Dodick, David W.

Abstract Objective To evaluate unmet needs among individuals with episodic migraine (EM) in the United States (US). Background Data are limited on the impact of headache frequency (HF) and preventive treatment failure (TF) on the burden of migraine in the US. Methods A retrospective, cross‐sectional analysis of 2019 National Health and Wellness Survey (NHWS) data was conducted from an opt‐in online survey that identified respondents (aged ≥18 years) in the US with self‐reported physician‐diagnosed migraine. Participants were stratified by HF (low: 0–3 days/month; moderate‐to‐high: 4–14 days/month) and prior preventive TF (preventive naive; 0–1 TF; ≥2 TFs). Comparisons were conducted between preventive TF groups using multivariable regression models controlling for patient demographic and health characteristics. Results Among individuals with moderate‐to‐high frequency EM, the NHWS identified 397 with ≥2 TFs, 334 with 0–1 TF, and 356 as preventive naive. The 36‐item Short‐Form Health Survey (version 2) Physical Component Summary scores were significantly lower among those with ≥2 TFs, at a mean (standard error [SE]) of 41.4 [0.8] versus the preventive‐naive 46.8 [0.9] and 0–1 TF 44.5 [0.9] groups; p < 0.001 for both). Migraine Disability Assessment Scale scores were significantly higher in the ≥2 TFs, at a mean (SE) of 37.7 (3.9) versus preventive‐naive 26.8 (2.9) ( p < 0.001) and 0–1 TF 30.1 (3.3) ( p = 0.011) groups. The percentages of time that respondents experienced absenteeism (mean [SE] 21.6% [5.5%] vs. 13.4% [3.6%]; p = 0.022), presenteeism (mean [SE] 55.0% [8.3%] vs. 40.8% [6.5%]; p = 0.015), overall work impairment (mean [SE] 59.4% [5.6%] vs. 45.0% [4.4%]; p < 0.001), and activity impairment (mean [SE] 56.8% [1.0%] vs. 44.4% [0.9%]; p < 0.001) were significantly higher in the ≥2 TFs versus preventive‐naive group. Emergency department visits (preventive‐naive, p = 0.006; 0–1 TF, p = 0.008) and hospitalizations ( p < 0.001 both) in the past 6 months were significantly higher in the ≥2 TFs group. Direct and indirect costs were significantly higher in the ≥2 TFs (mean [SE] $24,026 [3460]; $22,074 [20]) versus 0–1 TF ($10,897 [1636]; $17,965 [17]) and preventive‐naive ($11,497 [1715]; $17,167 [17]) groups ( p < 0.001 for all). Results were similar in the low‐frequency EM group. Conclusions In this NHWS analysis, individuals with more prior preventive TFs experienced significantly higher humanistic and economic burden regardless of HF.

Background Persistent headache attributed to traumatic injury to the head is divided into two subtypes, one attributed to moderate or severe traumatic injury and another attributed to mild traumatic injury (i.e., concussion). The latter is much more prevalent, in part because more than 90% of cases with traumatic brain injury are classified as mild. The pathophysiology of persistent post-traumatic headache is poorly understood and the underlying mechanisms are likely multifactorial. There is currently no approved treatment specifically for persistent post-traumatic headache, and management strategies rely on medications used for migraine or tension-type headache. Therefore, high-quality trials are urgently needed to support clinical decision-making and optimize management strategies. International guidelines can facilitate appropriate trial design and ensure the acquisition of high-quality data evaluating the efficacy, tolerability, and safety of available and novel pharmacological therapies for the preventive treatment of persistent post-traumatic headache. Methods The development of this guideline was based on a literature review of available studies in MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials, along with a review of previously published guidelines for controlled trials of preventive treatment for episodic and chronic migraine. The identified literature was critically appraised, and due to the scarcity of scientific evidence, recommendations were primarily based on the consensus of experts in the field. Objective To provide guidelines for designing state-of-the-art controlled clinical trials aimed at evaluating the effectiveness of preventive treatments for persistent post-traumatic headache attributed to mild traumatic brain injury.

