Safety and tolerability of atogepant for the preventive treatment of migraine: a post hoc analysis of pooled data from four clinical trials.

BACKGROUND: Conventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene-related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders. METHODS: This post hoc analysis was performed using data pooled from 2 (12-week) randomized, double-blind, placebo-controlled trials (RCTs) and 2 (40- and 52-week) open-label long-term safety (LTS) trials of oral atogepant for episodic migraine (EM). RESULTS: The safety population included 1550 participants from the pooled RCTs (atogepant, n = 1142; placebo, n = 408) and 1424 participants from the pooled LTS trials (atogepant, n = 1228; standard care [SC], n = 196). In total, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 treatment-emergent AEs (TEAEs) in the RCTs. In the LTS trials, 792/1228 (64.5%) of atogepant participants and 154/196 (78.6%) of SC participants experienced ≥ 1 TEAEs. The most commonly reported TEAEs (≥ 5%) in participants who received atogepant once daily were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). Additionally, weight loss appeared to be dose- and duration-dependent. Most TEAEs were considered unrelated to study drug and few led to discontinuation. CONCLUSIONS: Overall, atogepant is safe and well tolerated in pooled RCTs and LTS trials for the preventive treatment of EM in adults. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02848326 (MD-01), NCT03777059 (ADVANCE), NCT03700320 (study 302), NCT03939312 (study 309).

Real-world study of intranasal ketamine for use in patients with refractory chronic migraine: a retrospective analysis.

INTRODUCTION: Subanesthetic ketamine infusion has been used for managing refractory headache in inpatient or outpatient infusion settings. Intranasal ketamine may be an alternative option for outpatient care. METHODS: A retrospective study was conducted at a single tertiary headache center to assess the clinical effectiveness and tolerability of intranasal ketamine in patients with refractory chronic migraine. Candidates who received intranasal ketamine between January 2019 and February 2020 were screened through an electronic medical record query. Manual chart reviews and structured telephone interviews were conducted on obtaining informed consent. RESULTS: Of 242 subjects screened, 169 (79.9% women) of median (IQR) age 44 (22) years were interviewed. They reported a median (IQR) of 30 (9) monthly headache days and tried 4 (1) classes of preventive medications. Overall, they used 6 (6) sprays per day, with a median (IQR) of spray use of 10 (11) days per month. Intranasal ketamine was reported as 'very effective' in 49.1% and the quality of life was considered 'much better' in 35.5%. At the time of the interview, 65.1% remained current intranasal ketamine users and 74.0% reported at least one adverse event. CONCLUSION: In this descriptive study, intranasal ketamine served as an acute treatment for refractory chronic migraine by reducing headache intensity and improving quality of life with relatively tolerable adverse events. Most patients found intranasal ketamine effective and continued to use it despite these adverse events. Given the potential for overuse, it should be reserved for those clearly in need of more effective rescue treatment with appropriate safety precautions. Well-designed prospective placebo-controlled trials are necessary to demonstrate the efficacy and safety of intranasal ketamine in patients with migraine.

Safety and tolerability results of atogepant for the preventive treatment of episodic migraine from a 40-week, open-label multicenter extension of the phase 3 ADVANCE trial.

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.

Eptinezumab improved patient-reported outcomes in patients with migraine and medication-overuse headache: Subgroup analysis of the randomized PROMISE-2 trial.

