Trends in Nutrition-Related Risk Factors Identified Post-Operatively in Patients Treated for a Lower-Extremity Injury.

This study investigated trends within a custom Sports Nutrition Assessment for Consultation (SNAC) survey designed to identify nutrition-related risk factors among post-operative lower-extremity youth athletes. Athletes aged 8-18 years who completed the SNAC at a sports medicine institution after lower-extremity surgery were reviewed for associations between SNAC questions and age/sex differences. Of 477 patients (15.0 ± 2.0 years; 47.8% female), 319 (66.9%) answered 'yes' to at least one question and were identified for a consult, though 216 (64.3%) declined. The most frequent questions to prompt a consult were a desire to better understand nutrition for recovery (41.5%) and regularly skipping at least one meal a day (29.8%). Inter-question responses were often significantly related, especially regarding appetite changes, weight changes, and/or meal-skipping. While consult acceptance was not significantly different between sex/age, males were more likely to report a desire to better understand nutrition (p = 0.004) and a weight change (p = 0.019), and females were more likely to report struggling with dizziness/fatigue (p < 0.001). Additionally, older athletes reported an appetite change (p = 0.022), meal-skipping (p = 0.002), a desire to better understand nutrition (p < 0.001), a weight change (p < 0.001), and an effort/recommendation to change their body composition/weight (p = 0.005). These findings demonstrate a link between risky nutrition behaviors and physical detriments.

The impacts of migraine on functioning: Results from two qualitative studies of people living with migraine.

OBJECTIVE: To describe the impact of migraine on functioning based on comprehensive data collection, analysis, and reporting of patients' experiences. BACKGROUND: Qualitative research conducted to understand patients' perspectives on living with migraine has often focused on narrow topics or specific groups of patients or has been selectively reported. METHODS: Qualitative interviews with 71 participants were conducted during two concept elicitation studies as part of the Migraine Clinical Outcome Assessment System (MiCOAS) project, an FDA grant-funded program designed to develop a core set of patient-centered outcome measures for migraine clinical trials. Participants self-reported being diagnosed with migraine by a healthcare professional and participated in semi-structured qualitative interviews about their experiences with the symptoms and impacts of migraine. Interview transcripts were coded to identify and define concepts, which were then grouped into broad domains based on conceptual similarities. RESULTS: A total of 66 concepts were identified: 12 for physical functioning, 16 for cognitive functioning, 10 for social role functioning, 19 for emotional and psychological functioning, and 9 related to migraine management. Participants described a complex and varied relationship between migraine attack symptoms and impacts on functioning. Impacts from migraine were further influenced by numerous contextual factors, such as people's individual social environments and the level of day-to-day demand for functioning they face. CONCLUSION: Findings showed that migraine impacted individual functioning in multiple ways and the nature of these impacts was dependent on social-contextual factors. The results are being used in the development of core measures designed to improve our understanding of the burden of migraine and the efficacy of migraine therapies. The results also offer new insights and raise new questions about migraine experience that can be used to guide future research.

Plasma calcitonin gene-related peptide and nerve growth factor as headache and pain biomarkers in recently deployed soldiers with and without a recent concussion.

OBJECTIVE: The objective of this study was to characterize the utility of calcitonin gene-related peptide (CGRP) and nerve growth factor (NGF) as potential biomarkers for headache and pain disorders in the post-military deployment setting. BACKGROUND: The need to improve recognition, assessment, and prognoses of individuals with posttraumatic headache or other pain has increased interest in the potential of CGRP and NGF as biomarkers. METHODS: The Warrior Strong Study (NCT01847040) is an observational longitudinal study of United States-based soldiers who had recently returned from deployment to Afghanistan or Iraq from 2009 to 2014. The present nested cross-sectional analysis uses baseline data collected from soldiers returning to Fort Bragg, North Carolina. RESULTS: In total, 264 soldiers (mean (standard deviation [SD] age 28.1 [6.4] years, 230/264 [87.1%] men, 171/263 [65.0%] White) were analyzed. Mean (SD) plasma levels of CGRP were 1.3 (1.1) pg/mL and mean levels of NGF were 1.4 (0.4) pg/mL. Age was negatively correlated with NGF (-0.01 pg/mL per year, p = 0.007) but was not associated with CGRP. Men had higher mean (SD) CGRP plasma levels than women (1.4 95% confidence interval [CI; 1.2] vs. 0.9 95% CI [0.5] pg/mL, p < 0.002, Kruskal-Wallis test). CGRP levels were lower in participants who had a headache at the time of the blood draw (1.0 [0.6] pg/mL vs. 1.4 [1.2] pg/mL, p = 0.024). NGF was lower in participants with continuous pain (all types; 1.2 [0.4] vs. 1.4 [0.4] pg/mL, p = 0.027) and was lower in participants with traumatic brain injury (TBI) + posttraumatic headache (PTH) versus TBI without PTH (1.3 [0.3] vs. 1.4 [0.4] pg/mL, p = 0.021). Otherwise, CGRP and NGF were not associated with migraine-like headache, TBI status, or headache burden as measured by the number of medical encounters in crude or adjusted models. CONCLUSION: In this exploratory study, plasma levels of NGF and CGRP showed promise as biomarkers for headache and other types of pain. These findings need to be replicated in other cohorts.

