 3). In

order to explore the relation of major triggers in this sample with

ACE activity, we compute the correlations of BECK-II subdomains

as potential triggers correlates, that is, the BECK-II insomnia

domain for sleep deprivation trigger, and the irritability domain

for stress/irritability trigger. There was an inverse correlation

between changes (delta values) in BECKII insomnia domain

scores and ACE activity (r = -0.53, p = 0.035), while there was no

correlation between ACE activity and BECK-II irritability domain

scores (r= 0.022, p = 0.883).

Discussion

This study aimed at measuring the effect of a 12- week supervised

moderate aerobic exercise training on plasma ACE activity and

whether there would be any correlations with clinical outcomes.

To the best of our knowledge, this is the rst study to report a

stimulatory effect of regular aerobic exercise on plasma ACE

activity in migraine patients (nearly 50% increase), and a

correlation between plasma ACE activity and sleep quality

scores. Contrary to our hypothesis, we found no baseline ACE

activity differences between migraine and control groups.

Clinical studies have found elevated circulating ACE activity in

migraine patients in the interictal period

and increased plasma

AngII and aldosterone in patients experiencing salt-induced

migraine attacks

. At molecular level, an immunocytochemical

investigation has uncovered the presence of an angiotensinergic

system in the trigeminal ganglia of humans and rats

, suggesting

a role for this signaling system in migraine pathophysiology. At

genetic level, a meta-analysis found no association between ACE

I/D polymorphism and migraine, albeit in the Turkish population

ACE II polymorphism – which is characterized by lower ACE

expression than DD polymorphism - was associated with reduced

risk for migraine

. Furthermore, ACE inhibitors or AngII receptor

antagonists are common prophylactic drugs prescribed for migraine

15,16

As such, we expected that migraine patients would exhibit higher

baseline ACE activity that could be reversed by aerobic exercise

training with clinical implications, as observed in other pathological

conditions such as hypertension

, heart failure

, or chronic kidney

disease

6,18

, wherein there is a noticeable exaggerated RAS

activity. Our results indicate that the relationship between ACE

and migraine and its response to exercise is not as simplistic as

hypothesized. Possible explanations to our data may lie in the

etiological mechanisms of migraine, ACE response to exercise, and

the complex, less known ACE actions on pain and sleep physiology.

The response of ACE or AngII to exercise vary in the population,

with studies showing increase, decrease or no change following

either acute or chronic exercise

6,7

. Increased resting, interictal ACE

activity in migraine reported in a previous study was interpreted as

a compensatory mechanism over vasoactive/algogenic molecules

involved in migraine pathophysiology such as nitric oxide (NO) and

calcitonin gene-related peptide (CGRP)

. In fact, there are evidences

corroborating this hypothesis, showing an inhibitory effect of ACE on

and CGRP

production. A recent study showed an abnormal

cardiovascular response following the administration of the NO

donor nitroglycerin in migraine patients, suggesting heightened

sensitivity to NO in this population

. Moreover, aerobic exercise

is one of the more effective natural inducers of NO release - which

in turn has been also credited as the cause of exerciseprovoked

migraine attacks

. Thus, theoretically, this higher ACE activity

response to exercise training found here could represent a migraine-

specic compensatory mechanism to counteract exercise-induced

exaggerated NO actions in migraine patients.

The RAS system has been implicated in pain

11,23,24

and sleep

physiology. Preclinical and clinical studies suggest a dual action of

the RAS in pain perception, partly depending on whether its actions

are mediated by angiotensin type-1 (AT1) or type-2 (AT2) receptors

Figure 2. Beck II inventory scores (total and insomnia domain) at baseline and after intervention. Data are expressed as mean±SE. *: p < 0.05, compared

with migraine exercise group; **: p < 0.001, compared with control exercise and control waitlist groups; #: p < 0.001, compared with control exercise

group; †: p < 0.01, compared with baseline.

Oliveira AB et al.

Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis

It seems that through AT1 receptors, ACE-AngII can promote

algogenic effects in several models of neuropathic and nociceptive

pain by activating downstream signaling cascades culminating in

pro-inammatory cytokines upregulation, such as interleukin-6

(IL-6) and tumor necrosis factor-α (TNF-α)

. As pro-inammatory

cytokines are associated with migraine

, this could be a putative

mechanism through which ACE activity inhibitors or AT1 receptors

antagonists are efcacious for migraine prophylaxis

11,16

On the other hand, mounting evidence have suggested opposite

effects of ACE-AngII on pain through AT2 receptors-dependent

and -independent mechanisms centrally and in the periphery

As reviewed by Bali et al.

, microinjections of AnII administered

in the ventrolateral periachedutal gray matter (PAG) attenuates

nociception in pain paradigms such as tail ick test and incision

allodynia; intracerebroventricular administration of AngII promotes

increases of tail ick and thermoalgesic stimuli latencies in rats;

spontaneous hypertensive rats, which exhibit high RAS tone, have

decreased pain sensitivity, while peripheral administration of AnII

in normal rats decrease pain sensitivity. A higher RAS tone seems

to mediate higher pain tolerance in hypertensive patients, as

enalapril and losartan were shown to induce a lower dental pain

tolerance in these patients

The mechanisms by which ACE-AngII exerts hypoalgesic effects is

believed to involve its stimulatory action of AngII on β-endorphin

release, the participation of ACE in kinins degradation such

as the potent algogenic mediators bradykinin and substace

P (besides NO and CGRP aforementioned), and the formation

of other peptides derived from AngII with centrally-mediated

antinociceptive actions

11,23

The correlation between improved insomnia score and changes

in ACE activity following exercise training may involve also the

interaction between physical exercise and RAS in sleep regulation.

Regular aerobic exercise has been associated with improved

sleep

, and is considered a synchronizer of human circadian

rhythms, partly by modulating melatonin secretion

28,29

. The RAS

is believed to exerts stimulatory effects on melatonin production

Angiotensin, ACE, AngII, and AT1 receptors are present in the

pineal gland of rats, and pineal gland forms AngII at a higher rate

than other brain areas. Furthermore, oral administration of losartan,

an AT1 antagonist, reduces by 35% the melatonin secretion,

while pineal gland cultures treated with this drug yielded a 67.6%

reduction in melatonin secretion in rats

. Conversely, reduction in

ACE specic activity and mRNA relative levels was observed in

the hypothalamus and brainstem of rats under the paradoxal sleep

deprivation paradigm

Considering the prominent role of melatonin in migraine

pathophysiology

, and its modulation by the RAS

, along with

the inuence of physical exercise on both hormonal signaling

systems

6,7,28,29

, it is admissible to speculate on a possible causal

relation with regard the signicant inverse correlation between

BECK II insomnia score and plasma ACE activity in migraine patients

following aerobic exercise training.

At this point, it is worth mentioning some aspects of ACE biochemistry

in the body that should be considered when interpreting the data

here. ACE et al. can be found in either plasma soluble or membrane

bound forms, with tissue-specic production

. As underscored

by Visniauskas et al.

, as a cytoplasmatic membrane anchored

enzyme, ACE turnover may vary in tissues and suffer inuence of

other peptidases, as well as its catalytic effects may be dissociated

from AngII formation. Agreeably, the antihypertensive effects of

ACE inhibition have long been seen to fail to correlate with plasma

ACE inhibition

. Moreover, aerobic exercise can stimulate ACE-

independent AngII production

. Nonetheless, our data cannot be

extrapolated to assume that plasma ACE reect the actions of ACE-

AngII on pain and sleep processes in the brain.

The limitations of this study are as follows: this is a post hoc analysis

from a clinical trial, therefore, the primary outcome in this analysis

was not the original primary outcome. This per-protocol analysis

also included 7 chronic migraine patients excluded from primary

analysis. Also, the ndings here cannot be generalized to the

whole migraine population, as the data are underpowered, and

the sample´s clinical characteristics are different regarding exercise-

trigger attacks. For example, the fact that migraine participants

showed no exercisetrigger attack, which is commonly observed

Figure 3.Prevalence of triggers (%) and changes in the number of trigger-related attacks for sleep and stress/irritability (numeric changes from group's sum).

Oliveira AB et al.

Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis

in this population

, and voluntarily sought for exercise as a

therapeutic option for migraine may constitute selection biases.

