Long-Term Epidural Patching Outcomes and Predictors of Benefit in Patients With Suspected CSF Leak Nonconforming to ICHD-3 Criteria.

BACKGROUND AND OBJECTIVES: Spinal CSF leaks lead to spontaneous intracranial hypotension (SIH). While International Classification of Headache Disorders, Third Edition (ICHD-3) criteria necessitate imaging confirmation or low opening pressure (OP) for SIH diagnosis, their sensitivity may be limited. We offered epidural blood patches (EBPs) to patients with symptoms suggestive of SIH, with and without a documented low OP or confirmed leak on imaging. This study evaluates the efficacy of this strategy. METHODS: We conducted a prospective cohort study with a nested case-control design including all patients who presented to a tertiary headache clinic with clinical symptoms of SIH who completed study measures both before and after receiving an EBP between August 2016 and November 2018. RESULTS: The mean duration of symptoms was 8.7 ± 8.1 years. Of 85 patients assessed, 69 did not meet ICHD-3 criteria for SIH. At an average of 521 days after the initial EBP, this ICHD-3-negative subgroup experienced significant improvements in Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health score of +3.3 (95% CI 1.5-5.1), PROMIS Global Mental Health score of +1.8 (95% CI 0.0-3.5), Headache Impact Test (HIT)-6 head pain score of -3.8 (95% CI -5.7 to -1.8), Neck Disability Index of -4.8 (95% CI -9.0 to -0.6) and PROMIS Fatigue of -2.3 (95% CI -4.1 to -0.6). Fifty-four percent of ICHD-3-negative patients achieved clinically meaningful improvements in PROMIS Global Physical Health and 45% in HIT-6 scores. Pain relief following lying flat prior to treatment was strongly associated with sustained clinically meaningful improvement in global physical health at an average of 521 days (odds ratio 1.39, 95% CI 1.1-1.79; p < 0.003). ICHD-3-positive patients showed high rates of response and previously unreported, treatable levels of fatigue and cognitive deficits. DISCUSSION: Patients who did not conform to the ICHD-3 criteria for SIH showed moderate rates of sustained, clinically meaningful improvements in global physical health, global mental health, neck pain, fatigue, and head pain after EBP therapy. Pre-treatment improvement in head pain when flat was associated with later, sustained improvement after EBP therapy among patients who did not meet the ICHD-3 criteria. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that epidural blood patch is an effective treatment of suspected CSF leak not conforming to ICHD-3 criteria for SIH.

The Gut-brain Connection and Episodic Migraine: an Update.

PURPOSE OF REVIEW: Historical evidence suggests a shared underlying etiology for migraine and gastrointestinal (GI) disorders that involves the gut-brain axis. Here we provide narrative review of recent literature on the gut-brain connection and migraine to emphasize the importance of tailoring treatment plans for patients with episodic migraine who experience GI comorbidities and symptoms. RECENT FINDINGS: Recent population-based studies report the prevalence of migraine and GI disorders as comorbidities as well as overlapping symptomology. American Headache Society (AHS) guidelines have integrated GI symptoms as part of migraine diagnostic criteria and recommend nonoral therapies for patients with GI symptoms or conditions. Nasal delivery is a recommended nonoral alternative; however, it is important to understand potential adverse events that may cause or worsen GI symptoms in some patients due to the site of drug deposition within the nasal cavity with some nasal therapies. Lastly, clinical perspectives emphasize the importance of identifying GI symptoms and comorbidities in patients with episodic migraine to best individualize migraine management. Support for an association between the gut-brain axis and migraine continues to prevail in recent literature; however, the relationship remains complex and not well elucidated. The presence of GI comorbidities and symptoms must be carefully considered when making treatment decisions for patients with episodic migraine.

Using artificial intelligence to identify patients with migraine and associated symptoms and conditions within electronic health records.

