Compensated Hypogonadism Identified in Males with Cluster Headache: A Prospective Case-Controlled Study.

OBJECTIVE: Androgens have been hypothesized to be involved in the pathophysiology of cluster headache due to the male predominance, but whether androgens are altered in patients with cluster headache remains unclear. METHODS: We performed a prospective, case-controlled study in adult males with cluster headache. Sera were measured for hormones including testosterone, luteinizing hormone (LH), and sex hormone-binding globulin in 60 participants with episodic cluster headache (during a bout and in remission), 60 participants with chronic cluster headache, and 60 age- and sex-matched healthy controls. Free testosterone (fT) was calculated according to the Vermeulen equation. Shared genetic risk variants were assessed between cluster headache and testosterone concentrations. RESULTS: The mean fT/LH ratio was reduced by 35% (95% confidence interval [CI]: 21%-47%, p < 0.0001) in patients with chronic cluster headache and by 24% (95% CI: 9%-37%, p = 0.004) in patients with episodic cluster headache compared to controls after adjusting for age, sleep duration, and use of acute medication. Androgen concentrations did not differ between bouts and remissions. Furthermore, a shared genetic risk allele, rs112572874 (located in the intron of the microtubule associated protein tau (MAPT) gene on chromosome 17), between fT and cluster headache was identified. INTERPRETATION: Our results demonstrate that the male endocrine system is altered in patients with cluster headache to a state of compensated hypogonadism, and this is not an epiphenomenon associated with sleep or the use of acute medication. Together with the identified shared genetic risk allele, this may suggest a pathophysiological link between cluster headache and fT. ANN NEUROL 2024;95:1149-1161.

Cluster Headache Genomewide Association Study and Meta-Analysis Identifies Eight Loci and Implicates Smoking as Causal Risk Factor.

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.

Biomarkers in cluster headache: A systematic review.

OBJECTIVE: To systematically investigate previously examined biomarkers in blood, urine, cerebrospinal fluid, tear fluid, and saliva of patients with cluster headache. BACKGROUND: Cluster headache is a condition with extensive clinical challenges in terms of diagnosis and treatment. Identification of a biomarker with diagnostic implications or as a potential treatment target is highly warranted. METHODS: We conducted a systematic review including peer reviewed full text of studies that measured biochemical compounds in either blood, urine, cerebrospinal fluid, tear fluid, or saliva of patients with cluster headache diagnosed after the implementation of the International Classification of Headache Disorders (1988) written in English, Danish, Swedish, or Norwegian. Inclusion required a minimum of five participants. The search was conducted in PubMed and EMBASE, in September 2022, and extracted data were screened by two authors. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines for reporting systematic reviews were followed. The Newcastle-Ottawa Scale was used to assess the risk of bias in case-controlled studies. RESULTS: We included 40 studies involving 832 patients with cluster headache and 872 controls, evaluating 80 potential biomarkers. The risk of bias for case-controlled studies was a median of 6 (range: 3-8) and 20 studies out of 40 (50%) were of fair or good quality. Most studies were identified within three groups: hypothalamic-regulated hormones, inflammatory markers, and neuropeptides. Among the hypothalamic hormones, cortisol was the most frequently investigated (N = 7) and was elevated in cluster headache in most of the studies. The most frequently examined inflammatory marker was interleukin 1 (N = 3), but findings were divergent. Calcitonin gene-related peptide was the most investigated neuropeptide (N = 9) and all studies found increased levels during attacks. CONCLUSION: Biomarker findings have been inconsistent and widely non-specific for cluster headache, which explains why none of the previous studies succeeded in identifying a unique biomarker for cluster headache, but instead contributed to substantiating the underlying pathophysiologic mechanisms. Several of the examined biomarkers could hold promise as markers for disease activity but are unfit for a clear distinction from both controls and other headaches.

Intranasal ketamine for acute cluster headache attacks-Results from a proof-of-concept open-label trial.

