Robert P. Cowan, MD, FAAN, FAHS

All Publications

• Remote electrical neuromodulation for migraine prevention: A double-blind, randomized, placebo-controlled clinical trial. Headache Tepper, S. J., Rabany, L., Cowan, R. P., Smith, T. R., Grosberg, B. M., Torphy, B. D., Harris, D., Vizel, M., Ironi, A., Stark-Inbar, A., Blumenfeld, A. M. 2023

  Abstract

  OBJECTIVE: To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine.BACKGROUND: Preventive treatment is key to managing migraine, but it is often underutilized. REN, a non-pharmacological acute treatment for migraine, was evaluated as a method of migraine prevention in patients with episodic and chronic migraine.METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, multi-center trial, with 1:1 ratio. The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day. Throughout the study, participants reported their symptoms daily, via an electronic diary.RESULTS: Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0± SD of4.0days (1.3±4.0 in placebo, therapeutic gain=2.7 [confidence interval -3.9 to -1.5], p<0.001). The significance was maintained when analyzing the episodic (-3.2±3.4 vs. -1.0±3.6, p=0.003) and chronic (-4.7±4.4 vs. -1.6±4.4, p=0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8±3.9 vs. 2.2±3.6, p=0.005), reduction of headache days of all severities (4.5±4.1 vs. 1.8±4.6, p<0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p=0.033), and reduction in days of acute medication intake (3.5±4.1 vs. 1.4±4.3, p=0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group.CONCLUSION: Applied every other day, REN is effective and safe for the prevention of migraine.

  View details for DOI 10.1111/head.14469

  View details for PubMedID 36704988

• Eptinezumab improved patient-reported outcomes in patients with migraine and medication-overuse headache: Subgroup analysis of the randomized PROMISE-2 trial. Headache Starling, A. J., Cowan, R. P., Buse, D. C., Diener, H. C., Marmura, M. J., Hirman, J., Brevig, T., Cady, R. 2023

  Abstract

  To evaluate the effect of eptinezumab on patient-reported outcomes in patients with chronic migraine (CM) and medication-overuse headache (MOH).MOH is a secondary headache disorder commonly occurring in patients with CM and associated with functional and psychological impairments. Medication overuse and monthly headache and migraine days were reduced with eptinezumab compared with placebo as published previously; however, these outcomes do not fully capture the burden of migraine and treatment effect.PROMISE-2 was a phase 3, randomized, double-blind, placebo-controlled trial in adults with CM. Patients were randomized (1:1:1) to receive eptinezumab 100 mg, eptinezumab 300 mg, or placebo (up to 2 doses, 12 weeks apart). Patients completed the following patient-reported outcomes: 6-item Headache Impact Test (HIT-6), Patient Global Impression of Change (PGIC), patient-identified most bothersome symptom (PI-MBS), and 36-item Short-Form Health Survey (SF-36).A total of 431 CM patients (139, 147, and 145 patients in the eptinezumab 100 mg, eptinezumab 300 mg, and placebo groups, respectively) had MOH diagnosed at screening (40.2% of the total PROMISE-2 population [n = 1072]). In CM with MOH patients, both doses of eptinezumab were associated with clinically meaningful improvements in mean HIT-6 total scores by week 4 and remained improved throughout the 24-week study. Responder rates for individual HIT-6 items were greater with eptinezumab than with placebo at all time points. At week 12, almost twice as many eptinezumab-treated patients indicated the PGIC was "much" or "very much" improved (58.5% [79/135, 100 mg] and 67.4% [95/147, 300 mg] vs. 35.8% [48/134, placebo]). Patients in the eptinezumab groups showed numerically greater improvements over placebo in the PI-MBS and SF-36 scores.This subgroup analysis in patients with CM/MOH at baseline suggests that eptinezumab treatment is associated with early, sustained, and clinically meaningful improvements in patient-reported outcomes.

  View details for DOI 10.1111/head.14434

  View details for PubMedID 36633219

• Quantity changes in acute headache medication use among patients with chronic migraine treated with eptinezumab: subanalysis of the PROMISE-2 study. The journal of headache and pain Cowan, R. P., Marmura, M. J., Diener, H., Starling, A. J., Schim, J., Hirman, J., Brevig, T., Cady, R. 2022; 23 (1): 115

  Abstract

  BACKGROUND: Patients with chronic migraine (CM) treated with eptinezumab in the PROMISE-2 trial achieved greater reductions in migraine and headache frequency, impact, and acute headache medication (AHM) use than did patients who received placebo. This post hoc analysis examines relationships between headache frequency reductions and changes in AHM use in patients in PROMISE-2.METHODS: PROMISE-2 was a double-blind, placebo-controlled trial conducted in adults with CM. Patients were randomized to eptinezumab 100mg, 300mg, or placebo, administered intravenously once every 12weeks for up to two doses. Patients recorded headache/AHM information daily and for each event in an electronic diary; data from all days with daily reports were included. Shifts in headache frequency and AHM use were assessed in the three populations: total CM population, patients with CM and medication-overuse headache (MOH), and patients with CM and MOH who were≥50% responders during treatment (response over weeks 1-24).RESULTS: A total of 1072 adults with CM received treatment (eptinezumab, n=706; placebo, n=366). Mean baseline headache frequency was 20.5days; mean baseline AHM days was 13.4; 431 patients had MOH, of which 225 (52.2%) experienced ≥50% response over weeks 1-24. Relative to baseline, the proportion of days with both headache and AHM use decreased 25.1% (eptinezumab) versus 17.0% (placebo) in the total population (N=1072), 29.2% versus 18.4% in the MOH subpopulation (n=431), and 38.3% versus 31.5% in the CM with MOH population with ≥50% response subgroup (n=225) during weeks 1-24. The proportion of days with headache and triptan use decreased 9.1% (eptinezumab) versus 5.8% (placebo), 11.8% versus 7.2%, and 14.5% versus 12.6%, respectively. Reductions in other AHM types were smaller.CONCLUSIONS: In this post hoc analysis, eptinezumab use in patients with CM was associated with greater decreases in days with headache with AHM overall and with triptans in particular. The magnitude of effect was greater in the subgroup of CM patients with MOH and≥50% response.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02974153 . Eptinezumab reduces headache frequency and acute medication use in patients with chronic migraine.

  View details for DOI 10.1186/s10194-022-01482-0

  View details for PubMedID 36068494

• Three Dimensions of Association Link Migraine Symptoms and Functional Connectivity. The Journal of neuroscience : the official journal of the Society for Neuroscience Krimmel, S. R., DeSouza, D. D., Keaser, M. L., Sanjanwala, B. M., Cowan, R. P., Lindquist, M. A., Haythornthwaite, J. A., Seminowicz, D. A. 2022

  Abstract

  Migraine is a heterogeneous disorder with variable symptoms and responsiveness to therapy. Due to previous analytic shortcomings, variance in migraine symptoms has been inconsistently related to brain function. In the current analysis we used data from two sites (n=143, male and female humans), and performed Canonical Correlation Analysis (CCA), relating resting-state functional connectivity (RSFC) with a broad range of migraine symptoms ranging from headache characteristics to sleep abnormalities. This identified three dimensions of covariance between symptoms and RSFC. The first dimension related to headache intensity, headache frequency, pain catastrophizing, affect, sleep disturbances, and somatic abnormalities, and was associated with frontoparietal and dorsal attention network connectivity, both of which are major cognitive networks. Additionally, RSFC scores from this dimension - both the baseline value and the change from baseline to post-intervention - were associated with responsiveness to mind-body therapy. The second dimension was related to an inverse association between pain and anxiety, and to default mode network connectivity. The final dimension was related to pain catastrophizing, and salience, sensorimotor and default mode network connectivity. In addition to performing CCA, we evaluated the current clustering of migraine patients into episodic and chronic subtypes, and found no evidence to support this clustering. However, when using RSFC scores from the three significant dimensions, we identified a novel clustering of migraine patients into four biotypes with unique functional connectivity patterns. These findings provide new insight into individual variability in migraine, and could serve as the foundation for novel therapies that take advantage of migraine heterogeneity.SIGNIFICANCE STATEMENTUsing a large multi-site dataset of migraine patients we identified three dimensions of multivariate association between symptoms and functional connectivity. This analysis revealed neural networks that relate to all measured symptoms, but also to specific symptom ensembles, such as patient propensity to catastrophize painful events. Using these three dimensions, we found four biotypes of migraine informed by clinical and neural variation together. Such findings pave the way for precision medicine therapy for migraine.

  View details for DOI 10.1523/JNEUROSCI.1796-21.2022

  View details for PubMedID 35768210

• Diagnostic accuracy of an artificial intelligence online engine in migraine: A multi-center study. Headache Cowan, R. P., Rapoport, A. M., Blythe, J., Rothrock, J., Knievel, K., Peretz, A. M., Ekpo, E., Sanjanwala, B. M., Woldeamanuel, Y. W. 2022

  Abstract

  OBJECTIVE: This study assesses the concordance in migraine diagnosis between an online, self-administered, Computer-based, Diagnostic Engine (CDE) and semi-structured interview (SSI) by a headache specialist, both using International Classification of Headache Disorders, 3rd edition (ICHD-3) criteria.BACKGROUND: Delay in accurate diagnosis is a major barrier to headache care. Accurate computer-based algorithms may help reduce the need for SSI-based encounters to arrive at correct ICHD-3 diagnosis.METHODS: Between March 2018 and August 2019, adult participants were recruited from three academic headache centers and the community via advertising to our cross-sectional study. Participants completed two evaluations: phone interview conducted by headache specialists using the SSI and a web-based expert questionnaire and analytics, CDE. Participants were randomly assigned to either the SSI followed by the web-based questionnaire or the web-based questionnaire followed by the SSI. Participants completed protocols a few minutes apart. The concordance in migraine/probable migraine (M/PM) diagnosis between SSI and CDE was measured using Cohen's kappa statistics. The diagnostic accuracy of CDE was assessed using the SSI as reference standard.RESULTS: Of the 276 participants consented, 212 completed both SSI and CDE (study completion rate=77%; median age=32years [interquartile range: 28-40], female:male ratio=3:1). Concordance in M/PM diagnosis between SSI and CDE was: kappa=0.83 (95% confidence interval [CI]: 0.75-0.91). CDE diagnostic accuracy: sensitivity=90.1% (118/131), 95% CI: 83.6%-94.6%; specificity=95.8% (68/71), 95% CI: 88.1%-99.1%. Positive and negative predictive values=97.0% (95% CI: 91.3%-99.0%) and 86.6% (95% CI: 79.3%-91.5%), respectively, using identified migraine prevalence of 60%. Assuming a general migraine population prevalence of 10%, positive and negative predictive values were 70.3% (95% CI: 43.9%-87.8%) and 98.9% (95% CI: 98.1%-99.3%), respectively.CONCLUSION: The SSI and CDE have excellent concordance in diagnosing M/PM. Positive CDE helps rule in M/PM, through high specificity and positive likelihood ratio. A negative CDE helps rule out M/PM through high sensitivity and low negative likelihood ratio. CDE that mimics SSI logic is a valid tool for migraine diagnosis.