BACKGROUND: Real-world evidence (RWE)-based on information obtained from sources such as electronic health records (EHRs), claims and billing databases, product and disease registries, and personal devices and health applications-is increasingly used to support healthcare decision making. There is variability in the collection of EHR data, which includes "structured data" in predefined fields (e.g., problem list, open claims, medication list, etc.) and "unstructured data" as free text or narrative. Healthcare providers are likely to provide more complete information as free text, but extracting meaning from these fields requires newer technologies and a rigorous methodology to generate higher-quality evidence. Herein, an approach to identify concepts associated with the presence and progression of migraine was developed and validated using the complete patient record in EHR data, including both the structured and unstructured portions. METHODS: "Traditional RWE" approaches (i.e., capture from structured EHR fields and extraction using structured queries) and "Advanced RWE" approaches (i.e., capture from unstructured EHR data and processing by artificial intelligence [AI] technology, including natural language processing and AI-based inference) were evaluated against a manual chart abstraction reference standard for data collected from a tertiary care setting. The primary endpoint was recall; differences were compared using chi square. RESULTS: Compared with manual chart abstraction, recall for migraine and headache were 66.6% and 29.6%, respectively, for Traditional RWE, and 96.8% and 92.9% for Advanced RWE; differences were statistically significant (absolute differences, 30.2% and 63.3%; P < 0.001). Recall of 6 migraine-associated symptoms favored Advanced RWE over Traditional RWE to a greater extent (absolute differences, 71.5-88.8%; P < 0.001). The difference between traditional and advanced techniques for recall of migraine medications was less pronounced, approximately 80% for Traditional RWE and ≥ 98% for Advanced RWE (P < 0.001). CONCLUSION: Unstructured EHR data, processed using AI technologies, provides a more credible approach to enable RWE in migraine than using structured EHR and claims data alone. An algorithm was developed that could be used to further study and validate the use of RWE to support diagnosis and management of patients with migraine.

Development and validation of a novel model for characterizing migraine outcomes within real-world data.

BACKGROUND: In disease areas with 'soft' outcomes (i.e., the subjective aspects of a medical condition or its management) such as migraine or depression, extraction and validation of real-world evidence (RWE) from electronic health records (EHRs) and other routinely collected data can be challenging due to how the data are collected and recorded. In this study, we aimed to define and validate a scalable framework model to measure outcomes of migraine treatment and prevention by use of artificial intelligence (AI) algorithms within EHR data. METHODS: Headache specialists defined descriptive features based on routinely collected clinical data. Data elements were weighted to define a 10-point scale encompassing headache severity (1-7 points) and associated features (0-3 points). A test data set was identified, and a reference standard was manually produced by trained annotators. Automation (i.e., AI) was used to extract features from the unstructured data of patient encounters and compared to the reference standard. A threshold of 70% close agreement (within 1 point) between the automated score and the human annotator was considered to be a sufficient extraction accuracy. The accuracy of AI in identifying features used to construct the outcome model was also evaluated and success was defined as achieving an F1 score (i.e., the weighted harmonic mean of the precision and recall) of 80% in identifying encounters. RESULTS: Using data from 2,006 encounters, 11 features were identified and included in the model; the average F1 scores for automated extraction were 92.0% for AI applied to unstructured data. The outcome model had excellent accuracy in characterizing migraine status with an exact match for 77.2% of encounters and a close match (within 1 point) for 82.2%, compared with manual extraction scores-well above the 70% match threshold set prior to the study. CONCLUSION: Our findings indicate the feasibility of technology-enabled models for validated determination of soft outcomes such as migraine progression using the data elements typically captured in the real-world clinical setting, providing a scalable approach to credible EHR-based clinical studies.

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).

Hemicrania continua: Indomethacin induced myoclonus.

