OBJECTIVES:We examined associations between patients' socioeconomic and clinical factors and the thoroughness of clinical notes for children visiting the pediatric emergency department (ED) for headache. METHODS:This is a secondary analysis of data from a retrospective chart review of first-time visits for patients (ages 5-17) seen for headache at 1 pediatric ED, excluding visits related to infection or injury. We extracted fields from the provider note relevant to headache diagnosis (eg, pain severity) and used backward stepwise log-binomial regressions to identify demographic and clinical factors associated with missing data for a single field. For our sensitivity analysis, we included imputed pain severity as another predictor. RESULTS:From 1000 randomly selected ED visits, we found 629 eligible visits, skewing toward adolescents (median: 13.0 y [IQR: 10.0-15.8 y]) and females (58.5%). Non-Hispanic black children had lower odds of being triaged at moderate or severe acuity even after adjusting for pain severity, age, and sex assigned at birth (OR: 0.07 [95% CI: 0.03-0.16]). Older patients (RR 0.99 per year [0.98-0.99], P<0.001) and those with moderate (0.79 [0.75-0.82], P<0.001) or high-acuity (0.90 [0.85-0.96], P=0.001) triage scores had a decreased risk of missing data; boys had an increased risk (1.04 [1.00-1.08], P=0.046). After pain severity was included, patients with severe pain (0.92 [0.88-0.97], P=0.003) had a decreased risk of missing data while sex differences became nonsignificant (P=0.063). CONCLUSIONS:Provider notes for children seen in the ED for headache are less thorough for younger patients, boys, and those with lower triage acuity scores. After accounting for pain severity, patients reporting mild pain also had less thorough notes. If the quality of medical documentation represents the health care interaction, relationships between missingness and demographic factors such as sex warrant exploration of potential interventions.

BackgroundNew daily persistent headache (NDPH) is a primary headache disorder that often presents in adolescence. Presently, there is no effective treatment for NDPH and a paucity of clinical trials exploring therapeutic options. In this study, we explored the relative benefit of currently used treatments to help inform future trials and clinical decision-making.MethodsIn this retrospective chart review study, patients aged 5-17 years with abrupt onset continuous headache and headache duration of at least one month (constituting NDPH or probable NDPH) were identified based on responses to a Headache Questionnaire in child neurology clinic and confirmed with chart review. We included all treatments (transitional therapy, preventive supplement, preventive medication and preventive non-medication therapy) started during continuous headache until both break in continuous headache and sustained improvement in headache were achieved. For treatments tried by at least 10 patients and for the first treatment tried in each category, we calculated proportions of any documented benefit, including "Significant" (≥30% improvement lasting ≥4 weeks) and "Some improvement" (all other improvement) and proportions of negative outcome (those with worsened headaches or side effects warranting discontinuation), as well as median time to treatment. We used multivariable regression modeling to examine for factors associated with headache outcomes. Treatments may have overlapped.ResultsOf the 165 patients, the largest proportion of patients experienced benefit with the first transitional therapy (62/108; 57%), which was usually intravenous medications ± oral corticosteroids. The first supplement tried, usually riboflavin ± magnesium, offered benefit in (36/118; 31%), with few negative outcomes (3/118; 3%). The first prescription preventive tried, usually amitriptyline or topiramate, offered similar benefit (37/106; 35%) as the first supplement, but with more negative outcomes (25/106; 24%). Despite being tried after oral preventives, onabotulinumtoxinA injections offered benefit to the largest proportion of patients (14/20; 70%) without negative outcomes (0%). Overall, the time to first therapy was weeks to months into continuous headache: shortest for transitional therapies (median = 49 days, interquartile range = 17-92 days), and longest for non-medication therapies (median = 144 days, interquartile range = 61-381 days). Increased time to any first treatment was associated with decreased odds of headache improvement at one-year follow-up (odds ratio = 0.823, 95% confidence interval = 0.715-0.946, p = 0.006).ConclusionsChildren and adolescents with new onset continuous headache experience treatment delays which are associated with worse outcomes. Clinicians should consider use of transitional therapies in combination with preventive treatments as early as possible. Prospective natural history studies and trials are needed to improve treatment outcomes for pediatric patients with NDPH.