  View details for DOI 10.1111/head.14324

  View details for PubMedID 35657603

• Changes in Acute Headache Medication Use Among Patients With Chronic Migraine and Medication Overuse Headache: An Exploratory Analysis of PROMISE-2 Cowan, R., Marmura, M. J., Diener, H., Starling, A. J., Schim, J., Hirman, J., Brevig, T., Cady, R. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for Web of Science ID 000894020500125

• PREDICTIVE ENRICHMENT TO IDENTIFY RESPONSE TO SLEEP INTERVENTION IN CANCER SURVIVORS WITH HEADACHE - A PRECISION MEDICINE STUDY Woldeamanuel, Y. W., Kushida, C. A., Kesler, S., Jo, B., Neri, E., Edwards, K. S., Gore-Felton, C., Blayney, D. W., Cowan, R. P., Palesh, O. OXFORD UNIV PRESS INC. 2022: S523

  View details for Web of Science ID 000788118601467

• Computerized migraine diagnostic tools: a systematic review Therapeutic Advances in Chronic Disease. Woldeamanuel, Y. W., Cowan, R. P. 2022

  View details for DOI 10.1177/20406223211065235

• Preventive migraine treatment with eptinezumab reduced acute headache medication and headache frequency to below diagnostic thresholds in patients with chronic migraine and medication-overuse headache. Headache Marmura, M. J., Diener, H., Cowan, R. P., Tepper, S. J., Diamond, M. L., Starling, A. J., Hirman, J., Mehta, L., Brevig, T., Cady, R. 2021

  Abstract

  OBJECTIVE: This post hoc analysis in patients medically diagnosed with chronic migraine (CM) and medication-overuse headache (MOH) evaluated reductions in the use of acute headache medication (AHM) and sustained changes in the diagnostic status of CM and MOH following eptinezumab treatment in the PROMISE-2study.BACKGROUND: Eptinezumab, a monoclonal antibody that inhibits calcitonin gene-related peptide, is approved in the United States for the preventive treatment of migraine. A previous analysis showed that eptinezumab reduced monthly migraine days and was well tolerated in the subgroup of PROMISE-2 patients diagnosed with both CM and MOH.METHODS: The phase 3, double-blind, placebo-controlled PROMISE-2study (NCT02974153) randomized adults with CM to eptinezumab 100 mg, 300mg, or placebo (administered intravenously every 12weeks for up to two doses). MOH was prospectively diagnosed at screening by trained physicians based on 3months of medication history and International Classification of Headache Disorders-3beta criteria. This post hoc analysis evaluated changes in total and class-specific days of AHM usage, the percentage of patients using AHM at or above MOH diagnostic thresholds, and the percentage of patients experiencing monthly headache and migraine day frequency below diagnostic thresholds for MOH and/or CM.RESULTS: In PROMISE-2, 431/1072 (40.2%) patients with CM were diagnosed with MOH (eptinezumab 100mg, n=139; 300mg, n=147; placebo, n=145) and were included in this analysis. Total monthly AHM use decreased from 20.6days/month at baseline to 10.6days/month over 24weeks of treatment (49% decrease) with eptinezumab 100mg, from 20.7 to 10.5days/month (49% decrease) with eptinezumab 300mg, and from 19.8 to 14.0days/month (29% decrease) with placebo. Numerically greater decreases from baseline with eptinezumab were also observed for individual drug classes. In each study month, the percentages of patients who were below MOH thresholds were numerically higher for both eptinezumab doses compared with placebo, as were the percentages of patients experiencing headache and migraine frequency below CM thresholds. Of patients with available data across the entire treatment period, 29.0% (58/200) of patients treated with eptinezumab stopped meeting and remained below diagnostic thresholds for both CM and MOH during Weeks 1-24, as well as 6.3% (6/96) of patients who received placebo.CONCLUSIONS: Across 24weeks of treatment, eptinezumab reduced AHM use in patients diagnosed with CM and MOH. More than one-fourth (29%) of patients treated with eptinezumab did not meet the diagnostic thresholds for either CM or MOH for the entire treatment period.

  View details for DOI 10.1111/head.14206

  View details for PubMedID 34551130

• A new hypothesis linking oxytocin to menstrual migraine. Headache Bharadwaj, V. N., Porreca, F., Cowan, R. P., Kori, S., Silberstein, S. D., Yeomans, D. C. 2021

  Abstract

  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.

  View details for DOI 10.1111/head.14152

  View details for PubMedID 34125955

• Understanding the Impact of Sex and Race on the Migraine Patient's Journey in the United States: Analyses From an Annual Cross-Sectional Patient Chart Audit Cowan, R., Stabb, M., Robinson, N., Schobel, V. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283601309

• Altered Functional Network Connectivity in Chronic Migraine: a Replication-Extension Study DeSouza, D., Hindiyeh, N., Sanjanwala, B., Krimmel, S., Seminowicz, D., Cowan, R. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for Web of Science ID 000729283605040

• A patient perspective of complementary and integrative medicine (CIM) for migraine treatment: a social media survey. BMC complementary medicine and therapies Kuruvilla, D. E., Mehta, A., Ravishankar, N., Cowan, R. P. 2021; 21 (1): 58

  Abstract

  To survey persons with migraine who use social media about Complementary and Integrative Medicine (CIM) for the treatment of migraine.BACKGROUND: CIM encompasses medical treatments that are not part of but are used in concert with mainstream medicine. Between 28 and 82% of people with migraine use non-drug approaches, and approximately 50% of people with migraine do not discuss non-drug treatments with their healthcare providers (HCPs). It is important for providers to be conversant with CIM treatments and the available evidence-based data. To further this effort, people with migraine were surveyed directly through social media to identify CIM practices in which they engage.METHODS: In collaboration with the American Migraine foundation (AMF) and Yakkety Yak, a digital marketing agency, we conducted a cross-sectional survey study. Participants were recruited from the Move Against Migraine(MAM) Facebook group which has 20,000+ members. The goals of the survey were to assess the attitudes toward CIM among this group, to identify which CIM modalities are being used and to determine what patients considered to be the most effective CIM modalities. While Yakkety Yak posted the survey link on the group page, the survey itself was hosted on Qualtrics, a confidential survey service.RESULTS: 372 MAM members (approximately 2%) responded to the questionnaire, of which 335 reported using CIM; between 114 and 139 (34-42%) found CIM modalities to be at least mildly effective. Of note, 164 (49%) reported using cannabis derivatives or cannabinoids, specifically with, 64/164 (39%) reporting that cannabis was not effective for them.CONCLUSIONS: This study provides an initial investigation into the demographic and practice patterns of migraine patients who use CIM. While this sampling may not reflect CIM use across all individuals with migraine, it does strongly suggest the need for better education on the role of, and evidence for, CIM among headache care providers, and the need to ask patients specifically about their use of and interest in CIM.

  View details for DOI 10.1186/s12906-021-03226-0

  View details for PubMedID 33568112

• Evaluation of the 6-item Identify Chronic Migraine screener in a large medical group. Headache Pavlovic, J. M., Yu, J. S., Silberstein, S. D., Reed, M. L., Cowan, R. P., Dabbous, F., Pulicharam, R., Viswanathan, H. N., Lipton, R. B. 2021

  Abstract

  OBJECTIVE: To evaluate the sensitivity and specificity of the 6-item Identify Chronic Migraine screener (ID-CM[6]), designed to improve the detection of chronic migraine (CM).BACKGROUND: CM is often undertreated and underdiagnosed. Survey-based studies have found that approximately 75-80% of people meeting criteria for CM do not report having received an accurate diagnosis.METHODS: This study used claims data of patients enrolled in a large medical group who had at least one medical claim with an International Classification of Diseases 9th/10th revision diagnostic code for migraine in the 12-month prescreening period. The Identify Chronic Migraine survey was administered by e-mail, in-person, or over the telephone to all enrolled patients. A Semi-Structured Diagnostic Interview (SSDI) was administered by telephone by a trained physician. The ID-CM(6) and SSDI classifications of CM status were compared to evaluate sensitivity and specificity of the ID-CM(6) screening tool.RESULTS: The analysis of the ID-CM(6) screening tool included 109 patients, with 65/109 (59.6%) positive for CM based on the SSDI. The mean (standard deviation) age of the patient sample was 49 (15) years and 100/109 (91.7%) were female. Using the SSDI as the diagnostic gold standard, the ID-CM(6) had a sensitivity of 70.8% (46/65) and a specificity of 93.2% (41/44).CONCLUSION: The ID-CM(6) demonstrated acceptable sensitivity and good specificity in determining CM status. The results of this analysis support the real-world utility of the ID-CM(6) as a simple and useful tool to identify patients with CM.

  View details for DOI 10.1111/head.14035

  View details for PubMedID 33421098

• Evidence that blood-CSF barrier transport, but not inflammatory biomarkers, change in migraine, while CSF sVCAM1 associates with migraine frequency and CSF fibrinogen. Headache Cowan, R. P., Gross, N. B., Sweeney, M. D., Sagare, A. P., Montagne, A. n., Arakaki, X. n., Fonteh, A. N., Zlokovic, B. V., Pogoda, J. M., Harrington, M. G. 2021

  Abstract

  Our objective is to explore whether blood-cerebrospinal fluid (CSF) barrier biomarkers differ in episodic migraine (EM) or chronic migraine (CM) from controls.Reports of blood-brain barrier and blood-cerebrospinal fluid barrier (BCSFB) disruption in migraine vary. Our hypothesis is that investigation of biomarkers associated with blood, CSF, brain, cell adhesion, and inflammation will help elucidate migraine pathophysiology.We recruited 14 control volunteers without headache disorders and 42 individuals with EM or CM as classified using the International Classification of Headache Disorders, 3rd edition, criteria in a cross-sectional study located at our Pasadena and Stanford headache research centers in California. Blood and lumbar CSF samples were collected once from those diagnosed with CM or those with EM during two states: during a typical migraine, before rescue therapy, with at least 6/10 level of pain (ictal); and when migraine free for at least 48 h (interictal). The average number of headaches per month over the previous year was estimated by those with EM; this enabled comparison of biomarker changes between controls and three headache frequency groups: <2 per month, 2-14 per month, and CM. Blood and CSF biomarkers were determined using antibody-based methods.Antimigraine medication was only taken by the EM and CM groups. Compared to controls, the migraine group had significantly higher mean CSF-blood quotients of albumin (Qalb : mean ± standard deviation (SD): 5.6 ± 2.3 vs. 4.1 ± 1.9) and fibrinogen (Qfib mean ± SD: 1615 ± 99.0 vs. 86.1 ± 55.0). Mean CSF but not plasma soluble vascular cell adhesion molecule-1 (sVCAM-1) levels were significantly higher in those with more frequent migraine: (4.5 ng/mL ± 1.1 in those with <2 headache days a month; 5.5 ± 1.9 with 2-14 days a month; and 7.1 ± 2.9 in CM), while the Qfib ratio was inversely related to headache frequency. We did not find any difference in individuals with EM or CM from controls for CSF cell count, total protein, matrix metalloproteinase-9, soluble platelet-derived growth factor receptor β, tumor necrosis factor-alpha, interferon-gamma, interleukin (IL)-6, IL-8, IL-10, or C-reactive protein.The higher Qalb and Qfib ratios may indicate that the transport of these blood-derived proteins is disturbed at the BCSFB in persons with migraine. These changes most likely occur at the choroid plexus epithelium, as there are no signs of typical endothelial barrier disruption. The most striking finding in this hypothesis-generating study of migraine pathophysiology is that sVCAM-1 levels in CSF may be a biomarker of higher frequency of migraine and CM. An effect from migraine medications cannot be excluded, but there is no known mechanism to suggest they have a role in altering the CSF biomarkers.

  View details for DOI 10.1111/head.14088

  View details for PubMedID 33724462

• Plasma Lipolysis and Changes in Plasma and Cerebrospinal Fluid Signaling Lipids Reveal Abnormal Lipid Metabolism in Chronic Migraine. Frontiers in molecular neuroscience Castor, K., Dawlaty, J., Arakaki, X., Gross, N., Woldeamanuel, Y. W., Harrington, M. G., Cowan, R. P., Fonteh, A. N. 2021; 14: 691733

  Abstract

  Background: Lipids are a primary storage form of energy and the source of inflammatory and pain signaling molecules, yet knowledge of their importance in chronic migraine (CM) pathology is incomplete. We aim to determine if plasma and cerebrospinal fluid (CSF) lipid metabolism are associated with CM pathology.Methods: We obtained plasma and CSF from healthy controls (CT, n = 10) or CM subjects (n = 15) diagnosed using the International Headache Society criteria. We measured unesterified fatty acid (UFA) and esterified fatty acids (EFAs) using gas chromatography-mass spectrometry. Glycerophospholipids (GP) and sphingolipid (SP) levels were determined using LC-MS/MS, and phospholipase A2 (PLA2) activity was determined using fluorescent substrates.Results: Unesterified fatty acid levels were significantly higher in CM plasma but not in CSF. Unesterified levels of five saturated fatty acids (SAFAs), eight monounsaturated fatty acids (MUFAs), five omega-3 polyunsaturated fatty acids (PUFAs), and five omega-6 PUFAs are higher in CM plasma. Esterified levels of three SAFAs, eight MUFAs, five omega-3 PUFAs, and three omega-6 PUFAs, are higher in CM plasma. The ratios C20:4n-6/homo-gamma-C20:3n-6 representative of delta-5-desaturases (D5D) and the elongase ratio are lower in esterified and unesterified CM plasma, respectively. In the CSF, the esterified D5D index is lower in CM. While PLA2 activity was similar, the plasma UFA to EFA ratio is higher in CM. Of all plasma GP/SPs detected, only ceramide levels are lower (p = 0.0003) in CM (0.26 ± 0.07%) compared to CT (0.48 ± 0.06%). The GP/SP proportion of platelet-activating factor (PAF) is significantly lower in CM CSF.Conclusions: Plasma and CSF lipid changes are consistent with abnormal lipid metabolism in CM. Since plasma UFAs correspond to diet or adipose tissue levels, higher plasma fatty acids and UFA/EFA ratios suggest enhanced adipose lipolysis in CM. Differences in plasma and CSF desaturases and elongases suggest altered lipid metabolism in CM. A lower plasma ceramide level suggests reduced de novo synthesis or reduced sphingomyelin hydrolysis. Changes in CSF PAF suggest differences in brain lipid signaling pathways in CM. Together, this pilot study shows lipid metabolic abnormality in CM corresponding to altered energy homeostasis. We propose that controlling plasma lipolysis, desaturases, elongases, and lipid signaling pathways may relieve CM symptoms.

