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(CEP)
[1–10] [PREPRINTER stage]
Original Article
Sleep and chronobiology in cluster headache
Cephalalgia 0(0) 1–10 ! International Headache Society 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102414564892 cep.sagepub.com
M Barloese1, N Lund1, A Petersen1, M Rasmussen1, P Jennum2 and R Jensen1 Abstract Background and aim: Cluster headache (CH) is the headache disorder with the strongest chronobiological traits. The severe attacks of pain occur with diurnal and annual rhythmicity but the precise rhythm and involvement of potential zeitgebers is unknown. Patients complain of poor sleep quality yet this has never been studied. We investigated triggers, rhythms, sleep quality and chronotypes in CH. Methods: Patients and controls completed questionnaires and structured interviews composed of new and previously validated parts including the Pittsburgh Sleep Quality Index (PSQI) and Morningness-Eveningness Questionnaire (MEQ). Patients were characterized by a CH index, a unified measure of headache burden. Results: A total of 275 CH patients and 145 matched controls were included. The most common trigger was sleep (80%) and a relationship between clusters and daylight was identified. Of the patients, 82.2% reported diurnal and 56% annual rhythmicity. Patients reported impaired sleep quality (PSQI) (p < 0.0001) and an inverse relationship between time passed since last attack and sleep quality was identified (p < 0.0001). The CH index was positively related to the PSQI (p < 0.0001). Conclusion: Diurnally, CH exhibits a relationship with night-time and annually with daylight hours. Patients’ sleep quality is reduced compared with controls. Results suggest a complex relationship as sleep quality improves between clusters, but remains pathological. Keywords Cluster headache, chronobiology, hypothalamus, pain, sleep Date received: 5 September 2014; revised: 8 November 2014; accepted: 10 November 2014
Introduction Cluster headache (CH) is an extremely painful headache disorder that exhibits striking chronobiological features. In its classical description the regularity of the attacks and the features that set it apart from other primary headache disorders have seeded many interesting studies and results (1,2). CH typically presents in younger males as severe attacks of side-locked, unilateral headache with accompanying autonomic symptoms (3,4). The attacks are described to be predominantly related to nocturnal sleep and follow specific diurnal and annual rhythms that often afford a certain degree of predictability (5). Despite an increase in knowledge of the severe pain attacks, the relation to sleep-wake regulation and management, there are numerous unresolved issues in disease pathophysiology and the relation to circadian and intricate sleep-wake associations (6). A genetic link to
the hypocretin system (7), a relationship between CH and sleep apnea (8), and a particular temporal relationship with rapid eye movement (REM) sleep (9) have all been suggested. However, it appears that the association between CH and sleep apnea may not exist (10) and the attacks have recently been shown to occur in both non-REM (NREM) and REM sleep (10,11). 1
Danish Headache Center, Dept. of Neurology Danish Center for Sleep Medicine, Dept. of Neurophysiology, Glostrup Hospital, University of Copenhagen, Denmark 2
M.R. present address: PAIN, National Institutes of Health, Bethesda, MD, USA Corresponding author: Rigmor Jensen, Danish Headache Center, Nordre Ringvej 67, Omraade Nord, Bolig 14, Glostrup, DK-2600, Denmark. Email: [email protected]
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(CEP)
[1–10] [PREPRINTER stage]
2 Thus, the link between CH and sleep is complex as is also evident by the expansive anatomical and physiological overlap between sleep and headache (12). The first studies investigating CH chronobiology uncovered a unique diurnal and annual periodicity (1,13) that have later been corroborated to an extent (5,14). The annual rhythms seem to follow a biphasic pattern, but results are diverging as to a possible relation with the solstices or equinoxes. Diurnal rhythms may also be subject to local cultural influences (5,13,14) but the exact mechanisms are unclear. According to hypotheses the hypothalamus is intricately involved as demonstrated in both clinical investigations (15,16) and by the chronobiological features themselves (5). In CH, particularly the possible roles and close interaction between the suprachiasmatic nucleus and the posterior hypothalamus, shown to be exclusively activated during CH attacks (15), are fascinating. The aim of this study was, through descriptive epidemiology, to investigate self-reported sleep quality, chronotype, trigger factors and chronobiological features in a Danish population of CH patients. Further, we aimed to investigate whether possible poor sleep quality was confined to the cluster periods or universally present in this patient group.
