Background and ObjectiveLimited data are available describing the frequency, severity, and consistency of prodromal symptoms followed by headache. This analysis of the PRODROME trial screening period characterized prodromal symptoms in people with migraine, including the most common symptoms and their severity, and the frequency and consistency with which prodromal symptoms were followed by headache.MethodsPRODROME was a multicenter, randomized, double-blind, placebo-controlled, crossover trial conducted in the United States that enrolled adults with 2-8 migraine attacks per month who stated they could identify prodromal symptoms that were reliably followed by a headache. The trial included a 60-day screening period designed to test the predictive validity of "qualifying prodrome events" before the onset of headache. Participants used an eDiary to report qualifying prodrome events, defined as prodromal symptoms whereby the participant was confident a headache would follow within 1-6 hours. This analysis evaluated common prodromal symptoms and their severity, time from prodrome onset to headache onset, and the percentage of participants who identified prodromal symptoms that were followed by a headache >= 75% of the time over the 60-day screening period.ResultsA total of 920 participants entered eDiary data, with a mean of 5.2 qualifying prodrome events during the 60-day screening period. A total of 4,802 qualifying prodrome events were recorded. The most common prodromal symptoms identified were sensitivity to light (57.2%; 2,748/4,802), fatigue (50.1%; 2,408/4,802), neck pain (41.9%; 2,013/4,802), sensitivity to sound (33.9%; 1,630/4,802), either difficulty thinking or concentrating (30.0%; 1,442/4,802), and dizziness (27.8%; 1,333/4,802). Of all qualifying prodrome events reported, 81.5% (3,913/4,802) were followed by headache of any intensity within 1-6 hours. For each participant, a mean of 84.4% of their qualifying prodrome events were followed by a headache within 1-6 hours, with 76.9% of participants identifying qualifying prodrome events that were followed by headache within 1-6 hours >= 75% of the time.DiscussionParticipants were able to identify migraine attacks in which prodromal symptoms were reliably followed by a headache within 1-6 hours. These findings suggest the potential for initiating treatment during the prodrome to prevent headache.Trial Registration InformationClinicalTrials.gov NCT04492020. Submitted: July 27, 2020; First patient enrolled: August 21, 2020. clinicaltrials.gov/study/NCT04492020.

Introduction L’atogépant est un antagoniste oral du récepteur CGRP indiqué dans le traitement préventif de la migraine épisodique et de la migraine chronique (MC). Objectifs Évaluer le délai d’efficacité de l’atogépant comme traitement préventif de la MC. PROGRESS est une étude de phase 3, multicentrique, randomisée, en double-aveugle, contrôlée versus placebo. Méthodes Les participants, âgés de 18 à 80 ans, souffraient de MC et ont été randomisés (1:1:1) placebo, atogépant 30mg 2/j ou atogépant 60mg 1/j, pendant 12 semaines. Les critères d’évaluation comportaient le changement moyen de JMM par rapport à l’inclusion, les changements de jours de migraine hebdomadaire durant les 4 premières semaines et la proportion de participants avec une crise migraine durant les 7 premiers jours de traitement. Résultats Au total, 778 participants ont été randomisés ; 755 ont été inclus (pbo, n=246 ; atogepant 30mg 2/j, n=253 ; atogepant 60mg 1/j, n=256). À l’inclusion, les JMM étaient de 18,6–19,2. Entre S1–4, les variations moyennes des JMM (vs inclusion) étaient de −6,6 (atogépant 30mg), −6,2 (atogépant 60mg) et −3,7 (pbo) (p<0,001), avec un maintien les 4 semaines suivantes de la diminution plus importante des JMM dans les groupes atogépant vs pbo (p<0,001). Le nombre hebdomadaire de jours de migraine à l’inclusion était de 4,6–4,8. Discussion Au cours du 1er mois traitement, une réduction moyenne du nombre de jours hebdomadaires de migraine plus importante est observée dans les groupes atogépant vs pbo (p≤0,009). Les patients atogépant étaient significativement moins susceptibles de souffrir de migraine vs pbo (p≤0,03) à j1. Les EI (atogépant) les plus fréquents étaient : constipation (10,0–10,9 %) et nausées (7,8–9,6 %). Conclusion Dans la MC, l’atogépant a démontré une réduction précoce et durable des JMM et un effet statistiquement significatif du traitement. L’atogépant a été généralement bien toléré.

