Objective To evaluate individual and group long-term efficacy and safety of erenumab in individuals with episodic migraine (EM) for whom 2-4 prior preventatives had failed.Methods Participants... Show moreObjective To evaluate individual and group long-term efficacy and safety of erenumab in individuals with episodic migraine (EM) for whom 2-4 prior preventatives had failed.Methods Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could continue into an open-label extension phase (OLEP) receiving erenumab 140 mg monthly for up to 3 years. Main outcomes assessed at week 112 were: >= 50%, >= 75% and 100% reduction in monthly migraine days (MMD) as group responder rate and individual responder rates, MMD change from baseline, safety and tolerability.Results Overall 240/246 (97.6%) entered the OLEP (118 continuing erenumab, 122 switching from placebo). In total 181/240 (75.4%) reached 112 weeks, 24.6% discontinued, mainly due to lack of efficacy (44.0%), participant decision (37.0%) and adverse events (AEs; 12.0%). The >= 50% responder rate was 57.2% (99/173) at 112 weeks. Of >= 50% responders at the end of the DBTP, 36/52 (69.2%) remained responders at >= 50% and 22/52 (42.3%) at >80% of visits. Of the non-responders at the end of the DBTP, 60/185 (32.4%) converted to a50% responders in at least half the visits and 24/185 (13.0%) converted to >= 50% responders in >80% of visits. Change from baseline at 112 weeks in mean (SD) MMD was -4.2 (5.0) days. Common AEs (>= 10%) were nasopharyngitis, influenza and back pain.Conclusions Efficacy was sustained over 112 weeks in individuals with difficult-to-treat EM for whom 2-4 prior migraine preventives had failed. Erenumab treatment was safe and well tolerated, in-line with previous studies. Show less
Background: An increased risk of stroke in patients with migraine has been primarily found for women. The sex-dependent mechanisms underlying the migraine-stroke association, however, remain... Show moreBackground: An increased risk of stroke in patients with migraine has been primarily found for women. The sex-dependent mechanisms underlying the migraine-stroke association, however, remain unknown. This study aims to explore these sex differences to improve our understanding of pathophysiological mechanisms behind the migraine-stroke association.Methods: We included 2,492 patients with ischemic stroke from the prospective multicenter Dutch Parelsnoer Institute Initiative study, 425 (17%) of whom had a history of migraine. Cardiovascular risk profile, stroke cause (TOAST classification), and outcome [modified Rankin scale (mRS) at 3 months] were compared with both sexes between patients with and without migraine.Results: A history of migraine was not associated with sex differences in the prevalence of conventional cardiovascular risk factors. Women with migraine had an increased risk of stroke at young age (onset < 50 years) compared with women without migraine (RR: 1.7; 95% CI: 1.3-2.3). Men with migraine tended to have more often stroke in the TOAST category other determined etiology (RR: 1.7; 95% CI: 1.0-2.7) in comparison with men without migraine, whereas this increase was not found in women with migraine. Stroke outcome was similar for women with or without migraine (mRS >= 3 RR 1.1; 95% CI 0.7-1.5), whereas men seemed to have a higher risk of poor outcome compared with their counterparts without migraine (mRS >= 3 RR: 1.5; 95% CI: 1.0-2.1).Conclusion: Our results indicate possible sex differences in the pathophysiology underlying the migraine-stroke association, which are unrelated to conventional cardiovascular risk factors. Further research in larger cohorts is needed to validate these findings. Show less
Epidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally... Show moreEpidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally unrelated to seizures, or can occur before, during or after an episode; seizures and migraine attacks are mostly not temporally linked. The pathophysiological links between headaches (including migraine) and epilepsy are complex and have not yet been fully elucidated. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden. Here, we review the insights that have been made into the associations between headache and epilepsy over the past 5 years, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. We also discuss the current best practice for the management of headaches co-occurring with epilepsy and highlight future challenges for this area of research. Show less
