Reduced plasma calcitonin gene-related peptide level identified in cluster headache: A prospective and controlled study.

BACKGROUND: The role of calcitonin gene-related peptide (CGRP) in the cyclic pattern of cluster headache is unclear. To acquire biological insight and to comprehend why only episodic cluster headache responds to CGRP monoclonal antibodies, we examined whether plasma CGRP changes between disease states (i.e. bout, remission and chronic) and controls. METHODS: The present study is a prospective case-control study. Participants with episodic cluster headache were sampled twice (bout and remission). Participants with chronic cluster headache and controls were sampled once. CGRP concentrations were measured in plasma with a validated radioimmunoassay. RESULTS: Plasma was collected from 201 participants diagnosed with cluster headache according to the International Classification of Headache Disorders, 3rd edition, and from 100 age- and sex-matched controls. Overall, plasma CGRP levels were significantly lower in participants with cluster headache compared to controls (p < 0.05). In episodic cluster headache, CGRP levels were higher in bout than in remission (mean difference: 17.1 pmol/L, 95% confidence interval = 9.8-24.3, p < 0.0001). CGRP levels in bout were not different from chronic cluster headache (p = 0.266). CONCLUSIONS: Plasma CGRP is unsuitable as a diagnostic biomarker of cluster headache or its disease states. The identified reduced CGRP levels suggest that CGRPs role in cluster headache is highly complex and future investigations are needed into the modulation of CGRP and its receptors.

CCH attack frequency reduction after psilocybin correlates with hypothalamic functional connectivity.

OBJECTIVE: To evaluate the feasibility and prophylactic effect of psilocybin as well as its effects on hypothalamic functional connectivity (FC) in patients with chronic cluster headache (CCH). BACKGROUND: CCH is an excruciating and difficult-to-treat disorder with incompletely understood pathophysiology, although hypothalamic dysfunction has been implicated. Psilocybin may have beneficial prophylactic effects, but clinical evidence is limited. METHODS: In this small open-label clinical trial, 10 patients with CCH were included and maintained headache diaries for 10 weeks. Patients received three doses of peroral psilocybin (0.14 mg/kg) on the first day of weeks five, six, and seven. The first 4 weeks served as baseline and the last 4 weeks as follow-up. Hypothalamic FC was determined using functional magnetic resonance imaging the day before the first psilocybin dose and 1 week after the last dose. RESULTS: The treatment was well tolerated. Attack frequency was reduced by mean (standard deviation) 31% (31) from baseline to follow-up (pFWER = 0.008). One patient experienced 21 weeks of complete remission. Changes in hypothalamic-diencephalic FC correlated negatively with a percent change in attack frequency (pFWER = 0.03, R = -0.81), implicating this neural pathway in treatment response. CONCLUSION: Our results indicate that psilocybin may have prophylactic potential and implicates the hypothalamus in possible treatment response. Further clinical studies are warranted.

Induction of cluster headache after opening of adenosine triphosphate-sensitive potassium channels: a randomized clinical trial.

ABSTRACT: Activation of adenosine triphosphate-sensitive potassium (KATP) channels has been implicated in triggering migraine attacks. However, whether the opening of these channels provoke cluster headache attacks remains undetermined. The hallmark of cluster headache is a distinct cyclical pattern of recurrent, severe headache episodes, succeeded by intervals of remission where no symptoms are present. In our study, we enrolled 41 participants: 10 with episodic cluster headaches during a bout, 15 in the attack-free remission period, and 17 diagnosed with chronic cluster headaches. Over 2 distinct experimental days, participants underwent a continuous 20-minute infusion of levcromakalim, a KATP channel opener, or a placebo (isotonic saline), followed by a 90-minute observational period. The primary outcome was comparing the incidence of cluster headache attacks within the postinfusion observation period between the levcromakalim and placebo groups. Six of 10 participants (60%) with episodic cluster headaches in bout experienced attacks after levcromakalim infusion, vs just 1 of 10 (10%) with placebo (P = 0.037). Among those in the remission phase, 1 of 15 participants (7%) reported attacks after levcromakalim, whereas none did postplacebo (P = 0.50). In addition, 5 of 17 participants (29%) with chronic cluster headache had attacks after levcromakalim, in contrast to none after placebo (P = 0.037). These findings demonstrate that KATP channel activation can induce cluster headache attacks in participants with episodic cluster headaches in bout and chronic cluster headache, but not in those in the remission period. Our results underscore the potential utility of KATP channel inhibitors as therapeutic agents for cluster headaches.