OBJECTIVE:To evaluate the safety and tolerability of ubrogepant for the acute treatment of migraine in participants taking atogepant for the preventive treatment of episodic migraine (EM). BACKGROUND:Atogepant is an oral calcitonin gene-related peptide (CGRP) receptor antagonist approved for the preventive treatment of migraine in adults and ubrogepant is an oral CGRP receptor antagonist approved for the acute treatment of migraine in adults, with or without aura. The safety and tolerability of the concomitant use of ubrogepant and atogepant have not been previously evaluated in a clinical setting. METHODS:The TANDEM study, a phase 4, two-period, multicenter, open-label study conducted in the United States, enrolled adults with migraine, with or without aura, and <15 headache days/month. In Treatment Period 1, participants took atogepant 60 mg once daily (QD) for 12 weeks and their own non-gepant acute headache medication for breakthrough migraine attacks. In Treatment Period 2, participants continued taking atogepant 60 mg QD and ubrogepant 100 mg was taken as needed (PRN) for the treatment of breakthrough migraine attacks (up to eight per 4-week interval) for 12 weeks. In Treatment Period 2, an optional second ubrogepant dose or the participant's own acute medication could be used to rescue headaches that did not resolve within 2-24 h post initial ubrogepant dose. The primary objective evaluated the safety and tolerability of the concomitant use of ubrogepant and atogepant. RESULTS:Of 263 participants enrolled, 262 were treated in Treatment Period 1 (Safety Population 1) and 218 continued and were treated in Treatment Period 2 (Safety Population 2). The mean (standard deviation) number of ubrogepant use days in Treatment Period 2 was 6.6 (5.03) over the 12 weeks. In Treatment Periods 1 and 2, 49.6% and 43.1% of participants experienced a treatment-emergent adverse event (TEAE), respectively. The most common TEAEs (≥5%) in Treatment Period 1 and Treatment Period 2 were COVID-19 (8.4%, 3.2%), fatigue (6.5%, 1.4%), nausea (6.1%, 0.9%), decreased appetite (5.7%, 0.9%), and constipation (5.3%, 0.9%). In Treatment Period 2, no increase in the incidence and types of TEAEs in relation to the number of ubrogepant use days or doses taken were identified. During the whole treatment period, 9.9% of participants discontinued atogepant or ubrogepant treatment due to TEAEs. There was one serious TEAE in Treatment Period 1 (ureterolithiasis) and one in Treatment Period 2 (cervical myelopathy), and both were considered not related to study treatment by the study investigators. CONCLUSION:The use of atogepant 60 mg QD for the preventive treatment of EM and ubrogepant 100 mg PRN for the acute treatment of migraine over the 12-week open-label concomitant use treatment period was safe and well tolerated. The overall safety results were consistent with the known safety profiles of atogepant and ubrogepant when used alone and no new safety signals were identified.