OBJECTIVE: To evaluate the effect of eptinezumab on patient-reported outcomes in patients with chronic migraine (CM) and medication-overuse headache (MOH). BACKGROUND: MOH is a secondary headache disorder commonly occurring in patients with CM and associated with functional and psychological impairments. Medication overuse and monthly headache and migraine days were reduced with eptinezumab compared with placebo as published previously; however, these outcomes do not fully capture the burden of migraine and treatment effect. METHODS: PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled trial in adults with CM. Patients were randomized (1:1:1) to receive eptinezumab 100 mg, eptinezumab 300 mg, or placebo (up to 2 doses, 12 weeks apart). Patients completed the following patient-reported outcomes: 6-item Headache Impact Test (HIT-6), Patient Global Impression of Change (PGIC), patient-identified most bothersome symptom (PI-MBS), and 36-item Short-Form Health Survey (SF-36). RESULTS: A total of 431 CM patients (139, 147, and 145 patients in the eptinezumab 100 mg, eptinezumab 300 mg, and placebo groups, respectively) had MOH diagnosed at screening (40.2% of the total PROMISE-2 population [n = 1072]). In CM with MOH patients, both doses of eptinezumab were associated with clinically meaningful improvements in mean HIT-6 total scores by week 4 and remained improved throughout the 24-week study. Responder rates for individual HIT-6 items were greater with eptinezumab than with placebo at all time points. At week 12, almost twice as many eptinezumab-treated patients indicated the PGIC was "much" or "very much" improved (58.5% [79/135, 100 mg] and 67.4% [95/147, 300 mg] vs. 35.8% [48/134, placebo]). Patients in the eptinezumab groups showed numerically greater improvements over placebo in the PI-MBS and SF-36 scores. CONCLUSIONS: This subgroup analysis in patients with CM/MOH at baseline suggests that eptinezumab treatment is associated with early, sustained, and clinically meaningful improvements in patient-reported outcomes.

Quantity changes in acute headache medication use among patients with chronic migraine treated with eptinezumab: subanalysis of the PROMISE-2 study.

BACKGROUND: Patients with chronic migraine (CM) treated with eptinezumab in the PROMISE-2 trial achieved greater reductions in migraine and headache frequency, impact, and acute headache medication (AHM) use than did patients who received placebo. This post hoc analysis examines relationships between headache frequency reductions and changes in AHM use in patients in PROMISE-2. METHODS: PROMISE-2 was a double-blind, placebo-controlled trial conducted in adults with CM. Patients were randomized to eptinezumab 100 mg, 300 mg, or placebo, administered intravenously once every 12 weeks for up to two doses. Patients recorded headache/AHM information daily and for each event in an electronic diary; data from all days with daily reports were included. Shifts in headache frequency and AHM use were assessed in the three populations: total CM population, patients with CM and medication-overuse headache (MOH), and patients with CM and MOH who were ≥ 50% responders during treatment (response over weeks 1-24). RESULTS: A total of 1072 adults with CM received treatment (eptinezumab, n = 706; placebo, n = 366). Mean baseline headache frequency was 20.5 days; mean baseline AHM days was 13.4; 431 patients had MOH, of which 225 (52.2%) experienced ≥50% response over weeks 1-24. Relative to baseline, the proportion of days with both headache and AHM use decreased 25.1% (eptinezumab) versus 17.0% (placebo) in the total population (N = 1072), 29.2% versus 18.4% in the MOH subpopulation (n = 431), and 38.3% versus 31.5% in the CM with MOH population with ≥50% response subgroup (n = 225) during weeks 1-24. The proportion of days with headache and triptan use decreased 9.1% (eptinezumab) versus 5.8% (placebo), 11.8% versus 7.2%, and 14.5% versus 12.6%, respectively. Reductions in other AHM types were smaller. CONCLUSIONS: In this post hoc analysis, eptinezumab use in patients with CM was associated with greater decreases in days with headache with AHM overall and with triptans in particular. The magnitude of effect was greater in the subgroup of CM patients with MOH and ≥ 50% response. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02974153 . Eptinezumab reduces headache frequency and acute medication use in patients with chronic migraine.

The importance of an early onset of migraine prevention: an evidence-based, hypothesis-driven scoping literature review.

