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Cephalalgia : An International Journal... Aug 2023The management of cluster headache is similar to that of other primary headache disorders and can be broadly divided into acute and preventive treatments. Acute... (Review)
Review
BACKGROUND
The management of cluster headache is similar to that of other primary headache disorders and can be broadly divided into acute and preventive treatments. Acute treatments for cluster headache are primarily delivered via rapid, non-oral routes (such as inhalation, nasal, or subcutaneous) while preventives include a variety of unrelated treatments such as corticosteroids, verapamil, and galcanezumab. Neuromodulation is becoming an increasingly popular option, both non-invasively such as vagus nerve stimulation when medical treatment is contraindicated or side effects are intolerable, and invasively such as occipital nerve stimulation when medical treatment is ineffective. Clinically, this collection of treatment types provides a range of options for the informed clinician. Scientifically, this collection provides important insights into disease mechanisms.
METHODS
Two authors performed independent narrative reviews of the literature on guideline recommendations, clinical trials, real-world data, and mechanistic studies.
RESULTS
Cluster headache is treated with acute treatments, bridge treatments, and preventive treatments. Common first-line treatments include subcutaneous sumatriptan and high-flow oxygen as acute treatments, corticosteroids (oral or suboccipital injections) as bridge treatments, and verapamil as a preventive treatment. Some newer acute (non-invasive vagus nerve stimulation) and preventive (galcanezumab) treatments have excellent clinical trial data for episodic cluster headache, while other newer treatments (occipital nerve stimulation) have been specifically tested in treatment-refractory chronic cluster headache. Most treatments are suspected to act on the trigeminovascular system, the autonomic system, or the hypothalamus.
CONCLUSIONS
The first-line treatments have not changed in recent years, but new treatments have provided additional options for patients.
Topics: Humans; Cluster Headache; Oxygen; Sumatriptan; Autonomic Nervous System; Drug-Related Side Effects and Adverse Reactions
PubMed: 37652457
DOI: 10.1177/03331024231196808 -
Drugs Jan 2022Cluster headache belongs to the group of trigeminal autonomic headaches. This review summarizes drug therapy of cluster attacks and prophylactic treatment.... (Review)
Review
Cluster headache belongs to the group of trigeminal autonomic headaches. This review summarizes drug therapy of cluster attacks and prophylactic treatment. Neurostimulation methods are not addressed. The therapy for acute cluster attacks includes inhalation of 100% oxygen, subcutaneous administration of sumatriptan, and intranasal application of sumatriptan or zolmitriptan. Bridging therapy, which is used until oral prophylactic therapy is effective, is performed either with oral prednisolone or with a pharmacological block of the major occipital nerves. Best documented drugs for preventive treatment of cluster headache are verapamil and lithium, and possibly effective drugs are gabapentin, topiramate, divalproex sodium, and melatonin. The efficacy of monoclonal antibodies to the calcitonin gene-related peptide so far has been only demonstrated for episodic cluster headache. Several drug therapies are being investigated including ketamine, onabotulinumtoxinA, lysergic acid, and sodium oxybate.
Topics: Cluster Headache; Drug Administration Routes; Humans; Lithium; Oxazolidinones; Oxygen Inhalation Therapy; Prednisolone; Serotonin 5-HT1 Receptor Agonists; Sumatriptan; Tryptamines; Verapamil
PubMed: 34919214
DOI: 10.1007/s40265-021-01658-z -
Neurology India 2021Cluster headache is a highly disabling primary headache disorder which is widely described as the most painful condition a human can experience. (Review)
Review
BACKGROUND
Cluster headache is a highly disabling primary headache disorder which is widely described as the most painful condition a human can experience.
AIM
To provide an overview of the clinical characteristics, epidemiology, risk factors, differential diagnosis, pathophysiology and treatment options of cluster headache, with a focus on recent developments in the field.
METHODS
Structured review of the literature on cluster headache.