In conclusion, this study found a stimulatory effect of regular

aerobic exercise on plasma ACE activity in migraine patients,

which was inversely correlate with improved insomnia scores.

Further studies should explore the participation of the RAS, and

the relation of other ACE-derived peptides following exercise in

migraine patients in a larger cohort. Clinical aspects of migraine

such as trigger prole and its relationship with these molecules

could also provide insights for the participation of RAS in multiple

behavioral and homeostatic features of migraine.

Aknowlegements:

The authors appreciate the whole staff of the

Center for Studies in Psychobiology and Exercise for their support

in scheduling and conducting the exercise sessions and testing

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Headache Medicine 2020, 11(1):22-24 ISSN 2178-7468, e-ISSN 2763-6178

ASAA

DOI: 10.48208/HeadacheMed.2020.6

Headache Medicine

Original

Sociodemographic characteristics of patients with chronic

headache

Características sociodemográcas dos pacientes portadores de cefaleia crônica

Patrick Giordanni Gomes Sampaio

Hiago Diniz Maracajá

Sara Raquel Nóbrega Figueiredo

Virgínia

Gabriela Nóbrega Figueiredo

Túlio Carneiro Monteiro Temoteo

Nátalia Meg Adijuto de Melo

Neuroconance, Neurologia, Campina Grande, Paraíba, Brazil.

Unifacisa, Medicina, Campina Grande, Paraíba, Brazil.

Abstract

Introduction

Headache is an entity characterized by a painful process in the cephalic segment and may originate

from cranial or facial structures, being considered a common medical complaint. The chronication pro-

cess of the pain can present a decrease in quality, the functional capacity and the patient’s and labor

environment, and also as well as affect their interpersonal relationships, since the chronic cephalalgic

process can lead the patient to moments of social isolation, mood swings, depression.

Methods

The research was conducted through a retrospective cross-sectional study, performing the analysis of

medical records of patients seen at the Unifacisa’s outpatient neurology School Clinic complaining of

chronic headache, from February 1st to August 31, 2019.

Results

With the analysis of the medical records, 684 attendances were obtained, where 30 of the patients

treated had the diagnosis of chronic headache, 29 women and 01 man. These patients received the

following diagnoses: 18 (60%) patients with chronic migraine without aura, 4 (13.3%) patients with

chronic migraine with aura, 12 (40%) patients with chronic daily medication overuse headache, 9 (30%)

patients with chronic tensiontype headache (CTTH), 1 (3.3%) patient with basilar migraine, 2 (6.6%)

patients with secondary headache.

Conclusion

Although a small number of chronic headache patients were obtained, yet we realize that it is the

migraine that leads to a greater demand for specialized medical care. In addition, as expected due

to the latest research, a signicant number of patients with headache due to excessive use of common

painkillers.

Resumo

Introdução

Cefaleia é uma entidade caracterizada por um processo doloroso no segmento cefálico, podendo ter

origem em estruturas cranianas ou faciais, sendo considerada a queixa médica mais comum. O proces-

so de cronicação da dor pode apresentar uma diminuição na qualidade, da capacidade funcional

e laboral do paciente, assim como, também, afetar nas suas relações interpessoais, haja visto que o

processo cefalálgico crônico pode levar o paciente a momentos de isolamento social, mudanças de

humor, depressão.

Métodos

A pesquisa foi realizada através de um estudo transversal retrospectivo, realizando a análise de prontu-

ários de pacientes atendidos no ambulatório de neurologia da Clínica Escola da Unifacisa com queixa

de cefaleia crônica, de 1º de Fevereiro a 31 de Agosto, de 2019.

Resultados

Com a análise dos prontuários, obtevese a quantidade 684 atendimentos, onde 30 dos pacientes

atendidos tinha o diagnóstico de cefaleia crônica, sendo 29 mulheres e 01 homem. Estes pacientes,

receberam os seguintes diagnósticos: migrânea crônica sem aura 60%, migrânea crônica com aura

13,3%, cefaleia crônica diária por uso excessivo de analgésicos 40 %, cefaleia do tipo tensional crônica

(CTT) 30%, enxaqueca basilar 3,3%, cefaleia secundária 6,6%.

