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The ObserVational survey of the Epidemiology, tReatment and Care of MigrainE (OVERCOME; United States) study is a multicohort, longitudinal web survey that assesses symptomatology, consulting, diagnosis, treatment, and impact of migraine in the United States.Regularly updating population-based views of migraine in the United States provides a method for assessing the quality of ongoing migraine care and identifying unmet needs.The OVERCOME (US) 2018 migraine cohort involved: (I) creating a demographically representative sample of US adults using quota sampling (n = 97,478), (II) identifying people with active migraine in the past year via a validated migraine diagnostic questionnaire and/or self-reported medical diagnosis of migraine (n = 24,272), and (III) assessing consultation, diagnosis, and treatment of migraine (n = 21,143). The current manuscript evaluated whether those with low frequency episodic migraine (LFEM; 0-3 monthly headache days) differed from other categories on outcomes of interest.Among the migraine cohort (n = 21,143), 19,888 (94.1%) met our International Classification of Headache Disorders, 3rd edition-based case definition of migraine and 12,905 (61.0%) self-reported a medical diagnosis of migraine. Respondents' mean (SD) age was 42.2 (15.0) years; 15,697 (74.2%) were women. Having at least moderate disability was common (n = 8965; 42.4%) and around half (n = 10,783; 51.0%) had consulted a medical professional for migraine care in the past year. Only 4792 (22.7%) of respondents were currently using a triptan. Overall, 8539 (40.4%) were eligible for migraine preventive medication and 3555 (16.8%) were currently using migraine preventive medication. Those with LFEM differed from moderate and high frequency episodic migraine and chronic migraine on nearly all measures of consulting, diagnosis, and treatment.The OVERCOME (US) 2018 cohort revealed slow but steady progress in diagnosis and preventive treatment of migraine. However, despite significant impact among the population, many with migraine have unmet needs related to consulting for migraine, migraine diagnosis, and getting potentially beneficial migraine treatment. Moreover, it demonstrated the heterogeneity and varying unmet needs within episodic migraine.

Agustin Melo-Carrillo,1,2 Raul Rodriguez,3 Sait Ashina,1,2 Brittany Lipinski,3 Paul Hart,4 Rami Burstein1,2 1Department of Anesthesia, Critical Care and Pain Medicine, Beth Israel Deaconess Medical Center, Boston, MA, USA; 2Department of Anesthesia, Harvard Medical School, Boston, MA, USA; 3Delray Center for Healing, Delray Beach, FL, USA; 4Heart to Heart, Lenexa, KS, USACorrespondence: Rami Burstein, Tel +1 617 735-2832, Fax +1 617 735-2833, Email rburstei@bidmc.harvard.eduBackground and Goals: Psychotherapy is one of the most highly recommended and practiced approaches for the treatment of Generalized anxiety disorder (GAD). Commonly defined as excessive worry that is uncontrollable, GAD is one of the most prevalent psychiatric disorders. Anxiety is also one of the most common associated symptoms of migraine. Exposing migraineurs to narrow band green light (nbGL) reduces their anxiety and anxiety-like physiological symptoms such as throat tightness, shortness of breath, and palpitations. Here, we sought to determine whether the reduced anxiety described by our patients was secondary to the reduced headache or independent of it. The goal of the current study was therefore to determine whether exposure to nbGL can reduce anxiety in GAD patients who are not migraineurs.Patients and Methods: Included in this open-label, proof-of-concept, prospective study were 13 patients diagnosed with moderate-to-severe GAD. We used the State-Trait Anxiety Inventory Questionnaire (Y-1) to compare anxiety level before and after each 45-minutes psychotherapy session conducted in white light (WL) (intensity = 100± 5 candela/m2) vs nbGL (wavelength = 520± 10nm (peak ± range), intensity = 10± 5 candela/m2).Results: Here, we show that psychotherapy sessions conducted under nbGL increase positive and decrease negative feelings significantly more than psychotherapy sessions conducted under regular room light (χ2 = 0.0001).Conclusion: The findings provide initial evidence for the potential benefit of conducting psychotherapy sessions for patients suffering GAD under nbGL conditions. Given the absence of side effects or risks, we suggest that illuminating rooms used in psychotherapy with nbGL be considered an add-on to the treatment of GAD.Keywords: photophobia, migraine, psychotherapy, GAD, retina, depression

Objective To estimate the relative frequencies of hemicrania continua and its clinical features in adult patients who were evaluated for headache in a clinic-based setting. Methods PubMed and Embase were searched for observational, clinic-based studies published between 1 January 2004 and 1 February 2022, that reported on the relative frequencies of hemicrania continua and its clinical features. Two independent investigators (HMA and SA-K) screened titles, abstracts, and full text-articles. A random-effects meta-analysis was conducted to estimate pooled relative frequencies of hemicrania continua and its clinical features across clinic-based studies. Results Eleven clinic-based studies were deemed eligible for inclusion. Of these, eight studies reported on the relative frequency of hemicrania continua among adult patients (n = 9854) who were evaluated for headache in a tertiary care unit. The pooled relative frequency of hemicrania continua was found to be 1.8% (95% CI; 1.0–3.3). Considerable heterogeneity was noted across studies (I2 = 89.8%). The three most common symptoms associated with hemicrania continua were lacrimation (72.3%), conjunctival injection (69.8%), and restlessness/agitation (60.2%). Conclusion The findings of this meta-analysis suggest that there is limited epidemiologic data on the relative frequencies of hemicrania continua and its clinical features. Standardized data acquisition and reporting are needed to estimate prevalence rates more accurately and to better understand epidemiologic patterns. This, in turn, should increase awareness of the impact that hemicrania continua has in clinical practice.