BACKGROUND:To assess the accuracy of the Generalized Anxiety Disorder-2 (GAD-2) Scale for screening anxiety symptoms in children with headache and epilepsy. METHODS:Single-center and large-scale assessment of the two-item GAD-2 as compared to the seven-item Generalized Anxiety Disorder-7 (GAD-7) to screen for moderate-severe anxiety symptoms in children undergoing follow-up neurology appointments. RESULTS:The GAD-7 was fully completed for 3960 of 6060 (65%) encounters. Anxiety symptoms were moderate in 534 (13%) encounters and severe in 337 (9%) encounters. The GAD-2 and GAD-7 were very strongly correlated (spearman's rho 0.91; P < 0.001). When assessing moderate-severe anxiety symptoms based on the GAD-7, a GAD-2 score of ≥3 yielded an area under the receiver operating characteristics curve of 0.96, sensitivity 89%, specificity 91%, positive predictive value 74%, and negative predictive value 97%. If assessment stopped with the GAD-2 at the ≥3 cutoff, then 74% of encounters would be considered not to have anxiety symptoms and would not complete additional questions, but 11% of encounters with moderate-severe anxiety symptoms would not be identified, including 0.6% of patients with severe anxiety symptoms. CONCLUSIONS:Anxiety symptoms were common. Use of the GAD-2 would reduce the number of questions needing completion compared to the GAD-7 for 74% of patients but would fail to identify 11% of patients with moderate-severe anxiety symptoms, including 0.6% of patients with severe anxiety symptoms. These data indicate that the use of the GAD-2 may be appropriate as a briefer alternative to the GAD-7 which may be ideal in clinical settings with a substantial questionnaire burden.

Migraine is one of the most common chronic health problems in children and adolescents, resulting in high levels of functional disability. Symptoms frequently persist into and impact the course of adulthood for affected individuals. Current practice recommendations include a combined therapy approach of preventive medication and cognitive behavioral therapy (CBT); however, no trials have systematically assessed whether a combined therapy approach is superior to a cognitive behavioral monotherapy intervention. The REACH (Responding With Evidence and Access for Childhood Headaches) trial will compare the impact of a CBT monotherapy to a combined treatment for prevention of migraine in youth, while addressing barriers to CBT access by utilizing a teletherapy approach. The study will include youth with migraine between the ages of 10 and 17 years from 15 sites across the United States, who will be randomly assigned to a CBT + pill (amitriptyline) group or CBT-alone group. Both groups will complete six sessions of telehealth CBT, as well as three booster sessions, over the course of 6 months. Participants will report on headache and migraine frequency and related disability via a daily headache diary before (28-day baseline), during, and after completion of the intervention (the last 28 days on the protocol). The CBT + pill group will also undergo a dose titration of clinically prescribed amitriptyline throughout the active treatment phase. Primary treatment outcomes are a ≥50% reduction in headache days and reduction in migraine-related disability (i.e., Pediatric Migraine Disability Assessment score ≤20). Findings of the REACH study may confirm current practice guidelines or provide evidence of comparable effectiveness of combined therapy and CBT monotherapy for prevention of migraine. This trial is designed to reinforce current guidelines for preventive headache management strategies in youth with migraine. The study will also advance knowledge by determining whether CBT alone, without the potential side effects of medication, is sufficient.

Headache-associated symptoms (e.g., sensory sensitivity, nausea) are used to classify primary headache disorders and define treatment outcomes. We developed Cluster Analysis of Migraine-Associated Symptoms (CAMS) to provide an aggregate measure that captures relationships between several headache-associated symptoms. CAMS reveals that a greater number of symptoms, particularly if they include symptoms of autonomic and vestibular dysfunction, are associated with older age and greater headache burden in children and adolescents. Here, we aim to determine if CAMS is generalizable to adults. The Penn Online Evaluation of Migraine (POEM) survey collected headache characteristics on participants ( ≥ 18 years) who reported headache. CAMS models were generated based on the presence or absence of 12 headache-associated symptoms. Three models were compared: the original CAMS model developed for children and adolescents, a model generated with adult data, and a comparison pediatric model for data collected across the same timeframe as the adult data. Changes in CAMS as a function of age and headache burden were measured. CAMS generated from the adult (n = 350) and pediatric comparison (n = 471) datasets were consistent with the original CAMS model (n = 6,662). Across models, the first dimension (CAMS 1; 25.4–31.0