Objective Identifying common genetic variants that confergenetic risk for cluster headache. Methods We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis... Show moreObjective Identifying common genetic variants that confergenetic risk for cluster headache. Methods We conducted a case-control study in the Dutch Leiden University Cluster headache neuro-Analysis program (LUCA) study population (n = 840) and unselected controls from the Netherlands Epidemiology of Obesity Study (NEO; n = 1,457). Replication was performed in a Norwegian sample of 144 cases from the Trondheim Cluster headache sample and 1,800 controls from the Nord-Trondelag Health Survey (HUNT). Gene set and tissue enrichment analyses, blood cell-derived RNA-sequencing of genes around the risk loci and linkage disequilibrium score regression were part of the downstream analyses. Results An association was found with cluster headache for 4 independent loci (r(2) < 0.1) with genomewide significance (p < 5 x 10(-8)), rs11579212 (odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.33-1.72 near RP11-815 M8.1), rs6541998 (OR = 1.53, 95% CI = 1.37-1.74 near MERTK), rs10184573 (OR = 1.43, 95% CI = 1.26-1.61 near AC093590.1), and rs2499799 (OR = 0.62, 95% CI = 0.54-0.73 near UFL1/FHL5), collectively explaining 7.2% of the variance of cluster headache. SNPs rs11579212, rs10184573, and rs976357, as proxy SNP for rs2499799 (r(2) = 1.0), replicated in the Norwegian sample (p < 0.05). Gene-based mapping yielded ASZ1 as possible fifth locus. RNA-sequencing indicated differential expression of POLR1B and TMEM87B in cluster headache patients. Interpretation This genomewide association study (GWAS) identified and replicated genetic risk loci for cluster headaches with effect sizes larger than those typically seen in complex genetic disorders. ANN NEUROL 2021 Show less
The hypothalamus has been suggested to be important in the initiation cascade of migraine attacks based on clinical and biochemical observations. Previous imaging studies could not disentangle the... Show moreThe hypothalamus has been suggested to be important in the initiation cascade of migraine attacks based on clinical and biochemical observations. Previous imaging studies could not disentangle the changes due to the attack and those due to the trigger compound. With a novel approach, we assessed hypothalamic neuronal activity in early premonitory phases of glyceryl-trinitrate (GTN)-induced and spontaneous migraine attacks. We measured the hypothalamic blood oxygen level-dependent (BOLD) response to oral glucose ingestion with 3T-functional magnetic resonance imaging (MRI) in 27 women, 16 with migraine without aura and 11 controls group matched for age and body mass index (BMI), on 1 day without prior GTN administration and on a second day after GTN administration (to coincide with the premonitory phase of an induced attack). Interestingly, subgroups of patients with and without GTN-triggered attacks could be compared. Additionally, five migraineurs were investigated in a spontaneous premonitory phase. Linear mixed models were used to study between- and within-group effects. Without prior GTN infusion, the BOLD response to glucose was similar in migraine participants and controls (P = .41). After prior GTN infusion, recovery occurred steeper and faster in migraineurs (versus Day 1; P < .0001) and in those who developed an attack versus those who did not (P < .0001). Prior GTN infusion did not alter the glucose-induced response in controls (versus baseline; P = .71). Just before spontaneous attacks, the BOLD-response recovery was also faster (P < .0001). In this study, we found new and direct evidence of altered hypothalamic neuronal function in the immediate preclinical phase of both GTN-provoked and spontaneous migraine attacks. Show less
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... Show moreBackground 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 neardiscomfort (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. Copyright (C) 2021 Elsevier Ltd. All rights reserved. Show less