Faster Rate of Correction with Distal Femoral Transphyseal Screws Versus Plates in Hemiepiphysiodesis for Coronal-Plane Knee Deformity: Age- and Sex-Matched Cohorts of Skeletally Immature Patients.

BACKGROUND: Hemiepiphysiodesis (guided-growth) procedures have become the primary method of treatment for coronal-plane knee deformities in skeletally immature patients. Two leading techniques involve the use of a transphyseal screw or a growth modulation plate. However, clinical references for the estimation of correction are lacking, and no consensus has been reached regarding the superiority of one technique over the other. Therefore, the purpose of this study was to compare the rates of correction for distal femoral transphyseal screws and growth modulation plates in age- and sex-matched cohorts with coronal deformities. METHODS: Thirty-one knees were included in each cohort on the basis of propensity scoring by chronological age and sex, and radiographic images were retrospectively reviewed preoperatively and postoperatively. Each case was measured for limb length, mechanical axis deviation (MAD), mechanical lateral distal femoral angle (LDFA), and bone age. RESULTS: Both the MAD and LDFA rate of correction significantly differed between the screw and plate cohorts. The MAD rate of correction was observed to be 0.42 ± 0.37 mm/week (1.69 mm/month) in the plate cohort and 0.66 ± 0.51 mm/week (2.64 mm/month) in the screw cohort. The LDFA rate of correction was observed to be 0.12° ± 0.13°/week (0.50°/month) in the plate cohort and 0.19° ± 0.19°/week (0.77°/month) in the screw cohort. CONCLUSIONS: The current study provides simple clinical references for the rate of correction of MAD and the LDFA for 2 methods of hemiepiphysiodesis. The results suggest that transphyseal screws may correct coronal knee deformities during the initial treatment stage more quickly than growth modulation plates in distal femoral guided growth. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Priority acute and preventive migraine treatment benefits: Results of the Migraine Clinical Outcome Assessment System (MiCOAS) qualitative study of people living with migraine.

BACKGROUND: There is renewed emphasis on including patients in determining, defining, and prioritizing outcomes for migraine treatment. OBJECTIVES: To obtain insights directly from people living with migraine on their priorities for treatment. METHODS: A total of 40 qualitative interviews were conducted as part of the Migraine Clinical Outcome Assessment System project, a United States Food and Drug Administration grant-funded program to develop a core set of patient-centered outcome measures for migraine clinical trials. Interviews included a structured exercise in which participants rank-ordered pre-defined lists of potential benefits for acute and preventive migraine therapy. The 40 study participants who reported being diagnosed with migraine by a clinician ranked the benefits and explained their rationale. RESULTS: Study participants consistently ranked either pain relief or absence of pain as their top priority for acute treatment. Relief/absence of other migraine symptoms and improved functioning were also prioritized. For preventive treatment, participants prioritized reductions in migraine frequency, symptom severity, and attack duration. Few differences were found between participants with episodic migraine and those with chronic migraine. However, participants with chronic migraine ranked "increased predictability of attacks" much higher than those with episodic migraine. Participants' rankings were influenced by prior expectations and experiences of migraine treatments, which caused many participants to deprioritize desired benefits as unrealistic. Participants also identified several additional priorities, including limited side-effects and reliable treatment efficacy in both acute and preventive treatments. CONCLUSION: The results showed the participants prioritized treatment benefits aligned with existing core clinical outcomes used in migraine research, but also valued benefits that are not typically assessed, such as predictability. Participants also deprioritized important benefits when they believed treatment was unlikely to deliver those outcomes.

