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.
BACKGROUND:Intravenous nitroglycerin (NTG) is a well-established model for provoking migraine attacks, but it has not previously been used to characterize vestibular migraine (VM). Different types of nystagmus have been reported during spontaneous VM attacks. We aimed to measure changes in nystagmus during NTG-induced migraine in participants with VM. METHODS:We studied 20 participants with definite VM (Barany-International Classification of Headache Disorders, 3rd edition criteria) undergoing NTG provocation in a prospective, within-subject repeated-measures pharmacological provocation study under three conditions at the National Institute for Health and Care Research King's Clinical Research Facility, London, between November 2024 to December 2025. Median (interquartile range [IQR]) age was 32 (29 to 38) years, and 16/20 were female. 3D video-oculography was used to quantify total slow-phase velocity (SPV) (°/s) of nystagmus without fixation in the center, left, right, up, and down positions. Recordings were repeated before NTG, after NTG, and after subcutaneous sumatriptan. Subjective vestibular symptoms and headache intensity were quantified with an ordinal numeric scale. Longitudinal changes in SPV were analyzed. RESULTS:All the participants developed headache, with median peak severity 6/10 (IQR 4 to 7). Vestibular symptoms were triggered in 14/20 participants following NTG, with a median maximum intensity of 2.5 (IQR 0 to 4). Median (IQR) summed SPV (°/s) was 2 (1 to 3.25) at baseline, 1.5 (0 to 4.75) following NTG, and 1 (0 to 2.75) after sumatriptan. In Tweedie generalized linear mixed-effects models, no significant group-level effect of condition on total SPV was detected. Estimated marginal means were 1.87 (95% confidence interval [CI] 1.02 to 3.41) at baseline, 2.10 (95% CI 1.16 to 3.80) following NTG, and 1.73 (95% CI 0.93 to 3.19) after sumatriptan. Compared with baseline, neither NTG (β = 0.118, standard error [SE] = 0.267, P = 0.658) nor sumatriptan (β = -0.078, SE = 0.278, P = 0.780) showed significant effects. NTG provocation was associated with complex perceptions such as visual symptoms (10/20) and Alice in Wonderland syndrome type or dissociative symptoms (6/20), including derealization/depersonalization, metamorphopsia, macropsia and pelopsia, dysmorphopsia, and distorted passage of time. CONCLUSIONS:Quantitative slow phase velocity measures of nystagmus did not show a uniform group-level change during NTG provocation in VM, despite frequent subjective vestibular symptoms. VM episodes may reflect altered central sensory processing and vestibular hypersensitivity rather than changes in vestibulo-oculomotor output.
OBJECTIVE:The goal of this study was to synthesize the evidence on how "status migrainosus" is defined in research studies in comparison to established International Classification of Headache Disorders (ICHD) criteria. BACKGROUND:Current ICHD-3 criteria define status migrainosus as a headache attack occurring in a patient with a history of migraine with or without aura that is typical of previous attacks except for its duration (>72 h) and severity (debilitating). Despite the ICHD criteria, there are varying inclusion criteria noted in studies enrolling patients with status migrainosus. With this diagnostic uncertainty, there remains difficulty in studying this patient population. METHODS:This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Ovid MEDLINE, Ovid EMBASE, All Evidence-Based Medicine Reviews, the Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform were searched with the end search date of August 29, 2025. We included studies that were original research focused on status migrainosus, published in English after January 1, 1988, and also included diagnostic criteria to define this condition. The abstracts and full texts were screened by independent reviewers, with a third independent reviewer remaining available to settle disputes. There were 45 studies that underwent full text review, with 19 of these studies included. Data extraction was conducted recording the criteria used to define status migrainosus, headache characteristics, and goals of each study. RESULTS:We identified four common domains among studies of status migrainosus, including use of ICHD criteria, headache duration, symptom severity, and treatment response. Reference to ICHD criteria was variable, with only 68% (13/19) of studies specifying an edition of ICHD criteria applied in recruiting or studying patients with status migrainosus. The majority of studies (16/19; 84%) used a headache duration greater than 72 h to define status migrainosus. The use of symptom severity with "debilitating" or "severe" was present in 63% (12/19) of studies and depended on the edition of ICHD criteria that was referenced. Treatment response was rarely used as a condition in defining status migrainosus, with only 15% (3/19) of studies utilizing this stipulation in diagnostic criteria. CONCLUSION:The results of this systematic review show inconsistent application of ICHD criteria in research studies focusing on status migrainosus. These inconsistencies lead to ambiguity in how status migrainosus is defined in the research setting and limit the ability to replicate or compare studies. Guidelines outlining best practices for research of status migrainosus are necessary. For prospective studies, consistent utilization of ICHD criteria is necessary, with potential need to revise these criteria to better reflect the clinical realities of this entity. For retrospective studies, implementation of a standardized International Classification of Diseases code for status migrainosus would be of benefit to improve diagnostic clarity because the current codes are lengthy, cumbersome, and unclear.