Introduction Current prophylactic drugs for cluster headache are associated with limited efficacy, serious side effects and poor tolerability. Greater occipital nerve injection (GON-injection) has... Show moreIntroduction Current prophylactic drugs for cluster headache are associated with limited efficacy, serious side effects and poor tolerability. Greater occipital nerve injection (GON-injection) has been proven effective and safe as a single, one-time injection in episodic (ECH), and to a lesser extent, chronic cluster headache (CCH). We aim to analyse the effectiveness and safety of repeated GON-injections in medically intractable chronic cluster headache (MICCH). Methods Clinical data of all cluster headache patients who had received at least one GON-injection between 2014 and 2018 in our tertiary headache centre were retrieved from patients' medical records. Clinical history was taken as part of routine care shortly before and 6 weeks after GON-injection. Results We identified 47 MICCH patients (79 injections), and compared results with 22 non-MI CCH patients (30 injections) and 50 ECH patients (63 injections). Nineteen MICCH patients received repeated injections (32 in total, range 2-8). Rates of clinical relevant improvement to a first injection were similar in all groups (MICCH: 60%, non-MICCH 73%, ECH 76%; attack freedom: MICCH: 30%, non-MICCH 32%, ECH 43%). Furthermore, no difference in response to the first and second injection was shown between groups (all p > 0.29). Median effect duration in MICCH was 6 weeks (IQR 2.8-12 weeks). Side effects were only mild and local. Conclusion In this retrospective analysis, first and repeated GON-injections were well-tolerated and equally effective in MICCH as in non-MICCH, and ECH. Show less
Background and purpose This study was undertaken to investigate migraine prevalence in persons with hallucinogen persisting perception disorder (HPPD) presenting as visual snow syndrome (VSS)... Show moreBackground and purpose This study was undertaken to investigate migraine prevalence in persons with hallucinogen persisting perception disorder (HPPD) presenting as visual snow syndrome (VSS).Methods Persons with visual snow as a persisting symptom after illicit drug use (HPPD) were recruited via a Dutch consulting clinic for recreational drug use. A structured interview on (visual) perceptual symptomatology, details of drugs use, and medical and headache history was taken. As a control group, persons with visual snow who had never used illicit drugs prior to onset were included. The primary outcome was lifetime prevalence of migraine. Symptom severity was evaluated by the Visual Snow Handicap Inventory (VHI), a 25-item questionnaire.Results None of the 24 HPPD participants had migraine, whereas 20 of 37 (54.1%) controls had migraine (p < 0.001). VHI scores did not differ significantly between the two groups; in both groups, the median score was 38 of 100. In most HPPD cases (17/24, 70.9%), visual snow had started after intake of ecstasy; other psychedelic drugs reported included cannabis, psilocybin mushrooms, amphetamine, 4-fluoroamphetamine, 3-methylmethcathinone, 4-Bromo-2,5-dimethoxypenethylamine, and nitrous oxide.Conclusions Whereas none of the HPPD participants had migraine, more than half of the visual snow controls without prior use of illicit drugs had migraine. This suggests that at least partly different pathophysiological factors play a role in these disorders. Users of ecstasy and other hallucinogens should be warned of the risk of visual snow. Further studies are needed to enhance understanding of the underlying neurobiology of HPPD and VSS to enable better management of these conditions. Show less
Goadsby, P.J.; Reuter, U.; Lanteri-Minet, M.; Lima, G.P.D.; Hours-Zesiger, P.; Fernandes, C.; ... ; Klatt, J. 2021
