Substance use related cluster headache: A case series

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. 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. 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). 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.

ObjectiveInvestigate the immune system's role in cluster headache by analyzing cytokines in people with cluster headache and headache‐free controls, and explore if certain cytokines could predict a specific phenotype.MethodsWe measured 45 cytokines in adult participants from the Danish Cluster Headache Biobank in a prospective case–control setup. People with cluster headache were diagnosed according to the International Classification of Headache Disorders third‐edition. Controls were matched for age and sex.ResultsA total of 412 were analyzed deriving from 99 with chronic cluster headache, 108 with episodic cluster headache (ECH) in bout, 105 with ECH in remission, and 100 successfully matched controls. Compared with controls, 13 cytokines were altered for ECH in bout (p < 0.05), 3 in remission (p < 0.05), and 10 for chronic cluster headache (p < 0.05). Oncostatin m was significantly elevated in all 3 disease states compared with controls (p < 0.05). Overall, the investigated cytokines showed distinct patterns of alterations between chronic cluster headache and episodic cluster headache in bout and, interestingly, IL‐1β was significantly associated with having chronic cluster headache rather than episodic in bout in a logistic regression model adjusting for potential confounders (p < 0.05).InterpretationFindings show that the immune system is altered in all 3 states of cluster headache compared with controls. Oncostatin m was elevated, constituting a promising target for future studies. The distinct alterations between episodic and chronic cluster headache are striking and urges further research of the immune system in cluster headache to better understand its potential role in prediction of disease activity and treatment response. ANN NEUROL 2025;98:4–18

To investigate the role of calcitonin gene-related peptide, pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide in cluster headache, we measured these vasoactive peptides interictally and during experimentally induced cluster headache attacks. We included patients with episodic cluster headache in an active phase (n = 9), episodic cluster headache patients in remission (n = 9) and patients with chronic cluster headache (n = 13). Cluster headache attacks were induced by infusion of calcitonin gene-related peptide (1.5 µg/min) in a randomized, double-blind, placebo controlled, two-way cross-over study. At baseline, we collected interictal blood samples from all patients and during 11 calcitonin gene-related peptide-induced cluster headache attacks. At baseline, episodic cluster headache patients in remission had higher plasma levels of calcitonin gene-related peptide, 100.6 ± 36.3 pmol/l, compared to chronic cluster headache patients, 65.9 ± 30.5 pmol/l, ( p = 0.011). Episodic cluster headache patients in active phase had higher PACAP38 levels, 4.0 ± 0.8 pmol/l, compared to chronic cluster headache patients, 3.3 ± 0.7 pmol/l, ( p = 0.033). Baseline levels of vasoactive intestinal polypeptide did not differ between cluster headache groups. We found no attack-related increase in calcitonin gene-related peptide, PACAP38 or vasoactive intestinal polypeptide levels during calcitonin gene-related peptide-induced cluster headache attacks. This study suggests that cluster headache disease activity is associated with alterations of calcitonin gene-related peptide expression. Future studies should investigate the potential of using calcitonin gene-related peptide measurements in monitoring of disease state and predicting response to preventive treatments, including response to anti-calcitonin gene-related peptide monoclonal antibodies.

To investigate the safety and efficacy of intranasal ketamine for the treatment of a single cluster headache (CH) attack. 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. 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 15mg of intranasal ketamine every 6min a maximum of five times. The primary endpoint was a 50% reduction in pain intensity within 15min after initiating treatment. The primary endpoint was not met; 15min 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, 30min 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 15min after the first ketamine application and were therefore excluded from the analysis at 30min. Half of the patients preferred ketamine to oxygen and/or sumatriptan injection. No serious adverse events were identified during the trial. Intranasal ketamine may be an effective acute treatment for CH at 30min but should be tested in a larger controlled design. Patients and physicians should be conscious of the abuse potential of ketamine.