Recently approved migraine preventive therapies facilitate rapid control of migraine activity, potentially improving patients' lives and minimizing the societal burden of migraine. This review synthesizes available evidence on rates and timing of early onset of migraine prevention and identifies patient-level outcomes related to early onset prevention. This evidence-based scoping review identified all available clinical trial evidence regarding the early onset of prevention of migraine, under the hypothesis 'Patients with migraine (episodic or chronic) report additional benefits when receiving an approved migraine preventive treatment that demonstrates an early onset of prevention'. Early onset of prevention was defined as migraine preventive benefits within 30 days post-administration. PubMed, EMBASE, and CINAHL were searched for publications between 1988 and 2020. Overall, 16 publications described 18 studies. All studies were conducted in approved treatments [four anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies and one chemodenervation agent] in patients with episodic/chronic migraine; no publications were identified for traditional oral agents for early migraine prevention. Compared to placebo, erenumab (three studies) reduced weekly migraine days within 1 week; fremanezumab (six studies) increased reports of no headache of at least moderate severity on Day 1 and significantly reduced migraine frequency within 1 week; galcanezumab (three studies) significantly reduced the mean number of patients with migraine beginning Day 1 and each day of the first week; eptinezumab (four studies) significantly reduced migraine attack likelihood on Day 1 by > 50% versus baseline; and onabotulinumtoxinA (two studies) reduced headache and migraine days within 1 week. Four publications described function, disability, and quality of life improvements as early as Week 4; none reported cost-benefit. Anti-CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) and a chemodenervation agent (onabotulinumtoxinA) provide clinically relevant benefits during the first treatment week. Literature describing clinically relevant benefits regarding early onset of prevention in patients with migraine is limited.

International consensus statement on allergy and rhinology: Olfaction.

BACKGROUND: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O). METHODS: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus. RESULTS: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies. CONCLUSION: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further.

Non-invasive vagus nerve stimulation for prevention of migraine: The multicenter, randomized, double-blind, sham-controlled PREMIUM II trial.

AIM: Evaluate the efficacy and safety of non-invasive vagus nerve stimulation for migraine prevention. METHODS: After completing a 4-week diary run-in period, adults who had migraine with or without aura were randomly assigned to receive active non-invasive vagus nerve stimulation or sham therapy during a 12-week double-blind period. RESULTS: Of 336 enrolled participants, 113 (active, n = 56; sham, n = 57) completed ≥70 days of the double-blind period and were ≥66% adherent with treatment, comprising the prespecified modified intention-to-treat population. The COVID-19 pandemic led to early trial termination, and the population was ∼60% smaller than the statistical target for full power. Mean reduction in monthly migraine days (primary endpoint) was 3.12 for the active group and 2.29 days for the sham group (difference, -0.83; p = 0.2329). Responder rate (i.e. the percentage of participants with a ≥50% reduction in migraine days) was greater in the active group (44.87%) than the sham group (26.81%; p = 0.0481). Prespecified subgroup analysis suggested that participants with aura responded preferentially. No serious device-related adverse events were reported. CONCLUSIONS: These results suggest clinical utility of non-invasive vagus nerve stimulation for migraine prevention, particularly for patients who have migraine with aura, and reinforce the well-established safety and tolerability profile of this therapy.Trial Registration: ClinicalTrials.gov (NCT03716505).

Preventive migraine treatment with eptinezumab reduced acute headache medication and headache frequency to below diagnostic thresholds in patients with chronic migraine and medication-overuse headache.