OBJECTIVE:To assess patterns of statistical associations among migraine stigma, psychological factors, and disability during the active migraine attack phase (the ictal disability burden) and in between attacks (the interictal disability burden). BACKGROUND:Previous work suggests perceived stigma toward migraine is an important contributor to migraine disability. Yet, it is currently unclear how migraine stigma is connected to disability and vice versa. Psychological distress factors (i.e., perceived stress, anxiety symptoms, depression symptoms, and pain catastrophizing) are putative variables that might contribute to associations between stigma and disability. METHODS:This was a web-based cross-sectional survey study of 103 American adults with active migraine conducted during 2024 to 2025. Relationships among perceived migraine-related stigma, perceived stress, anxiety and depression symptoms, pain catastrophizing, ictal disability, and interictal disability were assessed. Information was collected using a battery of questionnaires including the Migraine-Related Stigma questionnaire, MIDAS, Migraine Interictal Burden Scale-4, Pain Catastrophizing Scale (headache version), Generalized Anxiety Disorder-7 questionnaire, Patient Health Questionnaire-9, and Perceived Stress Scale-4. Associational variable analysis, an alternative framework for nonexperimental cross-sectional mediation studies, was used to examine associational patterns. RESULTS:Perceived stress was shown to partially account for variance between perceived migraine stigma and ictal disability (effect = 0.10, 95% confidence interval [CI] [0.01, 0.24]), whereas pain catastrophizing was found to partially account for the association between stigma and interictal disability (effect = 0.04, 95% CI [0.01, 0.09]). Transposing stigma and disability to examine reverse associations, perceived stress was found to partially account for the ictal disability-stigma association (effect = 0.03, 95% CI [0.0002, 0.07]), whereas depressive symptoms (effect = 0.25, 95% CI [0.04, 0.54]) and pain catastrophizing (effect = 0.44, 95% CI [0.11, 0.91]) were shown to partially account for associations between interictal disability and stigma. CONCLUSIONS:Among psychological variables examined, perceived stress and pain catastrophizing carried significant portions of stigma's relationship with ictal and interictal disability, respectively. Moreover, perceived stress (ictally) and depression symptoms/pain catastrophizing (interictally) accounted for portions of disability's relationship with stigma.