Light exposure plays an important role in overall health because it entrains circadian rhythms. Recent technological advances in wearable light loggers allow measurement daily light exposure habits. Using a chest-worn light logger, our goal was to (1) develop methodology for differentiating adherent versus non-adherent use, and (2) define differences in lighting intensity in indoor and outdoor environments, to improve data reliability in future clinical studies using this technology. Four testers used a 10-channel chest worn light logging device under different conditions of wear and non-wear (experiment 1), and another tester made measurements with the light logger across a variety of indoor and outdoor lighting environments (experiment 2). In experiment 1, measurements from the light logger (photopic illuminance, device orientation, accelerometer data, time of day) were used to train models to differentiate wear from non-wear and correct nighttime placement. The most accurate model was then tested with the remaining data from testers (T1 - T4). This model was then applied to 20 adolescents and young adults with migraine who wore the light logger device for one week. In experiment 2, measurements of photopic illuminance and melanopic equivalent daytime illuminance (mEDI) of darker indoor versus brighter outdoor lighting environments were compared to identify the optimal indoor/outdoor distinction point for the chest-worn light logger. Movement, device orientation, light, and time-of-day used as predictors in a random forest model had excellent differentiation between wear, non-wear and nighttime use (overall accuracy 0.95), and retained good-to-excellent differentiation when applied to the test dataset (overall accuracy 0.76). When this model was applied to 20 participants with migraine, we found that 92.1% of participant-days and 77.9% of participant-nights demonstrated at least 80% appropriate use. Applying the wear/non-wear model to this dataset led to modest changes in light exposure measurements but did not change conclusions of our prior study. For differentiating indoor and outdoor lighting environments, the optimal cut-point was 442 lx for photopic illuminance, and 412 lx for mEDI. We demonstrate that internal measurements from a chest-worn light logging device can reliably differentiate wear from non-wear. We also found that the optimal cut-off to differentiate indoor and outdoor lighting environments was lower than 1,000 lx cut-offs traditionally used to define bright light conditions. These findings can be used to improve data reliability in studies of everyday light exposure in clinical populations using chest-worn light loggers.

BACKGROUND:Fremanezumab, a humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, is approved for the prevention of migraine in adults. Evidence from randomized, controlled trials in children and adolescents is needed. METHODS:We randomly assigned participants 6 to 17 years of age with a diagnosis of episodic migraine (defined as migraine for ≥6 months and a history of ≤14 headache days per month) to receive monthly subcutaneous injections of fremanezumab (120 mg for participants with a body weight of <45 kg and 225 mg for those with a body weight of ≥45 kg) or matched placebo for 3 months. Participants were allowed to use migraine-specific medications to treat acute headaches. The primary end point was the change from baseline in the average number of migraine days per month. Key secondary end points included the change in the number of days per month with headache of at least moderate severity and a reduction of 50% or more in the number of migraine days per month. RESULTS:Of 237 participants who underwent randomization, 234 were included in the full analysis population: 123 in the fremanezumab group (36 received the 120-mg dose and 87 received the 225-mg dose) and 111 in the placebo group. Fremanezumab reduced the number of migraine days per month by 2.5 as compared with 1.4 with placebo (difference, 1.1; P = 0.02) and the number of days per month with headache of at least moderate severity by 2.6 as compared with 1.5 with placebo (difference, 1.1; P = 0.02). The percentage of participants who had a reduction of 50% or more in the number of migraine days per month was 47.2% with fremanezumab and 27.0% with placebo (P = 0.002). Injection-site erythema was the most common adverse event with fremanezumab (9.8% of participants, vs. 5.4% with placebo). CONCLUSIONS:Among children and adolescents with episodic migraine, fremanezumab resulted in greater reductions in the number of migraine days and headache days than placebo. Injection-site erythema was the most common adverse event with fremanezumab. Longer follow-up is required to further understand the efficacy and safety of the drug in this population. (Funded by Teva Pharmaceuticals; ClinicalTrials.gov number, NCT04458857.).