Myoclonus has been described rarely as an adverse effect with some non-steroidal anti-inflammatory drugs, but never with indomethacin. Indomethacin is a common nonsteroidal anti-inflammatory drug used for various primary headache disorders, including hemicrania continua. We present a rare case of a 45-year-old male with hemicrania continua who developed myoclonus from indomethacin. These movements resolved completely following discontinuation of indomethacin. The disturbance on the serotonergic and GABAergic systems may be associated with indomethacin induced myoclonus. Clinicians and patients should be mindful with this potential side effect with indomethacin.

Long term safety, tolerability, and efficacy of intracutaneous zolmitriptan (M207) in the acute treatment of migraine.

OBJECTIVE: To determine the long-term safety and tolerability profile of M207 in the acute treatment of migraine. BACKGROUND: M207 is an investigational microneedle-based system for intracutaneous delivery of zolmitriptan for the treatment of migraine attacks. Following on the positive results of a Phase 2/3 placebo-controlled efficacy study (ZOTRIP), this study was designed to evaluate the safety of this novel product during repeated use for the treatment of migraine attacks. METHODS: In this 6-12 month open-label, multicenter observational study, participants used an eDiary to record headache symptoms and adverse events at specified intervals up to 48 h following treatment of a qualifying attack with M207 3.8 mg (intracutaneous zolmitriptan). Participants underwent clinical evaluations at specified intervals up to 12 months. RESULTS: Among 335 participants who treated ≥1 migraine attack, 257 completed 6 months and 127 completed 1 year of treatment. The most common reason for withdrawal from the study was a low frequency of reported attacks post randomization. Overall, 5963 migraine attacks were treated. Most participants (96%) experienced at least 1 adverse event, the vast majority of which concerned the application site, and > 95% of which were mild. Fifteen participants (4%) withdrew due to adverse events; 4 withdrew due to 7 application site reactions, 6 of which were mild. Participants achieved pain freedom in 2477/5617 (44%) of attacks, most bothersome symptom freedom in 3315/5330 (62%) of attacks, and pain relief 2 h post-dose in 4552/5617 (81%) of attacks. Sustained pain freedom 2-24 h was seen in 1761/4698 (38%) of attacks, and 2-48 h in 1534/4429 (35%) of attacks. CONCLUSIONS: The majority of participants experienced cutaneous adverse reactions such as application site erythema, swelling, and bleeding, and most reactions were scored as mild. These results are consistent with what was observed in the single migraine attack treatment ZOTRIP trial indicating that M207 is well tolerated in the setting of longer-term repeated use. Efficacy findings were also similar to those in the ZOTRIP trial. TRIAL REGISTRATION: Clinicaltrials.gov on September 13, 2017 ( NCT03282227 ).

A link between gastrointestinal disorders and migraine: Insights into the gut-brain connection.

BACKGROUND: Migraine is a complex, multifaceted, and disabling headache disease that is often complicated by gastrointestinal (GI) conditions, such as gastroparesis, functional dyspepsia, and cyclic vomiting syndrome (CVS). Functional dyspepsia and CVS are part of a spectrum of disorders newly classified as disorders of gut-brain interaction (DGBI). Gastroparesis and functional dyspepsia are both associated with delayed gastric emptying, while nausea and vomiting are prominent in CVS, which are also symptoms that commonly occur with migraine attacks. Furthermore, these gastric disorders are comorbidities frequently reported by patients with migraine. While very few studies assessing GI disorders in patients with migraine have been performed, they do demonstrate a physiological link between these conditions. OBJECTIVE: To summarize the available studies supporting a link between GI comorbidities and migraine, including historical and current scientific evidence, as well as provide evidence that symptoms of GI disorders are also observed outside of migraine attacks during the interictal period. Additionally, the importance of route of administration and formulation of migraine therapies for patients with GI symptoms will be discussed. METHODS: A literature search of PubMed for articles relating to the relationship between the gut and the brain with no restriction on the publication year was performed. Studies providing scientific support for associations of gastroparesis, functional dyspepsia, and CVS with migraine and the impact these associations may have on migraine treatment were the primary focus. This is a narrative review of identified studies. RESULTS: Although the association between migraine and GI disorders has received very little attention in the literature, the existing evidence suggests that they may share a common etiology. In particular, the relationship between migraine, gastric motility, and vomiting has important clinical implications in the treatment of migraine, as delayed gastric emptying and vomiting may affect oral dosing compliance, and thus, the absorption and efficacy of oral migraine treatments. CONCLUSIONS: There is evidence of a link between migraine and GI comorbidities, including those under the DGBI classification. Many patients do not find adequate relief with oral migraine therapies, which further necessitates increased recognition of GI disorders in patients with migraine by the headache community.