BACKGROUND AND OBJECTIVES:This systematic review (SR) provides updated evidence-based conclusions regarding the use of pharmacologic migraine prevention in adults to inform a new joint American Academy of Neurology (AAN) and American Headache Society practice guideline. METHODS:A multidisciplinary panel conducted an SR following the 2017 AAN Clinical Practice Guideline Process Manual. Randomized controlled trials evaluating pharmacologic preventive treatments for adults with episodic or chronic migraine were included. Searches encompassed MEDLINE, Embase, and ClinicalTrials.gov from database inception through June 6, 2024. Studies were screened in duplicate, with dual independent risk-of-bias assessment. Outcomes included change in monthly headache days, ≥50% responder rate, and validated patient-reported quality of life (QOL) measures. Raw mean differences, standardized mean differences, and risk ratios were calculated. A modified Grading of Recommendations Assessment, Development, and Evaluation process was used to classify certainty of evidence. RESULTS:A total of 217 studies met inclusion criteria. For episodic migraine, high-confidence evidence showed that galcanezumab and erenumab are more effective than placebo in reducing headache frequency. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, fremanezumab, propranolol, topiramate, and valproate. Several additional oral agents including amitriptyline, bisoprolol, flunarizine, fluoxetine, levetiracetam, metoprolol, nifedipine, pizotifen, and telmisartan had low-confidence evidence suggesting possible benefit. For chronic migraine, high-confidence evidence supported reductions in headache frequency with fremanezumab, galcanezumab, and onabotulinumtoxinA. Moderate-confidence evidence supported benefit from atogepant, eptinezumab, erenumab, topiramate and valproate. Across both episodic and chronic migraine populations, erenumab, fremanezumab, galcanezumab, eptinezumab, rimegepant, atogepant, topiramate and onabotulinumtoxinA demonstrated improvements in patient-reported QOL outcomes on validated instruments. Evidence comparing active treatments was limited and generally of low or very low confidence, restricting conclusions about comparative effectiveness. DISCUSSION:This SR provides a comprehensive synthesis of evidence on pharmacologic migraine prevention in adults. High- and moderate-confidence findings confirm the efficacy of several established and newer preventive therapies and demonstrate improvements in patient-reported outcomes across multiple validated measures. These conclusions informed the development of evidence-based recommendations, presented in a companion publication, to guide clinicians in selecting preventive medications for adults with episodic and chronic migraine.
This practice guideline provides updated evidence-based recommendations regarding the use of pharmacologic migraine prevention in adults. A multidisciplinary panel conducted a systematic review and developed practice recommendations following the process outlined in the 2017 edition of the American Academy of Neurology Clinical Practice Guideline Process Manual. The systematic review includes studies published through June 6, 2024, and is available in a companion publication. Recommendations are supported by structured rationales that integrate evidence from the systematic review, related evidence, principles of care, and inferences from evidence. Recommendations are provided on how to decide when it is appropriate to start a pharmacologic migraine preventive medication and how to decide which migraine preventive medication to start. Recommendations address decision making on appropriate choices of migraine preventive medications in specific situations and populations, including patients with fibromyalgia, obesity, or hypertension; considerations for older adults; treatment during pregnancy and lactation; sex-related factors in choosing medications; and treatment for patients with medication overuse. Recommendations on assessment of treatment efficacy, adverse effects, and discontinuing migraine preventive medications are provided.
OBJECTIVE:To present a practical, evidence-based framework for the management of headache disorders in pediatric patients with prior stroke or underlying cerebral vascular lesions, with particular attention to safety and efficacy of pharmacologic and non-pharmacologic therapies. BACKGROUND:Chronic headache is frequent after ischemic or hemorrhagic stroke (reported in 12-57% of patients) and is also common in cerebrovascular disorders. Pediatric patients with these conditions face unique therapeutic challenges because many typical headache medications have vasoactive or blood pressure-modulating effects that may increase cerebrovascular risk. METHODS:We performed a comprehensive MEDLINE literature review (July 2024) searching combinations of headache medication classes paired with specific neurovascular conditions. INCLUSION CRITERIA:English or translated articles since 1990, comprising human and animal in vitro/in vivo studies, narrative reviews, case series/reports. Extracted data were organized by vascular condition, with summary tables of preventive and acute interventions categorized by evidence of efficacy, safety, and theoretical risk. RESULTS:Across conditions, vasoconstrictive agents (triptans, ergots) remain generally contraindicated or used with extreme caution in patients with vascular lesions due to risk of ischemia or hemorrhage. Anti-hypertensive agents (β-blockers, calcium channel blockers [CCBs], angiotensin II receptor blockers [ARBs]) are generally safe and may confer additional vascular benefit in post-stroke headache. Calcitonin gene-related peptide (CGRP) -targeting therapies are not formally contraindicated but may impair compensatory vasodilation in flow-dependent vascular lesions. Anti-seizure medications, antidepressants, melatonin, and non-pharmacologic therapies appear to have favorable risk-benefit profiles, although direct data in these populations are limited. Interventions addressing underlying vascular lesions (e.g., arteriovenous fistulas [AVF] embolization, arteriovenous malformations [AVM] or cavernoma resection, pial synangiosis) often lead to headache improvement. CONCLUSION:In pediatric patients with cerebrovascular disease who have headaches, individualized management is essential. Drug selection must incorporate vascular pathophysiology, hemodynamic stability, and collateral flow considerations. More prospective, pediatric-specific and lesion-specific studies are needed to guide optimal headache therapies in this complex population.