RESULTS
Cluster headache affects approximately one in 1000 of the population. It is characterised by attacks of severe unilateral head pain associated with ipsilateral cranial autonomic symptoms, and the tendency for attacks to occur with circadian and circannual periodicity. The pathophysiology of cluster headache and other primary headache disorders has recently become better understood and is thought to involve the hypothalamus and trigeminovascular system. There is good quality evidence for acute treatment of attacks with parenteral triptans and high flow oxygen; preventive treatment with verapamil; and transitional treatment with oral corticosteroids or greater occipital nerve injection. New pharmacological and neuromodulation therapies have recently been developed.
CONCLUSION
Cluster headache causes distinctive symptoms, which once they are recognised can usually be managed with a variety of established treatments. Recent pathophysiological understanding has led to the development of newer pharmacological and neuromodulation therapies, which may soon become established in clinical practice.
Topics: Cluster Headache; Headache; Humans; Hypothalamus; Oxygen; Verapamil
PubMed: 34003158
DOI: 10.4103/0028-3886.315983 -
The Journal of Headache and Pain Apr 2023The glutamatergic neurotransmission has important role in the pathomechanism of primary headache disorders. The kynurenine metabolites derived from catabolism of...
BACKGROUND
The glutamatergic neurotransmission has important role in the pathomechanism of primary headache disorders. The kynurenine metabolites derived from catabolism of tryptophan (Trp) have significant involvement not only in glutamatergic processes, but also in the neuroinflammation, the oxidative stress and the mitochondrial dysfunctions. Previously we identified a depressed peripheral Trp metabolism in interictal period of episodic migraineurs, which prompted us to examine this pathway in patients with episodic cluster headache (CH) as well. Our aims were to compare the concentrations of compounds both in headache-free and attack periods, and to find correlations between Trp metabolism and the clinical features of CH. Levels of 11 molecules were determined in peripheral blood plasma of healthy controls (n = 22) and interbout/ictal periods of CH patients (n = 24) by neurochemical measurements.
FINDINGS
Significantly decreased L-kynurenine (KYN, p < 0.01), while increased quinolinic acid (QUINA, p < 0.005) plasma concentrations were detected in the interbout period of CH patients compared to healthy subjects. The levels of KYN are further reduced during the ictal period compared to the controls (p < 0.006). There was a moderate, negative correlation between disease duration and interbout QUINA levels (p < 0.048, R = - 0.459); and between the total number of CH attacks experienced during the lifetime of patients and the interbout KYN concentrations (p < 0.024, R = - 0.516). Linear regression models revealed negative associations between age and levels of Trp, kynurenic acid, 3-hdyroxyanthranilic acid and QUINA in healthy control subjects, as well as between age and ictal level of anthranilic acid.
CONCLUSIONS
Our results refer to a specifically altered Trp metabolism in CH patients. The onset of metabolic imbalance can be attributed to the interbout period, where the decreased KYN level is unable to perform its protective functions, while the concentration of QUINA, as a toxic compound, increases. These processes can trigger CH attacks, which may be associated with glutamate excess induced neurotoxicity, neuroinflammation and oxidative stress. Further studies are needed to elucidate the exact functions of these molecular alterations that can contribute to identify new, potential biomarkers in the therapy of CH.
Topics: Humans; Kynurenine; Cluster Headache; Neuroinflammatory Diseases; Tryptophan; Kynurenic Acid
PubMed: 37016290
DOI: 10.1186/s10194-023-01570-9 -
American Family Physician Jan 2022
Topics: Adult; Alcohol Drinking; Cluster Headache; Female; Humans; Male; Nitroglycerin; Oxygen; Pain; Physical Examination; Rhinorrhea; Tobacco Smoking; Young Adult
PubMed: 35029959
DOI: No ID Found -
Annals of Neurology Oct 2023The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
The objective of this study was to aggregate data for the first genomewide association study meta-analysis of cluster headache, to identify genetic risk variants, and gain biological insights.
METHODS
A total of 4,777 cases (3,348 men and 1,429 women) with clinically diagnosed cluster headache were recruited from 10 European and 1 East Asian cohorts. We first performed an inverse-variance genomewide association meta-analysis of 4,043 cases and 21,729 controls of European ancestry. In a secondary trans-ancestry meta-analysis, we included 734 cases and 9,846 controls of East Asian ancestry. Candidate causal genes were prioritized by 5 complementary methods: expression quantitative trait loci, transcriptome-wide association, fine-mapping of causal gene sets, genetically driven DNA methylation, and effects on protein structure. Gene set and tissue enrichment analyses, genetic correlation, genetic risk score analysis, and Mendelian randomization were part of the downstream analyses.
