i
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
El
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
de
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
G
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
ii
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
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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
I
SSN 2178-7468, e-ISSN 2763-6178
Headache Medicine, v.11, n.1, 2020
iv
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
1
ASAA
DOI: 10.48208/HeadacheMed.2020.1
Headache Medicine
© Copyright 2020
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
1
. 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.
1
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.
2
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.
3
Élcio Juliato Piovesan
piovesan1@hotmail.com
Received: February 12, 2020.
Accepted: March 16, 2020.
Edited by
Mario Fernando Prieto Peres
2
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.
5
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.
6
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
3
ASAA
DOI: 10.48208/HeadacheMed.2020.2
Headache Medicine
© Copyright 2020
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
1
Diego Afonso Cardoso Macedo
2
Simone Santos
e Silva Melo
2
Bárbara Louise Freire Barbosa
3
Larisse Giselle Barbosa Cruz
3
Raimundo Pereira
Silva-Néto
4
1
Doctorate in Nursing and Medical Student, Federal University of Delta of Parnaíba.
2
Master in Nursing and Medical Student, Federal University of
Delta of Parnaíba.
3
Medical Student, Federal University of Delta of Parnaíba.
4
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
4
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
T
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
1
.
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
2
.
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
3
.
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
4
. 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
5
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
20
.
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)
21
, 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
20
.
Headache was observed in patients of all age groups, both in
adults
7-13
, as in children
6
. 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
13
.
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
7
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
8
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
9
41 49.0 18-65 M=30; F=11 3 7. 3 NR
Liu et al., 2020
10
30 35.038 21-59 M=10; F=20 16 53.3
It appeared at the beginning of the
disease
Cheng et al., 2020
11
1,078 46.0 0.25-94 M=573; F=505 22 2.0 NR
Wang et al., 2020
12
31 7. 1 0.5-17 M=15; F=16 3 9.7 NR
Li et al., 2020
13
54 51.5 25-82 M=22; F=32 ? Rare NR
Chen et al., 2020
14
99 55.5313.1 21-82 M=67; F=32 8 8.0 NR
Liu et al., 2020
15
137 55.0316.0 20-82 M=61; F=76 13 9.5 NR
Mi et al., 2020
16
10 68.4318.5 34 -87 M=2; F=8 1 10.0 NR
Jin et al., 2020
17
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
18
5 50.239.8 39-66 M=2; F=3 2 40.0 NR
Zhang et al., 2020
19
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
6
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
17
.
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
19
.
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
10
. 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
study. Lancet 2002;395(10223):507-513.
15. Liu K, Fang YY, Deng Y, Liu W, Wang MF, Ma JP, et al. Clinical
characteristics of novel coronavirus cases in tertiary hospitals in
Hubei Province. Chin Med J (Engl) 2020;133(9):1025-1031. doi:
10.1097/CM9.0000000000000744. [Epub ahead of print].
16. Mi B, Chen L, Xiong Y, Xue H, Zhou W, Liu G. Characteristics
and early prognosis of COVID-19 infection in fracture patients.
J Bone Joint Surg Am 2020;102(9):750-758. doi: 10.2106/
JBJS.20.00390. [Epub ahead of print].
17. Jin X, Lian JS, Hu JH, Gao J, Zheng L, Zhang YM, et al. Epi-
demiological, clinical and virological characteristics of 74
cases of coronavirus-infected disease 2019 (COVID-19) with
gastrointestinal symptoms. Gut 2020;69(6):1002-1009
18. Ding Q, Lu P, Fan Y, Xia Y, Liu M. The clinical characteristics of
pneumonia patients co- infected with 2019 novel coronavirus
and inuenza virus in Wuhan, China. J Med Virol 2020 Mar
20. doi: 10.1002/jmv.25781. [Epub ahead of print].
19. Zhang X, Cai H, Hu J, Lian J, Gu J, Zhang S, et al. Epidemio-
logical, clinical characteristics of cases of SARSCoV-2 infection
with abnormal imaging ndings. Int J Infect Dis 2020;94:81-87.
20. Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential
of SARS-CoV2 may play a role in the respiratory failure of
COVID-19 patients. J Med Virol 2020 Feb 27. doi: 10.1002/
jmv.25728. [Epub ahead of print].
21. Headache Classication Subcommittee of the International
Headache Society. The International Classication of Headache
Disorders, 3rd edition. Cephalalgia 2018;38(1):1- 211.
Headache Medicine 2020, 11(1):7-9 ISSN 2178-7468, e-ISSN 2763-6178
7
ASAA
DOI: 10.48208/HeadacheMed.2020.3
Headache Medicine
© Copyright 2020
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
8
ASAA
Leroux E
The Migraine Tree: a shared tool for migraine information
Introduction
T
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
1
. 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
2
.
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
3
. 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
4
. 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.
9
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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 specic 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
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
10
ASAA
DOI: 10.48208/HeadacheMed.2020.4
Headache Medicine
© Copyright 2020
Original
Migraine aura: results from an art contest
Aura da enxaqueca: resultados de um concurso de arte
Bruna de Freitas Dias
1
Arao Belitardo de Oliveira
2
Juliane Prieto Peres Mercante
2
Michele Viana
6,7
Luiz Paulo de Queiroz
5
Mario Fernando Prieto Peres
2,3,4
1
Faculdade Israelita de Ciências e Saúde Albert Einstein (FICSAE) .