OBJECTIVE: To investigate the safety and efficacy of intranasal ketamine for the treatment of a single cluster headache (CH) attack. BACKGROUND: Acute treatment options for patients with CH who have an insufficient response to oxygen and triptans are limited. Intranasal ketamine has anecdotally been successful in treating a CH attack. METHODS: We conducted an open-label pilot study enrolling 23 patients with chronic CH (International Classification of Headache Disorders, 3rd edition), and of these, 20 patients treated a single CH attack with intranasal ketamine. Under in-hospital observation, patients received 15 mg of intranasal ketamine every 6 min a maximum of five times. The primary endpoint was a 50% reduction in pain intensity within 15 min after initiating treatment. RESULTS: The primary endpoint was not met; 15 min after the first ketamine administration, the mean reduction in pain intensity was 1.1 (95% confidence interval [CI]: -0.6 to 2.7, p = 0.188) on the numeric rating scale (NRS), equivalent to a 15% reduction in pain intensity. However, 30 min after the first application, the pain intensity was reduced by 59% on an 11-point NRS (mean difference: 4.3, 95% CI: 2.4-6.2, p < 0.001, N = 16) and 11 out of 16 (69%) scored 4 or below on the NRS. Four patients received rescue medication 15 min after the first ketamine application and were therefore excluded from the analysis at 30 min. Half of the patients preferred ketamine to oxygen and/or sumatriptan injection. No serious adverse events were identified during the trial. CONCLUSION: Intranasal ketamine may be an effective acute treatment for CH at 30 min but should be tested in a larger controlled design. Patients and physicians should be conscious of the abuse potential of ketamine.

Diagnostic delay of cluster headache: A cohort study from the Danish Cluster Headache Survey.

AIM: To investigate the influence of clinical and demographic features on diagnostic delay in cluster headache patients, in order to discuss diagnostic pitfalls and raise disease awareness. METHODS: A large, well-characterized cohort of 400 validated cluster headache patients from the Danish Cluster Headache Survey, diagnosed according to ICHD-II, were investigated. ANOVA was applied to investigate differences in diagnostic delay between groups. Selected independent variables were assessed in relation to diagnostic delay using a gamma regression model. RESULTS: Diagnostic delay was significantly reduced for each decade of cluster headache onset from 1950-2010 (p < 0.001). Onset after 1990 was associated with shorter diagnostic delay (OR = 0.28, p < 0.001), whereas attack duration > 180 minutes (OR = 1.62, p < 0.034), migraine-like features (OR = 1.30, p < 0.043) and nocturnal attacks (OR = 1.39, p < 0.021) were associated with prolonged diagnostic delay. Further, diagnostic delay decreased with age of onset (age < 20: 13.8 years, age 20-40: 5.4 years and age > 40: 2.1 years, p < 0.001). CONCLUSION: Diagnostic delay was reduced for every decade investigated, whereas some atypical cluster headache features were associated with prolonged diagnostic delay. Better medical education and more disease awareness are needed to prevent misdiagnosis and prolonged diagnostic delay.

Episodic and Chronic Cluster Headache: Differences in Family History, Traumatic Head Injury, and Chronorisk.

OBJECTIVE AND BACKGROUND: The diagnostic criteria of episodic and chronic cluster headache (cCH) were recently modified, yet pathophysiological differences between the two are still unclear. The aim of this cross-sectional study is to identify and characterize other differences between episodic and cCH. METHODS: Data from a retrospective, questionnaire- and interview-based study were analyzed with a focus on associated factors including traumatic head injury (THI), familial history, and change of phenotype. Attack patterns were analyzed using Gaussian and spectral modeling. RESULTS: 400 patients and 200 controls participated. A positive family history was more prevalent in chronic than episodic cluster headache (eCH) (34/146 (23%) vs 33/253 (13%), respectively, P = .008). A history of THI was more common in patients than controls (173/400 (43%) vs 51/200 (26%), respectively, P < .0001) and in chronic compared to eCH (77/146 (53%) vs 96/253 (37%), respectively, P = .004). Patients with a positive family history had a unique diurnal attack pattern with twice the risk of nocturnal attacks as patients who did not report family history. Patients reporting phenotype change had a chronobiological fingerprint similar to the phenotype they had experienced a transition into. A higher attack frequency in chronic patients was the only difference in symptom manifestation across all analyzed subgroups of patients. CONCLUSIONS: cCH is associated with a positive family history and THI. In familial CH, a peak in nocturnal chronorisk may implicate genes involved in diurnal-, sleep- and homeostatic regulation. The stereotypical nature of the CH attacks themselves is confirmed and differences between subgroups should be sought in other characteristics.

