Robert P. Cowan

Introduction: Migraine is a prevalent and disabling neurological disorder with subtypes mainly classified and managed based on monthly headache frequency. This study investigates a novel, data-driven clustering approach that uses comprehensive clinical features in addition to headache frequency to further understand migraine subtyping and management. Methods: This cross-sectional observational study included participants with a diagnosis of migraine based on self-reported surveys recruited from the Stanford Headache Clinic and surrounding community between 2012 and 2020. This study represents a secondary analysis of a previously collected cohort, incorporating newly added episodic migraine (EM) data alongside existing clinical and demographic variables. This approach extends prior work to refine data-driven migraine subtyping. Participants completed comprehensive surveys capturing clinical, demographic, and treatment-related information. A data-driven clustering approach was applied using hierarchical agglomerative clustering. To determine the optimal number of clusters, visual inspection of the dendrogram, scree plot, and principal component analysis was used. Descriptive statistics and logistic regression models were used to explore clinical characteristics and medication outcomes for each cluster. Results: 180 participants were included in the clustering analysis. Two distinct clusters were identified and compared. Cluster 1 ( n = 66; chronic migraine (CM) = 62; EM = 4) had a significantly ( p ≤ 0.001) higher migraine frequency, greater migraine-related disability, higher pain catastrophizing, and more comorbidities (including anxiety, depression, sleep disorders, post-traumatic stress disorder, and somatic symptoms). Cluster 2 ( n = 114; CM = 68; EM = 46) had significantly ( p ≤ 0.001) more years with headache and higher levels of pain self-efficacy. Treatment response differed significantly between clusters for acute medications, with Cluster 2 showing more favorable response rates to triptans and non-steroidal anti-inflammatory drugs ( p ≤ 0.001) and a higher proportion of individuals who indicated that acute medication helped to improve their migraine compared to Cluster 1. Conclusion: This study supports the potential use of a comprehensive phenotype-based clustering approach to determine migraine subtypes that correlate with acute treatment outcome.

Background and ObjectivesThe ability to anticipate an impending migraine attack has the potential to improve patients' well-being, yet previous models have shown limited performance. The current st...

Background: Menstrual-related migraine (MRM) is a subtype of migraine that significantly impacts women. Despite its high prevalence, MRM remains under-researched compared to other migraine types. This study investigates the phenotypic characteristics and treatment outcomes of MRM compared to non-menstrual migraine (non-MRM). Methods: This cross-sectional study included women aged 18 years or older with a diagnosis of migraine and an established menstruation pattern. Informed consent was properly obtained from all participants from the Stanford Headache Clinic and surrounding community between 2014 and 2024 prior to participation in the study. Data were collected from self-reported surveys, including demographic information, headache characteristics, physical and mental health status, and treatment outcomes from the Stanford Headache Clinic and surrounding community. Participants were then categorized into MRM and non-MRM groups. An exploratory analysis was performed to investigate phenotypic features, treatment outcomes, and brain volume through magnetic resonance imaging (MRI) study for each group. Statistical analyses included descriptive statistics, analysis of covariance (ANCOVA), and logistic regression. Results: A total of 84 subjects were included, with 38 in the MRM group and 46 in the non-MRM group. The mean age of participants was 34 (SD = 9) years. The MRM group (mean age 38 ± 9) showed significantly higher prevalences of recent change in migraine frequency, migraine attacks occurring in the same site, prodromal signs, speech aura, nausea, and vomiting associated with migraine, and a higher prevalence of reported family history of headache as compared with the non-MRM group (mean age 31 ± 10) (p < 0.05). MRM group also showed significantly higher rate of migraine improvement following the use of triptans and the overall acute and preventive medications (p < 0.05). No significant differences were found in brain volumes between the groups (p > 0.05). Conclusion: The MRM group was associated with significantly more bothersome symptoms associated with migraine, higher family history of headache, and more favorable response to overall acute medication especially triptan as compared with the non-MRM group.