Patient-reported experiences with migraine-related cognitive symptoms: Results of the MiCOAS qualitative study.

OBJECTIVES: To capture patients' perspectives on migraine-related cognitive symptoms during pre-headache, headache, post-headache, and interictal periods. BACKGROUND: Migraine-related cognitive symptoms are reported by people with migraine both during and between attacks. Associated with disability, they are increasingly viewed as a priority target for treatment. The Migraine Clinical Outcome Assessment System (MiCOAS) project is focused on developing a patient-centered core set of outcome measures for the evaluation of migraine treatments. The project focuses on incorporating the experience of people living with migraine and the outcomes most meaningful to them. This includes an examination of the presence and functional impact of migraine-related cognitive symptoms and their perceived impact on quality of life and disability. METHODS: Forty individuals with self-reported medically diagnosed migraine were recruited via iterative purposeful sampling for semi-structured qualitative interviews conducted using audio-only web conferencing. Thematic content analysis was performed to identify key concepts around migraine-related cognitive symptoms. Recruitment continued until concept saturation was achieved. RESULTS: Participants described symptoms consistent with migraine-related deficits in language/speech, sustained attention, executive function, and memory that manifest during pre-headache (36/40 [90%] reported ≥1 cognitive feature), headache (35/40 [88%] reported ≥1 cognitive feature), post-headache (27/40 [68%] reported ≥1 cognitive feature), and interictal periods (13/40 [33%] reported ≥1 cognitive feature). Among participants reporting cognitive symptoms during pre-headache, 32/40 (81%) endorsed 2-5 cognitive symptoms. Findings were similar during the headache phase. Participants reported language/speech problems consistent with, for example, impairments in receptive language, expressive language, and articulation. Issues with sustained attention included fogginess, confusion/disorientation, and trouble with concentration/focus. Deficits in executive function included difficulty processing information and reduced capacity for planning and decision-making. Memory issues were reported across all phases of the migraine attack. CONCLUSIONS: This patient-level qualitative study suggests that cognitive symptoms are common for persons with migraine, particularly in the pre-headache and headache phases. These findings highlight the importance of assessing and ameliorating these cognitive problems.

Longitudinal assessment of comorbidities and co-occurring conditions in adolescents with migraine: A secondary analysis of the National Longitudinal Study of Adolescent to Adult Health (Add Health).

