Genetic aspects of sleep in humans

Transcrição

ISSUE
VOLUME
5 4
ISSN 1984-0659
A publication of Associação Brasileira do Sono
(ABS) and Federação Latinoamericana de
Sociedades do Sono (FLASS)
2012
Oct/Dec
Full text
available for
download at
the web site
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ISSN 1984-0659
Official publication of Associação Brasileira de Sono e Federação
LatinoAmericana de Sociedades de Sono
Quarterly
Sleep Science 2012 v. 5, n. 4, p. 106 - 150, Oct/Dec 2012
Editor in Chief
Monica Levy Andersen
Associated Editors
Managing Editor
Claudia Moreno
Geraldo Lorenzi-Filho
Lia Rita Azeredo Bittencourt
Gabriel Natan Pires
Editorial Board
Arne Lowden (Stockholm, Sweden)
Dalva Poyares (São Paulo, Brazil)
Darwin Vizcarra (Lima, Peru)
David Gozal (Louisville, USA)
Denis Martinez (Porto Alegre, Brazil)
Diego Golombek (Buenos Aires, Argentina)
Ennio Vivaldi (Santiago, Chile)
Fernanda Louise Martinho (São Paulo, Brazil)
Fernanda Ribeiro Almeida (Vancouver, Canada)
Fernando Louzada (Curitiba, Brazil)
Francisco Hora (Salvador, Brazil)
James Krueger (Washington, USA)
John Araújo (Natal, Brazil)
Katsumasa Hoshino (Botucatu, Brazil)
Ligia Lucchesi (São Paulo, Brazil)
Lucia Rotenberg (Rio de Janeiro, Brazil)
SPONSORED BY
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Luciano Ribeiro Pinto Jr (São Paulo, Brazil)
Luiz Menna-Barreto (São Paulo, Brazil)
Michel Cahali (São Paulo, Brazil)
Nicola Montano (Milan, Italy)
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Pedro de Bruin (Fortaleza, Brazil)
Roberto Frussa Filho (São Paulo, Brazil)
Rogério Santos Silva (São Paulo, Brazil)
Rosana Alves (São Paulo, Brazil)
Sergio Tufik (São Paulo, Brazil)
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SUPPORTED BY
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©2012 - Sleep Science
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Contents
Quarterly
iii
Sleep Science 2012 v. 5, n. 4, p. 106 - 150, Oct./Dec. 2012
EDITORIAL
LETTER TO THE EDITOR
106
Is acupuncture a real alternative treatment for mild apnea?
Andréia Gomes Bezerra, Monica Levy Andersen, Sergio Tufik, Helena Hachul
ORIGINAL ARTICLES
107
Assessment of biological components associated with sleepiness in young working
college students
Avaliação de componentes biológicos associados à sonolência em jovens universitários trabalhadores
Liliane Reis Teixeira, Mário Pedrazzoli, Andrea Aparecida Luz, Samantha Lemos Turte, Letícia Pickersgill de Paula,
Daniel Valente, Sergio Tufik, Frida Marina Fischer
113
Mood, sleep patterns and the effect of physical activity on the life quality of brazilian
train operators
Perfil de humor, do sono e o efeito da atividade física na qualidade de vida de trabalhadores em turno
brasileiros
Luciana Oliveira e Silva, Andrea Maculano Esteves, Natália Novais Luz Alves, Adriana Neves da Silva Carvalho, Fernanda
Veruska Narciso, Lia R. A. Bittencourt, Sergio Tufik, Marco Tulio de Mello
SHORT COMMUNICATION
120
Overview of sleep disordered breathing management in 12 latin american sleep
centers
Panorama do gerenciamento dos distúrbios respiratórios de sono em 12 centros latino-americanos de
sono
Armando Castorena Maldonado, Dalva Poyares, Daniel Perez Chada, Flavio Magalhães Silveira, Geraldo Lorenzi-Filho,
Jorge Rey de Castro, Juan Facundo Nogueira, Leonardo Serra, Lia Bittencourt, Luciana Rabello de Oliveira, Maria Angélica Bazurto,
Maria Victorina Lopez Varela, Matilde Valencia Flores, Rafael A. Lobelo Garcia
REVIEW ARTICLE
125
Aspectos genéticos do sono em humanos
Camila Guindalini, Sergio Tufik
131
Sensory neurophysiologic functions participating in active sleep processes
Participação de funções sensoriais neurofisiológicas em processos ativos do sono
Ricardo A. Velluti, Marisa Pedemonte
139
Narcolepsy in childhood and adolescence
Narcolepsia na infância e na adolescência
Fernando M. S. Coelho, Flavio Aloe,Gustavo Moreira, Heidi H. Sander, Israel Roitman, Lucila F. Prado, Márcia Pradella-Hallinan,
Regina M. F. Fernandes, Rosana S. C. Alves
CASE REPORT
145
Acupuncture in obstructive sleep apnea/hypopnea syndrome: a case report with fifteen
months of follow-up
Acupuntura na síndrome da apneia/hipopneia obstrutiva do sono. Quinze meses de acompanhamento relato de caso
Kátia Savelli G. Bencz , Paulo A. D. Nabarro
149
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GUIDE FOR AUTHORS
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iii
EDITORIAL
This volume of Sleep Science includes 3 review articles, 2 original papers and a case report.
The review articles are of particular interest and quality, mostly due to the scarcity of the dealt
themes in current sleep literature.
The “Genetics aspects of Sleep in Humans”, from Guindalini and Tufik is certainly one of the
most comprehensive, updated and, most of all, clear revisions of this particular subject. It describes the
relevance of genes in the sleep organization, sleep characteristics and in the expression of some disorders.
The explanation of gene expression, together with the synthetic table summarizing and updating the present
knowledge on the field, are particularly relevant. For those less keen in this field the genes behind some circadian disorders, namely familiar sleep phase advance and phase delay, narcolepsy, sleep apnea and restless legs
become clear; the same happens for the genes behind certain phenotypes determining sleep characteristics,
namely, short sleep, sleep length, diurnal preference and sleep homeostasis.
The review on “Sensory Neurophysiologic functions participating in active sleep process” from
Velluti and Pedemonte, both from Uruguay, is another pearl in the field of difficult and infrequent literature, which, together with the revision puts forward some genuine new ideas. In spite of the current
knowledge that sleep is an active process, the idea of sleep as passive state with lower levels in many body
functions is still in the back mind of much sleep research. The authors postulate the opposite: sleep is
simply another “state” different from awake, and therefore the quest for “the function of sleep” is somehow obsolete. In this review the authors show how the sensory brain components are actively involved
in the sleep process, with data from animal and human studies. The auditory pathway is exhaustively used
as an example for the sensorial active role in the organization, disruption and reinforcement of sleep and
sleep stages.
The review on “Narcolepsy in childhood and adolescence” de Coelho et al, is the result of a team
work of several Brazilian experts, enhancing the name, the work and the memory of Flavio Aloe. This review is in fact another pearl of this issue, since it contains an update of a most forgotten topic: the clinical
characteristics of Narcolepsy in the first two decades of life. The corresponding peculiarities and specificities are well enhanced, namely its monosymptomatic presentation, the HLA and hypocretin association
and the diagnostic and treatment criteria. Early recognition of narcolepsy, mostly in these young ages, is of
paramount importance due to the possibility of preventing its progression with immunologic treatment.
The two original papers deal with clearly modern subjects, using both complex experimental approaches. One of them “Assessment of biological components associated with sleepiness in young working college students” from Teixeira et al, results from a collaborative work of several university groups of
São Paulo. The biological components associated with sleepiness include the study of variability of the Per
3 gene, via the evaluation of the VTNR (variable number tandem repeat); the environment is the “natural” student environment, both with and without social constraints. The experimental protocol includes: a
survey of living conditions and health; genotyping of the genes Per3 and HIOMT; actimetry; evaluation of
sleepiness; melatonin; evaluation of chronotypes, sleep patterns and Per3 in the course of a working week,
during weekends and days off in a population of 192 students. They conclude indeed that without social
restrictions for sleep onset/ outset, chronotypes express different sleep preferences, partly associated to
PER3 VNTR genotype. Their data further suggest an effect of HIOMT gene polymorphism on melatonin
secretion. The paper has therefore enormous practical consequences in a young population, from which
most is expected since they are putatively the future brains of a country, but to which a progressively bigger and eventually unnecessary stress is imposed.
The other paper “Mood, sleep patterns and the effect of physical activity on the life quality of
Brazilian train operators” from Oliveira e Silva et al, integrated in the group of Tulio de Mello e Tufik
addresses two important issues, namely, shift work, quality of life and physical activity. Their experimental
design is also complex and includes multiple questionnaires about sleep, sleepiness, stress, mood, quality of life and physical activity together with polysomnography. They demonstrate the positive effect of
physical activity upon quality of life. The importance of their results is enhanced by the fact that the exact
role of physical activity in sleep and wellbeing is far from being known, with frequent contradictory or
insufficient results. Furthermore they address the problem of shift work, work condition progressively
overspread worldwide, for which urgent solutions to improve workers quality of life are urgently needed.
The case report on “Acupuncture in obstructive sleep apnea/hypopnea syndrome: a case report
with fifteen months of follow-up” from Benez and Nabarro is an interesting approach to a case of difficult
treatment: mild obstructive sleep apnea. Paradoxically sleep apnea is treated with greater success in its severe
or moderate presentation then in the mild severity forms. The presented case shows an important therapeutic success with return to normal polysomnography values. The association with a reduction in the BMI
raises the question whether acupuncture contributes to it, or whether the clinical benefit is also associated
with reduction in body weight. Whatever one or several factors contributed to the clinical improvement, the
case report opens the way in to novel therapeutic approaches.
Dra. Teresa Paiva;
Faculdade de Medicina - Universidade de Lisboa.
Rua Conde das Antas, nº 105 - 1070-068. Lisboa - Portugal.
Sleep Sci. 2012;5(4):iii
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Rodrigues MM, Dibbern RS‚ Goulart CWK
106
LETTER TO THE EDITOR
Is acupuncture a real alternative treatment for
mild apnea?
Andréia Gomes Bezerra1, Monica Levy Andersen1, Sergio Tufik1, Helena Hachul1,2
TO THE EDITOR:
The article entitled “Acupuncture in obstructive sleep apnea/hypopnea syndrome: a case report
with fifteen months of follow-up”(1), published by
Bencz and Nabarro in this issue of Sleep Science
provides surprising data regarding the efficacy of
acupuncture as a treatment for mild apnea. Our
amazement is mainly due to the long term maintenance of these effects, since previous studies showed
only acute effects or effects sustained by continuous
treatment(2,3).
Based on the impact of the presented data,
some methodological caveats shall be stressed out, in
order to guarantee its applicability. First, it is convenient to keep caution concerning data generalization.
Sleep apnea has a multifactorial pathogenesis and we
do not believe that acupuncture would be effective in
all causes for this disorder. For example, it is not plausible to suppose that acupuncture will have any effect
upon sleep-disordered breathing caused by structural
malformations, such as retrognatia. We judge that
obesity or hypotonia/flaccidity of pharyngeal musculature are the main causes of apnea that are prone
to be treated by acupuncture. In the reported case,
both conditions are possible, as the patient presented
overweight and abnormal pharyngeal airspaces at the
beginning of the treatment. However, to fully conclude about acupuncture efficiency regardless of
weight loss, the authors should provide Body Mass
Index and cephalometric data during the whole follow up. Even so, we must keep in mind that this is a
case report and, thus, there is no certainty that these
results would be replicated in a large sample. Moreover, since there is no control group, it is not possible
to infer if this long term effects were due to acupuncture per se or by other factors, such as behavioral
changes or improvements in lifestyle. Hence, would
be interesting to reproduce the protocol employed in
this case in a larger sample, intending to evaluate if
the presented data were casual or if they are extendable to other individuals.
Further studies addressing this topic with
large samples would provide an additional promising approach, and be welcome to sleep medicine.
Obstructive sleep apnea is a highly prevalent condition(4). In special, mild obstructive apnea is a condition
that deserves attention, since it is underdiagnosed and
undertreated(5,6). Furthermore, the low compliance
for standard treatment approaches stimulates the applicability of alternative or complementary therapies,
such as acupuncture, in these cases. Finally, specifically to Brazilian population, these results would be
remarkably relevant, as since 2006 the public health
system encompasses acupuncture in its programs.
REFERENCES
1. Bencz KSG, Nabarro PAD. Acupuncture in obstructive sleep
apnea/hypopnea syndrome: a case report with fifiteen months
of follow-up. Sleep Sci. 2012;5(4):103-6.
2. Freire AO, Sugai GC, Chrispin FS, Togeiro SM, Yamamura Y,
Mello LE, Tufik S. Treatment of moderate obstructive sleep
apnea syndrome with acupuncture: a randomised, placebo-controlled pilot trial. Sleep Med. 2007;8(1):43-50.
3. Freire AO, Sugai GC, Togeiro SM, Mello LE, Tufik S. Immediate effect of acupuncture on the sleep pattern of patients with
obstructive sleep apnoea. Acupunct Med. 2010;28(3):115-9.
4. Tufik S, Santos-Silva R, Taddei JA, Bittencourt LR. Obstructive sleep apnea syndrome in the Sao Paulo Epidemiologic Sleep
Study. Sleep Med. 2010;11(5):441-6.
5. Kapur V, Strohl KP, Redline S, Iber C, O’Connor G, Nieto J.
Underdiagnosis of sleep apnea syndrome in U.S. communities.
Sleep Breath. 2002;6(2):49-54.
6. Fuhrman C, Fleury B, Nguyên XL, Delmas MC. Symptoms of
sleep apnea syndrome: high prevalence and underdiagnosis in
the French population. Sleep Med. 2012;13(7):852-8.
Study carried out at Universidade Federal de São Paulo.
1
Departamento de Psicobiologia - Universidade Federal de São Paulo.
2
Departamento de Ginecologia - Universidade Federal de São Paulo.
Corresponding author: Helena Hachul. Rua Napoleão de Barros, nº 925. Vila Clementino. São Paulo - SP. Brazil. CEP: 04024-002. Phone: (55 11) 21490155.
Fax: (55 11) 55725092. E-mail: [email protected]; [email protected]
Sleep Sci. 2012;5(4):106
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Teixeira LR, Pedrazzoli M, Luz AA, Turte SL, Paula LP, Valente D, et al.
107
ORIGINAL ARTICLE
Assessment of biological components associated
with sleepiness in young working college
students
Avaliação de componentes biológicos associados à sonolência em jovens
universitários trabalhadores
Liliane Reis Teixeira1, Mário Pedrazzoli2, Andrea Aparecida Luz3, Samantha Lemos Turte3,
Letícia Pickersgill de Paula3, Daniel Valente1, Sergio Tufik4, Frida Marina Fischer3
ABSTRACT
Objectives: An association, responsible for affecting circadian rhythms and sleep homeostasis, between PER3 gene variable number tandem repeat (VNTR) and sleep times has been described
in humans. The aim of this study was to evaluate the association
between clock genes VNTR and sleep duration, chronotype and
melatonin secretion. Methods: A hundred forty-six students filled a questionnaire about their sleep habits to determine individual
preferences. Salivary samples were also collected for DNA extraction. PER3 VNTR was genotyped using PCR. Results: Seventy
subjects were PER34/4 (47.9%), 61 PER34/5 (41.8%) and 15 PER35/5
(10.3%). Mean sleep duration of PER35/5, intermediate chronotype
students (8h) was higher than PER34/4, morningness chronotype
(5:58h). On days-off, for evening-types, sleep outset was delayed
(10:44h) when compared to morning-types (09:38h). Part of the
students took part in a study about bright light intervention and its
effects upon sleepiness. When exposed to bright light at 19:00h, the
students’ sleepiness growth went as expected. But, when exposed
at 21:00h, sleepiness slightly increased for the intermediates and
decreased at 22:00h for the evening-type students. Analyzing PER3
and HIOMT genotypes a specific haplotype, associated to melatonin levels at 19:00h and after bright light exposure, at 19:20h, was
detected. Conclusion: With no social restrictions for sleep onset/
outset, chronotypes express different sleep preferences, partly associated to PER3 VNTR genotype.
Keywords: chronobiology discipline, disorders of excessive somnolence, students.
RESUMO
Objetivos: Em humanos, já foi descrita a associação entre o
polimorfismo de repetição (VNTR) do gene PER3 e os horários de
dormir, afetando a ritmicidade circadiana e a homeostase do sono.
O objetivo foi avaliar a associação entre polimorfismos nos genes
PER3 e HIOMT com a duração do sono, cronotipo e secreção de
melatonina individual. Métodos: Cento e quarenta e seis estudantes
preencheram um questionário sobre seus hábitos de sono. Também
foram coletadas amostras de mucosa oral para extração de DNA.
Resultados: Setenta jovens eram PER34/4 (47,9%), 61 PER34/5
(41,8%) e 15 PER35/5 (10,3%). A duração média do sono, nos dias
letivos, dos estudantes PER35/5 com cronotipo intermediário foi
de 8h, maior que os estudantes de cronotipo matutino e PER34/4
(5:58h). Nos dias de folga, para os vespertinos, o fim do sono foi
atrasado (10:44h) quando comparado aos matutinos (09:38h). Ao
serem expostos à luz intensa às 19:00h, seguiram o padrão esperado
para aumento da sonolência quando na ausência de intervenções.
Mas, quando a exposição ocorreu às 21:00h, o aumento do nível de
sonolência para os intermediários foi menor que o padrão. E, para
os vespertinos, redução do nível de sonolência às 22:00h. Ao se
analisar os genótipos para os genes PER3 e HIOMT, foi verificado
um haplótipo específico para o gene HIOMT, que está associado
aos níveis de melatonina às 19h e também após a exposição à luz
intensa, às 19:20h. Conclusões: Quando não há limitantes sociais
para os horários de sono, os cronotipos expressam diferentes perfis
de sono, que são associados, em parte, com o genótipo do VNTR
do gene PER3.
Descritores: disciplina de cronobiologia, estudantes, hipersonia..
INTRODUCTION
The sleep-wake cycle (SWC) is a plastic biological
rhythm that changes according to information from internal and
external environments, such as socio-cultural factors(1); seasonal,
climatic, and geographical differences(2); and physiological and
psychological data(3). Daily activities may also reduce the available hours for sleep(4).
The SWC pattern also depends on individual characteristics, such as age, gender, chronotype (morningness, eveningness
or intermediary), the ability to tolerate sleepiness, sleep requirements (small and large sleepers), the predisposition for naps
(nappers and non-nappers), the number and duration of naps,
hormonal changes, and genetic factors(5).
Individuals identified as exhibiting morningness prefer to wake up early in the morning and find it difficult to
remain awake beyond their usual sleep time. These individuals exhibit higher levels of alertness upon waking, increased
numbers of awakenings during the last 2 hours of sleep, decreased frequencies of paradoxical sleep, and increased frequencies of stage 1 and shorter stage 2 compared to eveningness individuals(6).
Study carried out at Escola Nacional de Saúde Pública, Fiocruz, Rio de Janeiro, RJ.
1
Escola Nacional de Saúde Pública, Fiocruz, Rio de Janeiro, RJ.
2
Escola de Artes, Ciências e Humanidade (EACH). Universidade de São Paulo, São Paulo, SP.
3
Departamento de Saúde Ambiental, Escola de Saúde Pública - Universidade de São Paulo, São Paulo, SP.
4
Departamento de Psicobiologia, Universidade Federal de São Paulo, São Paulo, SP.
Corresponding author: Liliane Reis Teixeira. Centro de Estudos da Saúde do Trabalhador e Ecologia Humana. Escola Nacional de Saúde Pública Sergio Arouca,
FIOCRUZ. Rua Leopoldo Bulhões, nº 1480, sala 17. Rio de Janeiro - RJ. Brazil. CEP: 21041-210. E-mail: [email protected]
Received: December 19, 2011; Accepted: July 9, 2012.
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Young working college students sleepiness assessment
Eveningness individuals are characterized by late sleeping and waking, especially on the weekends. The time in bed is
reduced during the week, and it is compensated on days off. The
SWC is irregular, sleep efficiency is reduced, and naps are more
frequent during the day in these individuals(7).
Mecaci & Rocchetti(8) reported that eveningness is associated with greater symptoms of anxiety, depression, neuroticism, psychoticism, stress, and cardiovascular disease. Morningness individuals maintain greater regularity than eveningness
individuals, especially in SWC circadian rhythms, in both adolescents(9) and adults(10).
These differences in different chronotypes’ behaviors
are confirmed by the rhythmic parameters of cortisol, core temperature, heart rate, and melatonin secretion(11).
Differences in mean questionnaire scores between men
and women have been reported(12). However, other investigators
observe no correlation between gender and individual preferences(13). Ontogenetic variations in chronotype differentiation are well known. Young individuals generally exhibit more
eveningness, and the elderly exhibit more morningness(14).
Genetic mechanisms regulate circadian rhythms intracellularly, and genetic mutations alter circadian rhythms in mammals(15). The clock genes (Clock, BMAL1, Per1, Per2, PER3, Cry1,
Cry2, CKε, and CKσ) control circadian rhythms in mammals.
Polymorphisms in some rhythmic expression genes affect the circadian timing system, and these polymorphisms are
associated with chronotypes(16).
The PER3 gene is part of the PER gene family, and it
is located on chromosome 1. The function of PER3 is not well
understood, but it is highly expressed in the suprachiasmatic nuclei of the hypothalamus where it is likely associated with disturbances in the circadian rhythm(17).
Bae et al.(18) suggested that the PER3 gene is not essential
for circadian rhythmicity. However, its role in SWC regulation
is clear. Groeger et al.(19) demonstrated that PER35 homozygous individuals suffer greater effects of sleep deprivation than
PER34 homozygotes. Taillard et al.(7) observed that eveningness
people suffer fewer effects of sleep deprivation.
The genes that encode melatonin synthesis enzymes
(e.g., AANAT and HIOMT) are strong candidates for circadian
rhythmicity. Variations in these genes may interfere with the expression and control of melatonin synthesis and produce several
phenotypes, such as the morningness-eveningness character(20).
The expression of circadian rhythmicity from the SWC
and other rhythms that maintain stable phase relationships, such
as melatonin, cortisol, core temperature, and alertness and psychomotor performance rhythms, are dependent on biological
factors that are influenced by environmental and social surroundings. Exposure to intense light is an important modifying
factor of biological circadian rhythmicity. Intense light adjusts
biological rhythms in experimental studies, especially in individuals who suffer from seasonal depression, insomnia, and
excessive sleepiness shift, as well as night workers(21,22). Experimental studies using intense light treatment in young individuals have been performed. Duffy et al.(23) found adaptations in
body temperature phase with daily activities schedules after light
treatment (10,000 lux) for 20 min/hour for 3 consecutive days.
Lavoie et al.(24) observed suppression of melatonin secretion and
an increase in body temperature in young individuals subjected
to light treatment (3000 lux from 12:30 am to 4:30 am). Research on the genetic influence of intense light in daily social
surroundings is lacking. Therefore, the present study evaluated
the association between PER3 and HIOMT polymorphisms on
SWC, subjective chronotype, and individual melatonin secretion
during weekdays and on the weekend. We also evaluated differential responses to intense light exposure to reduce the sleepiness that is associated with chronotypes and the PER3 gene.
