Headache trajectories in children and adolescents with new onset continuous headache.

BACKGROUND: New daily persistent headache (NDPH) is a challenging and understudied primary headache disorder with no known effective treatment. Although the International Classification of Headache Disorders criteria require that the new onset continuous headache be present for at least three months before diagnosing NDPH, the biologic basis for when a new, continuous headache starts to behave as NDPH is unknown, and some pediatric headache experts consider that the minimum duration criterion could be shorter. METHODS: In this retrospective study, we reviewed the intake questionnaires and medical records of 5-17 year-olds seen in neurology clinic for headache at the Children's Hospital of Philadelphia. Those with a new onset continuous headache of at least one month in duration were eligible. The patient's self-report and clinician's description both had to indicate that the headache was new, of abrupt onset, and continuous to be included, although patients were allowed to have a prior history of infrequent headaches. We compared headache outcomes at last follow-up and at one year after continuous headache onset between those who had a continuous headache duration of 1 to <3 months ("new onset headache", or NOH) at first visit vs. those with ≥3 months (NDPH). We used multivariate regression modeling to examine for predictors of headache outcomes. RESULTS: Of 472 patient records reviewed, 172 met the inclusion criteria for analysis. Of these, 84 had a headache duration of 1 to <3 months in duration and 88 had a duration of ≥3 months. Those with shorter duration continuous headache were younger (median (interquartile range) 13.5 (11.1-15.7) vs. 15.1 (12.3-16.5) years, and less likely to have previously received a prescription preventive for the continuous headache (n = 14 (17%) vs. 26 (30%), p = 0.046), but were otherwise similar to those with NDPH in terms of baseline clinical and demographic variables. Sixty-five (74%) of those with NDPH and 60 (71%) with NOH had follow-up data. At last clinic follow-up, 41/65 (63%) with NDPH and 43/60 (72%) with NOH had experienced any headache benefit (p = 0.307), although 39/65 (60%) with NDPH and 29/60 (48%) with NOH still had continuous headache (p = 0.191). Headache duration was not associated with outcomes in multivariate regression modeling. CONCLUSIONS: Headache outcomes of children and adolescents with new onset continuous headache, whether of 1 to <3 months (NOH) or ≥3 months in duration (NDPH) are suboptimal. More research is needed to improve treatment outcomes for this patient population.

Clinical factors associated with day-to-day peak pain severity in individuals with chronic migraine: A cohort study using daily prospective diary data.

OBJECTIVE: To describe the association between day-to-day peak pain severity and clinical factors in individuals with chronic migraine (CM). BACKGROUND: Little is known about how clinical factors relate to day-to-day pain severity in individuals with CM. METHODS: Adults with CM were enrolled into this observational prospective cohort study that collected daily data about headache, associated symptoms, and lifestyle factors using a digital health platform (N1-Headache™) for 90 days. "Migraine days" were defined as days in which a headache occurred that had features described by the International Classification of Headache Disorders criteria. On these days, peak pain severity was recorded on a 4-point scale; on non-headache days peak pain severity was imputed as "0/none". The associations between peak pain severity and 12 clinical factors were modeled and adjusted for sex, age, daily headache, presence of menstrual bleeding, day of the week, and disability. All numerical and Likert scale variables were standardized prior to analysis. RESULTS: Data were available for 392 participants (35,280 tracked days). The sample was predominantly female (90.6%), with a mean (standard deviation) age of 39.9 (12.8) years. In the final multivariable model with random intercept and slopes, higher than typical self-reported levels of standardized stress (odds ratio [OR] 1.07, 95% confidence interval [CI] 1.04-1.11), standardized irritability (OR 1.05, 95% CI 1.02-1.08), standardized sadness (OR 1.05, 95% CI 1.02-1.07), fatigue (OR 1.25, 95% CI 1.15-1.36), eyestrain (OR 1.38, 95% CI 1.26-1.52), neck pain (OR 1.94, 95% CI 1.76-2.13), skin sensitivity (OR 1.61, 95% CI 1.44-1.80), and dehydration (OR 1.29, 95% CI 1.18-1.42) were associated with higher reported peak pain severity levels, while standardized sleep quality (OR 0.96, 95% CI 0.93-0.99) and standardized waking feeling refreshed (OR 0.84, 95% CI 0.81-0.88) were associated with lower reported peak pain severity levels. The inclusion of a random intercept and random slopes improved upon more parsimonious models and illustrated large differences in individuals' reporting of peak severity according to the levels of the associated clinical factors. CONCLUSION: Our data showed that the experience of CM, from a pain severity perspective, is complex, related to multiple clinical variables, and highly individualized. These results suggest that future work should aim to study a personalized approach to both medical and behavioral interventions for CM based on which clinical factors relate to the individual's experience of pain severity.