OBJECTIVE: To investigate the links between adolescent migraine and comorbid and co-occurring conditions using a large, nationally representative longitudinal study. BACKGROUND: Comorbidities and co-occurring conditions play an important role in the clinical treatment of individuals with migraine. Research in this area has focused largely on the adult population using cross-sectional data, but less is known about adolescents and how conditions may co-occur over time from a broader developmental perspective. The goals of this manuscript were to empirically evaluate the associations between adolescent migraine and several linked conditions and explore the relative timings of onset of these conditions from adolescence to adulthood. METHODS: Data came from the National Longitudinal Study of Adolescent to Adult Health (Add Health), a school-based study of the health-related behaviors and conditions of adolescents. The present study examined data from Wave 1 (W1, study years: 1994-1995), Wave 4 (W4, study years: 2008-2009), and Wave 5 (W5, study years: 2016-2018). Analyses and visual plots were used to evaluate potential links between parent-reported adolescent migraine status (PR-AdMig) at W1 and 15 medical conditions identified based on self-reported medical diagnoses (SR-MDs) at W4 and W5. Based on prior literature in adults, we identified 11 conditions predicted to be associated with PR-AdMig and four conditions predicted not to be associated with PR-AdMig. The analyses were exploratory and post hoc. RESULTS: The total sample size pooling over all analyses was n = 13,786, but the wave-specific sample sizes differed due to missing data (W4 analyses, n = 12,692; W5 analyses, n = 10,340); 7243/13,786 (unweighted: 52.5%; weighted: 50.5%) of participants were female, 7640/13,786 (unweighted: 55.4%; weighted: 68.6%) were White, and 1580/13,786 (unweighted: 11.5%; weighted: 12.0%) had PR-AdMig. The average ages were 15.8 years at W1, 28.7 years at W4, and 37.8 years at W5. Findings showed that PR-AdMig was associated with anxiety/panic disorder (W4: PR-AdMig vs. Control weighted %: 17.1% vs. 12.6%, unadjusted odds ratio [OR] = 1.43, 95% confidence interval [CI] 1.18-1.74, p = 0.0003; W5: 31.6% vs. 22.4%, OR = 1.60, 95% CI 1.28-2.02, p < 0.0001), asthma/chronic bronchitis/emphysema (W4: 20.0% vs. 14.7%, OR = 1.45, 95% CI 1.20-1.76, p < 0.001; W5: 21.0% vs. 14.6%, OR = 1.55, 95% CI 1.25-1.94, p < 0.001), attention deficit hyperactivity disorder (W4: 8.3% vs. 5.4%, OR = 1.58, 95% CI 1.18-2.10, p = 0.002), depression (W4: 23.7% vs. 15.4%, OR = 1.71, 95% CI 1.43-2.04, p < 0.0001; W5: 33.8% vs. 25.1%, OR = 1.53, 95% CI 1.22-1.90, p < 0.001), epilepsy/seizure disorder (W4: 2.2% vs. 1.2%, OR = 1.84, 95% CI 1.23-2.76, p = 0.004), migraine (W4: 38.8% vs. 11.9%, OR = 4.7, 95% CI 4.1-5.5, p < 0.001), post-traumatic stress disorder (W4: 4.1% vs. 2.8%, OR = 1.45, 95% CI 1.01-2.08, p = 0.042; W5: 11.3% vs. 7.1%, OR = 1.67, 95% CI 1.27-2.20, p < 0.001), and sleep apnea (W5: 11.0% vs. 7.6%, OR = 1.51, 95% CI 1.15-1.98, p = 0.003). Among theoretically unlinked conditions, only hepatitis C at W4 was shown to have a relationship with adolescent onset migraine (0.7% vs. 0.2%, OR = 3.63, 95% CI 1.32-10.0, p = 0.013). Visual plots suggested that the retrospective, self-report timing of onset of specific subsets of co-occurring conditions tended to group together over time. CONCLUSIONS: Consistent with the existing headache literature, results showed that adolescent migraine was associated with other medical and psychological conditions and visual plots suggested that there may be developmental patterns in the occurrence of migraine with other related conditions.

Differences in athletic identity, sport participation, and psychosocial factors following anterior cruciate ligament rehabilitation in youth athletes.

Introduction: While youth sports benefits the developing athlete, athletes may also be subject to injury and subsequent return-to-sport protocols. The current return-to-sport criteria emphasize physical measures; however, psychological measures may also be valuable to inform providers of an athlete's readiness. One such measure is athletic identity defined as the degree to which an individual identifies with the athlete role. To better understand athletic identity in return-to-sport, this study aimed to identify relationships and trends between the Athletic Identity Measurement Scale (AIMS), demographic variables, sport participation measures, and the Athletic Coping Skills Inventory-28 (ACSI-28) in youth athletes during rehabilitation following anterior cruciate ligament reconstruction (ACLR). Methods: A retrospective review was completed of patients who underwent ACLR at a sports medicine clinic between October 2019 and May 2021. Patients responded to a series of patient reported outcomes (PROs) regarding physical and psychological function at a pre-surgical baseline and after 1 year of rehabilitation. Patients were then divided into groups of high/low AIMS and an increased/decreased AIMS between 1 year and baseline for comparison. Independent samples t-tests and ANOVAs were performed as appropriate with a 95% confidence interval. Results: In the final sample, 87 patients (15.3 ± 1.8 years) were included, with 51.7% being females. Total AIMS scores decreased from 50.3 to 47.5 over rehabilitation (p = 0.019). Furthermore, results indicated that nearly all AIMS scores decreased during rehabilitation, with none showing an increase; however, not all domains were significant. Conversely, all sport participation and coping ability PROs increased over time points except for ACSI-Confidence and Achievement Motivation. Generally, those in the groups with high AIMS and an increase in AIMS also had higher scores in physical function and coping ability PROs, with the groups separated by high/low AIMS exhibiting more frequent statistical significance. Discussion: Given these results, it appears that athletes may lose identification with the athlete role after ACLR and struggle even 1 year for rehabilitation, but those who recover athletic identity the best may also be those able to cope most effectively with the stressors induced by injury.

Guidelines of the International Headache Society for Controlled Clinical Trials in Cluster Headache.