Conclusão

Apesar de ter sido obtido um número pequeno de pacientes com cefaleia crônica, ainda assim, perce-

bemos que são as migrâneas que levam a uma maior procura por atendimento médico especializado.

Além disso, constatou-se, como esperado devido as mais recentes pesquisas, um número expressivo de

pacientes portadores de cefaleia por uso excessivo de analgésicos comuns.

Patrick Giordanni Gomes Sampaio

giordannipatrick@gmail.com

Received: March 30, 2020.

Accepted: March 31, 2020.

Edited by

Mario Fernando Prieto Peres

Keywords:

Chronic Headache

Migraine

Painkillers

Palavras-chave:

Transtornos da Cefaleia

Transtornos de Enxaqueca

Analgésicos

ASAA

Sampaio PGG et al

Sociodemographic characteristics of patients with chronic headache

Introduction

eadache

is an entity characterized by a painful process in the

cephalic segment, may originate from cranial or facial structures,

being considered a common medical complaint

1,2

. This may also

occur episodically or chronically and may be classied in primary

or secondary.

Chronic headache may be associated with several reasons, one of

them being the abusive use of painkillers. Abusive use is characterized

by the use of simple analgesics for 15 days or more in a month or,

for triptans, ergotamines, opioids, caffeine and combined painkillers

for 10 or more days in a month

3-5

In addition, one can list as risk factors for the painfull process

chronication in the cephalic region: ineffective treatment of hea-

dache, obesity, psychiatric disorders, being female, low education,

daily stresses

. In this perspective, besides the clinical diagnosis of

headache type, it is of extreme importance to identify the potential

comorbidities that are chronifying factors, aiming at treating them

and thus avoiding the aggravation of chronication.

Thus, it was noted the need to analyze the epidemiological prole

of patients attended at the Unifacisa’s outpatient neurology cli-

nic. Mainly to determine if the demand for attendance occurs by

following the global epidemiological pattern or another, as well

as generating knowledge about the patients’ own prole attended

in this service.

Material and Methods

The research was conducted through a retrospective cross-sectional

study, performing the analysis of medical records of patients seen

at the Unifacisa’s outpatient neurology School Clinic complaining of

chronic headache, from February 1st to August 31, 2019, following

the classication criteria of the International Classication of Hea-

daches Disorders (ICHD-3). All patients were included, regardless

of gender or age, that met criteria for chronic headache, whether

primary or secondary, being excluded all patients who had heada-

che but did not meet the ICHD-3 chronication criterion or had not

yet received a diagnosis of headache.

Results

With the analysis of the medical records from February to August With the analysis of the medical records from February to August

2019, 684 attendances were obtained, where 30 of the patients tre-2019, 684 attendances were obtained, where 30 of the patients tre-

ated had the diagnosis of chronic headache, 29 women and 1 man.ated had the diagnosis of chronic headache, 29 women and 1 man.

As for the profession, most were health care professionals, teachers As for the profession, most were health care professionals, teachers

and students. These patients received the following diagnoses: 18 and students. These patients received the following diagnoses: 18

(60%) patients with chronic migraine without aura, 4 (13.3%) patients (60%) patients with chronic migraine without aura, 4 (13.3%) patients

with chronic migraine with aura, 12 (40%) patients with chronic dailywith chronic migraine with aura, 12 (40%) patients with chronic daily

medication overuse headache, 9 (30%) patients with CTTH, 1 (3.3%) medication overuse headache, 9 (30%) patients with CTTH, 1 (3.3%)

patient with basilar migraine, 2 (6.6%) patients with secondary patient with basilar migraine, 2 (6.6%) patients with secondary

headache. Some of these patients received a diagnosis combination headache. Some of these patients received a diagnosis combination

of chronic migraine or CTTH plus a chronic daily headache due toof chronic migraine or CTTH plus a chronic daily headache due to

excessive painkillers.excessive painkillers.