Background Women show increased prevalence and severity of migraine compared to men. Whether small molecule calcitonin gene-related peptide receptor (CGRP-R) antagonists (i.e., gepants) and monoclonal antibodies targeting either the CGRP-R or the CGRP peptide might show sexually dimorphic outcomes for acute and preventive therapy has not been established. Methods We conducted a subpopulation analysis of available published data from FDA reviews to evaluate potential sex differences in the response rates of ubrogepant, rimegepant and zavegepant for acute migraine therapy. Available data from FDA reviews of erenumab, fremanezumab, galcanezumab and eptinezumab, approved CGRP-R and CGRP monoclonal antibodies and of atogepant were examined for prevention outcomes based on patient sex. Preventive outcomes were analyzed separately for patients with episodic migraine and chronic migraine. Results In women, the three approved gepants produced statistically significant drug effects regardless of dose tested on the FDA mandated co-primary endpoints, the proportion of patients achieving two-hour pain-freedom and the proportion of patients free of their most bothersome symptom at two hours post-dose. In women, the average placebo-subtracted two-hour pain-freedom proportion was 9.5% (CI: 7.4 to 11.6) and the average numbers needed to treat was 11. The free from most bothersome symptom at two hours outcomes were also significant in women. The gepant drugs did not reach statistically significant effects on the two-hour pain-freedom endpoint in the men, with an average drug effect of 2.8% (CI: −2.5 to 8.2) and an average number needed to treat of 36. For freedom from most bothersome symptom at two hours post-dose endpoint, differences were not significant in male patients. The treatment effect in each of the gepant studies was always numerically greater in women than in men. In evaluation of prevention outcomes with the antibodies or atogepant using the change from the specified primary endpoint (e.g., monthly migraine days), the observed treatment effect for episodic migraine patients almost always favored drug over placebo in both women and men. For chronic migraine patients the treatment effects of antibodies were similar in men and women and always favored the drug treated group. Conclusion/Interpretation: Small molecule CGRP-R antagonists are effective in acute migraine therapy in women but available data do not demonstrate effectiveness in men. CGRP-targeting therapies are effective for migraine prevention in both male and female episodic migraine patients but possible sex differences remain uncertain. In male and female chronic migraine patients, CGRP/CGRP-R antibodies were similarly effective. The data highlight possible differential effects of CGRP targeted therapies in different patient populations and the need for increased understanding of CGRP neurobiology in men and women.

Abstract Background Erenumab is a monoclonal antibody that targets the calcitonin gene‐related peptide (CGRP) receptor and is approved for the preventative treatment of migraine in adults. CGRP is involved in the regulation of vasomotor tone under physiologic and pathologic conditions, including hypertension. While there has not been evidence of hypertension in preclinical models or clinical trials, post‐marketing data suggest erenumab may be associated with hypertension. This led to a warning in the United States Food and Drug Administration prescribing information for erenumab. Objective To determine the frequency of worsening blood pressure (BP) after initiation of erenumab in patients with migraine and how this is associated with hypertension. Methods This is an observational retrospective cohort study evaluating patients at a tertiary headache or neurology department. Systolic and diastolic BPs were compared between the initial visit prior to initiation of erenumab, and follow‐up visit while on erenumab. Worsening BP was defined as moving from a lower stage to a higher stage of BP, as defined by the American Heart Association. Serious adverse vascular events were also recorded. Results A total of 335 patients were included in the final analysis (mean [SD] age of 45.7 [14.40] years, 83.9% [281/335] female). At baseline, 20.9% (70/335) of patients had a prior diagnosis of hypertension. The median (interquartile range) time to follow‐up appointment from initial appointment was 20.5 (13.3–35.3) weeks. The mean (SD) BP at baseline was systolic 124.7 (15) mmHg and diastolic 77 (11) mmHg, and at follow‐up was systolic 124.0 (15) mmHg and diastolic 77.8 (9) mmHg. Overall, 23.3% (78/335) of all patients had worsening BP, whereas 13/225 (3.9%) patients had improvement in their BP. Patients with atrial fibrillation were more likely to develop worsening BP (odds ratio, 4.9, 95% confidence interval 1.12–21.4; p = 0.035). There was no association between worsening BP and pre‐existing hypertension, sex, body mass index, or age. One patient had non‐ST elevation myocardial infarction attributed to a hypertensive emergency while on erenumab. Conclusion We found that 23.3% of patients initiated on erenumab may have developed worsening BP, suggesting the need for BP monitoring in patients initiated on erenumab.