In 1995, a committee of the International Headache Society developed and published the first edition of the Guidelines for Controlled Trials of Drugs in Cluster Headache. These have not been revised. With the emergence of new medications, neuromodulation devices and trial designs, an updated version of the International Headache Society Guidelines for Controlled Clinical Trials in Cluster Headache is warranted. Given the scarcity of evidence-based data for cluster headache therapies, the update is largely consensus-based, but takes into account lessons learned from recent trials and demands by patients. It is intended to apply to both drug and neuromodulation treatments, with specific proposals for the latter when needed. The primary objective is to propose a template for designing high quality, state-of-the-art, controlled clinical trials of acute and preventive treatments in episodic and chronic cluster headache. The recommendations should not be regarded as dogma and alternative solutions to particular methodological problems should be explored in the future and scientifically validated.

Sport Participation and Psychosocial Factors Which Influence Athletic Identity in Youth Athletes With Anterior Cruciate Ligament Injury.

Athletic identity, or the degree with which individuals identify with the athlete role, is an important rehabilitation factor for sports care providers to consider; however, it lacks extensive study in youth. The purpose of this study was to identify demographic, sport participation, and psychosocial measures which correlate with youth athletic identity after anterior cruciate ligament injury. Participants completed standardized sports medicine intake and patient-reported outcome measures, including the Athletic Identity Measurement Scale (AIMS). A total of 226 participants were included, and two groups were created based on high or low total AIMS score. Results indicated that sex (p = 0.002), years active in sport (p = 0.049), activity level (p = 0.038), and ACSI-Coachability (p = 0.027) differed by AIMS score. While youth athletes appear resilient, these results emphasize that they identify strongly with the athlete role and may suffer psychosocial consequences after injury. Future work should evaluate similar factors over course of recovery in a larger, diversified population.

Evaluating the clinical utility of the patient-identified most bothersome symptom measure from PROMISE-2 for research in migraine prevention.

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.

Impact of the COVID-19 pandemic on people living with migraine: Results of the MiCOAS qualitative study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health crisis that has had a range of impacts on people living with migraine. METHODS: Qualitative interviews performed as part of the Migraine Clinical Outcome Assessment System project, a multi-stage Food and Drug Administration-grant funded program to develop a patient-centered core set of outcome measures for use in migraine clinical trials, offered an opportunity to explore the experience of living with migraine during the pandemic as well as to examine whether migraine treatment priorities, symptoms, and associated disability changed due to the pandemic. Semi-structured interviews were conducted in the United States between the summer and fall of 2020 with 40 individuals with self-reported, medically diagnosed migraine who self-reported that they had not tested positive for or been diagnosed with COVID-19. RESULTS: Seventy percent (n = 28) of the sample reported ≥1 pandemic-related impact on their life with migraine. Fourteen participants reported both positive and negative impacts, twelve reported negative impacts only, and two reported positive impacts only. Among those reporting ≥1 pandemic-related impact, nine participants (32%) reported more frequent and five (17%) reported less frequent migraine attacks. Other negative impacts included interrupted medical care (n = 9; 32%), and greater stress (n = 13; 46%). The most frequent positive impact reported was greater access to health care (n = 8; 29%). Ictal and interictal symptoms were not noted to change due to the pandemic, but some respondents reported less disability due to increased flexibility of schedules and reduced expectations. Treatment priorities did not change due to the pandemic. CONCLUSION: The global COVID-19 pandemic has resulted in both negative and positive impacts for people living with migraine. Lessons to be considered when moving into a post-pandemic world include benefits of and satisfaction with telehealth and the benefits and importance of healthy lifestyle habits and flexibility such as improved sleep, reduced stress, and fewer social expectations.

Measuring headache day severity using multiple features in daily diary designs.