The HortONS study. Treatment of chronic cluster headache with transcutaneous electrical nerve stimulation and occipital nerve stimulation: study protocol for a prospective, investigator-initiated, double-blinded, randomized, placebo-controlled trial.

BACKGROUND: Chronic cluster headache (CCH) is a debilitating primary headache disorder. Occipital nerve stimulation (ONS) has shown the potential to reduce attack frequency, but the occipital paresthesia evoked by conventional (tonic) stimulation challenges a blinded comparison of active stimulation and placebo. Burst ONS offers paresthesia-free stimulation, enabling a blinded, placebo-controlled study. Identification of a feasible preoperative test would help select the best candidates for implantation. This study aims to explore ONS as a preventive treatment for CCH, comparing burst stimulation to tonic stimulation and placebo, and possibly identifying a potential preoperative predictor. METHODS: An investigator-initiated, double-blinded, randomized, placebo-controlled trial is conducted, including 40 patients with CCH. Eligible patients complete a trial with the following elements: I) four weeks of baseline observation, II) 12 weeks of transcutaneous electrical nerve stimulation (TENS) of the occipital nerves, III) implantation of a full ONS system followed by 2 week grace period, IV) 12 weeks of blinded trial with 1:1 randomization to either placebo (deactivated ONS system) or burst (paresthesia-free) stimulation, and V) 12 weeks of tonic stimulation. The primary outcomes are the reduction in headache attack frequency with TENS and ONS and treatment safety. Secondary outcomes are treatment efficacy of burst versus tonic ONS, the feasibility of TENS as a predictor for ONS outcome, reduction in headache pain intensity (numeric rating scale), reduction in background headache, the patient's impression of change (PGIC), health-related quality of life (EuroQoL-5D), self-reported sleep quality, and symptoms of anxiety and depression (Hospital Anxiety and Depression Scale, HADS). Data on headache attack characteristics are registered weekly. Data on patient-reported outcomes are assessed after each trial phase. DISCUSSION: The study design allows a comparison between burst ONS and placebo in refractory CCH and enables a comparison of the efficacy of burst and tonic ONS. It will provide information about the effect of burst ONS and explore whether the addition of this stimulation paradigm may improve stimulation protocols. TENS is evaluated as a feasible preoperative screening tool for ONS outcomes by comparing the effect of attack prevention of TENS and tonic ONS. TRIAL REGISTRATION: The study is registered at Clinicaltrials.gov (trial registration number NCT05023460, registration date 07-27-2023).

Current treatment options for cluster headache: limitations and the unmet need for better and specific treatments-a consensus article.

AIM: Treatment for cluster headache is currently based on a trial-and-error approach. The available preventive treatment is unspecific and based on few and small studies not adhering to modern standards. Therefore, the authors collaborated to discuss acute and preventive treatment in cluster headache, addressing the unmet need of safe and tolerable preventive medication from the perspectives of people with cluster headache and society, headache specialist and cardiologist. FINDINGS: The impact of cluster headache on personal life is substantial. Mean annual direct and indirect costs of cluster headache are more than 11,000 Euros per patient. For acute treatment, the main problems are treatment response, availability, costs and, for triptans, contraindications and the maximum use allowed. Intermediate treatment with steroids and greater occipital nerve blocks are effective but cannot be used continuously. Preventive treatment is sparsely studied and overall limited by relatively low efficacy and side effects. Neurostimulation is a relevant option for treatment-refractory chronic patients. From a cardiologist's perspective use of verapamil and triptans may be worrisome and regular follow-up is essential when using verapamil and lithium. CONCLUSION: We find that there is a great and unmet need to pursue novel and targeted preventive modalities to suppress the horrific pain attacks for people with cluster headache.

Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response.

BACKGROUND AND PURPOSE: The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine. METHODS: In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache. RESULTS: Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found. CONCLUSION: The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.

Transition of cluster headache phenotype: An interview-based study.