BackgroundThere have been a few studies regarding the pre-attack symptoms (PAS) and pre-episode symptoms (PES) of cluster headache (CH), but none have been conducted in the Chinese population. The purpose of this study was to identify the prevalence and features of PAS and PES in Chinese patients, as well as to investigate their relationships with pertinent factors.MethodsThe study included patients who visited a tertiary headache center and nine other headache clinics between January 2019 and September 2021. A questionnaire was used to collect general data and information about PAS and PES.ResultsAmong the 327 patients who met the CH criteria (International Classification of Headache Disorders, 3rd edition), 269 (82.3%) patients experienced at least one PAS. The most common PAS were head and facial discomfort (74.4%). Multivariable logistic regression analysis depicted that the number of triggers (OR = 1.798, p = 0.001), and smoking history (OR = 2.067, p = 0.026) were correlated with increased odds of PAS. In total, 68 (20.8%) patients had PES. The most common symptoms were head and facial discomfort (23, 33.8%). Multivariable logistic regression analysis showed that the number of triggers were associated with increased odds of PES (OR = 1.372, p = 0.005).ConclusionsPAS are quite common in CH patients, demonstrating that CH attacks are not comprised of a pain phase alone; investigations of PAS and PES could help researchers better understand the pathophysiology of CH.

According to the International Classification of Headache Disorders diagnostic criteria, the differences between migraine and cluster headache (CH) are clear. In addition to headache attack duration and pain characteristics, the symptoms accompanying headache represent the key features in a differential diagnosis of these 2 primary headache disorders. Just a few studies of patients with CH exist examining the presence of nausea, vomiting, photophobia, phonophobia, and aura, the features commonly accompanying migraine headache. The aim of this study was to determine the presence of migraine-like features (MF) in patients with CH and establish the significance of these phenomena related to other clinical features and response to treatment. One hundred and fifty-five patients with CH were studied, and 24.5% of them experienced at least one of MF during every CH attack. Nausea and vomiting were the most frequently reported MF. The clinical presentation between CH patients with and without MF was not significantly different with the exception of aggravation of pain by effort (20.6% vs 4.1%) and facial sweating (13.2% vs 0.85%), both more frequent in CH patients with MF. Inferred from the results of our study, the presence of MF in CH patients had no important influence on the diagnosis and treatment of CH patients. The major differences of these 2 primary headache disorders, attack duration, lateralization, and the nature of associated symptoms, as delineated in the International Classification of Headache Disorders, are still useful tools for effective diagnosis.

Despite being an excruciating headache, little is known about the burden of cluster headache (CH) regarding its various subtypes. In a multicentre, prospective study, patients with chronic CH (n = 27), with episodic CH in the active (n = 26) and outside the active period (n = 22), migraine patients (n = 24) and healthy controls (n = 31) were included. Epidemiological data, the German version of the Headache Disability Inventory (HDI) and a screening for psychiatric complaints were applied. About 25% of chronic CH patients in our study received invalidity allowance due to CH. HDI scores (total and subscales emotion and function) indicated a severe headache-specific disability (one-way ANOVA: P < 0.01). Patients with chronic and active episodic CH were significantly more affected than patients with inactive CH and migraine. Healthy volunteers were significantly less affected than all headache patients. Symptoms suggestive of psychiatric co-morbidity were found predominantly in chronic CH: depressive symptoms (56%), signs of agoraphobia (33%) and suicidal tendencies (25%) were frequently reported. Patients with chronic and active episodic CH were severely impaired in non-economic and economic domains such as disability, working life and psychiatric complaints. Remarkably, psychiatric co-morbidity was highest in chronic CH. Thus, especially chronic CH warrants special medical and further supportive care.

Most previous studies on cluster headache (CH) focus on Western populations. This study aimed to investigate the clinical characteristics of CH in a neurology outpatient population in Taiwan. A cross-sectional survey was conducted from July 2015 to June 2019 in a medical college affiliated with a tertiary care hospital (Tri-Service General Hospital) in Taiwan. All consecutive patients reporting headache as their chief complaint were asked to participate in a face-to-face interview with a qualified headache specialist and to complete a detailed self-administered questionnaire. The diagnosis of CH was made according to the Third edition of the International Classification of Headache Disorders. The subjects comprised 80 consecutive new CH patients (13 women and 67 men; ratio, 1:5). The mean age at presentation was 36.0 ± 10.8 years (range, 16–64 years), mean age at onset was 27.2 ± 12.1 years (range, 5–65 years), and mean time lag before diagnosis was 9.3 ± 10.5 years (range, 0–46.4 years). Of the total CH patients, 25.3% reported feelings of restlessness during headache episodes. A seasonal predilection was reported by 18% of the CH patients. The use of tobacco was the most common (44/80 patients). Chronic CH was only observed in 5% of the patients and only one patient (1.3%) reported both a positive family history for CH and aura. Features of CH in Taiwanese patients differed from that of Caucasian patients; a lower prevalence of chronic CH, positive family history of CH, and occurrence of aura may be less common in the former than in the latter.