With recent data demonstrating that lecanemab treatment can slow cognitive and functional decline in early symptomatic Alzheimer disease (AD), it is widely anticipated that this drug and potentially other monoclonal antibody infusions targeting β-amyloid protein will imminently be realistic options for some patients with AD. Given that these new antiamyloid monoclonal antibodies (mAbs) are associated with nontrivial risks and burdens of treatment that are radically different from current mainstays of AD management, effectively and equitably translating their use to real-world clinical care will require systematic and practice-specific modifications to existing workflows and infrastructure. In this Emerging Issues in Neurology article, we provide practical guidance for a wide audience of neurology clinicians on logistic adaptations and decision making around emerging antiamyloid mAbs. Specifically, we briefly summarize the rationale and available evidence supporting antiamyloid mAb use in AD to facilitate appropriate communication with patients and care partners on potential benefits. We also discuss pragmatic approaches to optimizing patient selection and treatment monitoring, with a particular focus on the value of incorporating shared decision making and multidisciplinary collaboration. In addition, we review some of the recognized limitations of current knowledge and highlight areas of future evolution to guide the development of sustainable and flexible models for treatment and follow-up. As the field enters a new era with disease-modifying treatment options for AD, it will be critical for neurology practices to prepare and continually innovate to ensure optimal outcomes for patients.

BACKGROUND:Atogepant is a United States Food and Drug Administration-approved oral calcitonin gene-related peptide receptor antagonist for the preventive treatment of episodic migraine. The study objective was to evaluate the long-term safety and tolerability of atogepant in participants who completed the phase 3 ADVANCE trial (NCT03777059).METHODS:This 40-week, open-label extension trial (NCT03939312) monitored safety in participants receiving oral atogepant 60 mg once daily, followed by a four-week safety follow-up period.RESULTS:Of the 685 participants taking at least one dose of atogepant, the treatment period was completed by 74.6% of participants with a mean (standard deviation) treatment duration of 233.6 (89.3) days. Treatment-emergent adverse events occurred in 62.5% of participants, with upper respiratory tract infection (5.5%), urinary tract infection (5.3%), nasopharyngitis (4.8%), sinusitis (3.6%), constipation (3.4%), and nausea (3.4%) occurring at ≥3%. Serious adverse events were observed in 3.4% of participants (none were treatment-related), and there were no deaths. Adverse events leading to discontinuation occurring at >0.1% were nausea (0.4%) and abdominal pain, vomiting, weight decrease, dizziness, and migraine (0.3% each).CONCLUSION:These results are consistent with atogepant's known safety profile and support long-term use of atogepant 60 mg once daily dosing as safe and well tolerated.ClinicalTrials.gov Registration Number: NCT03939312.

With recent data demonstrating that lecanemab treatment can slow cognitive and functional decline in early symptomatic Alzheimer disease (AD), it is widely anticipated that this drug and potentially other monoclonal antibody infusions targeting β-amyloid protein will imminently be realistic options for some patients with AD. Given that these new antiamyloid monoclonal antibodies (mAbs) are associated with nontrivial risks and burdens of treatment that are radically different from current mainstays of AD management, effectively and equitably translating their use to real-world clinical care will require systematic and practice-specific modifications to existing workflows and infrastructure. In this Emerging Issues in Neurology article, we provide practical guidance for a wide audience of neurology clinicians on logistic adaptations and decision making around emerging antiamyloid mAbs. Specifically, we briefly summarize the rationale and available evidence supporting antiamyloid mAb use in AD to facilitate appropriate communication with patients and care partners on potential benefits. We also discuss pragmatic approaches to optimizing patient selection and treatment monitoring, with a particular focus on the value of incorporating shared decision making and multidisciplinary collaboration. In addition, we review some of the recognized limitations of current knowledge and highlight areas of future evolution to guide the development of sustainable and flexible models for treatment and follow-up. As the field enters a new era with disease-modifying treatment options for AD, it will be critical for neurology practices to prepare and continually innovate to ensure optimal outcomes for patients.

