The headache research priorities: Research goals from the American Headache Society and an international multistakeholder expert group.

OBJECTIVE: To identify and disseminate research priorities for the headache field that should be areas of research focus during the next 10 years. BACKGROUND: Establishing research priorities helps focus and synergize the work of headache investigators, allowing them to reach the most important research goals more efficiently and completely. METHODS: The Headache Research Priorities organizing and executive committees and working group chairs led a multistakeholder and international group of experts to develop headache research priorities. The research priorities were developed and reviewed by clinicians, scientists, people with headache, representatives from headache organizations, health-care industry representatives, and the public. Priorities were revised and finalized after receiving feedback from members of the research priorities working groups and after a public comment period. RESULTS: Twenty-five research priorities across eight categories were identified: human models, animal models, pathophysiology, diagnosis and management, treatment, inequities and disparities, research workforce development, and quality of life. The priorities address research models and methods, development and optimization of outcome measures and endpoints, pain and non-pain symptoms of primary and secondary headaches, investigations into mechanisms underlying headache attacks and chronification of headache disorders, treatment optimization, research workforce recruitment, development, expansion, and support, and inequities and disparities in the headache field. The priorities are focused enough that they help to guide headache research and broad enough that they are widely applicable to multiple headache types and various research methods. CONCLUSIONS: These research priorities serve as guidance for headache investigators when planning their research studies and as benchmarks by which the headache field can measure its progress over time. These priorities will need updating as research goals are met and new priorities arise.

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.

Trigeminal Autonomic Cephalalgias and Neuralgias in Children and Adolescents: a Narrative Review.

PURPOSE OF REVIEW: To summarize the available literature as well as the authors' experience on trigeminal autonomic cephalalgias (TACs) and cranial neuralgias in children and adolescents. RECENT FINDINGS: While TACs and cranial neuralgias are rare in children, several recent case series have been published. TACs in children share most of the clinical features of TACs in adults. However, there are many reported cases with clinical features which overlap more than one diagnosis, suggesting that TACs may be less differentiated in youth. Indomethacin-responsive cases of cluster headache and SUNCT/SUNA have been reported in children, whereas in adults indomethacin is usually reserved for paroxysmal hemicrania and hemicrania continua. Neuralgias appear to be rare in children. Clinical features are often similar to adult cases, though clinicians should maintain a high index of suspicion for underlying causes.

Melatonin for migraine prevention in children and adolescents: A randomized, double-blind, placebo-controlled trial after single-blind placebo lead-in.

BACKGROUND: Melatonin is effective for migraine prevention in adults. We hypothesized that melatonin would also be effective for migraine prevention in children and adolescents. METHODS: This was a randomized, double-blind trial of melatonin (3 mg or 6 mg) versus placebo for migraine prevention in 10-17 year-olds with 4-28/28 headache days at baseline. Participants were recruited from the UCSF Child & Adolescent Headache Program, UCSF child neurology clinic, and social media advertisements. Migraine diagnosis was confirmed by a headache specialist. Participants completed an 8-week single-blind placebo run-in. Those meeting randomization criteria (≥4 headache days and ≥23/28 electronic diary entries during weeks 5-8) were randomized 1:1:1 to placebo:melatonin 3 mg:melatonin 6 mg nightly for 8 weeks. The primary outcome measure was migraine days in weeks 5-8 of randomized treatment between melatonin (combined 6 mg + 3 mg) versus placebo. We aimed to enroll n = 210. RESULTS: The study closed early due to slow enrollment (n = 72). Two participants were in the single-blind phase when the study closed, therefore the meaningful n = 70. Sixteen percent (11/70) were lost to follow-up during the single-blind phase. An additional 21% (15/70) did not meet randomization criteria (<4 headache days: n = 5, <23/28 diary days: n = 7, both: n = 3). Sixty-three percent (44/70) were eligible to randomize, of whom 42 randomized (n = 14 per arm). Taking another preventive at enrollment (OR 8.3, 95% CI 1.01 to 68.9) was the only variable associated with meeting randomization criteria. Of those randomized, 91% (38/42) provided diary data in the final 4-weeks. However, given the amount of missing data, only those with ≥21/28 diary days were analyzed-7/14 (50%) in the placebo group, and 20/28 (71%) in the melatonin groups combined. Median (IQR) migraine/migrainous days in weeks 5-8 of double-blind treatment was 2 (1-7) in the placebo group versus 2 (1-12) in the melatonin groups combined; the difference in medians (95% CI for the difference) was 0 days (-9 to 3). There were no differences in adverse events between groups. CONCLUSIONS: When compared to recall at enrollment, headache days decreased across the single-blind placebo phase and the double-blind phase. There was no suggestion of superiority of melatonin; however, given the substantial portion of missing data, numerically higher in the placebo arm, and underpowering, this should not be interpreted as proof of inefficacy. Melatonin was generally well tolerated with no serious adverse events. Future migraine preventive trials in this age group may find this trial helpful for anticipating enrollment needs if using a single-blind placebo run-in. Enriching for those already on a migraine preventive may improve randomization rates in future trials, though would change the generalizability of results.

