Dodick, David W.

Background Retinal migraine is defined by fully reversible monocular visual phenomena. We present two cases that were complicated by permanent monocular vision deficits. Cases A 57-year-old man with history of retinal migraine experienced persistent monocular vision loss after one stereotypical retinal migraine, progressing to finger-count vision over 4 days. He developed paracentral acute middle maculopathy that progressed to central retinal artery occlusion. A 27-year-old man with history of retinal migraine presented with persistent right eye superotemporal scotoma after a retinal migraine. Relative afferent pupillary defect and superotemporal visual field defect were noted, consistent with ischemic optic neuropathy. Conclusion Retinal migraine can complicate with permanent monocular visual loss, suggesting potential migrainous infarction of the retina or optic nerve. A thorough cerebrovascular evaluation must be completed, which was unrevealing in our cases. Acute and preventive migraine therapy may be considered in retinal migraine patients, to mitigate rare but potentially permanent visual loss.

Abstract Objective To assess the risk of hypertension in patients with migraine who received erenumab in clinical trials and in the postmarketing setting. Background Erenumab is a monoclonal antibody for migraine prevention that targets the calcitonin gene‐related peptide (CGRP) receptor. Hypertension is a theoretical risk for inhibitors of the CGRP pathway. Although no evidence of an association between erenumab treatment and hypertension was observed during the clinical development program, adverse events (AEs) of hypertension have been identified in the postmarketing setting. Methods Safety data from four phase 2 and phase 3 clinical trials were used to perform a pooled analysis of hypertension AEs in patients with migraine receiving erenumab. Postmarketing AEs of hypertension were identified from the Amgen Global Safety database from May 17, 2018, through January 31, 2020. Results In the pooled analysis of clinical trials, hypertension AEs (placebo, 9/1043 [0.9%]; erenumab 70 mg, 7/893 [0.8%]; erenumab 140 mg, 1/507 [0.2%]) and percentage of patients initiating medication to treat hypertension (12/1043 [1.2%], 7/893 [0.8%], 1/507 [0.2%], respectively) were similar across treatment groups. A total of 362 AEs of hypertension were identified from the postmarketing setting, 26.2% (95/362) of which were serious, >245,000 patient‐years of exposure. The exposure‐adjusted incidence of hypertension was 0.144 per 100 patient‐years. Conclusions Clinical trials did not demonstrate an increased risk of hypertension with erenumab compared with placebo, and AE rates of hypertension reported with erenumab in the postmarketing setting were generally low. Additional data are needed to fully characterize the extent to which hypertension is a risk associated with erenumab.

Objective Determination of possible sex differences in mechanisms promoting migraine progression and the contribution of prolactin and the prolactin long (PRLR-L) and short (PRLR-S) receptor isoforms. Background The majority of patients with chronic migraine and medication overuse headache are female. Prolactin is present at higher levels in women and increases migraine. Prolactin signaling at the PRLR-S selectively sensitizes nociceptors in female rodents, while expression of the PRLR-L is protective. Methods Medication overuse headache was modeled by repeated sumatriptan administration in male and female mice. Periorbital and hindpaw cutaneous allodynia served as a surrogate of migraine-like pain. PRLR-L and PRLR-S isoforms were measured in the trigeminal ganglion with western blotting. Possible co-localization of PRLR with serotonin 5HT1B and 5HT1D receptors was determined with RNAscope. Cabergoline, a dopamine receptor agonist that inhibits circulating prolactin, was co-administered with sumatriptan. Nasal administration of CRISPR/Cas9 plasmid was used to edit expression of both PRLR isoforms. Results PRLR was co-localized with 5HT1B or 5HT1D receptors in the ophthalmic region of female trigeminal ganglion. A single injection of sumatriptan increased serum PRL levels in female mice. Repeated sumatriptan promoted cutaneous allodynia in both sexes but down-regulated trigeminal ganglion PRLR-L, without altering PRLR-S, only in females. Co-administration of sumatriptan with cabergoline prevented allodynia and down-regulation of PRLR-L only in females. CRISPR/Cas9 editing of both PRLR isoforms in the trigeminal ganglion prevented sumatriptan-induced periorbital allodynia in females. Interpretation We identified a sexually dimorphic mechanism of migraine chronification that involves down-regulation of PRLR-L and increased signaling of circulating prolactin at PRLR-S. These studies reveal a previously unrecognized neuroendocrine mechanism linking the hypothalamus to nociceptor sensitization that increases the risk of migraine pain in females and suggest opportunities for novel sex-specific therapies including gene editing through nasal delivery of CRISPR/Cas9 constructs.