The safety and efficacy of onabotulinumtoxinA injections for children and adolescents with chronic migraine: A systematic review and meta-analysis.

OBJECTIVE: To qualitatively and quantitatively summarize the evidence for the use of onabotulinumtoxinA injections in children and adolescents with migraine. BACKGROUND: There are limited evidence-based treatment options for youth with migraine, especially youth with chronic migraine (CM). OnabotulinumtoxinA injections are an established evidence-based treatment for adults with CM. While several studies have assessed their safety and efficacy among adolescents with CM, there are no published systematic reviews summarizing the pediatric evidence. METHODS: We carried out a systematic review, reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis, aiming to identify studies that included five or more children and adolescents aged ≤18 years with a diagnosis of migraine, who were treated with ≥50 units (U) of onabotulinumtoxinA and had outcomes assessed ≥4 weeks after one or more injection cycle. Both observational studies and randomized controlled trials (RCTs) were eligible for inclusion. Two investigators independently carried out the first (titles and abstracts) and second (full text) screening stages, as well as data extraction and quality appraisal. The American Academy of Neurology risk of bias grading scheme was used to assess study risk of bias. Studies with adequate data were pooled using random effects meta-analyses, and Hedge's g standardized mean differences with 95% confidence intervals (CIs) were generated to estimate the effect sizes of the continuous outcomes included. Studies lacking data required for meta-analysis were summarized qualitatively. RESULTS: We screened 634 studies and included 14 studies comprising 491 participants, of whom 489 had CM. Two studies were RCTs, 12 were observational uncontrolled studies, and all but one study included only youth with CM. Five Class IV observational uncontrolled studies were amenable to pooling in meta-analyses. After a mean of 2-2.6 injection cycles, headache frequency was shown to decrease significantly after treatment with onabotulinumtoxinA (Hedge's g = 0.97, 95% CI 0.58-1.35; p < 0.0001), as did severity (Hedge's g = 1.24, 95% CI 0.55-1.94; p = 0.0005), with both estimates having a large effect size magnitude. A Class I parallel-group RCT of one injection series (155 U, 74 U, or placebo), powered to detect a change in 4 headache days per month, did not find outcome differences between the active and placebo treatment arms. A Class IV crossover RCT showed superiority of active (155 U) versus placebo injections. The remaining Class IV observational studies that were excluded from the meta-analyses all showed improved outcomes with onabotulinumtoxinA injections over time. No serious adverse events related to treatment occurred. CONCLUSION: OnabotulinumtoxinA injections have established safety for use in children and adolescents with CM and are likely effective in reducing headache frequency and severity over time. However, in the absence of an adequately powered parallel-group RCT assessing the efficacy of multiple injection cycles, it remains unclear if this intervention is superior to placebo.

Remote electrical neuromodulation to treat children and adolescents with migraine in the emergency department: A randomized double-dummy pilot trial.