MATERIALS AND METHODS
Population
This study included 146 working college students aged
18 to 26 years who studied in a public university in São Paulo
from 7:30 pm-11:10 pm. Students who had been working for
more than three months with similar work schedules (approximately 40 hours per week) were selected for this research.
Ethical aspects
The students were personally contacted and read the
Statement of Informed Consent. All individuals agreed to participate in the study voluntarily by completing and signing the
consent document. The Ethics Committee of the School of
Public Health, University of São Paulo approved the consent
form.
Data collection
Data from 192 university students were collected from
08/11/2008 to 10/31/2008. Forty-six of these subjects (23.9%)
were discarded due to contamination of the material. Therefore,
a total of 146 students were included in the final sample. No
data were collected during holiday weeks.
The subjects initially answered the “Survey on the characterization of life, health, sleep, and work conditions.” Buccal mucosa cells were collected in the second stage, and the
students were instructed to rinse their mouth thoroughly with
water. Each participant scraped an individual sterile brush on
the inside of their cheeks approximately 20 times on each side.
Each brush with buccal mucosa cells was placed in an Eppendorf tube and stored under refrigeration for subsequent DNA
extraction.
Records on melatonin and SWC rhythms of the college
workers during and after intense light exposure were obtained
using subjective (daily activities report and Karolinska Sleepiness Scale) and objective (measurement of salivary melatonin
and actigraphy) methods in the third stage. A sub-sample (n =
23) was divided into two groups and exposed to intense light
(8,000 lux) for 20 minutes once a week for two weeks starting at
7:00 pm or 9:00 pm, alternately (crossover design). Saliva samples were collected for salivary melatonin measurement at 7:00
pm and 9:00 pm on exposure days and at the end of the exposure period (i.e., 7:20 pm in the week of exposure at 7:00 pm).
Survey of living conditions and health
Information on age, gender, family income, smoking and
alcohol habits, health condition, and daily and weekly working
hours were obtained. We obtained information on sleep location,
sleep and waking hours (weekdays and weekends), strategies for
sleep, sleep-related complaints(25), Epworth Sleepiness Scale(26),
and the identification survey of morningness and eveningness
character(27). The results of the morningness-eveningness survey
were categorized into two types: eveningness (16-41 points) and
indifferent (42-58 points).
Sleep Sci. 2012;5(4):107-112
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Genotyping of PER3 and HIOMT genes
VNTR genotyping of the PER3 gene was performed using the polymerase chain reaction (PCR). Polymorphism genotyping of the HIOMT gene was performed using the TaqMan
SNP Genotyping Assays methodology. The genotyped polymorphisms were analyzed for possible linkage disequilibrium
and arranged in haplotypes.
Actimetry
Actigraph (MicroMini-Motionlogger Actigraph, Ambulatory Monitoring, Inc®) was used on the non-dominant wrist
for 21 consecutive days. The students simultaneously completed
the daily activities reports to accurately determine the beginning
and end of nocturnal sleep (Sadeh et al., 1989). The Sadeh algorithm (Souza et al., 2003) was used in the present study, and
the following SWC variables were analyzed: beginning, end and
duration of nocturnal sleep, and the middle of the sleep phase.
Assessment of sleepiness
The Karolinska Sleepiness Scale (Akerstedt & Gillberg,
1990) includes nine points that range from extremely alert (1) to
very sleepy, fighting with sleep, and much effort to stay awake
(9). For example, an individual responded to the question “How
are you feeling now?” with the most appropriate value at that
time. The alertness perception self-assessment was performed
on Tuesdays, Wednesdays, and Thursdays at 7:00 pm, 8:30 pm,
and 9:00 pm.
Data analysis
Data analyses were performed using the following data:
gender; age; beginning, end, and middle of the sleep stage; daily
and weekly working hours; chronotype(27); and genetic material.
Two-factors ANOVA analyzed the beginning, end, and
middle sleep phase variables. PER3 gene genotype (4/4, 5/5,
4/5) and subjective chronotypes, which were obtained through
the survey of individual preferences (in tertiles), were used as factors. The analyses were performed separately for working days
(Monday through Friday) and days off (Saturday and Sunday).
The level of significance was 5% in all analyses. Statistics 5.0 software was used.
RESULTS
Description of the population
The participant population was 56% male. The main
working environment was an office (47.8%), and the main
function was as an intern (65.3%). The daily working hours
demonstrated that 30.4% worked more than 8 hours/day and
69.6% worked between 6 and 8 hours.
Analyses of the chronotype data revealed that 32.8% of
the population exhibited eveningness, 62.7% were indifferent,
and 4.5% exhibited morningness. Seventy subjects were PER34
homozygous (47.9%), 61 subjects were heterozygous (41.8%),
and 15 subjects were PER35 homozygous (10.3%). The
morningness-eveningness survey revealed that 31.6% of the
population was in the 1st tertile (eveningness), 34.2% were in
the 2nd tertile (intermediate), and 34.2% were in the 3rd tertile
(morningness). The cutoff points of Horne & Östberg were
used(27), for which 28.8% of the population exhibited moderate
or extreme eveningness, 62.8% were intermediate, and 8.4%
exhibited moderate morningness.
109
The descriptive statistics of sleep patterns (beginning,
middle and end phases of sleep and sleep duration) are detailed
in Table 1.
Sleep patterns, chronotype and PER3 on Monday
through Friday
The analyses of working day data demonstrated
statistically significant interactions between the chronotype and
PER3 on sleep duration (F = 3.31, p = 0.013) (Table 2). The
mean duration and standard deviation of sleep in students in
the intermediate tertile and PER35 homozygous was 8 hours
(± 1.8h), which is significantly higher than the morningness
chronotype with the same genotype (mean sleep duration 5.58h
± 1.78h) (Table 3).
Sleep patterns, chronotype and PER3 on days off
A statistically significant difference between chronotypes
and the end of sleep was observed (F = 3.47, p = 0.035) (Table 2).
The end of sleep was delayed in students with the eveningness
chronotype (10:44 am ± 1.42h) compared to students with a
morningness chronotype (9:38 am ± 94.28h). No associations
with PER3 alone or associated with chronotypes for the days off
were observed.
Sleep patterns, chronotype and PER3 on Sunday
through Monday
A statistically significant difference between chronotypes
was observed (F = 3.67, p = 0.03). Students with an intermediate
tertile chronotype exhibited delayed values (3:59 am ± 2.16h)
compared to students with a 3rd tertile chronotype (3:33 am ±
1.24h) (Figure 1). Significant interactions were observed between
the chronotype and genotype in the middle of sleep (F = 2.71, p
= 0.03) and sleep duration (F = 2.44, p = 0.05). However, these
differences could not be detected (Table 3).
Intense light exposure, sleepiness, and individual preferences (morningness-eveningness) on the Horne &
Östberg questionnaire and the PER3 gene
Analysis of the Karolinska Sleepiness Scale at 7:00 pm
and 9:00 pm on the intervention days revealed a chronotype effect at 9:00 pm (F = 2.73, p = 0.05). The students followed the
expected pattern in the absence of intervention and demonstrated increased sleepiness in the early evening with intense light exposure at 7:00 pm. However, a slight increase in sleepiness levels
in the intermediate (p = 0.02) and eveningness individuals, and a
reduction in the level of sleepiness at 9:00 pm was observed with
intense light exposure at 9:00 pm (p < 0.01) (Figure 2).
Genes and melatonin secretion
PER3 and HIOMT genotypes were compared to melatonin secretion. An HIOMT-specific haplotype was associated with melatonin concentrations at 7:00 pm and after
exposure to intense light at 7:20 pm (Figure 1).
DISCUSSION
Roenneberg et al.(28) identified a trend towards a normal curve distribution for chronotypes in the world population. Alam et al.(29) reported that 32% of college students in the
southern region of Brazil exhibited eveningness, 54% were intermediate, and 14% exhibited morningness. A study of 2,135
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110
Table 1. Mean, standard deviation, minimum, and maximum (in hours) of the beginning, middle, and end of sleep stages and duration of sleep
on workdays and days off.
Sleep onset
End of sleep
Middle of sleep
Mean ± SD
Max
Min
Mean ± SD
Max
Min
Mean ± SD
Max
Work days
00:37 am ± 1.51h
11:00 am
10:00
pm
06:54 am ±
1.05h
10:00 am
04:30
am
03:46 am ± 0.96h
08:30
am
Off days
01:52 am ± 1.47h
06:00 am
10:45
pm
10:12 am ±
1.58h
03:00 pm
05:45
am
06:01 am ± 1.35h
00:32 am ± 2.74h 12:30 pm
10:00
pm
06:56 am ±
1.09h
11:00 am
04:30
am
03:50 am ± 1.78h
Sunday through
Monday
Sleep duration
Min
Mean ± SD
Max
Min
01:30 am 6.48h ± 1.05h
10.0h
3.25h
09:30
am
03:15 am 8.34h ± 1.33h
12.25h
4.08h
02:45
pm
01:30 am 7.03h ± 1.26h
11.00h
3.33h
Table 2. Two-factors analysis of variance (ANOVA) - chronotype (1st tertile, intermediate, and 3rd tertile) and the VNTR polymorphism of the
PER3 gene (4/4, 4/5, 5/5) - of sleep variables (beginning, end and middle of sleep phase, and sleep duration) from Monday through Friday, on
days off, and from Sunday through Monday. São Paulo, 2007-2008.
Variables
Sleep Onset
End of sleep
Middle of sleep
Sleep duration
a
Factors
Monday through Friday
Off days
Sunday through Monday
F
p
F
p
F
p
Chronotype
0.74
0.479
1.60
0.207
0.14
0.864
PER3
0.37
0.691
0.54
0.579
0.37
0.688
Chronotype and PER3
0.44
0.780
0.61
0.656
0.58
0.677
Chronotype
0.27
0.757
3.47
0.035b
0.30
0.741
PER3
0.62
0.539
0.09
0.909
0.55
0.573
Chronotype and PER3
0.70
0.587
0.22
0.921
0.69
0.596
Chronotype
0.25
0.779
3.00
0.054
3.67
0.030c
PER3
2.56
0.081
0.27
0.757
1.77
0.174
Chronotype and PER3
0.91
0.460
0.12
0.972
2.71
0.030d
Chronotype
2.83
0.063
0.33
0.718
0.22
0.799
PER3
1.57
0.211
0.06
0.940
1.08
0.342
Chronotype and PER3
3.31
0.013a
1.68
0.161
2.44
0.050e
2nd tertile 55 > 3rd tertile 55; b 1st tertile > 3rd tertile; c 2nd tertile > 3rd tertile; d no difference was detected; e no difference was detected.
Table 3. Mean and standard deviation of sleep duration (in hours)
relative to the chronotype and PER3 interaction.
Chronotype: PER3
Mean ± SD
1 tertile: 44
6.14 ± 0.93
1st tertile: 45
6.49 ± 0.75
1st tertile: 55
7.00 ± 1.68
2 tertile: 44
6.44 ± 0.96
2nd tertile: 45
6.59 ± 0.96
2nd tertile: 55
8.00 ± 1.80
3 tertile: 44
6.50 ± 1.00
3rd tertile: 45
6.87 ± 0.64
3rd tertile: 55
5.58 ± 1.78
st
nd
rd
First tertile: eveningness; second tertile: indifferent; third tertile: morningness.
Italian and Spanish college students demonstrated that 24.54%
of these students exhibited eveningness, 59.62% were intermediate, and 15.84% exhibited morningness(30).
The chronotype is influenced by environmental factors, especially the time of light exposure, age, and genotype(31). Nadkarni et al.(32) demonstrated that the 4 repetitions
allele was the most common in 25 different ethnic groups in
Africa, Europe, and Asia. The frequency of this allele was lower
than 50% in the populations of Yemen, Ethiopia, and Papua
New Guinea.
Individuals with the intermediate chronotype (and
PER35/5 homozygous) exhibited longer sleep duration than
the morningness chronotype with the same genotype on
Figure 1. Melatonin levels for the haplotypes (H) H1 (GG), H2 (CG),
H3 (AG), and H4 (AC) in gentle light (DLMO) and after intense light
exposure for 20 minutes at 7:00 pm. * Statistically significant difference
(p < 0.05).
working days in the present study. Days off analysis revealed
differences between chronotypes at the end of sleep. Students
with the 1st tertile chronotype (eveningness) exhibited a delayed
end of sleep (10:44 am ± 1.42h) compared to the 3rd tertile
chronotype (9:38 am ± 1.57h). This result was expected because
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pm. The HIOMT enzyme is the last enzyme in the synthesis
of melatonin from serotonin. Our data suggest that these polymorphisms modulate the effect of light on melatonin secretion.
These data are the first studies in a natural environment
that suggest an effect of HIOMT gene polymorphism on melatonin secretion.
CONCLUSION
Figure 2. Mean and standard deviation of sleepiness levels (Karolinska Sleepiness Scale - KSS) according to chronotype (indifferent
and eveningness). KSS results at 7:00 pm, 8:30 pm, and 10:00 pm on
Wednesdays during intense light exposure at 7:00 pm and 9:00 pm.
* F = 2.73; p = 0.05.
the literature indicates that eveningness individuals exhibit
a greater delayed end of sleep tendency compared to other
chronotypes(9).
The association between chronotype and the end of
sleep on days off may be due to waking and sleeping hours on
working days, which is independent of the student’s wishes(33).
This schedule is different than days off, which lack the influence
of work on the time to sleep or wake-up. Students have greater
freedom to express their sleep needs on days off, which are mediated by their chronotypes.
Giannotti et al.(9) discovered differences between chronotypes
on weekdays (Monday through Friday) and weekends (Saturday and
Sunday) in young adults. Eveningness individuals demonstrated
delayed sleep onset and wakening and shorter sleep duration
compared to morningness individuals on weekdays and weekends.
However, the authors emphasized that the delay of the sleep phase on
weekends was more pronounced with the eveningness chronotype.
Korczak et al.(34) conducted a survey on college students
in Brazil and analyzed the relationship between chronotypes and
school days and days off. The authors observed associations
between the chronotype and sleep onset on school days:
morningness students exhibited earlier sleep onset (average at
11:00 pm) compared to intermediate and eveningness students
(average sleep onsets at 12:17 am and 12:27 am, respectively).
Morningness individuals began sleep at approximately the same
time on weekends (11:00 pm), but intermediate and eveningness
individuals began sleep at later times (approximately 1:20
am and 3:03 am, respectively). The end of sleep occurred at
approximately the same time during the week for the three
chronotypes. However, the end of sleep occurred later for all
chronotypes on days off: 7:51 am for morningness individuals,
9:16 am for the intermediate individuals, and approximately
11:20 am for the eveningness individuals.
The relationship between individual preferences and
sleepiness levels prior to and after intense light exposure at 9:00
pm was an interesting result. We observed that this intervention
was effective in eveningness students who reported reduced
sleepiness levels after the intervention using the Horne &
Östberg questionnaire and the PER3 gene. Griefahn et al.(35)
reported a greater phase delay in melatonin secretion in the
eveningness individuals who worked in shifts.
We found a significant association between a haplotype
in the promoter region of the HIOMT gene and the secretion
of melatonin prior to and after intense light intervention at 7:00
Our results suggest that social activities are important timing agents that should be valued in association studies between
circadian genes and phenotypes. Furthermore, the use of intense
light in working college students with an eveningness chronotype
may reduce sleepiness during class.
Study limitations
Some of the collected samples contained food residues
that contaminated the samples. These samples were discarded.
Data on the onset, end, and duration of sleep and the
middle period of the sleep phase were obtained through questionnaires, which can produce values that are slightly different
from objectively obtained values.
Financial support
CNPq (472153/2006-4; 307919/2006-4; 370152/2009-3;
490286/2004-6), CAPES, FAPESP (06/59053-2; 07/04648-4;
2008/03191-3; 2008-03193-6; 2009-05737-6), AFIP, Sleep Institute,
Federal University of São Paulo, Brazil.
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Silva LO, Esteves AM, Luz N, Carvalho ANS, Narciso FV, Bittencourt LRA, et al.
113
ORIGINAL ARTICLE
Mood, sleep patterns and the effect of physical
activity on the life quality of brazilian train
operators
Perfil de humor, do sono e o efeito da atividade física na qualidade de vida de
trabalhadores em turno brasileiros
Luciana Oliveira e Silva1, Andrea Maculano Esteves2, Natália Novais Luz Alves1, Adriana Neves da Silva
Carvalho1, Fernanda Veruska Narciso1, Lia R. A. Bittencourt3, Sergio Tufik3, Marco Tulio de Mello1,3
ABSTRACT
Objectives: Rotating or night shifts elicit rapid changes in physiology
which the body cannot quickly adapt. In addition, alterations in shift work
influence social and familial aspects that ultimately impact the quality of
life of these workers. The purpose of this study was to evaluate mood
and sleep patterns as well the effects of physical exercise on the quality
of life of train operators that work in shifts. Methods: This study was
performed with 336 male train operators who worked on a rotating shift in
a Brazilian company. The train operators underwent a polysomnography
and subjective evaluations were made through the use of the following
questionnaires: quality of life, work ability index, physical activity, anxiety,
depression and sleepiness. Statistical analysis was performed using
linear regressions, which the SF-36 scores were used as the dependent
variable, and the sleep pattern variables (REM and sleep efficacy) and
the subjective variables were used as independent variables. They were
all adjusted for age and body mass index. Results: Alterations in the
mood profile, low work capacity, sleepiness and altered of REM sleep
had a negative impact while physical exercise contributed positively to the
quality of life of Brazilian shift workers. Conclusion: Shift workers with
impaired mood profiles and sleep patterns have a negative impact on
quality of life, in contrast to shift workers who engage in physical activity.
Keywords: physical activity, quality of life, shift work.
RESUMO
É conhecido que as escalas de trabalho rotativas ou o trabalho em
turno noturno produzem mudanças rápidas no sistema fisiológico,
cujo organismo é incapaz de se adaptar em curto prazo. Além disso,
as alterações decorrentes do trabalho podem influenciar nos aspectos
sociais e familiares e acabam por impactar na qualidade de vida destes
trabalhadores. Objetivos: Avaliar o efeito da prática da atividade física,
perfil do humor e do sono na qualidade de vida de trabalhadores em
turno brasileiros. Métodos: O estudo foi realizado com 336 maquinistas
do sexo masculino, pertencentes a uma escala de trabalho sequencial de
uma empresa brasileira. Os maquinistas foram avaliados pelo exame da
polissonografia e as avaliações subjetivas da qualidade de vida, índice de
capacidade do trabalho, nível de atividade física, ansiedade, depressão
e sonolência. A análise estatística foi realizada pelo teste de Regressão
Linear, utilizados os escores do SF-36 como variáveis dependentes e como
variáveis preditoras foram utilizados os padrões de sono do estágio REM
e eficiência do sono e as variáveis subjetivas, ajustado por idade e IMC.
Resultados: Alterações no perfil do humor, baixa capacidade de trabalho,
sonolência e o estágio do sono REM alterado impactam negativamente
enquanto a atividade física contribuiu de forma positiva na qualidade de
vida dos trabalhadores em turno brasileiros. Conclusões: Trabalhadores
em turno com alterações do perfil do humor e no padrão do sono
possuem impacto negativo na qualidade de vida, em contrapartida ao
efeito da prática da atividade física.
Descritores: atividade física, qualidade de vida, trabalho em turnos.
INTRODUCTION
Among several shift work consequences are the
changes to the biological clock, which occur during irregular shifts and it seem to be a major accidents risk factor.
These are conditions lead to a low quality and efficacy of
work and have a decisive impact on worker health(1-3).
Currently, the “24-hour society” that aims for efficiency and productivity includes professionals from several sectors of the textile, utilities, customs, immigration,
shipping and health care industries(4). Shift work schedules
differ strikingly in terms of the timing and duration of
each shift as well as the type of activity and the speed of
shift rotation(1). Studies have demonstrated that 15%-24%
of workers in Europe and the United States of America
are engaged in shift work(4).
Studies have shown that an increase in fatigue,
sleepiness and manifestations of sleep disturbance lead
to changes in sleep and quality of life in shift workers(5,6).
Sleep disturbances occur in approximately 5%-62% of
shift workers(5-7). In addition to these factors, psychological stressors, such as alterations in mood, depression and
anxiety levels, are correlated with fatigue and have a negative impact on the health of shift workers(2,8,9).
Currently, research into potential interventions for
shift workers aims to understand the individual as a biophysio-social entity to integrate intrinsic well-being with
an optimal quality of life(10). The instrumental approach
to the quality of life assessments allows the integration
Study carried out at Centro Multidisciplinar em Sonolência e Acidentes, Brazil.
1
Centro Multidisciplinar em Sonolência e Acidentes, Brazil.
2
Faculdade de Ciências Aplicadas, Universidade Estadual de Campinas, Brazil.
3
Universidade Federal de São Paulo, Brazil.
Corresponding author: Marco Túlio de Mello, Andrea Maculano Esteves. Universidade Federal de São Paulo. Rua Francisco de Castro, nº 93. Vila Clementino. São
Paulo - SP. Brazil. Phone/Fax: 55 (11) 5572-0177. E-mail: [email protected]/[email protected]
Received: May 30, 2012; Accepted: September 5, 2012.
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Quality of life in Brazilian train operators
of the bio-physio-social determinants of health at different levels, classified by personal factors, such as attitudes,
beliefs, cultural heritage, social influences, and social variables, including opportunities and education(11).
Changes in behavior in this population, such as
physical exercise, phototherapy or sleep therapy, are
known to improve the quality of sleep and help with excessive sleepiness(12).
In shift workers, physical exercise is more difficult
to engage in because the working hours and sleep deprivation alter the worker’s subjective and biological responses.
In addition, there is no consensus in the literature on the
positive effects of physical exercise on the quality of sleep
in shift workers(1).
In this context, the current study evaluated factors
that may interfere with the quality of life and performance
of shift workers. Thus, the goal of this study was to evaluate
the effects of mood profile (depression and anxiety), physical activity and sleep patterns on the quality of life of shift
workers in the rail system owned by a Brazilian company.
METHODS
Subjects
422 male train operators of a Brazilian company
were evaluated between July to November. All subjects
were invited to participate in the study, but the sample
of study was composed of 336 train operators. The work
schedules belong to the sequential range (4 work days:
6X 24 hours). Subjects were informed about the procedures before signing the consent form for the study. This
study was approved by the Research Ethics Committee
of the Universidade Federal de São Paulo, UNIFESP
(No. 1597-1503).
The inclusion criteria were the consent to participate in the study, sex, complete all questionnaires and subsequent polysomnography (PSG) evaluation. Train operators with an apnea-hypopnea index (AHI) ≥ 15, classified
according to the standards of AASM (American Academy
of Sleep Medicine), were excluded from the sample(13).
Experimental design
The train operators underwent anthropometric assessments (weight, height, waist, hip and neck) to determine the body mass index (BMI). The BMI calculation
followed that suggested by the World Health Organization(14). After responding to the general questionnaires for
the assessment of the Epworth Sleepiness Scale (ESS),
physical activity, anxiety and depression, participants underwent a PSG to evaluate their sleep patterns. This sleep
recording was conducted in the hotel where participants
typically rested between workdays.