Background Erenumab (erenumab-aooe in the US) effectively reduces monthly migraine days in episodic and chronic migraine. This traditional outcome does not capture the intensity of headache pain on days with migraine. Methods This post hoc analysis of two pivotal randomized, placebo-controlled studies in patients with episodic migraine and chronic migraine examined the effect of erenumab 70 and 140 mg on migraine pain. Cumulative monthly migraine pain intensity is the sum of the peak pain intensity scores (0 = no migraine to 3 = migraine day with severe pain) on migraine days. Change from baseline in cumulative monthly migraine pain and average monthly pain intensity was assessed over months 4 to 6 for episodic migraine and month 3 for chronic migraine; change in average monthly pain intensity was assessed among monthly migraine days responders/non-responders. Results Efficacy analysis included 946 patients for the episodic migraine study and 656 patients for the chronic migraine study. Cumulative monthly migraine pain decreased significantly with erenumab versus placebo ( p < 0.001, for episodic migraine and chronic migraine). In addition, monthly average migraine pain intensity decreased significantly with erenumab versus placebo for episodic migraine ( p < 0.01); decreases were non-significant for chronic migraine. In comparison with placebo-treated patients, a greater proportion of erenumab-treated patients were pain intensity responders regardless of threshold used. Episodic migraine and chronic migraine patients with a ≥50% reduction in monthly migraine days (responders) had a greater reduction in monthly average pain intensity than non-responders. Conclusions Erenumab reduced cumulative monthly migraine pain in episodic migraine and chronic migraine patients and significantly reduced monthly average migraine pain in episodic migraine, demonstrating treatment benefit beyond reduction in migraine frequency. Clinical Trial Registration: ClinicalTrials.gov, NCT02456740; ClinicalTrials.gov, NCT02066415

Background: Atrial fibrillation (AF) is an important modifiable and independent risk factor for stroke. AF is associated with 2-4% annual risk for first time stroke and about 8% annually for recurrent stroke. Anticoagulant therapy reduces the risk by 60%, while the relative risk reduction (RRR) obtained from antiplatelet therapy is only 20%. The effect is more robust for secondary than for primary prevention. Risk stratification schemes are utilized to assess an individual’s risk of future stroke and to determine the optimal antithrombotic or anticoagulation regimen for stroke prevention. Despite Warfarin’s superiority over antiplatelet therapy to reduce the risk of AF related systemic embolism, Warfarin is largely underutilized. The aim of this study was to determine the frequency and reasons behind withholding anticoagulation in patient with AF related cardioembolic stroke in our institution. Method: We extracted patients from our Get With The Guideline’s (GWTG) database who were admitted to Mayo Clinic AZ between January 2004 and December 2009. Two authors (TK and NL) independently identified all patients with the diagnosis of atrial fibrillation who were not prescribed Warfarin therapy upon discharge, then reviewed to identify the reason(s) why anticoagulation was not initiated. Factors such as discharge disposition (home, acute rehabilitation, long term nursing facility, hospice, other) and functional status (able to ambulate independently, with assistance, unable to ambulate, or not documented) were also assessed to help support the decision process. Results: From a total of 1295 patients, 305 with AF were identified. Patients who expired 48 (3.7%) from un-related causes were excluded. Of the 257 patients, 206 (80.2%) were anticoagulated and 51 (19.8%) were not anticoagulated. We found that in the anticoagulated group, patients discharged home were more likely to receive anticoagulation (89.2%), followed by those discharged to acute rehabilitation and skilled nursing facilities (77%). Those discharged to hospice were the least likely to receive anticoagulation (6.4%). In addition, patients with greater functional ability were also more likely to receive anticoagulation (independent 89.8%, vs. assisted 76.7%, vs. non-ambulatory 33.3%; p<0.0001). Reasons to withhold anticoagulation therapy at discharge included terminal illness/comfort measures only (40.0%); risk/discomfort due to bleeding (24%); risk of falls (13.0%); and patient refusal (9.0%). Discussion: Based on the results, we conclude that functional status and disposition at discharge are significant factors influencing the decision to anticoagulate after cardioembolic stroke attributed to AF.