Background: Integrating brain structure and function may help characterize neurobiological heterogeneity in migraine alongside symptom presentation. Aim: To apply a multimodal, exploratory, data-driven approach to identify migraine subgroups using structural and functional MRI, and to describe the clinical characteristics of the resulting subgroups. Methods: Resting-state functional connectivity (FC) across cortical and subcortical regions, along with structural measures including cortical thickness, cortical volume, and subcortical volumes, were extracted from 111 individuals with migraine (75 chronic, 36 episodic) classified according to ICHD-3 criteria. After dimensionality reduction using principal component analysis, hierarchical agglomerative clustering was applied to identify multimodal imaging-derived subgroups. For comparison, secondary unimodal clustering models were constructed using functional-only and structural-only feature sets. The optimal number of clusters was determined using silhouette coefficients, and clustering concordance across models was quantified using the Adjusted Rand Index (ARI). Group differences in clinical characteristics, FC, and cortical and subcortical structure were assessed using covariate-adjusted statistical models with false discovery rate (FDR) correction. Results: Multimodal clustering identified two subgroups with distinct clinical and imaging profiles, Migraine Cluster 1 (M1 _{f + s} ) and Migraine Cluster 2 (M2 _{f + s} ). M2 _{f + s} showed older age, longer disease duration, greater migraine disability, widespread increases in cortical-subcortical FC (including Dorsal Attention, Somatomotor, and Visual networks), and reduced cortical volumes across frontal, parietal, temporal, and insular regions compared with M1 _{f + s} . This subgroup also exhibited increased connectivity relative to controls. In contrast, M1 _{f + s} showed preserved cortical structure and stronger Control-network–subcortical connectivity compared to M2 _{f + s} , and no significant functional or structural deviations from controls. Unimodal analyses revealed that Functional-only clustering aligned moderately with the multimodal cluster solution (ARI = 0.427), showing that FC was a primary determinant of the multimodal cluster structure, whereas structural-only clustering showed negligible overlap (ARI = 0.001), reflecting an orthogonal dimension of heterogeneity captured by structural variation. Conclusion: Data-driven multimodal neuroimaging-based clustering in migraine identified two subgroups with distinct clinical and imaging patterns, highlighting heterogeneity and providing a framework for further investigation of imaging-informed characterization.

Objective/Background: This study was undertaken to assess participants' impression of use and satisfaction with STS101 in a long‐term, open‐label safety study. The ASCEND study assessed the safety and tolerability of STS101, an investigational drug–device combination of 5.2 mg dihydroergotamine in a single‐use nasal delivery device for the acute treatment of migraine with/without aura, across 12 months. Methods: ASCEND (NCT04406649) was an open‐label, single‐arm, prospective interventional study in adults (18–65 years) with history of migraine from September 2020 to January 2023. Participants could self‐administer STS101 for ≤2 doses within 24 h to treat a single migraine attack and ≤12 doses/month. Data on patient global impression, ease‐of‐use impression, patient likelihood of use, and comparison of study medication with previously used migraine medication were collected at 3‐, 6‐, and 12‐month timepoints. Participants' ratings were assessed using a 5‐point Likert scale. Exploratory efficacy parameters (freedom from pain and most bothersome symptom) were recorded in participants' electronic diaries. Results: Overall, the majority of participants had favorable impressions of STS101, which were consistent across the assessments at 3‐, 6‐, and 12‐month timepoints. STS101 was considered easy or very easy to use by 92.3%, 92.9%, and 91.2% of participants at months 3, 6, and 12, respectively. After 3, 6, and 12 months of use, 78.9%, 80.5%, and 73.7% of participants indicated they were likely or very likely to use STS101 if it was available. When asked at the 3‐, 6‐, and 12‐month assessments to compare STS101 to their usual migraine medication, 63.9%, 74.1%, and 70.1% of participants agreed or strongly agreed that STS101 helped them return to normal faster than their usual medication. A total of 64.9%, 66.1%, and 69.3% of participants agreed or strongly agreed that STS101 worked faster and 67.0%, 73.7%, and 72.5% of participants agreed or strongly agreed that STS101 worked more consistently than their usual medication. Treatment with STS101 showed freedom from headache pain at 2, 4, 24, and 48 h postdose in 33.3%, 61.3%, 86.2%, and 91.1% of participants, respectively. Similar trends were seen in freedom from most bothersome symptom as reported by 53.3%, 78.0%, 91.9%, and 93.7% of participants at 2, 4, 24, and 48 h postdose, respectively. Conclusion: Participant impression data through 12 months suggest that STS101 was generally perceived as favorable by participants on multiple attributes. Most considered STS101 easy to use and indicated they would be likely to use the product if it were available. Exploratory efficacy evaluations indicated beneficial effects.