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.

More Than a Headache: Lived Experience of Migraine in Youth.

BACKGROUND: Migraine is the leading cause of disability among adolescents and young adults. We aimed to characterize the impact of migraine on the experience of children, adolescents, and caregivers. METHODS: This descriptive qualitative study recruited youth aged four to 18 years with migraine and their caregivers from the multicenter, prospective Pediatric Migraine Registry between 2020 and 2021. Participants completed semistructured interviews targeting the lived experience of migraine. A conventional content analysis approach was used to analyze data. RESULTS: Thirty enrolled dyads (n = 30 children and adolescents, n = 29 caregivers) completed 59 interviews (n = 29 child and adolescent interviews, n = 30 caregiver interviews). Children and adolescents had a median age of 15 years and experienced a median of 13.5 headache days per month. Caregivers had a median age of 44 years and predominantly identified as mothers (n = 28). We identified three themes: (1) Impact on emotional well-being: participants described how their migraine experience included feelings of isolation, depression, and irritability alongside the need for social support; (2) Impact on daily life: participants described how symptoms and unpredictability impacted their ability to perform activities of daily living; and (3) Impact on school: participants described how migraine impacted their school experience, including threatened attendance and worsened performance. CONCLUSIONS: In this cohort of youth and their caregivers, we identified salient themes to characterize the experience of migraine. Our findings underscore the urgent need for effective migraine treatments and interventions targeting co-occurring mental health conditions, peer relationships, and school support.

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.

Adverse Childhood Experiences Are Associated With Seizures in Children: A Cross-sectional Analysis.

Background and Objective: To assess the relationship between adverse childhood experiences (ACE/ACEs) and epilepsy. Methods: We performed a cross-sectional retrospective cohort analysis using population-based data from the 2018 and 2019 National Survey of Children's Health to examine caregiver-reported ACE exposures and their relationship to caregiver-reported physician diagnoses of epilepsy or seizure disorder in children. ACEs elicited in the survey included questions about experience of violence, household dysfunction, and food and housing insecurity. Adjusting for age, race, and income level, we used logistic regression to test the relationships between cumulative ACE score and current seizure disorder or epilepsy diagnosis and to examine which specific ACEs were individually associated with current seizure disorder or epilepsy diagnosis. Results: The study population consisted of 59,963 participants; 52.2% were female, and 47.8% were male. Participant ages ranged from 0 to 17 years. A current diagnosis of epilepsy or seizure disorder was reported in 377 (0.63%) participants, and 22,749 (37.9%) participants had one or more ACE exposures. As the number of ACEs increased, odds of current epilepsy or seizure disorder diagnosis increased by 1.14 (95% confidence interval 1.07-1.22). Five ACE exposures demonstrated a high association with a current diagnosis of epilepsy or seizure disorder: food/housing insecurity, witnessing domestic violence, household mental illness, neighborhood violence, and parent/guardian incarceration. Discussion: Multiple ACE exposures were individually associated with reporting a diagnosis of epilepsy or seizure disorder. An increase in cumulative ACE exposures increased odds of having current diagnosis of epilepsy or seizure disorder.

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 of the International Headache Society for Clinic-Based Headache Registries, 1st edition.

Clinic-based headache registries collect data for a wide variety of purposes including delineating disease characteristics, longitudinal natural disease courses, headache management approaches, quality of care, treatment safety and effectiveness, factors that predict treatment response, health care resource utilization, clinician adherence to guidelines, and cost-effectiveness. Registry data are valuable for numerous stakeholders, including individuals with headache disorders and their caregivers, healthcare providers, scientists, healthcare systems, regulatory authorities, pharmaceutical companies, employers, and policymakers. This International Headache Society document may serve as guidance for developing clinic-based headache registries. Use of registry data requires a formal research protocol that includes: 1) research aims; 2) methods for data collection, harmonization, analysis, privacy, and protection; 3) methods for human subject protection; and 4) publication and dissemination plans. Depending upon their objectives, headache registries should include validated headache-specific questionnaires, patient reported outcome measures, data elements that are used consistently across studies (i.e., "common data elements"), and medical record data. Amongst other data types, registries may be linked to healthcare and pharmacy claims data, biospecimens, and neuroimaging data. Headache diagnoses should be made according to the International Classification of Headache Disorders diagnostic criteria. The data from well-designed headache registries can provide wide-ranging and novel insights into the characteristics, burden, and treatment of headache disorders and ultimately lead to improvements in the management of patients with headache.