  View details for DOI 10.3389/fnmol.2021.691733

  View details for PubMedID 34531722

• Neuropathic pain in Mali: The current situation, comprehensive hypothesis, which therapeutic strategy for Africa? eNeurologicalSci Maiga, Y. n., Sangho, O. n., Konipo, F. n., Diallo, S. n., Coulibaly, S. D., Sangare, M. n., Péréon, Y. n., Giumelli, B. n., Sanou, M. n., Coulibaly, A. n., Diallo, S. n., Daou, M. n., Traoré, Z. n., Albakaye, M. n., Traoré, H. A., Guinto, C. O., Ouologem, M. n., Kuate-Tegueu, C. n., Bouhassira, D. n., Cowan, R. n., Nizard, J. n. 2021; 22: 100312

  Abstract

  According to the taxonomy of the International Association for the Study of Pain (IASP 2011), neuropathic pain (NeuP) is defined as "pain caused by a lesion or disease of the somatosensory nervous system". NeuP is currently well-defined clinically, despite a high degree of etiological variation, and it has become a significant public health problem. This work aimed to study the situation regarding NeuP in current practice in Mali, as well as to analyze the therapeutic environment of the patients.This was a retrospective and cross-sectional study, carried out in two phases: (1) compilation of the files of patients according to the ICD-11, over a period of 24 months (2) a second prospective phase regarding the Knowledge, Attitudes, and Practices (KAP) of general practitioners and neurologists in regard to NeuP. The focus of the first phase of the study was the files of the patients who had undergone a consultation at the Gabriel Touré UHC. The second phase of the study focused on the general practitioners (Community Health Centers (comHC) of Bamako) and neurologists (Malian or not).Over the period of the study, 7840 patients were seen in consultation in the Department of Neurology, of whom 903 for NeuP, thus amounting to a NeuP frequency of 11.5%. Women accounted for 58.9% (532/903), with a sex ratio of 1.4. Using a comparative normal law, the difference in frequency was statistically significant between males and females (p < 10-7) and between two age groups (p 〈10-3). The 49-58 years of age group was represented the most. Diabetic NeuP (21%), lumbar radiculopathies (14%), HIV/AIDS NeuP (13%), and post-stroke NeuP (11%) were the most represented. The survey among the carers revealed: a need for training, a low level of compliance with the therapeutic guidelines, and the use of traditional medicine by the patients.This work confirms that NeuP is encountered frequently in current practice, and its optimal management will involve specific training of carers and improvement of access to the medications recommended in this indication. In light of this issue, we revisit the debate regarding the concept of essential medications and the relevance of taking into account effective medications for the treatment of NeuP.

  View details for DOI 10.1016/j.ensci.2021.100312

  View details for PubMedID 33537467

  View details for PubMedCentralID PMC7841313

• Efficacy, tolerability, and safety of eptinezumab in patients with a dual diagnosis of chronic migraine and medication-overuse headache: Subgroup analysis of PROMISE-2. Headache Diener, H., Marmura, M. J., Tepper, S. J., Cowan, R., Starling, A. J., Diamond, M. L., Hirman, J., Mehta, L., Brevig, T., Sperling, B., Cady, R. 2020

  Abstract

  OBJECTIVE: To evaluate the efficacy, tolerability, and safety of eptinezumab 100 and 300mg compared with placebo in patients with the dual diagnosis of chronic migraine (CM) and medication-overuse headache (MOH).BACKGROUND: Eptinezumab, a humanized monoclonal antibody targeting calcitonin gene-related peptide, may be effective for treating patients with a dual diagnosis of CM and MOH.METHODS: PROMISE-2 (NCT02974153) was a double-blind, randomized, placebo-controlled, phase 3 study that comprised a screening visit, a 28-day pretreatment period, and a 32-week study duration. Patients in this exploratory analysis of a prespecified subgroup had confirmed diagnoses of both CM and MOH at screening. Patients were randomly assigned to receive intravenous eptinezumab 100, 300mg, or placebo every 12weeks. Efficacy outcomes included mean changes from baseline in monthly migraine days (MMDs) during weeks 1-12, migraine responder rates at week 12, and percentages of patients below International Classification of Headache Disorders thresholds for CM and MOH over weeks 1-24.RESULTS: There were 431 patients who were diagnosed with CM and MOH as specified in the protocol and received eptinezumab 100mg (n=139), 300mg (n=147), or placebo (n=145). During the baseline period, these patients experienced an average of 16.7 migraine days across treatment arms. Over weeks 1-12, eptinezumab-treated patients experienced greater reductions from baseline in MMDs than placebo patients (100mg, change from baseline=-8.4, difference from placebo [95% confidence interval (CI)]=-3.0 [-4.56, -1.52], p<0.0001 vs. placebo; 300mg, change from baseline=-8.6, difference from placebo [95% CI]=-3.2 [-4.66, -1.78], p<0.0001 vs. placebo; placebo, -5.4). Compared with placebo, more eptinezumab-treated patients were ≥50% migraine responders (100mg, 84/139 [60.4%]; 300mg, 91/147 [61.9%]; placebo, 50/145 [34.5%]) or ≥75% responders (100mg, 38/139 [27.3%]; 300mg, 44/147 [29.9%]; placebo, 21/145 [14.5%]) over weeks 1-12. Therapeutic benefits with eptinezumab were observed from day 1 after dosing, and improvements were sustained with an additional dose. For the full 24-week treatment period, 71/139 (51.1%), 80/147 (54.4%), and 47/145 (32.4%) of 100, 300mg, and placebo-treated patients, respectively, were below CM thresholds, and of the patients who provided sufficient acute medication data, 47/93 (50.5%), 53/107 (49.5%), and 26/96 (27.1%), respectively, were below medication-overuse thresholds.CONCLUSIONS: In patients diagnosed with both CM and MOH, eptinezumab treatment resulted in greater reductions in MMDs, higher responder rates, and fewer patients meeting CM and MOH criteria, thus demonstrating the efficacy and clinical utility of eptinezumab in this patient population.

  View details for DOI 10.1111/head.14036

  View details for PubMedID 33314079

• Estimating the Economic Burden of Migraine on US Employers AMERICAN JOURNAL OF MANAGED CARE Yucel, A., Thach, A., Kumar, S., Loden, C., Bensink, M., Goldfarb, N., Cowan, R. 2020; 26 (12): E403-+

  Abstract

  Migraine is a leading cause of disability globally. Individuals with migraine experience reduced work productivity and greater health care costs compared with the general population. The Migraine Impact Model (MIM) is an interactive calculator developed to estimate the economic burden of migraine on United States-based employers. We demonstrate use of the model with 4 case studies from different industries (education, manufacturing, retail/trade, and entertainment). The MIM estimates migraine prevalence among employees and the employer's annual migraine-associated costs by applying published, licensed, and publicly available data and several underlying assumptions to employee population information that is inputted by users. User inputs include the employer's industry, geographic location, and workforce characteristics (number of employees, gender distribution, and average age and compensation). Model outputs include estimated migraine prevalence, annual workdays affected by migraine, and annual migraine-associated indirect and direct costs to the employer. In the case studies presented, workforce size ranged from 18,800 to 250,000, representing midsized to larger employers. Employee gender distribution ranged from 29% to 74% women, and mean employee age was either 41 or 44 years. The model-estimated percentage of employees with migraine ranged from 14% to 19%. The model projected approximately 60,000 to 686,000 annual workdays to be affected by lost productive time due to migraine (often referred to as "absenteeism" and "presenteeism") and estimated annual indirect costs to total between 6.2 and 8.5 times the annual direct costs. The MIM estimates the economic burden of migraine on a company's workforce, which may aid employers in making data-driven decisions to reduce that burden for employees and business.

  View details for DOI 10.37765/ajmc.2020.88547

  View details for Web of Science ID 000600435800006

  View details for PubMedID 33315334

• Reimagining Headache Fellowships. Headache Zhang, N., Chan, T. L., Cowan, R. 2020

  Abstract

  InMarch 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.

  View details for DOI 10.1111/head.13965

  View details for PubMedID 32979226

• Improvements across a range of patient-reported domains with fremanezumab treatment: results from a patient survey study. The journal of headache and pain Buse, D. C., Gandhi, S. K., Cohen, J. M., Ramirez-Campos, V., Cloud, B., Yang, R., Cowan, R. P. 2020; 21 (1): 109

  Abstract

  BACKGROUND: The long-term safety and efficacy of fremanezumab were evaluated in a 52-week extension study (NCT02638103). Patient satisfaction with fremanezumab, dosing preferences, and patient-reported outcomes were assessed in a subpopulation who completed the extension study and consented to a follow-up questionnaire.METHODS: In the extension study (N=1842), adults with migraine were randomized to quarterly or monthly fremanezumab. After completing active treatment, patients answered a survey evaluating patient satisfaction, treatment and dosing preferences, and changes in patient-reported outcomes.RESULTS: Of the 557 patients who could have been contacted upon completing the extension study, 302 consented and 253 completed the survey. The mean (standard deviation) satisfaction rating for fremanezumab was 6.1 (1.4; 1="extremely dissatisfied" to 7="extremely satisfied"). Most patients (175 [69.2%]) preferred quarterly over monthly fremanezumab dosing. Among patients taking antiepileptics (most common class of prior preventive medication; n=130), 91.5% preferred fremanezumab. Patients reported improvements in anxiety (74 [67.9%]), sleep quality (143 [56.5%]), and quality of time spent with others (210 [83.0%]) with fremanezumab.CONCLUSION: In this study, treatment satisfaction with fremanezumab was high, most patients preferred quarterly fremanezumab dosing, and fremanezumab was generally preferred to prior preventive medications.TRIAL REGISTRATION: ClinicalTrials.gov NCT02638103 (HALO LTS), registered December 22, 2015.

  View details for DOI 10.1186/s10194-020-01177-4

  View details for PubMedID 32887548

• Endogenous glucocorticoids may serve as biomarkers for migraine chronification. Therapeutic advances in chronic disease Woldeamanuel, Y. W., Sanjanwala, B. M., Cowan, R. P. 2020; 11: 2040622320939793

  Abstract

  The aims of this study were to: (a) identify differences in serum and cerebrospinal fluid (CSF) glucocorticoids among episodic migraine (EM) and chronic migraine (CM) patients compared with controls; (b) determine longitudinal changes in serum glucocorticoids in CM patients; and (c) determine migraine-related clinical features contributing to glucocorticoid levels.Serum and CSF levels of cortisol and corticosterone were measured using liquid chromatography-mass spectrometry among adult patients with EM, CM, and controls. Serum and CSF samples were collected from 26 and four participants in each group, respectively. Serum glucocorticoids were measured at a second timepoint after 2 years among 10 of the CM patients, six of whom reverted to EM while four persisted as CM. Receiver operating characteristic (ROC) analysis was made to assess the migraine diagnostic performance of glucocorticoids. Regression analysis was conducted to determine the link between glucocorticoid levels and migraine-related clinical variables.CM patients exhibited significantly elevated serum and CSF levels of cortisol and corticosterone compared with controls and EM patients (age, sex, body mass index adjusted; Kruskal-Wallis p < 0.05). ROC showed area-under-curve of 0.89 to differentiate CM from EM. CM patients with remission had their serum glucocorticoids return to control or near EM levels (p < 0.05). Persistent CM showed unremitting serum glucocorticoids. Migraine frequency and disability contributed to increased cortisol, while pain self-efficacy predicted lower cortisol levels (p < 0.005).Endogenous glucocorticoids may be biomarkers for migraine progression and for monitoring treatment response. Improving pain self-efficacy skills may help optimize endogenous glucocorticoid levels, which in turn may prevent migraine attacks.

  View details for DOI 10.1177/2040622320939793

  View details for PubMedID 32973989

  View details for PubMedCentralID PMC7495027

• Insights into chronic migraine pathophysiology - what measures of gray matter reveal. Cephalalgia : an international journal of headache DeSouza, D. D., Cowan, R. P. 2020: 333102420933263

  View details for DOI 10.1177/0333102420933263

  View details for PubMedID 32536267

• Calcitonin Gene-Related Peptide Receptor Antagonists (Gepants) for the Acute Treatment of Nausea in Episodic Migraine: A Systematic Review and Meta-Analysis. Headache Chan, T. L., Cowan, R. P., Woldeamanuel, Y. W. 2020

  Abstract

  OBJECTIVE: To synthesize the evidence on the efficacy of calcitonin gene-related peptide receptor antagonists (gepants) from all clinical trials addressing nausea treatment for episodic migraine.INTRODUCTION: Nausea is one of the most bothersome symptoms in patients with migraine. The most bothersome symptom is part of the outcomes explored in clinical trials.METHODS: Published clinical trials for this project were identified via searches of 4 bibliographic databases: PubMed (includes MEDLINE), Embase, Web of Science, and the Cochrane Library. Individual search strategies included terms related to calcitonin gene-related peptide, nausea, and vomiting. Random-effects meta-analysis was conducted to estimate the overall efficacy of gepants for nausea treatment. Heterogeneity, publication bias, small-study bias, and potential confounders were explored using Galbraith plot, sensitivity analysis, meta-regression, and Egger's regression tests. Cumulative meta-analysis was done to detect temporal trend from accumulating trials.RESULTS: The meta-analysis involved 23,008 participants in 65 clinical trials from 14 published articles; 10,770 subjects participated in gepant treatment arms while 12,238 subjects participated in placebo or non-gepant arms (85% females, mean age 41years in both arms). Nearly all studies used a 2-hour incidence of nausea as an outcome measure. An overall combined effect size with an odds ratio of 1.29 (95% CI 1.18, 1.40, P=.001; I2 =42.8%) showed the efficacy of gepants for the treatment of nausea in episodic migraine. Galbraith plot demonstrated that 98.4% of studies were within 2 standard deviations from the regression line, indicating lack of significant heterogeneity and outliers. Meta-analysis results were robust to sensitivity analysis, small-study bias, and publication bias (Kendall's Tau -0.09, P=.29; Egger's regression P=.67). Meta-regression showed that both age and sex ratio were not confounding the meta-analysis (omnibus P=.69). Cumulative meta-analysis indicated that the effect size remained stable for studies conducted after 2011, with accumulating evidence continuing to favor efficacy of gepants for the treatment of nausea in episodic migraine.CONCLUSION: There is sufficient evidence to support the efficacy of gepants for the treatment of nausea in episodic migraine. Future research may focus on examining this efficacy in under-represented patient populations (males, older age groups) and in chronic migraine.