Eptinezumab for the prevention of chronic migraine: efficacy and safety through 24 weeks of treatment in the phase 3 PROMISE-2 (Prevention of migraine via intravenous ALD403 safety and efficacy-2) study.

BACKGROUND: PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy and safety of repeat intravenous (IV) doses of the calcitonin gene-related peptide-targeted monoclonal antibody eptinezumab (ALD403) for migraine prevention in adults with chronic migraine. This report describes the results of PROMISE-2 through 24 weeks of treatment. METHODS: Patients received up to two 30-min IV administrations of eptinezumab 100 mg, 300 mg, or placebo separated by 12 weeks. Patients recorded migraine and headache endpoints in a daily eDiary. Additional assessments, including patient-reported outcomes, were performed at regularly scheduled clinic visits throughout the 32-week study period (screening, day 0, and weeks 2, 4, 8, 12, 16, 20, 24, and 32). RESULTS: A total of 1072 adults received treatment: eptinezumab 100 mg, n = 356; eptinezumab 300 mg, n = 350; placebo, n = 366. The reduction in mean monthly migraine days observed during the first dosing interval (100 mg, - 7.7 days; 300 mg, - 8.2 days; placebo, - 5.6 days) was further decreased after an additional dose (100 mg, - 8.2 days; 300 mg, - 8.8 days; placebo, - 6.2 days), with both doses of eptinezumab demonstrating consistently greater reductions from baseline compared to placebo. The ≥50% and ≥ 75% migraine responder rates (MRRs) increased after a second dose, with more eptinezumab-treated patients experiencing migraine response than placebo patients (≥50% MRRs weeks 13-24: 100 mg, 61.0%; 300 mg, 64.0%; placebo, 44.0%; and ≥ 75% MRRs weeks 13-24: 100 mg, 39.3%; 300 mg, 43.1%; placebo, 23.8%). The percentages of patients who improved on patient-reported outcomes, including the Headache Impact Test and Patient Global Impression of Change, increased following the second dose administration at week 12, and were greater with eptinezumab than with placebo at all time points. No new safety concerns were identified with the second dose regarding the incidence, nature, and severity of treatment-emergent adverse events. CONCLUSION: Eptinezumab 100 mg or 300 mg administered IV at day 0 and repeated at week 12 provided sustained migraine preventive benefit over a full 24 weeks and demonstrated an acceptable safety profile in patients with chronic migraine. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02974153 ). Registered November 23, 2016.

The Role of Diet and Nutrition in Migraine Triggers and Treatment: A Systematic Literature Review.

