Efficacy of galcanezumab in patients with episodic cluster headaches and a history of preventive treatment failure

Objective: The efficacy of galcanezumab was evaluated in patients with episodic cluster headache and history of preventive treatment failure. Methods: In the randomized, 8-week, double-blind study (CGAL), patients with episodic cluster headache received once-monthly subcutaneous injections of galcanezumab 300 mg or placebo. Patients who completed CGAL and enrolled in an open-label study were queried for preventive treatment history. In a subset of patients with a known history of failure of verapamil or any other prior preventive treatment, a post hoc analysis of least square mean change from baseline in weekly cluster headache attack frequency across Weeks 1 to 3 was assessed. Results: Fifteen patients provided data for known history of prior preventive treatment failure (6 placebo, 9 galcanezumab), of whom 11 failed verapamil. The mean reduction in the weekly frequency of cluster headache attacks was greater with galcanezumab compared to placebo among patients with prior preventive treatment failure (8.2 versus 2.4); mean difference 5.8 (95% confidence interval [CI] 2.0, 13.6) and among patients with verapamil failure (10.1 versus 1.6); mean difference 8.5 (95% CI 0.4, 16.7). Conclusion: In this exploratory analysis of patients with a known history of prior preventive treatment failures, treatment with galcanezumab resulted in greater mean reductions in weekly cluster headache attacks compared with placebo. ClinicalTrials.gov: NCT02397473 (I5Q-MC-CGAL) NCT02797951 (I5Q-MC-CGAR)

Phase Specific Pain Localization in Cluster Headache Patients.

Background and Objective:Applying local treatments like neuromodulation or injections for cluster headache, requires exact knowledge of the anatomical structures and pain topography. However studies with emphasis on exact pain localization are rare although local treatments are increasingly used for patients in whom systemic pharmacotherapy is ineffective or contraindicated. Here, survey results with emphasis on exact pain location in cluster headache attacks for onset of pain, peak pain and radiation of pain, are presented. Methods: Data from 631 respondents were collected for 23 months using an online survey composed of 117 questions on pain location, epidemiology, and clinical features. 5260 datapoints on 44 pain locations were analyzed.Results: There is a periorbital concentration of pain during onset and peak phases of attacks. Pain locations outside the periorbital region were reported more frequently during radiation when compared to the onset and peak of attacks. Dorsal (occipital/nuchal) pain is more frequent during onset and radiation compared to peak: onset pain (13%) vs. peak pain (6%), p < 0,001. Pain radiation (22%) vs. peak pain (6%), p < 0,001. There is no significant difference in dorsal pain frequencies for pain radiation (22%) vs. onset (13%), p = 0,552. Furthermore, single pain spots differ significantly in frequency during the three attack phases.Conclusions: Analysis of the pain location data shows phase specific frequencies and distributions of pain location during the three stages of a cluster headache attack. Single pain spots differ significantly in frequency during the three attack phases. Dorsal pain is more frequent during onset and radiation, compared to peak. Extra-orbital pain locations are more frequent during pain radiation. These findings will help to better understand cluster headache and might help to identify further target structures for local treatments.

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).

The biological clock in cluster headache: A review and hypothesis

Objective To review and discuss the putative role of light, sleep, and the biological clock in cluster headache. Discussion Cluster headache attacks are believed to be modulated in the hypothalamus; moreover, the severe pain and typical autonomic cranial features associated with cluster headache are caused by abnormal activity of the trigeminal-autonomic reflex. The temporal pattern of cluster headache attacks suggests involvement of the biological clock, and the seasonal pattern is influenced by the number of daylight hours. Although sleep is often reported as a trigger for cluster headache attacks, to date no clear correlation has been established between these attacks and sleep stage. Conclusions We hypothesize that light, sleep, and the biological clock can change the brain’s state, thereby lowering the threshold for activating the trigeminal-autonomic reflex, resulting in a cluster headache attack. Understanding the mechanisms that contribute to the daily and seasonal fluctuations in cluster headache attacks may provide new therapeutic targets.

Increased suicidality in patients with cluster headache

Objective To investigate suicidality related to cluster headache and factors associated with increased suicidality in cluster headache patients. Methods In this multicenter study, 193 cluster headache patients were recruited between September 2016 and August 2018. Patients were asked about their suicidality during and between attacks, specifically about passive suicidal ideation, active suicidal ideation, suicide plan, and suicide attempt. Univariable and multivariable logistic regression analyses were performed to evaluate the factors associated with high ictal suicidality (sum of positive response ≥ 2). Patients were followed up when they were in the between-bouts period. Results A total of 175 cluster headache patients in the in-bout period were included in this study. Passive suicidal ideation, active suicidal ideation, suicidal planning, and suicidal attempt were reported by 111 (64.2%), 62 (35.8%), 10 (5.8%), and four (2.3%) patients during attacks; seven (4.0%), six (3.5%), five (2.9%) and two (1.2%) patients interictally; and none (0%), one (1.9%), one (1.9%), and none (0%) among patients in the between-bouts period. Factors associated with high ictal suicidality were longer disease duration, the Headache Impact Test score, and the Patient Health Question-9 score (multivariable OR = 1.90 per 10-year increase in disease duration, 95% CI = 1.18–3.05, p = 0.008; multivariable OR = 3.19 per 10-point increase in HIT-6, 95% CI = 1.73–5.87, p < 0.001; multivariable OR = 2.11 per 10-point increase in PHQ-9, 95% CI = 1.13–3.95, p = 0.020, respectively). Conclusions Cluster headache attack carries a high suicidality compared to the interictal or between-bouts state. An intensive treatment to reduce cluster headache burden may be helpful to alleviate suicide risk in cluster headache patients.