ObjectiveTo report the efficacy and safety of erenumab among patients with episodic migraine (EM) whowere unsuccessful on 2 to 4 preventive treatments observed at week 64 of the open-label... Show moreObjectiveTo report the efficacy and safety of erenumab among patients with episodic migraine (EM) whowere unsuccessful on 2 to 4 preventive treatments observed at week 64 of the open-label extension phase (OLEP) of A Study Evaluating the Effectiveness of AMG 334 Injection in Preventing Migraines in Adults Having Failed Other Therapies (LIBERTY) study (ClinicalTrials.gov NCT03096834).MethodsTheOLEP, evaluatingmonthly erenumab 140 mg for 3 years, enrolled 240 patients who completed the double-blind treatment phase (DBTP) of 12 weeks during which they received placebo or erenumab 140 mg subcutaneous injections every 4 weeks as monotherapy. Efficacy outcomes were evaluated through the initial 52weeks ofOLEP (fromDBTP baseline to total 64weeks) in the overall population, patients receiving erenumab in DBTP, and patients from the DBTP placebo arm who switched to erenumab in OLEP. Endpoints included reduction of >= 50% in monthly migraine days (MMD) from DBTP baseline and change inMMDfrom DBTP baseline, Headache Impact Test score, and Migraine Physical Function Impact Diary score (Physical Impairment and Everyday Activities).ResultsAltogether, the week 52 visit of theOLEP was completed by 204 of 240 (85.0%) patients. Among patients continuing erenumab, the 50% responder rate increased from 29.9% at weeks 9 to 12 to 44.3% at weeks 61 to 64. The 50% responder rate in patientswho initiated erenumab in theOLEP remained higher in the OLEP (50.0% at week 61-64) than during DBTP (14.2% at weeks 9-12) compared to patients in continuous erenumab arm. In the OLEP, the 50% responder rate for the overall population increased from weeks 13 to 16 until weeks 37 to 40 and then remained stable through weeks 61 to 64. Patients treated with erenumab in DBTP showed sustained effects on all efficacy outcomes; those initiating erenumab in theOLEP demonstrated continued improvement from week 13 onward. Adverse events (AEs) were reported, considering both treatment groups, by approximate to 80.8% (serious AEs by 6.7%), 76.3% (5.9%) in the continuing erenumab arm, and 85.2% (7.4%) in those starting erenumab in OLEP. No deaths were reported.ConclusionsIn patients with EM who were unsuccessful on 2 to 4 prior preventive treatments, the LIBERTY study demonstrated sustained efficacy on erenumab monotherapy treatment through 64 weeks in both treatment arms. Safety of erenumab was consistent with that observed in previous clinical trials. Show less
Lanteri-Minet, M.; Goadsby, P.J.; Reuter, U.; Wen, S.H.; Hours-Zesiger, P.; Ferrari, M.D.; Klatt, J. 2021
Objective To evaluate the effect of erenumab on patient-reported, functional outcomes in patients with episodic migraine (EM) in whom 2-4 preventives were not useful from the Phase 3b LIBERTY study... Show moreObjective To evaluate the effect of erenumab on patient-reported, functional outcomes in patients with episodic migraine (EM) in whom 2-4 preventives were not useful from the Phase 3b LIBERTY study.MethodsAs previously reported, 246 patients with EM with 2-4 prior failed preventives were randomised 1:1 to subcutaneous erenumab 140 mg or placebo every 4 weeks for 12 weeks. This analysis evaluated Migraine Physical Function Impact Diary (MPFID), Headache Impact Test (HIT-6) and Work Productivity and Activity Impairment (WPAI) scores at Week 12. P values were nominal without multiplicity adjustment.ResultsErenumab significantly improved MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores versus placebo (treatment difference (TD) (95% CI) MPFID-PI: -3.5 (-5.7 to -1.2) (p=0.003); MPFID-EA: -3.9 (-6.1 to -1.7)) (p<0.001) at 12 weeks. Patients on erenumab were more likely to have a >= 5-point reduction in MPFID score (OR vs placebo (95% CI) MPFID-EA: 2.1 (1.2 to 3.6); MPFID-PI: 2.5 (1.4 to 4.5)). A similar trend was observed for HIT-6 (TD: -3.0; p<0.001); significantly higher proportions of patients on erenumab reported a >= 5-point reduction (OR (95% CI): 2.4 (1.4 to 4.1)). In three out of four WPAI domains, erenumab showed improvement versus placebo.ConclusionAt 12 weeks, erenumab was efficacious on functional outcomes in patients with EM in whom 2-4 preventives were not useful. Show less
