The molecular clock gene cryptochrome 1 (CRY1) and its role in cluster headache

Background Cluster headache is a severe primary headache disorder commonly featuring a strikingly distinct circadian attack pattern. Therefore, the circadian system has been suggested to play a crucial role in the pathophysiology of cluster headache. Cryptochromes are key components of the molecular clock generating circadian rhythms and have previously been shown to be associated with several psychiatric disorders, including seasonal affective disorder, bipolar disorder, and depression. Methods In this case-control study, we investigated the role of cryptochrome ( CRY) genes in cluster headache by screening 628 cluster headache patients and 681 controls from Sweden for four known genetic variants in the CRY1 (rs2287161 and rs8192440) and CRY2 (rs10838524 and rs1554338) genes. In addition, we analyzed CRY1 gene expression in primary fibroblast cell lines from eleven patients and ten controls. Results The exonic CRY1 variant rs8192440 was associated with cluster headache on allelic level ( p=0.02) and this association was even more pronounced in a subgroup of patients with reported diurnal rhythmicity of attacks ( p=0.002). We found a small significant difference in CRY1 gene expression between cluster headache patients and control individuals ( p=0.04), but we could not identify an effect of the associated variant rs8192440 on CRY1 expression. Conclusions We discovered a disease-associated variant in the CRY1 gene and slightly increased CRY1 gene expression in tissue from cluster headache patients, strengthening the hypothesis of circadian dysregulation in cluster headache. How this gene variant may contribute to the pathophysiology of the disease remains subject to further studies.

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‘A cry in the dark’: a qualitative exploration of living with cluster headache

British Journal of Pain ◽

10.1177/2049463720976695 ◽

2020 ◽

pp. 204946372097669

Author(s):

Laura Andre ◽

Debbie Cavers

Keyword(s):

Primary Care ◽

Cluster Headache ◽

Lived Experience ◽

Social Contact ◽

Primary Headache ◽

Headache Disorder ◽

Psychosocial Needs ◽

Structured Interviews ◽

The Impact ◽

Headache Patients

Context: Cluster headache is a rare primary headache disorder said to be one of the most painful conditions in existence. Limited evidence demonstrates cluster headache patients have difficulties securing a diagnosis and poor access to services. There is a gap in research around psychosocial needs, meaning there are no evidence-based guidelines to inform optimal management of this patient group in primary care. Objectives: The aim of this study is to explore the perspectives of cluster headache patients in the United Kingdom in order to suggest ways their care can be improved. Methods: It is an in-depth qualitative study involving telephone interviews with 15 participants with either chronic or episodic cluster headache. Semi-structured interviews (43–58 minutes) were conducted, recorded and transcribed verbatim. Two researchers conducted thematic analysis to identify themes. Results: Participants described the impact cluster headache has on their quality of life. They also felt the legitimacy of their disorder was questioned. This situation was often exacerbated by a reported lack of awareness among General Practitioners (GPs), which negatively impacted their care in terms of diagnosis and access to treatments and specialists. They attempted to control the pain through treatments and avoiding triggers, often with detrimental consequences for their social contact and mental health. Conclusion: Findings indicate the need to improve the lived experience of cluster headache patients in two key areas: (1) raising awareness of the disorder and its impact among GPs, and (2) extending care beyond clinical treatment provision, supporting patients in self-management and addressing its psychosocial impact, with implications for the management of this group in primary care.

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A genetic CLOCK variant associated with cluster headache causing increased mRNA levels

Cephalalgia ◽

10.1177/0333102417698709 ◽

2017 ◽

Vol 38 (3) ◽

pp. 496-502 ◽

Cited By ~ 19

Author(s):

Carmen Fourier ◽

Caroline Ran ◽

Margret Zinnegger ◽

Anne-Sofie Johansson ◽

Christina Sjöstrand ◽

...