Objectives Evaluate the time course of efficacy of atogepant for the preventive treatment of Chronic Migraine (CM). Methods PROGRESS was a phase 3 trial which assessed the efficacy and safety of atogepant in patients with CM. This analysis evaluated the change from baseline in mean monthly migraine days (MMDs) during 4-week intervals, change in weekly migraine days during weeks 1–4, and the proportion of participants with a migraine on each day during the first 7 days of treatment. Results 755 participants were included. Baseline MMDs ranged from 18.6 to 19.2. During weeks 1–4 of treatment,mean changes in MMDs were −6.6 for atogepant 30mg BID, −6.2 for atogepant 60mg QD, and −3.7 for placebo (P<0.001). This decrease was maintained during weeks 5–8 (P<0.001). Baseline mean weekly migraine days ranged from 4.6 to 4.8. During each week of the 1–4 weeks, mean reductions in weekly migraine days were greater in both atogepant groups compared with placebo (P≤0.009). During the baseline period, daily rates of participants reporting a migraine day ranged from 66.3% to 68.4%. On the first day after treatment initiation, atogepant participants were less likely to have a migraine than placebo (P≤0.03). TEAEs were reported by 56.4–63.2% participants taking atogepant, compared with 49.4% participants taking placebo. The most common TEAEs for atogepant were constipation (10.0–10.9%) and nausea (7.8–9.6%). Conclusion Atogepant demonstrated early and sustained reduction in migraine days. Results showed a statistically significant effect as early as the first full day after study drug initiation. Atogepant was safe and well tolerated.

To evaluate the long-term safety and tolerability of atogepant over 40 weeks in participants who completed the pivotal 12-week ADVANCE trial.

We describe a process of organizational strategic future forecasting, with a horizon of 2035, as implemented by the American Academy of Neurology (AAN) on behalf of its members, and as a model approach for other organizations. The participants were members of the 2018-2020 AAN Boards of Directors and Executive Team, moderated by a consultant with expertise in future forecasting. Four predetermined model scenarios of import to our field (1 "expectable," 1 "challenging," and 2 "visionary") were discussed in small groups, with alternative scenarios developed in specific domains. Common themes emerged among all scenarios: the importance of thoughtful integration of biomedical and information technology tools into neurologic practice; continued demonstration of the value of neurologic care to society; and emphasis on population management and prevention of neurologic disease. Allowing for the inherent uncertainties of predicting the future, the AAN's integration of structured forecasting into its strategic planning process has allowed the organization to prepare more effectively for change, such as the disruptions stemming from the coronavirus disease 2019 (COVID-19) pandemic. The approaches outlined here will be integrated into future AAN operations and may be implemented to a similar effect by other organizations.

Objective To outline strategies for the treatment of migraine which do not require in-person visits to clinic or the emergency department, and to describe ways that health insurance companies can remove barriers to quality care for migraine. Background COVID-19 is a global pandemic causing widespread infections and death. To control the spread of infection we are called to observe "social distancing" and we have been asked to postpone any procedures which are not essential. Since procedural therapies are a mainstay of headache care, the inability to do procedures could negatively affect our patients with migraine. In this manuscript we review alternative therapies, with particular attention to those which may be contra-indicated in the setting of COVID-19 infection. Design/Results The manuscript reviews the use of telemedicine visits and acute, bridge, and preventive therapies for migraine. We focus on evidence-based treatment where possible, but also describe "real world" strategies which may be tried. In each section we call out areas where changes to rules from commercial health insurance companies would facilitate better migraine care. Conclusions Our common goal as health care providers is to maximize the health and safety of our patients. Successful management of migraine with avoidance of in-person clinic and emergency department visits further benefits the current urgent societal goal of maintaining social distance to contain the COVID-19 pandemic.

The coronavirus disease of 2019, or COVID-19, changed the world within a matter of weeks. The primary action to constrain the spread of the virus is social isolation. Given this public health principle, and the shortage of personal protective equipment during the global pandemic, all health care stakeholders need to reconsider the indications for face-to-face health care encounters in providing patient care. Which encounters are imperative and which ones can be switched to non–face-to-face care? What changes in laws, regulations, payment policies, and workflow are needed to enable this transition?1–3