Occipital headache, the perception of pain in the back of the head, is commonly described by patients diagnosed with migraine, tension-type headache, and occipital neuralgia. The greater and lesser occipital nerves play central role in the pathophysiology of occipital headache. In the clinical setup, such headaches are often treated with onabotulinumtoxinA, a neurotoxin capable of disrupting ability of nociceptors to get activated and/or release proinflammatory neuropeptides. Attempting to understand better onabotulinumtoxinA mechanism of action in reducing headache frequency, we sought to determine its effects on expression of inflammatory genes in injected occipital tissues. To achieve this goal, we injected 40 units of onabotulinumtoxinA into four muscle groups (occipitalis, splenius capitis, semispinalis capitis, and trapezius muscles—all located on one side of the occiput) of patients with chronic bilateral occipital headache scheduled for occipital nerve decompression surgery 1 month later. At the time of surgery, we collected discarded muscle, fascia and periosteum tissues from respective locations on both sides of the neck and occiput and performed targeted transcriptome analyses to determine expression level of inflammatory genes in onabotulinumtoxinA-injected and onabotulinumA-uninjected tissues. We found that (i) onabotulinumtoxinA alters expression of inflammatory genes largely in periosteum, minimally in muscle and not at all in fascia; (ii) expression of inflammatory genes in uninjected periosteum and muscle is significantly higher in historical onabotulinumA responders than historical non-responders; (iii) in historical responders’ periosteum, onabotulinumA decreases expression of nearly all significantly altered genes, gene sets that define well recognized inflammatory pathways (e.g. pathways involved in adaptive/innate immune response, lymphocyte activation, and cytokine, chemokine, NF-kB, TNF and interferon signalling), and abundance of 12 different immune cell classes (e.g. neutrophils, macrophages, cytotoxic T-, NK-, Th1-, B- and dendritic-cells), whereas in historical non-responders it increases gene expression but to a level that is nearly identical to the level observed in the uninjected periosteum and muscle of historical responders; and surprisingly (iv) that the anti-inflammatory effects of onabotulinumA are far less apparent in muscles and absent in fascia. These findings suggest that in historical responders’ periosteum—but not muscle or fascia—inflammation contributes to the pathophysiology of occipital headache, and that further consideration should be given to the possibility that onabotulinumA mechanism of action in migraine prevention could also be achieved through its ability to reduce pre-existing inflammation, likely through localized interaction that lead to reduction in abundance of immune cells in the calvarial periosteum.

Neck pain and headache are 2 of the most common complications of whiplash injury. Therefore, we performed a systematic literature search on PubMed and Embase for publications reporting on the prevalence of neck pain and headache after whiplash injury. The literature search identified 2709 citations of which 44 contained relevant original data. Of these, 27 studies provided data for the quantitative analysis. For non-population-based studies, the present metaanalysis showed that a pooled relative frequency of neck pain was 84% confidence interval (68–95%) and a pooled relative frequency of headache was 60% (46–73%), within 7 days after whiplash injury. At 12 months after injury, 38% (32–45%) of patients with whiplash still experienced neck pain, while 38% (18–60%) of whiplash patients reported headache at the same time interval after injury. However, we also found considerable heterogeneity among studies with I2-values ranging from 89% to 98% for the aforementioned meta-analyses. We believe that the considerable heterogeneity among studies underscores the need for clear-cut definitions of whiplash injury and standardized reporting guidelines for postwhiplash sequelae such as neck pain and headache. Future studies should seek to optimize these aspects paving the way for a better understanding of the clinical characteristics and natural course of whiplash-associated sequelae.

Suture-line injections of onabotulinumtoxinA alter a neuronal function along a central nervous system pathway involved in the pathophysiology of migraine that is secondary to appearance of SNAP25 in dural nerve fibers., OnabotulinumtoxinA (BoNT-A) is an Food and Drug Administration-approved, peripherally acting preventive migraine drug capable of inhibiting meningeal nociceptors. Expanding our view of how else this neurotoxin attenuates the activation of the meningeal nociceptors, we reasoned that if the stimulus that triggers the activation of the nociceptor is lessened, the magnitude and/or duration of the nociceptors' activation could diminish as well. In the current study, we further examine this possibility using electrocorticogram recording techniques, immunohistochemistry, and 2-photon microscopy. We report (1) that scalp (head) but not lumbar (back) injections of BoNT-A shorten the period of profound depression of spontaneous cortical activity that follows a pinprick-induced cortical spreading depression (CSD); (2) that neither scalp nor lumbar injections prevent the induction, occurrence, propagation, or spreading velocity of a single wave of CSD; (3) that cleaved SNAP25—one of the most convincing tools to determine the anatomical targeting of BoNT-A treatment—could easily be detected in pericranial muscles at the injection sites and in nerve fibers of the intracranial dura, but not within any cortical area affected by the CSD; (4) that the absence of cleaved SNAP25 within the cortex and pia is unrelated to whether the blood–brain barrier is intact or compromised; and (5) that BoNT-A does not alter vascular responses to CSD. To the best of our knowledge, this is the first report of peripherally applied BoNT-A's ability to alter a neuronal function along a central nervous system pathway involved in the pathophysiology of migraine.