  View details for DOI 10.1111/head.13858

  View details for PubMedID 32515018

• Cerebrospinal Fluid Leak in the context of Pars Interarticularis Fracture: A Case Series Chan, L., Cowan, R., Hindiyeh, N., Hashmi, S., Lanzman, B., Carroll, I. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058001010

• Patient Preference for Dosing Regimen and Perception of Dosing Flexibility With Fremanezumab for Migraine: Results From a Patient Survey Following Completion of a 1-Year Extension Study Cowan, R. P., Gandhi, S. K., Cloud, B., Cohen, J. M., Buse, D. C., Ramirez-Campos, V., Ahn, A. H., Lipton, R. B. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000536058006269

• Electrophysiology and Structural Connectivity of the Posterior Hypothalamic Region: Much to Learn From a Rare Indication of Deep Brain Stimulation. Frontiers in human neuroscience Kakusa, B. n., Saluja, S. n., Dadey, D. Y., Barbosa, D. A., Gattas, S. n., Miller, K. J., Cowan, R. P., Kouyoumdjian, Z. n., Pouratian, N. n., Halpern, C. H. 2020; 14: 164

  Abstract

  Cluster headache (CH) is among the most common and debilitating autonomic cephalalgias. We characterize clinical outcomes of deep brain stimulation (DBS) to the posterior hypothalamic region through a novel analysis of the electrophysiological topography and tractography-based structural connectivity. The left posterior hypothalamus was targeted ipsilateral to the refractory CH symptoms. Intraoperatively, field potentials were captured in 1 mm depth increments. Whole-brain probabilistic tractography was conducted to assess the structural connectivity of the estimated volume of activated tissue (VAT) associated with therapeutic response. Stimulation of the posterior hypothalamic region led to the resolution of CH symptoms, and this benefit has persisted for 1.5-years post-surgically. Active contacts were within the posterior hypothalamus and dorsoposterior border of the ventral anterior thalamus (VAp). Delta- (3 Hz) and alpha-band (8 Hz) powers increased and peaked with proximity to the posterior hypothalamus. In the posterior hypothalamus, the delta-band phase was coupled to beta-band amplitude, the latter of which has been shown to increase during CH attacks. Finally, we identified that the VAT encompassing these regions had a high proportion of streamlines of pain processing regions, including the insula, anterior cingulate gyrus, inferior parietal lobe, precentral gyrus, and the brainstem. Our unique case study of posterior hypothalamic region DBS supports durable efficacy and provides a platform using electrophysiological topography and structural connectivity, to improve mechanistic understanding of CH and this promising therapy.

  View details for DOI 10.3389/fnhum.2020.00164

  View details for PubMedID 32670034

  View details for PubMedCentralID PMC7326144

• Spinal cerebrospinal fluid leak in the context of pars interarticularis fracture. BMC neurology Chan, T. L., Cowan, R. n., Hindiyeh, N. n., Hashmi, S. n., Lanzman, B. n., Carroll, I. n. 2020; 20 (1): 162

  Abstract

  Spinal cerebrospinal fluid (CSF) leak can lead to intracranial hypotension and is an important differential diagnosis to consider in patients with sudden-onset chronic daily headaches. Pars interarticularis (PI) fracture is a potential rare cause of suspected spinal CSF leak.This is a retrospective case series of 6 patients with suspected spinal CSF leak evaluated between January 2016 and September 2019. All patients received a magnetic resonance imaging (MRI) of the brain with and without gadolinium, MRI whole spine and full spine computed tomography (CT) myelogram. Targeted epidural patches with fibrin sealant were performed. Treatment response at return visit (3 months post-patch) was documented.Six patients (4 females, 2 males) were diagnosed with a suspected spinal CSF leak and PI fracture. Mean age at the time of headache onset was 39 years old, and a range from 32 to 50 years old. Mean time to targeted epidural patches with fibrin sealant was 4.5 years. All 6 patients had PI fractures identified on CT myelogram and received targeted epidural patches with fibrin sealant at the site of the PI fracture. All patients had significant improvement in their headache intensity.Our study highlights: 1) the importance of PI fracture as a possible culprit of suspected spinal CSF leak in patients with intracranial hypotension; 2) the added benefit of CT imaging for detecting bony abnormalities such as fractures in patients with intracranial hypotension; and 3) the successful treatment of suspected spinal CSF leak when targeting the fracture site.

  View details for DOI 10.1186/s12883-020-01740-1

  View details for PubMedID 32349710

• Exploring Natural Clusters of Chronic Migraine Phenotypes: A Cross-Sectional Clinical Study. Scientific reports Woldeamanuel, Y. W., Sanjanwala, B. M., Peretz, A. M., Cowan, R. P. 2020; 10 (1): 2804

  Abstract

  Heterogeneity in chronic migraine (CM) presents significant challenge for diagnosis, management, and clinical trials. To explore naturally occurring clusters of CM, we utilized data reduction methods on migraine-related clinical dataset. Hierarchical agglomerative clustering and principal component analyses (PCA) were conducted to identify natural clusters in 100 CM patients using 14 migraine-related clinical variables. Three major clusters were identified. Cluster I (29 patients) - the severely impacted patient featured highest levels of depression and migraine-related disability. Cluster II (28 patients) - the minimally impacted patient exhibited highest levels of self-efficacy and exercise. Cluster III (43 patients) - the moderately impacted patient showed features ranging between Cluster I and II. The first 5 principal components (PC) of the PCA explained 65% of variability. The first PC (eigenvalue 4.2) showed one major pattern of clinical features positively loaded by migraine-related disability, depression, poor sleep quality, somatic symptoms, post-traumatic stress disorder, being overweight and negatively loaded by pain self-efficacy and exercise levels. CM patients can be classified into three naturally-occurring clusters. Patients with high self-efficacy and exercise levels had lower migraine-related disability, depression, sleep quality, and somatic symptoms. These results may ultimately inform different management strategies.

  View details for DOI 10.1038/s41598-020-59738-1

  View details for PubMedID 32071349

• Endogenous glucocorticoids may serve as biomarkers for migraine chronification Therapeutic Advances in Chronic Disease Woldeamanuel , Y. W., Sanjanwala, B. M., Cowan, R. P. 2020; 11

  View details for DOI 10.1177/2040622320939793

• Moving the Needle: Desiloing the Stakeholders in the Headache Space. Headache Cowan, R. P. 2020; 60 (9): 2041

  View details for DOI 10.1111/head.13938

  View details for PubMedID 32996137

• ACEP Guidelines on Acute Nontraumatic Headache Diagnosis and Management in the Emergency Department, Commentary on Behalf of the Refractory, Inpatient, Emergency Care Section of the American Headache Society. Headache Peretz, A. n., Dujari, S. n., Cowan, R. n., Minen, M. n. 2020

  Abstract

  The American College of Emergency Physicians (ACEP) published guidelines in July 2019 on the diagnosis and management of acute nontraumatic headaches in the emergency department, focusing predominantly on the diagnosis of subarachnoid hemorrhage and the role of imaging and lumbar puncture in diagnosis. The ACEP Clinical Policies document is intended to aide Emergency Physicians in their approach to patients presenting with acute headache and to improve the accuracy of diagnosis, while promoting safe patient care practices. The Clinical Policies document also highlights the need for future research into best practices to distinguish primary from secondary headaches and the efficacy and safety of current treatment options for acute headaches. The following commentary on these guidelines is intended to support and expand on these guidelines from the Headache specialists' perspective, written on behalf of the Refractory, Inpatient, Emergency Care section of the American Headache Society (AHS). The commentary have been reviewed and approved by Board of Directors of the AHS.

  View details for DOI 10.1111/head.13744

  View details for PubMedID 31944291

• Evaluation of the 6-Item Identify Chronic Migraine (ID-CM) Screener in a Large Medical Group Pavlovic, J. M., Yu, J. S., Silberstein, S. D., Reed, M. L., Kawahara, S. H., Cowan, R. P., Dabbous, F., Campbell, K. L., Pulicharam, R., Viswanathan, H. N., Lipton, R. B. SAGE PUBLICATIONS LTD. 2019: 283–84

  View details for Web of Science ID 000484588200437

• Aberrant Structural Network Architecture in Chronic Migraine DeSouza, D. D., Woldeamanuel, Y. W., Sanajanwala, B. M., Bissell, D., Bishop, J. H., Cowan, R. P. SAGE PUBLICATIONS LTD. 2019: 392

  View details for Web of Science ID 000491167100058

• Endogenous Glucocorticoids may be Potential Biomarkers for Migraine Chronification Woldeamanuel, Y. W., Sanjanwala, B. M., Cowan, R. P. SAGE PUBLICATIONS LTD. 2019: 379–80

  View details for Web of Science ID 000491167100037

• Patient preference for dosing regimen and perception of dosing flexibility with fremanezumab for migraine: results from a patient survey following completion of a 1-year extension study Cowan, R. P., Gandhi, S. K., Cloud, B., Cohen, J. M., Buse, D. C., Ramirez-Campos, V., Ahn, A. H., Lipton, R. B. SAGE PUBLICATIONS LTD. 2019: 263–64

  View details for Web of Science ID 000484588200406

• Patient preference for and satisfaction with fremanezumab following completion of a 1-year extension study Cowan, R. P., Gandhi, S. K., Cohen, J. M., Cloud, B., Buse, D. C., Ramirez-Campos, V., Ahn, A. H., Lipton, R. B. SAGE PUBLICATIONS LTD. 2019: 264–65

  View details for Web of Science ID 000484588200407

• Remote electrical neuromodulation (REN) in the acute treatment of migraine: a comparison with usual care and acute migraine medications. The journal of headache and pain Rapoport, A. M., Bonner, J. H., Lin, T., Harris, D., Gruper, Y., Ironi, A., Cowan, R. P. 2019; 20 (1): 83

  Abstract

  BACKGROUND: There is a significant unmet need for new, effective and well tolerated acute migraine treatments. A recent study has demonstrated that a novel remote electrical neuromodulation (REN) treatment provides superior clinically meaningful pain relief with a low rate of device-related adverse events. The results reported herein compare the efficacy of REN with current standard of care in the acute treatments of migraine.METHODS: We performed a post-hoc analysis on a subgroup of participants with migraine from a randomized, double-blind, parallel-group, sham-controlled, multicenter study on acute care. The original study included a 2-4weeks run-in phase, in which migraine attacks were treated according to patient preference (i.e., usual care) and reported in an electronic diary; next, participants entered a double-blind treatment phase in which they treated the attacks with an active or sham device. The efficacy of REN was compared to the efficacy of usual care or pharmacological treatments in the run-in phase in a within-subject design that included participants who treated at least one attack with the active REN device and reported pain intensity at 2h post-treatment.RESULTS: Of the 252 patients randomized, there were 99 participants available for analysis. At 2h post-treatment, pain relief was achieved in 66.7% of the participants using REN versus 52.5% participants with usual care (p<0.05). Pain relief at 2h in at least one of two attacks was achieved by 84.4% of participants versus 68.9% in usual care (p<0.05). REN and usual care were similarly effective for pain-free status at 2h. The results also demonstrate the non-inferiority of REN compared with acute pharmacological treatments and its non-dependency on preventive medication use.CONCLUSION: REN is an effective acute treatment for migraine with non-inferior efficacy compared to current acute migraine therapies. Together with a very favorable safety profile, these findings suggest that REN may offer a promising alternative for the acute treatment of migraine and could be considered first line treatment in some patients.TRIAL REGISTRATION: ClinicalTrials.gov NCT03361423 . Registered 18 November 2017.