Spinal CSF leaks lead to spontaneous intracranial hypotension (SIH). While International Classification of Headache Disorders, Third Edition (ICHD-3) criteria necessitate imaging confirmation or low opening pressure (OP) for SIH diagnosis, their sensitivity may be limited. We offered epidural blood patches (EBPs) to patients with symptoms suggestive of SIH, with and without a documented low OP or confirmed leak on imaging. This study evaluates the efficacy of this strategy. We conducted a prospective cohort study with a nested case-control design including all patients who presented to a tertiary headache clinic with clinical symptoms of SIH who completed study measures both before and after receiving an EBP between August 2016 and November 2018. The mean duration of symptoms was 8.7 ± 8.1 years. Of 85 patients assessed, 69 did not meet ICHD-3 criteria for SIH. At an average of 521 days after the initial EBP, this ICHD-3-negative subgroup experienced significant improvements in Patient-Reported Outcomes Measurement Information System (PROMIS) Global Physical Health score of +3.3 (95% CI 1.5-5.1), PROMIS Global Mental Health score of +1.8 (95% CI 0.0-3.5), Headache Impact Test (HIT)-6 head pain score of -3.8 (95% CI -5.7 to -1.8), Neck Disability Index of -4.8 (95% CI -9.0 to -0.6) and PROMIS Fatigue of -2.3 (95% CI -4.1 to -0.6). Fifty-four percent of ICHD-3-negative patients achieved clinically meaningful improvements in PROMIS Global Physical Health and 45% in HIT-6 scores. Pain relief following lying flat prior to treatment was strongly associated with sustained clinically meaningful improvement in global physical health at an average of 521 days (odds ratio 1.39, 95% CI 1.1-1.79; p < 0.003). ICHD-3-positive patients showed high rates of response and previously unreported, treatable levels of fatigue and cognitive deficits. Patients who did not conform to the ICHD-3 criteria for SIH showed moderate rates of sustained, clinically meaningful improvements in global physical health, global mental health, neck pain, fatigue, and head pain after EBP therapy. Pre-treatment improvement in head pain when flat was associated with later, sustained improvement after EBP therapy among patients who did not meet the ICHD-3 criteria. This study provides Class IV evidence that epidural blood patch is an effective treatment of suspected CSF leak not conforming to ICHD-3 criteria for SIH.

This review focuses on the challenges of diagnosing and treating spontaneous intracranial hypotension (SIH), a condition caused by spinal CSF leakage. It emphasizes the need for increased awareness and advocates for early and thoughtful use of empirical epidural blood patches (EBPs) in suspected cases. SIH diagnosis is hindered by variable symptoms and inconsistent imaging results, including normal brain MRI and unreliable spinal opening pressures. It is crucial to consider SIH in differential diagnoses, especially in patients with connective tissue disorders. Early EBP intervention is shown to improve outcomes. SIH remains underdiagnosed and undertreated, requiring heightened awareness and understanding. This review promotes proactive EBP use in managing suspected SIH and calls for continued research to advance diagnostic and treatment methods, emphasizing the need for innovative imaging techniques for accurate diagnosis and timely intervention.

Objective: To highlight the emerging understanding of oxytocin (OT) and oxytocin receptors (OTRs) in modulating menstrual‐related migraine (MRM). Background: MRM is highly debilitating and less responsive to therapy, and attacks are of longer duration than nonmenstrually related migraine. A clear understanding of the mechanisms underlying MRM is lacking. Methods: We present a narrative literature review on the developing understanding of the role of OT and the OTR in MRM. Literature on MRM on PubMed/MEDLINE database including clinical trials and basic science publications was reviewed using specific keywords. Results: OT is a cyclically released hypothalamic hormone/neurotransmitter that binds to the OTR resulting in inhibition of trigeminal neuronal excitability that can promote migraine pain including that of MRM. Estrogen regulates OT release as well as expression of the OTR. Coincident with menstruation, levels of both estrogen and OT decrease. Additionally, other serum biochemical factors, including magnesium and cholesterol, which positively modulate the affinity of OT for OTRs, both decrease during menstruation. Thus, during menstruation, multiple menstrually associated factors may lead to decreased circulating OT levels, decreased OT affinity for OTR, and decreased expression of the trigeminal OTR. Consistent with the view of migraine as a threshold disorder, these events may collectively result in decreased inhibition promoting lower thresholds for activation of meningeal trigeminal nociceptors and increasing the likelihood of an MRM attack. Conclusion: Trigeminal OTR may thus be a novel target for the development of MRM therapeutics.

In March of 2020, the COVID‐19 pandemic led to drastic changes in clinical practice and teaching methods. This article relates the experience of developing an almost virtual headache fellowship in response to the pandemic.

The objective of this article is to compare acute primary headache patient outcomes in those initially treated with parenteral opiates or non-opiate recommended headache medications in a large academic medical emergency department (ED). Many acute primary headache patients are not diagnosed with a specific headache type and are treated with opiates and nonspecific pain medications in the ED setting. This is inconsistent with multiple expert recommendations. Electronic charts were reviewed from 574 consecutive patients who visited the ED for acute primary headache (identified by chief complaint and ICD9 codes) and were treated with parenteral medications. Non-opiate recommended headache medications were given first line to 52.6% and opiates to 22.8% of all participants. Patients given opiates first had significantly longer length of stays (median 5.0 vs. 3.9 hours, p < 0.001) and higher rates of return ED visits within seven days (7.6% vs. 3.0%, p = 0.033) compared with those given non-opiate recommended medications in univariate analysis. Only the association with longer length of stay remained significant in multivariable regression including possible confounding variables. Initial opiate use is associated with longer length of stay compared with non-opiate first-line recommended medications for acute primary headache in the ED. This association remained strong and significant even after multivariable adjustment for headache diagnosis and other possible confounders.