Discussion

Chronic headache is dened when an individual who has a Chronic headache is dened when an individual who has a

cephalalgic process that happens for at least 15 days in a month cephalalgic process that happens for at least 15 days in a month

in 3 or more months in the year and may, in the case of migraine in 3 or more months in the year and may, in the case of migraine

processes, meet chronication criteria with only 8 days of pain per processes, meet chronication criteria with only 8 days of pain per

month at 3 or more months in the yearmonth at 3 or more months in the year

4-5,84-5,8

It is also possible to subdivide the main etiologies of chronic It is also possible to subdivide the main etiologies of chronic

headache: Transformed Migraine (TM), Chronic Tension-Type headache: Transformed Migraine (TM), Chronic Tension-Type

Headache (CTTH), New Daily Persistent Headache and continuous Headache (CTTH), New Daily Persistent Headache and continuous

hemicranial (CH)hemicranial (CH)

One of the main causes of the chronic headache process is the One of the main causes of the chronic headache process is the

abusive use of common painkillers or symptomatic drugs such as abusive use of common painkillers or symptomatic drugs such as

triptans, ergotamines, opioids, and it is estimated that 50% of triptans, ergotamines, opioids, and it is estimated that 50% of

patients who have a headache self-medicate. What leads to an patients who have a headache self-medicate. What leads to an

estimate in Latin America that 55-70% of patients that look for estimate in Latin America that 55-70% of patients that look for

specialized centers due to headache, receive the diagnosis of specialized centers due to headache, receive the diagnosis of

medication overuse headachemedication overuse headache

According to the World Health Organization’s Global Burden According to the World Health Organization’s Global Burden

of Disease, migraine is the second leading cause of disability of Disease, migraine is the second leading cause of disability

among all diseases, falling behind only mental disorders. Among among all diseases, falling behind only mental disorders. Among

people with migraine, within one year, 25% presented the same people with migraine, within one year, 25% presented the same

in episodic form, while 40% will oscillate between chronic and in episodic form, while 40% will oscillate between chronic and

episodicepisodic

“Episodic tension-type headache is the most common of primary “Episodic tension-type headache is the most common of primary

headaches, with peak prevalence in the fourth decade. In Brazil, headaches, with peak prevalence in the fourth decade. In Brazil,

the annual prevalence of migraine is 15.8%, affecting about 22% the annual prevalence of migraine is 15.8%, affecting about 22%

of women and 9% of men, with peak prevalence between 30 and of women and 9% of men, with peak prevalence between 30 and

50 years. Migraine without aura (75% of cases) is more frequent 50 years. Migraine without aura (75% of cases) is more frequent

than with aura (25% of cases)”. (Speciali et al. 2018)than with aura (25% of cases)”. (Speciali et al. 2018)

Due to the incapacitating process of chronic headaches, individuals Due to the incapacitating process of chronic headaches, individuals

affected by this disease tend to have, besides the loss of capacity or affected by this disease tend to have, besides the loss of capacity or

productivity, problems of a personal and social nature, generatedproductivity, problems of a personal and social nature, generated

by the painful process that tends to cause isolation, depression, by the painful process that tends to cause isolation, depression,

seclusionseclusion

6-86-8

Conclusion

Although a small number of chronic headache patients were obtai-

ned, since headache is one of the major medical complaint and the

highest prevalence of CTTHs in the general population, yet we realize

that it is the migraine that leads to a greater demand for specialized

medical care. Therefore, it is evident how migraines compromise

both the functionality of the individual, as well as the quality of life.

Moreover, the high and disproportionate prevalence of females over

males, evading epidemiological patterns for headache, is supposed

ASAA

Sampaio PGG et al

Sociodemographic characteristics of patients with chronic headache

to be due to lower male demand for medical appointments, as well as

fewer referrals from primary health care to more specialized centers.

In addition, as expected due to the latest research, a signicant num-

ber of patients with medication overuse headache. Thus, it becomes

evident the importance of the early diagnosis clinical treatment, in ad-

dition to optimal drug treatment and population’s awareness of the use

of painkillers in order to reduce the prevalence of headaches caused

by their abuse.

The small number of chronic headache care, about 4.32%, was at-

tributed to Unifacisa’s school clinic care model. It is in a metropolitan

region and is a reference for the specialized care of the surrounding

city areas where there is often inadequate screening and the com-

plaints of headaches are not referenced appropriately.