Methods A questionnaire composed of already validated sections (Pittsburgh Sleep Quality Index (PSQI), MorningnessEveningness Questionnaire (MEQ)) and new questions developed by authors MB and RJ were sent to patients and controls. The questionnaire as a whole was assessed by an expert panel including 10 senior headache experts (unpublished data). They were asked to evaluate the questions: Are the instructions clear, is the questionnaire coherent, are the questions relevant, is the questionnaire logically divided into parts, and are the questions formulated clearly. The questionnaire was also tested with a randomly selected population of 10 CH patients representing different ages, genders and diagnoses (episodic (ECH) and chronic (CCH)), and comments and suggestions were implemented. The Capital Region of Denmark Ethical Committee approved the study (H-2-2012-016).
Questionnaire The paper questionnaire contained 362 questions in seven sections: headache diagnosis, headache burden, treatment, sleep, work, lifestyle habits, and physical activity. It was estimated that it took the patients roughly one hour to complete the questionnaire. Following completion of the questionnaire, answers were verified and ambiguities ruled out by a structured
Cephalalgia 0(0) in-person or telephone interview conducted by a physician or a trained medical student (MB, NL, AP). If the patient or control invited to participate did not respond within 21 days, he or she was contacted again by letter and/or telephone and encouraged to complete the questionnaire. Only questionnaires for which all questions were answered were used. Only part of the data obtained by this study are available here as the remainder will be made available in subsequent publications. The PSQI (17) is a validated (18) 19-item measure of subjective sleep quality during the past month. The sum of seven component scores provides a global score, a higher value reflecting poorer sleep quality. A global score greater than 5 yields a high sensitivity and specificity in distinguishing ‘‘good and poor sleepers’’ (17). To assess daytime performance as a function of sleep quality, the Epworth Sleepiness Scale (19) (ESS) was used. The MEQ (20) uses 19 multiple-choice items to chronotype patients into five categories: definite morning, moderate morning, intermediate, moderate evening, definite evening. The tool has been validated in middle-aged populations (21). Chronotype reflects at what time of the day a person is active or inactive, often reduced to sleeping habits only, i.e. ‘‘lark’’ or ‘‘owl.’’ Regarding rhythmicity, patients were asked to report the hours of the day or the months of the year where attacks or clusters were most likely to occur. They also had the option to report no rhythmicity. Patients were asked if they smoked currently and could answer ‘‘yes, daily,’’ ‘‘yes, sometimes (less than one cigarette or equivalent per day),’’ ‘‘no, but I used to smoke daily,’’ ‘‘no, but I used to smoke sometimes (less than one cigarette or equivalent per day),’’ or ‘‘no, I have never smoked.’’ They were also asked for how many years they have smoked regularly, if they stopped, when, and finally how many cigarettes, cheroots, cigars or grams of pipe tobacco they smoked on average a day.
Patients Patients diagnosed with ECH or CCH were recruited from a register of present and former contacts at the Danish Headache Center. Additionally, a notice was posted in the newsletter and website of the Danish patient organization for cluster headache. Other headache clinics in Denmark were contacted and patients receiving treatment at these clinics were referred to the study in case of interest. Patients were included if they: were between 18 and 65 years old, had been diagnosed with ECH or CCH (International Classification of Headache Disorders, second edition (ICHD-II) criteria) and were able to tell CH attacks apart from other types of headache. Patients were excluded if they: had been diagnosed with another primary or secondary chronic headache
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(CEP)
[1–10] [PREPRINTER stage]
3
Barloese et al. (14 days/month) or did not speak and understand Danish. All patients’ diagnoses were verified by a headache specialist. Apart from the dichotomy of episodic/ chronic offered by existing diagnostic criteria, patients were characterized according to self-reported annual (months of the year during which clusters/bouts occur) and diurnal (hours of the day when individual attacks occur) attack patterns, whether sleep was a trigger and according to a CH index (described below).