Objectives Tension-type headache (TTH) is the most prevalent primary headache disorder. We assessed the cross-sectional impact of TTH on health related quality of life (HRQoL) in a general population. We also examined the association of HRQoL scores with headache frequency, disability, medication overuse, poor self-rated health, psychiatric comorbidity, and pain sensitivity in individuals with TTH. Methods A sample of 547 subjects completed a headache diagnostic interview, the SF-12 to calculate physical (PCS) and mental (MCS) health component scores, depression (major depression inventory [MDI]) and neuroticism (Eysenck Personality Questionnaire) measures. We defined the following headache diagnosis categories: pure TTH, pure migraine, and coexistent headache (TTH + migraine). Cases were further classified into chronic (≥15) or episodic ( Results Using generalized linear models (GLM) adjusted for age, sex and education, both PCS-12 and MCS-12 scores varied in groups distinguished by migraine and TTH status; scores were lower for individuals with coexistent headache (TTH + migraine; n=83), followed by pure TTH (n=97) and pure migraine (n=43) compared to the no headache group (n=324) (p≤0.001). In analyses considering chronicity, PCS-12 scores were lower in chronic coexistent headache followed by pure chronic TTH (CTTH), episodic migraine +/− episodic TTH (ETTH) and pure ETTH than in the no headache group (p≤0.001). MCS-12 scores were lower in pure CTTH, followed by chronic coexistent headache, episodic migraine +/− ETTH and pure ETTH compared to the no headache group (p≤0.001). Multiple regression models showed that in TTH, lower PCS-12 scores were associated with age (p=0.04), female sex (p=0.02), and poor self-rated health (p≤0.001). Lower MCS-12 scores in TTH were associated with depression (p≤0.001). Conclusions In a population sample, TTH, and to higher degree CTTH, are associated with decreased HRQoL.

ObjectiveTo assess the proportion of individuals who report dizziness and/or vertigo during the prodromal phase or headache phase of migraine.MethodsThe databases of MEDLINE and EMBASE were searched for studies on dizziness and/or vertigo during the prodromal phase or headache phase of migraine. Pooled relative frequencies were estimated using a random-effects meta-analysis.ResultsWe identified nine articles eligible for inclusion. Of these, one study reported results for the prodromal phase, seven studies for the headache phase and one study for both the prodromal and headache phase. In the prodromal phase, 9.0% of individuals with migraine reported dizziness, while 3.3% reported vertigo. During the headache phase, relative frequency of dizziness ranged from 6.7% to 59.6%, while vertigo ranged from 6.4% to 44.7%. The meta-analysis showed a relative frequency of 35.7% for dizziness (95% CI = 13.7–61.5%, I2 = 99%) and 33.9% for vertigo (95% CI = 26.7–41.5%, I2 = 87%). Study quality was rated 5/9 or below for seven studies and 6/9 or above for two studies.ConclusionWe found that there is a scarcity of literature on dizziness and vertigo as prodromal- and headache-associated symptoms in individuals with migraine. Methodological variations confound comparisons of epidemiological patterns, although it appears that dizziness and vertigo are more frequent during the headache phase of migraine, compared with the prodromal phase. Future studies should ensure use of standardized definitions and rigorous methodology to enable accurate measurements of dizziness and vertigo in migraine.

OBJECTIVE To systematically identify risk factors for the development of post-traumatic headache (PTH) attributed to traumatic brain injury (TBI) as defined in the International Classification of Headache Disorders (ICHD). BACKGROUND PTH is a common sequela of TBI and a leading cause of injury-related disability worldwide. However, little is known about risk factors for the development of PTH attributed to TBI. METHODS We searched PubMed and Embase for literature on risk factors for the development of acute and/or persistent PTH attributed to TBI in accordance with any version of the ICHD. Original studies published in English and of prospective, cross-sectional or retrospective design were considered for the review. Data extraction was performed independently by 2 investigators. RESULTS Of 1993 potentially relevant articles identified, 3 articles met the inclusion criteria. The following risk factors were assessed for the development of acute PTH: age, sex, type of injury, loss of consciousness, previous TBIs, history of primary headache disorders, history of chronic pain condition other than headache, current treatment for depression/anxiety, attention or learning disorders, body mass index, and other diseases (not further specified). None of the included studies assessed risk factors for the development of persistent PTH. CONCLUSIONS We found that there is little evidence for any risk factors involved in the development of acute PTH, whereas no study had assessed risk factors for the development of persistent PTH. Further studies are warranted and should be powered to examine possible risk factors for the development of PTH. Rigorous methodology and standardized monitoring should be prioritized to support high-quality research and validate potential findings.