Keyword(s):

Gene Expression ◽

Circadian Rhythm ◽

Cluster Headache ◽

Clock Gene ◽

Control Sample ◽

Mrna Levels ◽

Nucleotide Polymorphisms ◽

Primary Fibroblast ◽

Clock Gene Expression ◽

Diurnal Preference

Background Cluster headache is characterized by recurrent unilateral headache attacks of severe intensity. One of the main features in a majority of patients is a striking rhythmicity of attacks. The CLOCK ( Circadian Locomotor Output Cycles Kaput) gene encodes a transcription factor that serves as a basic driving force for circadian rhythm in humans and is therefore particularly interesting as a candidate gene for cluster headache. Methods We performed an association study on a large Swedish cluster headache case-control sample (449 patients and 677 controls) screening for three single nucleotide polymorphisms (SNPs) in the CLOCK gene implicated in diurnal preference (rs1801260) or sleep duration (rs11932595 and rs12649507), respectively. We further wanted to investigate the effect of identified associated SNPs on CLOCK gene expression. Results We found a significant association with rs12649507 and cluster headache ( p = 0.0069) and this data was strengthened when stratifying for reported diurnal rhythmicity of attacks ( p = 0.0009). We investigated the effect of rs12649507 on CLOCK gene expression in human primary fibroblast cultures and identified a significant increase in CLOCK mRNA expression ( p = 0.0232). Conclusions Our results strengthen the hypothesis of the involvement of circadian rhythm in cluster headache.

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Topiramate Versus Propranolol in the Prophylaxis of Migraine in Bangladeshi Population

Chattagram Maa-O-Shishu Hospital Medical College Journal ◽

10.3329/cmoshmcj.v18i2.47764 ◽

2020 ◽

Vol 18 (2) ◽

pp. 12-17

Author(s):

Muhammad Tayeb ◽

Md Hasanuzzaman ◽

Abul Mansur Md Rezaul Karim ◽

Mohammad Sanaullah ◽

Md Ashraful Islam

Keyword(s):

Migraine Attack ◽

Divided Dose ◽

Low Dose ◽

Primary Headache ◽

Headache Disorder ◽

Treatment Groups ◽

Primary Headache Disorder ◽

Significant Difference ◽

The Mean ◽

Bangladeshi Population

Background : Migraine is primary headache disorder characterized by recurring attacks of pain and associated symptoms. The management modality is still unsatisfactory due to poor understanding of its cause and pathogenesis. To assess the efficacy and safety of low dose Topiramate vs Propranolol in migraine prophylaxis. Materials and methods : A randomized clinical trial including 130 patients with frequent migraine headache >5 attacks per month was performed in the out patients Department of Medicine and Neurology, CMCH for a period of 12 weeks. The patients were randomly divided into two treatment groups – treated by Topiramate 50mg/day and Propranolol 80mg/day respectively. Topiramate started with 25mg/day for 7 days then increased up to 50mg/day in two divided dose. Propranolol started with 40mg/day for 7 days then increased up to 80mg/day in two divided dose. The patients were assessed at 0, 8 and 12 weeks of the study. Results: The Topiramate group showed a reduction in the mean (±SD) of frequency of migraine attack from 6.95(±2.88) to 1.75(±1.08) episode per month, headache days per month from 7.62(±4.14) to 1.83(±1.10), intensity of headache per attack from 8.98(±1.05) to 6.10(±2.50) based on VAS scale, duration of headache per episode from 11.56(±9.16) to 5.40(±2.97) per hour and MIDAS score from 16.19(±3.91) to 8.14(±3.93). In patient treated with Propranolol, the mean (±SD) of monthly frequency of migraine attack declined from 7.09(±2.87) to 1.92(±0.98) episode per month, headache days per month from 8.17(±4.52) to 1.86(±o.83), intensity of headache per attack from 8.47(±1.10) to 6.03(±2.05) based on VAS scale, duration of headache per episode from 11.16(±8.08) to 5.97(±3.45), MIDAS score from 15.48(±3.55) to7.77(±3.49). Pre- and post-treatment values were significantly different for individual groups but no significant difference observed between groups. Conclusion: This study demonstrated that both low dose Topiramate and propranolol could significantly reduce migraine frequency, intensity and duration. Chatt Maa Shi Hosp Med Coll J; Vol.18 (2); July 2019; Page 12-17

