Efficacy of Atogepant in Chronic Migraine With and Without Acute Medication Overuse in the Randomized, Double-Blind, Phase 3 PROGRESS Trial.

BACKGROUND AND OBJECTIVES: Atogepant is an oral, calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine. We evaluated the efficacy of atogepant for the preventive treatment of chronic migraine (CM) in participants with and without acute medication overuse. METHODS: This subgroup analysis of the phase 3, 12-week, randomized, double-blind, placebo-controlled PROGRESS trial evaluated adults with a ≥1-year history of CM, ≥15 monthly headache days (MHDs), and ≥8 monthly migraine days (MMDs) during the 4-week baseline period. Participants were randomized (1:1:1) to placebo, atogepant 30 mg twice daily (BID), or atogepant 60 mg once daily (QD) for 12 weeks and were analyzed by acute medication overuse status (triptans/ergots for ≥10 days per month, simple analgesics for ≥15 days per month, or combinations of triptans/ergots/simple analgesics for ≥10 days per month). Outcomes included change from baseline in mean MMDs, MHDs, and monthly acute medication use days; ≥50% reduction in mean MMDs across 12 weeks; and patient-reported outcome (PRO) measures. RESULTS: Of 755 participants in the modified intent-to-treat population, 500 (66.2%) met baseline acute medication overuse criteria (placebo, n = 169 [68.7%]; atogepant 30 mg BID, n = 161 [63.6%]; atogepant 60 mg QD, n = 170 [66.4%]). The least squares mean difference (LSMD) (95% CI) from placebo in MMDs was -2.7 (-4.0 to -1.4) with atogepant 30 mg BID and -1.9 (-3.2 to -0.6) with atogepant 60 mg QD. Mean MHDs (LSMD [95% CI] -2.8 [-4.0 to -1.5] and -2.1 [-3.3 to -0.8]) and mean acute medication use days (LSMD [95% CI] -2.8 [-4.1 to -1.6] and -2.6 [-3.9 to -1.3]) were reduced and a higher proportion of participants achieved ≥50% reduction in MMDs (odds ratio [95% CI] 2.5 [1.5-4.0] and 2.3 [1.4-3.7]) with atogepant 30 mg BID and atogepant 60 mg QD. There was a 52.1%-61.9% reduction in the proportion of atogepant-treated participants meeting acute medication overuse criteria over 12 weeks. Atogepant improved PRO measures. Similar results were observed in the subgroup without acute medication overuse. DISCUSSION: Atogepant was effective in participants with CM, with and without acute medication overuse, as evidenced by reductions in mean MMDs, MHDs, and acute medication use days; reductions in the proportion of participants meeting acute medication overuse criteria; and improvements in PROs. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT03855137. Submitted: February 25, 2019; first patient enrolled: March 11, 2019. clinicaltrials.gov/ct2/show/NCT03855137. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that atogepant reduces mean MMDs, MHDs, and monthly acute medication use days in adult patients with or without medication overuse.

Pituitary cyclase-activating polypeptide targeted treatments for the treatment of primary headache disorders.

OBJECTIVE: Migraine is a complex and disabling neurological disorder. Recent years have witnessed the development and emergence of novel treatments for the condition, namely those targeting calcitonin gene-related peptide (CGRP). However, there remains a substantial need for further treatments for those unresponsive to current therapies. Targeting pituitary adenylate cyclase-activating polypeptide (PACAP) as a possible therapeutic strategy in the primary headache disorders has gained interest over recent years. METHODS: This review will summarize what we know about PACAP to date: its expression, receptors, roles in migraine and cluster headache biology, insights gained from preclinical and clinical models of migraine, and therapeutic scope. RESULTS: PACAP shares homology with vasoactive intestinal polypeptide (VIP) and is one of several vasoactive neuropeptides along with CGRP and VIP, which has been implicated in migraine neurobiology. PACAP is widely expressed in areas of interest in migraine pathophysiology, such as the thalamus, trigeminal nucleus caudalis, and sphenopalatine ganglion. Preclinical evidence suggests a role for PACAP in trigeminovascular sensitization, while clinical evidence shows ictal release of PACAP in migraine and intravenous infusion of PACAP triggering attacks in susceptible individuals. PACAP leads to dural vasodilatation and secondary central phenomena via its binding to different G-protein-coupled receptors, and intracellular downstream effects through cyclic adenosine monophosphate (cAMP) and phosphokinase C (PKC). Targeting PACAP as a therapeutic strategy in headache has been explored using monoclonal antibodies developed against PACAP and against the PAC1 receptor, with initial positive results. INTERPRETATION: Future clinical trials hold considerable promise for a new therapeutic approach using PACAP-targeted therapies in both migraine and cluster headache.

