A prospective open label 2-8 year extension of the randomised controlled ICON trial on the long-term efficacy and safety of occipital nerve stimulation in medically intractable chronic cluster headache.

BACKGROUND: We demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety. METHODS: ICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals. FINDINGS: Of 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8-6.3), two (5.1; 3.5-7.6) and five years (4.1; 3.0-5.5) compared to baseline (16.2; 14.4-18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68-0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70-0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year-1 [0.28-0.41]). We didn't find predictive factors for effectiveness. INTERPRETATION: ONS is a safe, well-tolerated and long-term effective treatment for MICCH. FUNDING: The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.

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.

Intra- and interindividual attack frequency variability of chronic cluster headache.

BACKGROUND: The lack of knowledge about the intra- and interindividual attack frequency variability in chronic cluster headache complicates power and sample size calculations for baseline periods of trials, and consensus on their most optimal duration. METHODS: We analyzed the 12-week baseline of the ICON trial (occipital nerve stimulation in medically intractable chronic cluster headache) for: (i) weekly vs. instantaneous recording of attack frequency; (ii) intra-individual and seasonal variability of attack frequency; and (iii) the smallest number of weeks to obtain a reliable estimate of baseline attack frequency. RESULTS: Weekly median (14.4 [8.2-24.0]) and instantaneous (14.2 [8.0-24.5]) attack frequency recordings were similar (p = 0.20; Bland-Altman plot). Median weekly attack frequency was 15.3 (range 4.2-140) and highest during spring (p = 0.001) compared to the other seasons. Relative attack frequency variability decreased with increasing attack frequency (p = 0.010). We tabulated the weekly attack frequency estimation accuracies compared to, and the associated deviations from, the 12-week gold standard for different lengths of the observation period. CONCLUSION: Weekly retrospective attack frequency recording is as good as instantaneous recording and more convenient. Attack frequency is highest in spring. Participants with ≥3 daily attacks show less attack frequency variability than those with <3 daily attacks. An optimal balance between 90% accuracy and feasibility is achieved at a baseline period of seven weeks.The ICON trial is registered in ClinicalTrials.gov under number NCT01151631.

Safety and efficacy of occipital nerve stimulation for attack prevention in medically intractable chronic cluster headache (ICON): a randomised, double-blind, multicentre, phase 3, electrical dose-controlled trial.

BACKGROUND: Occipital nerve stimulation (ONS) has shown promising results in small uncontrolled trials in patients with medically intractable chronic cluster headache (MICCH). We aimed to establish whether ONS could serve as an effective treatment for patients with MICCH. METHODS: The ONS in MICCH (ICON) study is an investigator-initiated, international, multicentre, randomised, double-blind, phase 3, electrical dose-controlled clinical trial. The study took place at four hospitals in the Netherlands, one hospital in Belgium, one in Germany, and one in Hungary. After 12 weeks' baseline observation, patients with MICCH, at least four attacks per week, and history of being non-responsive to at least three standard preventive drugs, were randomly allocated (at a 1:1 ratio using a computer-generated permuted block) to 24 weeks of occipital nerve stimulation at either 100% or 30% of the individually determined range between paraesthesia threshold and near-discomfort (double-blind study phase). Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy. In weeks 25-48, participants received individually optimised open-label ONS. The primary outcome was the weekly mean attack frequency in weeks 21-24 compared with baseline across all patients and, if a decrease was shown, to show a group-wise difference. The trial is closed to recruitment (ClinicalTrials.gov NCT01151631). FINDINGS: Patients were enrolled between Oct 12, 2010, and Dec 3, 2017. We enrolled 150 patients and randomly assigned 131 (87%) to treatment; 65 (50%) patients to 100% ONS and 66 (50%) to 30% ONS. One of the 66 patients assigned to 30% ONS was not implanted and was therefore excluded from the intention-to-treat analysis. Because the weekly mean attack frequencies at baseline were skewed (median 15·75; IQR 9·44 to 24·75) we used log transformation to analyse the data and medians to present the results. Median weekly mean attack frequencies in the total population decreased from baseline to 7·38 (2·50 to 18·50; p<0·0001) in weeks 21-24, a median change of -5·21 (-11·18 to -0·19; p<0·0001) attacks per week. In the 100% ONS stimulation group, mean attack frequency decreased from 17·58 (9·83 to 29·33) at baseline to 9·50 (3·00 to 21·25) at 21-24 weeks (median change from baseline -4·08, -11·92 to -0·25), and for the 30% ONS stimulation group, mean attack frequency decreased from 15·00 (9·25 to 22·33) to 6·75 (1·50 to 16·50; -6·50, -10·83 to -0·08). The difference in median weekly mean attack frequency between groups at the end of the masked phase in weeks 21-24 was -2·42 (95% CI -5·17 to 3·33). In the masked study phase, 129 adverse events occurred with 100% ONS and 95 occurred with 30% ONS. None of the adverse events was unexpected but 17 with 100% ONS and eight with 30% ONS were labelled as serious, given they required brief hospital admission for minor hardware-related issues. The most common adverse events were local pain, impaired wound healing, neck stiffness, and hardware damage. INTERPRETATION: In patients with MICCH, both 100% ONS intensity and 30% ONS intensity substantially reduced attack frequency and were safe and well tolerated. Future research should focus on optimising stimulation protocols and disentangling the underlying mechanism of action. FUNDING: The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.