OBJECTIVE: Using a double-dummy pilot randomized controlled trial design, we aimed to determine the feasibility and acceptability of comparing remote electrical neuromodulation (REN) to typical care intravenous pharmacologic interventions for the treatment of children and adolescents visiting the emergency department (ED) with migraine, and to compare parallel-group versus crossover trial designs. BACKGROUND: There are limited data to guide the management of migraine in the ED. Children and adolescents are interested in neuromodulation, and specifically REN, for treatment in this setting, but there are no existing data on this approach. METHODS: We employed a double-dummy, double-blind, pilot randomized controlled trial that tested two designs in two phases: a parallel-group design and a crossover design (ClinicalTrials.gov identifier: NCT05102591). The intervention arms consisted of: (i) active REN stimulation with matched normal saline placebo intravenously, and (ii) matched sham REN stimulation, intravenous metoclopramide (0.15 mg/kg, maximum 10 mg), and intravenous ketorolac (0.5 mg/kg, maximum 30 mg). Youth aged 8.0-<18.0 years visiting a Canadian tertiary care pediatric ED with migraine attacks as per criteria B-E of the International Classification of Headache Disorders third edition were eligible. Primary outcomes were focused on trial feasibility and acceptability, and preliminary efficacy and safety data were also collected. RESULTS: A total of 34% (22/65) of those who screened eligible were enrolled. Three participants (14%) withdrew prior to receiving any study interventions. In all, 10 participants were allocated to typical care, and nine to REN. All treated participants (19/19) completed all assessments. Recruitment was higher during the parallel-group phase: 1.1 participants/month versus 0.6 participants/month, and 36% (17/47) versus 28% (five of 18) of screened eligible were enrolled in the parallel-group and crossover phases, respectively. Participants reported positive impressions of REN use in the ED, e.g., higher mean (standard deviation [SD]) levels of interest in using REN only at 3.7 (1.0) versus 2.8 (1.0) in using intravenous interventions only for a future ED visit. Participants and clinical staff reported overall positive impressions regarding the study protocol. Employing an 11-point pain numerical rating scale, the mean (SD) reduction in pain severity score was 2.1 (1.3) and 2.9 (2.9) from baseline to 1 h, and 2.4 (1.6) and 4.0 (3.5) from baseline to 2 h for REN and intravenous interventions, respectively. One participant in the typical care group and none in the REN group experienced adverse events. CONCLUSION: We demonstrated the feasibility and acceptability of our trial protocol and of using REN to treat youth presenting to the ED with migraine. The parallel-group design generated a higher recruitment rate than the crossover design. Our preliminary efficacy and safety data suggest that REN could be non-inferior to typical care, but we were not powered for these outcomes. Further research on REN's use in the ED setting is warranted.

Comparison of continuous headache features in youth with migraine, new daily persistent headache, and persistent post-traumatic headache.

OBJECTIVE: To compare clinical features in youth with continuous headache from migraine, persistent post-traumatic headache, and new daily persistent headache to determine if they are similar, contrary to their distinction in the International Classification of Headache Disorders. METHODS: We pursued a single center age- and sex-matched observational study comparing the clinical characteristics of 150 youth (11 - 17 years old) with continuous headache from migraine, persistent post-traumatic headache, and new daily persistent headache. A diagnostic algorithm based on international classification of headache disorders criteria was used to identify those with migraine (headache features of migraine with gradual onset), and persistent post-traumatic headache and new daily persistent headache (based on the circumstances of headache onset regardless of headache features). Fifty participants each with migraine, persistent post-traumatic headache, and new daily persistent headache were matched by age and sex. Participant survey responses on headache characteristics were compared. RESULTS: Median usual headache severity was 6.0 [95%CI 6.0, 6.0] and was not different across diagnostic groups (H statistic = 1.2, p = 0.55). Headache exacerbation frequency, disability, associated symptoms, and most triggers were not significantly different across groups. The majority of persistent post-traumatic headache and new daily persistent headache had headache features consistent with a diagnose of migraine (72% and 62%, respectively). CONCLUSION: Our findings suggest that most persistent post-traumatic headache and new daily persistent headache may represent abrupt onset of migraine.

Guidelines Update: Guidelines of the International Headache Society for controlled trials of preventive treatment of migraine in children and adolescents, 1st edition - An experience-based update.

BACKGROUND: Recent experience in designing and running clinical trials on new medications for the prevention of migraine in children and adolescents highlighted the need for revision of the 1st edition of the International Headache Society Guidelines for clinical trials of preventive treatment of migraine in children and adolescents which were published in 2019. METHODS: The authors of the 1st edition of the guidelines formed an informal focus group with aims of appraising the performance of the guidelines, clarifying any ambiguity and providing improvements, where needed, based on personal experience and expert analysis. RESULTS: This review and the following update were able to address issues related to the classification of migraine, the duration of migraine attacks, the age groups of children and adolescents, the use of electronic diaries, the assessment of outcome measures, the need for an interim analysis and the issues related to placebo response. CONCLUSIONS: This update provides necessary clarifications of the guidelines in order to enable better design and running of future clinical trials for the preventive treatment of migraine in children and adolescents.

Symptoms associated with headache in youth.