Recent advances in diagnosing, managing, and understanding the pathophysiology of cluster headache.

Cluster headache, characterised by attacks of severe, recurrent, unilateral headache and ipsilateral cranial autonomic symptoms, remains a primary headache with an elusive pathophysiology. Recent advances have introduced effective treatments and broadened understanding of the clinical features of cluster headache. These features are similar in patients globally, but regional differences in prevalence and burden exist. International collaborations have led to identification of eight genetic loci associated with cluster headache. The pathophysiological mechanisms are still not fully understood but recent studies show that targeting the trigeminal autonomic reflex by neurostimulation, or targeting the neuropeptide calcitonin gene-related peptide (CGRP), might lessen the attack burden. The US Food and Drug Administration has approved galcanezumab, a monoclonal antibody targeting CGRP, as the first specific preventive treatment for episodic cluster headache. However, a preventive effect was not replicated in chronic cluster headache, and the European Medicines Agency did not approve galcanezumab, restricting its availability in Europe. Owing to the low prevalence of cluster headache, continued collaboration through multicentre clinical trials and data sharing will be imperative for further breakthroughs in understanding and management.

Intervening in the Premonitory Phase to Prevent Migraine: Prospects for Pharmacotherapy.

Migraine is a common brain condition characterised by disabling attacks of headache with sensory sensitivities. Despite increasing understanding of migraine neurobiology and the impacts of this on therapeutic developments, there remains a need for treatment options for patients underserved by currently available therapies. The first specific drugs developed to treat migraine acutely, the serotonin-5-hydroxytryptamine [5-HT1B/1D] receptor agonists (triptans), seem to require headache onset in order to have an effect, while early treatment during mild pain before headache escalation improves short-term and long-term outcomes. Some patients find treating in the early window once headache has started but not escalated difficult, and migraine can arise from sleep or in the early hours of the morning, making prompt treatment after pain onset challenging. Triptans may be deemed unsuitable for use in patients with vascular disease and in those of older age and may not be effective in a proportion of patients. Headache is also increasingly recognised as being just one of the many facets of the migraine attack, and for some patients it is not the most disabling symptom. In many patients, painless symptoms can start prior to headache onset and can reliably warn of impending headache. There is, therefore, a need to identify therapeutic targets and agents that may be used as early as possible in the course of the attack, to prevent headache onset before it starts, and to reduce both headache and non-headache related attack burden. Early small studies using domperidone, naratriptan and dihydroergotamine have suggested that this approach could be useful; these studies were methodologically less rigorous than modern day treatment studies, of small sample size, and have not since been replicated. The emergence of novel targeted migraine treatments more recently, specifically calcitonin gene-related peptide (CGRP) receptor antagonists (gepants), has reignited interest in this strategy, with encouraging results. This review summarises historical and emerging data in this area, supporting use of the premonitory phase as an opportunity to intervene as early as possible in migraine to prevent attack-related morbidity.

Medication-overuse headache: a narrative review.

Medication-overuse headache (MOH), which potentially involves 1-2% of the population, is defined as a headache, on ≥ 15 days a month affected, along with overuse of one or other acute attack medications. MOH presents with significant challenges in the headache community, particularly in clinical settings raising various questions about its pathophysiology. Through a review of the current literature and our clinical experience, we have explored the mechanisms through which MOH may occur, provide an understanding of the current state of treatment and detail some possible views on the understanding and treatment of this condition. We evaluate the variations in treatment methods offered globally and understanding of the disorder. Above all interventions, patient education is crucial, which is underscored by an analysis of the academic publications. Given the condition is preventable, early intervention is imperative and patient awareness is highlighted as key. Globally, there is no uniform treatment methodology, which may be advantageous as approaches need to take local circumstances into account.

Extended Phenotyping of Migraine in Children: A Cross-Sectional Study in a Specialist Children's Headache Clinic.