BACKGROUND:Evidence suggests that infantile colic, a common condition in early infancy, shares pathophysiological features with migraine. OBJECTIVE:Aim was to examine the current evidence on the association between infantile colic and migraine, focusing on both maternal migraine as a risk factor for infantile colic and infantile colic as a predictor of later childhood migraine. DESIGN:We performed a scoping review. METHODS:We performed a scoping review and searched the PubMed, Scopus, and Web of Science databases from inception to 30 September 2025. Observational studies examining either maternal migraine and infantile colic or infantile colic and subsequent childhood migraine were included. Data were extracted on study design, population characteristics, and effect estimates. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were extracted where available, and crude ORs were calculated when necessary. RESULTS:Twelve observational studies published from 1997 through 2025 were included. Estimates varied widely across six studies focusing on maternal migraine and infant colic, with ORs ranging from 0.97 to 37.71, reflecting substantial heterogeneity in study design, populations, and definitions. Another six studies showed that infantile colic was associated with later migraine, with ORs ranging from 0.50 to 107.14, although estimates varied substantially and some CIs were wide. CONCLUSION:Available observational evidence suggests a consistent association between migraine and infantile colic. Infantile colic may represent an early-life marker of migraine susceptibility, but causality cannot be established. Further prospective studies are needed to clarify underlying mechanisms and clinical implications.
OBJECTIVES/BACKGROUND:Our objective was to determine the impact of migraine on women's fertility and birth planning. Migraine preferentially affects women of childbearing age, and previous studies have suggested that migraine negatively affects a woman's decision to have children. We used the Swedish National Registry to determine the impact of migraine on women's fertility patterns including overall likelihood of childbirth, number of children, age at first birth, and birthing outcomes. METHODS:Our study used a retrospective matched cohort design including all women born in Sweden between 1973 and 1996 who were registered in the Swedish Medical Birth Register and resided in Sweden as of 2018. Cases comprised women in the National Patient Register diagnosed with migraine between 2001 and 2018. Each case was matched by birth year to two controls without a recorded migraine diagnosis. We first assessed partum outcomes including number of children, age at first birth, length of gestation, and interval between first and second pregnancy. We then analyzed postpartum outcomes including birth weight less than 2500 g, preterm delivery before 37 weeks, Apgar score less than 7 at 5 min, postpartum depression, and preeclampsia. RESULTS:Our inclusion criteria yielded a cohort of 49,318 women with migraine and 98,636 women without, of whom 37,455 had data in the birth register: 7198 with a diagnosis of migraine before pregnancy (MBP), 6575 with migraine after pregnancy (MAP), and 23,682 with no diagnosis of migraine. Overall, women with any diagnosis of migraine in the study window had an increased likelihood of having any births relative to women without migraine (adjusted odds ratio = 1.21, 95% confidence interval [CI] = 1.18-1.24; p < 0.001) and had 0.072 more children (95% CI = 0.063-0.081; p < 0.001). However, when stratified by whether the diagnosis of migraine occurred before or after pregnancy, women with MBP had 0.23 fewer children (95% CI = -0.24 to -0.21; p < 0.001), whereas those with MAP had 0.33 more children (95% CI = +0.30 to +0.35; p < 0.001). Similarly, women with MBP were older than controls (+0.52 years, 95% CI = +0.40 to +0.63; p < 0.001), whereas those with MAP were younger by 1.65 years (95% CI = -1.77 to -1.53; p < 0.001). Women with MBP waited less time between pregnancies (-0.69 years, 95% CI = -0.74 to -0.64; p < 0.001), whereas those with MAP waited longer (+0.82, 95% CI = +0.74 to +0.90; p < 0.001). Preterm deliveries were increased only in MBP with aura. Vaginal deliveries only decreased in those with MAP, whereas postpartum depression was increased in those with both MBP and MAP. Preeclampsia was increased in those with MBP only. CONCLUSION:Our study suggests that women in Sweden with MBP delay having children, have fewer children, and are at an older age than women without migraine, but may wait less time between pregnancies. Our study further confirms the increased risk of preeclampsia and postpartum depression in mothers with migraine as well as preterm delivery in infants born to mothers with migraine with aura.