Background Status migrainosus is a condition with limited epidemiological knowledge, and no evidence-based treatment guideline or rational-driven assessment of successful treatment outcome. To fill this gap, we performed a prospective observational study in which we documented effectiveness of treatment approaches commonly used in a tertiary headache clinic. Material and methods Patients with episodic and chronic migraine who experienced continuous and prolonged attacks for more than 72 hours were treated with dexamethasone (4 mg orally twice daily for 3 days), ketorolac (60 mg intramuscularly), bilateral nerve blocks (1–2% lidocaine, 0.1–0.2 ml for both supraorbital and supratrochlear nerves, 1 ml for both auriculotemporal nerves, and 1 ml for both greater occipital nerves), or naratriptan (2.5 mg twice daily for 5 days). Hourly (for the first 24 hours) and daily (for first 30 days) change in headache intensity was documented using appropriate headache diaries. Results Fifty-four patients provided eligible data for 60 treatment attempts. The success rate of rendering patients pain free within 24 hours and maintaining the pain-free status for 48 hours was 4/13 (31%) for dexamethasone, 7/29 (24%) for nerve blocks, 1/9 (11%) for ketorolac and 1/9 (11%) for naratriptan. These success rates depended on time to remission, as the longer we allowed the treatments to begin to work and patients to become pain free (i.e. 2, 12, 24, 48, 72, or 96 hours), the more likely patients were to achieve and maintain a pain-free status for at least 48 hours. Discussion These findings suggest that current treatment approaches to terminating status migrainosus are not satisfactory and call attention to the need to develop a more scientific approach to define a treatment response for status migrainosus.

Objective To investigate clinical characteristics and treatment patterns in persistent post-traumatic headache attributed to mild traumatic brain injury. Methods A total of 100 individuals with persistent post-traumatic headache attributed to mild traumatic brain injury were enrolled between July 2018 and June 2019. Deep phenotyping was performed using a semi-structured interview while allodynia was assessed using the 12-item Allodynia Symptom Checklist. Results In 100 subjects with persistent post-traumatic headache, the mean headache frequency was 25.4 ± 7.1 days per month. The most common headache phenotype was chronic migraine-like headache (n = 61) followed by combined episodic migraine-like and tension-type-like headache (n = 29) while nine subjects reported “pure” chronic tension-type-like headache. The most frequent trigger factors were stress, lack of sleep, and bright lights. A history of preventive medication use was reported by 63 subjects, of which 79% reported failure of at least one preventive drug, while 19% reported failure of at least four preventive drugs. Cutaneous allodynia was absent in 54% of the subjects, mild in 23%, moderate in 17%, and severe in 6%. Conclusions The headache profile of individuals with persistent post-traumatic headache most often resembled a chronic migraine-like phenotype or a combined episodic migraine-like and tension-type-like headache phenotype. Migraine-specific preventive medications were largely reported to be ineffective. Therefore, there is a pressing need for pathophysiological insights and disease-specific therapies.

Background Neck pain is a frequent complaint among patients with migraine and seems to be correlated with the headache frequency. Neck pain is more common in patients with chronic migraine compared to episodic migraine. However, prevalence of neck pain in patients with migraine varies among studies. Objective To estimate the prevalence of neck pain in patients with migraine and non-headache controls in observational studies. Methods A systematic literature search on PubMed and Embase was conducted to identify studies reporting prevalence of neck pain in migraine patients. This review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Data was extracted by two independent investigators and results were pooled using random-effects meta-analysis. The protocol was registered with PROSPERO (CRD42021264898). Results The search identified 2490 citations of which 30 contained relevant original population based and clinic-based data. Among these, 24 studies provided data eligible for the analysis. The meta-analysis for clinic-based studies demonstrated that the pooled relative frequency of neck pain was 77.0% (95% CI: 69.0–86.4) in the migraine group and 23.2% (95% CI:18.6–28.5) in the non-headache control group. Neck pain was more frequent in patients with chronic migraine (87.0%, 95% CI: 77.0–93.0) compared to episodic migraine (77.0%, 95% CI: 69.0–84.0). Neck pain was 12 times more prevalent in migraine patients compared to non-headache controls and two times more prevalent in patients with chronic migraine compared to episodic migraine. The calculated heterogeneity (I2 values) ranged from 61.3% to 72.0%. Conclusion Neck pain is a frequent complaint among patients with migraine. The heterogeneity among the studies emphasize important aspects to consider in future research of neck pain in migraine to improve our understanding of the driving mechanisms of neck pain in a major group of migraine patients.

Objectives We aimed to investigate whether coexistent self-reported neck pain influences cephalic and extracephalic pain sensitivity in individuals with migraine and tension-type headache (TTH) in relation to diagnosis and headache frequency. Methods A population of 496 individuals completed a headache interview based on ICHD criteria, providing data collected by self-administered questionnaires, assessments of pericranial total tenderness score (TTS) and pressure pain thresholds (PPT). Stimulus-response (SR) functions for pressure vs. pain were recorded. Presence of neck pain in the past year was assessed by the self-administered questionnaire. We categorized participants by primary headache type. We also categorized participants into 3 groups by headache frequency: chronic (≥15) or episodic ( Results Individuals with chronic followed by episodic headache had higher TTS than controls (overall p≤0.001). The difference between chronic and episodic headache subgroups was significant in the group with neck pain (p≤0.001) but not in the group without neck pain. In individuals with neck pain, mean TTS was higher in coexistent headache (migraine and TTH), 23.2 ± 10.7, and pure TTH, 17.8 ± 10.3, compared to pure migraine, 15.9 ± 10.9 and no headache 11.0 ± 8.3 (overall p Conclusions Coexistent neck pain is associated with greater pericranial tenderness in individuals with chronic headache and to a lesser degree in those with episodic headache. Sensitization may be a substrate or consequence of neck pain and primary headache, but a longitudinal study would be needed for further clarification.