OBJECTIVE: To determine the underlying relationships between a broad range of headache-associated symptoms and how they relate to headache burden. BACKGROUND: Symptoms associated with head pain inform classification of headache disorders. However, many headache-associated symptoms are not included in the diagnostic criteria, which is largely based on expert opinion. Large symptom databases can assess headache-associated symptoms irrespective of pre-existing diagnostic categories. METHODS: We conducted a large single-center cross-sectional study on youth (6-17 years old) assessing patient-reported outpatient headache questionnaires between June 2017 and February 2022. Multiple correspondence analysis, an exploratory factor analysis, was applied to 13 headache-associated symptoms. RESULTS: 6662 participants (64% female; median age 13.6 years) were included. Multiple correspondence analysis dimension 1 (25.4% of the variance) captured the absence or abundance of headache-associated symptoms. A greater number of headache-associated symptoms correlated with greater headache burden. Dimension 2 (11.0% of the variance) revealed three symptom clusters: (1) cardinal features of migraine (light, sound, and smell sensitivity, nausea, and vomiting), (2) nonspecific global neurologic dysfunction symptoms (lightheadedness, trouble thinking, blurry vision), (3) vestibular and brainstem dysfunction symptoms (vertigo, balance problems, ear ringing, double vision). CONCLUSION: Assessing a broader range of headache-associated symptoms reveals clustering of symptomatology and a strong relationship with headache burden.

Efficacy and safety of monoclonal antibodies targeting CGRP in migraine prevention. GRADE tables elaborated by the ad hoc working group of the International Headache Society.

OBJECTIVES: Grading of Recommendations, Assessment Development and Evaluation (GRADE) tables were created using a standardized and independent assessment of the efficacy and side effects of treatments with monoclonal antibodies (mAb) against calcitonin gene-related peptide (CGRP) or the CGRP receptor for the prevention of migraine. We hope to provide support for author groups writing national or regional treatment or management guidelines for migraine prevention. METHODS: We formulated patient/population, intervention, comparison and outcomes (PICO) questions for the efficacy and safety of mAb against CGRP or the CGRP-receptor for the prevention of migraine attacks. We performed a systematic literature research for randomized studies with eptinezumab, erenumab, fremanezumab and galcanezumab and a pooled analysis was done, using RevMan 5.4 software. For dichotomous outcomes we used risk ratio, and for continuous outcomes we used the mean difference to compare and summarize the evidence between groups. The evidence across studies, for each outcome, except serious adverse events, was assessed using GRADE evidence tables. Additionally, we report the serious adverse effects in the tables of the characteristics of the studies. RESULTS: All mAb are superior to placebo for the reduction in monthly migraine days (days in which a headache consistent with migraine occurred) in participants with episodic and chronic migraine. There are no major differences between the mAb. CONCLUSIONS: The GRADE evidence summary tables provided will support author groups to write treatment guidelines for the prevention of migraine with mAb.

Longitudinal trajectories of posttraumatic headache after pediatric mild traumatic brain injury.

OBJECTIVE: This prospective, longitudinal cohort study examined the trajectory, classification, and features of posttraumatic headache after pediatric mild traumatic brain injury. METHODS: Children (N = 213; ages 8.00 to 16.99 years) were recruited from two pediatric emergency departments <24 hours of sustaining a mild traumatic brain injury or mild orthopedic injury. At 10 days, three months, and six months postinjury, parents completed a standardized questionnaire that was used to classify premorbid and posttraumatic headache as migraine, tension-type headache, or not otherwise classified. Multilevel mixed effects models were used to examine posttraumatic headache rate, severity, frequency, and duration in relation to group, time postinjury, and premorbid headache, controlling for age, sex, and site. RESULTS: PTH risk was greater after mild traumatic brain injury than mild orthopedic injury at 10 days (odds ratio = 197.41, p < .001) and three months postinjury (odds ratio = 3.50, p = .030), especially in children without premorbid headache. Posttraumatic headache was more frequent after mild traumatic brain injury than mild orthopedic injury, ß (95% confidence interval) = 0.80 (0.05, 1.55). Groups did not differ in other examined headache features and classification any time postinjury. CONCLUSIONS: Posttraumatic headache risk increases after mild traumatic brain injury relative to mild orthopedic injury for approximately three months postinjury, but is not clearly associated with a distinct phenotype.

Biopsychosocial treatment response among youth with continuous headache: A retrospective, clinic-based study.