OBJECTIVE:We aimed to evaluate multi-domain autonomic function in patients with spontaneous intracranial hypotension (SIH) and investigate its association with clinical and radiological features. BACKGROUND:SIH often presents with orthostatic symptoms that overlap with autonomic disorders; however, the prevalence and distribution of autonomic dysfunction in SIH remain poorly characterized. METHODS:In this cross-sectional study conducted at a tertiary care center in Seoul, Republic of Korea, 34 patients with imaging-confirmed SIH underwent a comprehensive autonomic function testing between October 2024 and February 2025. The autonomic function testing battery included heart rate response to deep breathing, Valsalva maneuver, head-up tilt test, and quantitative sudomotor axon reflex test. Hemodynamic responses during head-up tilt were monitored using both intermittent brachial and continuous beat-to-beat blood pressure measurements. Autonomic abnormalities were determined using age- and sex-matched Korean normative data. RESULTS:All enrolled patients presented with extradural fluid collection on spinal magnetic resonance imaging, indicating SIH due to dural tears. Autonomic dysfunction was identified in 18 of 34 (52.9%) of patients in the orthostatic domain, nine of 34 (26.5%) in the cardiovagal domain, and 10 of 34 (29.4%) in the sudomotor domain. Postural orthostatic tachycardia syndrome was the most frequent orthostatic abnormality, observed in 12 of 34 (35.3%) patients, followed by classical orthostatic hypotension in four of 34 (11.8%), syncope in one of 34 (2.9%), and delayed orthostatic hypotension in one of 34 (2.9%). No significant associations were identified between domains of autonomic dysfunction and the clinical or imaging features of SIH in false discovery rate-corrected analyses. CONCLUSION:In patients with SIH due to dural tears, orthostatic hemodynamic abnormalities were common, with postural orthostatic tachycardia syndrome being the most frequent phenotype.
OBJECTIVES/BACKGROUND:Migraine is a disabling neurological disorder with substantial interindividual variability. Predicting whether an ongoing migraine attack will persist into the following day remains challenging. We evaluated the feasibility and predictive performance of personalized machine learning models for predicting next-day migraine persistence using longitudinal digital headache diary data. METHODS:This prospective longitudinal cohort study was designed for prognostic prediction model development. Participants were recruited from two medical centers in Taiwan between February 2023 and October 2023, and each completed a 3-month digital headache diary observation period. Patients with 5-14 monthly headache days were included. Same-day diary records from index migraine days were used to predict next-day migraine persistence. Personalized and generalized models were developed using k-nearest neighbors (KNN), support vector machine, random forest, and eXtreme Gradient Boosting (XGBoost). Model performance was evaluated using discrimination, calibration, and sensitivity analyses. RESULTS:A total of 25 patients were included. Compared with the generalized KNN model, the personalized KNN model achieved significantly higher area under the curve (AUC) (0.83 ± 0.09 vs. 0.63 ± 0.04; ΔAUC = 0.20). Among personalized models, KNN also outperformed support vector machine, random forest, and eXtreme gradient boosting, with ΔAUC values of 0.23, 0.15, and 0.16, respectively; the corresponding Holm-adjusted p-values were <0.001, 0.003, and <0.001. The personalized KNN model showed the lowest Brier score (0.13 ± 0.04), with a calibration intercept of 0.08 and calibration slope of 0.80. Ablation analysis indicated that the KNN model performance was most sensitive to the removal of pain intensity, menstrual cycle status, perceived medication effectiveness, and pain location, with pain intensity showing the largest effect. CONCLUSION:Personalized machine learning models based on digital headache diary data may feasibly predict next-day persistence of ongoing migraine. Larger external validation studies are needed to confirm model generalizability and clinical applicability.