Experimental procedure
Polysomnography examination (PSG)
A full-night PSG was performed using digital TitaniumTM Embla Systems (Embla, Broomfield, USA). The
room used for the recordings had a comfortable bed, acoustic isolation and controlled light and temperature. The physiological recordings were monitored simultaneously and
continuously (by the professional responsible) with the following records: electroencephalogram (three channels: F4M1, C4-M1, and O2-M1),electrooculogram, chin and side
tibial electromyograms, electrocardiogram, airflow (thermal
sensor), thoracic-abdominal movements, snoring (a microphone was placed on the lateral neck), pulse oximetry and
body position. PSG recordings were performed according
to the criteria established by AASM(15). Electrode placement
was carried out according to the international 10-20 system(16). The parameters were analyzed: a) total sleep time
(in min), defined as the actual time spent asleep; b) sleep
latency (in min), defined as the time from lights out until
the onset of three consecutive epochs of stage 1 or deeper
sleep; c) sleep efficiency, defined as the percentage of the
total recording time spent asleep; d) wake after sleep onset
(in min) e) stages 1, 2, 3 and REM sleep, as percentages of
total sleep time; and f) the latency to REM, defined as the
time from sleep onset until the first epoch of REM sleep.
Quality of life (SF-36)
The questionnaire used to assess the subjective
quality of life was a multidimensional instrument comprising 36 items that assessed 8 dimensions: physical functioning (10 items), physical appearance (4 items), pain (2
items), general health (5 items), vitality (4 items), social aspects (2 items), emotional aspects (3 items), mental health
(5 items). In addition, one question is used to compare
the current health status to that of 1 year ago. To evaluate
the results, a score was determined for each of the questions and subsequently transformed into a scale of 0 to
100, scale on 0 (zero) corresponded to the worst health
level and in 100 was the best health level. Each factor was
analyzed separately(17).
Level of physical activity (Baecke)
The Baecke questionnaire consisted of 16 questions covering 3 habitual physical activity (HPA) scores
over the last 12 months: 1) occupational physical activity
score (8 questions); 2) physical exercise in leisure score
(PEL) (4 questions); and 3) leisure-time physical activity
and locomotion score (LTPS) (4 questions). In this study,
the scores of physical sports activities were used(18).
Sleepiness (Epworth)
Currently, the most commonly used scale for the
subjective assessment of daytime sleepiness is the Epworth
Sleepiness Scale, which can differentiate between people
with and without drowsiness from those with excessive
sleepiness. The Epworth consists of eight questions that
describe situations that can induce drowsiness. Each question is scored from 0 to 3 points. Scores above 10 indicate
significant daytime sleepiness and those above 15 are associated with the pathological sleepiness present in specific
conditions, such as sleep apnea and narcolepsy(19).
Beck Depression Inventory
The Beck Depression Inventory is a measurement
tool used to measuring the severity of depression. The
Portuguese version was validated by Gorenstein et al.(20).
Sleep Sci. 2012;5(4):113-119
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03/01/2013 16:47:17
The original assessment scale was composed of 21 items
with scores that ranged from 0 to 3. The items contained
in the survey attempt to evaluate the following symptoms
and attitudes: sadness, pessimism, sense of failure, lack of
satisfaction, sense of guilt, sense of punishment, self-deprecation, self-blame, suicidal thoughts, incidents of crying/
mourning, irritability, social isolation, distorted body image, work disruption, sleep disturbance, ease of tiredness,
loss of appetite, weight loss, somatic preoccupation and reduced libido. The classifications of the scores that suggest
depression are normal (0-9), mild (10-15), mild to moderate (16-19), moderate to severe (20-29) and severe (30-63).
Anxiety (State-Trait Anxiety Inventory, STAI)
The STAI is a self-assessment questionnaire divided
into two parts: the first assesses trait anxieties, and the second evaluates state anxieties. Each of these parts consists
of 20 statements that are scored from 1 to 4. The state
evaluation assesses how the subject feels “at the moment”,
while the trait evaluation measures how the subject typically feels (baseline). The score of each section can vary
from 20 to 80 points, and the scores may indicate a low
degree of anxiety (0-30), an intermediate level of anxiety
(31-49) or a high degree of anxiety (greater than or equal
to 50). Lower scores indicate a lower degree of anxiety(21).
Work Ability Index (WAI)
The work ability evaluation was done through the
Work Ability Index(22) based on workers’ self-perception.
It is composed of seven items: current work ability compared with the lifetime best, work ability in relation to
job demands, number of current diseases diagnosed by
a physician, estimated work impairment due to diseases,
sick leave during the past year (12 months), own prognosis
of work ability two years from now and mental resources.
The final score varies from 7 to 49 points, distributed across the following categories: poor (7-27), moderate
(28-36), good (37-43) and excellent work ability (44-49).
Statistical analysis
Statistical analysis was performed with the use of a
statistical software package (PASW Statistics for Windows,
version 18.0, SPSS Inc., Chicago, IL, USA).
The Kolmogorov-Smirnov test was used to test for
normal distribution. Descriptive statistics were used. The
data are presented as the means ± the standard deviation
(SD) and absolute and relative frequency (%).
To determine the effect of the variables on the quality of life (adjusted for BMI and age) multiple linear regressions were performed. Models were selected based on
the smallest residual sums of squares (RSS) and the highest coefficient of determination (R2) and enter method.
Durbin Watson statistic model was used to test the residuals from a linear multiple regression are independent. The
level of significance was set at α < 0.05.
The prediction model was established through the
cutoff scores of the questionnaires dichotomized to establish the risk level. Thus, a STAI score > 30 (trait and
state) was considered to be a risk factor (i.e., medium and
115
high anxiety vs. low anxiety). A Beck questionnaire score
≥ 10 was considered a risk factor (i.e., depression vs. no
depression). An Epworth questionnaire score ≥ 10 was
considered a risk factor (i.e., drowsiness vs. Epworth ≤ 9
no drowsiness). AWAI questionnaire score ≤ 36 was considered a risk factor (i.e., moderate and low WAI vs. high
and optimum WAI). The score´s Baecke questionnaire results and age were used as continuous variables.
The age and a BMI were used adjusted variables.
The BMI ≥ 25 kg/m² was considered a risk level versus
BMI < 25 kg/m².
After adjusting for the effect of multicollinearity of all
polysomnography variables, only the sleep efficiency and REM
profile were considered independent variables. The risk group
had an efficiency ≤ 85% and abnormal REM sleep profile.
RESULTS
The mean age was 36.2 ± 9.2 years. 211 (63%) had
overweight (BMI ≥ 25 Kg/m²). The overweight showed
negative impact on overall quality life and the age showed
negative correlation with the areas of functional capacity.
The descriptive data for the sample are shown in Table 1.
The sample consisted of 76 (22.6%) train operators with
daytime sleepiness. A total of 52 train operators (15.5%)
presented scores that are compatible with depression.
Table 2 demonstrates the effect of sleep quality,
sleepiness, anxiety, depression, physical activity and sleep
patterns on the quality of life, adjusted for age and BMI.
The mood profile and the depression scores variables showed a large negative impact on the overall quality
of life evaluated for weight of β coefficient negative.
The drowsiness showed negative effect (evaluated
by categorizing risk score showed a decrease in quality of
life compared to without risk of drowsiness) on overall
quality of life, functional capacity, general health, vitality,
emotional functioning and mental health.
The perception of low and moderate workload
showed a decrease in overall quality of life, and in the aspects of physical, social and pain.
Among the sleep parameters, REM sleep showed a
negative effect on functional capacity. 64.3% had anormal
values for the percentage expected at this stage.
These data are in contrast to the positive effect of
physical activity on the functional capacity, general health,
vitality, social functioning and mental health.
DISCUSSION
The quality of life is the subjective perception of
well-being in a multidimensional manner (physical, psychological and social), with both positive (mobility and
satisfaction) and negative (pain and fatigue) dimensions(23).
This study confirms that afirmation, since the predictive
models explained in this sample a range of 33% to 37% in
quality of life, which means not contemplated that other
factors have an effect on the quality of life of shift workers.
Depending on social and individual experiences,
similar health problems may have different effects on different people(24). In the current study, we show that, as well
as in the general population, in shift working train operaSleep Sci. 2012;5(4):113-119
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116
Table 1. Characterization of the sample (n = 336).
Variables
Table 2. Linear regression effect of physical activity, mood and sleep
on the quality of life.
Mean ± SD
Age (years)
Overall quality of lifea
36.2 ± 9.2
26.4 ± 3.6
Independent variables
F
Quality of life
Altered REM
-0.621
-0.02 (-2.94, 1.53)
Quality of life - total
85.0 ± 11.7
ICT ≤ 36
-3.648
-0.17 (-12.68, -3.79)**
Functional capacity
92.5 ± 11.5
Epworth ≥ 10
-2.472
-0.11 (-5.90, -0.67)*
Physical aspects
89.0 ± 25.0
BMI ≥ 25
-2.182
-0.10 (-4.72, -0.24)*
Pain
81.4 ± 19.0
Trait STAI > 30
-6.919
-0.37 (-0.92, -0.51)**
General health state
85.0 ± 15.3
Vitality
77.2 ± 14.0
Average physical activity
3.502
0.16 (1.68, 6.00)**
Social aspects
86.2 ± 18.3
Beck ≥ 10
-2.816
-0.15 (-8.45, -1.50)*
Emotional aspects
91.0 ± 23.5
Age
-0.086
-0.00 (-0.12, 0.11)
Mental health
82.4 ± 14.3
Efficiency ≤ 85
1.676
R² = 0.33 * p ≤ 0.05 ** p ≤ 0.001.
0.07 (-0.33, 4.18)
BMI (Kg/m )
2
Physical Activity
Physical sports activity
2.2 ± 0.8
Occupational physical activity
2.00 ± 0.47
Leisure physical activity
2.5 ± 0.6
2.1 ± 0.5
Total physical activity
7.5 ± 1.3
Mood
Mean ± SD
n (%)
Beck- Total
5.4 ± 4.9
336 (100)
Beck ≥ 10
14.1 ± 4.7
52 (15.5)
Beck < 10
3.8 ± 2.8
284 (84.5)
State STAI- Total
31.7 ± 6.7
336 (100)
State STAI > 30
36.0 ± 5.5
120 (35.7)
State STAI ≤ 30
26.0 ± 3.0
216 (64.3)
Trait STAI- Total
31.0 ± 7.0
336 (100)
Trait STAI > 30
26.0 ± 3.1
190 (56.5)
Trait STAI ≤ 30
35.4 ± 4.6
146 (43.5)
Work Ability
WAI- Total
43.5 ± 4.1
336 (100)
WAI ≤ 36
33.7 ± 2.3
23 (6.9)
WAI > 36
44.2 ± 3.1
313 (93.1)
Epworth- Total
6.7 ± 3.4
336 (100)
Epworth ≥ 10
11.5 ± 1.7
76 (22.6)
Epworth < 10
5.4 ± 2.3
260 (77.4)
Sleepiness
Sleep
Sleep Efficiency- Total
85.2± 9.0
336 (100)
Efficiency < 85
76.0 ± 8.2
125 (37.2)
Efficiency ≥ 85
90.6 ± 3.3
211 (62.8)
Sleep REM- Total
20.1 ± 6.3
336 (100)
Altered REM
19.0 ± 7.5
216 (64.3)
Normal REM (20-25%)
22.2 ± 1.6
120 (35.7)
The data are presented as the means and SD (±), absolute and relative
frequency (%).
tors, excessive weight, higher age, alterations in mood, low
work capacity, drowsiness and altered REM have a negative impact on the quality of life, while physical activity
positively contributes to the quality of life.
β coefficient (95% CI)
Functional Capacitya
F
Altered REM
-2.10
-0.11 (-5.23, -0.17)*
ICT ≤ 36
-1.83
-0.09 (-9.70, 0.33)
Epworth ≥ 10
-0.65
-0.03 (-3.94, 1.96)
BMI ≥ 25
0.28
0.01 (-2.16, 2.90)
Trait STAI > 30
0.96
-0.05 (-0.34, 0.11)
4.24
0.22 (2.82, 7.70)**
Beck ≥ 10
-2.44
-0.14 (-8.80, -0.94)*
Age
-2.18
-0.12 (-0.28, -0.01)*
Efficiency ≤ 85
0.93
R² = 0.13 * p ≤ 0.05 ** p ≤ 0.001.
0.05 (-1.34, 3.76)
Physical Aspectsa
F
Altered REM
-1.39
-0.07 (-9.38, 1.58)
ICT ≤ 36
-3.63
-0.19 (-31.01, -9.23)**
Epworth ≥ 10
-.065
-0.03 (-8.55, 4.26)
BMI ≥ 25
-1.74
-0.09 (-10.37, 0.61)
Trait STAI > 30
-2.38
-0.14 (-1.11, - 0.10)*
1.63
0.08 (-0.89, 9.68)
Beck ≥ 10
-1.06
-0.06 (-13.15, 3.90)
Age
-0.02
-0.00 (-0.29, 0.28)
1.44
0.07(-1.46, 9.61)
F
Altered REM
-0.66
-0.03 (-5.39, 2.66)
ICT ≤ 36
-3.70
-0.19 (-23.10, -7.08)**
Epworth ≥ 10
-1.41
-0.07 (-8.09, 1.32)
BMI ≥ 25
-0.87
-0.04 (-5.82, 2.24)
Trait STAI > 30
-4.00
-0.24 (-1.12, -0.38)**
Efficiency ≤ 85
R² = 0.11 ** p ≤ 0.001.
Paina
2.13
0.11 (0.33, 8.11)*
Beck ≥ 10
-0.44
-0.02 (-7.67, 4.85)
Age
-1.81
-0.09 (-0.41, 0.17)
Efficiency ≤ 85
0.88
R² = 0.13 * p ≤ 0.05 ** p ≤ 0.001.
0.04 (-2.25, 5.89)
Sleep Sci. 2012;5(4):113-119
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Continued Table 2.
Continued Table 2.
General Health Statusa
Mental Healtha
F
F
Altered REM
-0.04
-0.00 (-3.33, 3.20)
Altered REM
0.26
0.01 (-2.26, 2.96)
ICT ≤ 36
-0.66
-0.03 (-8.67, 4.31)
ICT ≤ 36
-1.02
-0.04 (-7.89, 2.48)
Epworth ≥ 10
-2.02
-0.11 (-7.75, -0.11)*
Epworth ≥ 10
-0.14
-0.01 (-3.28, 2.82)
BMI ≥ 25
-1.05
-0.05 (-5.02, 1.52)
BMI ≥ 25
-1.29
-0.05 (-4.33, 0.89)
Trait STAI > 30
-2.78
-0.13 (-0.72, -0.12)**
Trait STAI > 30
-10.02
-0.52 (-1.45, -0.98)**
2.66
0.14 (1.11, 7.42)**
1.48
0.06 (-0.61, 4.42)
Beck ≥ 10
-3.40
-0.24 (-13.87, -3.71)**
Beck ≥ 10
-2.39
-0.12 (-8.99, -0.87)*
Age
-1.10
-0.06 (-0.27, 0.07)
Age
2.16
0.10 (-0.01, 0.29)*
Efficiency ≤ 85
0.88
R2 = 0.15 * p ≤ 0.05 ** p ≤ 0.001.
0.04 (-1.82, 4.78)
Vitalitya
F
Altered REM
2.12
0.09 (0.21, 5.57)
ICT ≤ 36
-1.12
-0.05 (-8.36, 2.27)
Epworth ≥ 10
-3.13
-0.15 (-8.11, -1.85)*
BMI ≥ 25
-1.12
-0.05 (-4.22, 1.14)
Trait STAI > 30
-7.80
-0.26 (-1.21, -0.72)**
3.39
0.17 (1.87, 7.04)**
Beck ≥ 10
-2.02
-0.23 (-8.45, -0.12)*
Age
0.32
0.00 (-0.11, 0.16)
1.38
0.05 (-0.80, 4.60)
Efficiency ≤ 85
R2 = 0.32 ** p ≤ 0.001.
Social Aspectsa
F
Altered REM
-0.45
-0.02 (-4.72, 2.96)
ICT ≤ 36
-2.83
-0.14 (-18.64, - 3.37)*
Epworth ≥ 10
-2.46
-0.12 (-10.11, -1.12)*
BMI ≥ 25
-1.73
-0.08 (-7.25, 0.44)
Trait STAI > 30
-5.00
-0.29 (-1.24, -0.54)**
1.70
0.08 (-0.49, 6.92)
Beck ≥ 10
-1.06
-0.06 (-9.20, 2.74)
Age
1.11
0.05 (-0.08, 0.32)
Efficiency ≤ 85
1.81
R2 = 0.18 * p ≤ 0.05 ** p ≤ 0.001.
0.09 (-0.30, 7.45)
Emotional Aspectsa
F
Altered REM
-0.03
-0.00 (-5.27, 5.09)
ICT ≤ 36
-1.34
-0.07 (-17.33, 3.25)
Epworth ≥ 10
-1.62
-0.08 (-11.06, 1.04)
BMI ≥ 25
-1.87
-0.10 (-10.13, 0.24)
Trait STAI > 30
-3.39
-0.21 (-1.29, -0.34)**
0.98
0.05 (-2.49, 7.50)
Beck ≥ 10
-1.81
-0.11 (-15.48, -0.63)**
Age
0.85
0.04 (-0.15, 0.39)
0.59
0.03 (-3.65, 6.81)
Efficiency ≤ 85
R2 = 0.11 ** p ≤ 0.001.
117
Efficiency ≤ 85
-0.28
-0.01 (-3.41, 2.23)
R2 = 0.37 ** p ≤ 0.001.
Dependent Variable; F: F statistic. Data are adjusted for age and BMI;
a
R²: indicates the output variance accounted for each of the predictors;
95% CI: Confidence Interval; β: regression coefficient - The negative
coefficient for categorical data is that the risk score (predictor variable)
shows a decrease in quality of life in contrast to the group without risk.
Studies have shown that shift workers are more
prone to a number of health problems and have an increased risk of developing long-term nutritional and metabolic problems(2). These data agree with the findings of
the current study.
Gonçalves et al.(25) evaluated the quality of life of
train operators and found deficits in general and mental
health as well as in vitality. The authors also reported that
health problems impair the quality of life. These findings
are in agreement with a study by Nena et al.(6), the authors showed a trend of lower scores for vitality, general
and mental health in train operators. The results of these
two studies agree with the results of the current study,
the vitality showed the lowest score on the quality of life
assessment.
In shift workers, the desynchronization caused by
abrupt changes in working hours manifest as sleep disorders, drowsiness, feelings of malaise, gastrointestinal
complications, fluctuations in mood, reductions in performance and impacts on interpersonal relationships(26).
In addition, other factors related to work may impact the health of workers, such as the work environment
and the perception of workload. These factors directly affect the quality of life, specifically in relation to the functional capacity, health and general sense of well-being(27,28).
The consequences of the physical and mental demands
involved in the perception of workload, as well as their
effect on health and performance, have recently been investigated(28). In our study, reduced work capacity had a
negative impact on overall quality of life, physical/social
aspects and pain.
The negative relationship and magnitude of the
coefficient β showed that the profile of mood, assessed by
the proclivity to depression and anxiety had major negative impact on quality of life.
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118
A low quality of life and cognitive and social performance are commonly evaluated in shift workers; sleepiness is the most common symptom of a sleep disorders,
along with decreased duration and efficiency of sleep(29-31).
Drowsiness is strongly regulated by homeostatic influences and is primarily related to a lack of sleep and the
length of time spent awake(29). In our sample, we found
that 22.6% of train operators exhibited excessive daytime
sleepiness. Sleepiness had a negative impact on the quality
of life, with specific effects on the overall quality of life,
general health, vitality and social aspects. This result can
be justified in error prone and accidents often associated
with population general(30,32).
Shift work induces the development of early clinical manifestations of metabolic disorders(2,8,9,33). According to the literature, obesity is associated with factors
such as gender, age and lifestyle habits, including smoking
and alcohol consumption(34). Since the sample was composed by 63% overweight subjects had significant effect
on overall quality of life of the current sample. In contrast,
we found that when the data were adjusted for age and BMI,
physical activity had a positive effect on the quality of life.
In general, it has been shown that physical exercise
improves the consequences of sleep, supported by hypotheses that are based on thermoregulation, body repair
and conservation of energy(35,36).
Patients who engage in exercise with concurrent
improvements in depression symptoms also show benefits
in sleep behavior. Psychiatric disorders are often observed
in shift workers, which confirms the need for intervention
strategies(24). Although there is a general consensus that
physical activity reduces mood disorder levels, there is no
agreement on how this action occurs, which depends on
an understanding of the etiology of the psychiatric disorder and the intensity and duration of exercise(35).
Physical exercise also has benefits on work capacity because it improves productivity and decreases absence
rates(36). In addition, exercise improves general health,
which corroborates the findings of the current study
showing the positive effect of physical activity on quality
of life of shift workers in Brazil, in contrast the principal changes in sleep, mood, low perception of workload,
demonstrated in present study.
In agreement with other studies, our data show that
employees who work in shifts and participate in physical
activities, in combination with other healthy lifestyle habits, will have an activity profile that helps them work in
shifts and tolerate the stresses of the working hours(37).
In our sample, we found a high prevalence of 56.5% dispositional anxiety. The dispositional anxiety impairs the
long-term sleep quality(38),which may explain the finding
that 64.3% of train operators show altered REM sleep
patterns. The association between job characteristics and
psychosocial factors arising from the deprivation of a social life manifest themselves as symptoms of depression in
the health of workers(39).
Recent studies have focused on the management
of primary health care for depression(39). In the current
study, we found that 15.5% of train operators had com-
patible with the depression scores, which were negatively
associated with the quality of life. In general, shift work,
mainly rotating schedules, leads to reduced hours of sleep
and changes in circadian rhythms that affect not only
the health of the individual but also their family life and
professional performance due to the presence circadian
rhythms(40).
Improvements in the reorganization of work
schedules and work models should better address this
population. Both the demand for productivity of the
service from segments of society and the personal
and family needs of each professional should be met
to provide optimal well-being and safety at work(26).
Potential limitations in this study include parameters of
physical activity that were not assessed in this study. For
example, the level of intensity, frequency, type of exercise
and duration of physical activity were not measured.
In addition, biological and behavioral results relevant
to bio-physio-social health have not been studied in
this population sample(1). However, it is important to
emphasize the importance of specific questionnaires as
a method to address the global dimension of individual
perceptions in the various sectors of the economy and the
health of shift workers.
In this study, we found that the factors that had the
greatest negative effect on the quality of life of Brazilian
train operators were related to their mood profile, including
anxiety and depression, followed by low work capacity,
drowsiness and changes in sleep patterns. In contrast,
physical activity was shown to be a positive factor in the
quality of life, which should be further investigated in the
management of the health of shift workers.
Moreover, the results of this study agree with previous studies by revealing the urgent need for initiatives
and improvements in the health system, particularly at the
primary level, by a multidisciplinary team specializing in
various sectors of the so-called “24-hour society”(1,2).
In conclusion this study demonstrates the importance of interventions that should be used to integrate biophysio-social factors and minimize the range of detrimental
effects given the prevalence characterized by this sample, as
well as the individual impact of shift work on health.