BACKGROUND: The pediatric migraine phenotype may exhibit differences to adults, leading to diagnostic challenges. We aimed to perform a cross-sectional systematic study to characterize the extended phenotype of pediatric migraine. METHODS: New migraine patients presenting to the Children's Headache Clinic were included (n = 105). Data were collected via a detailed symptom questionnaire at the first clinical encounter and were analyzed using descriptive statistics, Cohen kappa (k), Spearman correlation (ρ), and Poisson and binomial logistic regression models within SPSS. RESULTS: Patients were 65% female and aged five to 17 years (median 14, interquartile range [IQR] 11 to 15), with a mean disease duration of 4.7 years (S.D. 2.8). Monthly headache frequency was 1 to 30 days (median 30, IQR 12 to 30). Attack duration varied between 2 and 168 hours (median 12, IQR 5 to 72). The majority (81%) experienced bilateral headache. Premonitory symptoms (PS) were reported by 93% (range 0 to 7; mood change and tiredness most commonly), cranial autonomic symptoms (CAS) by 58% (range 0 to 6; pallor and lacrimation most commonly), and premonitory CAS by 23%. Vertigo (53%) and allodynia (16%) were present. The laterality of headache and CAS showed agreement (k = 0.5, P < 0.001). For every year of disease duration, 1.07 times more PS were reported (95% confidence interval [CI] 1.03 to 1.12, P < 0.001). The number of CAS (odds ratio 2.13, 95% CI 1.2 to 3.8, P = 0.01) significantly predicted allodynia. CONCLUSIONS: Children display a more enriched PS phenotype with disease chronicity. CAS and allodynia may be markers of central sensitization with shared neurobiological mechanisms in the absence of peripheral nociceptor activation.

Indomethacin-Responsive Headache Disorders.

OBJECTIVE: This article describes the clinical features and treatment of the indomethacin-responsive headache disorders paroxysmal hemicrania and hemicrania continua. LATEST DEVELOPMENTS: Both paroxysmal hemicrania and hemicrania continua are treated with indomethacin at the lowest clinically useful dose. It has recently become clear that some patients with either condition may respond to treatment with noninvasive vagus nerve stimulation, which can be both indomethacin sparing and, in some cases, headache controlling. Given the lifelong nature of both paroxysmal hemicrania and hemicrania continua, brain imaging with MRI is recommended when the conditions are identified, specifically including pituitary views. ESSENTIAL POINTS: Paroxysmal hemicrania and hemicrania continua are indomethacin-responsive headache disorders that offer a rewarding and unique opportunity to provide marked clinical improvement when recognized and treated appropriately. These disorders share the final common pathway of the trigeminal-autonomic reflex, with head pain and cranial autonomic features, and are differentiated pathophysiologically by the pattern of brain involvement, which can be seen using functional imaging. They have distinct differential diagnoses to which the clinician needs to remain alert.

Efficacy and Safety of Erenumab in Participants With Episodic Migraine in Whom 2-4 Prior Preventive Treatments Had Failed: LIBERTY 3-Year Study.

BACKGROUND AND OBJECTIVES: The LIBERTY study assessed the efficacy and safety of erenumab in participants with episodic migraine (EM) and 2-4 prior preventive treatment failures. The results have been presented after 3 years of erenumab exposure in its open-label extension phase (OLEP). METHODS: Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could enter the OLEP and receive 140 mg of erenumab once monthly for 3 years. The main outcomes included the proportion of participants achieving ≥50% reduction in monthly migraine days (MMDs), the mean MMD change from baseline, and tolerability and safety. RESULTS: Overall, 240/246 (97.6%) participants entered the OLEP and 168/240 (70.0%) completed the study (85/118 continuing erenumab [n = 1 lost during follow-up]; 83/122 switching from placebo [n = 2 lost during follow-up]). In the overall population, 79/151 participants (52.3%) with valid data points achieved ≥50% reduction in MMDs at week 168 (i.e., responders). In the continuous erenumab group, 35/117 participants (29.9%) were ≥50% responders at week 12 of the DBTP and 26/35 (74.3%) remained ≥50% responders in at least half of OLEP visits. Of the 82/117 participants (70.1%) not achieving responder status at week 12 in the continuous erenumab group, 17/82 (20.7%) converted to ≥50% responders in at least half of OLEP visits. Of 103/120 participants (85.8%) not achieving responder status at week 12 in the placebo-erenumab group, 42/103 (40.8%) converted to ≥50% responders in at least half of OLEP visits after switching to erenumab. Overall, the mean (SD) MMD change from baseline showed sustained improvement over 3 years (-4.4 [3.9] days at week 168). The most common treatment-emergent AEs (per 100 person-years) were nasopharyngitis (28.8), influenza (7.5), and back pain (5.8). Overall, 9.6% (3.9 per 100 person-years) and 6.7% (2.7 per 100 person-years) of participants reported events of treatment-emergent hypertension and constipation, respectively. The safety and tolerability profile remained consistent with earlier studies. DISCUSSION: Erenumab (140 mg) showed sustained efficacy over 3 years in participants with EM and 2-4 prior preventive treatment failures. No new safety signals were observed. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov Identifier: NCT03096834.