  View details for DOI 10.1186/s10194-019-1033-9

  View details for PubMedID 31331265

• Deep Brain Stimulation for Chronic Cluster Headache: A Review NEUROMODULATION Vyas, D. B., Ho, A. L., Dadey, D. Y., Pendharkar, A. V., Sussman, E. S., Cowan, R., Halpern, C. H. 2019; 22 (4): 388–97

  View details for DOI 10.1111/ner.12869

  View details for Web of Science ID 000471831000003

• Subarachnoid Hemorrhage and Headache. Current pain and headache reports Ogunlaja, O. I., Cowan, R. 2019; 23 (6): 44

  Abstract

  PURPOSE FOR REVIEW: Subarachnoid hemorrhage is a serious and life-threatening medical condition which commonly presents with an acute headache. Unfortunately, it remains frequently misdiagnosed at initial presentation with dire consequences in terms of patient morbidity and mortality. The goal of this paper is to review salient features in the clinical history, as well as recently developed clinical decision rules, which can help determine which patients warrant further investigation for subarachnoid hemorrhage when the initial presentation is that of an acute headache.RECENT FINDINGS: A recent prospective observational study showed that occipital location, stabbing quality, presence of meningism, and onset of headache during exertion were characteristics in the clinical history that can distinguish the headache of SAH from other causes. The Ottawa headache rule is a clinical decision tool which was developed to help identify patients presenting to the ED with acute non-traumatic headache who require investigation to rule out subarachnoid hemorrhage. Using this tool, it is recommended that patients who meet any one of the following 6 criteria are investigated further: Onset greater than or equal to 40years, presence of neck pain or stiffness, witnessed loss of consciousness, onset during exertion, thunder clap headache (pain peaking within 1s), or limited neck flexion on exam. An informed and thoughtful approach that takes into account the timing, presentation, risk factors, and resources, as discussed here, should help distinguish between the patient that warrants further evaluation and intervention for SAH and one who does not. The Ottawa SAH rule is a useful clinical decision tool for young inexperienced clinicians in order to avoid missed diagnoses. However, its clinical value is limited by its low specificity. Clinical decision tools with higher specificity are needed.

  View details for DOI 10.1007/s11916-019-0785-x

  View details for PubMedID 31123920

• Physician and patient preferences for dosing options in migraine prevention JOURNAL OF HEADACHE AND PAIN Cowan, R., Cohen, J. M., Rosenman, E., Iyer, R. 2019; 20

  View details for DOI 10.1186/s10194-019-0998-8

  View details for Web of Science ID 000467599400002

• Altered Permeability Blood-CSF of Barriers in Migraine Cowan, R., Sweeney, M., Sagare, A., Ekpo, E., Sanjanwala, B., Gross, N., Arakaki, X., Fonteh, A., Zlokovic, B., Harrington, M. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965902189

• The Impact of Offering Monthly and Quarterly Dosing Options for a New Class of Migraine Preventive Therapy on Likelihood of Acceptance and Adherence in Adults With Migraine Cowan, R., Cohen, J., Rosenman, E., Iyer, R. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965902175

• Exploring Natural Cohorts of Chronic Migraine Phenotype Woldeamanuel, Y., Sanjanwala, B., Peretz, A., Cowan, R. LIPPINCOTT WILLIAMS & WILKINS. 2019

  View details for Web of Science ID 000475965903299

• Toward a Philosophy of Migraine HEADACHE Cowan, R. P. 2019; 59 (4): 481–83

  View details for DOI 10.1111/head.13517

  View details for Web of Science ID 000465079700001

• Development of a claims-based algorithm to identify potentially undiagnosed chronic migraine patients CEPHALALGIA Pavlovic, J. M., Yu, J. S., Silberstein, S. D., Reed, M. L., Kawahara, S. H., Cowan, R. P., Dabbous, F., Campbell, K. L., Shewale, A. R., Pulicharam, R., Kowalski, J. W., Viswanathan, H. N., Lipton, R. B. 2019; 39 (4): 465-476

  View details for DOI 10.1177/0333102418825373

  View details for Web of Science ID 000464511900002

• Toward a Philosophy of Migraine. Headache Cowan, R. P. 2019; 59 (4): 481–83

  View details for PubMedID 30973195

• Development of a claims-based algorithm to identify potentially undiagnosed chronic migraine patients. Cephalalgia : an international journal of headache Pavlovic, J. M., Yu, J. S., Silberstein, S. D., Reed, M. L., Kawahara, S. H., Cowan, R. P., Dabbous, F., Campbell, K. L., Shewale, A. R., Pulicharam, R., Kowalski, J. W., Viswanathan, H. N., Lipton, R. B. 2019: 333102418825373

  Abstract

  OBJECTIVE: To develop a claims-based algorithm to identify undiagnosed chronic migraine among patients enrolled in a healthcare system.METHODS: An observational study using claims and patient survey data was conducted in a large medical group. Eligible patients had an International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) migraine diagnosis, without a chronic migraine diagnosis, in the 12 months before screening and did not have a migraine-related onabotulinumtoxinA claim in the 12 months before enrollment. Trained clinicians administered a semi-structured diagnostic interview, which served as the gold standard to diagnose chronic migraine, to enrolled patients. Potential claims-based predictors of chronic migraine that differentiated semi-structured diagnostic interview-positive (chronic migraine) and semi-structured diagnostic interview-negative (non-chronic migraine) patients were identified in bivariate analyses for inclusion in a logistic regression model.RESULTS: The final sample included 108 patients (chronic migraine=64; non-chronic migraine=44). Four significant predictors for chronic migraine were identified using claims in the 12 months before enrollment: ≥15 versus <15 claims for acute treatment of migraine, including opioids (odds ratio=5.87 [95% confidence interval: 1.34-25.63]); ≥24 versus <24 healthcare visits (odds ratio=2.80 [confidence interval: 1.08-7.25]); female versus male sex (odds ratio=9.17 [confidence interval: 1.26-66.50); claims for ≥2 versus 0 unique migraine preventive classes (odds ratio=4.39 [confidence interval: 1.19-16.22]). Model sensitivity was 78.1%; specificity was 72.7%.CONCLUSIONS: The claims-based algorithm identified undiagnosed chronic migraine with sufficient sensitivity and specificity to have potential utility as a chronic migraine case-finding tool using health claims data. Research to further validate the algorithm is recommended.

  View details for PubMedID 30854881

• Clinical Features Contributing to Cortical Thickness Changes in Chronic Migraine - A Pilot Study HEADACHE Woldeamanuel, Y. W., DeSouza, D. D., Sanjanwala, B. M., Cowan, R. P. 2019; 59 (2): 180–91

  View details for DOI 10.1111/head.13452

  View details for Web of Science ID 000457474500004

• Altered structural brain network topology in chronic migraine. Brain structure & function DeSouza, D. D., Woldeamanuel, Y. W., Sanjanwala, B. M., Bissell, D. A., Bishop, J. H., Peretz, A. n., Cowan, R. P. 2019

  Abstract

  Despite its prevalence and high disease burden, the pathophysiological mechanisms underlying chronic migraine (CM) are not well understood. As CM is a complex disorder associated with a range of sensory, cognitive, and affective comorbidities, examining structural network disruption may provide additional insights into CM symptomology beyond studies of focal brain regions. Here, we compared structural interconnections in patients with CM (n = 52) and healthy controls (HC) (n = 48) using MRI measures of cortical thickness and subcortical volume combined with graph theoretical network analyses. The analysis focused on both local (nodal) and global measures of topology to examine network integration, efficiency, centrality, and segregation. Our results indicated that patients with CM had altered global network properties that were characterized as less integrated and efficient (lower global and local efficiency) and more highly segregated (higher transitivity). Patients also demonstrated aberrant local network topology that was less integrated (higher path length), less central (lower closeness centrality), less efficient (lower local efficiency) and less segregated (lower clustering). These network differences not only were most prominent in the limbic and insular cortices but also occurred in frontal, temporal, and brainstem regions, and occurred in the absence of group differences in focal brain regions. Taken together, examining structural correlations between brain areas may be a more sensitive means to detect altered brain structure and understand CM symptomology at the network level. These findings contribute to an increased understanding of structural connectivity in CM and provide a novel approach to potentially track and predict the progression of migraine disorders.This study is registered on ClinicalTrials.gov (Identifier: NCT03304886).

  View details for DOI 10.1007/s00429-019-01994-7

  View details for PubMedID 31792696

• On Making a Headache Medicine Rotation Mandatory in Neurology Training. Headache Zhang, N. n., Cowan, R. P. 2019

  View details for DOI 10.1111/head.13667

  View details for PubMedID 31562640

• Endogenous Na+, K+-ATPase inhibitors and CSF [Na+] contribute to migraine formation. PloS one Gross, N. B., Abad, N. n., Lichtstein, D. n., Taron, S. n., Aparicio, L. n., Fonteh, A. N., Arakaki, X. n., Cowan, R. P., Grant, S. C., Harrington, M. G. 2019; 14 (6): e0218041

  Abstract

  There is strong evidence that neuronal hyper-excitability underlies migraine, and may or may not be preceded by cortical spreading depression. However, the mechanisms for cortical spreading depression and/or migraine are not established. Previous studies reported that cerebrospinal fluid (CSF) [Na+] is higher during migraine, and that higher extracellular [Na+] leads to hyper-excitability. We raise the hypothesis that altered choroid plexus Na+, K+-ATPase activity can cause both migraine phenomena: inhibition raises CSF [K+] and initiates cortical spreading depression, while activation raises CSF [Na+] and causes migraine. In this study, we examined levels of specific Na+, K+-ATPase inhibitors, endogenous ouabain-like compounds (EOLC), in CSF from migraineurs and controls. CSF EOLC levels were significantly lower during ictal migraine (0.4 nM +/- 0.09) than from either controls (1.8 nM +/- 0.4) or interictal migraineurs (3.1 nM +/- 1.9). Blood plasma EOLC levels were higher in migraineurs than controls, but did not differ between ictal and interictal states. In a Sprague-Dawley rat model of nitroglycerin-triggered central sensitization, we changed the concentrations of EOLC and CSF sodium, and measured aversive mechanical threshold (von Frey hairs), trigeminal nucleus caudalis activation (cFos), and CSF [Na+] (ultra-high field 23Na MRI). Animals were sensitized by three independent treatments: intraperitoneal nitroglycerin, immunodepleting EOLC from cerebral ventricles, or cerebroventricular infusion of higher CSF [Na+]. Conversely, nitroglycerin-triggered sensitization was prevented by either vascular or cerebroventricular delivery of the specific Na+, K+-ATPase inhibitor, ouabain. These results affirm our hypothesis that higher CSF [Na+] is linked to human migraine and to a rodent migraine model, and demonstrate that EOLC regulates them both. Our data suggest that altered choroid plexus Na+, K+-ATPase activity is a common source of these changes, and may be the initiating mechanism in migraine.

  View details for DOI 10.1371/journal.pone.0218041

  View details for PubMedID 31173612

• Physician and patient preferences for dosing options in migraine prevention. The journal of headache and pain Cowan, R. n., Cohen, J. M., Rosenman, E. n., Iyer, R. n. 2019; 20 (1): 50

  Abstract

  Adherence to a therapy, though a key factor for successful treatment, is low among patients with chronic conditions such as migraine. Dose frequency plays a major role in adherence. This study evaluated the impact of having flexible dosing options on acceptance of and adherence to a new migraine preventive therapy class among adults with migraine.In this observational study, two 20-min online surveys were completed: one by physicians currently treating adult patients with migraine and the other by adults with migraine. Both surveys presented the participants with three scenarios: 1) only monthly, 2) only quarterly, and 3) both dosing options of the new medication are available. Physicians estimated the proportion of their migraine patients who would receive the new medication in each scenario. Patients were asked about their dosing preference when either or both options are available. Respondents were asked to rate the likelihood of their acceptance of and adherence to the therapy.400 physicians and 417 US adults with migraine completed the surveys. The availability of both dosing options yielded a significant increase in the proportion of patients expected to receive the new medication. The overall proportion of patients favoring monthly dosing (35%) was similar to the proportion favoring quarterly dosing (40%). Among those who preferred monthly dosing (n = 147), a greater proportion indicated they are more likely to fill the prescription (77% vs 56%, P < 0.05) and remain adherent (80% vs 57%, P < 0.05) when only monthly is available versus when only quarterly is available. Similarly, among those who preferred quarterly dosing (n = 166), a greater proportion indicated they are likely to fill (63% vs 55%, P < 0.05) and remain adherent (62% vs 54%, P < 0.05) when only quarterly is available compared with when only monthly is available.Physicians anticipated that the proportion of patients to receive the new medication would increase when both dosing options are available. Patients stated that they are more likely to fill the prescription and adhere to the new therapy when their preferred dosing regimen is available.