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Genetics of cluster headache

Cephalalgia ◽

10.1177/0333102418815503 ◽

2019 ◽

Vol 39 (10) ◽

pp. 1298-1312 ◽

Cited By ~ 8

Author(s):

Kate F Gibson ◽

Anita Dos Santos ◽

Nunu Lund ◽

Rigmor Jensen ◽

Ioannis M Stylianou

Keyword(s):

Cluster Headache ◽

Candidate Gene ◽

Gene Selection ◽

Association Studies ◽

Twin Studies ◽

Primary Headache ◽

Headache Disorder ◽

Genome Wide Association Studies ◽

Genetic Studies ◽

Primary Headache Disorder

Background Cluster headache is the most severe primary headache disorder. A genetic basis has long been suggested by family and twin studies; however, little is understood about the genetic variants that contribute to cluster headache susceptibility. Methods We conducted a literature search of the MEDLINE database using the PubMed search engine to identify all human genetic studies for cluster headache. In this article we provide a review of those genetic studies, along with an overview of the pathophysiology of cluster headache and a brief review of migraine genetics, which have both been significant drivers of cluster headache candidate gene selection. Results The investigation of cluster headache genetic etiology has been dominated by candidate gene studies. Candidate selection has largely been driven by the pathophysiology, such as the striking rhythmic nature of the attacks, which spurred close examination of the circadian rhythm genes CLOCK and HCRTR2. More recently, unbiased genetic approaches such as genome-wide association studies (GWAS) have yielded new genetic avenues of interest including ADCYAP1R1 and MME. Conclusions The majority of candidate genes studied for cluster headache suffer from poor reproducibility. Broader genetic interrogation through larger unbiased GWAS, exome, and whole genome studies may provide more robust candidates, and in turn provide a clearer understanding of the causes of cluster headache.

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Headache

10.1093/med/9780199658602.003.0003 ◽

2015 ◽

Cited By ~ 1

Author(s):

Peter J. Goadsby

Keyword(s):

Cluster Headache ◽

Severe Pain ◽

Primary Headache ◽

Headache Disorder ◽

Headache Disorders ◽

Important Work ◽

Pain Experience ◽

Global Impact ◽

Primary Headache Disorder ◽

The World

Headache disorders are the dominant cause of neurological disability in the world and the most common reason for neurological referral in any country studied. Yet for much of the first half the twentieth century, research was mired in peripheral mechanistic sideshows. Migraine, the most common disabling primary headache disorder, has been established as primarily a brain problem, with important advances in classification, treatment, and biological understanding. Cluster headache, perhaps the most severe pain experience of humans, has found its nidus in the diencephalon; treatments are evolving and biology being unravelled. Contributions to headache disorders resonate across humanity, so important work here has a global impact for good.

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Abnormal tyrosine metabolism in chronic cluster headache

Cephalalgia ◽

10.1177/0333102416640502 ◽

2016 ◽

Vol 37 (2) ◽

pp. 148-153 ◽

Cited By ~ 14

Author(s):

Giovanni D’Andrea ◽

Massimo Leone ◽

Gennaro Bussone ◽

Paola Di Fiore ◽

Andrea Bolner ◽

...