An economic evaluation of eptinezumab for the preventive treatment of migraine in the UK, with consideration for natural history and work productivity.

BACKGROUND: Migraine is a highly prevalent neurological disease with a substantial societal burden due to lost productivity. From a societal perspective, we assessed the cost-effectiveness of eptinezumab for the preventive treatment of migraine. METHODS: An individual patient simulation of discrete competing events was developed to evaluate eptinezumab cost-effectiveness compared to best supportive care for adults in the United Kingdom with ≥ 4 migraine days per month and prior failure of ≥ 3 preventive migraine treatments. Individuals with sampled baseline characteristics were created to represent this population, which comprised dedicated episodic and chronic migraine subpopulations. Clinical efficacy, utility, and work productivity inputs were based on results from the DELIVER randomised controlled trial (NCT04418765). Timing of natural history events and treatment holidays-informed by the literature-were simulated to unmask any natural improvement of the disease unrelated to treatment. The primary outcomes were monthly migraine days, migraine-associated costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio, and net monetary benefit, each evaluated over a 5-year time horizon from 2020. Secondary analyses explored a lifetime horizon and an alternative treatment stopping rule. RESULTS: Treatment with eptinezumab resulted in an average of 0.231 QALYs gained at a saving of £4,894 over 5 years, making eptinezumab dominant over best supportive care (i.e., better health outcomes and less costly). This result was confirmed by the probabilistic analysis and all alternative assumption scenarios under the same societal perspective. Univariate testing of inputs showed net monetary benefit was most sensitive to the number of days of productivity loss, and monthly salary. CONCLUSIONS: This economic evaluation shows that from a societal perspective, eptinezumab is a cost-effective treatment in patients with ≥ 4 migraine days per month and for whom ≥ 3 other preventive migraine treatments have failed. TRIAL REGISTRATION: N/A.

Vestibular migraine: an update.

PURPOSE OF REVIEW: We performed a narrative review of the recent findings in epidemiology, clinical presentation, mechanisms and treatment of vestibular migraine. RECENT FINDINGS: Vestibular migraine is an underdiagnosed condition that has a high prevalence among general, headache and neuro-otology clinics. Vestibular migraine has a bimodal presentation probably associated with a hormonal component in women. These patients could have a complex clinical phenotype including concomitant autonomic, inflammatory or connective tissue conditions that have a higher prevalence of psychological symptoms, which may mistakenly lead to a diagnosis of a functional neurological disorder. A high proportion of patients with postural perceptual persistent dizziness have a migraine phenotype. Independently of the clinical presentation and past medical history, patients with the vestibular migraine phenotype can respond to regular migraine preventive treatments, including those targeting the calcitonin gene-related peptide pathways. SUMMARY: Vestibular migraine is an underdiagnosed migraine phenotype that shares the pathophysiological mechanisms of migraine, with growing interest in recent years. A thorough anamnesis is essential to increase sensitivity in patients with unknown cause of dizziness and migraine treatment should be considered (see supplemental video-abstract).

Melatonin in hemicrania continua and paroxysmal hemicrania.