BACKGROUND: Youth with continuous (always present) headache are vastly understudied; much remains to be understood regarding treatment response in this population. OBJECTIVE: To describe and explore biopsychosocial factors related to initial clinical outcomes among treatment-seeking youth with continuous headache. METHODS: This retrospective cohort study extracted data of 782 pediatric patients (i.e., aged <18 years) with continuous headache from a large clinical repository. Youth in this study had experienced continuous headache for ≥1 month before presenting to a multidisciplinary headache specialty clinic appointment. Extracted data from this appointment included patients' headache history, clinical diagnoses, and headache-related disability, as well as information about biopsychosocial factors implicated in headache management and/or maintenance (e.g., healthy lifestyle habits, history of feeling anxious or depressed). Additional data regarding patient headache characteristics, disability, and lifestyle habits were extracted from a subset of 529 youth who returned to clinic 4-16 weeks after their initial follow-up visit. After characterizing initial treatment response, exploratory analyses compared youth with the best and worst treatment outcomes on several potentially influential factors. RESULTS: Approximately half of youth (280/526; 53.2%) continued to have continuous headache at follow-up, ~20% of youth (51/526) reported a significant (≥50%) reduction in headache frequency. Improvements in average headache severity (e.g., percentage with severe headaches at initial visit: 45.3% [354/771]; percentage with severe headaches at follow-up visit: 29.8% [156/524]) and headache-related disability were also observed (e.g., percentage severe disability at initial visit: 62.9% [490/779]; percentage severe disability at initial follow-up visit: 34.2% [181/529]). Individuals with the worst headache frequency and disability had a longer history of continuous headache (mean difference estimate = 5.76, p = 0.013) and worse initial disability than the best responders (χ2 [3, 264] = 23.49, p < 0.001). They were also more likely to have new daily persistent headache (χ2 [2, 264] = 12.61, p = 0.002), and were more likely to endorse feeling depressed (χ2 [1, 260] = 11.46, p < 0.001). CONCLUSION: A notable percentage of youth with continuous headache show initial improvements in headache status. Prospective, longitudinal research is needed to rigorously examine factors associated with continuous headache treatment response.

Validity of self-reported migraine in adolescents and children.

OBJECTIVE: To assess agreement for migraine day between self-report and diagnostic guidelines for children and adolescents using a headache diary. BACKGROUND: Trial guidelines recommend prospective collection of headache features and adoption of migraine day as an outcome measure, but there is no clear consensus on the definition of migraine day. METHODS: This is a secondary analysis of data from two projects-a prospective cohort study validating a pediatric scale of treatment expectancy and a clinical trial of occipital nerve blocks to treat status migrainosus. Participants completed a text message-based diary for 4 or 12 weeks (depending on treatment), and a detailed headache assessment on a random 20% of headache days. Using this assessment, we determined whether a headache day qualified for migraine or probable migraine, based on the International Classification of Headache Disorders, 3rd edition (ICHD-3). RESULTS: Of 122 enrolled children and adolescents, 106 (86.9%) completed ≥1 detailed headache assessment (438 entries). We found moderate agreement between self-reported and ICHD-derived migraine day, with a Cohen's Kappa of 0.50 (positive predictive value [PPV]: 0.66; negative predictive value [NPV]: 0.85; correlation: 0.51). Allowing for ICHD-derived probable migraine significantly increased PPV (0.66 vs. 0.94; 95% CI: 0.57-0.74 vs. 0.90-0.97), but decreased NPV (0.85 vs. 0.293; CI: 0.77-0.90 vs. 0.199-0.40), Cohen's Kappa (0.50 vs. 0.237; CI: 0. 389-0.60 vs. 0.139-0.352), and correlation (r = 0.51 vs. 0.302; CI: 0.41-0.61 vs. 0.192-0.41). Pain severity (OR: 5.7; CI: 2.39-13.8), photophobia (OR: 4.1; CI: 1.02-16.6), and phonophobia (OR: 7.5; CI: 1.95-29.3) were significantly associated with participants' perception of migraine. CONCLUSION: We found only moderate agreement between self-reported and ICHD-derived migraine day, suggesting both measures are not equal but may represent overlapping aspects of migraine as a disease. This highlights the difficulty of applying ICHD criteria to individual attacks. We recommend greater methodological transparency in future research to avoid readers conflating both measures.

Impact of preventive pill-based treatment on migraine days: A secondary outcome study of the Childhood and Adolescent Migraine Prevention (CHAMP) trial and a comparison of self-report to nosology-derived assessments.