Objectives To assess the accuracy of the Generalized Anxiety Disorder Scale (GAD-2) for screening anxiety symptoms in children with headache and epilepsy. Methods Single-center and large-scale assessment of the two-item GAD-2 as compared to the seven-item GAD-7 to screen for moderate-severe anxiety symptoms in children undergoing follow-up neurology appointments. Results The GAD-7 was fully completed for 3,960 of 6,060 (65%) encounters. Anxiety symptoms were moderate in 534 (13%) encounters and severe in 337 (9%) encounters. The GAD-2 and GAD-7 were very strongly correlated (spearman’s rho 0.91; p<0.001). When assessing moderate-severe anxiety symptoms based on the GAD-7, a GAD-2 score of ≥3 yielded an area under the receiver operating characteristics curve of 0.96, sensitivity 89%, specificity 91%, positive predictive value 74%, and negative predictive value 97%. If assessment stopped with the GAD-2 at the ≥3 cutoff, then 74% of encounters would be considered not to have anxiety symptoms and would not complete additional questions, but 11% of encounters with moderate-severe anxiety symptoms would not be identified, including 0.6% of patients with severe anxiety symptoms. Conclusions Anxiety symptoms were common. Use of the GAD-2 would reduce the number of questions needing completion compared to the GAD-7 for 74% of patients but would fail to identify 11% of patients with moderate-severe anxiety symptoms, including 0.6% of patients with severe anxiety symptoms. These data indicate that the use of the GAD-2 may be appropriate as a briefer alternative to the GAD-7 which may be ideal in clinical settings with a substantial questionnaire burden.

Plain Language Summary It remains unclear whether avoiding uncomfortable light is the best strategy to manage light sensitivity associated with migraine, or if restricting light exposure increases intolerance over time. We found that youth with migraine were more likely to report light sensitivity in the winter when light exposure tends to be lower. This finding suggests that light sensitivity is worse when light exposure is lower, but further research is needed to confirm this relationship.

ObjectiveTo investigate the relationship between the evolution of continuous headache and headache-related disability in children.MethodsThis was a single site cross-sectional study using patient-entered questionnaires from children aged 6-17 who presented to neurology clinic between November 2022-May 2024 with continuous headache. Participants were categorized as sudden onset (no evolution), rapidly evolved (< 3 months), or gradually evolved (≥ 3 months) continuous headache. Analysis examined the relationship between the pattern of headache evolution and headache-related disability (PedMIDAS score), accounting for demographic, headache characteristic, and onset factors.ResultsOf 751 respondents, 42.5% reported sudden onset, 35.0% rapid evolution, and 22.5% gradual evolution to continuous headache. There was no significant difference in PedMIDAS score in children who reported sudden onset compared to children with rapid (6.9 [-2.7, 16.4], p = 0.159) or gradual evolution (10.3 [-0.8, 21.3], p = 0.068) of headache onset. Older age (3.3 per year [1.8, 4.8], p < 0.001) and patient reported trigger (17.1 [8.8, 25.5], p < 0.001) at the onset of continuous headache were both associated with greater headache-related disability, accounting for other covariates.ConclusionChildren transitioned to continuous headache quickly, consistent with prior studies. Older children and those who associated onset of continuous headache with a trigger reported higher rates of headache-related disability.