BACKGROUND: Hemicrania continua (HC) and paroxysmal hemicrania (PH) belong to a group of primary headache disorders called trigeminal autonomic cephalalgias. One of the diagnostic criteria for both HC and PH is the absolute response to the therapeutic dose of indomethacin. However, indomethacin is discontinued in many patients as a result of intolerance to its side effects. Melatonin, a pineal hormone, which shares similar chemical structure to indomethacin, has been reported to have some efficacy for HC in previous case reports and series. To our knowledge, there is no literature regarding the use of melatonin in PH. We aimed to describe the clinical use of melatonin in the preventive management of HC and PH. METHODS: Patient level data were extracted as an audit from routinely collected clinical records in consecutive patients seen in outpatient neurology clinic at King's College Hospital, London, UK, from September 2014 to April 2023. Our cohort of patients were identified through a search using the keywords: hemicrania continua, paroxysmal hemicrania, melatonin and indomethacin. Descriptive statistics including absolute and relative frequencies, mean ± SD, median and interquartile range (IQR) were used. RESULTS: Fifty-six HC patients were included with a mean ± SD age of 52 ± 16 years; 43 of 56 (77%) patients were female. Melatonin was taken by 23 (41%) patients. Of these 23 patients, 19 (83%) stopped indomethacin because of different side effects. The doses of melatonin used ranged from 0.5 mg to 21 mg, with a median dose of 10 mg (IQR = 6-13 mg). Fourteen (61%) patients reported positive relief for headache, whereas the remaining nine (39%) patients reported no headache preventive effect. None of the patients reported that they were completely pain free. Two patients continued indomethacin and melatonin concurrently for better symptom relief. Eight patients continued melatonin as the single preventive treatment. Side effects from melatonin were rare. Twenty-two PH patients were included with mean ± SD age of 50 ± 17 years; 17 of 22 (77%) patients were female. Melatonin was given to six (27%) patients. The median dose of melatonin used was 8 mg (IQR = 6-10 mg). Three (50%) patients responded to melatonin treatment. One of them used melatonin as adjunctive treatment with indomethacin. CONCLUSIONS: Melatonin showed some efficacy in the treatment of HC and PH with a well-tolerated side effect profile. It does not have the same absolute responsiveness as indomethacin, at the doses used, although it does offer a well-tolerated option that can have significant ameliorating effects in a substantial cohort of patients.

Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update.

OBJECTIVE: To provide a position statement update from The American Headache Society specifically regarding therapies targeting calcitonin gene-related peptide (CGRP) for the prevention of migraine. BACKGROUND: All migraine preventive therapies previously considered to be first-line treatments were developed for other indications and adopted later for migraine. Adherence to these therapies is often poor due to issues with efficacy and tolerability. Multiple new migraine-specific therapies have been developed based on a broad foundation of pre-clinical and clinical evidence showing that CGRP plays a key role in the pathogenesis of migraine. These CGRP-targeting therapies have had a transformational impact on the management of migraine but are still not widely considered to be first-line approaches. METHODS: Evidence regarding migraine preventive therapies including primary and secondary endpoints from randomized placebo-controlled clinical trials, post hoc analyses and open-label extensions of these trials, and prospective and retrospective observational studies were collected from a variety of sources including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the Board of Directors of The American Headache Society to confirm consistency with clinical experience and to achieve consensus. RESULTS: The evidence for the efficacy, tolerability, and safety of CGRP-targeting migraine preventive therapies (the monoclonal antibodies: erenumab, fremanezumab, galcanezumab, and eptinezumab, and the gepants: rimegepant and atogepant) is substantial, and vastly exceeds that for any other preventive treatment approach. The evidence remains consistent across different individual CGRP-targeting treatments and is corroborated by extensive "real-world" clinical experience. The data indicates that the efficacy and tolerability of CGRP-targeting therapies are equal to or greater than those of previous first-line therapies and that serious adverse events associated with CGRP-targeting therapies are rare. CONCLUSION: The CGRP-targeting therapies should be considered as a first-line approach for migraine prevention along with previous first-line treatments without a requirement for prior failure of other classes of migraine preventive treatment.

Structural equation modeling for identifying the drivers of health-related quality of life improvement experienced by patients with migraine receiving eptinezumab.