Aim Evaluate the efficacy and safety of non-invasive vagus nerve stimulation for migraine prevention. Methods After completing a 4-week diary run-in period, adults who had migraine with or without aura were randomly assigned to receive active non-invasive vagus nerve stimulation or sham therapy during a 12-week double-blind period. Results Of 336 enrolled participants, 113 (active, n = 56; sham, n = 57) completed ≥70 days of the double-blind period and were ≥66% adherent with treatment, comprising the prespecified modified intention-to-treat population. The COVID-19 pandemic led to early trial termination, and the population was ∼60% smaller than the statistical target for full power. Mean reduction in monthly migraine days (primary endpoint) was 3.12 for the active group and 2.29 days for the sham group (difference, −0.83; p = 0.2329). Responder rate (i.e. the percentage of participants with a ≥50% reduction in migraine days) was greater in the active group (44.87%) than the sham group (26.81%; p = 0.0481). Prespecified subgroup analysis suggested that participants with aura responded preferentially. No serious device-related adverse events were reported. Conclusions These results suggest clinical utility of non-invasive vagus nerve stimulation for migraine prevention, particularly for patients who have migraine with aura, and reinforce the well-established safety and tolerability profile of this therapy. Trial Registration: ClinicalTrials.gov (NCT03716505).

Background Migraine is a complex neurological disorder involving generalized abnormalities in processing sensory information. Adopting evidence that central sensitization imposes major hurdles in the treatment of migraine, we hypothesized that it is the non-ictal (rather than ictal) allodynia that may determine the outcome of migraine prevention with peripherally-acting drugs. Methods To test this hypothesis, we used Quantitative Sensory Testing to determine whether it is possible to identify a patient’s response to prophylactic treatment with galcanezumab based on presence/absence of cephalic and/or extracephalic allodynia during the pre-treatment non-ictal phase of migraine. Results Using strict criteria for allodynia (heat 32–40°C, cold 32–20°C, mechanical 50% decrease in monthly migraine days) and 85% in the 19 non-responders; (b) the incidence of non-ictal extracephalic allodynia distinguishes responders from non-responders less accurately; and that (c) the incidence of non-ictal cephalic allodynia was similar in the chronic migraine and high-frequency episodic migraine groups. Conclusions Clinically, the findings suggest that presence/absence of non-ictal allodynia can be used to identify galcanezumab responders with nearly 80% accuracy and galcanezumab non-responders with nearly 85% accuracy. Mechanistically, the presence of non-ictal allodynia (reflecting a state of activity-independent central sensitization) in both chronic migraine and high-frequency episodic migraine patients raises the possibility that the state of non-ictal allodynia may be attributed to physiological properties of central trigeminovascular neurons that are due to the genetic load of the individual patient rather than their migraine frequency.

Objective To investigate the association of psychiatric and cognitive comorbidities with persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). Methods A total of 100 patients with persistent PTH attributed to mild TBI and 100 age- and gender-matched healthy controls free of mild TBI were enrolled between July 2018 and June 2019. Quality of sleep was evaluated using the Pittsburgh Sleep Quality Index, while symptoms of anxiety and depression were assessed using the Hospital Anxiety and Depression Scale. Cognitive impairment was evaluated using the Montreal Cognitive Assessment questionnaire, while post-traumatic stress disorder (PTSD) was assessed using the Harvard Trauma Questionnaire. Results In 100 patients with persistent PTH, 85% reported poor quality sleep, compared with 42% of healthy controls (P P P Conclusions Poor quality of sleep as well as symptoms suggestive of anxiety and depression were more common in patients with persistent PTH than healthy controls. Clinicians should screen patients with persistent PTH for these comorbidities and develop treatment plans that account for their presence.

Objective Pain specialists treat patients with headache and interface with those who use opioids more so than neurologists and headache specialists. We assessed the headache medicine knowledge and needs of pain specialists. Design/Setting Cross-sectional online survey. Subjects Members of the American Academy of Pain Medicine. Methods Survey was based on a prior survey of primary care providers’ knowledge and needs and was iteratively updated by four headache specialists, two with pain medicine affiliations. Results Of the 105 respondents, 71.4% were physicians, 34.3% were women, and they averaged 20.0 ± 13.6 years in practice. The most common specialty was anesthesia (36.1%, n = 35/97) followed by neurology (14.4%, n = 14/97). About half of providers (55.7%, n = 34/61 and 53.3%, n = 32/60) were familiar with the American Academy of Neurology Guidelines for pharmacological migraine prevention and the Choosing Wisely Campaign recommendations for limiting neuroimaging and opioids. Less than half of all providers (39.7%, n = 23/58) were familiar with the American Headache Society guidelines for emergency management of migraine. Providers were aware of Level A evidence-based nonpharmacological therapies, with over three-fourths recognizing cognitive behavioral therapy (80.7%, n = 50/62) and biofeedback (75.8%, n = 47/62) as evidence-based interventions. About 80% of providers (n = 50/64) estimate making migraine diagnoses in ≤50% of their patients with headache. Providers consider starting preventive headache therapy at 7.1 ± 3.9 days/month and report referring 34.3%±34.2% of patients to behavioral interventions. Conclusions Dissemination and implementation of headache guidelines is needed for pain medicine specialists. Providers may need help diagnosing migraine based on currently accepted guidelines and referring for evidence-based behavioral therapies.