OBJECTIVES/BACKGROUND:This study was undertaken to synthesize evidence on the benefits and harms of behavioral interventions for migraine prevention in children and adults. The efficacy and safety of behavioral interventions for migraine prevention have not been tested in recent systematic reviews. METHODS:An expert panel including clinical psychologists, neurologists, primary care physicians, researchers, funders, individuals with migraine, and their caregivers informed the scope and methods. We searched MEDLINE, Embase, PsycINFO, PubMed, the Cochrane Database of Systematic Reviews, clinicaltrials.gov, and gray literature for English-language randomized trials (January 1, 1975 to August 24, 2023) of behavioral interventions for preventing migraine attacks. Primary outcomes were migraine/headache frequency, migraine disability, and migraine-related quality of life. One reviewer extracted data and rated the risk of bias, and a second verified data for completeness and accuracy. Data were synthesized with meta-analysis when deemed appropriate, and we rated the strength of evidence (SOE) using established methods. RESULTS:For adults, we included 50 trials (77 publications, N = 6024 adults). Most interventions were multicomponent (e.g., cognitive behavioral therapy [CBT], biofeedback, relaxation training, mindfulness-based therapies, and/or education). Most trials were at high risk of bias, primarily due to possible measurement bias and incomplete data. For adults, we found that any of three components (CBT, relaxation training, mindfulness-based therapies) may reduce migraine/headache attack frequency (SOE: low). Education alone that targets behavior may improve migraine-related disability (SOE: low). For three other interventions (biofeedback, acceptance and commitment therapy, and hypnotherapy), evidence was insufficient to permit conclusions. We also found that mindfulness-based therapies may reduce migraine disability more than education, and relaxation + education may improve migraine-related quality of life more than propranolol (SOE: low). For children/adolescents, we included 13 trials (16 publications, N = 1444 children), but the evidence was only sufficient to conclude that CBT + biofeedback + relaxation training may reduce migraine attack frequency and disability more than education alone (SOE: low). CONCLUSION:Results suggest that for adults, CBT, relaxation training, and mindfulness-based therapies may each reduce the frequency of migraine/headache attacks, and education alone may reduce disability. For children/adolescents, CBT + biofeedback + relaxation training may reduce migraine attack frequency and disability more than education alone. Evidence consisted primarily of underpowered trials of multicomponent interventions compared with various types of control groups. Limitations include semantic inconsistencies in the literature since 1975, differential usage of treatment components, expectation effects for subjectively reported outcomes, incomplete data, and unclear dosing effects. Future research should enroll children and adolescents, standardize intervention components when possible to improve reproducibility, consider smart study designs and personalized therapies based on individual characteristics, use comparison groups that control for expectation, which is a known challenge in behavioral trials, enroll and retain larger samples, study emerging digital and telehealth modes of care delivery, improve the completeness of data collection, and establish or update clinical trial conduct and reporting guidelines that are appropriate for the conduct of studies of behavioral therapies.

Background:Light exposure plays an important role in overall health because it entrains circadian rhythms. Recent technological advances in wearable light loggers allow measurement daily light exposure habits. Using a chest-worn light logger, our goal was to 1) develop methodology for differentiating adherent versus non-adherent use, and 2) define differences in lighting intensity in indoor and outdoor environments, to improve data reliability in future clinical studies using this technology. Methods:Five testers used a 10-channel chest worn light logging device under different conditions of wear and non-wear, and across a variety of indoor and outdoor lighting environments. Measurements from the light logger (photopic illuminance, device orientation, accelerometer data, time of day) were used to train and validate a logistic regression model to differentiate wear from non-wear and correct nighttime placement. This model was then applied to 20 adolescents and young adults with migraine who wore the light logger device for one week. Furthermore, measurements of photopic illuminance and melanopic equivalent daytime illuminance (mEDI) of indoor versus outdoor lighting environments were compared to identify the optimal distinction point between darker indoor and brighter outdoor environments for the chest-worn light logger. Results:Movement, device orientation, light, and time-of-day used as predictors in a logistic regression model had excellent differentiation between wear, non-wear and nighttime use (AUC 0.93 - 0.94), and retained good-to-excellent differentiation when applied to the validation dataset (AUC 0.84 - 0.91). When this model was applied to 20 participants with migraine, we found that 92.9% of participant-days and 71.4% of participant-nights demonstrated at least 80% appropriate use. For differentiating indoor and outdoor lighting environments, the optimal cut-point was 442 lux for photopic illuminance, and 412 lux for mEDI. Conclusions:We demonstrate that internal measurements from a chest-worn light logging device can reliably differentiate wear from non-wear. We also found that the optimal cut-off to differentiate indoor and outdoor lighting environments was similar though slightly lower than then 1,000 lux cut-offs traditionally used to define bright light conditions. These findings can be used to improve data reliability in studies of everyday light exposure in clinical populations using chest-worn light loggers.