ACKNOWLEDGEMENTS
This work was supported by grants from the Associação de Fundo e Incentivo à Pesquisa - AFIP, Fundação
de Amparo a Pesquisa do Estado de São Paulo - FAPESP
(CEPID No. 98/14303-3 to ST), Centro Multidisciplinar
em Sonolência e Acidentes - CEMSA and Centro de Estudos em Psicobiologia e Exercício - CEPE.
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Sleep Sci. 2012;5(4):113-119
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Maldonado AC, Poyares D, Chada DP, Silveira FM, Lorenzi-Filho G, Castro JR, et al.
120
SHORT COMMUNICATION
Overview of sleep disordered breathing
management in 12 latin american sleep centers
Panorama do gerenciamento dos distúrbios respiratórios de sono em 12 centros
latino-americanos de sono
Armando Castorena Maldonado1, Dalva Poyares2, Daniel Perez Chada3, Flavio Magalhães Silveira4,
Geraldo Lorenzi-Filho5, Jorge Rey de Castro6, Juan Facundo Nogueira7, Leonardo Serra8, Lia Bittencourt2,
Luciana Rabello de Oliveira9, Maria Angélica Bazurto10, Maria Victorina Lopez Varela11, Matilde Valencia Flores12,
Rafael A. Lobelo Garcia13
ABSTRACT
Objectives: Sleep Disordered Breathing (SDB) still remains unrecognized by the medical community, health-care providers and patients despite its high prevalence and association with other major
health conditions. The aim of this study was to describe data about
the SDB management, collected from 12 different Latin American sleep centers. Methods: Thirteen physicians from these sleep
centers completed an electronic survey about SDB recognition,
number of Sleep Physicians and Sleep Centers, as well as Sleep Medicine training in their respective countries. Results: Seventy-seven
percent of the participants responded that Sleep Medicine is not
recognized as a medical specialty in their country but despite that,
69% reported that there is specific and official training in Sleep
Medicine and for Sleep Lab technicians in their countries. Sleep
labs are officially registered only in Brazil and Colombia and only
in Brazil sleep labs are certified by a scientific society. The 12 sleep
centers studied summed up more than 45.500 sleep studies performed every year with an average of 60-80% positive studies for
SDB. Most of the sleep centers (85%) perform Home Sleep Testing and use unattended Auto CPAP for home titrations. Eighty-five of the sleep centers have a CPAP clinic to support their patients
with the PAP therapy set up. Conclusion: Sleep Medicine is still
not recognized as a medical specialty in most of Latin America and
all participants agree that education should be number one priority
to grow SDB awareness in Latin America.
Keywords: apnea, latin america, sleep, sleep disorders, sleep medicine
specialty.
RESUMO
Objetivos: Os distúrbios respiratórios do sono (DRS) ainda
permanecem desconhecidos pela comunidade médica, provedores
de serviços de saúde e pacientes, apesar de sua alta prevalência e
associação com outros problemas graves de saúde. O objetivo deste
artigo foi descrever informações sobre o gerenciamento dos DRS,
coletados de 12 diferentes centros de sono da latinoamericanos.
Métodos: Treze médicos desses centros de sono completaram uma
pesquisa eletrônica sobre o reconhecimento dos DRS, clínicas de
sono e treinamento em medicina do sono em seus respectivos países.
Resultados: Setenta e sete porcento dos participantes responderam
que a medicina do Sono não é reconhecida como especialidade
médica em seu país, apesar disso, 69% dos participantes relataram que
existe em seus países treinamento específico e oficial em medicina do
sono e para técnicos de laboratórios do sono. Laboratórios do sono
são oficialmente reconhecidos no Brasil e Colombia e somente no
Brasil os laboratórios são certificados por uma sociedade científica.
Os 12 centros de sono estudados somam mais de 45.500 estudos
de sono por ano com, em média, 60%-80% dos estudos positivos
para DRS. A maioria dos centros de sono (85%) realizam estudo de
sono domiciliar e usam Auto CPAP para titulações em domicílio.
Oitenta e cinco porcento dos centros de sono possuem uma clinica
de CPAP para apoiar seus pacientes com a adaptação à terapia.
Conclusões: A medicina do sono ainda não é reconhecida como
especialidade médica na maioria dos países latino-americanos e
todos os participantes concordam que educação dever ser prioridade
número 1 para aumentar o conhecimento dos DRS.
Descritores: américa latina, apnéia do sono, distúrbios do sono,
medicina do sono.
INTRODUCTION
Sleep Disordered Breathing (SDB) is recognized as
a major public health concern(1). Considering the higher
prevalence of sleep disorders(2-8) and its major risk for
public health due to its associated factors, such as sleepiness(9,10), neuropsychological and mood alterations(11-13),
cardiovascular diseases(14-19), increased risk of automo-
Study carried out at Laboratorio del Sueño del INER - México City - México.
1
Laboratorio del Sueño del INER - México City - México.
2
Instituto do Sono de São Paulo - São Paulo - Brazil.
3
Centro de Estudios de Alteraciones del Sueño - Buenos Aires - Argentina.
4
SLEEP Lab - Centro Médico Barra Shopping - Rio de Janeiro - Brazil.
5
Laboratorio do Sono do Instituto do Coração, HC FMUSP - São Paulo - Brazil.
6
CENTRES Clinica Anglo Americana - Lima - Peru.
7
Laboratorio del Sueño IADIN - Buenos Aires - Argentina.
8
Centro de Trastornos del Sueño Clinica Alemana - Santiago - Chile.
9
ResMed Corp - Latin America.
10
Fundación Neumologica Colombiana - Bogotá - Colombia.
11
Laboratório del Sueño CASMU - Montevideo - Uruguay.
12
Clínica de Trastornos del Dormir, INCMNSZ/UNAM -México City - Mexico.
13
Clinica ONDINA - Bogotá - Colombia.
Corresponding author: Lia Rita Azeredo Bittencourt. Departamento de Psicobiologia. Rua Napoleão de Barros, nº 925. CEP: 04024-002. São Paulo - SP, Brazil.
Phone: 55 (11) 2149-0155. Fax: 55 (11) 5572-5092. E-mail: [email protected]
Received: September 24, 2012; Accepted: October 24, 2012.
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121
Sleep disordered breathing management in Latin America
bile or workplace accidents(20-22) and metabolic dysfunction(23,24), basic knowledge in sleep medicine is expected
by medical clinicians. However, studies have shown that
sleep disordered breathing still remain not well recognized
by the medical community or health-care providers(25-30),
suggesting that people who suffer from sleep disorders do
not receive adequate treatment. This lack of knowledge
and attitudes toward sleep disorders may be attributed to
the negligence in incorporating sleep medicine as part of
medical education(31-36) and relative areas.
Sleep Centers in different countries have sought to
fill this gap through fellowship programs in sleep medicine
or even through outreach programs designed for healthcare professionals(31-36). Other factors contributing to sleep
disorders under diagnosis are the patient’s misperceptions
of symptoms(37-40) and high demand and cost of diagnosis
and treatment(9).
There is scarce information on the Latin American
situation of Sleep Medicine. During the XII Congress of
the Federation of the Latin American Sleep Societies and
the I Congress of the Peruvian Association of Sleep Medicine held in Lima, Peru, in October 2008 a meeting of
representatives from different countries of Latin America
was organized to implement a plan of actions for Sleep
Medicine in Latin America. Participants from Argentina,
Bolivia, Brazil, Chile, Colombia, Ecuador, Mexico, Peru,
and Uruguay described the organization of their societies,
sleep study facilities, care and research in the area of sleep
medicine, human resources and training events as well as
their participation into education in each country.
At that time, very few countries like Argentina,
Colombia, and Uruguay had health systems that cover
polysomnographic studies or continuous positive airway
pressure therapy. In the majority of countries, there was
no formal training in sleep medicine, neither an inclusion
of sleep medicine courses in medical school curricula. The
development of Sleep Medicine in Latin America was clear
to be very uneven and the availability of resources very
different between countries. The analysis of the region
as a whole indicated a major deficiency in the practice
of sleep medicine, an underserved population, and very
few participation of sleep medicine in undergraduate and
postgraduate medicine programs. Sleep medicine, as a
field, is still young and with great development potential(41).
Since 2008, no data from Sleep Medicine in Latin
America was collected. The aim of this manuscript is to
describe the data collected from different Latin American
sleep centers during the III KOLLA group meeting in October 2011.
METHODS
On October 8, 2011 the III KOLLA (Key Opinion
Leaders from Latin America) group meeting was held in
Miami. The KOLLA group consists of sleep physicians
who help develop and shape Sleep Medicine in the various countries of Latin America. The group and the meetings are sponsored by ResMed Corp with the main goal
of promoting discussions and exchanging of experience
to further develop Sleep Medicine in Latin America. The
III KOLLA group meeting had the objective of creating
a document that states the panorama of the Sleep Disordered Breathing Management in Latin America and that
can serve as an important local reference.
Thirteen physicians attended the meeting, 4 from
Brazil, 2 from Argentina, 2 from Mexico, 2 from Colombia, 1 from Peru, 1 from Uruguay and 1 from Chile. These
participants had to complete an electronic survey about
Sleep Medicine recognition, Sleep Physicians, Sleep Center
and Sleep Medicine training in their respective countries.
RESULTS
The results here presented belong to 12 Sleep Centers from 7 different countries in Latin America (Table 1).
Table 1. Twelve participant Sleep Centers.
1. Centro de estudios de Alteracimes del Sueiño - Buenos Aires Argentina
2. Laboratorio del Sueño IADIN - Buenos Aires - Argentina
3. Centro de Transtornos del Sueño Clinica Alemana - Santiago - Clile
4. CENTRES Clinica Anglo Americana - Lima - Peru
5. Instituto do Sono de São Paulo - Sao Paulo - Brazil
6. Laboratório do Sono do Instituto do Coração, HC FMUSP - São
Paulo - Brazil
7. SLEEP Lab - Centro Médico Barra Shopping - Rio de Janeiro Brazil
8. Laboratorio del Sueño del INER - Mexico City - Mexico
9. Clínica de Trastomos del Dormir, INCMNSZ/UNAM - México
City - Mexico
10. Laboratório del Sueño CASMU - Montevideo - Uruguay
11. Clinica ONDINA - Bogota - Colombia
12. Fundación Neumologia Colombiana - Bogota - Colombia
From 13 KOLLA participants, 77% responded that
Sleep Medicine is not recognized as a medical specialty in
their country. Sleep Medicine is officially recognized just
in Brazil and Mexico. Despite that 69% of the participants
reported that there is specific and official training in Sleep
Medicine in their country. The different types of training in Sleep Medicine are shown in Figure 1. Most of the
Sleep Specialists on the countries studied are Neurologists
and Pulmonologists as reported on Table 2.
Figure 1. Types of training in Sleep Medicine reported from the
participant countries.
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Table 2. The estimated rate of each medical specialist w ho is also a
Sleep Specialist.
Pulmonologists
Neurologists
ENTs
Other Specialties
0-20%
20-40%
4-60%
60-80%
N/A
3
4
4
1
1
23%
31%
31%
8%
8%
5
3
4
0
1
38%
23%
31%
0%
8%
5
0
2
1
1
56%
0%
22%
11%
11%
7
0
0
0
1
88%
0%
0%
0%
12%
Top number is the count of respondents selecting the option. Bottom
% is percent of the total respondents selecting the option.
When asked about what needs to be done so that
Sleep Medicine can grow more in Latin America all 13
KOLLA members agreed that Education should be the
number one priority. Other challenges to increase SDB
awareness in Latin America are cited by the participants
as being:
• The need of better education for General Physicians and Medical students;
• Lack of public awareness;
• The need for public and private policies for
sleep studies and PAP therapy reimbursement/
coverage - Lack of government support;
• Lack of local Clinical guidelines for Sleep Medicine;
• Simplified sleep studies should become more
popular.
69% of KOLLA group participants answered that
there are specific trainings for Sleep Lab technicians in
their country. The types of training for Sleep Lab technicians are shown on Figure 2.
Figure 2. Types of training reported for Sleep Lab technicians.
From the seven countries studied there seems to
be a Sleep lab registry only in Brazil and in Colombia, and
only in Brazil Sleep Labs are certified by a scientific society.
The average cost for a private patient of full PSG is
between US$ 250 - US$ 1.000, with Argentina having the
lowest cost and Mexico the highest. On all of the countries investigated there’s a partial or complete reimbursement of a full PSG by public and private health insurances. Public health insurances in Latin America pay Sleep
Labs an average of US$ 200 for a full PSG and private
122
health insurances an average of US$ 300. In Mexico these
values can be as high as US$ 800 for public insurances and
US$ 1,000 for private. The reimbursement of a full PSG
in the referred countries according to the different payer
systems are listed on Table 3.
Table 3. Reimbursement of a full PSG in the countries studied according to different payer systems.
Public Health
System
Prepaid Health
Systems
Social Security
Health Systems
100%
Partially
Not
reimbursed
reimbursed
reimbursed
N/A
5
4
2
1
42%
33%
17%
8%
8
5
-
-
62%
38%
0%
0
6
1
2
1
60%
10%
20%
10%
Top number is the count of respondents selecting the option. Bottom
% is percent of the total respondents selecting the option.
The 12 Sleep Centers surveyed summed up 145
Sleep beds and more than 45,500 sleep studies performed
every year. From these sleep studies on average 60%-80%
are positive for sleep apnea according to the participants.
Children are studied in 8 of the participant sleep
centers (62%). Most of the sleep centers (77%) perform
in-lab simplified sleep studies (respiratory polygraphy)
when appropriate and almost every lab (85%) offers the
Home Sleep Testing (HST) services to their patients.
When it comes to the titration of positive pressure in the
lab, manual titrations are more common (69%) than automatic attended titrations with an Auto CPAP (46%), but
for titrations at home, unattended Auto CPAP is most used
(69%). Bilevel positive pressure titrations are performed in
all of these labs for cases of Overlap Syndrome, Hypoventilation, Neuromuscular Diseases and when high (usually
above 15 cm H2O) positive pressure is required. Adaptive Servo Ventilation (ASV) titrations are performed in
85% of the labs for cases of Periodic Breathing, Complex
Sleep Apnea and Central Sleep Apnea.
Eighty five % of the sleep centers have a CPAP
clinic to support patients with the PAP therapy set up. The
management protocols of the clinics include mainly the
following steps:
• Formal education on SDB and PAP therapy
management with the aid of audio visual and
printed materials. Educational sessions can be
performed individually or in groups and they
are usually conducted by Respiratory Therapists or Nurses;
• Desensitization for PAP therapy which includes
different masks fitting and trying PAP therapy
in different pressure levels (which sometimes
begin on the night of the titration study);
• Psychological consultations are scheduled
when necessary;
• Follow up calls or visits after the first week of
treatment, then 1 month and after 6 months of
PAP therapy initiation.
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Sleep disordered breathing management in Latin America
DISCUSSION
The main and perhaps the most alarming result of
this survey, is the fact that Sleep Medicine is still not recognized as a medical specialty in most of the Latin American
countries, despite the increasing demand of sick patients
and availability of scientific data showing that Sleep Disorders are a major public health burden(42).
Many studies addressed the lack of knowledge in
sleep medicine as part of medical education(31-36). Schotland & Jeffe in 2003 showed that in a sample of 115 physicians very few of them considered SDB as a clinically important problem(43). The problem is even worse for SDB
in children. Uong et al. in 2005 and Tamay et al. in 2006
concluded that there a need for education on SDB for
both undergraduate and graduate medical students(44), as
well as for Pediatric medical residents(29). Sleep Centers in
different countries have sought to fill this gap through fellow programs in sleep medicine or even through outreach
programs designed for healthcare professionals(31-36).
In 2011, Averbuch et al. reported that there was no
formal training in sleep medicinein the majority of Latin
American countries, neither an inclusion of sleep medicine
courses in medical school curricula. The development of
Sleep Medicine in LA was clear to be very uneven and the
availability of resources very different among countries.
The analysis of the region as a whole indicated a major
deficiency in the practice of sleep medicine, an underserved
population, and low inclusion of sleep medicine in
undergraduate and postgraduate medicine programs(41).
Three years after this report, 69% of the KOLLA
group participants reported that there is specific and official training in Sleep Medicine and for PSG technicians in
their countries. Most of them are post graduate fellowship
and specialization courses.
Sleep specialists from the LA countries are mainly
Neurologists and Pulmonologists. It’s remarkable to find
out such an increase in the offering of training in Sleep
Medicine in LA. It may reflect the increase in the demand
for specific knowledge in these countries.
Other challenges to increase SDB awareness in LA
are cited by the participants as being: lack of public awareness; the need for public and private policies for sleep
studies and PAP therapy reimbursement/coverage - Lack
of government support; lack of local Clinical guidelines
for Sleep Medicine and simplified sleep studies should become more popular. Perhaps, a future survey should include investigation on whether this scenario has changed.
Patients often approach their primary care physicians
with a variety of symptoms, and it may take several visits
and/or referral to a pulmonologist, neurologist or otolaryngologist to uncover the root cause. Too often, time is wasted
treating superficial signs of SDB with medications or other
ineffective methods. Specialists and generalists alike have an
opportunity to improve this process by adopting a proactive
approach to identifying and screening for SDB(45).
Full night attended polysomnography is still the
gold standard diagnosis tool(46) but ambulatory cardiopulmonary monitoring for SDB diagnosis has recently gained
ground(47,48).
The cost of diagnosis and treatment of sleep disorders is high. A full PSG can cost a private patient in LA
somewhere between US$ 250 - US$ 1,000 and we wonder
whether simplified in-lab or home diagnostic tests could
reduce costs. Most of the LA sleep centers (77%) perform in-lab simplified sleep studies (respiratory polygraphy) when appropriate and almost every lab (85%) offer
the Home Sleep Testing (HST) services to their patients.
It has been shown that the setting of unattended
respiratory monitoring (home or sleep laboratory) influences neither the number of valid studies nor the results
of the respiratory parameters measured with the advantage that most patients prefer home studies(49).
Despite the high costs to the patients, on average
Public Health Insurances in Latin America pay Sleep Labs
US$ 200 for a full PSG and Private Health Insurances an
average of US$ 300, which is very low considering the
maintenance and personnel costs of a sleep lab.
The PSG full night CPAP manual titration is the best
practice recommended(50). This routine in LA is more common (69%) than automatic attended titrations with an Auto
CPAP (46%), but for titrations at home, Auto CPAP is most
used (69%). It has been shown that home unattended titrations with Auto CPAPs are efficacious and cost-effective
for patients with moderate to severe OSA without significant comorbidities(51). Perhaps newer equipments with better algorithms to recognize central apneas would also help
improve the accuracy of unattended Auto CPAP titrations.
Clinical pathways utilizing PSG and portable monitoring and autotitration have shown to result in similar
CPAP treatment acceptance, adherence, and clinical outcomes. Similarly, a systematic pathway using HST and
unattended autotitration (Auto CPAP) can be effective in
patients with a high likelihood of having OSA(52).
Education about CPAP use is the most important
factor to improve the treatment adherence(53). In agreement with this assumption 85% of the LA sleep centers
have a CPAP clinic to support their patients with the PAP
therapy set up. The management protocols include desensitization, formal education on SDB and PAP therapy
management, psychological consultations and follow up
calls or visits. Most of the studies published about CPAP
education found better results when a robust program is
used compared with a simple approach(53). This result suggests that sleep centers in Latin America are investing in
their patients’ education as a way of increasing treatment
acceptance and compliance.
In conclusion, Sleep Medicine is not recognized
as a medical specialty in most Latin American countries,
despite of that, there are specific and official training for
physicians and technicians. Education in Latin America
should be a priority for the growth of Sleep Medicine in
the region.
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Guindalini C, Tufik S
125
REVIEW
Aspectos genéticos do sono em humanos
Camila Guindalini1, Sergio Tufik1
ABSTRACT
Together with the environment, genetic factors can significantly
influence sleep and its architecture. Monozygotic twins have
greater similarity in terms of latency and duration of sleep cycles
than dizygotic twins, in addition to almost identical spectral
patterns. These observations indicate a genetic contribution to
sleep regulation and suggest that inter-individual variations in its
parameters may be associated with genetic modulators. With the
advent of techniques and molecular-genetic approaches, a number
of genetic factors have been systematically identified that appear
to contribute to the large variability observed in the normal sleep
patterns of individuals and to a greater predisposition to the
development of sleep disorders. This review aims to address the
main scientific discoveries on the genetics of sleep in humans,
presenting an overview of the current situation and future prospects
in this constantly evolving area.
Keywords: genetics, genome, sleep.
RESUMO
Estudos recentes têm demonstrado que fatores genéticos podem,
em conjunto com o ambiente, influenciar o sono e sua arquitetura
de maneira significativa. Gêmeos monozigóticos apresentam maior
similaridade em termos de latência e duração dos ciclos do sono,
além de padrões espectrais praticamente idênticos, quando comparados aos gêmeos dizigóticos. Essas observações evidenciam a
contribuição genética na regulação do sono e sugerem que variações interindividuais em seus parâmetros podem estar associadas a
fatores genéticos moduladores. Com o advento das técnicas e abordagens da genética molecular, uma série de fatores genéticos têm
sido sistematicamente identificados, os quais parecem contribuir
tanto para a ampla variabilidade observada no sono normal do indivíduos, como para uma maior predisposição ao desenvolvimento
de distúrbios do sono. Essa revisão pretende abordar as principais
descobertas científicas acerca do tema da genética do sono em humanos, apresentando um panorama da situação atual e das perspectivas futuras em uma área em constante evolução.
Descritores: genoma, genética, sono.
GENETICS AND SLEEP
Sleep is a complex behavior characterized by interactions between genetic and environmental factors(1,2). In humans,
among the biological factors that contribute to the large individual variability observed in sleep parameters, studies in twins
indicate a significant participation of genetic factors. A study
assessing the sleep of 213 pairs of twins, with a mean age of
16 years, observed that monozygotic (MZ) twins show great
similarity in all frequency bands of the electroencephalogram
(EEG). Indices of heritability of 76%, 89%, 89%, and 86%
were estimated for the delta, theta, alpha, and beta frequency
bands, respectively, in all tested areas of the brain(3). More recently, De Gennaro et al.(4) showed that the EEG pattern in the
8-16 Hz range is far more similar in MZ twins than in dizygotic
(DZ) twins. With a heritability estimate of 96%, this EEG pattern is considered one of the most heritable traits in humans.
These findings show the extraordinary contribution of genetics to normal sleep regulation and suggest that inter-individual
variations observed in sleep parameters may be associated with
genetic modulators.
GENETIC FACTORS INVOLVED IN HUMAN
SLEEP
Clock genes
A growing number of studies have attempted to identify
candidate genes underlying the wide inter-individual variability
observed in sleep parameters and related phenotypes(5). The association between a common variant observed in the period-3
(PER3) gene and diurnal preference is possibly the most widely
studied genetic polymorphism in the field of sleep (Table 1).