The spectrum of cluster headache: A case report of 4600 attacks

Introduction Knowledge of the clinical features of cluster headache is mainly based on retrospective and cross-sectional studies. Here, we present a case of a chronic cluster headache patient who prospectively recorded timing and clinical features of all attacks for 6 years, aiming to describe the clinical spectrum and timing of cluster headache symptoms experienced and to identify daily and/or seasonal rhythmicity. Methods Registration of attack timing, duration, associated symptoms and severity was done prospectively on a smartphone application. Pain severity was recorded on a 0–10 scale. Attacks were divided into mild, moderate, severe, and very severe. We analysed diurnal rhythmicity by multimodal Gaussian analysis and spectral analysis. Results In total, 4600 attacks were registered (mean duration 39.3 (SD 18.5) min. Mean severity 3.6 (SD 1.28)). Mild attacks accounted for 14.2%, moderate 65.7%, severe 16.9% and very severe 3.2% of all attacks. Nocturnal attacks were more severe than daytime attacks. The number of autonomic symptoms and duration of attacks increased with pain severity. Peak chronorisk (risk of attacks occurring according to hour of day) was at 12.48 in the registration period. Over time, circadian rhythmicity and attack frequency varied. Conclusion Clinical characteristics of cluster headache attacks can vary greatly within the individual patient. Clinicians attempting to personalise the administration of preventive treatment should pay notice to the variation over time in diurnal rhythmicity. The recorded self-limiting mild attacks that do not fulfill the ICHD-3 criteria for a cluster headache attack warrant further investigation, as they could hold important information about disease activity.

THUR 084 Cranial autonomic symptoms in cluster headache induced by nitroglycerin

IntroductionCluster headache (CH) is characterised by attacks of unilateral excruciating headache, ipsilateral cranial autonomic symptoms (CAS) and/or agitation. Studying of CAS can further our understanding of CH pathophysiology, but is limited by the episodic nature of the disease. Nitroglycerin (NTG) is known to induce CH. The aim of this study is to characterise CAS induced by NTG.MethodsCH patients received intravenous NTG 0.5 mcg/kg/min over 20 min. CAS and headache phenotype were recorded. The study was approved by the NHS Research Ethics Committee.ResultsTwenty-three patients participated: 83% male and 61% episodic cluster headache. The most common spontaneous CAS reported were lacrimation, nasal congestion and conjunctival injection. Agitation was reported in 96%. Nitroglycerin induced ipsilateral CAS in 91% of the patients, with 74% with ipsilateral pain. Most commonly induced CAS were nasal congestion, lacrimation and periorbital swelling. Agitation was reported in 61%. The majority of the CAS (80%) induced by NTG presented before the onset of severe pain.ConclusionWe demonstrate that NTG effectively triggers ipsilateral cranial autonomic symptoms in CH patients and that they often present in a phase before the onset of pain reflecting the underlying pathways during a cluster headache attack.

Pre-attack signs and symptoms in cluster headache: Characteristics and time profile

Introduction In contrast to the premonitory phase of migraine, little is known about the pre-attack (prodromal) phase of a cluster headache. We aimed to describe the nature, prevalence, and duration of pre-attack symptoms in cluster headache. Methods Eighty patients with episodic cluster headache or chronic cluster headache, according to ICHD-3 beta criteria, were invited to participate. In this observational study, patients underwent a semi-structured interview where they were asked about the presence of 31 symptoms/signs in relation to a typical cluster headache attack. Symptoms included previously reported cluster headache pre-attack symptoms, premonitory migraine symptoms and accompanying symptoms of migraine and cluster headache. Results Pre-attack symptoms were reported by 83.3% of patients, with an average of 4.25 (SD 3.9) per patient. Local and painful symptoms, occurring with a median of 10 minutes before attack, were reported by 70%. Local and painless symptoms and signs, occurring with a median of 10 minutes before attack, were reported by 43.8% and general symptoms, occurring with a median of 20 minutes before attack, were reported by 62.5% of patients. Apart from a dull/aching sensation in the attack area being significantly ( p < 0.05) more frequent among men and episodic patients, compared with women and chronic patients respectively, no other differences in the prevalence of pre-attack symptoms were identified between groups. Conclusion Pre-attack symptoms are frequent in cluster headache. Since the origin of cluster headache attacks is still unresolved, studies of pre-attack symptoms could contribute to the understanding of cluster headache pathophysiology. Furthermore, identification and recognition of pre-attack symptoms could potentially allow earlier abortive treatment.

The use of oxygen in cluster headache treatment worldwide – a survey of the International Headache Society (IHS)

Background Oxygen is recommended for the treatment of acute cluster headache attacks. However, it is not available worldwide. Methods The International Headache Society performed a survey among its national member societies on the availability and the restrictions for oxygen in the treatment of cluster headache. Results Oxygen is reimbursed in 50% of all countries responding ( n = 22). There are additional restrictions in the reimbursement of the facial mask and with respect to age. Conclusion Oxygen for the treatment of cluster headache attack is not reimbursed worldwide. Headache societies should pressure national/public health authorities to reimburse oxygen for cluster headache in all countries.