Chronobiology and Sleep in Cluster Headache.

BACKGROUND: Cluster headache attacks follow a striking circadian rhythm with an intriguing influence of sleep. We aim to investigate differences in sleep quality, chronotype, and the ability to alter individual sleep rhythms in episodic and chronic cluster headache patients vs controls. METHODS: Cluster headache patients and non-headache controls from the Dutch Leiden University Cluster headache neuro-Analysis program aged 18 and above completed web-based questionnaires in a cross-sectional study. RESULTS: A total of 478 episodic, 147 chronic cluster headache patients and 367 controls participated. Chronic cluster headache patients had more often early chronotypes than controls, as measured by mid-sleep phase (P = .021 adjusted B -15.85 minutes CI -29.30; -2.40). Compared to controls, chronic cluster headache participants were less able to alter their sleep rhythms (P < .001 adjusted B -1.65 CI -2.55; 0.74), while episodic cluster headache participants reported more difficulty in coping with reduced sleep (P = .025 adjusted B 0.75 CI 0.09; 1.40). Sleep quality was reduced in both types of cluster headache compared to controls ("poor sleepers": 71.4% (105/147) in chronic and 48.3% (235/367) in episodic cluster headache vs 25.6% (94/367) in controls; both P < .001; episodic adjusted B -1.71 CI 0.10; 0.32; chronic adjusted B -0.93 CI 0.24; 0.65). CONCLUSION: Sleep quality is decreased in both episodic and chronic cluster headache, most likely caused by cluster headache attacks that strike during the night. Episodic cluster headache patients report more difficulty in coping with reduced sleep, while chronic patients are less able to alter their sleep rhythm. Although not directly proven, cluster headache patients will likely benefit from a structured, regular daily schedule.

Increased use of illicit drugs in a Dutch cluster headache population.

INTRODUCTION: Many patients with cluster headache report use of illicit drugs. We systematically assessed the use of illicit drugs and their effects in a well-defined Dutch cluster headache population. METHODS: In this cross-sectional explorative study, 756 people with cluster headache received a questionnaire on lifetime use and perceived effects of illicit drugs. Results were compared with age and sex-matched official data from the Dutch general population. RESULTS: Compared to the data from the general population, there were more illicit drug users in the cluster headache group (31.7% vs. 23.8%; p < 0.01). Reduction in attack frequency was reported by 56% (n = 22) of psilocybin mushroom, 60% (n = 3) of lysergic acid diethylamide and 50% (n = 2) of heroin users, and a decreased attack duration was reported by 46% (n = 18) of PSI, 50% (n = 2) of heroin and 36% (n = 8) of amphetamine users. CONCLUSION: In the Netherlands, people with cluster headache use illicit drugs more often than the general population. The question remains whether this is due to an actual alleviatory effect, placebo response, conviction, or common pathophysiological background between cluster headache and addictive behaviours such as drug use.