2
Associação Brasileira de Cefaleia em Salvas e Enxaqueca (ABRACES).
3
Instituto
de Psiquiatria do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (IPQ-HCFMUSP).
4
Instituto Israelita de Pesquisa
Albert Einstein Hospital Israelita Albert Einstein (HIAE).
5
Universidade Federal de Santa Catarina
6
Headache Group, Department of Basic and Clini-
cal Neurosciences, King’s College London, London, UK.
7
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
11
Dias BF, et al.
Migraine aura: results from an art contest
Introduction
M
igraine is a common primary headache and a major cause
of disability
1
. 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
2
. Patients have episodic attacks
separated by interictal phases. The attack is an interplay between
genetic
3
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)
6
, 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
7
. 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
8
. Since visual auras varies in form, severity
and duration both among patients and within each patient
9
, 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
10
. The consequences are chronic migraine,
decreased quality of life and work productivity
1113
. 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
th
until October 6
th
, 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
12
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
15
.
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.
13
Dias BF, et al.
Migraine aura: results from an art contest
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2. Merikangas KR. Contributions of epidemiology to our un-
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Headache Medicine 2020, 11(1):14-21 ISSN 2178-7468, e-ISSN 2763-6178
14
ASAA
DOI: 10.48208/HeadacheMed.2020.5
Headache Medicine
© Copyright 2020
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
3
Jair Ribeiro Chagas
4
Mario Peres
2,5
1
Universidade Federal de São Paulo, Neurologia e Neurocirurgia, São Paulo, São Paulo, Brazil.
2
Hospital Israelita Alber Einstein, Instituto do Cerebro,
São Paulo, São Paulo, Brazil.
3
Tulane University School of Medicine, Department of Physiology, New Orleans, Louisiana, Estados Unidos.
4
Universi-
dade Federal de São Paulo, Biologia Molecular, São Paulo, São Paulo, Brazil.
5
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
15
Oliveira AB et al.
Plasma ACE activity after aerobic exercise training is related to sleep in migraine patients: A secondary, per protocol analysis
Introduction
A
erobic exercise training exerts prophylactic effects on migrai-
ne
1,2
, and also promotes anxiolytic effects
2
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
8
and sleep regulation
9
,
which are associated with migraine triggers
10
, and pain perception
11
.
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
2
. 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
nd
version of the International Classication
of Headache Disorders
12
. 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
16
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
2
.
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
13
. 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 triggers prevalence in the patients’ sample. Correlations
were calculated by Pearson’s correlation coefcients or Spearmans
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 signicant 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 ANOVAs 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
17
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
2
) 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
VO
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 signicant main effects of time
or group, neither interaction was observed for BECK-II irritability
domain.
18
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
3
and increased plasma
AngII and aldosterone in patients experiencing salt-induced
migraine attacks
14
. At molecular level, an immunocytochemical
investigation has uncovered the presence of an angiotensinergic
system in the trigeminal ganglia of humans and rats
5
, 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
4
. 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
17
, heart failure
18
, 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)
3
. In fact, there are evidences
corroborating this hypothesis, showing an inhibitory effect of ACE on
NO
19
and CGRP
20
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
21
. 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
22
. 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
25
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
11
.
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.
19
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)
11
. As pro-inammatory
cytokines are associated with migraine
26
, 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
11
.
As reviewed by Bali et al.
11
, 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
24
.
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
27
, 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
9
.
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
25
. 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
30
.
Considering the prominent role of melatonin in migraine
pathophysiology
31
, and its modulation by the RAS
9
, 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
30
. As underscored
by Visniauskas et al.
30
, 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
32
. Moreover, aerobic exercise can stimulate ACE-
independent AngII production
33
. 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).
20
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
10
, 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
22
ASAA
DOI: 10.48208/HeadacheMed.2020.6
Headache Medicine
© Copyright 2020
Original
Sociodemographic characteristics of patients with chronic
headache
Características sociodemográcas dos pacientes portadores de cefaleia crônica
Patrick Giordanni Gomes Sampaio
1
Hiago Diniz Maracajá
2
Sara Raquel Nóbrega Figueiredo
2
Virgínia
Gabriela Nóbrega Figueiredo
2
Túlio Carneiro Monteiro Temoteo
2
Nátalia Meg Adijuto de Melo
2
1
Neuroconance, Neurologia, Campina Grande, Paraíba, Brazil.
2
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
23
ASAA
Sampaio PGG et al
Sociodemographic characteristics of patients with chronic headache
Introduction
H
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
6
. 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)
88
..
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
55
..
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
55
..
“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
24
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
25
ASAA
DOI: 10.48208/HeadacheMed.2020.7
Headache Medicine
© Copyright 2020
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.
1
In migraine patients, CGRP infusion generates migraine-like headaches
2
, and during
spontaneous attacks this peptide is released in the extracerebral circulation
3
. 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.
4
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.
3
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.
5
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.
6
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.
7
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
26
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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