The PER3 gene, together with the PER1, PER2, CLOCK, and
brain and muscle Arnt-like protein 1 (BMAL1) genes, among
others, is part of a set of genes regulating the mammalian circadian timing system. This system consists of protein transcription and translation feedback loops, with positive and negative
elements. The CLOCK and BMAL1 proteins unite to form a
heterodimer, which is responsible for promoting the transcription of PER1, PER2, PER3, and the cryptochrome genes CRY1
and CRY2. In turn, proteins encoded by these genes combine in
the cytoplasm and form a complex that returns to the nucleus
and blocks the action of the CLOCK/BMAL1 heterodimer,
which ultimately inhibits the transcription of its own genes in a
negative-feedback loop that lasts approximately 24 hours. The
described process is the basis of the circadian rhythmicity(6).
In humans, the PER3 gene presents a repeat polymorphism in which a region of 54 base pairs may be repeated four
or five times, producing the genotypes PER34/4, PER34/5, and
PER35/5. In 2003, Archer et al. showed that the long five-repeat
allele of the repeat polymorphism in the PER3 gene was associated with diurnal preference, whereas the short four-repeat
allele was more common in individuals classified as evening individuals, according to the Horne-Ostberg questionnaire(7). Furthermore, the study also showed that 75% of individuals with
delayed sleep-phase syndrome (DSPS), a disorder that results
Study carried out at Departamento de Psicobiologia - Universidade Federal de São Paulo - SP. Brazil.
1
Departamento de Psicobiologia - Universidade Federal de São Paulo - SP. Brazil.
Corresponding author: Camila Guindalini. Rua Napoleão de Barros, nº 925. Vila Clementino. São Paulo - SP. Brazil. CEP: 04021-002. Phone: 55 (11) 2149-0155.
Fax: 55 (11) 5572-5092. E-mail: [email protected]
Received: April 26, 2012; Accepted: July 23, 2012.
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126
Table 1. Review of the genes associated with sleep disorders or phenotypes, with results replied at least once in an independent sample and/or
confirmed in functional assays.
Sleep phenotype
Identified gene
References
Sleep Apnea
Tumoral Necrosis Factor - alpha (TNF-α)
Varvarigou et al. 201141
Human Leucocyte Antigen (HLA) (DQB1*0602)
Mignot et al. 199819
T Cell Receptor Alpha Locus (TRA-alfa)
Hallmayer et al. 200921
Carnitine Palmitoyl Transferase 1B (CPTB1)
Miyagawa et al. 200822
Choline Kinase Beta (CHKB)
Miyagawa et al. 200822
Human Leucocyte Antigen (HLA) (DQA2)
Hor et al. 201023
Purinergic Receptor, Subtype P2Y11 (P2RY11)
Kornum et al. 201124
BTB (POZ) domain-containing 9 (BTBD9)
Stefansson & Winkelmann et al. 200726, 27
Myeloid ecotropic viral integration site homeobox 1
(MEIS1)
Winkelmann et al. 200727
Mitogen activated protein kinase kinase 5 (MAP2K5)
Ladybird homeobox co-repressor 1 (LBXCOR1)
Receptor-type tyrosine-protein phosphatase delta
(PTPRD)
Schormair et al. 200833
TOX high mobility group box family member 3
(TOX3)
Non-coding RNA BC034767
Period 2 (PER2)
Toh et al. 200110
Casein Kinase 1 delta (CKI-delta)
Xu et al. 200512
Period 3 (PER3)
Archer et al. 20037, Pereira et al. 20058
DEC2
He et al. 200913
Period 3 (PER3)
Archer et al. 20037, Pereira et al. 20058
ATP-binding cassette, sub-family C- 9 (ABCC9),
Allebrandt et al. 201114
Adenosine Deaminase (ADA)
Rétey et al.200517, Mazzotti et al. 201115
Narcolepsy
Restless legs syndrome
Familial Advanced Sleep Phase Syndrome
Familial Delayed Sleep Phase Syndrome
Short Sleepers
Diurnal Preference
Sleep length
Sleep Homeostasis
in symptoms similar to insomnia (presenting difficulty waking
up at the desired time in the morning) were homozygous for
the short allele (PER34/4). A subsequent study in Brazil confirmed the increased propensity for eveningness in subjects with
the short allele(8) and showed that, unlike a previous study conducted in England, the long five-repeat allele is associated with
DSPS(8), indicating that the difference in latitude could influence
the effects of clock genes.
Studies conducted on healthy subjects have also shown
that PER3 gene polymorphism appears to be related not only
to diurnal preference but also to the homeostatic regulation
of sleep(9). Compared to individuals homozygous for the fourrepeat allele (PER34/4), people with the PER35/5 genotype have
a worse cognitive performance after a period of sleep deprivation. Furthermore, a series of markers of sleep homeostasis
is increased in people with PER35/5, including slow-wave sleep,
rapid eye movement (REM) sleep, and alpha and theta activity
during wakefulness(9).
Familial advanced sleep-phase syndrome (FASPS), an
autosomal-dominant disorder, is characterized by an episode of
early sleep, with an onset at the early evening hours and spon-
taneous awakening in the early morning. A genetic study conducted on a family with multiple FASPS individuals found an
association between a region of chromosome 2q and the presentation of FASPS. Following this initial finding, the region was
sequenced, and a mutation of the candidate gene PER2 was
identified in all affected members of the family(10). This mutation causes a serine-to-glycine change specifically in the region
where the PER2 protein is phosphorylated. In a subsequent
study, Xu et al.(11) showed that the insertion of the human mutation in transgenic mice generated a phenotype similar to FASPS,
where animals showed a marked advance in their rest-activity
cycle. This study confirmed the functionality of the mutation
found in the family. The importance of the phosphorylation
of proteins involved in maintaining the biological rhythm was
reinforced by another study, in which a mutation in the casein
kinase I delta (CSNK1D) gene, also responsible for the phosphorylation of the clock genes, was found in a second family
with FASPS(12).
Another rare, large-effect mutation influencing sleep
duration was identified in the DEC2 gene, a transcriptional repressor, in a small family with the early-awakening phenotype(13).
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The DEC2 gene is also a clock gene that negatively regulates the
mechanism of circadian rhythm. The identified mutation, which
causes the amino acid proline to be substituted with arginine in
the protein, was found in two women (mother and daughter)
who, despite initiating sleep at the same time as other individuals in the family, presented a much earlier awakening, with an
average duration of 6.25 hours of sleep. These individuals, considered natural “short sleepers”, report shorter total sleep duration than patients with FASPS or control individuals, without
it negatively affecting their daily routine(13). Studies conducted
on transgenic mice carrying the mutation confirmed that these
animals present shorter sleep duration than wild-type animals.
Moreover, the mutation confers a significant reduction in sleep
rebound after a period of sleep deprivation, suggesting that
even though the DEC2 gene is considered a clock gene, it also
seems to be involved in the homeostatic processes of sleep(13).
A recent study used functional measures to evaluate
seven European populations (N = 4,251) in a genome-wide association study (GWAS), an impartial technique to study complex genetic diseases by simultaneously analyzing approximately
500,000 to 1 million polymorphisms distributed throughout the
genome(14) (Figure 1). In this GWAS, Allebrandt et al. identified
a variant (rs11046205) in the ATP-binding cassette, sub-family
C-9 (ABCC9) gene, which appears to explain ~5% of the interindividual variation related to sleep duration. Individuals homozygous for the variant slept approximately 30 minutes longer
than individuals without the genetic variant. The ABCC9 gene
encodes a subunit of the ATP-dependent potassium channel
(SUR2) and serves as an intracellular energy sensor. Furthermore, SUR2 participates in the etiology of cardiomyopathies,
disorders that are closely related to body mass index and hypertension, which are endophenotypes correlated with the duration of sleep. Experiments using RNA interference showed that
when the gene homologous to ABCC9 in Drosophila neurons
was knocked down, the animals did not sleep during the first 3
hours of the night. These results provide more consistent evidence regarding the involvement of ABCC9 in the regulation
of sleep duration.
Adenosine deaminase
Caffeine, a widely consumed stimulant, induces wakefulness and blocks adenosine receptors, resulting in the inhibition
of its endogenous activity(15). Several recent lines of evidence
confirm that the activation of A1 and A2A adenosine receptors
and the regulation of adenosine production and degradation are
essential for sleep induction and adequate control of the sleepwake cycle(16). The gene that encodes the enzyme adenosine
deaminase (ADA), responsible for the conversion of adenosine
to inosine, contains a G/A single-nucleotide polymorphism
(SNP) at nucleotide 22 of exon 1 (G22A), whose A allele leads to
the substitution of asparagine for aspartic acid in the protein(17).
The enzymatic activity of ADA is 20-30% lower in erythrocytes
and lymphocytes of individuals with a G/A genotype, highlighting this polymorphism as a potential marker for adenosinergic
homeostatic regulation of sleep(18). Interestingly, in 2005, Rétey
et al.(17) reported that healthy carriers of the gene variant had
a greater duration and intensity of slow-wave sleep and fewer
awakenings. Corroborating these findings, our group has recently
shown that individuals carrying the A allele (with a G/A or A/A
genotype) have a higher sleep efficiency and greater percentage
of REM sleep compared to individuals with the G/G geno-
127
type(19). However, this effect was only evident in subjects who
consumed coffee on the day of the polysomnography. No effect
was observed in the absence of coffee. Our data support the role
of the G22A polymorphism and the ADA gene in sleep regulation and suggest that caffeine can modulate its functional effects
(Table 1).
GENETIC FACTORS INVOLVED IN SLEEP
DISORDERS
Narcolepsy
Narcolepsy is a recognized familial sleep disorder. The
concordance rate between monozygotic twins is ~30%, which
suggests the involvement of genetic factors, in addition to environmental factors, in its development(20). The allele known as
DQB1*0602, located in the human major histocompatibility
complex (HLA), is considered a genetic marker strongly related
to an increased risk for developing narcolepsy, particularly in
Caucasian subjects. This allele is present in up to 95% of patients with cataplexy in this ethnic group, compared to a frequency of ~24% in the general population(15), which confirms
the complexity of narcolepsy and the involvement of multiple
genes in its manifestation.
Due to the strong association with the HLA complex
and the fact that patients with narcolepsy and cataplexy present
a reduction or absence of orexin (hypocretin) in the cerebrospinal fluid and in the number of orexin cells in the lateral hypothalamus, an autoimmune etiology for narcolepsy has been
suggested; however, this etiology has not been confirmed, even
after decades of research(20). Recent results from GWASs have
offered new scientific support for this hypothesis (Table 1).
In a study involving a total of 807 cases, all positive for the
DQB1*0602 allele, and 1,074 Caucasian controls, Hallmayer et
al.(21) used microarray technology to evaluate > 500,000 polymorphisms and the risk for developing narcolepsy. In this initial phase, positive associations were observed with three SNPs,
all located in the locus of the alpha chain of the T-cell receptor (TRA-alpha), which, together with proteins from the HLA
system, participates in the process of antigen recognition. As
occurs in GWASs, the results were subjected to replication in
different ethnic groups and confirmed in a second sample of
Caucasians and a sample of 866 Japanese and 300 Koreans, but
not in a smaller sample of African American individuals, most
likely due to the low statistical power of the latter(21).
In 2008, Miyagawa et al.(22) reported an association between a marker located between the carnitine palmitoyltransferase 1B (CPT1B) and choline kinase beta (CHKB) genes and
the risk for narcolepsy with cataplexy in a Japanese population.
The results were replicated in an independent sample of Japanese individuals as well as a sample of Koreans, but not in Europeans or African Americans, most likely due to lower frequencies
of the risk allele in these two populations. Still, the meta-analysis
including all ethnic groups showed significant results, with the
risk allele being associated with an almost two-fold increase in
the risk for developing narcolepsy. Furthermore, the expression
levels of both genes were reduced in individuals carrying the risk
allele compared to individuals with two non-risk alleles. Plausible biological explanations support the participation of CPT1B
and CHKβ in the pathophysiology of narcolepsy. CPT1B is a
rate-limiting enzyme for the beta-oxidation of long-chain fatty
acids in muscle mitochondria. Carnitine transport, an important
step in fatty acid oxidation, plays an important role in phenoSleep Sci. 2012;5(4):125-130
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128
Figure 1. Experimental design used in Genome-Wide Association Studies (GWAS). In a primary case-control sample, the DNA from hundreds of
individuals is subjected to microarray assays, in which thousands of Single Nucleotide Polymorphisms (SNPs) are analyzed simultaneously. After the
statistical analysis and correction by multiple tests, only the SNPs the fill the selection criteria are re-analyzed in one or more replication samples for
confirmation in despite of results due to ethnic differences.
types related to narcolepsy. The enzyme CHKβ is involved in
the synthesis of cytidine 5’-diphosphocholine, which seems to
increase the release of acetylcholine, a neurotransmitter known
to promote wakefulness and REM sleep(22).
In 2010, Hor et al.(23) conducted a GWAS accompanied
by an independent replication sample in heterozygous individuals
for the haplotype DRB1*1501-DQB1*0602. The results showed
a significant association with a variant near the HLA-DQA2 locus
(rs2858884), which is closely related to DRB1*03-DQB1*02 and
DRB1*1301-DQB1*0603. Surprisingly, patients with narcolepsy
rarely presented the haplotype DRB1*1301-DQB1*0603 (odds
ratio = 0.02; p < 6×10−14), which suggests a highly protective effect of the identified variant and confirms the importance of the
HLA locus in the development of narcolepsy.
More recently, a third GWAS with replications in three
different ethnic groups (3,406 individuals with European ancestry, 2,414 Asians, and 302 African Americans) reported a positive
relationship between narcolepsy and a SNP located in the 3’-untranslated region of the gene that encodes the P2Y11 subtype of
the purinergic receptor (P2RY11)(24). The allele variant associated
with increased risk for developing narcolepsy showed a significant
correlation with reduced expression of the P2RY11 gene and resistance of T lymphocytes and natural killer cells to cell death.
These results highlight the P2RY11 gene as an important regulator of immune cell survival and, together with the study by Hallmayer et al.(21), provide extremely robust data that strengthen the
autoimmune hypothesis in the pathophysiology of narcolepsy.
Restless legs syndrome
Restless legs syndrome (RLS) has familial and sporadic
presentations. Cases of early onset (before the age of 30) are
often familial, whereas secondary causes include pregnancy,
renal failure subject to dialysis, and iron deficiency(5). The first
approach to identify genes involved in the development of
the disease initially included studies of family links. Although
chromosome regions 14q, 9p, 2q, 20p, and 19p were identified
as regions of interest, no specific genes or mutations were
identified(25). Instead, in 2007, two nearly simultaneous GWASs
on RLS published consistent findings of great scientific value
(Table 1).
The first study, evaluating an Icelandic population consisting of 306 cases and > 15,000 controls, found a significant
association between an intronic SNP located in the gene BTB
(POZ) domain-containing 9 (BTBD9) and an increased risk of
~50% for the manifestation of RLS associated with periodic leg
movement(26). This result was replicated in a second phase, in an
independent sample of Icelanders and a sample of American
individuals. Moreover, the risk allele variant was associated with
lower levels of ferritin, corroborating the previously described
risk factor for RLS, iron deficiency.
Using a different approach for subject selection, Winkelmann et al.(27) published a second GWAS involving only
patients with a clear family history of RLS in an attempt to
reduce the phenotypic heterogeneity. When evaluating more
than 4,000 individuals, associations with SNPs located in the
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following regions were identified: the BTBD9 gene on chromosome 6p (replicating the findings of the previous study), the
myeloid ecotropic viral integration site homeobox 1 (MEIS1)
gene on chromosome 2p, and a third region in chromosome
15q that contains the genes mitogen-activated protein kinase kinase 5 (MAP2K5) and ladybird homeobox co-repressor 1 (LBXCOR1). A subsequent study in an American sample replicated
the association between RLS and the MEIS1 and BTBD9 genes
only(28). The association of BTBD9 with sporadic and familial
RLS was verified in a European sample of individuals from the
Czech Republic, Austria, and Finland. However, the contributions of the MEIS1 and MAP2K5/LBXCOR1 genes were only
confirmed in familial cases of RLS(29).
Little is known about the biological functions of the
identified genes and their relationships with RLS. MAP2K5 is
a protein kinase, and LBXCOR1 inhibits LBX1, which is a homeobox gene involved in sensory pathways in the dorsal horn
of the spinal cord(27). Both BTBD9 and MEIS1 have been associated with the embryonic development of the limbs(30,31).
An independent study has shown a reduction in the levels of
MEIS1 mRNA and protein in peripheral blood and in post mortem samples of the thalamus of subjects with the risk allele of
the gene(32), suggesting that a reduced function of this protein
may contribute to the pathogenesis of RLS.
Using a different approach, Schormair et al.(33) performed
a detailed analysis involving 3,270 SNPs located exclusively in
the chromosome 9p region and found strong evidence of an
association between RLS and two SNPs, both in the protein
tyrosine phosphatase receptor delta (PTPRD) gene, in German,
Czech, and Canadian patients. Studies conducted on knock-out
mice revealed that PTPRD plays an important role in neuronal
development and axonal direction(34).
Winkelmann et al.(35) reported the results of a GWAS
that included more than 12,000 individuals. The authors replicated previously observed significant associations between the
development of RLS and the loci in MEIS1, BTBD9, PTPRD,
and MAP2K5/SKOR1 and reported two new susceptibility loci
on chromosomes 2p14 and 16q12.1, with the possible involvement of the gene TOX high-mobility group box family member 3 (TOX3), which plays an important role in the modulation
of calcium-dependent transcription in neurons, and the noncoding RNA BC034767. The physiological relationship between
these new susceptibility loci and the pathogenesis of RLS has
yet to be clarified.
Overall, functional studies in vitro and in animal models
are still needed so that the results from the GWASs can help us
understand the molecular basis of RLS and be applied in the
clinic.
Obstructive sleep apnea/hypopnea syndrome
Obstructive sleep apnea/hypopnea syndrome (OSAHS),
like other complex phenotypes, is considered a polygenic disorder with a considerable contribution from environmental
factors(36,37). Furthermore, it is argued that in the case of OSAHS, intermediate phenotypes, such as variations in craniofacial morphology, obesity, cardiovascular disease, and respiratory
control instability, interact across various dimensions to produce
the final phenotype of OSAHS(36). This variety of contributing factors hinders a consistent definition of the phenotype being studied, which ultimately influences the outcome of studies
129
on OSAHS. Therefore, in contrast to narcolepsy and RLS, the
progress in determining the genetic basis of OSAHS has been
slower.
The genetic involvement in the development of OSAHS
is indisputable(37). It has been estimated that up to 40% of the
total variance observed for the apnea/hypopnea index in family
members can be attributed to genetic factors(37). A study evaluating a total of 1,937 pairs of twins showed that the correlation
between MZ twins is significantly greater than that of DZ twins
for the symptoms of apnea, with indices of heritability that
range from 48% (95% confidence interval: 37-58%) for daytime sleepiness to 52% (95% confidence interval: 36-68%) for
snoring(38). Redline et al.(39) estimated the level of familial aggregation for a number of OSAHS symptoms. Habitual snoring,
excessive daytime sleepiness, and apnea were reported two to
four times more often among first-degree relatives of patients
with OSAHS compared to control individuals(39). A number of
variants in candidate genes have been examined in the search
for genetic markers that may influence the risk of developing
OSAHS. Significant associations with OSAHS or any related
phenotype were observed in the angiotensin-converting enzyme
(ACE), apolipoprotein E (APOE), endothelin receptor subtype
A (EDNRA), endothelial nitric oxide synthase (NOS3), tumor
necrosis factor alpha (TNF), interleukin 6 (IL6), and serotonergic system genes, among others(40). However, most of the
studies mentioned above require replications of independent
samples, with a large numbers of individuals of different ethnic origins, before being considered true susceptibility markers.
Furthermore, no GWAS has been published on OSAHS, which
limits the results to genes and variants that are already known
and are hypothetically part of the pathophysiology of the disease. One of the great advantages of the GWAS is that it is a
relatively hypothesis-free approach, which enables the discovery
of new risk factors not previously associated with the phenotype of interest. More recently, a meta-analysis accompanied by
a systematic literature review on sleep apnea genetics reported
that only four polymorphisms had been investigated, by at least
three independent studies: rs1800629 in the TNF gene, an insertion/deletion in the ACE gene, and alleles ε2 and ε4 in the
APOE gene(41). The authors concluded that only rs1800629 in
TNF was significantly associated with the development of apnea and could be considered a risk factor for the disease, according to published data.
CONCLUSIONS AND FUTURE DIRECTIONS
Recent scientific and technological advances in the field
of human genetics promise to revolutionize the way medicine
is conducted in the future. We can currently move from
the expensive curative medicine to an effectively preventive
medicine, capable of delaying the onset of diseases and making
longevity available to everyone. The impressive advances in the
field of biotechnology are undeniable and definitely irreversible.
Technology and scientific knowledge in the biomedical sciences
has proceeded with unprecedented speed in the last two
decades. Initiated in the 1990’s, the Human Genome Project
continued for 13 years until the official announcement of its
completion in 2003. The entire project had an estimated cost
of approximately 3 billion dollars, which included funding for
the development of previously non-existent laboratory and
computational methods. Today, with the advent of techniques
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130
such as the microarray, which has allowed for the evaluation of
several genes in a single experiment, and the “next-generation
sequencers”, which have drastically reduced the cost of gene
sequencing, major discoveries in the field of sleep genetics
will become increasingly common. The great challenge will be
in explaining, in biological terms and in a pathophysiological
context, how the identified genetic variants affect disease
manifestation. Otherwise, the findings, although robust, will
remain mere statistical associations. Therefore, functional
studies using animal models and in vitro experiments have been
and will continue to be a major pillar for the understanding of
the genetic mechanisms of sleep regulation.
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Velluti RA, Pedemonte M
131
REVIEW
Sensory neurophysiologic functions participating
in active sleep processes
Participação de funções sensoriais neurofisiológicas em processos ativos do sono
Ricardo A. Velluti1, Marisa Pedemonte2
ABSTRACT
The main concepts presented in this review are that sleep is not
a function but a state diverse from the waking one. A lot of physiologic functions are carried out during sleep, cardiovascular, respiratory, endocrine, sensory, etc., although in a different way. This
state occurs because there is a shifts in all/some cell assemblies
-neuronal networks passing from a waking mode into a sleeping mode,
perhaps organized by some unknown hub neurons. Since Bremer
(1935) postulated a passive sleep theory i.e., the lack of sensory
input would be the sleep cause, many active processes have being
described. Moreover, since the nineteen sixties, several sensory
approaches began to emphasize the role of the sensory input regarding sleep. We are proposing that at least a percentage of sleep
generation is due to shifts in the sensory input to the brain determining changes in the cell assemblies-neuronal networks shift into
a different mode the sleeping one. Many experimental data, from
unitary recordings to every sensory system evoked potentials in human and animals as well as more recent magnetic evoked responses
and brain imaging, support the notion of a sensory participation on
sleep. The auditory, olfactory, vestibular and somesthetic system,
developed introducing more sensory data which progressively shaped a brain that began to reach its completion, leading to a dynamic
end: the genetically established sleep-waking cycle features. A proportion of “passive” effects must be associated with active functions for entering and maintaining normal sleep. Sleep generation,
maintenance and every related event, are part of central processes
that involve the whole brain.
Keywords: audio feedback, sensorimotor feedback, sensory feedback,
sleep, visual feedback.