OBJECTIVE: This post hoc analysis in patients medically diagnosed with chronic migraine (CM) and medication-overuse headache (MOH) evaluated reductions in the use of acute headache medication (AHM) and sustained changes in the diagnostic status of CM and MOH following eptinezumab treatment in the PROMISE-2 study. BACKGROUND: Eptinezumab, a monoclonal antibody that inhibits calcitonin gene-related peptide, is approved in the United States for the preventive treatment of migraine. A previous analysis showed that eptinezumab reduced monthly migraine days and was well tolerated in the subgroup of PROMISE-2 patients diagnosed with both CM and MOH. METHODS: The phase 3, double-blind, placebo-controlled PROMISE-2 study (NCT02974153) randomized adults with CM to eptinezumab 100 mg, 300 mg, or placebo (administered intravenously every 12 weeks for up to two doses). MOH was prospectively diagnosed at screening by trained physicians based on 3 months of medication history and International Classification of Headache Disorders-3ß criteria. This post hoc analysis evaluated changes in total and class-specific days of AHM usage, the percentage of patients using AHM at or above MOH diagnostic thresholds, and the percentage of patients experiencing monthly headache and migraine day frequency below diagnostic thresholds for MOH and/or CM. RESULTS: In PROMISE-2, 431/1072 (40.2%) patients with CM were diagnosed with MOH (eptinezumab 100 mg, n = 139; 300 mg, n = 147; placebo, n = 145) and were included in this analysis. Total monthly AHM use decreased from 20.6 days/month at baseline to 10.6 days/month over 24 weeks of treatment (49% decrease) with eptinezumab 100 mg, from 20.7 to 10.5 days/month (49% decrease) with eptinezumab 300 mg, and from 19.8 to 14.0 days/month (29% decrease) with placebo. Numerically greater decreases from baseline with eptinezumab were also observed for individual drug classes. In each study month, the percentages of patients who were below MOH thresholds were numerically higher for both eptinezumab doses compared with placebo, as were the percentages of patients experiencing headache and migraine frequency below CM thresholds. Of patients with available data across the entire treatment period, 29.0% (58/200) of patients treated with eptinezumab stopped meeting and remained below diagnostic thresholds for both CM and MOH during Weeks 1-24, as well as 6.3% (6/96) of patients who received placebo. CONCLUSIONS: Across 24 weeks of treatment, eptinezumab reduced AHM use in patients diagnosed with CM and MOH. More than one-fourth (29%) of patients treated with eptinezumab did not meet the diagnostic thresholds for either CM or MOH for the entire treatment period.

Treatment benefit among migraine patients taking fremanezumab: results from a post hoc responder analysis of two placebo-controlled trials.

BACKGROUND: Monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway, including the fully humanized monoclonal antibody (IgG2Δa) fremanezumab, have demonstrated safety and efficacy for migraine prevention. Clinical trials include responders and nonresponders; efficacy outcomes describe mean values across both groups and thus provide little insight into the clinical benefit in responders. Clinicians and their patients want to understand the extent of clinical improvement in patients who respond. This post hoc analysis of fremanezumab treatment attempts to answer this question: what is the benefit in subjects who responded to treatment during the two, phase 3 HALO clinical trials? METHODS: We included subjects with episodic migraine (EM) or chronic migraine (CM) who received fremanezumab quarterly (675 mg/placebo/placebo) or monthly (EM: 225 mg/225 mg/225 mg; CM: 675 mg/225 mg/225 mg) during the 12-week randomized, double-blind, placebo-controlled HALO EM and HALO CM clinical trials. EM and CM responders were defined as participants with a reduction of ≥ 2 or ≥ 4 monthly migraine days, respectively. Treatment benefits evaluated included reductions in monthly migraine days, acute headache medication use, and headache-related disability, and changes in health-related quality of life (HRQoL). RESULTS: Overall, 857 participants from the HALO trials were identified as responders (EM: 429 [73.8%]; CM: 428 [56.7%]). Reductions in the monthly average number of migraine days were greater among EM (quarterly: 5.4 days; monthly: 5.5 days) and CM (quarterly: 8.7 days; monthly: 9.1 days) responders compared with the overall population. The proportion of participants achieving ≥ 50% reduction in the average monthly number of migraine days was also greater in responders (EM: quarterly, 59.8%; monthly, 63.7%; CM: quarterly, 52.8%; monthly, 59.0%) than in the overall population. Greater reductions in the average number of days of acute headache medication use, greater reductions in headache-related disability scores, and larger improvements in HRQoL were observed among EM and CM responders compared with the overall populations. CONCLUSIONS: Fremanezumab responders achieved clinically meaningful improvements in all outcomes. The magnitude of improvements with fremanezumab across efficacy outcomes was far greater in responders than in the overall trial population, providing insight into expected treatment benefits in participants who respond to fremanezumab in clinical practice. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02629861 (HALO EM) and NCT02621931 (HALO CM).