Aura in Cluster Headache: A Cross-Sectional Study.

BACKGROUND: Aura symptoms have been reported in up to 23% of cluster headache patients, but it is not known whether clinical characteristics are different in participants with and without aura. METHODS: Using validated web-based questionnaires we assessed the presence and characteristics of attack-related aura and other clinical features in 629 subjects available for analysis from an initial cohort of 756 cluster headache subjects. Participants who screened positive for aura were contacted by telephone for confirmation of the ICHD-III criteria for aura. RESULTS: Typical aura symptoms before or during cluster headache attacks were found in 44/629 participants (7.0%) mainly involving visual symptoms (61.4%). Except for lower alcohol consumption and higher prevalence of frontal pain in participants with aura, no differences in clinical characteristics were found compared with participants without aura. CONCLUSION: At least 7.0% of the participants with cluster headache in our large cohort reported typical aura symptoms, which most often involved visual symptoms. No major clinical differences were found between participants with and without aura.

Allodynia in cluster headache.

Cutaneous allodynia is an established marker for central sensitization in migraine. There is debate whether cutaneous allodynia may also occur in cluster headache, another episodic headache disorder. Here, we examined the presence and severity of allodynia in a large well-defined nationwide population of people with cluster headache. Using validated questionnaires we assessed, cross-sectionally, ictal allodynia and comorbid depression and migraine in the nationwide "Leiden University Cluster headache neuro-Analysis" (LUCA) study. Participants with cluster headache were diagnosed according to the International Classification of Headache Disorders criteria. Multivariate regression models were used, with correction for demographic factors and cluster headache subtype (chronic vs episodic; recent attacks <1 month vs no recent attacks). In total, 606/798 (75.9%) participants with cluster headache responded; of whom, 218/606 (36%) had allodynia during attacks. Female gender (odds ratio [OR] 2.05, 95% confidence interval [95% CI] 1.28-3.29), low age at onset (OR 0.98, 95% CI 0.96-0.99), lifetime depression (OR 1.63, 95% CI 1.06-2.50), comorbid migraine (OR 1.96, 95% CI 1.02-3.79), and having recent attacks (OR 1.80, 95% CI 1.13-2.86), but not duration of attacks and chronic cluster headache, were independent risk factors for allodynia. The high prevalence of cutaneous allodynia with similar risk factors for allodynia as found for migraine suggests that central sensitization, like in migraine, also occurs in cluster headache. In clinical practice, awareness that people with cluster headache may suffer from allodynia can in the future be an important feature in treatment options.

Cluster headache and depression.

OBJECTIVE: As cluster headache (CH) is often referred to as "suicide headache," we wanted to assess the prevalence of depression in CH patients, and to investigate determinants of depression such as sleep disturbances. METHODS: In a cross-sectional, web-based, validated questionnaire study among 462 well-defined CH patients and 177 controls, we diagnosed CH according to the ICHD-III. We assessed depression using the Hospital Anxiety and Depression Scale (HADS-D) and the Center for Epidemiologic Studies Depression scale (CES-D) with supplementary questions to assess lifetime depression. Data were analyzed with logistic and linear regression models. RESULTS: Lifetime depression showed almost 3 times higher odds in CH patients (n = 462) than controls (n = 177) (odds ratio 2.77; 95% confidence interval 1.70-4.51). Chronic (n = 67) vs episodic (n = 394) patients had a higher prevalence of lifetime depression and more sleeping problems. Current depression was associated with having active attacks (last attack <1 month) (adjusted p = 0.02), but no effect remained after correction for sleep disturbances. CONCLUSIONS: CH is associated with an almost 3 times increased odds of lifetime depression. Current depression is highly prevalent in patients with active disease, in part related to sleep disturbances due to current nocturnal attacks.

Symptomatic Trigeminal Autonomic Cephalalgias.