The coronavirus disease of 2019, or COVID-19, changed the world within a matter of weeks. The primary action to constrain the spread of the virus is social isolation. Given this public health principle, and the shortage of personal protective equipment during the global pandemic, all health care stakeholders need to reconsider the indications for face-to-face health care encounters in providing patient care. Which encounters are imperative and which ones can be switched to non-face-to-face care? What changes in laws, regulations, payment policies, and workflow are needed to enable this transition?(1-3)

Premise The science of migraine pathophysiology has advanced significantly since the 1930's. Imaging techniques, neurochemical analysis, clinical trials, and the clinical experience of providers treating migraine patients have not only sharpened our understanding of the disease, but have also led to the development of novel neural-based targets. Targeted therapies such as calcitonin gene-related peptide (CGRP) antibodies and "Second Generation" CGRP receptor antagonists (Gepants) have not only demonstrated efficacy, but have not resulted in any significant cardiovascular nor other serious adverse events. "First Generation" Gepants were associated with liver toxicity. Problem Triptans and dihydroergotamine (DHE) are contraindicated in patients with hemiplegic and basilar migraine based on theories of migraine pathophysiology from the 1930s. While our understanding of migraine has evolved substantially, perceived concerns of safety from almost a century ago continue to preclude their use in certain patient populations. Potential solution While migraine aura was once thought to be primarily due to vasoconstriction, current evidence debunks this concept. For instance, hemiplegic migraine is the consequence of genetic mutations resulting in channelopathies without evidence of cerebral ischemia or infarction. Evidence of basilar artery constriction as postulated in basilar migraine is also lacking. This recognition has led the International Headache Society to rename basilar-type migraine to migraine with brainstem aura. The following discussion reviews current literature with respect to migraine as a neuronal disorder, as well as the published data on the safety of triptans, DHE, Ditans (a novel class of 5-HT1f receptor agonists), CGRP antibodies, and Gepants.

Objective To assess the association of neurologist ambulatory care with healthcare utilization and expenditure in headache. Methods This was a longitudinal cohort study from two-year duration panel data, pooled from 2002–2013, of adult respondents identified with diagnostic codes for headache in the Medical Expenditure Panel Survey. Those with a neurologist ambulatory care visit in year one of panel participation were compared with those who did not for the change in annual aggregate direct headache-related health care costs from year one to year two of panel participation, inflated to 2015 US dollars. Results were adjusted via multiple linear regression for demographic and clinical variables, utilizing survey variables for accurate estimates and standard errors. Results Eight hundred and eighty-seven respondents were included, with 23.3% (207/887) seeing a neurologist in year one. The neurologist group had higher year-one mean headache-related expenditures ($3032 vs. $1636), but nearly equal mean year-two expenditures compared to controls ($1900 vs. $1929). Adjusted association between neurologist care and difference in mean annual expenditures from year two to year one was −$1579 (95% CI −$2468, −$690, p < 0.001). Conclusion Among headache sufferers, particularly those with higher headache-related healthcare expenditures, neurologist care is associated with a significant reduction in costs over two years.

BACKGROUND:Patients with basilar migraine (BM) and hemiplegic migraine (HM) have been excluded from triptan and DHE clinical trials due to a potential risk of ischemic vascular events, and the FDA mandates that package labeling state that they are contraindicated in BM and HM. The objective of this study was to demonstrate that triptans and DHE can be used for the abortive treatment of BM and HM without significant adverse ischemic vascular events.METHODS:A retrospective chart review of patients with BM features or HM who received acute abortive treatment with either triptans or DHE was conducted at 4 headache centers to assess the frequency of ischemic vascular events after administration. The diagnoses of BM or HM were made by headache specialists based on The International Classification of Headache Disorders, 2nd edition (ICHD-II). Searchable terms included BM, vertigo, dysarthria, diplopia, hemiplegia/hemiparesis, facial droop, weakness, confusion, altered consciousness, confusion, ataxia, and aphasia, as well as all triptans or DHE.RESULTS:The study included 67 patients with BM features and 13 patients with HM. Among those receiving triptans, 40 were in the BM group and 5 were in the HM group. Among those receiving DHE, 27 were included in the BM group and 8 were in the HM group. No side effects of stroke or myocardial infarction were reported. In the triptan group, 5 patients reported adverse effects that included GI upset, rash, neck dystonia, nightmares, and flushing. In the DHE group, 5 patients had adverse events that included chest tightness, dystonic reaction, transient asymptomatic anterior T wave inversion, and agitation.CONCLUSION:In this retrospective study, triptans and DHE were used with no reported, subsequent acute/subacute ischemic vascular events for the abortive treatment of migraines with basilar and hemiplegic-type features. Although the small sample sizes generated theoretical statistical event rates of 4.5% for BM and 23% for HM, there has been no clear evidence that BM and HM carry an actual elevated risk for vascular events compared with migraine with aura.