Long-term safety, tolerability, and efficacy of eptinezumab in chronic cluster headache (CHRONICLE): an open-label safety trial.

The administration of nitroderivatives in cluster headache (CH) sufferers is the most reproducible experimental paradigm to induce spontaneous-like pain attacks. Previous uncontrolled studies have reported that the local use of anaesthetic agents in the area of the sphenopalatine fossa is able to extinguish nitroglycerin (NTG)-induced pain in CH. The present study, carried out according to a double-blind placebo-controlled design, included 15 CH patients, six with episodic CH (mean +/- SD age of 36.8+/-5.6 years), and nine with chronic CH (37.8+/-10.4 years). Patients had undergone a standard NTG test (0.9 mg sublingually), during which the intensity of pain was scored using a visuoanalogic scale (VAS, range 0-10). Nine patients (two with the episodic form, seven with the chronic form) experienced a typical, spontaneous-like attack on the usual side, occurring in all cases within 45 min. In these patients, the test was repeated with an interval of 2 days, and once pain intensity reached 5 on the VAS, a 10% solution of cocaine hydrochloride (1 ml, mean amount per application 40-50 mg), or 10% lidocaine (1 ml), or saline was applied using a cotton swab in the area corresponding to the sphenopalatine fossa, under anterior rhinoscopy. This was done in both the symptomatic and the non-symptomatic side, for 5 min. Treatments were always performed randomly, in separate sessions. All patients responded promptly to both anaesthetic agents, with complete cessation of induced pain occurring after 31.3+/-13.1 min for cocaine and 37.0+/-7.8 min for lidocaine (M+/-SD). In the case of saline application, pain severity increased thereafter, and extinction of the provoked attacks occurred with a latency of 59.3+/-12.3 min (P<0.01 and P<0.01 vs. cocaine and lidocaine, respectively, Mann-Whitney U-test). While further suggesting that the sphenopalatine ganglion participates in the mechanisms of pain, these findings indicate that the local administration of the anaesthetic agents cocaine and lidocaine is effective on NTG-induced CH attacks, and may be used in the symptomatic treatment of this disorder.