OBJECTIVE: To examine group differences in self-reported migraine days among youth who completed the Childhood and Adolescent Migraine Prevention (CHAMP) trial prior to its closure and explore the relationship between self-reported and "nosology-derived" (i.e., International Classification of Headache Disorders, 3rd edition [ICHD-3]) migraine days. BACKGROUND: The CHAMP trial compared amitriptyline and topiramate to placebo for migraine prevention in youth and proposed to analyze change in migraine days as a secondary outcome. There is considerable variability in the field regarding what constitutes a "migraine day," how this is determined and reported in trials, and how consistent these measures are with diagnostic nosology. METHODS: CHAMP trial completers (N = 175) were randomized to receive amitriptyline (n = 77), topiramate (n = 63), or placebo (n = 35). Participants maintained daily headache diaries where they reported each day with headache and if they considered that headache to be a migraine. For each headache day, participants completed a symptom record and reported about symptoms such as pain location(s) and presence of nausea/vomiting or photophobia and phonophobia. We examined group differences in self-reported migraine days at trial completion (summed from trial weeks 20-24) compared to baseline. We also used an algorithm to determine whether participants' symptom reports met ICHD-3 criteria for migraine without aura, and examined the association between self-reported and "nosology-derived" migraine days. RESULTS: Results showed no significant differences between groups in self-reported migraine days over the course of the trial. Self-reported and "nosology-derived" migraine days during the baseline and treatment phases were strongly associated (r's = 0.73 and 0.83, respectively; p's < 0.001). CONCLUSION: Regardless of treatment, CHAMP trial completers showed clinically important reductions in self-reported migraine days over the course of the trial (about 3.8 days less). The strong association between self-reported and "nosology-derived" migraine days suggests youth with migraine can recognize a day with migraine and reliably report their headache features and symptoms. Greater rigor and transparency in the calculation and reporting of migraine days in trials is needed.

Patient headache questionnaires can improve headache diagnosis and treatment in children.

OBJECTIVE: To examine trends in diagnosis of headache and migraine in a large pediatric neurology cohort, and test whether an electronic health record (EHR)-integrated headache questionnaire can increase specificity of diagnosis and likelihood of prescribing migraine treatment. BACKGROUND: Under-diagnosis of migraine contributes to the burden of disease. As we founded our Pediatric Headache Program in 2013, we recognized that the proportion of patients with headache who were given a diagnosis of migraine was much lower than expected. METHODS: We developed a patient headache questionnaire, initially on paper (2013-2014), then in an electronic database (2014-2016), and finally integrated into our electronic health record (pilot: 2016, full: May 2017). We compared diagnoses and prescribed treatments for new patients who were given a headache diagnosis, looking at trends in the proportion of patients given specific diagnoses (migraine, etc.) versus the non-specific diagnosis, "headache." Next, we conducted a prospective cohort study to test for association between provider use of the form and the presence of a specific diagnosis, then for an association between specific diagnosis and prescription of migraine treatment. RESULTS: Between July 2011 and December 2022 the proportion of new headache patients who were given a diagnosis of migraine increased 9.7% and non-specific headache diagnoses decreased 21.0%. In the EHR cohort (June 2017-December 2022, n = 15,122), use of the provider form increased the rate of specific diagnosis to 87.2% (1839/2109) compared to 75.5% (5708/7560) without a patient questionnaire, nearly doubling the odds of making a specific diagnosis (odds ratio [OR] 1.90, 95% confidence interval [CI]: 1.65-2.19). Compared to those given only a non-specific headache diagnosis who were prescribed a migraine therapy 53.7% (1766/3286) of the time, 75.3% (8914/11836) of those given a specific diagnosis received a migraine therapy, more than doubling the odds of prescription (OR 2.39, 95% CI: 2.20-2.60). CONCLUSIONS: Interventions to improve specificity of diagnosis were effective and led to increased rates of prescription of migraine treatments. These results have been sustained over several years. This headache questionnaire was adapted into the Foundation system of EpicCare, so it is broadly available as a clinical and research tool for institutions that use this EHR software.

Development of a text message-based headache diary in adolescents and children.

BACKGROUND: International guidelines recommend diaries in migraine trials for prospective collection of headache symptoms. Studies in other patient populations suggest higher adherence with electronic diaries instead of pen-and-paper. This study examines the feasibility of a text message-based (texting) diary for children and adolescents with headache. METHODS: This is a secondary analysis of data from a study validating a pediatric scale of treatment expectancy. We developed a Health Insurance Portability and Accountability Act-compliant texting diary collecting headache characteristics, medication use, and disability with 3-5 core daily questions for 4 or 12 weeks depending on headache treatment. Adherence was incentivized. RESULTS: 93 participants consented to the expectancy study. Five participants opted for a paper diary for follow-up. 88 participants chose the texting diary with 28 4-week and 60 12-week participants. Five participants did not complete the enrollment visit. Of those remaining 83, 89% of 4-week and 93% of 12-week participants responded on at least 80% of days. On average, participants fully completed 88% (4-week cohort) and 90% (12-week) of diary entries. CONCLUSIONS: Text messages are a promising method for collecting patient-reported data. Adherence was similar to that reported for paper diaries in other pediatric migraine trials, but time-stamped entries ensure real-time data collection.