OBJECTIVE:To evaluate whether thyroid dysfunction, including hypothyroidism and hyperthyroidism, is associated with migraine across racial and age groups using a large, multinational electronic health record database. BACKGROUND:Thyroid disorders are highly prevalent worldwide, with hypothyroidism affecting over 200 million individuals and hyperthyroidism affecting approximately 2.5% of adults. Migraine is a leading cause of disability globally. Prior studies have suggested potential links between thyroid dysfunction and migraine, but evidence has been limited by small sample sizes, restricted population diversity, and inadequate control of confounding. Whether associations differ by thyroid subtype, race, or age remains unclear. METHODS:We performed two parallel retrospective cohort analyses within the TriNetX Global Collaborative Network, comprising over 200 million patients across 21 countries, using patient records from January 2004 to December 2024. Adults aged 18-100 years with hypothyroidism or hyperthyroidism, defined by ≥3 clinical encounters within 20 years, were identified. Individuals with psychiatric disorders (including mood, anxiety, and stress-related disorders), sleep disorders, epilepsy or recurrent seizures, or known migraine-related genetic mutations were excluded. Each thyroid cohort was compared with a control group without thyroid disease, with groups balanced on key demographic and clinical characteristics including age, sex, and hypertension; beta-blocker use was additionally considered in the hyperthyroidism cohort. The primary outcome was diagnosis of migraine (International Classification of Diseases, 10th Revision, code G43) within 5 years of index date. Subgroup analyses were conducted by race (Caucasian, African American/Black, Asian) and age (18-40, 40-65, 65-100 years). Sensitivity analyses assessed robustness to alternative visit thresholds and expanded covariate adjustment. RESULTS:A total of 33,327,750 patients were included in the hypothyroidism analysis and 28,182,377 in the hyperthyroidism analysis. Baseline differences between groups were minimized after cohort balancing. Hypothyroidism was associated with higher odds of migraine across all racial groups, strongest among African American/Black (odds ratio [OR] 2.04; 95% confidence interval [CI] 1.91-2.17), followed by White (OR 1.93; 95% CI 1.89-1.96) and Asian (OR 1.83; 95% CI 1.69-1.98). Hyperthyroidism was similarly associated with increased migraine odds, most prominently among White (OR 1.64; 95% CI 1.59-1.70), with smaller but significant associations in African American/Black (OR 1.28; 95% CI 1.14-1.44) and Asian (OR 1.18; 95% CI 1.07-1.29). Elevated odds were observed across all age strata, generally increasing with age. Findings were consistent in sensitivity analyses. CONCLUSION:In this large, multinational real-world study, both hypothyroidism and hyperthyroidism were independently associated with increased migraine prevalence across diverse racial and age groups. These results highlight thyroid dysfunction as an important comorbid condition in migraine and support further prospective and mechanistic investigation.
OBJECTIVE:This study aimed to identify predictors of epidural blood patch (EBP) success in patients with intracranial hypotension syndrome. BACKGROUND:The epidural blood patch remains the gold standard treatment for intracranial hypotension syndrome, yet its effectiveness varies, and predictors of sustained success remain uncertain. METHODS:We performed a single-center retrospective cohort study. We analyzed 139 epidural blood patches performed for non-obstetric intracranial hypotension syndrome between April 2015 and July 2025. Demographic, clinical, biological, radiological, and procedural data were collected. Complete symptom resolution or highly significant improvement at 1 month was defined as treatment success. RESULTS:Among 93 patients, 1-month complete success was achieved after 31% of procedures (43/139). Early improvement within 48 h was associated with higher odds of 1-month EBP success (adjusted odds ratio [aOR] = 9.70, 95% confidence interval [CI]: 3.66-28.96; p < 0.001) as was the occurrence of rebound headache (aOR = 5.34, 95% CI: 1.27-26.44; p = 0.028). Conversely, symptom exacerbation during the Valsalva maneuver was associated with lower odds of 1-month EBP success (aOR = 0.30, 95% CI: 0.10-0.81; p = 0.020). Lower baseline platelet and fibrinogen levels and osteophytic leaks were negatively associated with early effectiveness but not with 1-month outcome. Targeted epidural blood patches and shorter delay from symptom onset to procedure were associated with higher success rates in univariate analysis, though not independently. Model performance was robust with an area under the curve (AUC) of 0.88 (95% CI: 0.80-0.90). No infectious complications were observed; rebound headaches and transient back pain were the most common secondary events. CONCLUSION:Early clinical improvement and rebound headache are strong positive predictors of durable epidural blood patch effectiveness in intracranial hypotension syndrome, whereas Valsalva-related symptom worsening indicates a higher risk of failure. Radiological severity did not predict outcomes in our study. These easily identifiable clinical factors can assist in individualized management and reduce unnecessary repeat procedures.