Abstract Migraine and sleep disorders are common co-morbidities. Patients frequently link their sleep to migraine attacks suggesting a potential causal relationship between these conditions. However, whether migraine pain promotes or disrupts sleep or whether sleep disruption can increase the risk of migraine remains unknown. We assessed the potential impact of periorbital allodynia, a measure consistent with migraine-like pain, from multiple preclinical models on sleep quantity and quality. Additionally, we evaluated the possible consequences of sleep deprivation in promoting susceptibility to migraine-like pain. Following the implantation of electroencephalogram/electromyography electrodes to record sleep, mice were treated with either single or repeated systemic injections of nitroglycerin at the onset of their active phase (i.e. nocturnal awake period). Neither single nor repeated nitroglycerin affected the total sleep time, non-rapid eye movement sleep, rapid eye movement sleep, sleep depth or other measures of sleep architecture. To account for the possible disruptive effects of the surgical implantation of electroencephalogram/electromyography electrodes, we used immobility recordings as a non-invasive method for assessing sleep-wake behaviour. Neither single nor repeated nitroglycerin administration during either the mouse sleep (i.e. daylight) or active (i.e. night) periods influenced immobility-defined sleep time. Administration of an inflammatory mediator mixture onto the dura mater at either sleep or active phases also did not affect immobility-defined sleep time. Additionally, inhalational umbellulone-induced migraine-like pain in restraint-stressed primed mice did not alter immobility-defined sleep time. The possible influence of sleep disruption on susceptibility to migraine-like pain was evaluated by depriving female mice of sleep over 6 h with novel objects, a method that does not increase circulating stress hormones. Migraine-like pain was not observed following acute sleep deprivation. However, in sleep-deprived mice, subthreshold doses of systemic nitroglycerin or dural calcitonin gene-related peptide induced periorbital cutaneous allodynia consistent with migraine-like pain. Our data reveal that while migraine-like pain does not significantly disrupt sleep, sleep disruption increases vulnerability to migraine-like pain suggesting that a therapeutic strategy focused on improving sleep may diminish migraine attacks.

AbstractBackgroundChronic traumatic encephalopathy (CTE) is a neurodegenerative disease thought to be caused, in part, by repetitive head impact (RHI) exposure and characterized by phosphorylated tau deposition with varying patterns in the cerebral cortex. Flortaucipir tau PET data from the DIAGNOSE CTE Research Project was examined to investigate tau PET patterns and its relation to RHI exposure in former professional and college American football players.MethodIn this study, 218 DIAGNOSE CTE participants, ages 45‐74, with flortaucipir PET were included; 104 were former National Football League players (PRO), 58 were former college football players (COL), and 56 had no history of contact sports, other exposure to RHI, or traumatic brain injury (UE). Regional flortaucipir uptake was quantified using established procedures for three previously defined statistical regions (superior frontal, left parietal, and medial temporal) and compared across the three groups. Association analyses were also performed to examine the relationship between flortaucipir uptake and exposure to RHI using the cumulative head impact index for linear acceleration g‐force (CHII‐G). The potential clinical utility of flortaucipir PET for CTE was also investigated by examining its ability to differentiate participants meeting criteria for traumatic encephalopathy syndrome (TES) and probable or possible level of certainty for CTE pathology from those who do not meet those criteria.ResultSignificantly higher flortaucipir uptake was observed in former football players than in participants without RHI exposure, controlling for age and race for the superior frontal region (Fig. 1A), left parietal, and medial temporal regions. Association between regional flortaucipir uptake and CHII‐G was only observed in the superior frontal region in former players (PRO+COL) 60 years and older (Fig. 1B) and no association was observed in the full PRO+COL group. Flortaucipir PET was not able to differentiate TES groups in former football players (Fig. 1C).ConclusionElevated flortaucipir uptake was observed in former American football players to a group of unexposed men. The association between flortaucipir uptake and exposure to RHI may require a long latent period to manifest. Further investigation of more sensitive tau PET tracers and quantification techniques is warranted to better characterize CTE related tau pathology.