Sirs: Cluster headache (CH) is a primary headache characterized by severe unilateral pain, ipsilateral autonomic symptoms and, in many cases, restlessness. The etiology of CH is still unclear, although clinical, endocrine and neuroimaging studies implicate the hypothalamus. Hypothalamic involvement is also supported by the efficacy of stereotactic deep brain stimulation of the posterior hypothalamic area in chronic drug resistant CH [1]. The increased familial risk of CH suggests a genetic liability with inheritance likely to be autosomal dominant with low penetrance, although autosomal recessive or multifactorial inheritance have also been suggested in some families [2]. A polymorphism of the hypocretin receptor 2 gene has recently been associated with CH [3], a remarkable association since hypocretin-containing cells are located exclusively in the posterolateral hypothalamus. A striking feature of CH is its diurnal and seasonal periodicity, suggesting that circadian and infradian rhythms regulate CH attacks. Polymorphisms in the CLOCK gene, a highly conserved circadian gene, influence the circadian phase in humans [4] and circadian mood fluctuations in bipolar patients [5]. We performed a genetic association study to evaluate whether the T3111C CLOCK polymorphism (also known as T3092C) might be related to CH susceptibility under the assumption of autosomal dominant inheritance. A total of 101 consecutive, unrelated Italian patients (79 men and 22 women) with CH (85 episodic and 16 chronic CH) gave informed consent to the study. All patients were diagnosed after direct interview by a neurologist expert in headache disorders and according to ICHD-II criteria [6]. Of the 101 patients, 87 described a clear circadian rhythmicity of the attacks. 100 healthy individuals, in whom CH and migraine were excluded by direct interview, served as controls. The control sample came from the same geographical region as the CH patients. We analyzed a single nucleotide polymorphism, T3111C, in the 3’ flanking region of the CLOCK gene [4]. DNA was extracted from whole blood by standard methods [7]. PCR primers and methods were those reported by Katzenberg et al. [4]. The T3111C polymorphism was detected by enzymatic digestion with Sdu I (Fermentas) and electrophoresed on MetaPhor agarose 2 % gel. The allelic and genotypic frequencies were compared by means of the Fisher’s exact test. The Hardy-Weinberg equilibrium was verified for all tested populations, and alleles were in Hardy-Weinberg equilibrium in both controls and patients. We found no significant difference in allelic and genotypic frequencies between the total CH patient group and the control subjects (χ2 = 1.261, p = 0.261; χ2 = 5.791, p = 0.055) (Table 1). Nor was a significant difference found when considering the 87 CH patients with circadian rhythmicity of the attacks alone. Our study does not support the hypothesis that the T3111C CLOCK polymorphism is associated with CH. It therefore strengthens the similar negative results reported previously by Rianero et al. [8]. Our analysis moreover resulted in nonsignificant differences when the 87 CH patients reporting a clear periodicity of the attacks were considered separately. It thus appears that CLOCK gene T3111C polymorphism does not influence CH, but our result of course cannot exclude that polymorphic variations at other biological rhythm genes LETTER TO THE EDITORS

BackgroundGalcanezumab of 300 mg monthly is the FDA approved preventive medication for cluster headache (CH) during the cluster period. Compared to the 120 mg galcanezumab syringe for the treatment of migraines, the 100 mg syringe for CH has globally not been as widely available. The aim of our study was to investigate the preventive efficacy and tolerability of two 120 mg galcanezumab doses for episodic CH in clinical practices.MethodsWe evaluated patients with CH who received at least 1 dose of 240 mg (2 prefilled syringe of 120 mg) of galcanezumab in the 3 university hospitals from February 2020 to September 2021. In the patients with episodic CH, the efficacy and safety data of galcanezumab were analyzed regarding to the presence of the conventional preventive therapy at the timing of therapy of galcanezumab. The data of other subtypes of CH were separately described.ResultsIn 47 patients with episodic CH, galcanezumab was started median 18 days after the onset of current bout (range 1–62 days) and 4 patients (10.8%) received second dose of galcanezumab. The median time to the first occurrence of 100% reduction from baseline in CH attacks per week after galcanezumab therapy was 17 days (25% to 75% quartile range: 5.0 ~ 29.5) in all patients with episodic CH, 15.5 days (3.8 ~ 22.1) in 36 patients with galcanezumab therapy add-on conventional preventive therapy, 21.0 days (12.0 ~ 31.5) in 11 patients started galcanezumab as initial preventive therapy. Among 33 patients with headache diary, the proportion of patients with 50% or more reduction in weekly CH attacks at week 3 from baseline were 78.8%. There was no significant difference in the proportion of patients with a reduction of at least 50% in weekly frequency of CH attacks at week 3 between 24 patients received galcanezumab therapy add-on conventional preventive therapy and 9 patient who received initial galcanezumab therapy. (83.3%, vs 66.7%, p = 0.36). There were no significant differences in proportion of “very much better or “much better” between 36 patients received galcanezumab therapy add-on conventional preventive therapy and 11 patient who received initial GT (86.1%, vs 63.6%, p = 0.18).ConclusionOne 240 mg dose of galcanezumab with/without conventional therapy for the prevention of CH is considered effective and safe in clinical practices, as seen in the clinical trial of galcanezumab.