Thus, it is noted that the need to better track patients with complaints

of headache and make the service more visible so that more and more

patients can reach the most specialized centers and receive the most

appropriate service for their complaints, thus reducing headaches

related comorbidities.

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Headache Medicine 2020, 11(1):25-26 ISSN 2178-7468, e-ISSN 2763-6178

ASAA

DOI: 10.48208/HeadacheMed.2020.7

Headache Medicine

Thesis

Peripheral projections of the trigeminovascular system as

antimigraine target

Projeções periféricas do sistema trigeminovascular como alvo anti-enxaqueca

Alejandro Labastida-Ramírez Antoinette Maassen Van Den Brink

Erasmus MC, Division of Vascular Medicine and Pharmacology, Rotterdam, Zuid Holland, Holland.

Calcitonin gene-related peptide (CGRP) is a key neuropeptide, highly expressed in the

central and peripheral trigeminovascular system, involved in craniofacial nociceptive modu-

lation.

In migraine patients, CGRP infusion generates migraine-like headaches

, and during

spontaneous attacks this peptide is released in the extracerebral circulation

. The treatment

of choice currently available for terminating migraine attacks are the triptans, 5-HT1B/1D

receptor agonists, of which some also display afnity for the 5-HT1F receptor.

These drugs

have the ability to decrease elevated CGRP levels by inhibiting further release from trige-

minal perivascular afferents and consequently decrease nociceptive transmission from the

periphery to the central nervous system.

However, due to their coronary vasoconstrictor

potential, they are contraindicated in patients with cardiovascular diseases. This concern

has resulted in the development of novel drugs devoid of vascular side-effects, such as mo-

noclonal antibodies targeting CGRP or its receptor. Moreover, these drugs have shown that

migraine attacks can be prevented exclusively via peripheral blockade of CGRP. This thesis

focused on the pharmacological modulation of the peripheral CGRPergic projections of the

trigeminovascular system.

We investigated in rodents the modulation of trigeminal CGRP release by lasmiditan, a

highly selective 5-HT1F receptor agonist (ditan), and comparatively studied sumatriptan.

CGRP release was diminished similarly by both drugs in all the trigeminovascular system

components (dura mater, trigeminal ganglion and trigeminal nucleus caudalis) ex vivo. In

vivo, lasmiditan or higher doses of sumatriptan signicantly attenuated endogenous CGRP

release, but not exogenous CGRP effects. These ndings suggest that selective 5HT1F receptor

activation (by lasmiditan) is sufcient to presynaptically inhibit CGRP release in peripheral

and central trigeminal nerve terminals, and, consequently, attenuate nociceptive transmission

in the trigeminovascular system.

Since activation of 5HT1F receptors is not associated with

coronary vasoconstriction, lasmiditan may represent a cardiovascular safety advantage over

the vasoactive triptans.

In addition to the trigeminovascular CGRP release inhibition by lasmiditan, further (anti-

migraine) mechanisms of action described with previous 5HT1F receptor agonists include

modulation of glutamate release from sensory bers.

The co-localization of 5HT1F receptors

and glutamate in the vestibular nuclei of rats, suggests that the 5HT1F receptor might also

modulate glutamate release in CNS structures.

Moreover, since glutamate receptor anta-

gonism prevents the initiation of cortical spreading depressions (CSDs), a key pathogenic

event in migraine with aura, 5-HT1F receptor agonism could attenuate CSDs via a central

inhibition of glutamate. Therefore, after taking into account these additional mechanisms,

future experiments are needed to determine whether lasmiditan can: (I) inhibit glutamatergic

neurons in the central nervous system, or (II) attenuate CSDs initiation and its associated

hyperaemia; and if all or none of these mechanisms are associated with ts clinical antimi-

graine efcacy.

Alejandro Labastida-Ramírez

a.labastidaramirez@erasmusmc.nl

Received: March 6, 2020.

Accepted: March 11, 2020.

Edited by

Mario Fernando Prieto Peres

ASAA

Labastida-Ramírez A, Van Den Brink AM

Peripheral projections of the trigeminovascular

Competing Interests:

The authors declare that they have no

competing interests.

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