Dodick, David W.

Abstract Objective To assess the utility of the novel patient‐identified (PI) most bothersome symptom (MBS) measure from PROMISE‐2, a phase 3 trial of eptinezumab for the preventive treatment of chronic migraine. Background Relief of bothersome migraine symptoms can influence satisfaction with treatment and therapeutic persistence. Understanding the impact of preventive treatment on a PI‐MBS could improve clinical decision‐making. Methods In PROMISE‐2, patients with chronic migraine received eptinezumab 100, 300 mg, or placebo administered intravenously every 12 weeks for up to 2 doses ( n = 1072). PI‐MBS was an exploratory outcome requiring each patient to self‐report their MBS in response to an open‐ended question. At baseline and week 12, patients rated overall improvement in PI‐MBS. The relationships among PI‐MBS at week 12 and change in monthly migraine days (MMDs) from baseline to month 3 (weeks 9–12), Patient Global Impression of Change at week 12, and changes from baseline to week 12 in the 6‐item Headache Impact Test total, EuroQol 5‐dimensions 5‐levels visual analog scale, and 36‐item Short‐Form Health Survey component scores were assessed. Results Treatment groups had similar baseline characteristics and reported a total of 23 unique PI‐MBS, most commonly light sensitivity (200/1072, 18.7%), nausea/vomiting (162/1072, 15.1%), and pain with activity (147/1072, 13.7%). Improvements in PI‐MBS at week 12 correlated with changes in MMDs ( ρ = −0.49; p < 0.0001) and other patient‐reported outcomes. Controlling for changes in MMDs, PI‐MBS improvement predicted other patient‐reported outcomes in expected directions. The magnitude of the standardized mean differences between placebo and active treatment for PI‐MBS were 0.31 ( p < 0.0001 vs. placebo) and 0.54 ( p < 0.0001 vs. placebo) for eptinezumab 100 and 300 mg, respectively. Conclusions Improvement in PI‐MBS at week 12 was associated with improvement in other patient‐reported outcome measures, and PI‐MBS may be an important patient‐centered measure of treatment benefits in patients with chronic migraine.

Abstract Objective To provide a review of challenges in clinical trials for the preventive treatment of cluster headache (CH) and highlight considerations for future studies. Background Current guidelines for preventive treatment of CH are largely based on off‐label therapies supported by a limited number of small randomized controlled trials. Guidelines for clinical trial design for CH treatments from the International Headache Society were last issued in 1995. Methods/Results Randomized controlled clinical trials were identified in the European and/or United States clinical trial registries with a search term of “cluster headache,” and manually reviewed. Cumulatively, there were 27 unique placebo‐controlled prevention trials for episodic and/or chronic CH, of which 12 were either ongoing, not yet recruiting, or the status was unknown. Of the remaining 15 trials, 5 were terminated early and 7 of the 10 completed trials enrolled fewer patients than planned or did not report the planned sample size. A systematic search of PubMed was also utilized to identify published manuscripts reporting results from placebo‐controlled preventive trials of CH. This search yielded 16 publications, of which 7 were registered. Through critical review of trial data and published manuscripts, challenges and complexities encountered in clinical trials for the preventive treatment of CH were identified. For example, the excruciating pain associated with CH demands a suitably limited baseline duration, rapid treatment efficacy onset, and poses a specific issue regarding duration of investigational treatment period and length of exposure to placebo. In episodic CH, spontaneous remission as part of natural history, and the unpredictability and irregularity of cluster periods across patients present additional key challenges. Conclusions Optimal CH trial design should balance sound methodology to demonstrate efficacy of a potential treatment with patient needs and the natural history of the disease, including unique outcome measures and endpoint timings for chronic versus episodic CH.