OBJECTIVE: Though migraine is thought of as a symptom complex, symptoms are typically assessed one at a time. For use in clinical research, we developed a composite measure of headache day severity by combining eight well-known symptoms captured in daily diaries. SUBJECTS AND METHODS: Data came from adults with a self-reported diagnosis of migraine (n = 4380) who provided daily diary information assessed using a novel digital platform. Nine observed features theoretically linked to headache day severity were analyzed using latent variable modeling to create a psychometrically robust headache day severity score. Logistic regression was used to assess the cross-sectional relationships of headache day severity scores against an array of clinically-relevant outcomes. RESULTS: Participants were largely females (90%), approaching middle age (mean age of 37.3) and living in the United States (49%) or United Kingdom (23%). Findings supported a single latent headache day severity construct based on eight observed headache features. Headache day severity scores were associated with an increased odds of physician visits (Odds ratio[95% CI]: 1.71[1.32-2.21]), emergency department visits (4.12[2.23-7.60]), missed school/work (2.90[2.56-3.29]), missed household work (3.37[3.06-3.72]), and missed other activities (3.29[2.97-3.64]) (p < .0001 for all). CONCLUSIONS: Modern measurement techniques support a single headache day severity construct that reflects migraine is a symptom complex. The headache day severity scores were associated with external validators and initial visualizations showed how headache day severity scores can be applied broadly in clinical practice and research.

What do people want to know about "Growing Up with Migraine"? Results of a preference survey of people with lived experience to guide future research.

In recent years, emphasis has been placed on conducting headache research that is patient-centered to more explicitly incorporate the input of people who live with headache diseases. The Growing Up with Migraine Study was developed with this intention using a two-step process: 1. develop and administer a survey to identify research areas that matter most to people with adolescent migraine and/or their caregivers and 2. use the survey results to guide future secondary data analyses. This brief report summarizes the survey results from 373 individuals impacted by adolescent migraine. Findings suggested that people with history of adolescent migraine and/or their caregivers are most interested in research about migraine comorbidities and effects on psychological/social/emotional health, along with health-related outcomes and family-related topics. Future quantitative studies are planned that will explore these patient-identified priorities through secondary data analysis of an existing dataset.

Systematic review of outcomes and endpoints in acute migraine clinical trials.

BACKGROUND/OBJECTIVE: To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials. METHOD: A systematic literature review, following a prespecified (but unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to understand endpoints and outcomes used in acute migraine clinical trials. Predefined terms were searched in PubMed to locate clinical trials assessing acute migraine treatments. Final database search was conducted on October 28, 2019. Identified publications were reviewed against established inclusion and exclusion criteria to determine eligibility. Data related to general trial design characteristics, sample characteristics, and outcomes and endpoints reported in each publication were extracted from eligible publications. Descriptive summaries of design features, sample characteristics, and the endpoints and outcomes employed across publications were constructed. Outcomes are presented within four broad categories: (a) pain-related outcomes (pain relief, pain freedom, etc.), (b) associated symptoms (nausea, photophobia, etc.), (c) disability/impairment/impact, (d) patient-reported outcome measures (PROMs, general health and migraine/headache-specific). Endpoint types were categorized within three broad categories: (a) change from baseline, (b) fixed timepoint, and (c) responder definitions (e.g., 50% reduction). This review focuses on a subset of recent (1998 or later) randomized and blinded publications evaluating drugs or medical devices. RESULTS: Of 1567 publications found through the initial search and reference section reviews, 705 met criteria and were included for data extraction. Inter-rater agreement kappas for the descriptive variables extracted had an average kappa estimate of 0.86. The more recent, randomized and blinded pharmaceutical and medical device article subset includes 451 publications (451/705, 63.9%). The outcomes and endpoints varied substantially across trials, ranging from pain relief or freedom, freedom from or relief of migraine-associated symptoms, use of acute or rescue medication, and various other PROMs, including measures of satisfaction and quality of life. Within the recent randomized and blinded article subset, most articles examined ≥1 pain-related outcome (430/451, 95.3%). Of the publications that examined pain, outcomes most often used were pain relief (310/430, 72.1%), pain freedom (279/430, 64.9%), and headache recurrence (202/43,051, 47.0%) or rescue medication use (278/430, 64.9%). Associated symptoms such as nausea, photophobia, and phonophobia were more frequently measured (299/451, 66.3%) compared to most bothersome associated symptom (16/451, 3.5%), as it is a new addition to regulatory guidance. Over one-third of eligible publications examined disability/impairment (186/451, 41.2%) or ≥1 PROM (159/451, 35.3%). The definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of "responders" to treatment based on wide variety of "responder definitions") also differed substantially across publications. CONCLUSION: Acute migraine clinical trials exhibit a large amount of variability in outcomes and endpoints used, in addition to the variability in how outcomes and endpoints were used from trial-to-trial. There were some common elements across trials that align with guidance from the International Headache Society, the Food and Drug Administration and other regulatory agencies (e.g., assessing pain and associated symptoms, 2-hour post-treatment). Other aspects of acute migraine clinical trial design did not follow guidance. For example, multi-item PROMs intended to measure constructs (e.g., scales) are rarely used, the use of pain-related outcomes is inconsistent, some associated symptom assessments are idiosyncratic, and the timing of the assessment of primary endpoints is variable. The development of a core set of outcomes and endpoints for acute migraine clinical trials that are patient-centered and statistically robust could improve the conduct of individual trials, facilitate cross-trial comparisons, and better support informed treatment decisions by healthcare professionals and patients.

