How Sex Hormones Affect Migraine: An Interdisciplinary Preclinical Research Panel Review.

Sex hormones and migraine are closely interlinked. Women report higher levels of migraine symptoms during periods of sex hormone fluctuation, particularly during puberty, pregnancy, and perimenopause. Ovarian steroids, such as estrogen and progesterone, exert complex effects on the peripheral and central nervous systems, including pain, a variety of special sensory and autonomic functions, and affective processing. A panel of basic scientists, when challenged to explain what was known about how sex hormones affect the nervous system, focused on two hormones: estrogen and oxytocin. Notably, other hormones, such as progesterone, testosterone, and vasopressin, are less well studied but are also highlighted in this review. When discussing what new therapeutic agent might be an alternative to hormone therapy and menopause replacement therapy for migraine treatment, the panel pointed to oxytocin delivered as a nasal spray. Overall, the conclusion was that progress in the preclinical study of hormones on the nervous system has been challenging and slow, that there remain substantial gaps in our understanding of the complex roles sex hormones play in migraine, and that opportunities remain for improved or novel therapeutic agents. Manipulation of sex hormones, perhaps through biochemical modifications where its positive effects are selected for and side effects are minimized, remains a theoretical goal, one that might have an impact on migraine disease and other symptoms of menopause. This review is a call to action for increased interest and funding for preclinical research on sex hormones, their metabolites, and their receptors. Interdisciplinary research, perhaps facilitated by a collaborative communication network or panel, is a possible strategy to achieve this goal.

Left- vs right-sided migraine: a scoping review.

BACKGROUND: Migraine is a historically unilateral head pain condition, the cause of which is not currently known. A growing body of literature suggests individuals who experience migraine with left-sided headache ("left-sided migraine") may be distinguished from those who experience migraine with right-sided headache ("right-sided migraine"). OBJECTIVE: In this scoping review, we explore migraine unilaterality by summarizing what is currently known about left- and right-sided migraine. METHODS: Two senior medical librarians worked with the lead authors to construct and refine a set of search terms to identify studies of subjects with left- or right-sided migraine published between 1988, which is the year of publication of the first edition of the International Classification of Headache Disorders (ICHD), and December 8, 2021 (the date the searches were conducted). The following databases were searched: Medline, Embase, PsycINFO, PubMed, Cochrane Library, and Web of Science. Abstracts were loaded into Covidence review software, deduplicated, then screened by two authors to determine study eligibility. Eligible studies were those involving subjects diagnosed with migraine (according to ICHD criteria) in which the authors either: a) compared left- to right-sided migraine; or b) described (with analysis) a characteristic that differentiated the two. Data were extracted by the lead author, including ICHD version, the definition of unilateral migraine used by the authors, sample size, whether the findings were collected during or between attacks, and their key findings. The key findings were grouped into the following themes: handedness, symptoms, psychiatric assessments, cognitive testing, autonomic function, and imaging. RESULTS: After deduplication, the search yielded 5428 abstracts for screening. Of these, 179 met eligibility criteria and underwent full text review. 26 articles were included in the final analysis. All of the studies were observational. One study was performed during attack, nineteen between attacks, and six both during and between attacks. Left- and right-sided migraine were found to differ across multiple domains. In several cases, reciprocal findings were reported in left- and right-migraine. For example, both left- and right-sided migraine were associated with ipsilateral handedness, tinnitus, onset of first Parkinson's symptoms, changes in blood flow across the face, white matter hyperintensities on MRI, activation of the dorsal pons, hippocampal sclerosis, and thalamic NAA/Cho and NAA/Cr concentrations. In other cases, however, the findings were specific to one migraine laterality. For example, left-sided migraine was associated with worse quality of life, anxiety, bipolar disorder, PTSD, lower sympathetic activity, and higher parasympathetic activity. Whereas right-sided migraine was associated with poorer performance on multiple cognitive tests, a greater degree of anisocoria, changes in skin temperature, higher diastolic blood pressure, changes in blood flow through the middle cerebral and basilar arteries, and changes on EEG. CONCLUSION: Left- and right-sided migraine differed across a wide range of domains, raising the possibility that the pathophysiology of left- and right-migraine may not be identical.

Legal Aspects of Migraine in the Workplace.