Trigeminal autonomic cephalalgias (TACs) are primary headache syndromes that share some clinical features such as a trigeminal distribution of the pain and accompanying ipsilateral autonomic symptoms. By definition, no underlying structural lesion for the phenotype is found. There are, however, many descriptions in the literature of patients with structural lesions causing symptoms that are indistinguishable from those of idiopathic TACs. In this article, we review the recent insights in symptomatic TACs by comparing and categorizing newly published cases. We confirm that symptomatic TACs can have typical phenotypes. It is of crucial importance to identify symptomatic TACs, as the underlying cause will influence treatment and outcome. Our update focuses on when a structural lesion should be sought.

Cluster headache and the hypocretin receptor 2 reconsidered: a genetic association study and meta-analysis.

BACKGROUND: Cluster headache is a severe neurological disorder with a complex genetic background. A missense single nucleotide polymorphism (rs2653349; p.Ile308Val) in the HCRTR2 gene that encodes the hypocretin receptor 2 is the only genetic factor that is reported to be associated with cluster headache in different studies. However, as there are conflicting results between studies, we re-evaluated its role in cluster headache. METHODS: We performed a genetic association analysis for rs2653349 in our large Leiden University Cluster headache Analysis (LUCA) program study population. Systematic selection of the literature yielded three additional studies comprising five study populations, which were included in our meta-analysis. Data were extracted according to predefined criteria. RESULTS: A total of 575 cluster headache patients from our LUCA study and 874 controls were genotyped for HCRTR2 SNP rs2653349 but no significant association with cluster headache was found (odds ratio 0.91 (95% confidence intervals 0.75-1.10), p = 0.319). In contrast, the meta-analysis that included in total 1167 cluster headache cases and 1618 controls from the six study populations, which were part of four different studies, showed association of the single nucleotide polymorphism with cluster headache (random effect odds ratio 0.69 (95% confidence intervals 0.53-0.90), p = 0.006). The association became weaker, as the odds ratio increased to 0.80, when the meta-analysis was repeated without the initial single South European study with the largest effect size. CONCLUSIONS: Although we did not find evidence for association of rs2653349 in our LUCA study, which is the largest investigated study population thus far, our meta-analysis provides genetic evidence for a role of HCRTR2 in cluster headache. Regardless, we feel that the association should be interpreted with caution as meta-analyses with individual populations that have limited power have diminished validity.

Cluster-tic syndrome: a cross-sectional study of cluster headache patients.

OBJECTIVE: To determine the prevalence and nature of trigeminal neuralgia in a large group of cluster headache patients. BACKGROUND: Cluster-tic syndrome is a rare headache syndrome in which trigeminal neuralgia and cluster headache co-occur. The existence of cluster-tic syndrome as a separate entity is questioned, and figures on prevalence of simultaneous existence of cluster headache and trigeminal neuralgia are not available. METHODS: As part of a nationwide study on headache mechanisms in cluster headache (Leiden University Medical Centre Cluster headache Neuro Analysis programme), we collected clinical data of 244 cluster headache patients using a semistructured telephone interview in a cross-sectional design. RESULTS: In 11 (4.5%) cluster headache patients, attacks fulfilling International Headache Society criteria for trigeminal neuralgia were also present. In all cases, trigeminal neuralgia occurred ipsilateral to cluster headache and in the majority (82%) in the ophthalmic branch. In 8 of these 11 patients (73%), the frequency and time pattern of trigeminal neuralgia seemed to parallel cluster headache and was likely a part of the cluster headache spectrum. In the 3 remaining patients, cluster headache and trigeminal neuralgia were unrelated in time and appeared to occur independently. CONCLUSION: Trigeminal neuralgia co-occurred in 11/244 (4.5%) of cluster headache patients. In only 3 (1.2%) patients, trigeminal neuralgia seemed to occur independently from cluster headache episodes. Trigeminal neuralgia (-like) attacks in cluster headache patients are most of the time part of the cluster headache spectrum and should then probably not be treated separately. A shared underlying pathophysiological mechanism of cluster headache and trigeminal neuralgia is not supported by this study.