Background Post-traumatic headache (PTH) is associated with considerable disability and reduced health-related quality of life. Despite the very high prevalence of PTH, there are no evidence-based guidelines for PTH treatment. Thus, we found it timely to provide a systematic review of the current literature on acute and preventive pharmacological treatment of PTH using PubMed and Embase databases. Findings Included studies involved acute and preventive pharmacological treatment of headache attributed to traumatic injury to the head in adherence to the International Classification of Headache Disorders (ICHD) criteria. Of 1424 potentially relevant articles identified, 63 were retrieved for detailed evaluation and seven studies (one prospective and six retrospective) met the inclusion criteria. None of the seven included studies were randomized clinical trials (RCTs) or used a placebo-controlled study design. Conclusion We found that there is a lack of high-quality evidence-based studies on the pharmacological treatment of PTH. Future studies are highly needed and must emphasize open-label studies with rigorous methodology or RCTs with a placebo-controlled design.

Background Botulinum neurotoxin type A, an FDA-approved prophylactic drug for chronic migraine, is thought to achieve its therapeutic effect through blocking activation of unmyelinated meningeal nociceptors and their downstream communications with myelinated nociceptors and potentially the vasculature and immune cells. Prior investigations to determine botulinum neurotoxin type A effects on meningeal nociceptors were carried out in male rats and tested with stimuli that act outside the blood brain barrier. Here, we sought to explore the effects of extracranial injections of botulinum neurotoxin type A on activation of meningeal nociceptors by cortical spreading depression, an event which occurs inside the blood brain barrier, in female rats. Material and methods Using single-unit recording, we studied myelinated C- and unmyelinated Aδ-meningeal nociceptors' responses to cortical spreading depression 7–14 days after injection of botulinum neurotoxin type A or saline along calvarial sutures. Results In female rats, responses to cortical spreading depression were typically more prolonged and, in some cases, began at relatively longer latencies post-cortical spreading depression, than had been observed in previous studies in male rats. Extracranial administration of botulinum neurotoxin type A reduced significantly the prolonged firing of the meningeal nociceptors, in the combined sample of Aδ- and C-fiber, but not their response probability. Discussion The findings suggest that the mechanism of action by which botulinum neurotoxin type A prevents migraine differ from the one by which calcitonin gene-related peptide monoclonal antibodies prevent migraine and that even when the origin of migraine is central (i.e. in the cortex), a peripherally acting drug can intercept/prevent the headache.

Tension-type headache is the most common primary headache disorder. The life-time prevalence of tension-type headache in general population is between 30 to 78%. Tension-type has the tremendous socio-economic impact on the individual and the society. Unfortunately, it is the least studied primary headache. The pathophysiology of this headache disorder is not fully understood. The diagnosis of tension-type headache is based on the history, and general and neurological examinations. Abnormalities in peripheral and central nociceptive nervous systems in combination with environmental and genetic factors may play a role in the pathophysiology of tension-type headache. The pharmacotherapy of episodic tension-type headache is non-specific and includes simple analgesics and nonsteroidal anti-inflammatory drugs. Tricyclic antidepressants are the mainstay in the prophylactic treatment of chronic tension-type headache.

The Phase 3b FOCUS study demonstrated the efficacy and tolerability of fremanezumab, a humanised IgG2Δa monoclonal antibody that selectively targets the calcitonin gene-related peptide, for migraine prevention in patients with documented inadequate response to 2-4 prior preventive treatment classes. This subgroup analysis aimed to evaluate acute medication use in fremanezumab treated patients who had baseline medication overuse (MO; any acute medication ≥15 days/month or triptans, ergots, or combination medications ≥10 days/month).In the double-blind (DB) period (DBP) of FOCUS, patients were randomised (1:1:1) to quarterly/monthly fremanezumab, or placebo. Patients completing the DBP entered the open-label extension (OLE) and received monthly fremanezumab; results from OLE are stratified by DB randomisation group. Changes from baseline in monthly average days of acute medication use and proportions of patients reverting to no MO were evaluated.Patients with MO (427/838) had significant reductions in acute medication use with quarterly (least squares mean change, −3.8) or monthly (−4.7) fremanezumab during the DBP, versus placebo (−0.7; PFremanezumab patients with prior inadequate response to 2-4 prior classes of preventive medications and MO experienced a reduction in acute headache MO.