Keyword(s):

Cluster Headache ◽

Plasma Levels ◽

Primary Headache ◽

Chronic Cluster Headache ◽

Predisposing Factor ◽

Episodic Cluster Headache ◽

Tyrosine Metabolism ◽

Low Levels ◽

And Control ◽

Headache Patients

Objective Episodic cluster headache is characterized by abnormalities in tyrosine metabolism (i.e. elevated levels of dopamine, tyramine, octopamine and synephrine and low levels of noradrenalin in plasma and platelets.) It is unknown, however, if such biochemical anomalies are present and/or constitute a predisposing factor in chronic cluster headache. To test this hypothesis, we measured the levels of dopamine and noradrenaline together with those of elusive amines, such as tyramine, octopamine and synephrine, in plasma of chronic cluster patients and control individuals. Methods Plasma levels of dopamine, noradrenaline and trace amines, including tyramine, octopamine and synephrine, were measured in a group of 23 chronic cluster headache patients (10 chronic cluster ab initio and 13 transformed from episodic cluster), and 16 control participants. Results The plasma levels of dopamine, noradrenaline and tyramine were several times higher in chronic cluster headache patients compared with controls. The levels of octopamine and synephrine were significantly lower in plasma of these patients with respect to control individuals. Conclusions These results suggest that anomalies in tyrosine metabolism play a role in the pathogenesis of chronic cluster headache and constitute a predisposing factor for the transformation of the episodic into a chronic form of this primary headache.

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Update on Treatment of Cluster Headache

Journal of the Korean Neurological Association ◽

10.17340/jkna.2021.3.1 ◽

2021 ◽

Vol 39 (3) ◽

pp. 113-120

Author(s):

Jong-Hee Sohn ◽

Mi Ji Lee ◽

Soo-Jin Cho

Keyword(s):

Cluster Headache ◽

Preventive Treatment ◽

Primary Headache ◽

Headache Disorder ◽

Preventive Therapy ◽

Systemic Steroid ◽

Novel Treatments ◽

Primary Headache Disorder ◽

Cranial Autonomic Symptoms ◽

High Flow Oxygen

Cluster headache (CH) is characterized by severe unilateral short-lasting headache attacks, accompanying ipsilateral cranial autonomic symptoms or the sense of restlessness and agitation, or both. CH is a highly disabling primary headache disorder but often not optimally treated. High-flow oxygen and parenteral triptans are the most effective treatment to treat an acute CH attack. Transitional treatments include systemic steroid therapy and sub-occipital steroid injection. For preventive therapy, verapamil and lithium are recommended as first-line treatments. Novel treatments have appeared, such as neuromodulation and medication targeting calcitonin gene-related peptide (CGRP) or its receptor. Galcanezumab, the only anti-CGRP receptor monoclonal antibody with proven efficacy for the preventive treatment of episodic CH, represents an important advance for pharmacological treatment of CH. Neuromodulation strategies, such as the non-invasive vagus nerve stimulation and the sphenopalatine ganglion stimulation, have been proven effective in reducing the intensity and frequency of attacks, and also to be safe and well tolerated.

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CACNA1A Gene Polymorphisms in Cluster Headache

Cephalalgia ◽

10.1046/j.1468-2982.2001.00281.x ◽

2001 ◽

Vol 21 (10) ◽

pp. 953-958 ◽

Cited By ~ 30

Author(s):

C Sjöstrand ◽

V Giedratis ◽

K Ekbom ◽

E Waldenlind ◽

J Hillert

Keyword(s):

Cluster Headache ◽

Primary Headache ◽

Headache Disorder ◽

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Promising Candidate ◽

Primary Headache Disorder ◽

Increased Risk ◽

Ihs Criteria ◽

Cacna1a Gene

Cluster headache (CH) is a primary headache disorder where the aetiological and pathophysiological mechanisms still are largely unknown. An increased risk of CH in first- and second-degree relatives suggests the importance of genetic factors. Mutations of the P/Q type calcium channel alpha 1 subunit (CACNA1A) gene on chromosome 19p13 have been shown to cause several neurological disorders with a wide clinical spectrum, mainly episodic diseases. Missence mutations of the gene cause familial hemiplegic migraine (FHM) and it is also likely to be involved in the more common forms of migraine. The CACNA1A gene is thus a promising candidate gene for CH. In this study we performed an association analysis of an intragenic polymorphic (CA)n-repeat with marker D19S1150 and a (CAG)n-repeat in the 3′UTR region, in 75 patients with CH according to IHS criteria and 108 matched controls. Genotypes and allele frequencies were similarly distributed in patients and controls. Linkage disequilibrium between the two markers was similar in patients and controls. We conclude that an importance of the CACNA1A gene in sporadic CH is unlikely.