Controls were recruited via notices posted on the Internet and in work places and sport clubs in the Capital Region of Denmark. Controls were matched for sex and age based on means. Controls were required to be between 18 and 65 years old and headache free (1 day of headache/month). They were excluded if they had severe symptoms of sleep disorders.
A CH index was calculated by the following equation: (attacks per day hours per attack) (days per cluster clusters per year) and is a measure of the area under the curve – the total time/year that the patient has CH. In this specific calculation, for CCH patients, number of clusters/year was set at one and cluster duration was set at 365 days. The motivation for calculating this index is to provide one number that reflects headache burden, as this is sometimes not completely clear, taking into consideration clusters, cluster duration, attacks and attack duration. Further, we wanted to characterize the patients beyond the dichotomy of episodic/chronic as some episodic patients in fact may experience far more headache than some chronic. Body mass index (BMI) was calculated from self-reported height and weight (BMI ¼ kg/m2). Tobacco pack-years was calculated as number of cigarettes (or equivalent) smoked daily/20 number of years smoking.
Statistical methods
Results
Analysis of variance (ANOVA) was used for comparison between more than two groups and Bonferroni corrections were applied in the analysis of PSQI. Chisquare test was used to calculate differences in gender composition, smoking status, MEQ groups, consumption of sleep medication and laterality. Wilcoxon rank sums were used for non-parametric data. Linear regression was used to describe the association between daylight hours for the months of the year and corresponding cluster occurrence as well as the ESS, CH index and PSQI. Two-sample t-test was used to compare means of two groups. A p value
(CEP)
[1–10] [PREPRINTER stage]
Original Article
Sleep and chronobiology in cluster headache
Cephalalgia 0(0) 1–10 ! International Headache Society 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102414564892 cep.sagepub.com
M Barloese1, N Lund1, A Petersen1, M Rasmussen1, P Jennum2 and R Jensen1 Abstract Background and aim: Cluster headache (CH) is the headache disorder with the strongest chronobiological traits. The severe attacks of pain occur with diurnal and annual rhythmicity but the precise rhythm and involvement of potential zeitgebers is unknown. Patients complain of poor sleep quality yet this has never been studied. We investigated triggers, rhythms, sleep quality and chronotypes in CH. Methods: Patients and controls completed questionnaires and structured interviews composed of new and previously validated parts including the Pittsburgh Sleep Quality Index (PSQI) and Morningness-Eveningness Questionnaire (MEQ). Patients were characterized by a CH index, a unified measure of headache burden. Results: A total of 275 CH patients and 145 matched controls were included. The most common trigger was sleep (80%) and a relationship between clusters and daylight was identified. Of the patients, 82.2% reported diurnal and 56% annual rhythmicity. Patients reported impaired sleep quality (PSQI) (p < 0.0001) and an inverse relationship between time passed since last attack and sleep quality was identified (p < 0.0001). The CH index was positively related to the PSQI (p < 0.0001). Conclusion: Diurnally, CH exhibits a relationship with night-time and annually with daylight hours. Patients’ sleep quality is reduced compared with controls. Results suggest a complex relationship as sleep quality improves between clusters, but remains pathological. Keywords Cluster headache, chronobiology, hypothalamus, pain, sleep Date received: 5 September 2014; revised: 8 November 2014; accepted: 10 November 2014