BACKGROUND: Migraine is a disabling primary headache disorder often associated with triggers. Diet-related triggers are a common cause of migraine and certain diets have been reported to decrease the frequency of migraine attacks if dietary triggers or patterns are adjusted. OBJECTIVE: The systematic literature review was conducted to qualitatively summarize evidence from the published literature regarding the role of diet patterns, diet-related triggers, and diet interventions in people with migraine. METHODS: A literature search was carried out on diet patterns, diet-related triggers, and diet interventions used to treat and/or prevent migraine attacks, using an a priori protocol. MEDLINE and EMBASE databases were searched to identify studies assessing the effect of diet, food, and nutrition in people with migraine aged ≥18 years. Only primary literature sources (randomized controlled trials or observational studies) were included and searches were conducted from January 2000 to March 2019. The NICE checklist was used to assess the quality of the included studies of randomized controlled trials and the Downs and Black checklist was used for the assessment of observational studies. RESULTS: A total of 43 studies were included in this review, of which 11 assessed diet patterns, 12 assessed diet interventions, and 20 assessed diet-related triggers. The overall quality of evidence was low, as most of the (68%) studies assessing diet patterns and diet-related triggers were cross-sectional studies or patient surveys. The studies regarding diet interventions assessed a variety of diets, such as ketogenic diet, elimination diets, and low-fat diets. Alcohol and caffeine uses were the most common diet patterns and diet-related triggers associated with increased frequency of migraine attacks. Most of the diet interventions, such as low-fat and elimination diets, were related to a decrease in the frequency of migraine attacks. CONCLUSIONS: There is limited high-quality randomized controlled trial data on diet patterns or diet-related triggers. A few small randomized controlled trials have assessed diet interventions in preventing migraine attacks without strong results. Although many patients already reported avoiding personal diet-related triggers in their migraine management, high-quality research is needed to confirm the effect of diet in people with migraine.

Spinal cerebrospinal fluid leak in the context of pars interarticularis fracture.

BACKGROUND: Spinal cerebrospinal fluid (CSF) leak can lead to intracranial hypotension and is an important differential diagnosis to consider in patients with sudden-onset chronic daily headaches. Pars interarticularis (PI) fracture is a potential rare cause of suspected spinal CSF leak. METHODS: This is a retrospective case series of 6 patients with suspected spinal CSF leak evaluated between January 2016 and September 2019. All patients received a magnetic resonance imaging (MRI) of the brain with and without gadolinium, MRI whole spine and full spine computed tomography (CT) myelogram. Targeted epidural patches with fibrin sealant were performed. Treatment response at return visit (3 months post-patch) was documented. RESULTS: Six patients (4 females, 2 males) were diagnosed with a suspected spinal CSF leak and PI fracture. Mean age at the time of headache onset was 39 years old, and a range from 32 to 50 years old. Mean time to targeted epidural patches with fibrin sealant was 4.5 years. All 6 patients had PI fractures identified on CT myelogram and received targeted epidural patches with fibrin sealant at the site of the PI fracture. All patients had significant improvement in their headache intensity. CONCLUSION: Our study highlights: 1) the importance of PI fracture as a possible culprit of suspected spinal CSF leak in patients with intracranial hypotension; 2) the added benefit of CT imaging for detecting bony abnormalities such as fractures in patients with intracranial hypotension; and 3) the successful treatment of suspected spinal CSF leak when targeting the fracture site.

Assessment of immunogenicity from galcanezumab phase 3 trials in patients with episodic or chronic migraine.

BACKGROUND: This analysis characterizes the immunogenicity profile of galcanezumab, a humanized monoclonal antibody that selectively binds calcitonin gene-related peptide and inhibits its activity, in phase 3 migraine trials. METHODS: Immunogenicity data were analyzed from baseline and double-blind, placebo-controlled phases of the 3-month chronic migraine study REGAIN, the 6-month episodic migraine studies EVOLVE-1 and EVOLVE-2, and from baseline and open-label phases of the 12-month chronic and episodic migraine Study CGAJ. The incidence of baseline antidrug antibodies, treatment-emergent antidrug antibodies, neutralizing antidrug antibodies, and the effect of antidrug antibody titer on pharmacokinetics and pharmacodynamics were assessed. The relationship between antidrug antibody status and efficacy was explored using average change in monthly migraine headache days. Safety analyses assessed the potential relationship between treatment-emergent antidrug antibodies and hypersensitivity events or adverse events related to injection sites. FINDINGS: Across studies, 5.9-11.2% of patients had baseline antidrug antibodies. The incidence of treatment-emergent antidrug antibodies was 2.6-12.4% in the galcanezumab group and 0.5-1.7% in the placebo group. The majority of treatment-emergent antidrug antibodies were detected approximately 3-6 months after first study drug dose. Overall, the observed antidrug antibody titer did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or galcanezumab efficacy. There was no evidence that hypersensitivity events or adverse events related to injection sites were mediated by treatment-emergent antidrug antibodies. INTERPRETATION: These data showed that immunogenicity did not impact galcanezumab concentrations, calcitonin gene-related peptide concentrations, or the efficacy and hypersensitivity profile of galcanezumab in patients with migraine.