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Association between Body Mass Index and Migraine: A Survey of Adult Population in China

Behavioural Neurology ◽

10.1155/2018/6585734 ◽

2018 ◽

Vol 2018 ◽

pp. 1-6 ◽

Cited By ~ 4

Author(s):

Qingqing Huang ◽

Xiping Liang ◽

Shiqiang Wang ◽

Xiaosong Mu

Keyword(s):

Body Mass Index ◽

Chronic Migraine ◽

Body Mass ◽

Adult Population ◽

Primary Headache ◽

Control Group ◽

Morbidly Obese ◽

Significant Difference ◽

Headache Onset ◽

Headache Patients

Both migraine and obesity are prevalent disorders in the general population, which are characterized by disability and impaired quality of life. Although so many researches had studied the association between migraine and obesity, there are still no full knowledge of the relationship between body mass index (BMI) and migraine, especially chronic migraine (CM). In this study, we analyzed a previous epidemiological survey data of primary headache patients in Chongqing, which surveyed consecutive neurological outpatients through face-to-face interview with physicians using a headache questionnaire. 166 episodic migraine (EM) patients and 134 chronic migraine (CM) patients were included in the study out of 1327 primary headache patients. And 200 healthy adults from the physical examination center were included as a control group. Finally, we found that the patients with migraine (EM and CM) were more likely to be overweight, obese, or morbidly obese compared to those in the healthy group. Significant difference was found between BMI and frequency of migraine attacks but not severity or duration of headache onset. And no significant difference was found in severity and duration of headache onset between episodic and chronic migraine among different BMI classifications. Such may update our knowledge about the clinical features of migraine and BMI, revealing that the frequency of attacks may be associated with being overweight, obese, or morbidly obese in patients with migraine and that the extent of being overweight, obese, or morbidly obese in CM patients was lower than that in EM patients.

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Hypofunctionality of Gi Proteins as Aetiopathogenic Mechanism for Migraine and Cluster Headache

Cephalalgia ◽

10.1046/j.1468-2982.2001.00142.x ◽

2001 ◽

Vol 21 (1) ◽

pp. 38-45 ◽

Cited By ~ 22

Author(s):

N Galeotti ◽

C Ghelardini ◽

M Zoppi ◽

E Del Bene ◽

L Raimondi ◽

...

Keyword(s):

Cluster Headache ◽

Pain Perception ◽

Primary Headache ◽

Adenylyl Cyclase Activity ◽

Protein Levels ◽

Gi Protein ◽

Camp Levels ◽

Reduced Activity ◽

Gi Proteins ◽

Headache Patients

The involvement of Gi proteins in the modulation of pain perception has been widely established, and mutations in G-proteins have already been identified as the aetiopathological cause of human diseases. The aim of the present study was to determine whether a deficiency or a hypofunctionality of the Gi proteins occurred in primary headache. The functionality and the level of expression of Gi proteins were investigated in lymphocytes from migraine without aura, migraine with aura and cluster headache sufferers. A reduced capability to inhibit forskolin-stimulated adenylyl cyclase activity in headache patients was observed. Migraine patients also showed basal adenosine cAMP levels about four times higher than controls. The reduced activity of Gi proteins seems not to be related to a reduction of protein levels since no significant reduction of the Giα subunits was observed. These results indicate Gi protein hypofunctionality as an aetiopathogenic mechanism in migraine and cluster headache.

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