Efficacy, tolerability, and safety of eptinezumab in patients with a dual diagnosis of chronic migraine and medication-overuse headache: Subgroup analysis of PROMISE-2.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of eptinezumab 100 and 300 mg compared with placebo in patients with the dual diagnosis of chronic migraine (CM) and medication-overuse headache (MOH). BACKGROUND: Eptinezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, may be effective for treating patients with a dual diagnosis of CM and MOH. METHODS: PROMISE-2 (NCT02974153) was a double-blind, randomized, placebo-controlled, phase 3 study that comprised a screening visit, a 28-day pretreatment period, and a 32-week study duration. Patients in this exploratory analysis of a prespecified subgroup had confirmed diagnoses of both CM and MOH at screening. Patients were randomly assigned to receive intravenous eptinezumab 100, 300 mg, or placebo every 12 weeks. Efficacy outcomes included mean changes from baseline in monthly migraine days (MMDs) during weeks 1-12, migraine responder rates at week 12, and percentages of patients below International Classification of Headache Disorders thresholds for CM and MOH over weeks 1-24. RESULTS: There were 431 patients who were diagnosed with CM and MOH as specified in the protocol and received eptinezumab 100 mg (n = 139), 300 mg (n = 147), or placebo (n = 145). During the baseline period, these patients experienced an average of 16.7 migraine days across treatment arms. Over weeks 1-12, eptinezumab-treated patients experienced greater reductions from baseline in MMDs than placebo patients (100 mg, change from baseline = -8.4, difference from placebo [95% confidence interval (CI)] = -3.0 [-4.56, -1.52], p < 0.0001 vs. placebo; 300 mg, change from baseline = -8.6, difference from placebo [95% CI] = -3.2 [-4.66, -1.78], p < 0.0001 vs. placebo; placebo, -5.4). Compared with placebo, more eptinezumab-treated patients were ≥50% migraine responders (100 mg, 84/139 [60.4%]; 300 mg, 91/147 [61.9%]; placebo, 50/145 [34.5%]) or ≥75% responders (100 mg, 38/139 [27.3%]; 300 mg, 44/147 [29.9%]; placebo, 21/145 [14.5%]) over weeks 1-12. Therapeutic benefits with eptinezumab were observed from day 1 after dosing, and improvements were sustained with an additional dose. For the full 24-week treatment period, 71/139 (51.1%), 80/147 (54.4%), and 47/145 (32.4%) of 100, 300 mg, and placebo-treated patients, respectively, were below CM thresholds, and of the patients who provided sufficient acute medication data, 47/93 (50.5%), 53/107 (49.5%), and 26/96 (27.1%), respectively, were below medication-overuse thresholds. CONCLUSIONS: In patients diagnosed with both CM and MOH, eptinezumab treatment resulted in greater reductions in MMDs, higher responder rates, and fewer patients meeting CM and MOH criteria, thus demonstrating the efficacy and clinical utility of eptinezumab in this patient population.

Incorporating Remote Electrical Neuromodulation (REN) Into Usual Care Reduces Acute Migraine Medication Use: An Open-Label Extension Study.

Background: A recent randomized controlled study showed that 66.7% (66/99) and 37.4% (37/99) of people undergoing remote electrical neuromodulation (REN), a novel non-pharmacological migraine treatment, achieve pain relief and pain freedom, respectively, at 2 h post-treatment. The participants who completed the 6-weeks double-blind phase of this study were offered to participate in an open-label extension (OLE) with an active REN device. Objective: This study investigated the clinical use of REN, focusing on its potential in reducing the use of acute migraine medications. Methods: The parent study for this open-label extension (OLE) was a randomized, double-blind, sham-controlled study of acute treatment conducted on 296 participants enrolled at 12 sites in the USA and Israel. This study included a run-in phase, in which migraine attacks were treated with usual care, and an 8-weeks double-blind treatment phase. One hundred sixty participants continued in an 8-weeks OLE phase in which they could incorporate a REN device into their usual care. Medication use rate (percentage of participants who treated their attacks only with REN and avoided medications in all their attacks) and pain outcomes at 2 h post-treatment were compared between the OLE and the run-in phase in a within-subject design. Results: The analyses were performed on 117 participants with episodic migraine. During the OLE, 89.7% of the participants treated their attacks only with REN and avoided medications in all their attacks compared with 15.4% in the run-in phase (p < 0.0001). The rates of pain relief and pain-free in at least 50% of the treatments at 2 h post-treatment were comparable (pain relief: 58.1% in the run-in phase and 57.3% in the OLE, p = 0.999; pain-free: 23.1% in the run-in vs. 30.8% in the OLE, p = 0.175). Conclusions: REN may reduce the use of acute migraine medications. Thus, incorporating REN into usual care may reduce the risk for medication overuse headache (MOH). Future studies should evaluate whether REN reduces the use of acute migraine medications in a population at risk for MOH.