RESULTS
The estimated single nucleotide polymorphism (SNP)-based heritability of cluster headache was 14.5%. We identified 9 independent signals in 7 genomewide significant loci in the primary meta-analysis, and one additional locus in the trans-ethnic meta-analysis. Five of the loci were previously known. The 20 genes prioritized as potentially causal for cluster headache showed enrichment to artery and brain tissue. Cluster headache was genetically correlated with cigarette smoking, risk-taking behavior, attention deficit hyperactivity disorder (ADHD), depression, and musculoskeletal pain. Mendelian randomization analysis indicated a causal effect of cigarette smoking intensity on cluster headache. Three of the identified loci were shared with migraine.
INTERPRETATION
This first genomewide association study meta-analysis gives clues to the biological basis of cluster headache and indicates that smoking is a causal risk factor. ANN NEUROL 2023;94:713-726.
Topics: Male; Humans; Female; Cluster Headache; Risk Factors; Genome-Wide Association Study; Migraine Disorders; Smoking; Polymorphism, Single Nucleotide; Genetic Predisposition to Disease
PubMed: 37486023
DOI: 10.1002/ana.26743 -
Neurology May 2023Cluster headache and migraine have circadian features at multiple levels (cellular, systems, and behavioral). A thorough understanding of their circadian features... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND OBJECTIVES
Cluster headache and migraine have circadian features at multiple levels (cellular, systems, and behavioral). A thorough understanding of their circadian features informs their pathophysiologies.
METHODS
A librarian created search criteria in MEDLINE Ovid, Embase, PsycINFO, Web of Science, and Cochrane Library. Two physicians independently performed the remainder of the systematic review/meta-analysis using Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines. Separate from the systematic review/meta-analysis, we performed a genetic analysis for genes with a circadian pattern of expression (clock-controlled genes or CCGs) by cross-referencing genome-wide association studies (GWASs) of headache, a nonhuman primate study of CCGs in a variety of tissues, and recent reviews of brain areas relevant in headache disorders. Altogether, this allowed us to catalog circadian features at the behavioral level (circadian timing, time of day, time of year, and chronotype), systems level (relevant brain areas where CCGs are active, melatonin and corticosteroid levels), and cellular level (core circadian genes and CCGs).
RESULTS
For the systematic review and meta-analysis, 1,513 studies were found, and 72 met the inclusion criteria; for the genetic analysis, we found 16 GWASs, 1 nonhuman primate study, and 16 imaging reviews. For cluster headache behavior, meta-analyses showed a circadian pattern of attacks in 70.5% (3,490/4,953) of participants across 16 studies, with a clear circadian peak between 21:00 and 03:00 and circannual peaks in spring and autumn. Chronotype was highly variable across studies. At the systems level, lower melatonin and higher cortisol levels were reported in cluster headache participants. At the cellular level, cluster headache was associated with core circadian genes and , and 5 of the 9 cluster headache susceptibility genes were CCGs. For migraine behavior, meta-analyses showed a circadian pattern of attacks in 50.1% (2,698/5,385) of participants across 8 studies, with a clear circadian trough between 23:00 and 07:00 and a broad circannual peak between April and October. Chronotype was highly variable across studies. At the systems level, urinary melatonin levels were lower in participants with migraine and even lower during an attack. At the cellular level, migraine was associated with core circadian genes and , and 110 of the 168 migraine susceptibility genes were CCGs.
DISCUSSION
Cluster headache and migraine are highly circadian at multiple levels, reinforcing the importance of the hypothalamus. This review provides a pathophysiologic foundation for circadian-targeted research into these disorders.
TRIAL REGISTRATION INFORMATION
The study was registered with PROSPERO (registration number CRD42021234238).