  View details for PubMedID 31072307

• The impact of offering monthly and quarterly dosing options for a new class of migraine preventive therapy on likelihood of acceptance and adherence in adults with migraine (vol 19, pg P137, 2018) JOURNAL OF HEADACHE AND PAIN Cowan, R., Cohen, J., Rosenman, E., Fitzgerald, T., Iyer, R. 2018; 19

  View details for Web of Science ID 000452530400014

• The Future of Migraine Prevention HEADACHE Cowan, R. P. 2018; 58: 291–97

  View details for DOI 10.1111/head.13418

  View details for Web of Science ID 000449847000006

• The Future of Migraine Prevention. Headache Cowan, R. P. 2018

  Abstract

  Barring unforeseen circumstances, we anticipate the arrival of the first mechanism-specific class of molecules for migraine prevention in 2018. Despite many ground-breaking advances in the field over the last several years, these agents, broadly identified as calcitonin gene-related peptide-based pharmaceuticals, have captured the imagination and attention of the lay press and much of the headache community. This paper will address the factors, both class-specific and systems-based, that are likely to affect the launch, access, compliance, and adherence related to this new class, as well as attempt to place these novel medications in context of the current state and anticipated changes in headache medicine.

  View details for PubMedID 30311219

• Deep Brain Stimulation for Chronic Cluster Headache: A Review. Neuromodulation : journal of the International Neuromodulation Society Vyas, D. B., Ho, A. L., Dadey, D. Y., Pendharkar, A. V., Sussman, E. S., Cowan, R., Halpern, C. H. 2018

  Abstract

  OBJECTIVES: Cluster headaches are a set of episodic and chronic pain syndromes that are sources of significant morbidity for patients. The standard of care for cluster headaches remains medication therapy, however a minority of patients will remain refractory to treatment despite changes to dosage and therapeutic combinations. In these patients, functional neuromodulation using Deep Brain Stimulation (DBS) presents the opportunity to alleviate the significant pain that is experienced by targeting the neurophysiological substrates that mediate pain.MATERIAL AND METHODS: We review the literature on chronic cluster headache, including the growing number of DBS case reports and series that describe the alleviation of pain in a majority of patients through conventional or endoventricular targeting of the posterior hypothalamus and ventral tegmental area, with a minimal side effect profile.RESULTS: In this review, the history and outcomes of DBS use for medication-refractory cluster headaches are examined, with discussion on future directions for improving this novel treatment modality and providing efficacious, longer-lasting pain relief in headache patients.CONCLUSION: In patients with chronic cluster headache, functional neuromodulation using DBS presents the opportunity to alleviate the significant pain that is experienced by targeting the neurophysiological substrates that mediate pain.

  View details for PubMedID 30303584

• American Headache Society Survey About Urgent and Emergency Management of Headache Patients HEADACHE Minen, M. T., Ortega, E., Lipton, R. B., Cowan, R. 2018; 58 (9): 1389–96

  Abstract

  Emergency department (ED) visits for migraine are burdensome to patients and to the larger healthcare system and society. Thus, it is important to determine strategies used to prevent ED visits and the common communication patterns between headache specialists and the ED team.We sought to understand: (1) Whether headache specialists use headache management protocols. (2) The strategies they use to try and reduce the number of ED visits for headache. (3) Whether protocols are used in the EDs with which they are affiliated. (4) The level of satisfaction with the coordination of care between headache physicians and the ED.We surveyed via SurveyMonkey members of the American Headache Society Emergency Department/Refractory/Inpatient (EDRI) Section to understand their practice regarding patients who call their office to be seen urgently, and to understand their communication with their local EDs.There were 96 eligible AHS members, 50 of whom responded to questionnaires either by email or in person (52%). Of these, 59% of respondents reported giving rescue treatment to their patients to manage acute attacks. Fifty-four percent reported using standard protocols for outpatients not responding to usual acute treatments. In the event of a request for urgent care, 12% of specialists reported bringing patients into the office most or all of the time, and 20% reported sending patients to the ED some or most of the time for headache management. Thirty-six percent reported prescribing a new medicine and 30% reported providing telephone counseling some/most/all of the time. Sixty percent reported that their ED has a protocol for migraine management. Overall, 38% were usually or very satisfied with the headache care in the ED.A substantial number of headache specialists are dissatisfied with the care their patients receive in the ED. More standardized protocols for ED visits by patients with known headache disorders, and clear guidelines for communication between ED providers and treating physicians, along with better methods for follow-up following discharge from the ED, might appear to improve this issue.

  View details for DOI 10.1111/head.13387

  View details for Web of Science ID 000448841600005

  View details for PubMedID 30207384

• Obesity-Related Cortical Thickness Changes in Chronic Migraine Woldeamanuel, Y. W., DeSouza, D. D., Sanjanwala, B. M., Cowan, R. P. WILEY. 2018: S83

  View details for Web of Science ID 000446520900106

• The impact on physician prescribing of monthly and quarterly dosing options for a new class of migraine preventive therapy Cowan, R., Rosenman, E., Fitzgerald, T., Cohen, J., Iyer, R. SPRINGEROPEN. 2018

  View details for Web of Science ID 000452730900253

• Evaluation of the 6-Item Identify Chronic Migraine (ID-CM) Screener in a Large Medical Group Pavlovic, J. M., Yu, J. S., Silberstein, S. D., Reed, M. L., Kawahara, S. H., Cowan, R. P., Dabbous, F., Campbell, K. L., Pulicharam, R., Viswanathan, H. N., Lipton, R. B. SPRINGEROPEN. 2018

  View details for Web of Science ID 000452730900269

• The impact of offering monthly and quarterly dosing options for a new class of migraine preventive therapy on likelihood of acceptance and adherence in adults with migraine Cowan, R., Cohen, J., Rosenman, E., Fitzgerald, T., Iyer, R. SPRINGEROPEN. 2018

  View details for Web of Science ID 000452730900240

• Evaluation of the Identify Chronic Migraine (ID-CM) Screener in a Large Medical Group Yu, J. S., Pavlovic, J. M., Silberstein, S. D., Reed, M. L., Kawahara, S. H., Cowan, R. P., Dabbous, F., Campbell, K., Pulicharam, R., Viswanathan, H. N., Lipton, R. B. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090805411

• Development of a Claims-Based Algorithm for Use in Patients with Migraine to Identify Potentially Undiagnosed Chronic Migraine Patients Pavlovic, J., Yu, J. S., Silbertsein, S. D., Reed, M. L., Kawahara, S. H., Cowan, R. P., Dabbous, F., Campbell, K., Shewale, A. R., Pulicharam, R., Kowalski, J. W., Viswanathan, H. N., Lipton, R. B. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090802091

• Migraine Treatment Patterns and Opioid Use Among Chronic and Episodic Migraine Patients Identified by a Clinician-Administered Semi-Structured Diagnostic Interview Pavlovic, J. M., Yu, J. S., Silberstein, S. D., Reed, M. L., Kawahara, S. H., Cowan, R. P., Dabbous, F., Campbell, K., Pulicharam, R., Viswanathan, H. N., Lipton, R. B. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090805340

• American Headache Society Survey about Urgent and Emergency Management of Headache Patients Minen, M., Ortega, E., Lipton, R., Cowan, R. LIPPINCOTT WILLIAMS & WILKINS. 2018

  View details for Web of Science ID 000453090803069

• Migraine Action Plan (MAP). Headache Peretz, A. M., Minen, M. T., Cowan, R., Strauss, L. D. 2018; 58 (2): 355–56

  View details for PubMedID 29411363

• Introducing the Migraine Action Plan HEADACHE Peretz, A. M., Minen, M. T., Cowan, R., Strauss, L. D. 2018; 58 (2): 195

  View details for PubMedID 29411373

• Clinical Features Contributing to Cortical Thickness Changes in Chronic Migraine - A Pilot Study. Headache Woldeamanuel, Y. W., DeSouza, D. D., Sanjanwala, B. M., Cowan, R. P. 2018

  Abstract

  The objectives of this cross-sectional pilot study were threefold: to identify regions of cortical thickness that differentiate chronic migraine (CM) from controls, to assess group differences in interregional cortical thickness covariance, and to determine group differences in associations between clinical variables and cortical thickness.Cortical thickness alterations in relation to clinical features have not been adequately explored in CM. Assessment of this relationship can be useful to describe cortical substrates for disease progression in migraine and to identify clinical variables that warrant management emphasis.Thirty CM cases (mean age 40 years; male-to-female 1:4) and 30 sex-matched healthy controls (mean age 40 years) were enrolled. Participants completed self-administered and standardized questionnaires assessing headache-related clinical features and common psychological comorbidities. T1-weighted brain images were acquired on a 3T MRI. A whole-brain cortical thickness analysis was performed. Additionally, correlations between all brain regions were assessed to examine interregional cortical thickness covariance. Interactions were analyzed to identify clinical variables that were significantly associated with cortical thickness.The whole brain cortical thickness analysis revealed no significant differences between CM patients and controls. However, significant associations between clinical features and cortical thickness were observed for the patients only. These associations included the right superior temporal sulcus (R2  = 0.72, P = .001) and the right insula (R2  = 0.71, P = .002) with distinct clinical variables ie, longer history of CM, posttraumatic stress disorder (PTSD), sleep quality, pain self-efficacy, and somatic symptoms. Higher interregional cortical covariance was found in CM compared to controls (OR = 3.1, CI 2.10-4.56, P < .0001), such that cortical thickness between regions tended to be more correlated in patients, particularly in the temporal and frontal lobes.CM patients have significantly greater cortical covariance compared to controls. Cortical thickness in CM patients was predominantly accounted for by CM duration, PTSD, and poor sleep quality, while improved pain self-efficacy buffered cortical thickness. While it is important to address all CM features and comorbidities, it may be useful to emphasize optimizing the management of certain clinical features that contribute to cortical abnormalities including managing PTSD, early management to shorten duration of CM, and improving pain self-efficacy and sleep quality.

  View details for PubMedID 30468246

• Development of a claims-based algorithm for use in patients with migraine to identify potentially undiagnosed chronic migraine patients Pavlovic, J. M., Yu, J. S., Silberstein, S. D., Reed, M. L., Kawahara, S. H., Cowan, R. P., Dabbous, F., Campbell, K. L., Shewale, A. S., Pulicharam, R., Kowalski, J. W., Viswanathan, H. N., Lipton, R. B. SPRINGER-VERLAG ITALIA SRL. 2017

  View details for Web of Science ID 000416982100190

• Migraine Treatment Patterns and Opioid Use Among Chronic and Episodic Migraine Patients Identified by a Clinician-Administered Semi-Structured Diagnostic Interview Yu, J. S., Pavlovic, J. M., Silberstein, S. D., Reed, M. L., Kawahara, S. H., Cowan, R. P., Dabbous, F., Campbell, K. L., Pulicharam, R., Viswanathan, H. N., Lipton, R. B. SAGE PUBLICATIONS LTD. 2017: 365–66

  View details for Web of Science ID 000416844600060

• Interactions between affective measures and amygdala volume in chronic migraine: associations in the absence of group volumetric differences Desouza, D. D., Woldeamanuel, Y. W., Peretz, A. M., Sanjanwala, B. M., Cowan, R. P. SAGE PUBLICATIONS LTD. 2017: 47–48

  View details for Web of Science ID 000410068300064

• Evaluation of the Identify Chronic Migraine (ID-CM) screener in an accountable care organization Yu, J. S., Pavlovic, J. M., Silberstein, S. D., Reed, M. L., Kawahara, S. H., Cowan, R. P., Dabbous, F., Campbell, K., Pulicharam, R., Viswanathan, H. N., Lipton, R. B. SAGE PUBLICATIONS LTD. 2017: 188–89

  View details for Web of Science ID 000410068300267

• Use of Most Bothersome Symptom as a Co-Primary Endpoint in an Acute Treatment of Migraine Trial Dodick, D. W., Tepper, S. J., Friedaman, D., Gelfand, A., Cowan, R. P., Schmidt, P., Engels, J., Rapoport, A., Kellerman, D. J. SAGE PUBLICATIONS LTD. 2017: 361–62

  View details for Web of Science ID 000416844600055

• Effect of Educating the Primary Care Physician About Headache to Help Reduce "Trivial" Referrals and Improve the Number and Quality of "Substantial" Referrals that Truly Need Subspecialty Headache Medicine Care. Current treatment options in neurology Cowan, R., Barad, M. 2017; 19 (7): 25-?

  Abstract

  Technology is likely to play an increasingly important role in the delivery of healthcare as the disparity between provider availability/expertise and patient numbers/needs increases. This article is intended to lend insight into the ways in which technology can facilitate the evaluation of patients with headache disorders and improve the ongoing monitoring of disease progression and response to therapy, following proper diagnosis. While it is not possible to prognosticate the impact of technologies not yet available, the article addresses potential novel usage of currently existing technology to standardize intake, expedite evaluations, ensure adequate history and documentation, and monitoring of patient care.