Introduction Cluster headache (CH) is an extremely painful headache disorder that exhibits striking chronobiological features. In its classical description the regularity of the attacks and the features that set it apart from other primary headache disorders have seeded many interesting studies and results (1,2). CH typically presents in younger males as severe attacks of side-locked, unilateral headache with accompanying autonomic symptoms (3,4). The attacks are described to be predominantly related to nocturnal sleep and follow specific diurnal and annual rhythms that often afford a certain degree of predictability (5). Despite an increase in knowledge of the severe pain attacks, the relation to sleep-wake regulation and management, there are numerous unresolved issues in disease pathophysiology and the relation to circadian and intricate sleep-wake associations (6). A genetic link to
the hypocretin system (7), a relationship between CH and sleep apnea (8), and a particular temporal relationship with rapid eye movement (REM) sleep (9) have all been suggested. However, it appears that the association between CH and sleep apnea may not exist (10) and the attacks have recently been shown to occur in both non-REM (NREM) and REM sleep (10,11). 1
Danish Headache Center, Dept. of Neurology Danish Center for Sleep Medicine, Dept. of Neurophysiology, Glostrup Hospital, University of Copenhagen, Denmark 2
M.R. present address: PAIN, National Institutes of Health, Bethesda, MD, USA Corresponding author: Rigmor Jensen, Danish Headache Center, Nordre Ringvej 67, Omraade Nord, Bolig 14, Glostrup, DK-2600, Denmark. Email: [email protected]
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(CEP)
[1–10] [PREPRINTER stage]
2 Thus, the link between CH and sleep is complex as is also evident by the expansive anatomical and physiological overlap between sleep and headache (12). The first studies investigating CH chronobiology uncovered a unique diurnal and annual periodicity (1,13) that have later been corroborated to an extent (5,14). The annual rhythms seem to follow a biphasic pattern, but results are diverging as to a possible relation with the solstices or equinoxes. Diurnal rhythms may also be subject to local cultural influences (5,13,14) but the exact mechanisms are unclear. According to hypotheses the hypothalamus is intricately involved as demonstrated in both clinical investigations (15,16) and by the chronobiological features themselves (5). In CH, particularly the possible roles and close interaction between the suprachiasmatic nucleus and the posterior hypothalamus, shown to be exclusively activated during CH attacks (15), are fascinating. The aim of this study was, through descriptive epidemiology, to investigate self-reported sleep quality, chronotype, trigger factors and chronobiological features in a Danish population of CH patients. Further, we aimed to investigate whether possible poor sleep quality was confined to the cluster periods or universally present in this patient group.
Methods A questionnaire composed of already validated sections (Pittsburgh Sleep Quality Index (PSQI), MorningnessEveningness Questionnaire (MEQ)) and new questions developed by authors MB and RJ were sent to patients and controls. The questionnaire as a whole was assessed by an expert panel including 10 senior headache experts (unpublished data). They were asked to evaluate the questions: Are the instructions clear, is the questionnaire coherent, are the questions relevant, is the questionnaire logically divided into parts, and are the questions formulated clearly. The questionnaire was also tested with a randomly selected population of 10 CH patients representing different ages, genders and diagnoses (episodic (ECH) and chronic (CCH)), and comments and suggestions were implemented. The Capital Region of Denmark Ethical Committee approved the study (H-2-2012-016).