Topics: Animals; Cluster Headache; Melatonin; Genome-Wide Association Study; Migraine Disorders; Primates
PubMed: 36990725
DOI: 10.1212/WNL.0000000000207240 -
Cephalalgia : An International Journal... Oct 2023Cluster headache displays uniquely rhythmic patterns in its attack manifestation. This strong chronobiological influence suggests that part of the pathophysiology of... (Review)
Review
BACKGROUND/HYPOTHESIS
Cluster headache displays uniquely rhythmic patterns in its attack manifestation. This strong chronobiological influence suggests that part of the pathophysiology of cluster headache is distinctly different from migraine and has prompted genetic investigations probing these systems.
METHODS
This is a narrative overview of the cluster headache chronobiological phenotype from the point of view of genetics covering existing knowledge, highlighting the specific challenges in cluster headache and suggesting novel research approaches to overcome these.
RESULTS
The chronobiological features of cluster headache are a hallmark of the disorder and while discrepancies between study results do exist, the main findings are highly reproducible across populations and time. Particular findings in subgroups indicate that the heritability of the disorder is linked to chronobiological systems. Meanwhile, genetic markers of circadian rhythm genes have been implicated in cluster headache, but with conflicting results. However, in two recently published genome wide association studies two of the identified four loci include genes with an involvement in circadian rhythm, MER proto-oncogene, tyrosine kinase and four and a half LIM domains 5. These findings strengthen the involvement of circadian rhythm in cluster headache pathophysiology.
CONCLUSION/INTERPRETATION
Studying chronobiology and genetics in cluster headache presents challenges unique to the disorder. Researchers are overcoming these challenges by pooling various data from different cohorts and performing meta-analyses providing novel insights into a classically enigmatic disorder. Further progress can likely be made by combining deep pheno- and genotyping.
Topics: Humans; Cluster Headache; Genome-Wide Association Study; Circadian Rhythm; Phenotype; Migraine Disorders
PubMed: 37851671
DOI: 10.1177/03331024231208126 -
American Family Physician Jul 2013Cluster headache causes severe unilateral temporal or periorbital pain, lasting 15 to 180 minutes and accompanied by autonomic symptoms in the nose, eyes, and face.... (Review)
Review
Cluster headache causes severe unilateral temporal or periorbital pain, lasting 15 to 180 minutes and accompanied by autonomic symptoms in the nose, eyes, and face. Headaches often recur at the same time each day during the cluster period, which can last for weeks to months. Some patients have chronic cluster headache without remission periods. The pathophysiology of cluster headache is not fully understood, but may include a genetic component. Cluster headache is more prevalent in men and typically begins between 20 and 40 years of age. Treatment focuses on avoiding triggers and includes abortive therapies, prophylaxis during the cluster period, and long-term treatment in patients with chronic cluster headache. Evidence supports the use of supplemental oxygen, sumatriptan, and zolmitriptan for acute treatment of episodic cluster headache. Verapamil is first-line prophylactic therapy and can also be used to treat chronic cluster headache. More invasive treatments, including nerve stimulation and surgery, may be helpful in refractory cases.
Topics: Adult; Chronic Disease; Cluster Headache; Diagnosis, Differential; Female; Humans; Male; Young Adult
PubMed: 23939643
DOI: No ID Found -
The Journal of Headache and Pain Nov 2022Cluster headache and migraine are regarded as distinct primary headaches. While cluster headache and migraine differ in multiple aspects such as gender-related and... (Review)
Review
Cluster headache and migraine are regarded as distinct primary headaches. While cluster headache and migraine differ in multiple aspects such as gender-related and headache specific features (e.g., attack duration and frequency), both show clinical similarities in trigger factors (e.g., alcohol) and treatment response (e.g., triptans). Here, we review the similarities and differences in anatomy and pathophysiology that underlie cluster headache and migraine, discuss whether cluster headache and migraine should indeed be considered as two distinct primary headaches, and propose recommendations for future studies. Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at https://www.youtube.com/watch?v=uUimmnDVTTE .
Topics: Humans; Cluster Headache; Headache Disorders; Headache; Migraine Disorders; Tryptamines
PubMed: 36447146
DOI: 10.1186/s10194-022-01504-x