Background and ObjectivesHeadache evaluation and treatment are believed to be influenced by race and ethnicity. Specific headache diagnosis assigned in the pediatric emergency department (ED) may compound disparities. We sought to investigate racial and ethnic disparities in the diagnosis, testing, and treatment of pediatric patients with headache presenting to the ED. MethodsWe performed a cross-sectional analysis of ED visits from 49 children's hospitals between 2016 and 2022 from the Pediatric Health Information System, an administrative database of ED and hospitalized encounters within children's hospitals in the United States. Index encounters in the ED from patients (aged 5-21 years, median age 13 [10-15]) with a primary diagnosis of migraine, headache, new daily persistent headache, or tension-type headache were included. Encounters with trauma, infection, and malignancy where secondary headache was possible were excluded. The primary outcomes were the rates of migraine diagnosis, testing, and treatment. We used generalized estimating equations to estimate associations between race and ethnicity and outcomes after adjusting for demographic factors, medical complexity, visit timing, and final headache diagnosis. ResultsA total of 309,678 encounters were included while 61,677 repeat visits, 81,821 visits with diagnoses suggestive of secondary headache, and 5,714 visits from 3 hospitals with sparse data on patient race/ethnicity were excluded. Of 160,466 eligible visits (59.8% female), 41% were by non-Hispanic White (NHW) children, 24.8% non-Hispanic Black (NHB), and 26.0% Hispanic/Latino (HL). NHW children were more frequently diagnosed with migraine (45.5% vs NHB 28.2% and HL 28.3%, p < 0.001). NHB and HL children compared with NHW children received less testing including brain MRI scans (adjusted odds ratio [aOR]: NHB 0.56 [95% CI 0.46-0.69] and HL 0.54 [0.36-0.82]). There was no difference in the proportion of visits without administration of headache-related medications (NHW 23.3% vs NHB 24.6% and HL 23.4%, p = 0.64). NHB and HL children were more likely to receive only oral medications (aOR: NHB 1.37 [1.2-1.56] and HL 1.54 [1.34-1.76]) and less likely to be admitted inpatient (aOR: NHB 0.8 [0.66-0.97] and HL 0.65 [0.44-0.94]). DiscussionNHB and HL children in the pediatric ED with headache receive fewer migraine diagnoses, less testing, and less intensive treatment compared with NHW children. Beyond affecting headache management, this inequity in migraine diagnosis requires further consideration to include children from marginalized racial and ethnic groups in future migraine research.

BACKGROUND:Triptans are used to treat migraine attacks, but little to no evidence supports their use for youth with post-traumatic headache (PTH). This study evaluated patterns of use and benefit of triptans in the treatment of acute headache worsening in youth with PTH. METHODS:A single-center retrospective cohort study was conducted by reviewing charts for 332 patients aged eight to 17 years seen in a child neurology clinic for PTH within one year of concussion. Treatment responses and side effects were recorded. Demographic and headache characteristics associated with triptan use and treatment response were examined. RESULTS:Eighty of 332 patients (24.1%) used a triptan. Of those, 34 (42.5%) had acute (less than three months) PTH and 46 (57.5%) had persistent (greater than or equal to three months) PTH. Median time from injury to triptan prescription was 123 days (interquartile range, 50, 242). Older patients, those with headache phenotype consistent with migraine, those who previously used a greater number of treatments for acute headache worsening, and those seen by the headache program were more likely to use triptans (χ2 > 7.00, P < 0.01). Sixty percent reported at least partial headache relief with their first triptan, whereas 25% reported side effects, all of which were minor. CONCLUSIONS:These findings show triptans are more likely to be used for youth with PTH with phenotype consistent with migraine that are unrelieved by other treatments for acute headache worsening. Triptans may be an effective treatment for acute headache worsening in youth with PTH, although randomized controlled trials are needed.