Background Cluster headache exists diagnostically in a chronic and episodic variant between which patients can convert. We aimed to describe how many patients change phenotype, elucidate possible factors associated with this transition and identify differences in clinical features between primary and secondary phenotypes.Methods 540 well-defined cluster headache patients according to current ICHD-criteria completed a cross-sectional semi-structured interview.Results Total transition-incidence for the cohort was 20.7%. Conversion from chronic to episodic was reported by 6.3% and transition from episodic to chronic by 14.4% with attack side shift as a possible predictor (p = 0.007). Compared to primary chronic patients, secondary chronic patients had more frequent (60 vs 34 per month, p = 0.0487), but shorter (60 vs 90 minutes, p = 0.041) attacks. Secondary episodic patients experienced shorter remission periods than primary episodic patients (6 vs 11 months, p = 0.010). Treatment response was poor in all groups and only one third had effective prevention.Conclusion Cluster headache is a fluctuating disorder with a fifth of our cohort having experienced at least one phenotype change during course of disease. Apart from attack side shifts, no predictors for transition were identified. Severity differed between primary and secondary subtypes. Overall, there is an urgent need for better understanding of cluster headache.

Debate: Are cluster headache and migraine distinct headache disorders?

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 .

The economic and personal burden of cluster headache: a controlled cross-sectional study.

BACKGROUND: Cluster headache is a less-prevalent primary headache disorder but is overrepresented with regards to use of health care and social services. More insight into the socioeconomic impact is required. METHODS: We investigated both the personal and societal disease burden and cost in 400 patients with well-classified cluster headache according to the ICHD-criteria and 200 sex- and age matched controls. All participants completed a cross sectional questionnaire and semi-structured interview. RESULTS: Patients with chronic cluster headache constituted 146 out of 400 (37%). Overall, restriction in personal and/or professional life was reported by 94% of patients during attack periods. Even in remission, nine times as many episodic patients rated their health as poor/very poor compared to controls (9% vs 1%, p = 0.002). For chronic patients, the odds of rating health as good/very good were ten times lower compared to controls (OR:10.10, 95%CI:5.29-18.79. p < 0.001) and three times lower compared to episodic patients in remission (OR:3.22, 95%CI:1.90-5.47, p < 0.001). Additionally, chronic cluster headache patients were 5 times more likely to receive disability pension compared to episodic (OR:5.0, 95%CI:2.3-10.9, p < 0.001). The mean direct annual costs amounted to 9,158€ and 2,763€ for chronic and episodic patients, respectively (p < 0.001). We identified a substantial loss of productivity due to absence from work resulting in a higher indirect cost of 11,809 €/year/patient in the chronic population and 3,558 €/year/patient in the episodic population. Presenteeism could not be quantified but productivity was reduced in patients by 65% in periods with attacks compared to controls. CONCLUSION: Cluster headache has a major negative impact on personal life, self-perceived health, and societal cost. Patients with the chronic variant are vastly more burdened. Patients with the episodic form were still markedly affected during the remission period. This study highlights the need for more effective therapy to lighten the burden on patients and society.

Real-life treatment of cluster headache in a tertiary headache center - results from the Danish Cluster Headache Survey.

BACKGROUND: Pharmacological treatment of cluster headache constitutes the core of clinical management, but evidence is sparse. We aimed to generate insight in the existing treatment and identify associations between clinical features and treatment response. METHODS: Patients aged 18-65 diagnosed with cluster headache according to the ICHD-2 completed a questionnaire followed by a structured interview. Multiple logistic regression was used to identify associations. RESULTS: The population consisted of 400 patients with an episodic: chronic ratio of 1.7:1. Episodic patients were more likely to respond to triptans (odds ratio = 1.77, confidence interval: 1.08-2.91, p = 0.023) and oxygen (odds ratio = 1.64, confidence interval: 1.05-2.57, p = 0.031) than chronic. Oxygen response was less likely if pain intensity was very severe (odds ratio = 0.53, confidence interval: 0.33-2.57, p = 0.006) and the risk of a poor response increased with disease duration (odds ratio = 0.79, confidence interval: 0.65-0.96, p = 0.016). Among current users of sumatriptan injection and oxygen, the proportion achieving 100% relief was higher with sumatriptan injection (p > 0.001) than with oxygen. No associations were identified regarding verapamil. Only 57% of current users of preventive medication responded at a 50% level. CONCLUSION: Episodic cluster headache is more responsive to acute therapy than chronic. Further, sumatriptan injection was more effective than oxygen and the responder-rate was limited with verapamil. More effective acute and preventive therapies are needed for cluster headache patients.