RESUMO
Os principais conceitos desta revisão postulam que o sono não é
uma função, mas um estado distinto da vigília. Diversas funções
fisiológicas ocorrem durante durante o sono, no âmbitos cardiovasculares, respiratórios, endócrinos, sensoriais, etc. embora de modo
diferente. Este estado ocorre devido a mudanças em todas ou várias
assembléias ou redes neuronais, passando de um estado de vigília para um estado de sono, talvez organizado por algum grupo
neuronal-chave desconhecido. Desde que Bremer (1935) postulou
a teoria passiva do sono, i.e. a falta de recebimento de informações
sensoriais seria a causadora do sono, muitos processos ativos foram descrito. Além disso, desde os anos 60, diversas abordagens
sensoriais começaram a enfatizar o papel do recebimento do input
sensorial em relação ao sono. Nós propomos que pelo menos uma
porcentagem da gênese do sono é devida a mudanças no input sensorial ao cérebro, determinando mudanças em assembléias ou redes
neuronais, levando do estado de vigília ao estado de sono. Diversos
dados experimentais advindos de registros unitários a potenciais
evocados, tanto em humanos quanto em animais, bem como recentes evidências de imageamento cerebral dão suporte à participação
do sistema sensorial ao sono. Uma proporção de efeitos “passivos”
pode ser associada a funções ativas para o início e manutenção do
sono. A gênese e manutenção do sono, bem como qualquer evento relacionado, são parte de eventos centrais que envolvem todo o
cérebro.
Descritores: feedback sensorial, feedback visual, sono.
INTRODUCTION
The fundamental problem of communication is
that of reproducing at one point, either exactly or approximately, a message selected at another point. From a
cognitive viewpoint, information processing is an instrument to try to reach the understanding of human memory
storage or learning processes. Therefore, equivalent objectives can be followed also in sleep. Besides, all the sleeping brain behaves differently, i.e. their neuronal-networks
changed from a waking mode to a sleeping mode.
The sensory input represents the whole fan of
information the central nervous system (CNS) receives
whose output responses, after complex processing, are
elicited, e.g., motor, endocrine, neurovegetative, behavioural responses or changes in the CNS capacities such
as memory, learning, and so on. The information coming from the outer and the inner worlds during life is a
meaningful influence on the brain phenotypical development and, in our particular topic, on sleep organization.
An important purpose of the brain evolution is to allow
the organism to properly interact with both environments,
the external and the internal one (the body). In early developmental stages, from phylogenetic and ontogenetic
viewpoints, the sensory information constitutes a relevant
drive that controls the brain function and the general
physiology in many ways. The development of each brain
is genetically conditionated although a germane component is the continuous information incoming through the
senses from both the two worlds, a phenomenon that continues throughout life, i.e., an endless process. Since the
sensory information in general is continuously reaching
the CNS, its processing will be differentiated according
Study carried out at Neuro-Otología Experimental y Sueño. ORL., Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay.
1
Neuro-Otología Experimental y Sueño. ORL, Hospital de Clínicas, Universidad de la República, Montevideo, Uruguay.
2
Cátedra de Fisiología. Facultad de Medicina, Instituto Universitario CLAEH. Punta del Este, Uruguay.
Corresponding author: Ricardo A. Velluti. Neuro-Otología Experimental y Sueño. ORL, Hospital de Clínicas, Universidad de la República. Av. Italia, s/n.
Montevideo. Uruguay. Tel: (598) 99 210 425. E-mail: [email protected]
Received: July 23, 2012; Accepted: September 21, 2012.
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132
Sensory functions and active sleep processes
to the current physiological state of the brain during: 1)
Wakefulness (W), 2) Sleep stages I and II (or N2); Slow
Wave Sleep (SWS) stages III-IV (or N3), and, 3) Paradoxical sleep (PS, or REM -Rapid Eye Movements-, or desinchronized, or R); according to the Manual for scoring
sleep (2007) of the American Academy of Sleep Medicine, or Rechtschaffen and Kales, 1968 (Techniques and
Scoring System for Sleep Stages in Human Subjects, Public Health Service Publication No 204. US Government
Printing Office, Washington, DC).
An important point should be added, which is that the
brain itself can condition its own sensory input by controlling
all receptors and nuclei through the sensory efferent systems,
which are present in every incoming pathway. Thus, by using
this feedback possibility the complex processing circuit may
be completed through a functional “closed-loop” system.
The natural light-dark sequence, a phylogenetically
archaic information, through the light receptor and its processing system, profoundly influences the sleep-wakefulness cycle. The circadian rhythm of melatonin- produced
in most organisms from algae to mammals- is generated in
the latter by a central pacemaker located in the suprachiasmatic nucleus of the hypothalamus largely synchronized
by cues from the light-dark cycle(1). Since the beginning of
life, the brain and sensory systems complexity are in constant and mutual enrichment from both anatomical and
functional perspectives. The auditory, olfactory, vestibular
and somesthetic system, developed introducing more sensory data which progressively shaped a brain that began to
reach its completion, leading to a dynamic end: the genetically established sleep-waking cycle features.
Early in the twentieth century, the concept of sleep
as the result of a blockage of the auditory inflow was introduced while, later on, Bremer (1935)(2) proposed that it was
the extensive deafferentation of ascending sensory impulses to the isolated brain that resulted in sleep. He became the
outstanding proponent of the deafferentation sleep theory
known as the passive theory, implicating the existence of
a tonus on the CNS played by the senses. The description
by Moruzzi & Magoun (1949)(3) of the activating ascending reticular system seemed to confirm Bremer’s concepts:
every sensory input would also release information (tonus?)
to the activating reticular formation of the brainstem.
A brief history of sleep active processes
A clinical observation of a continuous and prolonged sleep state, easily arousable at the beginning, was
reported by Soca(4). in a young patient with a tumour located over the sella turcica, probably a craniopharyngioma,
which compressed the anterior hypothalamic region. Later
on, von Economo(5) proposed the anterior hypothalamus
as a sleep facilitatory area in patients with encephalitis
with post mortem lesions in this region.
The electrical stimulation of thalamic areas(6) provoking sleep was the final step towards admitting sleep
as an active process. Later on, Clemente & Sterman(7),
showed that electrical stimulation of the lateral preoptic
area evokes bilateral EEG synchronization. On the side
of neurotransmitters as participants in sleep generation,
acetylcholine (ACh) was one of the first ones to be used in
that sense by the pioneering work carried out by Dikshit(8)
and particularly by Hernández-Peón et al.(9), who introduced ACh crystals directly into the medial forebrain bundle and produced sleep in cats; ACh microinjections into
the brainstem led to the occurrence of paradoxical sleepsigns in cats(10). Furthermore, the sleep generated by ACh
crystals applied into the preoptic area could be blocked by
introducing atropine in a posterior regions, by Velluti and
Hernández Peón (1963)(11). Active processes in the sleep
production were also proposed by Moruzzi (1963)(12), and
by Jouvet (1961; 1962)(13,14). Several recent reports support
in general the tenet of sleep as actively produced. Electrophysiological approaches as unitary recordings, immunoreactive staining techniques as well as functional magnetic
resonance imaging in humans, are some contributions to
such concept(15-17). In this instance, we are including the
sensory systems postulated as a important factor in actively participation in sleep processes(18-21). A special consideration should be restated: sleep generation, maintenance
and every related event, are part of central processes that
involve the whole brain.
The sensory activity interacting with sleep neurophysiology
The processing of sensory information is definitely
present during sleep, however profound modifications occur. All sensory systems reviewed, visual, auditory, somesthetic, olfactory as well as temperature receptors, etc.,
demonstrate some influence on sleep and, at the same
time, the sensory systems undergo changes that depend
on the CNS sleep or waking condition. Thus, different
modalities encoded by their specific receptors, nuclei and
cortices may alter the sleep-wakefulness neurophysiology,
although the sleeping brain imposes rules on the incoming
information. We are proposing that the neural networks/
cell assemblies responsible for sleep processes are actively
modulated by sensory inputs in order to support the widely distributed brain changes occurring on entering into
sleep. Thus, the CNS and its sensory input have reciprocal interactions on which the normal sleep-waking cycling
and behaviour depend to a great extent(18-20).
Neuronal Network/Cell Assembly
The concept of neuronal assemblies is defined by
the temporally correlated neuronal firing associated to
some functional aim. The most likely information coding is the ensemble coding by cell assemblies(22). Neuronal
groups connected with several other neurons or groups
can carry out cooperation and integration among widely
distributed cells even with different functional properties to sub-serve a new state or condition. On the other
hand, an individual neurone receives several thousands of
synaptic contacts on its membrane that make its activity a
continuous membrane potential fluctuation, which determines a very instable physiological condition to constitute
a basic code for information processing. Furthermore,
the neuronal network/cell assembly may provide selective
synaptic activity enhancement referring to a dynamic and
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transient efficacy, which we suggest to be correlated to
the behavioural dynamic modulation of the sleep process.
That is, a neurone firing in a functional associated group
may process some information and, some time later may
become associated to other competing and activated neuronal groups for different functional purposes, e.g., after
passing from wakefulness into sleep. Moreover, it has recently proposed the existence of brain hub distributing information on neuronal networks.
The hub neurons have very extensive axonal arborisations projected over larger distances and make a greater
number of and stronger synaptic connections than non-hub
neurons. Finally, they are also more responsive to inputs and
quicker to fire action potentials themselves, placing them in
a position to orchestrate the responses of an entire network.
Though hub neurons have so far only been observed in the
hippocampus it seems almost certain that they will also be
found in the cortex, where their effects may be fundamental
for the information processing capabilities of the brain(23).
These diverse associations may occur also during
the W states, during stages SWS. III IV, in human stage
N2, II and also during PS, R, phasic REM or tonic epochs.
Figure 1 explains very simple possibilities or properties
of a cell assembly coding. Schematically it shows a partial
overlapping of neurones in which some of them belong
to two different neuronal networks while a second physiological possibility is the switch from one state to another,
i.e., construction and reconstruction of assemblies(22).
Figure 1. The arrows indicate possible and minimal dynamics of
constructions and reconstructions of cell assemblies. This is an
oversimplification of what can occur throughout the brain during the
sleep-waking shifting (Modified from Velluti, 2008)(20).
The quasi-total sensory deafferentation
The surgical section of the olfactory, optic, statoacoustic, and trigeminal nerves, one vagus nerve and the
spinal cord posterior paths in cats, that is, quasi total deafferentation, was carried out by Vital-Durand & Michel
(1971)(24). Studying this model with polygraphic control,
the animals under quasi-total deafferentation revealed a
sleep-waking cycle showing the following changes: a) The
waking time was reduced from 44.9% to 18.5%. When
asleep the cats could be awakened easily at any moment;
b) The time spent in SWS was reduced from 41.7% to
29.6%. A quasi-constant “somnolence” was described and
characterized by the sphinx position and a sequential fast
and slow EEG activity. In contrast, the subcortical hippocampus and amygdala activity was that of a quiet W indicative of a distinct state, both from a behavioural and a
bioelectrical viewpoint; c) The total amount of PS (phasic
“REM”) was slightly diminished (from 13.4% to 11.2%)
with normal episode length and frequency. Human sen-
133
sory deprivation experiments are different in the way that
they may be better viewed as a reduction of sensory input(25). This leads to the notion that when a human subject
is placed in an environment without patterned and changing stimulation, they may fall into a state of profound lowered arousal and subsequently, sleep.
THE AUDITORY SYSTEM DURING SLEEP
From several viewpoints, the auditory is a special
system related to sleep neurophysiology, exhibiting a series
of unique associated changes(19,21,26). The auditory incoming signals to the CNS may change the sleep characteristics,
while, conversely, the CNS can control by feedback mechanisms the auditory input carried out in close correlation
with the sleep-wakefulness cycle(18,20). Receptor and auditory nerve action potentials exhibited amplitude changes
when analysed during quiet W, SWS and PS in guineapigs(27). Besides, auditory evoked potentials recorded from
the primary cortical area in rats, also exhibited amplitude
shifts when the animal passes from W to sleep. Moreover,
all evoked potentials components of the averaged waveform were larger during SWS than in W or PS(28).
Auditory system single cell recordings
The effects of sleep and wakefulness on auditory
evoked activity at the mesencephalic reticular formation, were
reported showing the activity of the non-lemniscal neuronal
auditory pathway to vary between sleep and W in cats. The
units evoked activity was most marked during quiet W (~50%)
and diminished during SWS; however, ~30% of the neuronal
responses during SWS presented an equal or even greater firing than during W. During PS, the auditory responses were
diminished in all the studied neurones (n = 16); meanwhile
some of them (n = 5) exhibited no evoked activity(29).
The analysis of the unitary responses to sound,
now at the auditory cortex, revealed the following scenery:
Neuronal discharge rate shifts. The data from the guinea
pig´s auditory cortex(30) was recently confirmed in primates(31).
Around 50% of the auditory cortical (AI) units recorded during SWS and PS maintained a firing similar to the ones recorded during quiet W, postulated to continue monitoring the
environment. Another set of cortical neurones were divided
into those that increased and those that decreased their firing
on passing from W to SWS or from SWS to PS. This latter
group, although responding to the sound stimuli, is proposed
to be engaged -associated to other neuronal network/cell assembly -in sleep-active processes (Figure 2). Our hypothesis
support the notion that both units, the auditory cortex and
the preoptic one, belong to the same sleep-related network,
perhap organized by a common hub neuron.
A different proportion of auditory units firing was
seen in the brainstem nuclei. In those loci, most of the
units exhibited increasing and decreasing firing, while
those units responding in sleep as during quiet W were
present in a smaller number than in the auditory cortex.
This suggests that the auditory brainstem neurones that
increase/decrease firing in sleep, are postulated to be engaged in some sleep processes, particularly participating in
sleep-active cell assemblies/networks.
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134
Figure 2. A: two auditory cortical guinea pig neurons (A1) activity.
Upper plot: spontaneous discharge as a function of time. After fluctuating during slow wave sleep (SWS), the firing rate markedly decreases
during paradoxical sleep (PS). The number of spikes is quantified over
50 ms epochs, 10 minutes of continuous recording. Lower plot: discharge as a function of time. The firing rate shows peaks during SWS
and a quasi-tonic increase, on passing to PS. The number of spikes is
quantified over 450 ms epochs, 7.5 minutes of continuous recording
ofwakefulness (W), SWS, and PS, (Modified from Peña et al. 1999)(30);
B: discharge of a “sleep-ON” or “sleep related” neuron during W, SWS
and PS, recorded in the median preoptic nucleus of an unrestrained rat.
Its firing-rate is low during waking, increases at sleep onset and during
SWS, and reaches even higher levels in PS (Modified from Suntsova et
al. 2002 J. Physiol., 543:665-77). Both units, the auditory cortex and the
preoptic one, belong to the same sleep-related network, perhap organized by a common hub neuron/s.
A most salient fact is that no auditory neurone exhibited a firing stop on passing to sleep.
The main question introduced by the figure is: Why
not to believe that both neurons the preoptic one and the auditory
cortical belong to the same neuronal assembly at least during PS, as
we support based on both experimental approaches?
Neuronal discharge pattern shifts. The firing pattern
change may support a different possibility of sound analysis as well as suggest a different mode of relation to other
cell assembly/network which we are herein postulating as
actively related to sleep. The same neurone may exhibit
a pattern during SWS and a different one during PS, to
recover the initial firing distribution at the following W
epoch. Moreover, diverse patterns could be observed
throughout the sleep-waking cycle (Figure 3)(21).
On the other hand, auditory stimuli that are only
slightly above hearing threshold appear to be processed
extensively during a 200 to 400 ms interval in both NREM,
N2, N3 and R, REM sleep. The nature of this processing
is, however, very different compared to the waking state(32).
Figure 3. Examples of post stimulus time histograms of unitary activity in the auditory cortex (A1) during wakefulnessand sleep in a guinea
pig. The pies indicate percentages of firing shift on passing from wakefulness (W) to slow wave sleep (SWS) and from SWS to paradoxical
sleep(PS), (Modified from Velluti 2005)(55).
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Hippocampal theta rhythm
Time is a variable that could be controlled by the hippocampus represented by the theta rhythm, postulated as a
meaningful factor in the temporal processing of auditory
signals(19,25,26,33). Vinogradova (2001)(34) supports the notion
of theta rhythm influences, e.g., a regulatory system, linking the hippocampus to brainstem structures, sensing the
attention level and, most important to our proposal, introducing a primary information on the changes in the environment. Besides, this hippocampal field activity, present in
every behavioural condition, shown by Pedemontre et al.(33),
is remarkable in regularity and amplitude, during active W
and particularly in PS, exhibiting phase-locking with auditory
neuronal discharge also in sleep(19). Recordings carried out in
the primary auditory cortex, showed evoked neuronal firing
shifts elicited by electrical stimulation of the hippocampus,
indicating an interconnection between these brain regions
that exhibit a functional relationship, and thus supporting
the notion that an auditory-hippocampal (the, so far, only
neuronal hub was located in the hippocampus) shared functional interaction, although unknown in detail, may be present(35). This new factor -auditory units phase-locked with
theta rhythm- may not be just part of the sensory processing
but also of sleep processes in the context of neuronal networks/cell assemblies dynamics, and the known relationship
between paradoxical sleep and hippocampal theta rhythm.
135
port the postulated on animals’ auditory input effects on
sleep. A profound post-lingual deaf person surely undergoes changes in their central auditory neuronal networks
organisation -cortical plasticity- that, in turn, would affect
many other brain cell assemblies/networks. On the other
hand after an intra-cochlear implant, the hearing recovery would produce networks re-organisation that in turn
could provoke the sleep architecture to shift to different
sleep stages percentages(41).
Analysing human auditory responses
During sleep, a normal reaction to any supra-threshold sensory stimulation drives back to a wakeful condition.
Human auditory responses recorded from the vertex have
been reported by several investigators. In all subjects, the
major changes observed in the auditory evoked response,
when changing from the awake state to the four stages of
SWS sleep consisted on a steady increase in peak to peak
amplitude while during PS the amplitude was lower and
approximated that of the waking state (Figure 4)(42-45).
Noise and human sleep
Human sleep organisation is extremely sensitive
to acoustic stimuli(36), and noise generally exerts an arousing influence on it(37). A noisy night-time ambiance leads
to a decrease in total sleep time and in delta wave sleep
(Stage IV, N3) and R, PS, with the consequent increase in
the time spent in Stage II, N2 and W(38,39). Moreover, the
remarkable sleep improvement after noise abatement(38),
suggests that the environment is continuously scanned by
the auditory system, notion also supported by the unitary
analysis in sleeping animals(19,21).
Absence of auditory input
The quasi-total deafferentation experiments have
demonstrated the influence of the inputs on sleep organisation. The total auditory deprivation in guinea-pigs, by
surgical removal of both cochleae, enhances SWS and PS
by a similar proportion while reducing W, for up to 45 days
post-lesion(40). We propose that the relative isolation from
the outside world may be part of the change observed in
deaf guinea-pigs, although it cannot be discarded that it
may mean the lack of an active influence. Thus, eliminating an input to a complex set of networks/cell assemblies,
as the ones that may regulate the sleep-waking cycle, would
introduce functional shifts meaning that such input is significant for the sleep/waking behaviour. Furthermore, a
similar analysis was carried out in human deaf patients.
An intra-cochlear surgical implant may improve, to a great
extent, their auditory capacity. The sleep analyses of those
post-lingual deaf human patients -successfully implanted
with an intra-cochlear device- were studied to further sup-
Figure 4. Human auditory evoked potentials during wakefulness (A)
and sleep (B). Superposition of 5 averaged responses showing amplitude increment and waves complexity on passing to sleep. A mixture of
both, near-field and far-field potentials are part of this response. Click
stimuli at 1/s. (Modified from Vanzulli et al. 1961)(42).
The early evoked auditory responses, reflecting the
activation of the cortical level, exhibited an amplitude
decrement in Stage II, N2 while remained unmodified
in a report by Erwin and Buchwald (1986)(46). Using
different stimulus rate, an attenuation of the early cortical
response was obtained with fast stimulation frequency(47),
while a triphasic Pa wave response with a stimulus rate
of 3 to 5 Hz. was reported during sleep(48). Onthe other
hand, auditory stimuli that are only slightly above hearing
threshold appear to be processed extensively during a 200
to 400 ms interval in both NREM, N2, N3 and R, REM
sleep. The nature of this processing is, however, very
different compared to the waking state(32).
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136
Experimental data gathered by using the far fieldpotential recording technique in humans showed no sleep
effects on the brainstem auditory evoked potentials(49,50).
In addition, the constancy of the response was maintained
whether sound stimuli were of high or low intensity.
The brainstem auditory evoked potential- a human
far-field recorded activity- is a technical coarse image that
cannot reveal the effects of sleep. However, the significant
unitary firing shifts produced during sleep in the brainstem
auditory nuclei, described in guinea-pigs, are surely present
although not reflected by the human far-field technique(21,27).
In addition, another phenomenon also aims to
sleep actions on the auditory receptor itself, namely the
transiently evoked oto-acoustic emission (sound emitted by the cochlea reflecting the outer hair cell motility
controlled by the auditory efferent system). It has been
reported in humans as being modified in general during
sleep although independently of the sleep phase(51).
The far-field technique data on the sleep effects on
middle latency auditory evoked potentials- perhaps arising from the reticular formation, thalamus, and primary
cortex- are much less consistent. While early studies indicated that these components were either not affected
or only slightly affected by sleep, more recent reports
showed marked changes most notably on the later evoked
potential components(46,47,49,52). The late components of
the evoked potential, also called the slow potentials or late
auditory evoked responses, are most altered during sleep.
As reported by Bastuji and García-Larrea(50), a high amplitude complex waveform dominates in Stages II and III-IV
which are the result of summed K-complexes evoked by
sensory stimuli.
Semantic information is possible in stage II and
PS(50), whereas the presence of P3 seems to be essential
to stimulus encoding, despite the fact that the question if
W and sleep P3 could be considered equivalent, remains
to be studied(50).
The mismatch negativity was reported in SWS(47)
and during PS(53). Moreover, this negativity has recently
been reported also in newborns “quiet sleep” and linked
to learning(54).
CONCLUSIONS AND FINAL PROPOSAL
Now we are introducing the notion that sleep is not
a function but a complete different CNS state.
Sleep and sensory input in general
The analysis of sensory functions during sleep-waking cycle leads to the conclusion that normal sleep depends
in many ways on the sensory input. It is suggested that the
sleep and waking control networks are modulated by several
inputs, and therefore a proportion of “passive” effects must
be associated with active functions for entering and maintaining normal sleep. Among the many possible inputs, the
sensory is a relevant one. Thus, the total amount of sleep
increases under some experimental conditions: a) Continuous somatosensory stimulation induces EEG synchronisation and sleep; b) Total darkness increases sleep although
only during a few days; c) Total silence, after bilateral coch-
lear destruction, increases the amount of sleep and episode
frequency; d) Sleep stages percentages are different when a
deaf human is compared with themselves after recovering
hearing with an intracochlear implant(41).
Furthermore, partial increments in the frequency
of specific sleep stages are observed: a) When rats are
stimulated with sounds during any sleep stage; b) During stimulation with bright light, which produces SWS increases in humans; c) During electrical stimulation of the
olfactory bulb, which produces SWS increases in cats(18,55).