AbstractMigraine headache results from activation of meningeal nociceptors, however, the hypothalamus is activated many hours before the emergence of pain. How hypothalamic neural mechanisms may influence trigeminal nociceptor function remains unknown. Stress is a common migraine trigger that engages hypothalamic dynorphin/kappa opioid receptor (KOR) signalling and increases circulating prolactin. Prolactin acts at both long and short prolactin receptor isoforms that are expressed in trigeminal afferents. Following downregulation of the prolactin receptor long isoform, prolactin signalling at the prolactin receptor short isoform sensitizes nociceptors selectively in females. We hypothesized that stress may activate the kappa opioid receptor on tuberoinfundibular dopaminergic neurons to increase circulating prolactin leading to female-selective sensitization of trigeminal nociceptors through dysregulation of prolactin receptor isoforms.A mouse two-hit hyperalgesic priming model of migraine was used. Repeated restraint stress promoted vulnerability (i.e. first-hit priming) to a subsequent subthreshold (i.e. second-hit) stimulus from inhalational umbellulone, a TRPA1 agonist. Periorbital cutaneous allodynia served as a surrogate of migraine-like pain. Female and male KORCre; R26lsl-Sun1-GFP mice showed a high percentage of KORCre labelled neurons co-localized in tyrosine hydroxylase-positive cells in the hypothalamic arcuate nucleus. Restraint stress increased circulating prolactin to a greater degree in females. Stress-primed, but not control, mice of both sexes developed periorbital allodynia following inhalational umbellulone. Gi-DREADD activation (i.e. inhibition through Gi-coupled signalling) in KORCre neurons in the arcuate nucleus also increased circulating prolactin and repeated chemogenetic manipulation of these neurons primed mice of both sexes to umbellulone. Clustered regularly interspaced short palindromic repeats–Cas9 deletion of the arcuate nucleus KOR prevented restraint stress-induced prolactin release in female mice and priming from repeated stress episodes in both sexes. Inhibition of circulating prolactin occurred with systemic cabergoline, a dopamine D2 receptor agonist, blocked priming selectively in females. Repeated restraint stress downregulated the prolactin receptor long isoform in the trigeminal ganglia of female mice. Deletion of prolactin receptor in trigeminal ganglia by nasal clustered regularly interspaced short palindromic repeats–Cas9 targeting both prolactin receptor isoforms prevented stress-induced priming in female mice.Stress-induced activation of hypothalamic KOR increases circulating prolactin resulting in trigeminal downregulation of prolactin receptor long and pain responses to a normally innocuous TRPA1 stimulus. These are the first data that provide a mechanistic link between stress-induced hypothalamic activation and the trigeminal nociceptor effectors that produce trigeminal sensitization and migraine-like pain. This sexually dimorphic mechanism may help to explain female prevalence of migraine. KOR antagonists, currently in phase II clinical trials, may be useful as migraine preventives in both sexes, while dopamine agonists and prolactin/ prolactin receptor antibodies may improve therapy for migraine, and other stress-related neurological disorders, in females.

Background: Each year, nearly 700,000 Americans suffer from strokes, resulting in 150,000 deaths and significant disability among survivors. Despite advances in therapeutic options for acute stroke within a critical time window, patient delay in seeking medical attention remains a significant barrier to improving outcomes. In a recent study of the effect of marital status on the timing of presentation for medical care in patients with chest pain, married men presented earlier than married women. In this study, we hypothesize that marital status is a predictor of earlier health-seeking behavior following the onset of stroke symptoms. Methods: We conducted a retrospective review of 100 patients with acute stroke symptoms in our stroke alert quality initiative database who were brought by Emergency Medical Services (EMS) to the Mayo Clinic Hospital, Arizona between December 1, 2010 and June 30, 2011. Nine patients were excluded due to lack of data. The database contains the following information for each patient: age, gender, marital status, the time of symptom awareness, and the time of EMS dispatch. Using both an independent samples t-Test and ANOVA, we compared the time from symptom awareness to EMS dispatch both between married and single patients, and between men and women, (married and single). Results: The mean age of the 91 patients studied was 76 years (SD = 12.5 years) and 52% were women. Forty-five patients (49.5%) were married, and 46 (50.5%) were single. The mean time from symptom awareness to EMS activation was 52 minutes (median 21.0, SD 87.3, range 2-519 minutes.) Categorized by marital status, married patients activated EMS earlier that single patients, but this difference was not significant (43 versus 60 minutes, p=0.35.). Analyzing the data separately for gender, we found that married men activated EMS significantly earlier than married women (26 versus 72 minutes, p=0.04.). Single men activated EMS earlier than single women, but this difference was not significant (50 versus 66 minutes, p=0.60.) Conclusions: Among persons with acute stroke symptoms, earlier medical-seeking behavior was seen in married compared to single persons, and particularly in married men. We plan to analyze a larger sample of patients, and if these preliminary findings are confirmed, we will conduct a prospective study evaluating reasons why married men with stroke symptoms seek medical attention earlier.