Between and within-woman differences in the association between menstruation and migraine days.

OBJECTIVE: To investigate between and within-woman differences in the association between menstruation and migraine days. BACKGROUND: Prior diary studies have shown that at the population level, aggregating across individuals, the odds of migraine increase during the perimenstrual window (from day -2 to day +3, where +1 is the first day of bleeding). These studies have been neither long nor large enough to assess the association between migraine and menses from an individual perspective. Consequently, existing research on menstrual-related migraine has largely overlooked between and within-woman variation that is critical for progressing clinical understanding and practice. METHODS: Intensive longitudinal data for the current study were collected in a digital platform (N1-Headache® ) that tracks individual migraine-related factors daily. Participants for the current study were actively menstruating adult (18+ years old) women who used the platform. Two variables were of primary interest, migraine day (no/yes) and menstrual status (inside or outside the 5-day perimenstrual window). RESULTS: The sample consisted of 203 women with a mean age of 35.6 (SD = 8.7) years. At baseline, the women reported an average of 30.6 (SD = 23.6) headache days over the last 3 months. Analyses were based on a total of 53,302 days (median of 150 per person), 18,520 of which were migraine days (median of 44 per person), and a total of 2,126 menstrual cycles (median of 7 per person). Results showed that the 5-day perimenstrual window was associated with a 34% increase in odds of a migraine day compared to other days (OR = 1.34, 95% CI: 1.23-1.45, p < 0.0001). Importantly, there was between and within-woman variability in the association between menses and migraine days (between-woman variability: p = 0.002; within-woman [between-cycles] variability: p < 0.0001). Exploration of these individual differences demonstrated that relationship between menses and migraine days varied more within-person across cycles than between women. DISCUSSION: This study supports previous research and demonstrates that the odds of migraine days are elevated from day -2 to day +3 of the menstrual cycle. We also show that the effect of menses on migraine days varies more within-woman than between-women. This work provides an initial foundation for better understanding menstrual-related migraine from the perspective of the individual patient.

Systematic review of outcomes and endpoints in preventive migraine clinical trials.

BACKGROUND: Over the last six decades (earliest included publication from 1959), clinical trials of migraine preventive treatments have led to the regulatory approval of many medications and devices. Despite similar clinical goals, the outcomes and endpoints used in these trials are broad and not well standardized. OBJECTIVE: To describe results from a systematic literature review focused on outcomes and endpoints used in preventive migraine clinical trials. METHOD: A systematic literature review, following a pre-specified (unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, was conducted to characterize the endpoints and outcomes used in preventive migraine clinical trials. Predetermined terms were searched in PubMed on October 28, 2019. Data related to trial design, subject characteristics, outcomes, and endpoints reported in each publication were extracted. Descriptive summaries of these features were tabulated for the recent subset of publications, published during or after 1988, that were randomized, blinded, and focused on pharmacological or device therapies for the preventive treatment of migraine. RESULTS: The initial literature search identified 1506 publications, of which 757 publications were eligible for data extraction. Of specific clinical interest were the recent subset of 268 articles (268/757, 35.4%) fulfilling the targeted criteria. Results showed that the outcomes used to define endpoints varied substantially across publications. For example, in the recent subset of publications, 68.7% (184/268) of the publications examined ≥1 migraine-specific outcome, 39.6% (106/268) examined ≥1 headache-specific outcome, 50.7% (136/268) examined ≥1 acute/rescue medication use outcome, 40.3% (108/268) examined ≥1 headache-related patient-reported outcome measure (PROM), and 22.0% (59/268) examined ≥1 non-headache-specific PROM. Furthermore, the definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of "responders" to treatment based on wide variety of "responder definitions") also differed across publications. CONCLUSION: Publications from clinical trials of preventive migraine pharmacologic and device treatments differed in terms of study design, endpoint definitions, and how endpoints and outcomes were measured. Although there were common outcomes and endpoints used across publications, no clear "standardized" set of endpoints and outcomes emerged. The inconsistencies in endpoints and outcomes within this literature suggest that the development of a uniform set of outcomes and endpoints could improve the clinical meaningfulness of clinical trial results, facilitate cross-trial comparisons and better inform patient care. This standard set of outcomes and endpoints should be statistically robust and informed by the priorities of various stakeholders, most importantly, the needs and preferences of people living with migraine.