Despite the growing awareness across the general population, migraine is often underdiagnosed and undertreated in socially and economically marginalized groups. The present study aimed to investigate the differential effects of race and income on other sociodemographic data and hospital length of stay in patients admitted to hospital with a primary diagnosis of migraine headache.We utilized the Nationwide Inpatient Sample (NIS) database to identify patients admitted from 2004 to 2017 with a primary diagnosis of migraine. Information on demographic and length of stay data was obtained. Only patients older than 18 years were selected and age outliers were excluded. Race groups were identified as "Caucasian", "African American", "Hispanic", "Asian or Pacific Islander", "Native American", or "Others". Income was identified as the estimated median household income of residents in the patient's ZIP Code.A total of 106,761,737 valid cases were identified. After applying our case inclusion criteria, only 61453 (median age = 42 years, range = 18-78 years) were included. Patients identified as "African American", "Hispanic" or "Native American" were more likely to have lower household income (p0.001), whereas higher income was found for the patients identified as "Caucasian", even when men and women were considered separately (p0.001). No effects of race and/or household income was found on the length of stay in hospital.The occurrence of migraine diagnosis on hospital admission in the USA can be impacted by culturally driven patient-clinician communication differences between ethnic groups.

Tension-type headache (TTH) is the most prevalent neurological disorder worldwide and is characterized by recurrent headaches of mild to moderate intensity, bilateral location, pressing or tightening quality, and no aggravation by routine physical activity. Diagnosis is based on headache history and the exclusion of alternative diagnoses, with clinical criteria provided by the International Classification of Headache Disorders, third edition. Although the biological underpinnings remain unresolved, it seems likely that peripheral mechanisms are responsible for the genesis of pain in TTH, whereas central sensitization may be involved in transformation from episodic to chronic TTH. Pharmacological therapy is the mainstay of clinical management and can be divided into acute and preventive treatments. Simple analgesics have evidence-based effectiveness and are widely regarded as first-line medications for the acute treatment of TTH. Preventive treatment should be considered in individuals with frequent episodic and chronic TTH, and if simple analgesics are ineffective, poorly tolerated or contraindicated. Recommended preventive treatments include amitriptyline, venlafaxine and mirtazapine, as well as some selected non-pharmacological therapies. Despite the widespread prevalence and associated disability of TTH, little progress has been made since the early 2000s owing to a lack of attention and resource allocation by scientists, funding bodies and the pharmaceutical industry.

Tension-type headache (TTH) is the most prevalent neurological disorder worldwide and is characterized by recurrent headaches of mild to moderate intensity, bilateral location, pressing or tightening quality, and no aggravation by routine physical activity. Diagnosis is based on headache history and the exclusion of alternative diagnoses, with clinical criteria provided by the International Classification of Headache Disorders, third edition. Although the biological underpinnings remain unresolved, it seems likely that peripheral mechanisms are responsible for the genesis of pain in TTH, whereas central sensitization may be involved in transformation from episodic to chronic TTH. Pharmacological therapy is the mainstay of clinical management and can be divided into acute and preventive treatments. Simple analgesics have evidence-based effectiveness and are widely regarded as first-line medications for the acute treatment of TTH. Preventive treatment should be considered in individuals with frequent episodic and chronic TTH, and if simple analgesics are ineffective, poorly tolerated or contraindicated. Recommended preventive treatments include amitriptyline, venlafaxine and mirtazapine, as well as some selected non-pharmacological therapies. Despite the widespread prevalence and associated disability of TTH, little progress has been made since the early 2000s owing to a lack of attention and resource allocation by scientists, funding bodies and the pharmaceutical industry.

Migraine is a prevalent primary headache disorder and is usually considered as benign. However, structural and functional changes in the brain of individuals with migraine have been reported. High frequency of white matter abnormalities, silent infarct-like lesions, and volumetric changes in both gray and white matter in individuals with migraine compared to controls have been demonstrated. Functional magnetic resonance imaging (MRI) studies found altered connectivity in both the interictal and ictal phase of migraine. MR spectroscopy and positron emission tomography studies suggest abnormal energy metabolism and mitochondrial dysfunction, as well as other metabolic changes in individuals with migraine. In this review, we provide a brief overview of neuroimaging studies that have helped us to characterize some of these changes and discuss their limitations, including small sample sizes and poorly defined control groups. A better understanding of alterations in the brains of patients with migraine could help not only in the diagnosis but may potentially lead to the optimization of a targeted anti-migraine therapy.

Objective To investigate the role of calcitonin gene-related peptide (CGRP) in persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI). Methods A total of 100 individuals with persistent PTH attributed to mild TBI and 100 age- and gender-matched healthy controls were enrolled between July 2018 and June 2019. Blood was drawn from the antecubital vein and subsequently analyzed using a validated radioimmunoassay for human CGRP. Measurements were performed on coded samples by a board-certified laboratory technician who was blind to clinical information. Results CGRP plasma levels were lower in subjects with persistent PTH (mean, 75.8 pmol/L; SD, 26.4 pmol/L), compared with age- and gender-matched healthy controls (mean, 88.0 pmol/L; SD, 34.1 pmol/L) ( p = 0.04). No correlation was found of CGRP plasma levels with monthly headache days ( r = −0.11; p = 0.27), monthly migraine-like days ( r = 0.15; p = 0.13), headache quality ( r = −0.14; p = 0.15), or a chronic migraine-like headache phenotype ( r = −0.02; p = 0.85). Conclusions CGRP plasma measurements are unlikely a feasible blood-based biomarker of persistent PTH. Future studies should assess whether CGRP plasma measurements can be used to predict development of persistent PTH.