Aim: Sensitivity to light and noise is commonly associated with headache. It is unclear if exposure to more intense sensory environments, or exposure to more restricted sensory environments leading to intolerance, worsens sensory sensitivity more over time. We aimed to determine if photophobia is more common during the winter months when daily light exposure is reduced. Methods: We conducted a single-center cross-sectional study from a pediatric headache clinic in the Philadelphia area assessing patient-reported headache-related photophobia and phonophobia from an outpatient headache intake questionnaire. Rates were compared in the 3 months surrounding the winter and summer solstice, which has an average daylight difference of 5 hours between these time windows. Monthly symptom rates were fitted to a sinusoid across the 12-month calendar to characterize seasonal variation. Results: A total of 2,040 headache intake questionnaires were included in the analysis. Headache-associated photophobia was significantly more common in the winter compared to summer (OR 1.38, p = 0.018), but this seasonal variation was not observed for phonophobia (p = 0.698). Conclusion: Headache-related photophobia is more prevalent near the winter, compared to the summer, solstice. ### Competing Interest Statement C.P.G.: Dr. Patterson Gentile is currently funded by the National Institutes of Health/National Institute of Neurological Disorders and Stroke (K23 NS124986) and the CHOP Foerderer Institutional grant. A.D.H.: Dr. Hershey or his institution have received compensation for serving as a consultant for AbbVie, Amgen, Biohaven, Eli Lilly, Lundbeck, Supernus, Teva, Theranica and Upsher-Smith. His institution has also received research support from Amgen, Biohaven, Eli Lilly, Theranica, Upsher-Smith, and the NIH NINDS/NICHDS. G.K.A.: Dr. Aguirre receives funding/grant support from the National Institute of Neurological Disorders and Stroke, the National Eye Institute, and the Binational Science Foundation. C.L.S.: Dr. Szperka has received research/grant support from the PCORI. Dr. Szperka or her institution have received compensation for her consulting work for Eli Lilly; Teva Pharmaceutical Industries Ltd; Upsher-Smith Laboratories, LLC; Abbvie; and Lundbeck. ### Funding Statement This work was supported by the National Institutes of Health National Institute of Neurological Disorders and Stroke (K23NS124986 to C.P.G). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Children's Hospital of Philadelphia Institutional Review Board approved the extraction of the data from the electronic health record into a research registry, with a waiver of consent and assent to maximize generalizability. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors.

Aim:To determine how migraine-associated symptoms change over time, and if they are predictive of outcome at first follow-up visit. Symptoms associated with headache-photophobia and phonophobia, nausea, and/or vomiting-are required criteria for the diagnosis of migraine. Individuals with migraine also report high rates of other symptoms (e.g. lightheadedness, difficulty thinking). We have developed cluster analysis of migraine-associated symptoms (CAMS), which is a composite representation of an expanded set of migraine-associated symptoms that is associated with headache burden. It is unknown if CAMS can change with treatment response or predict outcomes. Methods:We conducted a secondary analysis of prospectively collected clinician-guided patient questionnaire data from youth (6-17 years) with migraine who were seen at a specialized pediatric headache clinic. Data were collected at time of presentation and at the first follow-up within 30 to 90 days from the first visit. CAMS were implemented to assess associations between 11 migraine-associated symptoms. We determined if CAMS changed over time and as a function of treatment outcome, and if CAMS could be used to predict outcome at first follow-up. Results:Youth with migraine (n = 8008, 67.1% female, median 13 years old) were included in this study. CAMS revealed that the number of reported migraine-associated symptoms decreased at follow-up, particularly for those who improved. Resolution of nausea and vomiting were most common. CAMS at the initial visit differed between youth who improved and youth who did not, but the effect was clinically negligible and could not reliably predict outcome (AUC 0.53). Conclusion:Migraine-associated symptoms as captured by CAMS changed over time based on whether youth noted improvement or not but was not predictive of who improved at follow-up.