Headache complexity (number of symptom features) differentiates post-traumatic from non-traumatic headaches.

BACKGROUND: Post-traumatic headaches are a common sequela of mild traumatic brain injury (concussion). It is unclear whether or how these headaches differ phenotypically from primary headaches. OBJECTIVE: Determine whether there is an overarching unobserved latent trait that drives the expression of observed features of post-traumatic headache and other headaches. METHODS: Data from this post-hoc analysis come from the Warrior Strong Cohort Study conducted from 2010 through 2015. Approximately 25,000 soldiers were screened for concussion history at routine post-deployment health assessments. A random sample was invited to participate, enrolling 1567. Twelve observed headache phenotypic features were used to measure "headache complexity", the latent trait of clinical interest, using single factor confirmatory factor analysis. We compared headache complexity between groups and determined whether headache complexity predicted accessing medical care for headache. RESULTS: Of 1094 soldiers with headaches, 198 were classified as having post-traumatic headache. These headaches were compared to those in the other soldiers (647 without concussion history and 249 with concussion history). Soldiers with post-traumatic headache had greater endorsement of all 12 headache features compared to the soldiers with non-concussive headaches. The confirmatory factor analysis showed good model fit (χ2 (51) = 95.59, p = 0.0002, RMSEA = 0.03, comparative fit index = 0.99, and Tucker-Lewis index = 0.99), providing empirical support for the headache complexity construct. Soldier groups differed in their mean headache complexity level (p < 0.001) such that post-traumatic headache soldiers had greater headache complexity compared to non-concussed soldiers (standardized mean difference = 0.91, 95% confidence interval: 0.72-1.09, p < 0.001 and to concussed soldiers with coincidental headaches standardized mean difference = 0.75, 95% confidence interval: 0.53-0.96, p < 0.001). Increasing headache complexity predicted medical encounters for headache (odds ratio = 1.87, 95% confidence interval: 1.49-2.35, p < 0.001) and migraine (odds ratio = 3.74, 95% confidence interval: 2.33-5.98, p < 0.001) during the year following deployment.Conclusions and relevance: The current study provided support for a single latent trait, characterized by observed headache symptoms, that differentiates between concussive and non-concussive headaches and predicts use of medical care for headache. The single trait confirmatory factor analysis suggests that post-traumatic headaches differ from non-concussive headaches by severity more than kind, based on the symptoms assessed.ClinicalTrials.gov identifier NCT01847040.

Reliability and validity of the 6-item Headache Impact Test in chronic migraine from the PROMISE-2 study.

PURPOSE: We examined the reliability and validity of the 6-item Headache Impact Test (HIT-6) specifically on patients with chronic migraine (CM) from the PROMISE-2 clinical trial. METHODS: The conceptual framework of HIT-6 was evaluated using baseline data from the PROMISE-2 study (NCT02974153; N = 1072). A unidimensional graded response model within the item response theory (IRT) framework was used to evaluate model fit and item characteristics. Using baseline and week 12 data, convergent and discriminant validity of the HIT-6 was evaluated by correlation coefficients. Sensitivity to change was assessed by evaluating correlations between HIT-6 scores and change scores for other established reference measures. All examined correlations were specified a priori with respect to direction and magnitude. Known-groups analyses were anchored using Patient Global Impression of Change and monthly headache days at week 12. RESULTS: A unidimensional model fit the data well, supporting that the 6 items measure a single construct. All item slopes and thresholds were within acceptable ranges. In both the validity and sensitivity to change analyses, all observed correlations conformed to directional expectations, and most conformed to magnitude expectations. Known-groups analyses demonstrated that the HIT-6 total score can distinguish between clinically meaningful CM subgroups. CONCLUSION: The HIT-6 was successfully calibrated using IRT with data from PROMISE-2. Results from these analyses were generally consistent with previous literature and provided supportive evidence that the HIT-6 is well suited for measuring the impact of headache and migraine in the CM population.