Background We evaluated the efficacy of fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, in patients with chronic migraine (CM) with and without medication overuse (MO). Methods In a 12-week, phase 3 trial, patients with CM were randomized to fremanezumab quarterly (675 mg/placebo/placebo), monthly (675 mg/225 mg/225 mg), or placebo. Post hoc analyses assessed the impact of fremanezumab in patients with and without MO (monthly use of acute headache medication ≥15 days, migraine-specific acute medication ≥10 days, or combination medication ≥10 days) on efficacy outcomes, including headache days of at least moderate severity (HDs), and six-item Headache Impact Test (HIT-6) and Migraine-Specific Quality of Life (MSQoL) questionnaire scores. Results Of 1130 patients enrolled, 587 (51.9%) had baseline MO. Fremanezumab reduced placebo-adjusted least-squares mean (95% confidence interval) monthly HDs (− 2.2 [− 3.1 to − 1.2] and − 2.7 [− 3.7 to − 1.8]; P P = 0.0026; monthly − 1.4 [− 2.3 to − 0.6], P = 0.0017). Significantly more fremanezumab-treated patients had ≥ 50% reduction in HDs versus placebo, regardless of baseline MO (with: quarterly 70/201 [34.8%], monthly 78/198 [39.4%] vs placebo 26/188 [13.8%]; without: quarterly 71/174 [40.8%], monthly 75/177 [42.4%] vs placebo 41/183 [22.4%]). Fremanezumab improved HIT-6 and MSQoL scores. Significantly more fremanezumab-treated patients reverted to no MO (quarterly 111/201 [55.2%], monthly 120/198 [60.6%]) versus placebo (87/188 [46.3%]). Conclusions Fremanezumab is effective for prevention of migraine in patients with CM, regardless of MO, and demonstrated a benefit over placebo in reducing MO. Trial registration ClinicalTrials.gov NCT02621931 (HALO CM), registered December 12, 2012.

To assess the proportion of pediatric patients who develop post-traumatic stress disorder (PTSD) attributed to traumatic brain injury (TBI).PubMed and Embase were searched from database inception until January 26, 2019. Two independent investigators screened titles, abstracts, and subsequently, full-text articles. Following this, the same investigators also extracted data relevant for the scope of this review.Ten articles were included in this review. In these, six unique cohorts were described, with relative frequencies of PTSD attributed TBI ranging from 3.3% to 48.5%. Two studies also found that PTSD was more common in children after TBI compared to pediatric orthopedic controls. Study quality was determined as high or very high for all six included cohorts, although the studies differed considerably in terms of methodology.Methodological variations confound comparisons of relative frequency assessments of PTSD attributed to TBI. However, PTSD is associated with considerable long-term disability and undetected PTSD in children should raise public concern. Thus, large scale, prospective studies are needed to ascertain the clinical course of PTSD attributed to TBI in children and adolescence.

Migraine is a neurovascular disorder that affects over 1 billion people worldwide. Its widespread prevalence, and associated disability, have a range of negative and substantial effects not only on those immediately affected but also on their families, colleagues, employers, and society. To reduce this global burden, concerted efforts are needed to implement and improve migraine care that is supported by informed health-care policies. In this Series paper, we summarise the data on migraine epidemiology, including estimates of its very considerable burden on the global economy. First, we present the challenges that continue to obstruct provision of adequate care worldwide. Second, we outline the advantages of integrated and coordinated systems of care, in which primary and specialist care complement and support each other; the use of comprehensive referral and linkage protocols should enable continuity of care between these systems levels. Finally, we describe challenges in low and middle-income countries, including countries with poor public health education, inadequate access to medication, and insufficient formal education and training of health-care professionals resulting in misdiagnosis, mismanagement, and wastage of resources.

Nonsteroidal anti-inflammatory drugs, commonly known as COX-1/COX-2 inhibitors, can be effective in treating mild to moderate migraine headache. However, neither the mechanism by which these drugs act in migraine is known, nor is the specific contribution of COX-1 vs COX-2. We sought to investigate these unknowns using celecoxib, which selectively inhibits the enzymatic activity of COX-2, by determining its effects on several migraine-associated vascular and inflammatory events. Using in vivo 2-photon microscopy, we determined intraperitoneal celecoxib effects on cortical spreading depression (CSD)-induced blood vessel responses, plasma protein extravasation, and immune cell activation in the dura and pia of mice and rats. Compared to vehicle (control group), celecoxib reduced CSD-induced dilatation of dural arteries and activation of dural and pial macrophages significantly, but not dilatation or constriction of pial arteries and veins, or the occurrence of plasma protein extravasation. Collectively, these findings suggest that a mechanism by which celecoxib-mediated COX-2 inhibition might ease the intensity of migraine headache and potentially terminate an attack is by attenuating dural macrophages' activation and arterial dilatation outside the blood-brain barrier, and pial macrophages' activation inside the blood-brain barrier.