Neuroimaging for Migraine: The American Headache Society Systematic Review and Evidence-Based Guideline.

OBJECTIVE: To provide updated evidence-based recommendations about when to obtain neuroimaging in patients with migraine. METHODS: Articles were included in the systematic review if they studied adults 18 and over who were seeking outpatient treatment for any type of migraine and who underwent neuroimaging (MRI or CT). Medline, Web of Science, and Cochrane Clinical Trials were searched from 1973 to August 31, 2018. Reviewers identified studies, extracted data, and assessed the quality of the evidence in duplicate. We assessed study quality using the Newcastle-Ottawa Scale. RESULTS: The initial search yielded 2269 publications. Twenty three articles met inclusion criteria and were included in the final review. The majority of studies were retrospective cohort or cross-sectional studies. There were 4 prospective observational studies. Ten studies evaluated the utility of CT only, 9 MRI only, and 4 evaluated both. Common abnormalities included chronic ischemia or atrophy with CT and MRI scanning, and non-specific white matter lesions with MRI. Clinically meaningful abnormalities requiring intervention were relatively rare. Clinically significant neuroimaging abnormalities in patients with headaches consistent with migraine without atypical features or red flags appeared no more common than in the general population. RECOMMENDATIONS: There is no necessity to do neuroimaging in patients with headaches consistent with migraine who have a normal neurologic examination, and there are no atypical features or red flags present. Grade A Neuroimaging may be considered for presumed migraine for the following reasons: unusual, prolonged, or persistent aura; increasing frequency, severity, or change in clinical features, first or worst migraine, migraine with brainstem aura, migraine with confusion, migraine with motor manifestations (hemiplegic migraine), late-life migraine accompaniments, aura without headache, side-locked headache, and posttraumatic headache. Most of these are consensus based with little or no literature support. Grade C.

Inpatient Management of Migraine.

Migraine is a frequently disabling neurologic condition which can be complicated by medication overuse headache and comorbid medical disorders, including obesity, anxiety and depression. Although most migraine management takes place in outpatient clinics, inpatient treatment is indicated for migraine refractory to multiple outpatient treatments, with intractable nausea or vomiting, need for detoxification from medication overuse (such as opioids and barbiturates), and significant medical and psychiatric disease. The goals of inpatient treatment include breaking the current cycle of headache pain, reducing the frequency and/or severity of future attacks, monitored detoxification of overused medications, and reducing disability and improving quality of life.

Triggers, Protectors, and Predictors in Episodic Migraine.

PURPOSE OF REVIEW: A wide variety of triggers prompt attacks in episodic migraine. Although experimental triggers such as glyceryl trinitrate reliably produce migraine, natural triggers are much less predictable and vary in importance between individuals. This review describes the most common triggers in episodic migraine and provides strategies for managing them in clinical practice. RECENT FINDINGS: Multiple migraine attack triggers have been established based on patient surveys, diary studies, and clinical trials. Stress, menstrual cycle changes, weather changes, sleep disturbances, alcohol, and other foods are among the most common factors mentioned. Clinical studies have verified that fasting, premenstrual periods in women, "letdown" after stress, and most likely low barometric pressures are migraine triggers. Premonitory symptoms such as neck pain, fatigue, and sensitivity to lights, sounds, or odors may mimic triggers. Multiple studies clearly demonstrate triggers in episodic migraine, often related to change in homeostasis or environment. Many common migraine triggers are not easily modifiable, and avoiding triggers may not be realistic. Healthy lifestyle choices such as exercise, adequate sleep, stress management, and eating regularly may prevent triggers and transformation to chronic migraine over time.