Systematic Review: Acupuncture vs Standard Pharmacological Therapy for Migraine Prevention.

BACKGROUND: Standard pharmacological treatment of migraine has many shortcomings. Acupuncture is becoming a more widely used therapy for the prevention and treatment of migraine, but its effectiveness is still in question when compared to the pharmacological treatments even though very few of these have Class A and B evidence for migraine prevention. This is a systematic review of data from existing randomized trials that compare the effectiveness of acupuncture treatment with conventional migraine preventative medications. METHODS: Custom-designed strategy was used for searching Pubmed (includes MEDLINE), Scopus (includes EMBASE). The inclusion criteria were English language and randomized trials. No date restriction was utilized. We included randomized trials and randomized controlled trials in adult patients that compared the clinical effects of acupuncture with a standard migraine preventive medication in patients with a diagnosis of chronic or episodic migraine with or without aura. We excluded letters and studies on acupuncture for headaches other than migraine. Two reviewers checked eligibility; extracted information on patients, interventions, methods, and results; and assessed the quality of the acupuncture intervention based on the American Academy of Neurology Classification of evidence matrix for therapeutic trials. The present review was not registered. RESULTS: Out of the 706 search results, 7 clinical trials, with a total of 1430 participants, met inclusion criteria for trials comparing the effectiveness of acupuncture to standard pharmacologic treatment. Several of the studies showed acupuncture to be more effective than standard pharmacological treatments for migraine prevention; however, methodological heterogeneity precluded aggregation of these data. CONCLUSIONS: There is growing evidence that acupuncture is just as effective and has fewer side effects than many of the standard pharmaceutical agents that are currently used. However, the heterogeneity of the existing studies limits the effective comparison and analysis.

Combined hormonal contraception and migraine: are we being too strict?

PURPOSE OF REVIEW: Combined hormonal contraception has been contraindicated in migraines, especially in migraines with aura, because of ischemic stroke risk. Newer formulations are now available and physicians may unnecessarily be limiting access to contraceptive and medical therapeutic options for patients with migraines. This review summarizes the available data regarding ischemic stroke risk of modern combined hormonal contraception in the setting of migraines. RECENT FINDINGS: Limited data exists on current formulations of combined hormonal contraception and outcomes in migraine patients. Studies indicate ischemic stroke risk may be estrogen dose related with high dose formulations having the highest risk. Absolute risk of ischemic stroke with combined hormonal contraception and migraines is low. SUMMARY: Ischemic stroke risk in combined hormonal contraception users in the setting of migraines is low and an individual approach may be more appropriate than current guidelines.

Review of Acute Treatment of Migraine Trial Results With the New FDA Endpoints: Design Implications for Future Trials.