  View details for DOI 10.1007/s11940-017-0462-5

  View details for PubMedID 28536899

• Comprehensive Headache Experience in Collegiate Student-Athletes: An Initial Report From the NCAA Headache Task Force HEADACHE Seifert, T., Sufrinko, A., Cowan, R., Black, W., Watson, D., Edwards, B., Livingston, S., Webster, K., Akers, D., Lively, M., Kontos, A. P. 2017; 57 (6): 877–86

  Abstract

  The prevalence of primary headache disorders in the general population provides a unique challenge in the evaluation of headache occurring in the context of sport. Despite a wealth of studies exploring the epidemiology of headache in the layperson, little is known about the prevalence and nature of headaches in collegiate student-athletes. These scenarios are challenging in the return to play context, as it is often unclear whether an athlete has an exacerbation of a primary headache disorder, new onset headache unrelated to trauma, or has suffered a concussive injury.To establish the prevalence and nature of headaches in collegiate student-athletes.Retrospective cross-sectional survey.This cross-sectional survey evaluated the characteristics and prevalence of headache in 834 student-athletes from four NCAA Division-I institutions. Because headache occurrence may vary by sport (collision, contact, non-contact), by sex, and medical history, our sample included male and female athletes in a variety of sports, with differing degrees of contact exposure. The 20 question survey collected data on personal and family history of headache, as well as concussion history.A total of 23.7% (n = 198) of participants reported having a personal history of migraine, 25.2% (n = 210) history of sinus headache, and 12.3% (n = 103) history of tension type headache. Among athletes with a prior history of concussion, 46.3% (n = 25) of females reported a history of migraine, while only 32.2% of males reported history of migraine (χ2  = 3.421, P = .064).The etiology of increased prevalence of migraine in our study is unclear. Whether this is due to increased awareness of headache disorders, a consequence of contact exposure, or a predisposition for migraine development in this age group remains unclear. Further studies are indicated.

  View details for PubMedID 28480575

• Migraine affects 1 in 10 people worldwide featuring recent rise: A systematic review and meta-analysis of community-based studies involving 6 million participants JOURNAL OF THE NEUROLOGICAL SCIENCES Woldeamanuel, Y. W., Cowan, R. P. 2017; 372: 307-315

  Abstract

  To study the weighted average global prevalence of migraine at the community level.A systematic review using advanced search strategies employing PubMed/MEDLINE, Scopus, and Web of Science was conducted for community-based and non-clinical studies by combining the terms "migraine", "community-based", and names of every country worldwide spanning all previous years from January 1, 1920 until August 31, 2015. Methods were in accordance with PRISMA and MOOSE guidelines. A meta-analysis with subgroup analysis was performed to identify pooled migraine prevalence and examine cohort heterogeneity.A total of 302 community-based studies involving 6,216,995 participants (median age 35years, male-to-female ratio of 0.91) were included. Global migraine prevalence was 11.6% (95% CI 10.7-12.6%; random effects); 10.4% in Africa, 10.1% in Asia, 11.4% in Europe, 9.7% in North America, 16.4% in Central and South America. When the pooled cohort was stratified, the prevalence was 13.8% among females, 6.9% among males, 11.2% among urban residents, 8.4% among rural residents, and 12.4% among school/college students. Our result showed a pattern of rising global migraine prevalence.Migraine affects one in ten people worldwide featuring recent rise. Higher prevalence was found among females, students, and urban residents.

  View details for DOI 10.1016/j.jns.2016.11.071

  View details for Web of Science ID 000393002500060

  View details for PubMedID 28017235

• Migraine and Complex Regional Pain Syndrome: A Case-Referent Clinical Study. BioMed research international Woldeamanuel, Y. W., Cooley, C. n., Foley-Saldena, K. n., Cowan, R. P. 2017; 2017: 5714673

  Abstract

  We studied clinical phenotype differences between migraineurs with CRPS (Mig + CRPS) and those without (Mig - CRPS). Mig + CRPS cases and Mig - CRPS referents aged ≥18 years were enrolled. Diagnosis was made in accordance with International Classification of Headache Disorders-3 beta (ICHD-3 beta) for migraine and Budapest Criteria for CRPS. Migraines both with and without aura were included. A total of 70 Mig + CRPS cases (13% males, mean age 48 years) and 80 Mig - CRPS referents (17% males, mean age 51 years) were included. 33% of Mig + CRPS and 38% of Mig - CRPS exhibited episodic migraine (EM) while 66% of Mig + CRPS and 62% of Mig - CRPS had chronic migraine (CM) (OR = 0.98, CI 0.36, 2.67). Median duration of CRPS was 3 years among EM + CRPS and 6 years among CM + CRPS cohort (p < 0.02). Mig + CRPS (57%) carried higher psychological and medical comorbidities compared to Mig - CRPS (6%) (OR 16.7, CI 10.2, 23.6). Higher migraine frequency was associated with longer CRPS duration. Migraineurs who developed CRPS had higher prevalence of psychological and medical disorders. Alleviating migraineurs' psychological and medical comorbidities may help lower CRPS occurrence.

  View details for PubMedID 29214172

  View details for PubMedCentralID PMC5682894

• Spontaneous extracranial hemorrhagic phenomena in primary headache disorders: A systematic review of published cases CEPHALALGIA Peretz, A. M., Woldeamanuel, Y. W., Rapoport, A. M., Cowan, R. P. 2016; 36 (13): 1257-1267

  Abstract

  Head pain is a cardinal feature of primary headache disorders (PHDs) and is often accompanied by autonomic and vasomotor symptoms and/or signs. Spontaneous extracranial hemorrhagic phenomena (SEHP), including epistaxis, ecchymosis, and hematohidrosis (a disorder of bleeding through sweat glands), are poorly characterized features of PHDs.To critically appraise the association between SEHP and PHDs by systematically reviewing and pooling all reports of SEHP associated with headaches.Advanced searches using the PubMed/MEDLINE, Web of Science, Cochrane Library, Google Scholar, and ResearchGate databases were carried out for clinical studies by combining the terms "headache AND ecchymosis", "headache AND epistaxis", and "headache AND hematohidrosis" spanning all medical literature prior to October 10, 2015. Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines were applied.A total of 105 cases of SEHP associated with PHDs (83% migraine and 17% trigeminal autonomic cephalgias) were identified (median age 27 years, male to female ratio 1:2.3); 63% had epistaxis, 33% ecchymosis, and 4% hematohidrosis. Eighty-three percent of studies applied the International Classification of Headache Disorders diagnostic criteria. Eighty percent of the reported headaches were episodic and 20% were chronic. Twenty-four percent of studies reported recurrent episodes of SEHP.Our results suggest that SEHP may be rare features of PHDs. Future studies would benefit from the systematic characterization of these phenomena.

  View details for DOI 10.1177/0333102415618951

  View details for Web of Science ID 000387693900006

• Journal Club: Change in brain network connectivity during PACAP38-induced migraine attacks. Neurology DeSouza, D. D., O'Hare, M., Woldeamanuel, Y. W., Cowan, R. P. 2016; 87 (16): e199-e202

  View details for PubMedID 27754916

• Journal Club: Exacerbation of headache during dihydroergotamine for chronic migraine does not alter outcome. Neurology Woldeamanuel, Y. W., O'Hare, M., DeSouza, D. D., Cowan, R. P. 2016; 87 (16): e196-e198

  Abstract

  Transient headache exacerbation during IV dihydroergotamine (DHE) therapy of migraine may prompt clinicians to prematurely discontinue DHE therapy, potentially depriving patients of the full benefit of DHE infusion. In a recent Neurology® article, Eller et al. evaluated whether or not worsening headache during DHE infusion was associated with suboptimal medium-term headache outcomes.

  View details for PubMedID 27754915

• Migraine and Complex Regional Pain Syndrome: A Case-Referent Clinical Study Woldeamanuel, Y. W., Cooley, C., Foley-Saldena, K., Cowan, R. P. WILEY-BLACKWELL. 2016: S169

  View details for Web of Science ID 000388569900331

• Severe Headache or Migraine History Is Inversely Correlated With Dietary Sodium Intake: NHANES 1999-2004: A Response HEADACHE Pogoda, J. M., Gross, N. B., Arakaki, X., Fonteh, A. N., Cowan, R. P., Harrington, M. G. 2016; 56 (7): 1216–18

  View details for PubMedID 27432628

• Worldwide Migraine Epidemiology: Systematic Review and Meta-Analysis of 302 Community-Based Studies Involving 6,216,995 Participants Woldeamanuel, Y., Cowan, R. LIPPINCOTT WILLIAMS & WILKINS. 2016

  View details for Web of Science ID 000411328607483

• The impact of regular lifestyle behavior in migraine: a prevalence case-referent study JOURNAL OF NEUROLOGY Woldeamanuel, Y. W., Cowan, R. P. 2016; 263 (4): 669-676

  Abstract

  Regular lifestyle behaviors (RLBs) of sleep, exercise, mealtime pattern and hydration status independently affect migraine occurrence. We aimed herein to evaluate the differences in migraine occurrence among participants who do and do not maintain the RLB triumvirate. Cases of chronic migraine (CM) and referents of episodic migraine (EM) ≥aged 15 years with charts regularly documenting RLB notes were continuously enrolled from a retrospective case-referent cohort study performed on electronic chart review from January 1, 2014 to January 1, 2015 at the Stanford Headache and Facial Pain Program. Association between RLB prevalence and migraine occurrence was studied. 175 CM and 175 EM patients were enrolled (mean age 44.4 years, 22 % males). Migraine was diagnosed according to the ICHD-3 beta criteria, and was confirmed by a Headache Specialist attending the Clinic. The CM cohort (22 %) exhibited less RLB than the EM cohort (69 %), with crude odds ratio of 0.13 (95 % confidence interval or CI 0.08-0.21). The adjusted odds ratio and adjusted relative risk between RLB+, Meds+ (those taking medication) and CM were 0.67 (95 % CI 0.32-1.40) and 0.74 (95 % CI 0.43-1.28), indicating no significant effect modification. Engaging in regular lifestyle behavior helps quell chronic migraine.

  View details for DOI 10.1007/s00415-016-8031-5

  View details for Web of Science ID 000373742600006

  View details for PubMedID 26810728

• Severe Headache or Migraine History Is Inversely Correlated With Dietary Sodium Intake: NHANES 1999-2004 HEADACHE Pogoda, J. M., Gross, N. B., Arakaki, X., Fonteh, A. N., Cowan, R. P., Harrington, M. G. 2016; 56 (4): 688-698

  Abstract

  We investigated whether dietary sodium intake from respondents of a national cross-sectional nutritional study differed by history of migraine or severe headaches.Several lines of evidence support a disruption of sodium homeostasis in migraine.Our analysis population was 8819 adults in the 1999-2004 National Health and Nutrition Examination Survey (NHANES) with reliable data on diet and headache history. We classified respondents who reported a history of migraine or severe headaches as having probable history of migraine. To reduce the diagnostic conflict from medication overuse headache, we excluded respondents who reported taking analgesic medications. Dietary sodium intake was measured using validated estimates of self-reported total grams of daily sodium consumption and was analyzed as the residual value from the linear regression of total grams of sodium on total calories. Multivariable logistic regression that accounted for the stratified, multistage probability cluster sampling design of NHANES was used to analyze the relationship between migraine and dietary sodium.Odds of probable migraine history decreased with increasing dietary sodium intake (odds ratio = 0.93, 95% confidence interval = 0.87, 1.00, P = .0455). This relationship was maintained after adjusting for age, sex, and body mass index (BMI) with slightly reduced significance (P = .0505). In women, this inverse relationship was limited to those with lower BMI (P = .007), while in men the relationship did not differ by BMI. We likely excluded some migraineurs by omitting frequent analgesic users; however, a sensitivity analysis suggested little effect from this exclusion.This study is the first evidence of an inverse relationship between migraine and dietary sodium intake. These results are consistent with altered sodium homeostasis in migraine and our hypothesis that dietary sodium may affect brain extracellular fluid sodium concentrations and neuronal excitability.

  View details for DOI 10.1111/head.12792

  View details for Web of Science ID 000374696100006

  View details for PubMedID 27016121

  View details for PubMedCentralID PMC4836999

• Spontaneous extracranial hemorrhagic phenomena in primary headache disorders: A systematic review of published cases. Cephalalgia Peretz, A. M., Woldeamanuel, Y. W., Rapoport, A. M., Cowan, R. P. 2015

  Abstract

  Head pain is a cardinal feature of primary headache disorders (PHDs) and is often accompanied by autonomic and vasomotor symptoms and/or signs. Spontaneous extracranial hemorrhagic phenomena (SEHP), including epistaxis, ecchymosis, and hematohidrosis (a disorder of bleeding through sweat glands), are poorly characterized features of PHDs.To critically appraise the association between SEHP and PHDs by systematically reviewing and pooling all reports of SEHP associated with headaches.Advanced searches using the PubMed/MEDLINE, Web of Science, Cochrane Library, Google Scholar, and ResearchGate databases were carried out for clinical studies by combining the terms "headache AND ecchymosis", "headache AND epistaxis", and "headache AND hematohidrosis" spanning all medical literature prior to October 10, 2015. Preferred Reporting Items for Systematic Reviews and Meta-analyses and Meta-analysis of Observational Studies in Epidemiology guidelines were applied.A total of 105 cases of SEHP associated with PHDs (83% migraine and 17% trigeminal autonomic cephalgias) were identified (median age 27 years, male to female ratio 1:2.3); 63% had epistaxis, 33% ecchymosis, and 4% hematohidrosis. Eighty-three percent of studies applied the International Classification of Headache Disorders diagnostic criteria. Eighty percent of the reported headaches were episodic and 20% were chronic. Twenty-four percent of studies reported recurrent episodes of SEHP.Our results suggest that SEHP may be rare features of PHDs. Future studies would benefit from the systematic characterization of these phenomena.