Verapamil and Cluster Headache: Still a Mystery. A Narrative Review of Efficacy, Mechanisms and Perspectives.

OBJECTIVE: A evaluation of the effect of verapamil and other calcium channel blockers in cluster headache (CH) treatment and an investigation of possible effect mechanisms. BACKGROUND: Verapamil has been used in the prevention of CH for almost 3 decades, however, the mode of action and therapeutic target is still unknown. METHODS: A Pubmed search was conducted: "Verapamil"[Mesh] and "Cluster Headache"[Mesh]. We identified 5 relevant studies for CH. Publications were included if they made a substantial contribution within 3 prespecified areas: Efficacy (randomized controlled-trials or open labels studies), safety, and mechanism of effect. RESULTS: Clinical effect: Clinical preventive treatment of CH with verapamil is based on 2 randomized controlled studies and 3 open-label studies. In total, 183 CH patients participated. Verapamil 360 mg/day was used in both controlled studies. Half of the chronic patients experienced benefit from verapamil treatment and the attack burden of episodic patients was, on average, reduced by 1 attack/day. Open-label studies support a dose-dependent level of efficacy. Mechanism of effect: Human and animal studies indicate that verapamil may exert its effect by modulating circadian rhythms, perhaps in central pacemakers, and/or by affecting release of calcitonin gene-related peptide. CONCLUSION: Verapamil appears to be an effective prophylactic drug in the treatment of CH and despite the scarcity of controlled trials, it is still the drug of choice. A chronotherapeutic approach might increase the effect. More basic and pharmacokinetic research is needed before the mechanism can be fully understood.

Oxygen therapy for cluster headache. A mask comparison trial. A single-blinded, placebo-controlled, crossover study.

Purpose The purpose of this article is to investigate possible differences in effect between three types of masks in the acute treatment of cluster headache (CH). Patients and methods Fifty-seven CH patients according to ICHD-II-criteria participated in a single-blinded, semi-randomized, placebo-controlled, crossover inpatient study, and 102 CH attacks were treated with 100% oxygen delivered by demand valve oxygen (DVO), O2ptimask or simple mask (15 liters/min) or placebo delivered by DVO for 15 minutes. Primary endpoint: Two-point decrease of pain on a five-point rating scale within 15 minutes. Results Only 10 CH patients had multiple attacks and reached the point of placebo. There were no significant differences between masks in the primary endpoints ( p = 0.412). After 15 minutes 48% had a two-point decrease using the DVO compared to 45% with placebo ( p = 0.867). After 30 minutes 68% were pain free or had pain relief using DVO and 45% by placebo ( p = 0.061). The DVO was preferred by 62% compared to 5% and 33% for simple mask ( p < 0.0001) and O2ptimask ( p = 0.061). In the first attack the DVO was significantly better at achieving pain relief at 15 minutes ( p = 0.018). Treatment with DVO or O2ptimask reduced the need for rescue medication compared to the simple mask (23%, 19%, 50%, respectively). No treatment-related adverse events were observed. Conclusion The primary endpoint with pain relief at 15 minutes was non-significant; however, a post hoc analysis of the first attack significantly favored DVO. Further, therapy by O2ptimask and DVO resulted in a decreased need for rescue medication. We recommend that CH patients be offered DVO or O2ptimask before oxygen therapy is abandoned.