AbstractBackgroundRepetitive head impacts (RHI) from American football can lead to tau and non‐tau pathologies that might present as white matter hyperintensities (WMH) on FLAIR MRI. In 2022, we published a study in Alzheimer’s & Dementia that examined WMH and their association with risk factors and clinical function in former elite football players. That study will be presented during this symposium along with new unpublished data that used imaging and fluid biomarkers to examine etiological correlates (tau, amyloid, neurodegeneration, axonal injury, neuroinflammation) of WMH in the same cohort.MethodsThe multi‐site DIAGNOSE CTE Research Project recruited 180 football players and 60 asymptomatic males without RHI (“controls”), all 45‐74 years (Table 1). Participants completed MRI, lumbar puncture, and neuropsychological testing. Lesion Segmentation Toolbox estimated FLAIR WMH, FreeSurfer derived total cortical thickness, and a diffusion pipeline derived average global FA. CSF was analyzed for p‐tau181, Aβ1‐42, NfL, and sTREM2. Tobit regressions compared football players (n = 149) and controls (n = 53) on total and regional log‐WMH and estimated the effects of years of football and age of first exposure (AFE) to football on log‐WMH. Linear regressions evaluated log‐WMH and clinical associations in football players. Structural equation modeling (SEM) examined effects between log‐WMH and cortical thickness, FA, and the CSF biomarkers. Analyses accounted for age, race, revised Framingham Stroke Risk Profile (rFSRP), body mass index, APOE ε4, and evaluation site.ResultsAlosco et al. (2022) found older (i.e., 60+) but not younger football players had greater total, frontal, temporal and parietal log‐WMH compared to controls (FDR‐adjusted p‐values<0.05; Table 2). Among older football players, younger AFE was associated with greater log‐WMH (beta = ‐0.13, 95% CI = ‐0.23,‐0.02). Greater log‐WMH corresponded to worse Trails A‐B (beta = ‐4.32, 95% CI = ‐8.59,‐0.05) and List Learning Long Delay scores (beta = ‐0.56, 95% CI = ‐0.93,‐0.19). Subsequent unpublished SEM analyses in football players (Figure 1) showed the following direct effects on log‐WMH: higher rFSRP, higher CSF p‐tau181, lower FA, and reduced cortical thickness. There were no indirect effects. Compared to controls, SEM associations were stronger in football players exception for cortical thickness.ConclusionsFLAIR WMH might have unique imaging characteristics, risk factors, and pathological underpinnings in people exposed to RHI.

AbstractINTRODUCTIONTau is a key pathology in chronic traumatic encephalopathy (CTE). Here, we report our findings in tau positron emission tomography (PET) measurements from the DIAGNOSE CTE Research Project.METHODWe compare flortaucipir PET measures from 104 former professional players (PRO), 58 former college football players (COL), and 56 same‐age men without exposure to repetitive head impacts (RHI) or traumatic brain injury (unexposed [UE]); characterize their associations with RHI exposure; and compare players who did or did not meet diagnostic criteria for traumatic encephalopathy syndrome (TES).RESULTSSignificantly elevated flortaucipir uptake was observed in former football players (PRO+COL) in prespecified regions (p < 0.05). Association between regional flortaucipir uptake and estimated cumulative head impact exposure was only observed in the superior frontal region in former players over 60 years old. Flortaucipir PET was not able to differentiate TES groups.DISCUSSIONAdditional studies are needed to further understand tau pathology in CTE and other individuals with a history of RHI.