BACKGROUND: As new migraine therapies emerge, it is crucial for measures to capture the complexities of health-related quality of life (HRQoL) improvement beyond improvements in monthly migraine day (MMD) reduction. Investigations into the correlations between MMD reduction, symptom management, and HRQoL are lacking, particularly those that focus on improvements in canonical symptoms and improvement in patient-identified most-bothersome symptoms (PI-MBS), in patients treated with eptinezumab. This exploratory analysis identified efficacy measures mediating the effect of eptinezumab on HRQoL improvements in patients with migraine. METHODS: Data from the DELIVER study of patients with 2-4 prior preventive migraine treatment failures (NCT04418765) were inputted to two structural equation models describing sources of HRQoL improvement via Migraine-Specific Quality-of-Life Questionnaire (MSQ) scores. A single latent variable was defined to represent HRQoL and describe the sources of HRQoL in DELIVER. One model included all migraine symptoms while the second model included the PI-MBS as the only migraine symptom. Mediating variables capturing different aspects of efficacy included MMDs, other canonical symptoms, and PI-MBS. RESULTS: In the first model, reductions in MMDs and other canonical symptoms accounted for 35% (standardized effect size [SES] - 0.11) and 25% (SES - 0.08) of HRQoL improvement, respectively, with 41% (SES - 0.13) of improvement comprising "direct treatment effect," i.e., unexplained by mediators. In the second model, substantial HRQoL improvement with eptinezumab (86%; SES - 0.26) is due to MMD reduction (17%; SES - 0.05) and change in PI-MBS (69%; SES - 0.21). CONCLUSIONS: Improvements in HRQoL experienced by patients treated with eptinezumab can be substantially explained by its effect on migraine frequency and PI-MBS. Therefore, in addition to MMD reduction, healthcare providers should discuss PI-MBS improvements, since this may impact HRQoL. Health technology policymakers should consider implications of these findings in economic evaluation, as they point to alternative measurement of quality-adjusted life years to capture fully treatment benefits in cost-utility analyses. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT04418765 ; EudraCT (Identifier: 2019-004497-25; URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2019-004497-25 ).

Pathophysiology of cluster headache: From the trigeminovascular system to the cerebral networks.

BACKGROUND: Despite advances in neuroimaging and electrophysiology, cluster headache's pathogenesis remains unclear. This review will examine clinical neurophysiology studies, including electrophysiological and functional neuroimaging, to determine if they might help us construct a neurophysiological model of cluster headache. RESULTS: Clinical, biochemical, and electrophysiological research have implicated the trigeminal-parasympathetic system in cluster headache pain generation, although the order in which these two systems are activated, which may be somewhat independent, is unknown. Electrophysiology and neuroimaging have found one or more central factors that may cause seasonal and circadian attacks. The well-known posterior hypothalamus, with its primary circadian pacemaker suprachiasmatic nucleus, the brainstem monoaminergic systems, the midbrain, with an emphasis on the dopaminergic system, especially when cluster headache is chronic, and the descending pain control systems appear to be involved. Functional connection investigations have verified electrophysiological evidence of functional changes in distant brain regions connecting to wide cerebral networks other than pain. CONCLUSION: We propose that under the impact of external time, an inherited misalignment between the primary circadian pacemaker suprachiasmatic nucleus and other secondary extra- suprachiasmatic nucleus clocks may promote disturbance of the body's internal physiological clock, lowering the threshold for bout recurrence.

Management of cervical CSF-venous fistula causing acute cognitive impairment and coma.

CSF-venous fistulas (CVFs) are increasingly recognised as a cause of spontaneous intracranial hypotension. They may present atypically including with brain sagging pseudo-dementia. Cervical CVFs are rare and their management can be difficult due to associated eloquent nerve roots. We report the case of a 49-year-old woman who presented with cognitive decline progressing to coma. Brain imaging showed features of spontaneous intracranial hypotension and a right C7 CVF was identified at digital subtraction and CT myelography. Initial treatment with CT-guided injection of fibrin sealant produced temporary improvement in symptoms before surgical treatment resulted in total clinical remission and radiological resolution.

PACAP-38 related modulation of the cranial parasympathetic projection: A novel mechanism and therapeutic target in severe primary headache.