Beyond pain control: Outcome and treatment preferences in pediatric migraine.

OBJECTIVE: The objective of this study was to describe treatment preferences and perceived quality of existing outcome measures among children and adolescents with migraine and their caregivers. BACKGROUND: Across disciplines, there is increasing recognition of the value of direct input from stakeholders. Little empirical work has been done to determine what outcomes matter most to pediatric patients with migraine and their caregivers. METHODS: In this qualitative study, we recruited participants from the multicenter, prospective Pediatric Migraine Registry. We used stratified purposive sampling to recruit children and adolescents of varied ages and headache frequency. Patients with migraine and their caregivers completed semistructured interviews targeting treatment preferences and perceived quality of existing outcome measures. Emergent themes and subthemes were identified using conventional content analysis. RESULTS: Thirty dyads of children/adolescents and their caregivers were enrolled and completed 59 interviews (n = 29 children/adolescent interviews and n = 30 caregiver interviews). Three themes emerged. (1) Symptom relief: Looking beyond headache resolution: Participants described the value of outcomes in addition to pain relief, including a reduction in migraine intensity and improvement in non-pain symptoms. (2) Trade-offs between side effects and relief: Participants described cost-benefit analyses that can occur with headache treatment and acknowledged the impact of drug side effects on daily life and medication adherence. (3) Child-centered treatment: Participants described medication attributes salient to the pediatric context, including age-appropriate routes of administration and adequate safety data. CONCLUSIONS: Children, adolescents, and caregivers impacted by migraine value outcomes in addition to traditionally studied migraine endpoints. Participants valued decreased pain severity, even in the absence of pain resolution. Participants also prioritized the absence of side effects and key medication attributes, including fast onset and age-appropriate routes of administration. These results highlight an opportunity to design patient-centered clinical trials, develop drugs, and support product labeling that align with the outcomes valued most by children and adolescents with migraine and their caregivers.

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.

Acute and chronic management of posttraumatic headache in children: A systematic review.

OBJECTIVES: The goal of this paper is to provide a compilation of the evidence for the treatment of posttraumatic headache (PTH) in the pediatric population. Headache features and timing of therapy were considered. BACKGROUND: Headache is the most common symptom following mild traumatic brain injury (mTBI), affecting more than 80% of children and adolescents. It is unclear whether treatment for PTH should be tailored based on headache characteristics, particularly the presence of migraine features, and/or chronicity of the headache. METHODS: Systematic literature searches of PubMed, Embase, Scopus, and Cochrane databases (1985-2021, limited to English) were performed, and key characteristics of included studies were entered into RedCAP® (Prospero ID CRD42020198703). Articles and conference abstracts that described randomized controlled trials (RCTs), cohort studies, retrospective analyses, and case series were included. Participants included youth under 18 years of age with acute (<3 months) and persistent (≥3 months) PTH. Studies that commented on headache improvement in response to therapy were included. RESULTS: Twenty-seven unique studies met criteria for inclusion describing abortive pharmacologic therapies (9), preventative pharmacotherapies (5), neuromodulation (1), procedures (5), physical therapy and exercise (6), and behavioral therapy (2). Five RCTs were identified. Studies that focused on abortive pharmacotherapies were completed in the first 2 weeks post-mTBI, whereas other treatment modalities focused on outcomes 1 month to over 1-year post-injury. Few studies reported on migrainous features (7), personal history of migraine (7), or family history of migraine (3). CONCLUSIONS: There is limited evidence on the timing and types of therapies that are effective for treating PTH in the pediatric population. Prospective studies that account for headache characteristics and thoughtfully address the timing of therapies and outcome measurement are needed.

Autism Spectrum Disorder in Pediatric Idiopathic Intracranial Hypertension.

In recent years, the substantial burden of medical comorbidities in autism spectrum disorder (ASD) populations has been described. We report a retrospective observational case series of pediatric patients with suspected idiopathic intracranial hypertension (IIH) and concurrent ASD. Pediatric subjects with suspected IIH aged 2-18 years were identified by review of a pediatric neuro-ophthalmologist's database spanning from July 1993 to April 2013. ASD diagnoses were identified within this cohort by an ICD-9 diagnosis code search and database review. Three subjects had concurrent ASD diagnoses; all were non-obese males. Since the retrospective observational case series was performed in April 2013, we identified three additional IIH cases in boys with ASD. Our experience suggests that IIH may be a comorbidity of ASD, particularly in non-obese boys.