Questionnaire The paper questionnaire contained 362 questions in seven sections: headache diagnosis, headache burden, treatment, sleep, work, lifestyle habits, and physical activity. It was estimated that it took the patients roughly one hour to complete the questionnaire. Following completion of the questionnaire, answers were verified and ambiguities ruled out by a structured
Cephalalgia 0(0) in-person or telephone interview conducted by a physician or a trained medical student (MB, NL, AP). If the patient or control invited to participate did not respond within 21 days, he or she was contacted again by letter and/or telephone and encouraged to complete the questionnaire. Only questionnaires for which all questions were answered were used. Only part of the data obtained by this study are available here as the remainder will be made available in subsequent publications. The PSQI (17) is a validated (18) 19-item measure of subjective sleep quality during the past month. The sum of seven component scores provides a global score, a higher value reflecting poorer sleep quality. A global score greater than 5 yields a high sensitivity and specificity in distinguishing ‘‘good and poor sleepers’’ (17). To assess daytime performance as a function of sleep quality, the Epworth Sleepiness Scale (19) (ESS) was used. The MEQ (20) uses 19 multiple-choice items to chronotype patients into five categories: definite morning, moderate morning, intermediate, moderate evening, definite evening. The tool has been validated in middle-aged populations (21). Chronotype reflects at what time of the day a person is active or inactive, often reduced to sleeping habits only, i.e. ‘‘lark’’ or ‘‘owl.’’ Regarding rhythmicity, patients were asked to report the hours of the day or the months of the year where attacks or clusters were most likely to occur. They also had the option to report no rhythmicity. Patients were asked if they smoked currently and could answer ‘‘yes, daily,’’ ‘‘yes, sometimes (less than one cigarette or equivalent per day),’’ ‘‘no, but I used to smoke daily,’’ ‘‘no, but I used to smoke sometimes (less than one cigarette or equivalent per day),’’ or ‘‘no, I have never smoked.’’ They were also asked for how many years they have smoked regularly, if they stopped, when, and finally how many cigarettes, cheroots, cigars or grams of pipe tobacco they smoked on average a day.
Patients Patients diagnosed with ECH or CCH were recruited from a register of present and former contacts at the Danish Headache Center. Additionally, a notice was posted in the newsletter and website of the Danish patient organization for cluster headache. Other headache clinics in Denmark were contacted and patients receiving treatment at these clinics were referred to the study in case of interest. Patients were included if they: were between 18 and 65 years old, had been diagnosed with ECH or CCH (International Classification of Headache Disorders, second edition (ICHD-II) criteria) and were able to tell CH attacks apart from other types of headache. Patients were excluded if they: had been diagnosed with another primary or secondary chronic headache
XML Template (2015) [7.1.2015–10:45am] //blrnas3.glyph.com/cenpro/ApplicationFiles/Journals/SAGE/3B2/CEPJ/Vol00000/140201/APPFile/SG-CEPJ140201.3d
(CEP)
[1–10] [PREPRINTER stage]
3
Barloese et al. (14 days/month) or did not speak and understand Danish. All patients’ diagnoses were verified by a headache specialist. Apart from the dichotomy of episodic/ chronic offered by existing diagnostic criteria, patients were characterized according to self-reported annual (months of the year during which clusters/bouts occur) and diurnal (hours of the day when individual attacks occur) attack patterns, whether sleep was a trigger and according to a CH index (described below).
Controls were recruited via notices posted on the Internet and in work places and sport clubs in the Capital Region of Denmark. Controls were matched for sex and age based on means. Controls were required to be between 18 and 65 years old and headache free (1 day of headache/month). They were excluded if they had severe symptoms of sleep disorders.
A CH index was calculated by the following equation: (attacks per day hours per attack) (days per cluster clusters per year) and is a measure of the area under the curve – the total time/year that the patient has CH. In this specific calculation, for CCH patients, number of clusters/year was set at one and cluster duration was set at 365 days. The motivation for calculating this index is to provide one number that reflects headache burden, as this is sometimes not completely clear, taking into consideration clusters, cluster duration, attacks and attack duration. Further, we wanted to characterize the patients beyond the dichotomy of episodic/chronic as some episodic patients in fact may experience far more headache than some chronic. Body mass index (BMI) was calculated from self-reported height and weight (BMI ¼ kg/m2). Tobacco pack-years was calculated as number of cigarettes (or equivalent) smoked daily/20 number of years smoking.
Statistical methods
Results
Analysis of variance (ANOVA) was used for comparison between more than two groups and Bonferroni corrections were applied in the analysis of PSQI. Chisquare test was used to calculate differences in gender composition, smoking status, MEQ groups, consumption of sleep medication and laterality. Wilcoxon rank sums were used for non-parametric data. Linear regression was used to describe the association between daylight hours for the months of the year and corresponding cluster occurrence as well as the ESS, CH index and PSQI. Two-sample t-test was used to compare means of two groups. A p value