OBJECTIVE:This study was conducted to characterize plasma arginine, histidine, 1-methylhistidine, and 3-methylhistidine in chronic migraine and to evaluate their discriminatory ability and association with early clinical response to onabotulinumtoxinA (BoNT-A). BACKGROUND:Alterations in nitric oxide- and histamine-related metabolic pathways may contribute to chronic migraine biology and may provide circulating biomarkers for disease stratification and treatment monitoring. Targeted liquid chromatography-tandem mass spectrometry profiling enables precise quantification of candidate amino acids and derivatives implicated in these pathways. METHODS:This retrospective secondary analysis was conducted as a case-control study with an embedded uncontrolled pre-post analysis and included 30 adults with chronic migraine receiving BoNT-A and 30 age- and sex-matched healthy controls from Istanbul Atlas University Hospital, based on clinical and laboratory data collected between May 15, 2023, and December 15, 2024. Plasma arginine, histidine, 1-methylhistidine, and 3-methylhistidine were quantified by liquid chromatography-tandem mass spectrometry. In the chronic migraine group, pain intensity (visual analog scale [VAS]) and monthly migraine attack frequency were assessed at baseline and 1 month after BoNT-A. Between-group comparisons and within-subject pre-post comparisons were performed, and exploratory analyses evaluated relationships between metabolite levels and clinical outcomes. RESULTS:At baseline, compared with controls, patients with chronic migraine had higher plasma arginine (57.3 ± 13.8 vs. 35.9 ± 10.1 μmol/L; p < 0.001) and 3-methylhistidine (1.0 ± 0.4 vs. 0.7 ± 0.4 μmol/L; p = 0.004), and lower histidine (51.7 ± 10.2 vs. 61.5 ± 6.8 μmol/L; p < 0.001); 1-methylhistidine did not differ significantly (p = 0.217). After BoNT-A, median VAS decreased from 8.0 (7.0-9.0) to 2.0 (0.0-3.0) (p < 0.001) and median monthly migraine attack frequency decreased from 11.0 (6.0-14.8) to 1.0 (0.0-1.8) (p < 0.001). Histidine increased from 54.10 μmol/L (45.27-59.81) to 60.23 μmol/L (57.87-64.45); p = 0.003) whereas 3-methylhistidine decreased from 0.85 μmol/L (0.69-1.23) to 0.66 μmol/L (0.59-0.83); p < 0.001). 1-Methylhistidine did not change significantly, with median values of 5.39 μmol/L (3.41-14.28) at baseline and 6.84 μmol/L (3.36-15.33) at month 1 (p = 0.658). Arginine also did not change significantly with median values of 56.74 μmol/L (46.56-65.95) at baseline and 52.83 μmol/L (44.22-66.30) at month 1 (p = 0.248). Change in histidine was not associated with ΔVAS, and exploratory regression analyses did not identify a robust independent association between baseline variables and pain reduction. In receiver operating characteristic analyses, histidine (area under the curve [AUC] = 0.79) and 3-methylhistidine (AUC = 0.71) showed moderate discrimination, whereas arginine showed higher apparent discrimination (AUC = 0.91). An exploratory combined biomarker model incorporating arginine, histidine, and 3-methylhistidine showed higher apparent discrimination (AUC = 0.94; leave-one-out cross-validated AUC = 0.92). CONCLUSION:Chronic migraine is associated with an arginine-histidine metabolic signature characterized by elevated arginine and 3-methylhistidine and reduced histidine. Early response to BoNT-A is accompanied by substantial clinical improvement and selective modulation of histidine-related metabolites. Histidine and 3-methylhistidine may have value as candidate biomarkers within a broader chronic migraine stratification framework, warranting validation in larger prospective cohorts.