BACKGROUND AND PURPOSE: Little is known of how cranial autonomic symptoms (CAS) in cluster headache and migraine may contribute to their severe headache phenotype. This strong association suggests the involvement of the cranial parasympathetic efferent pathway. To investigate its contribution, we studied the role of pituitary adenylate cyclase activating polypeptide-38 (PACAP-38), a potent sensory and parasympathetic neuropeptide, in modulating pre- and post-ganglionic cranial parasympathetic projection neurons, and their influence on headache-related trigeminal-autonomic responses. EXPERIMENTAL APPROACH: Using PACAP-38 and PACAP-38 responsive receptor antagonists, electrophysiological, behavioural and facial neurovascular-blood flow was measured in rats to probe trigeminal- and parasympathetic-neuronal, periorbital thresholds and cranial-autonomic outcomes, as they relate to primary headaches. KEY RESULTS: Sumatriptan attenuated the development of PACAP-38 mediated activation and sensitization of trigeminocervical neurons and related periorbital allodynia. PACAP-38 also caused activation and enhanced responses of dural-responsive pre-ganglionic pontine-superior salivatory parasympathetic neurons. Further, the PACAP-38 responsive receptor antagonists dissected a role of VPAC1 and PAC1 receptors in attenuating cranial-autonomic and trigeminal-neuronal responses to activation of the cranial parasympathetic projection, which requires post-ganglionic parasympathetic neurotransmission. CONCLUSION AND IMPLICATIONS: Given the prevailing view that sumatriptan acts to some degree via a peripheral mechanism, our data support that PACAP-38 mediated receptor activation modulates headache-related cranial-autonomic and trigeminovascular responses via peripheral and central components of the cranial parasympathetic projection. This provides a mechanistic rationale for the association of CAS with more severe headache phenotypes in cluster headache and migraine, and supports the cranial parasympathetic projection as a potential novel locus for treatment by selectively targeting PACAP-38 or PACAP-38 responsive VPAC1 /PAC1 receptors.

Comparing the Efficacy and Safety of Galcanezumab Versus Rimegepant for Prevention of Episodic Migraine: Results from a Randomized, Controlled Clinical Trial.

INTRODUCTION: There have been no prior trials directly comparing the efficacy of different calcitonin gene-related peptide (CGRP) antagonists for migraine prevention. Reported are the results from the first head-to-head study of two CGRP antagonists, galcanezumab (monoclonal antibody) versus rimegepant (gepant), for the prevention of episodic migraine. METHODS: In this 3-month, double-blind, double-dummy study, participants were randomized (1:1) to subcutaneous (SC) galcanezumab 120 mg per month (after a 240 mg loading dose) and a placebo oral disintegrating tablet (ODT) every other day (q.o.d.) or to rimegepant 75 mg ODT q.o.d. and a monthly SC placebo. The primary endpoint was the proportion of participants with a ≥ 50% reduction in migraine headache days per month from baseline across the 3-month double-blind treatment period. Key secondary endpoints were overall mean change from baseline in: migraine headache days per month across 3 months and at month 3, 2, and 1; migraine headache days per month with acute migraine medication use; Migraine-Specific Quality of Life Questionnaire Role Function-Restrictive domain score at month 3; and a ≥ 75% and 100% reduction from baseline in migraine headache days per month across 3 months. RESULTS: Of 580 randomized participants (galcanezumab: 287, rimegepant: 293; mean age: 42 years), 83% were female and 81% Caucasian. Galcanezumab was not superior to rimegepant in achieving a ≥ 50% reduction from baseline in migraine headache days per month (62% versus 61% respectively; P = 0.70). Given the pre-specified multiple testing procedure, key secondary endpoints cannot be considered statistically significant. Overall, treatment-emergent adverse events were reported by 21% of participants, with no significant differences between study intervention groups. CONCLUSIONS: Galcanezumab was not superior to rimegepant for the primary endpoint; however, both interventions demonstrated efficacy as preventive treatments in participants with episodic migraine. The efficacy and safety profiles observed in galcanezumab-treated participants were consistent with previous studies. TRIAL REGISTRATION: ClinTrials.gov-NCT05127486 (I5Q-MC-CGBD).

Galcanezumab and rimegepant are preventive treatments for episodic migraine. The goal of this study was to compare the efficacy of galcanezumab and rimegepant in reducing the number of monthly migraine headaches and to determine if galcanezumab was better than rimegepant. The study provides important information to doctors and their patients when making treatment decisions.People with episodic migraine were assigned to the galcanezumab (given as an injection under the skin) or rimegepant (given as a tablet that dissolves in the mouth) group and treated for 3 months. The doctor and the patient did not know which group they were assigned to, and to keep it unknown to both, people in the galcanezumab group got an injection with real medicine and a fake tablet, and people in the rimegepant group got a tablet with real medicine and a fake injection. The researchers wanted to know how many people in each group had at least a 50% reduction in their monthly migraine headaches.Of the 580 people in the study, 287 were assigned to galcanezumab and 293 to rimegepant. In both groups, most were female and white. After 3 months of treatment, 62% of the people in the galcanezumab group and 61% of people in the rimegepant group had at least a 50% reduction in monthly migraine headaches. Both treatments were effective, but galcanezumab was not better than rimegepant. About 20% of the people in each treatment group had a side effect from the medication, and most were mild or moderate in severity.