Background Anatomical and experimental data indicate that onabotulinimtoxin A could be more efficient and cost-effective for treating chronic migraine with injections targeting the cranial sutures, where collaterals from the meninges penetrate the skull. Methods A new injection paradigm (FollowTheSutures) was tested for safety, tolerability and feasibility in a Phase II, open-label, non-controlled, single-center pilot study. Ninety units of onabotulinimtoxin A (Botox®), were injected in 18 sites over the area of the cranial sutures. Adverse events and potential beneficial effects were recorded in a headache diary at least 4 weeks before, and for 12 weeks after the injections. A higher dilution than normal of onabotulinimtoxin A was used to get better diffusion. Results Nineteen (of 20 included) women with chronic migraine received the injections and were evaluable. There was only one treatment-related adverse event (reduced power of chewing for some weeks). Otherwise, the procedure was overall well tolerated. Patients improved on most efficacy parameters after the injections. There was little or no effect on glabellar or forehead lines. Conclusions The protocol was safe and well tolerated. Lower risk of unblinding due to the absence of cosmetic effects should make the injection procedure well suited for a large, randomized, placebo-controlled study. If efficacy is confirmed, it will be markedly less costly than the standard procedure. Trial registration: EUDRACT (2017-002516-13), ClinicalTrials.gov (NCT03543254).

Background: Cluster headache (CH) is one of the most painful conditions in humans and there is limited epidemiological data on this debilitating condition. Objectives: To describe the epidemiology of CH in Norway Methods: We conducted a nationwide study to investigate the prevalence, incidence, and comorbidity of CH in Norway between January 1 2008 and December 31 2016. Treatment and outcome data from the Norwegian patient registry and the Norwegian prescription database were linked on an individual basis. Results: Among 3,892,260 individuals ≥18 years old of age, we identified a total of 1891 patients with CH. The prevalence of CH was 48.6 per 100,000, and the male-to-female ratio was 1.47. The estimated incidence of CH was 3.0 per 100,000/year. Among patients with CH, increased age and sex adjusted odds ratios ([OR], all with p-values <0.0001, were observed for medication-induced headache (OR 50.7, 95% CI 36.7–69.9), migraine (OR 25.2, 95% CI 22.5–28.3), chronic posttraumatic headache (OR 22.2, 95% CI 12.8–38.45), history of cranial trauma (OR 1.9, 95% CI 1.5–2.4), somatoform disorders (OR 4.2, 95% CI 3.0–5.8), suicide attempt (OR 3.9, 95% CI 2.6–5.8), personality disorder (OR 3.6, 95% CI 2.6–4.9), bipolar disorder (OR 3.6, 95% CI 2.8–4.8), peptic ulcer (OR 2.8, 95% CI 2.3–3.3), depression (OR 2.8, 95% CI 2.4–3.1), substance abuse (OR 2.6, 95% CI 2.0–3.3), and cerebrovascular disease (OR 2.4, 95% CI 1.8–3.1). Use of opioid analgesics during the study period was more common among patients with CH compared to others (81% vs. 22%, sex and age adjusted OR 23.4, 95% CI 20.8–26.2, p < 0.0001).