On the other hand, the sensory influence on sleep
are, e.g., the abolition or decrement of a sleep sign or stage
produced by: a) Continuous light stimulation in rats that
decreases PS for ~20 days; b) Bilateral lesions of some
vestibular nuclei that abolishes rapid eye movements during PS up to 36 days; c) A long exposure to cold that produces decrement of PS leading to PS deprivation; d) Olfactory bulbectomy that decreases PS frequency episodes
and its total amount for up to 15 days. In the original papers, carefully cited in the Velluti´s review(18,20), that introduced such sleep changes, should be considered that the
sleep shifts may not be due to the sensory input alone but
also to stress and or depression provoked by the experimental coditions.
The lack of sensory inputs as well as their enhancement can produce sleep/waking imbalances, augmenting or diminishing their proportions. Thus, the induced
changes in the waking and sleep networks lead to the cited
imbalances not simply for passive sleep production but
introducing sensory sleep-active influences:
1. Sleep and sound are closely related. Environmental
noise as well as regular, monotonous, auditory stimuli, e.g.,
mother lullaby, are influences impeding or facilitating sleep.
2. The CNS and auditory system bioelectrical field
activity- evoked potentials- shown from the early electrophysiological studies, vary in close correlation with W
epochs and specially during sleep stages. The mismatch
negativity is also related to memory in sleep and possible
in newborn auditory learning.
3. The auditory system neuronal firing exhibits a
variety of changes in all of its nuclei and primary cortical
loci linked to the sleep-wakefulness cycle in many ways: i.e.,
increasing or decreasing their firing on passing to sleep,
firing as during W, changing the discharge pattern, exhibiting theta rhythm phase-locking, while no auditory neurone stopped firing on passing to sleep.
Edeline et al. (2001)(56) also reported changes in the
receptive field of cortical auditory neurones. Therefore,
it can be concluded that when asleep many auditory units
are sleep-active probably associated to diverse sleep relevant cell assemblies. Moreover, when functionally shifting into a different neuronal network/cell assembly, a unit
may contribute to the sleep process just by increasing, decreasing or showing no firing shift, according to the new
role in the new cell association.
4. A magnetoencephalographic (MEG) approach
described amplitude changes and anatomical place shifts
of the sound evoked dipole in the human primary auditory
cortex on passing from W to sleep Stage II, N2(57). The
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dipole anatomical position shift obtained with MEG implicated a change to a new neuronal group already indirectly
supported by unitary studies. The evoked activity during
sleep -its dipole- appears in a different cortical region (a
few milimeters) from that during W, thus suggesting a new
cell assembly/neuronal network participation (Figure 5).
137
pation in different sleep-related cell assemblies. We have
previously postulated that the auditory neurones firing in
sleep at the same rate and pattern as during W are those
neurones that monitor the environment. These cells are increasing their percentages at the auditory primary cortical
level (Figure 2). At the brainstem, on the other hand, the
auditory loci firing percentages are approximately divided
by thirds. The units that increase or decrease their firing
are postulated to be sleep-related neuronal-networks, at
cortical as well as at brainstem levels. The sensory input
is not only a passive but also an active contributor to the
whole brain change on passing from W to sleep, although
maintaining the environment monitoring.
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Figure 5. Planun temporale auditory cortical location of the M100
magnetoencephalographic (MEG) component observed in response to
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REVIEW
Narcolepsy in childhood and adolescence
Narcolepsia na infância e na adolescência
Fernando M. S. Coelho1,2, Flavio Aloe5†,Gustavo Moreira1, Heidi H. Sander3, Israel Roitman1, Lucila F. Prado1,
Márcia Pradella-Hallinan1, Regina M. F. Fernandes4, Rosana S. C. Alves3
ABSTRACT
The present review article discusses the most important aspects
of narcolepsy in children. The main objective of this review is to
describe the clinical and laboratory characteristics of narcolepsy
in patients within a targeted age range and to discuss hypotheses
regarding the physiopathology of this disease. Excessive daytime
sleepiness is reported by up to 20% of schoolchildren and adolescents. In 16% of these cases, narcolepsy begins before the age
of 10 years, whereas 30% of narcoleptic patients exhibit its initial symptoms during childhood. A delayed diagnosis might lead
to severe, negative future consequences for the affected patients.
Human narcolepsy is a complex disease. The association of HLA
-DQB1*0602 with low hypocretin levels indicates a genetic susceptibility with an associated immune component. Narcolepsy is characterized by excessive daytime sleepiness and cataplexy and might
be associated with hypnagogic hallucinations, sleep paralysis, and
sleep fragmentation. The diagnosis of narcolepsy depends on the
clinical assessment and the performance of multiple sleep latency
tests preceded by polysomnography. In children, the search for secondary causes of narcolepsy is important because approximately
25% of these patients are symptomatic. The treatment of narcolepsy in children is basically symptomatic, and most cases require
behavioral and pharmacological approaches. New therapeutic modalities which impede progression of the disease at the onset of
symptoms have also been investigated.
Keywords: adolescent, child, narcolepsy.
RESUMO
Este é um artigo de revisão que busca abordar os pontos mais importantes da narcolepsia em crianças. Os principais objetivos deste
artigo são alertar os leitores sobre as principais características clínicas e laboratoriais dos pacientes com narcolepsia nesta faixa etária,
além de discutir algumas hipóteses da fisiopatologia da doença. A
queixa de sonolência excessiva diurna é referida em até 20% das
crianças em idade escolar e adolescentes. A narcolepsia pode iniciar-se em 16% dos casos antes dos 10 anos de idade e 30% dos
casos de narcolepsia apresentavam sintomas iniciais na infância. O
atraso no diagnóstico pode levar a sérias repercussões negativas no
futuro destes pacientes. A narcolepsia humana é uma doença complexa. A associação entre o antígeno HLA-DQB1*0602 e níveis
reduzidos de hipocretina sugere uma suscetibilidade genética com
componente imunológico associado. A narcolepsia se caracteriza
por sonolência excessiva diurna e cataplexia, podendo ter associação de alucinações hipnagógicas, paralisia do sono e fragmentação
do sono. O diagnóstico depende do acompanhamento clínico e da
realização do teste das latências múltiplas de sono precedido pela
polissonografia. Na infância é importante a pesquisa de causas secundárias para a narcolepsia, uma vez que ao redor de 25% dos casos pode ser sintomático. O tratamento da narcolepsia em crianças
é atualmente essencialmente sintomático e, na maioria dos casos,
exige a abordagem comportamental e farmacológica. Novas modalidades terapêuticas com bloqueio da evolução da doença no início
dos sintomas têm sido estudadas.
Descritores: adolescente, criança, narcolepsia.
INTRODUCTION
During the first few years of life, episodes of daytime sleep
may be considered normal, and most children will take routine naps
until they are 3 years of age. In children and adults, excessive sleepiness (ES) is defined as the tendency to sleep (or the actual occurrence of sleep) during the wakeful period, with a frequency or duration that does not correspond to a given age range, prolonged night
sleep, or the necessity of a greater number of night sleep hours(1-3).
ES complaints are presented by up to 20% of school-age
children and adolescents(4). Although narcolepsy is not often diagnosed during the pediatric age range, the condition can begin
before the age of 10 in 16% of the patients. Approximately 30%
of narcoleptic patients exhibit initial symptoms during childhood.
The phenotypic expression of narcolepsy in childhood is variable,
and the onset of the disease is often monosymptomatic(4).
Narcolepsy should always be considered in cases where
children display marked ES. Narcoleptic children can fall asleep
as they talk, eat, or play, and the attacks of irresistible sleep
might occur several times during the day. During the early stages
of the disease, these children might have difficulty waking up in
the morning at their usual times. They may also exhibit impairments in their performance at school. The differential diagnosis
includes several sleep disorders that cause ES in children and
adolescents. At the onset of narcolepsy, the patients may be
mistakenly considered to be lazy or to have behavioral disorders.
Delays in diagnosing this disease might result in severe issues
during the literacy stage, psychosocial disorders, weight gain,
and improper drug treatment (e.g., anticonvulsants, antipsychotics, antidepressants), among other adverse effects.
A study of narcoleptic patients in the United Kingdom(5)
demonstrated that the symptoms began during an age range of
1 to 68 years, with onset at an average age of 18 years. However,
Study carried out at Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil.
1
Universidade Federal de São Paulo (UNIFESP), São Paulo (SP), Brazil.
2
Instituto Israelita de Ensino e Pesquisa do Hospital Israelita Albert Einstein, São Paulo (SP), Brazil.
3
Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (FMUSP).
4
Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.
5†
In memorian.
Corresponding author: Marcia Pradella-Hallinan. Rua Marselhesa, nº 500, 14º andar. Vila Clementino. São Paulo - SP. Brazil. CEP: 04020-060.
Tel: 55 (11) 5908-7000. E-mail: [email protected]; [email protected]
Received: January 19, 2012; Accepted: April 19, 2012.
Financial support: AFIP & FAPESP - CEPID 98/14303-3.
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Narcolepsy in children
the diagnosis was determined at an average of 15 years after the
first symptoms appeared. Delays in the diagnosis might be associated with several factors: the absence of cataplexy as the initial
manifestation of the disease, which delays the search for treatment and hinders an accurate diagnosis by non-specialists; misdiagnoses in this particular age range because the symptoms are
attributed to psychiatric or other neurological diseases; the failure
of pediatricians to specifically request an investigation of sleep
disorders; and the ignorance of pediatricians regarding the signs
and symptoms of narcolepsy.
A Brazilian study(6) demonstrated that the children and/
or adolescents with ES symptoms infrequently sought medical
help (i.e., 34 out of 290 patients [11.7%] over 4 years). The average age of the patients in that study was 13.5 ± 4.1 years, varying
between 5 and 17 years of age, independently of their gender.
The symptoms had begun an average of 3.0 ± 3.5 years before
the first visit. Narcolepsy was confirmed in 13 out of 34 youths
(38%). Only one adolescent sought assistance due to sleep paralysis, whereas the remainder of the patients exhibited marked
ES, with 1.5 ± 2.8 minutes of sleep latency during the multiple
sleep latency test (MSLT). In that sample, cataplexy was identified in 92% of the patients, sleep paralysis was identified in 23%
of the patients, and hypnagogic hallucinations were identified in
46% of the patients.
PHYSIOPATHOLOGY
Hypocretinergic system dysfunction
Hypocretins (or orexins), which were discovered in
1998(7), are peptides that are exclusively produced by a well-defined set of cells located in the dorsolateral hypothalamus; these
cells exhibit several projections into the cerebral cortex, brainstem, hypothalamus, and thalamus. The hypocretinergic system
is predominantly excitatory and exerts effects on the monoaminergic (dopamine, norepinephrine, serotonin, and histamine)
and cholinergic systems(8). The hypocretin-producing hypothalamic neurons are active during the wakeful period and reduce
their activity during rapid eye movement (REM) and non-REM
(NREM) sleep. The hypocretinergic activity progressively increases during wakefulness and during sleep deprivation to
counterbalance the need for sleep, which increases proportionally with the hours of wakefulness (homeostatic factor). In narcoleptic patients, especially those with cataplexy (85% to 90%),
significant reductions in the hypocretin levels were measured in
the cerebrospinal fluid (CSF).
Human narcolepsy is a complex disease. The association
between HLA-DQB1*0602 and reduced hypocretin levels indicates a genetic susceptibility for developing hypocretinergic
neuronal injury. Genetic mutations that affect other monoaminergic systems are associated with sporadic cases of the disease(7),
as are chromosomes 4p and 21q(9).
Although the presence of a positive HLA is not required
for the development of narcolepsy, 88% to 98% of cataplexy
cases exhibit positive HLA-DQB1*0602. However, in one study
of Brazilian children, positive HLA-DQB1*0602 was found in
only 29% of the patients(6).
Recent investigations have demonstrated that seasonality significantly affects narcoleptic children, associated with
infections by Streptococcus pyogenes and H1N1 influenza as well
as H1N1 vaccination. Some authors believe that infections and
vaccine antigens might be important triggers of autoimmune attacks to the central nervous system (CNS). Patients carrying the
HLA-DQB1*0602 allele more than likely have a unique immunological response to streptococcal infections, as do individuals
with rheumatic fever(10).
Other genetic aspects appear to be involved in the genetics of narcolepsy. The enzyme catechol-O-methyltransferase
(COMT) is responsible for most of the metabolic inactivation
of dopamine in the CNS. The COMT gene is located on chromosome 21 and exhibits a single functional nucleotide polymorphism, which alters the amino acid sequence in its molecule by
exchanging valine and methionine at codon 158 (Val158Met)
and, in turn, results in the reduction of COMT activity. Valine
(ValVal) homozygous COMT genotypes exhibit three or four
times more COMT activity and, therefore, less prefrontal dopaminergic signalization than does the methionine (MetMet)
genotype. Non-European populations predominantly exhibit
the ValVal genotype, which is associated with differences in
the intensity of neuropsychiatric symptoms among the various populations. This COMT polymorphism modulates the
dopaminergic and noradrenergic neurotransmission in healthy
individuals, the symptoms exhibited by narcoleptic individuals, and the response to treatment with modafinil. The MetMet
polymorphism is more common among Caucasian females, and
when associated with a narcoleptic phenotype, it influences the
intensity of SE, sleep latency in the MSLT, and the response to
modafinil. Environmental factors such as infections, pregnancy,
brain trauma, and stress might precede the onset of symptoms
in up to 50% of the cases(9).
No definitive explanation exists regarding the higher
incidence of narcolepsy during adolescence. One hypothesis
states that, in this age, some individuals response to infections by
agents such as streptococci or viruses provoke an autoimmune
reaction that can elicit the symptoms of narcolepsy. However,
this hypothesis should be tested as more knowledge regarding
the physiopathology of narcolepsy is generated(6).
CLINICAL PICTURE
Excessive Daytime Sleepiness (EDS)
EDS is the initial symptom that is most commonly reported by patients. The condition occurs alone in 46.1% of the cases
and is associated with other symptoms in 32.9% of the cases. It
should be emphasized that EDS might be particularly difficult to
recognize in children because, due to the physiological ultradian
rhythm, infants usually nap in the morning and afternoon and preschoolers usually nap in the afternoon. Moreover, ES might paradoxically present in many children as an increase in motor activity,
which is often mistaken for attention deficit hyperactivity disorder (ADHD). After the age of 6 years, hypersomnia should be
suspected when children require daytime naps, particularly when
these naps are long (duration of 30 to 90 minutes). The differential
diagnosis also includes psychiatric disorders such as behavioral and
oppositional-defiant disorders, depression, apathy, and mental retardation, as well as generalized absence-like epileptic seizures(11,12).
Cataplexy
In a Brazilian study(13), cataplexy appeared as a single
symptom in approximately 5% of the cases and was associated
with other symptoms in 39%(6). According to the literature, cataplexy occurs in 80.5% of the patients with idiopathic narcolepsy.
Cataplexy usually appears after the onset of EDS and
might be mistaken for syncope, atonic-type epileptic seizures, or
psychological symptoms. Because of its high prevalence, assess-
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ment of the presence of cataplexy is of paramount importance,
although pediatricians often have difficulty recognizing the condition. The frequency of cataplectic episodes tends to decrease
with age(3).
Hallucinations
Hypnagogic (at the onset of sleep) and hypnopompic
(in the morning, at the end of the nighttime sleep) hallucinations occur in two-thirds of individuals with narcolepsy. Usually, these hallucinations are visual; more rarely, their nature is
tactile, auditory, or somatosensory. The hallucinations might
reflect everyday scenes, animals, life events, family members, or
other persons, and the episodes are sometimes accompanied by
sleep paralysis, which terrifies the children even more. When
these episodes are misdiagnosed, they might be mistaken for
hallucinatory psychotic symptoms, temporal lobe epilepsy, night
terrors, nightmares, or panic attacks(12,14).
Sleep Paralysis
Episodes of sleep paralysis occur in 60% of the individuals with narcolepsy, and the frequency is variable, eventually
occurring daily. Moaning, difficulty breathing, chest tightness,
paresthesias such as pins and needles, or anesthesia of the limbs
might occur together with paralysis. These episodes usually
last a few seconds and spontaneously end when the children
or touched or moved. These patients may also learn to recover
their motor activity by moving their eyes or breathing slowly.
When these episodes are misdiagnosed, they might be mistaken
for psychiatric symptoms, intense fatigue, or certain neuromuscular diseases(5).
Other associated characteristics
Certain additional signs and symptoms are recognized
to be associated with narcolepsy, including sleep fragmentation
with frequent awakenings, which occurs in up to one-third of
the patients.
Narcoleptic children exhibit important differences in
their behavioral features, emotional status, quality of life, educational development, and the impact of the disease on their
families(14). EDS appears to be a common limiting factor in these
patients’ quality of life. Narcoleptic patients are often considered to be lazy and are eventually discriminated against by their
families, schoolmates, and friends. Furthermore, the accurate
diagnosis of narcolepsy is important because many of these patients are inaccurately treated for depression(15).
A higher body mass index (BMI) is increasingly found
among adults and in approximately 25% of children with narcolepsy compared to individuals without this disease(16). A tendency to gain weight appears inherent to childhood narcolepsy
and the early manifestation of this disease, and a correlation between hypocretin and leptin levels has been discovered. Leptin
is a peptide hormone secreted by adipocytes and is associated
with the feeling of satiety.
Several other sleep disorders might coexist with narcolepsy during childhood, including night terrors, nightmares,
obstructive sleep apnea (OSA), periodic limb movement disorder (PLMD), restless leg syndrome, muscular disorder, or REM
sleep behavior disorder.
Narcolepsy is seldom associated with hypothalamic tumors. However, cases associated with precocious puberty, hyperandrogenism, and insulin resistance have been reported(17).
141
Some authors suggest that children with narcolepsy and
cataplexy develop a complex movement disorder that resolves
over time. However, it is not yet known whether this movement
disorder is associated with low hypocretin-1 levels or with the
alteration of another neurotransmitter(18).
DIAGNOSIS
The diagnosis of narcolepsy is established according to
clinical symptoms. However, an accurate diagnosis might be difficult at the disease onset and in cases where the ES episodes
are short. The use of sleep diaries written by the patients and/
or their caretakers might be very helpful, as are questionnaires
for the assessment of sleepiness, such as the Epworth Sleepiness Scale modified for children(12,19) and the Pediatric Daytime
Sleepiness Scale (PDSS)(20), which can be applied to patients as
young as 11 years of age.
Diagnostic confirmation requires long follow-up periods
and the performance of an MSLT that has been preceded by
polysomnography (PSG) on the prior night.
PSG is indicated whenever narcolepsy is suspected; this
test enables the exclusion of other causes of ES and other sleep
disorders that might coexist with narcolepsy, such as OSA and
PLMD. MSLT is recommended for children who are at least
8 years of age and for adolescents. False negative results can
be obtained at the onset of the disease, whereas false positive
results might appear in adolescents due to the physiological delay in their sleep rhythm phase, poor sleep hygiene, or chronic
sleep deprivation. In younger children, the diagnosis is mainly
based on the clinical history and the exclusion of other diagnoses, when possible(21).
Twenty-four-hour video-PSG monitoring performed
with an extended EEG montage (international 10 - 20 system
for EEG) is suggested for children who are of preschool age.
This technique allows for the identification and distinction between sleep and cataplectic episodes and their differential diagnosis from epileptic seizures(22,23).
Narcoleptic patients might exhibit REM sleep within 15
minutes from the test onset. The sleep efficiency is usually high
(above 90%); however, sleep fragmentation might occur, caused by
an increased number of awakenings. Reduced REM sleep latency
among adolescents might suggest a diagnosis of narcolepsy. In general, the number of REM sleep episodes decreases in narcoleptic
patients, and their sleep latency increases progressively with increasing age.
MSLT yields quantitative data on the degree of sleepiness and qualitative information on the nature of the wakesleep transition, i.e., from the wakeful state to NREM or REM
sleep. In narcolepsy, a direct transition from the wakeful state to
REM sleep is a common finding, as is the occurrence of REM
sleep immediately after the sleep onset (SOREMP = “sleep onset REM period”). The occurrence of two or more SOREMPs
might not be observed at the early stages of narcolepsy in children or teenagers; consequently, several tests are required to establish a definitive diagnosis(21). The PSG and MSLT results that
are obtained from adults must be adjusted to prepubertal children (between 8 and 11 years of age), who are usually alert during the daytime. Opinions diverge as to the sleep latency values
in pre-adolescents, which vary between 15.5 and 18.8 minutes
but might also be higher than 20 minutes(1).
Notably, the discontinuation of all CNS stimulant medications, hypnotics, antidepressants, and other psychotropic
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agents is required for the performance of PSG. All of these
medications must be discontinued at least two weeks prior to
the exam because they can alter the sleep architecture.
A recent study of a population of narcoleptic children,
for whom PSG and MSLT data were available, revealed reductions in the sleep latency (average of 5.3 +/- 3.6 minutes) and
the REM sleep latency (14.4 +/- 23.0 minutes) [16]. MSLT
demonstrated an average latency of 3.5 +/- 2.4 minutes, and all
of the children exhibited two or more SOREMPs. During the
tests, attempts were made to trigger cataplexy. Laughter was the
main triggering factor, and anger, tickling, and surprise were less
frequent elicitors. The cataplectic episodes lasted 1 to 180 seconds with several manifestations: knee weakness; neck flexion;
drooping of the eyelids, jaw, or arms; chest flexion; decreased
ability to smile or facial hypomimia, slurred speech; and irregular breathing.
Drooping eyelids, facial hypomimia, an open mouth with
stuck out tongue characterize a “cataplectic facies,” which was
observed in 35% of the patients. This clinical manifestation was
more frequently associated with an early onset of cataplexy, increased BMI, and a higher number of SOREMPs. Further intercritical manifestations included repetitive automatic behaviors
such as touching certain body parts, scratching, or head shaking.
All of these manifestations improved with specific treatments
and were thus considered to be cataplectic equivalents.
HLA-DQB1*0602 testing is a useful diagnostic tool in
children, whereas its diagnostic sensitivity is higher in patients
with narcolepsy accompanied by cataplexy, among whom the
condition is present in up to 95% of individuals compared with
approximately 25% of the general population. However, the diagnostic specificity is low. A positive HLA-DQB1*0602 result is
an additional piece of data that indicates a diagnosis of narcolepsy, especially in the early stage of the disease. Moreover, the
test may be performed on patients at any age.
The measurement of hypocretin-1 in the CSF is invasive,
exhibits a low sensitivity in cases without cataplexy, and is available at few institutions. Hypocretin levels lower than 110 pg/ml
yield a high diagnostic specificity. The measurement of hypocretin in the CSF is particularly useful for the diagnosis of patients who are taking psychotropic (anti-cataplectic or stimulant)
agents that cannot be discontinued, patients with diseases that
interfere with the performance of the MSLT, children younger
than 8 years of age, or individuals who exhibit difficulties complying with the MSLT instructions.
Actigraphy is a diagnostic technique that allows the performance of a longitudinal assessment of the sleep-wake cycle
over several days or weeks(24). However, its pediatric use has not
yet been validated.
DIFFERENTIAL DIAGNOSIS
Investigation of secondary causes of narcolepsy is crucial
in children because one-fifth to one-third of cases are symptomatic for diseases such as Niemann-Pick disease type C, Norrie disease, Prader-Willi syndrome, Moebius syndrome, multiple
sclerosis, CNS tumors, and brain trauma (particularly involving
hypothalamic localization)(7,13,25).