Occipital nerve stimulation in medically intractable, chronic cluster headache. The ICON study: rationale and protocol of a randomised trial.

BACKGROUND: About 10% of cluster headache patients have the chronic form. At least 10% of this chronic group is intractable to or cannot tolerate medical treatment. Open pilot studies suggest that occipital nerve stimulation (ONS) might offer effective prevention in these patients. Controlled neuromodulation studies in treatments inducing paraesthesias have a general problem in blinding. We have introduced a new design in pain neuromodulation by which we think we can overcome this problem. METHODS/DESIGN: We propose a prospective, randomised, double-blind, parallel-group international clinical study in medically intractable, chronic cluster headache patients of high- versus low-amplitude ONS. Primary outcome measure is the mean number of attacks over the last four weeks. After a study period of six months there is an open extension phase of six months. Alongside the randomised trial an economic evaluation study is performed. DISCUSSION: The ICON study will show if ONS is an effective preventive therapy for patients suffering medically intractable chronic cluster headache and if there is a difference between high- and low-amplitude stimulation. The innovative design of the study will, for the first time, assess efficacy of ONS in a blinded way.

Stepwise web-based questionnaires for diagnosing cluster headache: LUCA and QATCH.

BACKGROUND: Cluster headache (CH) is a primary headache disorder that is diagnosed based on the patient's history. For large-scale epidemiologic and genetic studies, a web-based, preferably short, questionnaire can be a feasible alternative to replace time-consuming clinical interviews. METHODS: Self-reported CH patients were enrolled via our research website. Participants meeting screening criteria were directed to the Leiden University Cluster headache Analysis program (LUCA) questionnaire. Individual diagnoses were calculated using an algorithm based on International Headache Society criteria. Subsequently, semi-structured telephone interviews were carried out to validate the LUCA questionnaire. The shorter Quick Ascertainment of Cluster Headache (QATCH) questionnaire for diagnosing CH was constructed by using logistic regression to select the most predictive questions. RESULTS: Via our website 437 self-reported CH patients were recruited. Of these, 291 patients were included in this cross-sectional study. The LUCA questionnaire was valid and accurate. Using logistic regression, three questions (QATCH) provided similar sensitivity (53.8% vs. 57.2%), specificity (88.9% vs. 87.5%), positive predictive value (95.5% vs. 95.9%) and negative predictive value (30.8% vs. 28.8%) compared with the LUCA questionnaire. CONCLUSION: The web-based LUCA questionnaire was accurate and reliable in diagnosing CH among self-reported patients. Males with headache attacks of short duration and long headache-free intervals (months to years) are very likely to have CH.

Neuroimaging in trigeminal autonomic cephalgias: when, how, and of what?

PURPOSE OF REVIEW: Trigeminal autonomic cephalgias (TACs) are characterized by frequent, short-lasting headache attacks with ipsilateral facial autonomic features. They include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. The pathogenesis of TACs is largely unknown, but many case reports in the literature suggest that TACs are secondary to structural lesions. Thus, the question arises whether TAC patients should undergo neuroimaging. Here, we review the recent literature on secondary TACs and attempt to formulate guidelines for neuroimaging. RECENT FINDINGS: Recently, we published two reviews of, in total, 33 case reports of patients with a secondary TAC or TAC-like syndrome. Since then, 23 additional cases have been published. Here, we provide a summary of these 56 case reports. TACs were found to be associated with a wide range of both intracranial and extracranial neurovascular and structural lesions. We could not identify a 'typical' clinical warning profile for secondary TACs as these patients could present with clinical features that are entirely characteristic of a TAC, including alternating attack and attack-free periods, and excellent response to TAC-specific treatments. SUMMARY: Even clinically typical TACs can be caused by structural lesions. There are no 'typical' warning signs or symptoms. Neuroimaging should be considered in all patients with TAC or TAC-like syndromes, notably in those with atypical presentation. Depending on the degree of suspicion, additional imaging should be considered assessing intracranial and cervical vasculature, and the sellar and paranasal region.