AbstractBackgroundLittle is known about sleep in those with a history of contact sports, who are at increased risk for neurodegenerative disease(s). Sleep disruption and disorders are increasingly recognized as having a bidirectional relationship with Alzheimer’s disease neuropathology. Here, we investigated self‐reported sleep disruption and disorders in male former college and professional American football players.Method116 former National Football League (NFL) players, 60 former college football players, and 60 asymptomatic men without a history of traumatic brain injury or repetitive head impacts (controls), all between 45‐74 years, completed the Mayo Sleep Questionnaire (MSQ) which includes the Epworth Sleepiness Scale (ESS). Former American football players were enrolled across the spectrum of symptom severity (asymptomatic to mild dementia). Using binary logistic regression or analysis of covariance, comparisons (controlling for age, racial identity, body mass index, APOE e4 status) on each of the MSQ items and the ESS were made between each of the study groups.ResultCompared to controls, former NFL players were more likely to restless legs (OR = 7.32, 95% CI = 1.63‐32.97*), sleepwalking (OR = 8.65, 95% CI = 1.08‐69.22*), observed apnea (OR = 2.25, 95% CI = 1.04‐4.85*), lower alertness levels (marginal mean diff. = 0.90**) and had higher ESS (marginal mean diff. = 2.37**). Former college football players reported greater sleep disturbances compared with controls: restless legs (OR = 10.82, 95% CI = 1.86‐62.89**), sleepwalking (OR = 10.45, 95% CI = 1.12‐97.58*), alertness levels (marginal mean diff. = 1.48**) and ESS (marginal mean diff. = 2.76*). There were no college vs control differences for observed apnea. There were no differences between former NFL players and former college football players on any sleep metric. **p<.005, *p<.05.ConclusionSleep disturbances may be an important factor to investigate in those with a history of participation in American football.

Abstract Objective To evaluate the content validity and psychometric properties of the Activity Impairment in Migraine Diary (AIM‐D). Background Measuring treatment effects on migraine impairment requires a psychometrically sound patient‐reported outcome (PRO) measure developed consistent with U.S. Food and Drug Administration guidance. Methods The AIM‐D was created from concepts that emerged during qualitative interviews with five clinicians experienced in treating migraine and concept elicitation (CE) interviews with 40 adults with episodic migraine (EM) or chronic migraine (CM). The initial version was refined based on three waves of cognitive interviews with 38 adults with EM or CM and input from a panel of clinical and measurement experts. The AIM‐D was psychometrically evaluated using data from 316 adults with EM or CM who participated in a 13‐week prospective observational study. Study participants completed PRO assessments including the AIM‐D and a daily headache diary. Exploratory and confirmatory factor analysis were used to determine the factor structure. The reliability, validity, and responsiveness of the AIM‐D were assessed. Additional PRO measures including the Patient Global Impression – Severity (PGI‐S), Migraine Specific Quality of Life Questionnaire, Version 2.1 Role Function‐Restrictive domain, and Headache Impact Test were used for psychometric evaluation of the AIM‐D. Results Based on CE interviews with adults with migraine and input from an expert panel, activity impairment was identified as the target in the preliminary conceptual framework, which had two domains: performance of daily activities (PDAs) and physical impairment (PI). Revision of the draft AIM‐D through multiple rounds of cognitive interviews and expert panel meetings resulted in a content valid 11‐item version. Exploratory factor analysis supported both one‐ and two‐domain structures for the AIM‐D, which were further supported by confirmatory factor analysis (factor loadings all >0.90). The AIM‐D domains (PDA and PI) and total score showed high internal consistency reliability (Cronbach's alpha 0.95–0.97), acceptable test–retest reliability for weekly average scores (intraclass correlation coefficient >0.60 for participants with no change in PGI‐S between baseline and week 2), and good convergent and known‐groups validity. There was evidence of responsiveness based on changes in PGI‐S score and monthly migraine days. Conclusion The AIM‐D is a content valid and psychometrically sound measure designed to evaluate activity impairment and is suitable for use in clinical trials of preventive treatments for EM or CM.