  View details for PubMedID 26611681

• Comparison of parenteral treatments of acute primary headache in a large academic emergency department cohort. Cephalalgia McCarthy, L. H., Cowan, R. P. 2015; 35 (9): 807-815

  Abstract

  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.

  View details for DOI 10.1177/0333102414557703

  View details for PubMedID 25366551

  View details for PubMedCentralID PMC4417651

• Prevalence of migraine headache and its weight on neurological burden in Africa: a 43-year systematic review and meta-analysis of community-based studies. Journal of the neurological sciences Woldeamanuel, Y. W., Andreou, A. P., Cowan, R. P. 2014; 342 (1-2): 1-15

  Abstract

  Headache burden is not adequately explored in Africa. Here, we measured weighted migraine prevalence from community-based studies in Africa.PubMed search was employed using terms 'headache in Africa' AND/OR 'migraine in Africa' for published literature from 1970 until January 31, 2014. PRISMA was applied for systematic review. Forest-plot meta-analysis, inter-study heterogeneity, and odds ratio were used to measure weighted prevalence, inter-gender, and urban-rural differences. Disability adjusted life years (DALYs) for migraine and other neurologic disorders in Africa were extracted from Global Burden of Diseases (GBD) 2000-2030.Among 21 community-based studies included (n=137,277), pooled migraine prevalence was 5.61% (95% CI 4.61, 6.70; random effects) among general population; while 14.89% (14.06, 15.74; fixed effects) among student cohorts. Female students had weighted OR of 2.13 (1.34, 3.37; p=0.0013). Prevalence of migraine was higher among urban population compared to rural settings. Migraine burden is bound to increase by more than 10% DALYs within the next decade.Africa has a crude estimate of 56 million people suffering from migraine. By virtue of mainly afflicting the younger working-age group, migraine disability has wider socioeconomic implications. Improving early headache management access points at community-level, training and research at facility-level, and healthy lifestyle modification among urban residents can help reduce this costly and disabling chronic progressive health problem.

  View details for DOI 10.1016/j.jns.2014.04.019

  View details for PubMedID 24814950

• Prevalence of migraine headache and its weight on neurological burden in Africa: A 43-year systematic review and Meta-analysis of community-based studies JOURNAL OF THE NEUROLOGICAL SCIENCES Woldeamanuel, Y. W., Andreou, A. P., Cowan, R. P. 2014; 342 (1-2): 1-15

  Abstract

  Headache burden is not adequately explored in Africa. Here, we measured weighted migraine prevalence from community-based studies in Africa.PubMed search was employed using terms 'headache in Africa' AND/OR 'migraine in Africa' for published literature from 1970 until January 31, 2014. PRISMA was applied for systematic review. Forest-plot meta-analysis, inter-study heterogeneity, and odds ratio were used to measure weighted prevalence, inter-gender, and urban-rural differences. Disability adjusted life years (DALYs) for migraine and other neurologic disorders in Africa were extracted from Global Burden of Diseases (GBD) 2000-2030.Among 21 community-based studies included (n=137,277), pooled migraine prevalence was 5.61% (95% CI 4.61, 6.70; random effects) among general population; while 14.89% (14.06, 15.74; fixed effects) among student cohorts. Female students had weighted OR of 2.13 (1.34, 3.37; p=0.0013). Prevalence of migraine was higher among urban population compared to rural settings. Migraine burden is bound to increase by more than 10% DALYs within the next decade.Africa has a crude estimate of 56 million people suffering from migraine. By virtue of mainly afflicting the younger working-age group, migraine disability has wider socioeconomic implications. Improving early headache management access points at community-level, training and research at facility-level, and healthy lifestyle modification among urban residents can help reduce this costly and disabling chronic progressive health problem.

  View details for DOI 10.1016/j.jns.2014.04.019

  View details for Web of Science ID 000338414500001

• CAM in the Real World: You May Practice Evidence-Based Medicine, But Your Patients Don't. Headache Cowan, R. P. 2014; 54 (6): 1097-1102

  Abstract

  Complementary and Alternative Medicine (CAM) approaches are widely used among individuals suffering from headache. The medical literature has focused on the evidence base for such use and has largely ignored the fact that these approaches are in wide use despite that evidence base.This article focuses on the uses of CAM by patients and suggests strategies for understanding and addressing this use without referring back to the evidence base. The rationale for this discussion pivots on the observation that patients are already using these approaches, and for many there are anecdotal and historical bases for use which patients find persuasive in the absence of scientific evidence.Until such time as the body of scientific literature adequately addresses non-conventional approaches, physicians must acknowledge and understand, as best as possible, CAM approaches which are in common use by patients. This is illustrated with a case study and examples from practice. This article does not review the evidence base for various CAM practices as this has been done well elsewhere.

  View details for DOI 10.1111/head.12364

  View details for PubMedID 24766436

• Does exercise make migraines worse and tension type headaches better? Current pain and headache reports Hindiyeh, N. A., Krusz, J. C., Cowan, R. P. 2013; 17 (12): 380-?

  Abstract

  Many non-pharmacological treatments have been implicated in the treatment of primary headache, with exercise being a common recommendation. In this review we first provide an overview of the relationship between exercise and primary headaches. We then review the physiology of pain modulation, with focus on the endogenous opioids, endocannabinoids, and neuropeptides calcitonin gene-related peptide (CGRP) and brain-derived neurotrophic factor (BDNF), and their associations with primary headache and exercise. Finally, we summarize current literature evaluating effects of exercise on primary headache in an effort to understand the benefits and disadvantages of exercise in primary headaches.

  View details for DOI 10.1007/s11916-013-0380-5

  View details for PubMedID 24234818

• Does exercise make migraines worse and tension type headaches better? Current pain and headache reports Hindiyeh, N. A., Krusz, J. C., Cowan, R. P. 2013; 17 (12): 380-?

  Abstract

  Many non-pharmacological treatments have been implicated in the treatment of primary headache, with exercise being a common recommendation. In this review we first provide an overview of the relationship between exercise and primary headaches. We then review the physiology of pain modulation, with focus on the endogenous opioids, endocannabinoids, and neuropeptides calcitonin gene-related peptide (CGRP) and brain-derived neurotrophic factor (BDNF), and their associations with primary headache and exercise. Finally, we summarize current literature evaluating effects of exercise on primary headache in an effort to understand the benefits and disadvantages of exercise in primary headaches.

  View details for DOI 10.1007/s11916-013-0380-5

  View details for PubMedID 24234818

• Executive Function Changes before Memory in Preclinical Alzheimer's Pathology: A Prospective, Cross-Sectional, Case Control Study PLOS ONE Harrington, M. G., Chiang, J., Pogoda, J. M., Gomez, M., Thomas, K., Marion, S. D., Miller, K. J., Siddarth, P., Yi, X., Zhou, F., Lee, S., Arakaki, X., Cowan, R. P., Thao Tran, T., Charleswell, C., Ross, B. D., Fonteh, A. N. 2013; 8 (11)

  Abstract

  Early treatment of Alzheimer's disease may reduce its devastating effects. By focusing research on asymptomatic individuals with Alzheimer's disease pathology (the preclinical stage), earlier indicators of disease may be discovered. Decreasing cerebrospinal fluid beta-amyloid42 is the first indicator of preclinical disorder, but it is not known which pathology causes the first clinical effects. Our hypothesis is that neuropsychological changes within the normal range will help to predict preclinical disease and locate early pathology.We recruited adults with probable Alzheimer's disease or asymptomatic cognitively healthy adults, classified after medical and neuropsychological examination. By logistic regression, we derived a cutoff for the cerebrospinal fluid beta amyloid42/tau ratios that correctly classified 85% of those with Alzheimer's disease. We separated the asymptomatic group into those with (n = 34; preclinical Alzheimer's disease) and without (n = 36; controls) abnormal beta amyloid42/tau ratios; these subgroups had similar distributions of age, gender, education, medications, apolipoprotein-ε genotype, vascular risk factors, and magnetic resonance imaging features of small vessel disease. Multivariable analysis of neuropsychological data revealed that only Stroop Interference (response inhibition) independently predicted preclinical pathology (OR = 0.13, 95% CI = 0.04-0.42). Lack of longitudinal and post-mortem data, older age, and small population size are limitations of this study.Our data suggest that clinical effects from early amyloid pathophysiology precede those from hippocampal intraneuronal neurofibrillary pathology. Altered cerebrospinal fluid beta amyloid42 with decreased executive performance before memory impairment matches the deposits of extracellular amyloid that appear in the basal isocortex first, and only later involve the hippocampus. We propose that Stroop Interference may be an additional important screen for early pathology and useful to monitor treatment of preclinical Alzheimer's disease; measures of executive and memory functions in a longitudinal design will be necessary to more fully evaluate this approach.

  View details for DOI 10.1371/journal.pone.0079378

  View details for Web of Science ID 000327308500055

  View details for PubMedID 24260210

  View details for PubMedCentralID PMC3832547

• Phospholipase C activity increases in cerebrospinal fluid from migraineurs in proportion to the number of comorbid conditions: a case-control study JOURNAL OF HEADACHE AND PAIN Fonteh, A. N., Pogoda, J. M., Chung, R., Cowan, R. P., Harrington, M. G. 2013; 14

  Abstract

  Migraineurs are more often afflicted by comorbid conditions than those without primary headache disorders, though the linking pathophysiological mechanism(s) is not known. We previously reported that phosphatidylcholine-specific phospholipase C (PC-PLC) activity in cerebrospinal fluid (CSF) increased during migraine compared to the same individual's well state. Here, we examined whether PC-PLC activity from a larger group of well-state migraineurs is related to the number of their migraine comorbidities.In a case-control study, migraineurs were diagnosed using International Headache Society criteria, and controls had no primary headache disorder or family history of migraine. Medication use, migraine frequency, and physician-diagnosed comorbidities were recorded for all participants. Lumbar CSF was collected between the hours of 1 and 5 pm, examined immediately for cells and total protein, and stored at -80°C. PC-PLC activity in thawed CSF was measured using a fluorometric enzyme assay. Multivariable logistic regression was used to evaluate age, gender, medication use, migraine frequency, personality scores, and comorbidities as potential predictors of PC-PLC activity in CSF.A total of 18 migraineurs-without-aura and 17 controls participated. In a multivariable analysis, only the number of comorbidities was related to PC-PLC activity in CSF, and only in migraineurs [parameter estimate (standard error) = 1.77, p = 0.009].PC-PLC activity in CSF increases with increasing number of comorbidities in migraine-without-aura. These data support involvement of a common lipid signaling pathway in migraine and in the comorbid conditions.

  View details for DOI 10.1186/1129-2377-14-60

  View details for Web of Science ID 000321647800001

  View details for PubMedID 23826990

  View details for PubMedCentralID PMC3704687

• Chronic daily headache NEUROPSYCHIATRY OF HEADACHE Cowan, R. P., Green, M. W., Muskin, P. R. 2013: 95–105

  View details for Web of Science ID 000321964200010

• Cerebrospinal fluid phosopholipase C activity increases in migraine. Cephalalgia Alfred N Fonteh, Rainbow Chung, Tara L Sharma, R Danielle Fisher, Janice M Pogoda, Robert Cowan, Michael G Harrington 2011; 31 (4): 456-462
• Capillary Endothelial Na+, K+, ATPase Transporter Homeostasis and a New Theory for Migraine Pathophysiology. Headache Harrington, M.G., Fonteh, A.N., Arakaki, X., Cowan, R.P., Ecke, L.E., Foster, H., Huhmer, A.F., & Biringer, R. 2010; 50 (3): 459-78
• The morphology and biochemistry of nanostructures provide evidence for synthesis and signaling functions in human cerebrospinal fluid. Cerebrospinal Fluid Res. Harrington MG, Fonteh AN, Oborina E, Liao P, Cowan RP, McComb G, Chavez JN, Rush J, Biringer RG, Huhmer AF. 2009: 6:10
• Prostaglandin D Synthase Isoforms from Cerebrospinal Fluid Vary with Brain Physiology. Disease Markers Harrinton MG, Fonteh AN, Biringer RG, Huhmer AF, Cowan RP. 2006; 22 (1-2): 73-81
• Cerebrospinal Fluid Sodium Increases in Migraine Headache Harrington MG, Fonteh AN, Cowan RP, Perrine K, Pogoda JM, Biringer, RG, Huhmer AFR. 2006; 46 (7): 1128-1135