BACKGROUND: In October 2014, the US Food and Drug Administration released a draft guidance for the development of drugs for the acute treatment of migraine. This guidance offered the option of replacing the previously required 4 co-primary endpoints: pain freedom, freedom from nausea, freedom from photophobia, and freedom from phonophobia, all at 2 hours posttreatment, with 2 co-primary endpoints: pain freedom and freedom from most bothersome symptom (MBS) other than pain, both at 2 hours posttreatment. At the time the new draft guidance was released, no large clinical trials had been undertaken with these 2 co-primary endpoints, posing a challenge in determining the sample size that might be required to achieve statistical significance. As a number of trials have now been completed, we conducted a review of the observed placebo responses, drug effect sizes, and sample sizes to better inform the design of future trials. METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane library for primary publications of phase 3 randomized, placebo-controlled, double-blind acute migraine treatment trials that used pain freedom and MBS freedom as primary or planned secondary endpoints. For each endpoint, placebo response rates were determined and used to generate estimates of sample size, assuming differences between placebo and active treatment groups of 10%, 15%, and 20%. Sample size calculations were based on 80% power using a 2-group continuity corrected chi-square test with a 5% 2-sided significance level. RESULTS: We identified abstracts or full-length papers describing results of 8 clinical trials employing the new co-primary endpoints. The mean placebo response rate for 2-hour pain freedom was 16.75% (range 11.8-21.3%) and treatment effect (difference in response rates between active and placebo groups) ranged from 5.0% to 27.2%. For 2-hour MBS freedom, the mean placebo response rate was 32.8% (range 25.2-48.1%), and the range of treatment effect was 8.9% to 25.4%. Based on a placebo response rate of 17% for pain freedom, the sample sizes that would have been required to achieve statistical significance were n = 269, n = 128, and n = 77, for treatment effect sizes of 10%, 15%, and 20%, respectively. For MBS, assuming a placebo response rate of 33%, the corresponding required sample sizes would have been n = 389, n = 181, and n = 105. CONCLUSIONS: The observed range of placebo response and treatment effect sizes suggests that use of the newly recommended 2 co-primary endpoints could reduce the sample sizes required to achieve significance compared with past trials using 4 primary endpoints (in which mean and median group sizes for recent trials were 375 and 362, respectively). However, the initial trials using the newly recommended co-primary endpoints tended to treat more participants than would have been minimally required. We anticipate that with the growing body of information regarding the use of these new endpoints, samples sizes may be more aligned with treatment efficacy, enabling faster and more cost-effective trials for acute migraine treatment.

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.

Improving the detection of chronic migraine: Development and validation of Identify Chronic Migraine (ID-CM).

BACKGROUND: Migraine, particularly chronic migraine (CM), is underdiagnosed and undertreated worldwide. Our objective was to develop and validate a self-administered tool (ID-CM) to identify migraine and CM. METHODS: ID-CM was developed in four stages. (1) Expert clinicians suggested candidate items from existing instruments and experience (Delphi Panel method). (2) Candidate items were reviewed by people with CM during cognitive debriefing interviews. (3) Items were administered to a Web panel of people with severe headache to assess psychometric properties and refine ID-CM. (4) Classification accuracy was assessed using an ICHD-3ß gold-standard clinician diagnosis. RESULTS: Stages 1 and 2 identified 20 items selected for psychometric validation in stage 3 (n = 1562). The 12 psychometrically robust items from stage 3 underwent validity testing in stage 4. A scoring algorithm applied to four symptom items (moderate/severe pain intensity, photophobia, phonophobia, nausea) accurately classified most migraine cases among 111 people (sensitivity = 83.5%, specificity = 88.5%). Augmenting this algorithm with eight items assessing headache frequency, disability, medication use, and planning disruption correctly classified most CM cases (sensitivity = 80.6%, specificity = 88.6%). DISCUSSION: ID-CM is a simple yet accurate tool that correctly classifies most individuals with migraine and CM. Further testing in other settings will also be valuable.

What the Gut Can Teach Us About Migraine.

During gestation, cells of the brain and gut develop almost simultaneously into the central nervous system (CNS) and enteric nervous system (ENS), respectively. They remain connected via the vagal nerve lifelong. While it is well known that the brain sends signal to the gut, communication is in fact bidirectional. Just as the brain can modulate gut functioning, the gut, and likely what we ingest, can in fact influence our brain functioning. We will first review both gastrointestinal (GI) function and migraine pathophysiology and then discuss evidence linking the migraine brain to various GI disorders. Lastly, we discuss the effects of gut microbiota on brain functioning and speculate how the gut and particularly diet may affect migraine.