The spectrum of indomethacin-responsive headaches in children and adolescents.

BACKGROUND: Headaches with marked, specific response to indomethacin occur in children, but the phenotypic spectrum of this phenomenon has not been well-studied. METHODS: We reviewed pediatric patients with headache showing ≥80% improvement with indomethacin, from seven academic medical centers. RESULTS: We included 32 pediatric patients (16 females). Mean headache onset age was 10.9 y (range 2-16 y). Headache syndromes included hemicrania continua (n = 13), paroxysmal hemicrania (n = 10), primary stabbing headache (n = 2), short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (n = 1), primary exercise headache (n = 1) and primary cough headache (n = 1). Adverse events were reported in 13, most commonly gastrointestinal symptoms, which often improved with co-administration of gastro-protective agents. CONCLUSION: Indomethacin-responsive headaches occur in children and adolescents, and include headache syndromes, such as primary cough headache, previously thought to present only in adulthood. The incidence of adverse events is high, and patients must be co-treated with a gastroprotective agent.

Trajectory of treatment response in the child and adolescent migraine prevention (CHAMP) study: A randomized clinical trial.

OBJECTIVE: Identify preventive medication treatment response trajectories among youth participating in the Childhood and Adolescent Migraine Prevention study. METHODS: Data were evaluated from 328 youth (ages 8-17). Childhood and Adolescent Migraine Prevention study participants completed headache diaries during a 28-day baseline period and a 168-day active treatment period during which youth took amitriptyline, topiramate, or placebo. Daily headache occurrence trajectories were established across baseline and active treatment periods using longitudinal hierarchical linear modeling. We tested potential treatment group differences. We also compared final models to trajectory findings from a clinical trial of cognitive behavioral therapy plus amitriptyline for youth with chronic migraine to test for reproducibility. RESULTS: Daily headache occurrence showed stability across baseline. Active treatment models revealed decreases in headache frequency that were most notable early in the trial period. Baseline and active treatment models did not differ by treatment group and replicated trajectory cognitive behavioral therapy plus amitriptyline trial findings. CONCLUSIONS: Replicating headache frequency trajectories across clinical trials provides strong evidence that youth can improve quickly. Given no effect for medication, we need to better understand what drives this clinically meaningful improvement. Results also suggest an expected trajectory of treatment response for use in designing and determining endpoints for future clinical trials.Trial Registration. ClinicalTrials.gov Identifier: NCT01581281.

New insight into the neural mechanisms of migraine in adolescents: Relationships with sleep.

OBJECTIVE: This case-control study examines if measures of subjective and objective (actigraphic) sleep difficulties mediate alterations in amygdalar connectivity in adolescents with migraine compared to healthy adolescents. BACKGROUND: Adolescents with migraine have different functional connectivity of the amygdala compared to individuals without migraine. Sleep is often disturbed in adolescents with migraine, and could contribute to the alterations in functional connectivity. METHODS: Twenty adolescents with migraine and 20 healthy controls were recruited from Cincinnati Children's Hospital. Participants completed surveys about their headaches and overall sleep quality, sleep hygiene, and perceived sleep difficulties (Insomnia Severity Scale [ISI]); completed wrist-worn actigraphy; and underwent a magnetic resonance imaging scan. RESULTS: Adolescents with migraine differed from healthy controls only in perceived difficulty in sleep initiation and maintenance (ISI: 8.5 ± 4.7 and 4.5 ± 3.7 [mean ± standard deviation], -4.00 [95% confidence: -6.7 to -1.3], p = 0.005) and had greater functional connectivity between the amygdala and the posterior cingulate cortex, precuneus, dorsolateral prefrontal, sensorimotor, and the occipital cortexes. The differences in functional connectivity of the amygdala were not mediated by the subjective/objective sleep measures (ISI/wake minutes after sleep onset). CONCLUSIONS: Adolescents with migraine have greater connectivity between the amygdala and areas involved in sensory, affective, and cognitive aspects of pain. These alterations may not be due to higher levels of sleep difficulties in adolescents with migraine, suggesting that both amygdala and sleep alterations may play an independent role in migraine pathophysiology. This advances the understanding of the mechanisms underlying pediatric migraine and can potentially advance migraine management.