Cluster headache (CH) is characterized by recurrent attacks of short-lasting excruciating pain accompanied by signs of autonomic dysfunction. Although neuroimaging results are usually normal in primary headaches, rarely structural lesions may be associated with CH like presentation. Most symptomatic CH is due to pituitary tumors and less commonly due to arteriovenous malformations (AVM) and aneurysms. Here we describe a case of 44-year-old male who presented to us with new onset episodic CH with headache features typical. Initially, headache responded to treatment, but later the headache became continuous, severe in intensity and refractory to treatment. Since magnetic resonance imaging was normal, he was subjected to digital substraction angiography (DSA) to rule out aneurysm or AVM. DSA revealed indirect carotid-cavernous fistula (CCF). Once the fistula was obliterated with onyx embolization, headache subsided completely. MRI brain is often routinely performed in CH to rule out secondary causes. When MRI brain is normal, detailed vascular imaging with DSA must be performed in patients with CH with especially in those with atypical features. Like continuous pain refractory to treatment, sudden increase in severity in the first episode, minimal or absent autonomic features and abnormal physical findings like persistent ptosis in the headache-free period. Although many cases of symptomatic CH have been reported in literature we report the first case of CCF presenting as CH. Early identification is essential as it is completely curable with endovascular treatment.

To investigate the relation between cluster headache (CH) and lifestyle, some lifestyle factors were considered in a population of 374 CH male patients consecutively referred to the same headache center, including 306 with episodic CH, 22 with chronic CH unremitting from onset, 20 with chronic CH evolved from episodic, and 26 with CH periodicity undetermined CH patients had jobs involving greater responsibilities and were more frequently self-employed than controls. In addition, their past medical histories often reported head injury, either with loss of consciousness (13.4%) or without loss of consciousness (23.5% of cases). As regards nonessential consumption habits, both cigarette-smoking and coffee and alcohol intake were more frequently reported in CH patients than in the general population, with a higher prevalence in chronic CH as opposed to episodic CH sufferers. In particular, smokers accounted for 78.9% of episodic CH patients and 87.8% of chronic CH patients--12.9% of episodic CH patients and 19.6% of chronic CH patients smoked over 30 cigarettes a day. Alcohol abuse was reported in 16.2% of episodic and 26.8% of chronic CH patients, while coffee abuse was reported in 6.9% of episodic and in 36.6% of chronic CH patients. Rather than pointing to a single lifestyle factor directly implicated in CH onset, my review suggests a common trend among CH patients to overindulge in certain living habits.

Corticosteroids (C) rapidly suppress Cluster Headache (CH) attacks during the time required for the preventative agent verapamil (V), to have effects [1]. However, both drugs are often unsatisfactory. We present the case of a woman, affected by Chronic Cluster Headache (CCH), successfully treated with high doses of C and V. Moreover, we treated similarly 20 Episodic Cluster Headache (ECH) patients with satisfactory results. A 62-years old housewife, in 2006 had an isolated cluster (ICHD-II) of 40 days duration, unresponsive to NSAIDs. In 2008, she had a second cluster, responsive to 6 mg sc sumatriptan; oxygen inhalation was ineffective. Patient was successfully treated with V 240 mg and prednisone (P) 50 mg/day per os for 7 days, tapered in a month.In January 2009, she had a new cluster, that became chronic with 2-8 attacks/24 hours, not responsive to P 50 mg/day, V 320 mg/day, lithium (750 mg/day), valproate (1000 mg/day). When we saw her, in August 2011, she had 5 attacks/24 h, despite taking V per os 320 mg/day. Patient was administered methylprednisolone (MP) 500 mg iv/day for 2 days, then 250 mg for 3 days, followed by P 25 mg per os for 2 days, tapered in 8 days. V was increased gradually to 600 mg/day. In the following month there were no attacks. In September, she presented 1-3 attacks/24h nocturnal and mild, lasting 15 min. V was increased to 680 mg/day with disappearance of attacks. In November, V was slowly reduced to 320 with no recurrence. To the best of our knowledge this is the first report about high doses of iv MP associated with high doses of V per os being effective in CCH. Data are being elaborated on a group of 20 ECH patients treated similarly with good results. If confirmed, our findings warrant the reevaluation of the doses and timing of these drugs in CH with appropriate clinical trials.