The effect of pituitary adenylate cyclase-activating peptide-38 and vasoactive intestinal peptide in cluster headache.

BACKGROUND: Previously reported increases in serum levels of vasodilating neuropeptides pituitary adenylate cyclase-activating peptide-38 (PACAP38) and vasoactive intestinal peptide (VIP) during attacks of cluster headache could indicate their involvement in cluster headache attack initiation. We investigated the attack-inducing effects of PACAP38 and vasoactive intestinal peptide in cluster headache, hypothesising that PACAP38, but not vasoactive intestinal peptide, would induce cluster-like attacks in episodic active phase and chronic cluster headache patients. METHODS: In a double-blind crossover study, 14 episodic cluster headache patients in active phase, 15 episodic cluster headache patients in remission phase and 15 chronic cluster headache patients were randomly allocated to receive intravenous infusion of PACAP38 (10 pmol/kg/min) or vasoactive intestinal peptide (8 pmol/kg/min) over 20 min on two study days separated by at least 7 days. We recorded headache intensity, incidence of cluster-like attacks, cranial autonomic symptoms and vital signs using a questionnaire (0-90 min). RESULTS: In episodic cluster headache active phase, PACAP38 induced cluster-like attacks in 6/14 patients and vasoactive intestinal peptide induced cluster-like attacks in 5/14 patients (p = 1.000). In chronic cluster headache, PACAP38 and vasoactive intestinal peptide both induced cluster-like attacks in 7/15 patients (p = 0.765). In episodic cluster headache remission phase, neither PACAP38 nor vasoactive intestinal peptide induced cluster-like attacks. CONCLUSIONS: Contrary to our hypothesis, attack induction was lower than expected and roughly equal by PACAP38 and vasoactive intestinal peptide in episodic active phase and chronic cluster headache patients, which contradicts the PAC1-receptor as being solely responsible for attack induction.Trial registration: clinicaltrials.gov (identifier NCT03814226).

[Shewanella algae bacteriaemia after a vacation in Thailand].

This is a case report of a 56-year-old man, who presented with a very rare cause of erysipelas and bacteraemia caused by the Gram-negative bacillus Shewanella algae. To our knowledge, this is the first reported case of imported Shewanella-infection in Denmark. The patient, who had a history of liver cirrhosis, returned home from a one-month vacation in Thailand. All four blood cultures were positive for S. algae. The patient was treated successfully with IV meropenem and oral ciprofloxacin. S. algae can cause severe local and systemic infection and is not sensitive to standard treatment with penicillin.

Cranial parasympathetic activation induces autonomic symptoms but no cluster headache attacks.

Background Low frequency (LF) stimulation of the sphenopalatine ganglion (SPG) may increase parasympathetic outflow and provoke cluster headache (CH) attacks in CH patients implanted with an SPG neurostimulator. Methods In a double-blind randomized sham-controlled crossover study, 20 CH patients received LF or sham stimulation for 30 min on two separate days. We recorded headache characteristics, cephalic autonomic symptoms (CAS), plasma levels of parasympathetic markers such as pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal peptide (VIP), and mechanical detection and pain thresholds as a marker of sensory modulation. Results In the immediate phase (0-60 min), 16 (80%) patients experienced CAS after LF stimulation, while nine patients (45%) reported CAS after sham ( p = 0.046). We found no difference in induction of cluster-like attacks between LF stimulation (n = 7) and sham stimulation (n = 5) ( p = 0.724). There was no difference in mechanical detection and pain thresholds, and in PACAP and VIP plasma concentrations between LF and sham stimulation ( p ≥ 0.162). Conclusion LF stimulation of the SPG induced autonomic symptoms, but no CH attacks. These data suggest that increased parasympathetic outflow is not sufficient to induce CH attacks in patients. Study protocol ClinicalTrials.gov registration number NCT02510729.