Among the main differential diagnoses of narcolepsy in
children (Table 1), Klein-Levine Syndrome (KLS) is the most
prominent. KLS is characterized by recurrent episodes of sleepiness, and in its typical form, children exhibit episodes of hypersomnia, hyperphagia, mental disorders, and increased serum pro-
lactin. These episodes last between 12 hours and 3 or 4 weeks
(usually 4 to 7 days), and the intervals between episodes might last
months or years. During crises, patients sleep for long periods (18
to 20 hours) and awake (still feeling sleepy) only to eat voraciously.
In addition, sexual behavior disorders, aggressiveness, memory
disorders, depressive symptoms, and hallucinations might occur.
During the intervals between episodes, the patients appear to be
fully normal and usually do not have any memory of their crises.
SKL is a rare disease that is more frequent among males, and its
etiopathogenesis is unknown. SKL must be distinguished from
disorders accompanied by intermittent sleepiness (such as thirdventricle tumors, encephalitis, and brain trauma) and from psychiatric disorders.
Circadian rhythm disorders and sleep deprivation represent another important category in the differential diagnosis.
Children and adolescents might exhibit marked sleep-rhythm
disorders and sleep deprivation; moreover, adolescents with
poor sleep hygiene often exhibit an exacerbation of the wellestablished pattern of physiological phase delay. These patients experience excessive morning sleepiness (due to insufficient sleep) while in the classroom; notably, their symptoms
lead to dozing and poor school performance and can be misdiagnosed as narcolepsy. The differential diagnosis is established by collecting detailed information on the adolescents’
sleep schedules, which often requires the use of sleep diaries
or even actigraphy and the monitoring of their habits and lifestyles(26).
TREATMENT
The treatment of narcolepsy in children is basically
symptomatic, and a combination of behavioral and pharmacological approaches is necessary in most cases.
Behavioral treatment
Non-pharmacological therapies for narcolepsy in children are crucial to achieve adequate control of the disease. The
chronic nature of narcolepsy, provision of appropriate information to teachers and school coordinators, professional counseling, and explanations regarding the risks associated with driving and performing sports are among the features that must be
thoroughly discussed with these patients and their parents.
Psychological or psychiatric assistance is often required,
particularly for patients who develop depressive symptoms.
Furthermore, the establishment of routines that specifically include regular sleep schedules and naps that are scheduled
for the periods of marked daytime sleepiness should always be
recommended(27).
Possible side effects of chronic medication should be
monitored, and these adverse events include the following: the
development of tolerance and potential addictions, systemic arterial hypertension, liver dysfunction, and psychiatric symptoms
(irritability, nausea, headache, sleeplessness, anorexia, depression, anxiety, mania, and psychosis). Special attention must be
paid to the appearance of psychotic symptoms when amphetamines, methylphenidate, or modafinil are used(28).
Pharmacological treatment
No double-blind placebo-controlled trials that target the
treatment of narcolepsy in children have been conducted.
Stimulants (methylphenidate) and wakefulness enhancers
(modafinil) are the first-choice drugs for the treatment of EDS.
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Table 1. Differential diagnosis of narcolepsy in children and adolescents.
Causes of insufficient sleep
1.
Behavioral
Sleep onset association disorder
Social adjustment disorder
Lack of limits
Chronic sleep deprivation
Idiopathic sleeplessness (diagnosis of exclusion)
2.
Circadian Rhythm Disorders
Sleep phase delay
Non-24-hour sleep-wake cycle or free-running cycle
Irregular sleep-wake pattern
3.
Sleep fragmentation
1. Behavioral
2. Sleep association disorder
3. Parasomnias
4. Sleep respiratory disorders
5. Other clinical causes
6. Environmental
4.
Increased need of sleep
1. Narcolepsy
2. Occasional or transient hypersomnia
3. Recurrent hypersomnia
Depression
Klein-Levine Syndrome
Relation to menstrual cycles
5.
Idiopathic hypersomnia
Modafinil has only been approved in Northern Hemisphere countries for children who are older than 12 years. Its
initial dosage is 100 mg/day to avoid adverse effects such as
headache, irritability, and nausea. The dosage must be gradually
increased and can be divided into two daily doses. In adults, the
average dosage varies between 200 and 400 mg/day. The use of
modafinil must be avoided after 14:00h, due to its long half-life
of 12-13 hours. Few studies of the use of this drug in children
have been conducted(29).
Currently, modafinil appears to be safe for the treatment of children with narcolepsy; however, certain allergic reactions have been reported. Angioedema, severe skin rashes,
and Stevens-Johnson syndrome have been reported, but these
adverse effects to modafinil are not frequent and do not differ significantly from their prevalence in the general population.
Modafinil must be discontinued at the first sign of a skin rash
because children exhibit the highest risk of allergic reactions.
Allergic reactions in several organs and systems, including myocarditis, hepatitis, eosinophilia, leukopenia, thrombocytopenia,
and asthenia, have also been reported. No clinical markers are
available to predict these adverse effects.
Methylphenidate can be used in either immediate-release
or controlled-release formulations at a dosage of 0.5-1 mg/kg/
day (to a maximum of 60 mg/day) in two or three doses after
meals to avoid gastric symptoms.
Low-dose tricyclic agents (amitriptyline, imipramine,
clomipramine) or dually selective inhibitors (such as the serotonin-noradrenaline reuptake inhibitor venlafaxine with an initial,
low dose of 37.5 mg/day) are indicated for the treatment of
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cataplexy, sleep paralysis, and hypnagogic hallucinations. Selective serotonin reuptake inhibitors (SSRI), such as fluoxetine (1020 mg/kg), are used in the treatment of cataplexy.
Nocturnal sleep fragmentation seldom occurs in narcoleptic children and can be treated with benzodiazepines (clonazepam, 0.2-0.5 mg/day) and non-benzodiazepine hypnotics
(zolpidem, zopiclone, or zaleplon) in children who are older
than 12 years, using smaller dosages than those for adults.
Lecendreux et al.(30) treated one 10-year-old narcoleptic
child with high doses of an intravenous immunoglobulin, and
the patient exhibited a significant improvement during the first
months of treatment. A recent study demonstrated that treatment with an immunoglobulin within 9 months of the onset of
narcolepsy is efficacious. The low hypocretin-1 levels of patients
with narcolepsy and cataplexy indicate an autoimmune condition; thus, early immune intervention might be beneficial(31).
Conversely, treatment with prednisolone did not appear to affect the expression of the disease in an 8-year-old patient(22,32).
Early treatment might alter the natural course of narcolepsy;
however, additional controlled trials of immunosuppressants
are necessary to confirm this hypothesis.
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López-Esteban P, Vicario JL, et al. Clinical, polysomnographic and laboratory characteristics of narcolepsy-cataplexy in a sample of children
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145
CASE REPORT
Acupuncture in obstructive sleep apnea/hypopnea
syndrome: a case report with fifteen months of
follow-up
Acupuntura na síndrome da apneia/hipopneia obstrutiva do sono. Quinze
meses de acompanhamento - relato de caso
Kátia Savelli G. Bencz1, Paulo A. D. Nabarro2
ABSTRACT
This study aimed to investigate the efficacy of acupuncture for the
treatment of patients with obstructive sleep apnea/hypopnea syndrome (OSAHS). The present work describes a clinical case study of a male patient who was clinically and polysomnographically
diagnosed with mild OSAHS. There was a significant reduction in
the apnea/hypopnea index (AHI) from 13.1 to 0.5 after 10 weeks
of treatment and to 3.3 at 15 months after treatment. In addition,
there was a reduction of respiratory events from 90 to 3 after 10
weeks and to 9 after 15 months. Acupuncture was effective in treating mild OSAHS; however, treatment for this disease should be
initiated immediately after diagnosis to prevent progression.
Keywords: acupuncture, acupuncture points, sleep apnea syndrome.
RESUMO
O objetivo deste estudo foi investigar a eficácia da acupuntura no
tratamento em pacientes portadores da Síndrome da Apneia/Hipopneia Obstrutiva do Sono (SAHOS). O presente trabalho mostra
o estudo de um caso clínico em paciente do sexo masculino, previamente diagnosticado clínica e polissonograficamente com SAHOS
leve. Houve redução significativa do índice da apneia/hipopneia
(IAH) de 13,1 para 0,5 após 10 semanas e 3,3 após 15 meses do tratamento, bem como uma redução dos eventos respiratórios de 90
para 3 após 10 semanas e para 9 após 15 meses. A acupuntura mostrou-se eficaz no tratamento da SAHOS leve; contudo, recomendase que o tratamento desta doença deve ser iniciado imediatamente
após o diagnóstico, para evitar sua progressão.
Descritores: acupuntura, pontos de acupuntura, síndrome da apneia
do sono.
INTRODUCTION
In recent decades, the search for alternative treatments
has allowed acupuncture to be incorporated into the therapeutic
arsenal of Western medicine by the recognition of the need to
treat the whole individual and not just a portion(1). Currently, acupuncture is being used to treat various pathological conditions(2).
According to the NIH Consensus Development Panel
on Acupuncture (1998), scientific studies using rigorous methodology have demonstrated the applicability of this therapeutic
intervention with positive results in several clinical situations(3,4).
Acupuncture increases melatonin secretion and reduces insomnia(5) and anxiety at night(2). Melatonin secretion over a 24-hour
period is accepted as a measure of circadian activity in humans,
which is interrupted by insomnia. Melatonin deficiency may be
the key to the anxiety associated with insomnia, as acupuncture acts by promoting the increase of melatonin in the pineal
gland and the hippocampus(2). Acupuncture is also effective in
the treatment of bruxism(3,5), which is a sleep-related disorder(4,6)
involving an elevated muscle tone of the masseter and the anterior temporal muscles that causes clenching and grinding of the
teeth during sleep(6). In this case, acupuncture increases the release of serotonin, which acts in the cerebral cortex to decrease
feelings of stress and anxiety(1).
In patients with OSAHS, there is a collapse of the side
walls of the oropharynx, a drop of the tongue on the palatal
veil, and a concentric closing of the hypopharynx during sleep(6),
causing decreased pharyngeal airspace. The functioning of the
upper airway (UA) depends on the dynamic equilibrium between
the expansion forces, the tonic and phasic activity of pharyngeal
dilators, and the collapse forces(7). Recent research has shown a
rupture of the UA sensory nerve and a reduction of the excitatory unit from the serotonergic caudal raphe neurons that are
responsible for the excitatory opening of the upper airway muscles, leading to worsening of the pharyngeal collapse(8). Acupuncture acts to treat OSAHS through an increase in serotonin
in the caudal raphe nucleus in the endogenous opioid system
(such as endorphins and enkephalins) and also through the involvement of the sympathetic nervous system(3,4,8).
CASE REPORT
A 65-year-old male with a body mass index (BMI) of
28.40 kg/m² and a neck circumference of 45 cm was referred
by a neurologist with complaints of difficulty concentrating,
memory loss, and excessive daytime sleepiness to assess the
possibility of OSAHS treatment with acupuncture. The basal
polysomnography (PSG; Table 1) exam indicated the following: an apnea/hypopnea index (AHI) of 13.1; apnea index (AI)
Study carried out at Pontíficia Universidade Católica do Paraná - Curitiba, Brazil.
1
Pontíficia Universidade Católica do Paraná - Curitiba, Brazil.
2
Maringaense Dental Association, Maringá (PR), Brazil.
Corresponding author: Kátia Savelli G. Bencz. Av Jose C. de Oliveira, nº 1425. Centro. Campo Mourão - PR. Brazil. CEP: 87300-020. Phone (44) 3016-4650.
Received: July 19, 2011; Accepted: July 12, 2012.
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Acupuncture and OSAS
Table 1. Basal polysomnography values prior to treatment.
Date
Type
AHI
AI
HI
SaO2 maximum
SaO2 minimum
Sleep efficiency
% REM
TTS
09/22/09
Basal
13.1
3.2
9.9
98%
86%
88.6%
17.8%
413
AHI: apnea/hypopnea index; AI: apnea index; HI: hypopnea index; SaO2: oxygen saturation; REM: rapid eye movement; TST: total sleep time.
of 3.2; hypopnea index (HI) of 9.9; minimum oxygen saturation (SaO2) of 86%; sleep efficiency of 88.6%; and REM sleep
of 17.8%. The patient’s Epworth Sleepiness Scale (ESS) was
11. Intraoral examination revealed a Grade 2 tongue, a Grade
4 Mallampati, a normal palate, and the absence of tonsils. A
lateral cephalometric radiography with a report for apnea
was requested to evaluate the airway dimensions(9) (Table 2).
Table 2. Lateral Cephalometry.
Analysis
Value mm
Normal
Anterior skull base
74.95
80.00 ± 2.00
Maxillary length
56.42
62.50 ± 4.00
Mandibular length
70.44
84.50 ± 5.00
Upper pharyngeal space
14.18
26.00 ± 4.00
PAS - Posterior airspace
9.64
15.50 ± 3.50
IAS - Inferior airspace
8.79
17.50 ± 4.00
Hyoid distance - mandibular plane
21.57
19.00 ± 6.00
Disposable, stainless steel, coil cord, sterilized acupuncture needles of 25/30 mm (Dongbang) were used. This experiment used points in the oropharyngeal region that are relevant
to sleep apnea disturbance(3,4,8,10,11) (Figures 1 and 2) and distant
points that function in systemic toning, the harmonization of
the upper and lower energy centers, the activation of energy
flow (Qi), and as general energy regulators(3,4,8,10) (Figure 3).
The location and depth of insertion were based on traditional
texts(10). Systemic and auricular acupuncture were used concomitantly(10,12). The auricular pavilion is innervated mainly by the
spinal nerves of the brachial plexus such as the great auricular
nerve and the lesser occipital nerve and by cranial nerves such as
the auriculotemporal, facial, glossopharyngeal, vagus, and sympathetic branches(10,12,13).
Figure 2. Needle application at the selected points in the neck (extra).
Figure 3. Points selected.
Figure 1. Extra points (neck).
The points used in this study included the following: GV 20
(Bahui), at 7 tsun (tsun or cun is the distance used in acupuncture
to locate the points corresponding to the size of the thumb at the
height of the patient’s inguinal matrix) above the hair insertion on
the nape; CV 22 (Tiantu), at half tsun above the jugular notch; CV
23 (Lianquan), above the upper border of the hyoid bone; LI 4 (He
Gu), in the middle of the second metacarpal bone of the radial
side; SI 17 (Tianrong), below the angle of the mandible; and S 36
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Bencz KSG, Nabarro PAD
(Zusanli), at 3 tsun below the lateral depression of the patella and
1 tsun lateral to the anterior margin of the tibia. The extra points,
which are outside the standard meridians, included the following:
Shanglianquan, at 1 tsun above the prominence of the thyroid cartilage, between the mandible and the hyoid bone; Panglianquan, at
half tsun lateral to the Lianquan point; Jinjin (left side); and Yuye
(right side), at half tsun lateral to the Shanglianquan, on the lingual
frenulum(10,11) (Figures 1 and 2; Table 3). The treatment continued
for a period of 10 weeks with weekly applications. After 3 months
from the beginning of the treatment and at 15 months after the
completion of the applications, a PSG evaluation was performed
to evaluate the acupuncture treatment efficacy (Table 4). This report was approved by the research ethics committee of Plataforma
Brazil under reference 02676312.5.0000.0109.
Table 3. Selection of the acupuncture points used.
Single points
Bilateral points (leg and hand)
Extra points (neck)
GV 20
LI 4
Jinjin
CV 22
S 36
Yuye
CV 23
SI 17
Shanglianquan
Panglianquan
GV: governing vessel; CV: conception vessel; LI: large intestine;
S: stomach; SI: small intestine.
RESULTS
The comparison between the basal PSG values and the
values after 10 weeks of acupuncture treatment and 15 months
after the end of treatment shows the efficacy of acupuncture
use in a patient with mild to moderate OSAHS (Table 4). At the
first evaluation, after 10 weeks of acupuncture treatment, there
was a significant improvement in the following indices: 96.4%
for AHI; 93.75% for AI; 96.97% for HI; and an increase of
87.20% for REM sleep.
With an interruption of the acupuncture treatment after
the first evaluation, another PSG exam was performed 15 months
later. A split-night PSG was performed (comparative between acupuncture and IOA, not used for this study) with the following results: 74.8% improvement in AHI; 100% for AI; 66.6% for HI; and
a REM sleep increase of 89.33%. The Epworth Sleepiness Scale
(ESS) showed a 66% improvement at the first evaluation and 80%
at 15 months, with the report of subjective symptoms such as
snoring, nocturnal awakenings, excessive daytime sleepiness, and
memory loss virtually eliminated.
DISCUSSION
The present study showed strong evidence for the efficacy
of acupuncture in a patient with mild to moderate OSAHS(2,4,8).
The acupuncture treatment effects continued even after a period
147
without treatment(14,15) as measured by PSG examination. According to Han et al. (1984), the possible prolonged effect is due to
the mesolimbic loop(14,15). The influence of the tongue muscle
activity strongly correlates with the causal factors of OSAHS.
In this work, the acupuncture points were applied mainly in the
oropharyngeal region from the point above the hyoid bone extending to the base of the mandible and over the digastric muscle
including the mylohyoid and geniohyoid muscles. The function
and basic action of these acupoints are to alleviate throat distension, difficulty swallowing, and speech difficulty and to increase
tongue mobility(10,11,16). The acupuncture mechanism of action is
based on the activation of the nerves being stimulated by the needles. These nerves send messages to the CNS, especially to the
reticular formation(15), which is involved in the actions of sleep
and wakefulness cycles, filtering of sensory stimuli, regulation of
breathing, pupillary opening, swallowing, and somatic motor activities(15). The reticular formation nuclei include the hypoglossal
nuclei, whose fibers and neurons innervate the muscles that move
the tongue. The neurochemicals released in the reticular formation include endorphins, serotonin, monoamines, or cortisol that
would be responsible for the clinical effects of acupuncture at
both the segmental and intersegmental levels(15).
The segmental level, known as dermatomes, are symmetrically arranged in the human body and are the cutaneous distribution territory for the sensory and motor nerve roots that originate from a dorsal root ganglion(13,15). These dermatomes have no
specific limits, and their neighboring roots overlap one another(15).
For this reason, in acupuncture, it is possible to use distant points
to treat certain disorders (such as using a point situated at the foot
for treating an ocular disorder). Therefore, an afferent impulse
caused by acupuncture stimulation travels from the periphery to
the spinal cord, ascends through the spinal cord to the reticular
formation, from which the effector impulses responsible for the
therapeutic effects of acupuncture originate. In this case, we can
consider acupuncture as a reflex treatment involving a complex
reflex called somatotrophic, from a nociceptive stimulation, to
optimize the adaptive capacity of the body to stressors(15).
CONCLUSIONS
This study determined that a patient with mild OSAHS
under weekly acupuncture treatment obtained a better quality of
life with changes in sleep patterns, particularly of REM sleep,
and with a significant reduction in OSAHS (AHI from 13.1 to
0.5 at 3 months and to 3.3 after 15 months).
Thus, this study provides the basis for investigating the
clinical efficacy of acupuncture in patients with severe OSAHS.
However, this particular study should be continued, as it is not
possible to determine the duration of the acupuncture effect
on the body.
Table 4. Comparative polysomnography values before treatment, at 3 months after the beginning of acupuncture treatment, and at 15 months
after completion of treatment.
BASAL, IOA ACUPUNTURE
Date
AHI
AI
HI
SaO2 max
SaO2 min
Sleep effic.
TST minutes
% REM
BMI
Basal
9/22/09
13.1
3.2
9.9
98%
86%
88.6%
413
17.8%
28.41
Acupuncture
6/01/10
0.5
0.2
0.3
97%
83%
81.3%
394.5
22.8%
28.41
Split night
9/06/11
Acupuncture
3.3
-
3.3
96%
88%
69.2%
163
19.0%
26.94
IOA*
2.0
-
2.0
83.0%
210.5
21.1%
26.94
AHI: apnea/hypopnea index; AI: apnea index; HI: hypopnea index; SaO2 max: maximum oxygen saturation; SaO2 min: minimum oxygen saturation;
Sleep effic: sleep efficiency; TST: total sleep time; REM: rapid eye movement; BMI: body mass index; IOA: intraoral appliance (*was not compared
in this study).
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Guide for authors:
how to submit your manuscript
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http://www.ncbi.nlm.nih.gov/entrez/journals/loftext.noprov.html.
A total of six authors may be listed. For works with
more than six authors, list the first six, followed by ‹et al.›
Examples:
Journal articles
1. Tufik S, Lindsey CJ, Carlini EA. Does REM sleep deprivation induce a supersensitivity of dopaminergic receptors in the rat brain? Pharmacology. 1978;16(2):98-105.
2. Andersen ML, Poyares D, Alves RS, Skomro R, Tufik S. Sexsomnia: abnormal sexual behavior during sleep. Brain Res Rev.
2007;56:271-82.
Abstracts
3. Moreno CRC, Carvalho FA, Matuzaki LA, Louzada FM. Effects of irregular working hours on sleep and alertness in Brazilian truck drivers [abstract]. Sleep. 2002;25:399.
Chapter in a book
4. Andersen ML, Bittencourt LR. Fisiologia do sono. In: Tufik
S, editor. Medicina e biologia do sono. São Paulo: Manole; 2007.
P. 48-58.
Official publications
5. World Health Organization. Guidelines for surveillance of
drug resistance in tuberculosis. 2nd ed. Geneva: WHO; 2003.
p. 1-24.
Thesis
6. Bittencourt L. Avaliação davariabilidade do Índice de apnéia
e hipopnéia em pacientes portadores da síndrome da apnéia e
hipopnéia do sono obstrutiva [tese]. São Paulo: Universidade
Federal de São Paulo; 1999.
Electronic publications
7. Abood S. Quality improvement initiative in nursing homes:
the ANA acts in an advisory role. Am J Nurs [Internet]. 2002
[cited 2002 Aug 12];102(6):[about 3 p.]. Available from: http://
www.nursingworld.org/AJN/2002/june/Wawatch.htm
Homepages/URLs
8. Cancer-Pain.org [Internet]. New York: Association of Cancer
Online Resources, Inc., c2000-01 [updated 2002 May 16; cited
2002 Jul 9]. Available from: http://www.cancer-pain.org/
Other situations:
In other situations not mentioned in these author instructions,
the recommendations given by the ICMJE should be followed,
specifically those in the article Uniform Requirements for Manuscripts Submitted to Biomedical Journals: Writing and Editing
for Biomedical Publication (Updated October 200 9), available
from: http://www.icmje.org/. Additional examples for special
situations involving references can be obtained at: www.nlm.nih.
gov/bsd/uniform_requirements.html
SUBMISSION OF MANUSCRIPT
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authors, with permission for publication and a statement that is
unprecedented and has not been submitted for publication in
another journal or book. That letter must include: a) conflicts
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investigation involves experiments on humans or animals; c)
disclosure of the possible sources of funding work; d) a statement that participants provided signed consent forms, in the
case of medical research on humans; e) letter of transfer of
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Important note: the journal Sleep Science in support of
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Sleep Sci. 2012;5(4):149-150
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