Background Dihydroergotamine (DHE) use is contraindicated in hemiplegic migraine (HM) and basilar type migraine (BTM) for fear of migrainous infarction. Objective The purpose of this study was to determine the tolerability of DHE administration in patients with symptoms of HM or BTM. Methods A retrospective analysis of a case series of patients who received intravenous DHE for migraine meeting ICHD II criteria with one or more symptoms to suggest HM or BTM was performed. All electronic (inpatient) and paper (outpatient) medical records from October 2008 to October 2011 were reviewed consecutively and independently by two investigators to identify patients meeting specific inclusion criteria. Frequency and types of adverse events, prior triptan use, and pain levels were reviewed and analyzed. Results Thirty five patients' charts meeting inclusion criteria were reviewed; 28 (80%) were female. Mean age was 37.4 years. 74% of patients had previously used a triptan without serious adverse events. After DHE infusion, the mean pain severity decreased from 6.8 ±2.1 to 2.2±2.4 on a 10 point visual analog scale (p <0.0005). Only 5 (14%) patients experienced minor side effects (e.g., EKG changes and chest pain) during DHE infusion. None (0/35 (95% CI: 0-34%) of the patients had an ischemic stroke or myocardial infarction. Conclusion Dihydroergotamine use showed no serious adverse events in this case series of patients meeting ICHD II criteria for migraine in whom HM or BTM was suggested. Study limitations preclude generalizability of results to other populations. Additional case series are needed before prospective trials can be justified.

OBJECTIVE:To describe a standardized methodology for the performance of peripheral nerve blocks (PNBs) in the treatment of headache disorders. BACKGROUND:PNBs have long been employed in the management of headache disorders, but a wide variety of techniques are utilized in literature reports and clinical practice. METHODS:The American Headache Society Special Interest Section for PNBs and other Interventional Procedures convened meetings during 2010-2011 featuring formal discussions and agreements about the procedural details for occipital and trigeminal PNBs. A subcommittee then generated a narrative review detailing the methodology. RESULTS:PNB indications may include select primary headache disorders, secondary headache disorders, and cranial neuralgias. Special procedural considerations may be necessary in certain patient populations, including pregnancy, the elderly, anesthetic allergy, prior vasovagal attacks, an open skull defect, antiplatelet/anticoagulant use, and cosmetic concerns. PNBs described include greater occipital, lesser occipital, supratrochlear, supraorbital, and auriculotemporal injections. Technical success of the PNB should result in cutaneous anesthesia. Targeted clinical outcomes depend on the indication, and include relief of an acute headache attack, terminating a headache cycle, and transitioning out of a medication-overuse pattern. Reinjection frequency is variable, depending on the indications and agents used, and the addition of corticosteroids may be most appropriate when treating cluster headache. CONCLUSIONS:These recommendations from the American Headache Society Special Interest Section for PNBs and other Interventional Procedures members for PNB methodology in headache disorder treatment are derived from the available literature and expert consensus. With the exception of cluster headache, there is a paucity of evidence, and further research may result in the revision of these recommendations to improve the outcome and safety of these interventions.