Oxygen treatment of cluster headache: a review.

PURPOSE: Our aim was to review the existing literature to document oxygen's therapeutic effect on cluster headache. METHOD: A PubMed search resulted in 28 hits, and from these and their references we found in total 11 relevant studies. We included six studies that investigated the efficacy of oxygen treatment. One study is observational and the remaining five are RCTs. Another five studies were on hyperbaric oxygen treatment hereof two case studies. CONCLUSION: Oxygen therapy can be administered at different flow rates. Three studies investigate the effect of low-flow oxygen, 6-7 l/min, and found a positive response in 56%, 75% and 82%, respectively, of the patients. One study investigates high-flow oxygen, 12 l/min, and found efficacy in 78% of attacks. The effect of hyperbaric oxygen therapy has been investigated in a few small studies and there is evidence only for an acute, but not a prophylactic effect. Despite the fact that only a few high-quality RCT studies are available, oxygen treatment is close to an ideal treatment because it is effective and safe. However, sufferers of cluster headache do not always have access to oxygen because of logistic and financial concerns.

Recent advances in diagnosing, managing, and understanding the pathophysiology of cluster headache.

Cluster headache, characterised by attacks of severe, recurrent, unilateral headache and ipsilateral cranial autonomic symptoms, remains a primary headache with an elusive pathophysiology. Recent advances have introduced effective treatments and broadened understanding of the clinical features of cluster headache. These features are similar in patients globally, but regional differences in prevalence and burden exist. International collaborations have led to identification of eight genetic loci associated with cluster headache. The pathophysiological mechanisms are still not fully understood but recent studies show that targeting the trigeminal autonomic reflex by neurostimulation, or targeting the neuropeptide calcitonin gene-related peptide (CGRP), might lessen the attack burden. The US Food and Drug Administration has approved galcanezumab, a monoclonal antibody targeting CGRP, as the first specific preventive treatment for episodic cluster headache. However, a preventive effect was not replicated in chronic cluster headache, and the European Medicines Agency did not approve galcanezumab, restricting its availability in Europe. Owing to the low prevalence of cluster headache, continued collaboration through multicentre clinical trials and data sharing will be imperative for further breakthroughs in understanding and management.

Sphenopalatine ganglion stimulation induces changes in cardiac autonomic regulation in cluster headache.

INTRODUCTION: Cluster headache is characterized by attacks of severe unilateral pain accompanied by cranial and systemic autonomic changes. Our knowledge of the latter is imperfect. This study aimed to investigate the effect of low-frequency sphenopalatine ganglion stimulation on cardiac autonomic regulation. MATERIALS AND METHODS: In a double-blind, randomized, sham-controlled crossover design, patients received low-frequency and sham stimulation. RR intervals were recorded, and heart rate variability was analysed (time-domain, frequency-domain, nonlinear parameters). Headache characteristics, including cranial autonomic symptoms, were recorded at baseline and every 10 min for 60 min. RESULTS: Sixteen patients were included. Changes in heart rate variability from baseline in the analysed parameters differed significantly between low-frequency and sham stimulation. Initially, during low-frequency stimulation, there was a greater increase in heart rate compared to sham (P<0·05) and changes in the frequency, nonlinear and time domain (P<0·05) reflecting a higher sympathetic tone. These preceded the observed cranial autonomic symptoms. Ten episodes of cluster-like attacks were reported (six following low-frequency stimulation, four following sham). During these, parasympathetic tone (P<0·05) was higher compared to baseline. CONCLUSIONS: In cluster headache patients subjected to low-frequency and sham stimulation of the sphenopalatine ganglion, we found changes indicating higher sympathetic tone during low-frequency stimulation preceding cranial autonomic symptoms or cluster pain. During cluster pain, regardless of stimulation parameters, we saw increased parasympathetic activity, congruent with previous reports. The results indicate involvement of cardiac autonomic regulation before and during cluster headache attacks.