Abstract Objective To evaluate whether the 15‐day threshold of headache days per month adequately reflects substantial differences in disability across the full spectrum of migraine. Background The monthly frequency of headache days defines migraine subtypes and has crucial implications for epidemiological and clinical research as well as access to care. Methods The patients with migraine ( N = 836) who participated in the American Registry for Migraine Research, which is a multicenter, longitudinal patient registry, between February 2016 and March 2020, were divided into four groups based on monthly headache frequency: Group 1 (0–7 headache days/month, n = 286), Group 2 (8–14 headache days/month, n = 180), Group 3 (15–23 headache days/month, n = 153), Group 4 (≥24 headache days/month, n = 217). Disability (MIDAS), Pain intensity (NRS), Work Productivity and Activity Impairment (WPAI), Pain Interference (PROMIS‐PI), Patient Health Questionnaire‐4 (PHQ‐4), and General Anxiety Disorder‐7 (GAD‐7) scores were compared. Results Mean (standard deviation [SD]) age was 46 (13) years (87.9% [735/836] female). The proportion of patients in each group was as follows: Group 1 (34.2% [286/836]), Group 2 (21.5% [180/836]), Group 3 (18.3% [153/836]), and Group 4 (26.0% [217/836]). There were significant relationships with increasing disability, lost productive time, and pain interference in higher headache frequency categories. There were no significant differences between Group 2 and Group 3 for most measures (NRS, all WPAI scores, PROMIS‐PI, GAD‐7, and PHQ‐4), although MIDAS scores differed (median [interquartile range (IQR)]; 38 [20–58] vs. 55 [30–90], p < 0.001). Patients in Group 1 had significantly lower MIDAS (median [IQR];16 [7–30], p < 0.001), WPAI‐% total active impairment (mean (SD): Group 1 [30.9 (26.8)] vs. Group 2 [39.2 (24.5), p = 0.017], vs. Group 3 [45.9 (24.1), p < 0.001], vs. Group 4 [55.3 (23.0), p < 0.001], and PROMIS‐PI‐T score (Group 1 [60.3 (7.3)] vs. Group 2 [62.6 (6.4), p = 0.008], vs. Group 3 [64.6 (5.6), p < 0.001], vs. Group 4 [66.8 (5.9), p < 0.001]) compared to all other groups. Patients in Group 4 had significantly higher MIDAS (median (IQR): Group 4 [90 (52–138)] vs. Group 1 [16 (7–30), p < 0.001], vs. Group 2 [38 (20–58), p < 0.001], vs. Group 3 [55 (30–90), p < 0.001], WPAI‐%Presenteeism (Group 4 [50.4 (24.4)] vs. Group 1 [28.8 (24.9), p < 0.001], vs. Group 2 [34.9 (22.3), p < 0.001], vs. Group 3 [40.9 (22.3), p = 0.048], WPAI‐% total work productivity impairment (Group 4 [55.9 (26.1)] vs. Group 1 [32.1 (37.6), p < 0.001], vs. Group 2 [38.3 (24.0), p < 0.001], vs. Group 3 [44.6 (24.4), p = 0.019]), and WPAI‐%Total activity impairment (Group 4 [55.3 (23.0)] vs. Group 1 [30.9 (26.8), p < 0.001], vs. Group 2 [39.2 (24.5), p < 0.001], vs. Group 3 [45.9 (24.1), p = 0.025]) scores compared with all other groups. Conclusion Our data suggest that the use of a 15 headache day/month threshold to distinguish episodic and chronic migraine does not capture the burden of illness nor reflect the treatment needs of patients. These results have important implications for future refinements in the classification of migraine.

Abstract Objective We sought to investigate the patient experience of telemedicine for headache care during the coronavirus disease 2019 (COVID‐19) pandemic. Background The use of telemedicine has rapidly expanded and evolved since the beginning of the COVID‐19 pandemic. Telemedicine eliminates the physical and geographic barriers to health care, preserves personal protective equipment, and prevents the spread of COVID‐19 by allowing encounters to happen in a socially distanced way. However, few studies have assessed the patient perspective of telemedicine for headache care. Methods The American Migraine Foundation (AMF) designed a standardized electronic questionnaire to assess the patient experience of telemedicine for headache care between March and September 2020 to help inform future quality improvement as part of its patient advocacy initiative. The date parameters were identified as the emergence of severe acute respiratory syndrome coronavirus 2 disease and the declaration of a national emergency in the United States. The questionnaire was distributed electronically to more than 100,000 members of the AMF community through social media platforms and the AMF email database. Results A total of 1172 patients responded to our electronic questionnaire, with 1098 complete responses. The majority, 1081/1153 (93.8%) patients, had a previous headache diagnosis prior to the telemedicine encounter. A total of 648/1127 (57.5%) patients reported that they had used telemedicine for headache care during the study period. Among those who participated in telehealth visits, 553/647 (85.5%) patients used it for follow‐up visits; 94/647 (14.5%) patients used it for new patient visits. During the telemedicine encounters, 282/645 (43.7%) patients were evaluated by headache specialists, 222/645 (34.4%) patients by general neurologists, 198/645 (30.7%) patients by primary care providers, 73/645 (11.3%) patients by headache nurse practitioners, and 21/645 (3.2%) patients by headache nurses. Only 47/633 (7.4%) patients received a new headache diagnosis from telemedicine evaluation, whereas the other 586/633 (92.6%) patients did not have a change in their diagnoses. During these visits, a new treatment was prescribed for 358/636 (52.3%) patients, whereas 278/636 (43.7%) patients did not have changes made to their treatment plan. The number (%) of patients who rated the telemedicine headache care experience as “very good,” “good,” “fair,” “poor,” and “other” were 396/638 (62.1%), 132/638 (20.7%), 67/638 (10.5%), 23/638 (3.6%), and 20/638 (3.1%), respectively. Detailed reasons for “other” are listed in the manuscript. Most patients, 573/638 (89.8%), indicated that they would prefer to continue to use telemedicine for their headache care, 45/638 (7.1%) patients would not, and 20/638 (3.1%) patients were unsure. Conclusions Our study evaluating the patient perspective demonstrated that telemedicine facilitated headache care for many patients during the COVID‐19 pandemic, resulting in high patient satisfaction rates, and a desire to continue to use telemedicine for future headache care among those who completed the online survey.