Refining the Benefit/Risk Profile of Anti-Epileptic Drugs in Headache Disorders.

Anti-epileptic drugs are among the most effective drugs for migraine prophylaxis, and will likely continue to have a role even as new therapies emerge. Topiramate and valproate are effective for the preventive treatment of migraine, and other medications such as gabapentin or lamotrigine may have a role in the treatment of those with allodynia or frequent aura, respectively. Oxcarbazepine, carbamazepine, phenytoin, gabapentin, and others may alleviate pain in trigeminal neuralgia. While many anti-epileptic drugs can be effective in those with migraine or other headaches, most of these agents can potentially cause serious side effects. In particular, valproate, topiramate, carbamazepine, and phenytoin may lead to adverse outcomes for infants of exposed mothers. Valproate should not be given to women of childbearing potential for migraine prevention.

A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study).

Objective To evaluate the efficacy and tolerability of single pulse transcranial magnetic stimulation (sTMS) for the preventive treatment of migraine. Background sTMS was originally developed for the acute treatment of migraine with aura. Open label experience has suggested a preventive benefit. The objective of this trial was to evaluate the efficacy and tolerability of sTMS for migraine prevention. Methods The eNeura SpringTMS Post-Market Observational U.S. Study of Migraine (ESPOUSE) Study was a multicenter, prospective, open label, observational study. From December 2014 to March 2016, patients with migraine (n = 263) were consented to complete a 1-month baseline headache diary followed by 3 months of treatment. The treatment protocol consisted of preventive (four pulses twice daily) and acute (three pulses repeated up to three times for each attack) treatment. Patients reported daily headache status, medication use, and device use with a monthly headache diary. The primary endpoint, mean reduction of headache days compared to baseline, was measured over the 28-day period during weeks 9 to 12. The primary endpoint was compared to a statistically-derived placebo estimate (performance goal). Secondary endpoints included: 50% responder rate, acute headache medication consumption, HIT-6, and mean reduction in total headache days from baseline of any intensity. Results Of a total of 263 consented subjects, 229 completed a baseline diary, and 220 were found to be eligible based on the number of headache days. The device was assigned to 217 subjects (Safety Data Set) and 132 were included in the intention to treat Full Analysis Set. For the primary endpoint, there was a -2.75 ± 0.40 mean reduction of headache days from baseline (9.06 days) compared to the performance goal (-0.63 days) ( p < 0.0001). The 50% responder rate of 46% (95% CI 37%, 56%) was also significantly higher ( p < 0.0001) than the performance goal (20%). There was a reduction of -2.93 (5.24) days of acute medication use, headache impact measured by HIT-6, -3.1 (6.4) ( p < 0.0001), and total headache days of any intensity -3.16 days (5.21) compared to the performance goal (-0.63 days) ( p < 0.0001). The most common adverse events were lightheadedness (3.7%), tingling (3.2%), and tinnitus (3.2%). There were no serious adverse events. Conclusions This open label study suggests that sTMS may be an effective, well-tolerated treatment option for migraine prevention. Trial registration number NCT02357381.

Current Treatment Options: Vestibular Migraine.

OPINION STATEMENT: Vestibular migraine (VM) is a disorder with a spectrum of clinical presentations and among the most common causes of chronic vestibular symptoms. Some present with attacks before or during typical migraine, but many others have fluctuating or daily symptoms. While the symptoms and pathogenesis of vestibular migraine may have elements of both central and peripheral disorders, hearing loss should be absent. VM typically worsens with activity and head movements in general, and encompasses symptoms of vertigo, disequilibrium, or imbalance. While it is possible to confuse other disorders such as Meniere's disease with migraine, it is worth making the diagnosis of vestibular migraine on clinical grounds after ruling out other possible causes. For acute attack treatment, migraine-specific medications such as triptans may be effective. In patients with frequent or disabling attacks, preventive treatment is essential. Vestibular rehabilitation may be helpful as well as medications used for migraine prevention such as including propranolol, venlafaxine, topiramate, and amitriptyline. For refractory patients, use of acetazolamide or lamotrigine may be reasonable.