PURPOSE OF REVIEW: This study explores legal aspects of migraine in the workplace. While the high prevalence of migraine is well-documented, its effects on the livelihoods of those living with the disease are less understood. Because migraine symptoms are often invisible, discussions concerning migraine in the workplace can be challenging. What are the rights of persons with migraine in the workplace? Time off may provide a brief respite, but it is not a long-term solution. Claiming disability for migraine has challenges, including barriers to doing so and required paperwork. How can persons with migraine remain employed and productive? How can persons with migraine receive accommodation from their employer or take time off to treat their condition? RECENT FINDINGS: Many employers offer comprehensive benefit packages that allow for sick days, time off, mental health days, and accommodations that may give persons with migraine temporary reprieve. However, it may not be sufficient, particularly for those with chronic migraine. Further, not all employers offer comprehensive benefits. Employees with migraine may need to seek protection under the law. Our research closely examines the primary legal avenues that persons with migraine may pursue while living and working with migraine. In exploring the legal aspects of migraine, we couple our exploration with relevant case law. Through this lens, we conclude that migraine is becoming less stigmatized and more legitimized in the eyes of the court. It is the belief of the authors that at least some of the change in the attitude towards migraine is the result of strong patient advocacy and significant advances in research over the past several years.

Episodic Migraine and Older Adults.

PURPOSE OF REVIEW: Migraine is and continues to be a significant medical issue in older adults. Migraine can have different characteristics in older adults and specific diagnostic and treatment considerations need to be applied when managing headache and migraine in this population, which is increasing in both size and diversity. Contrary to widely held beliefs, migraine may not improve in older women following menopause and can have new onset in older age. The purpose of this review is to give an update on the diagnosis and treatment of episodic migraine in older adults. RECENT FINDINGS: As the population ages, migraine in older adults will become a more significant public health issue. Migraine in older adults can present with different clinical symptoms than in a younger population and is primarily a diagnosis of exclusion in older adults. Migraine treatment considerations for older adults should include comorbidities and medication interactions. Recent findings suggest there are medications that should be avoided when treating seniors with migraine. The purpose of this review is to give an update on the most important aspects regarding the diagnosis and treatment of headache and migraine in older adults. In addition, recommendations will be made concerning medications that need careful consideration when prescribing to seniors.

Efficacy and Safety of Repetitive Intravenous Sodium Valproate in Pediatric Patients With Refractory Chronic Headache Disorders: A Retrospective Review.

BACKGROUND: Chronic headache disorders can cause substantial disability and be treatment refractory. Often, these patients are excluded from clinical trials with leaving little evidence to guide treatment. In adults, divalproex sodium is an effective preventive migraine treatment. METHODS: All pediatric patients admitted for first-time sodium valproate infusions to treat refractory, chronic migraine (CM), new daily persistent headache, or persistent headache attributed to head trauma from January 2017 to October 2020 were identified for review. Each patient underwent a standardized, 4-day protocol. A new preventive was started one week after discharge. Data on headache frequency, severity, and acute medication use were collected through preadmission and postadmission clinic notes. Safety and tolerability were evaluated. Results were evaluated using descriptive statistics and compared with paired t-tests. RESULTS: Forty-five patients were identified for review. Patients with CM had a median of 7 previous preventive trials, and 85% had previously received alternative intravenous treatment for headache. Baseline headache pain significant decreased from 6.9/10 to 5.4/10 by 7-week postadmission follow up, (95% confidence interval = -0.7 to -2.4), P < 0.001. Use of medications for acute headache treatment decreased significantly from 2.1 days/week to 1.5 days/week, (95% confidence interval = -0.3 to -1), P < 0.001. Baseline headache frequency did not significantly change. At postadmission follow-up, 26 of 39 (67%) patients saw improvements in headache frequency, headache intensity, and/or acute pain medication usage. There were no serious adverse events. CONCLUSIONS: Repetitive sodium valproate infusions were well tolerated and significantly reduced baseline headache intensity and acute medication usage in pediatric patients with refractory, chronic headache disorders.

The Use of Behavioral Modalities for Headache During Pregnancy and Breastfeeding.