Objective We propose a new outcome measure to assess the efficacy of migraine treatments translating the approach of the Global Burden of Disease studies from a societal to an individual level:... Show moreObjective We propose a new outcome measure to assess the efficacy of migraine treatments translating the approach of the Global Burden of Disease studies from a societal to an individual level: Instead of calculating "years lived with disability", we suggest estimating "time lost due to an attack".MethodsTime lost due to an attack is calculated by multiplying the duration and the degree of impaired functioning during an attack.ResultsTime lost due to an attack, different from other outcome measures, does not just focus on the short-term analgesic effects of treatments, but rather on the improvement of all migraine symptoms and restoration of functioning, also considering therapy-related impairment. Importantly, time lost due to an attack measures the entire time patients are not functioning normally, from onset to complete resolution.ConclusionsTime lost due to an attack represents a new paradigm to assess migraine burden in single patients for a patient-centered evaluation of both acute and prophylactic treatments. Show less
Objective The main objective of this study was to compare cerebrospinal fluid (CSF) collection time and patient's discomfort between 20G (a)traumatic and 22G atraumatic needles.Background Risk of... Show moreObjective The main objective of this study was to compare cerebrospinal fluid (CSF) collection time and patient's discomfort between 20G (a)traumatic and 22G atraumatic needles.Background Risk of post-dural puncture headache (PDPH) is decreased using atraumatic needles. Smaller needles may give lower risk but possibly at the cost of increased CSF collection time (due to lower flow), leading to additional patient's discomfort.Methods We performed a retrospective study of lumbar puncture data from a research program on CSF metabolomics and compared traumatic 20G (n = 210) with atraumatic 20G (n = 39) and 22G (n = 105) needles. In this cohort, incidence of PDPH was prospectively registered with other procedure details. Primary outcome was CSF collection time (time to fill the tube). Secondary outcomes were pain and stress scores during procedure, and incidence of PDPH.Results The time to collect 10 mL of CSF was longer for 22G needles (6.1 minutes; 95% CI 5.8-6.5) than for 20G traumatic (2.2 minutes; 95% CI 2.1-2.2) and 20G atraumatic needles (2.9 minutes; 95% CI 2.8-3.1). There were no differences in pain and stress scores. PDPH was lower for 22G atraumatic needles: odds ratio 0.41 (95% CI 0.25-0.66) versus 20G traumatic needles and 0.53 (95% CI 0.40-0.69) versus 20G atraumatic needles. Absolute PDPH rates were 69/210 (32.9%) for 20G traumatic, 13/39 (33.3%) for 20G atraumatic, and 19/105 (18.1%) for 22G atraumatic needles.Conclusions CSF collection time is slightly longer for smaller 22G needles, but this does not lead to more discomfort for the patient. Show less
Enhanced activity of the glutamatergic system has been linked to migraine pathophysiology. The present study aimed to assess the involvement of the glutamatergic system in the onset of attacks. We... Show moreEnhanced activity of the glutamatergic system has been linked to migraine pathophysiology. The present study aimed to assess the involvement of the glutamatergic system in the onset of attacks. We provoked attacks by infusion of glyceryl trinitrate (GTN; 0.5 mu g/kg/min over 20 min) in 24 female episodic migraineurs without aura and 13 female age-matched healthy controls. Over the course of a single day participants were scanned three times at fixed time slots (baseline before GTN infusion, 90 min and 270 min after start of GTN infusion). Single volume proton magnetic resonance spectra (H-1-MRS) were acquired at 7 Tesla from a volume of interest (VOI, 2x2x3 cm) in the visual cortex. We assessed the concentrations of glutamate, its major precursor glutamine, and its product gamma-aminobutyric acid (GABA) over the course of a provoked attack. The preictal state was defined as the period after GTN infusion until the migraine-like headache started, independent of possible experienced premonitory symptoms, and the ictal state was defined as the period with provoked migraine-like headache. Data were analyzed using a linear mixed-effect model for repeated measures. Glutamate and glutamine levels did not change from interictal to the preictal and ictal state. GABA levels increased from interictal towards the preictal state for migraine patients compared with healthy controls. We conclude that high resolution 7T MRS is able to show changes in the glutamatergic system towards a triggered migraine attack, by revealing an increased GABA concentration associated with the onset of a migraine attack. Show less