Multimodal Assessment of Medication Adherence Among Youth With Migraine: An Ancillary Study of the CHAMP Trial.

OBJECTIVE: Examine preventive medication adherence among youth with migraine. METHODS: Adherence (self-report, pill count, and blood serum drug levels) was assessed as an ancillary study that utilized data from 328 CHAMP Study participants (ages 8-17). CHAMP was a multisite trial of preventive medications. Participants completed a prospective headache diary during a six-month active treatment period during which youth took amitriptyline, topiramate, or placebo pill twice daily. Self-reported medication adherence was collected via daily diary. At monthly study visits, pill count measures were captured. At trial month 3 (trial midpoint) and 6 (end of active trial), blood serum drug levels were obtained. Self-report and pill count adherence percentages were calculated for the active trial period, at each monthly study visit, and in the days prior to participants' mid-trial blood draw. Percentages of nonzero drug levels were calculated to assess blood serum drug level data. Adherence measures were compared and assessed in context of several sociodemographic factors. Multiple regression analyses investigated medication adherence as a predictor of headache outcomes. RESULTS: Self-report and pill count adherence rates were high (over 90%) and sustained over the course of the trial period. Serum drug level adherence rates were somewhat lower and decreased significantly (from 84% to 76%) across the trial period [t (198) = 3.23, p = .001]. Adherence measures did not predict headache days at trial end; trial midpoint serum drug levels predicted headache-related disability. CONCLUSIONS: Youth with migraine can demonstrate and sustain relatively high levels of medication adherence over the course of a clinical trial.

Comparison of Remote Electrical Neuromodulation and Standard-Care Medications for Acute Treatment of Migraine in Adolescents: A Post Hoc Analysis.

OBJECTIVE: There is an unmet need for new, efficacious, well-tolerated, acute treatments for migraine in adolescents. Remote electrical neuromodulation (REN) is a novel, nonpharmacological treatment that provides significant symptom relief with good tolerability. The current post hoc analysis compared the efficacy of REN to that of standard-care medications for the acute treatment of migraine in adolescents. DESIGN: Within-participant post hoc analysis of data from a clinical trial. SETTING: Data from a clinical trial. SUBJECTS: Data from 35 adolescent participants were analyzed. METHODS: Efficacy was compared between a run-in phase, in which attacks were treated with standard-care medications (triptans or over-the-counter medications), and an intervention phase, in which attacks were treated with REN. Efficacy was compared within participants through the use of McNemar's test at four endpoints (2 hours after treatment): single-treatment pain freedom and pain relief, and consistency of pain freedom and pain relief (defined as response in at least 50% of the available first four treatments). RESULTS: At 2 hours after treatment, pain freedom was achieved by 37.1% of the participants with REN, vs 8.6% of the participants with medications (P = 0.004). Pain relief was achieved by 71.4% with REN, vs 57.1% with medications (P = 0.225). Consistency of pain freedom was achieved by 40% with REN, vs 8.6% with medications (P < 0.001). Consistency of pain relief was achieved by 80.0% with REN, vs 57.2% with medications (P = 0.033). CONCLUSIONS: Our results suggest that REN may have higher efficacy than certain standard-care medications for the acute treatment of migraine in adolescents. A larger-scale, blinded comparative-effectiveness and tolerability study is needed.

Predictors of Improvement in Pediatric Chronic Migraine: Results from the Cognitive-Behavioral Therapy and Amitriptyline Trial.

Explore predictors of improvement in headache days and migraine-related disability through a secondary analysis of the cognitive-behavioral therapy plus amitriptyline trial in children and adolescents (Clinical Trials Registration Number: NCT00389038). Participants were 135 youth aged 10-17 years old diagnosed with chronic migraine. Predictor variables included group assignment (treatment or control), baseline scores from depression and quality of life measures, and demographic variables. Criterion variables included headache days and migraine-related disability. Higher baseline depression scores were indicative of more days with headache post-treatment regardless of group assignment. Family income at the higher-end of the low-income range was significantly associated with less migraine-related disability regardless of group assignment (Household Income: HINC-01 in The United States Census Bureau. Bureau, U, 2020). Results from this secondary analysis identify depression symptoms and family income as predictors that can impact headache frequency and migraine-related disability. Self-reported symptoms of depression and family income are important factors to consider as part of the biopsychosocial model of care.