PURPOSE OF REVIEW: Migraine is primary headache which commonly affects women of childbearing age. Migraine and other primary headache disorders are also common during pregnancy. Understanding which treatments are effective and can be safely given to patients with primary headache during pregnancy and lactation is essential in supporting these patients before, during, and after childbirth. Behavioral modalities have the potential to improve the health of both mother and baby, while empowering patients to make informed decisions in family planning and creating future treatment plans. RECENT FINDINGS: Research shows that behavioral therapies can be powerful tools to treat pain conditions with minimal side effects. Recent literature prioritizes behavioral therapies in preparation for pregnancy, during pregnancy, and during lactation due to the superior safety profile of such therapies. Digital resources for behavioral therapy are another well-received recent direction supported by growing evidence of both efficacy and safety. Popular with patients and headache specialists, digital behavioral therapy has taken various forms during the pandemic, such as telemedicine, online psychology support groups, and smartphone applications that patients can interact with on their own time. In summary, the purpose of this review is to equip providers with important information and updates on the use of behavioral modalities for the treatment of primary headache during pregnancy and lactation.

Telehealth as a new care delivery model: The headache provider experience.

OBJECTIVE: To assess telehealth practice for headache visits in the United States. BACKGROUND: The rapid roll out of telehealth during the COVID-19 pandemic impacted headache specialists. METHODS: American Headache Society (AHS) members were emailed an anonymous survey (9/9/20-10/12/20) to complete if they had logged ≥2 months or 50+ headache visits via telehealth. RESULTS: Out of 1348 members, 225 (16.7%) responded. Most were female (59.8%; 113/189). Median age was 47 (interquartile range [IQR] 37-57) (N = 154). The majority were MD/DOs (83.7%; 159/190) or NP/PAs (14.7%; 28/190), and most (65.1%; 123/189) were in academia. Years in practice were 0-3: 28; 4-10: 58; 11-20: 42; 20+: 61. Median number of telehealth visits was 120 (IQR 77.5-250) in the prior 3 months. Respondents were "comfortable/very comfortable" treating via telehealth (a) new patient with a chief complaint of headache (median, IQR 4 [3-5]); (b) follow-up for migraine (median, IQR 5 [5-5]); (c) follow-up for secondary headache (median, IQR 4 [3-4]). About half (51.1%; 97/190) offer urgent telehealth. Beyond being unable to perform procedures, top barriers were conducting parts of the neurologic exam (157/189), absence of vital signs (117/189), and socioeconomic/technologic barriers (91/189). Top positive attributes were patient convenience (185/190), reducing patient travel stress (172/190), patient cost reduction (151/190), flexibility with personal matters (128/190), patient comfort at home (114/190), and patient medications nearby (103/190). Only 21.3% (33/155) of providers said telehealth visit length differed from in-person visits, and 55.3% (105/190) believe that the no-show rate improved. On a 1-5 Likert scale, providers were "interested"/"very interested" in digitally prescribing headache apps (median 4, IQR 3-5) and "interested"/"very interested" in remotely monitoring patient symptoms (median 4, IQR 3-5). CONCLUSIONS: Respondents were comfortable treating patients with migraine via telehealth. They note positive attributes for patients and how access may be improved. Technology innovations (remote vital signs, digitally prescribing headache apps) and remote symptom monitoring are areas of interest and warrant future research.

Ten Eleven Things Not to Say to Healthcare Professionals During the Coronavirus Disease 2019 Pandemic.

On March 11, 2020, the infection caused by the coronavirus disease 2019 (COVID-19) virus was declared a pandemic. Throughout this pandemic, healthcare professionals (HCPs) have experienced difficulties stemming from poor communications, resource scarcity, lack of transparency, disbelief, and threats to the safety of their loved ones, their patients, and themselves. As part of these hardships, negative statements have been heard repeatedly. This paper describes 11 scenarios of unhelpful and dysfunctional messages heard by the authors and their colleagues during the COVID-19 pandemic, reported to us by a combination of peers, administrative leadership, and the public. We explain why not to use such messaging, and we suggest more helpful and compassionate expressions based upon recommendations published by scientific organizations and well-established psychological principles. The first 10 scenarios discussed include (1) lack of understanding regarding the extent of the pandemic; (2) shaming over not seeing patients in person; (3) lack of clear and consistent communication from leadership on pandemic-related practice changes; (4) opinions that personal protective equipment (PPE) use by HCPs causes fear or is unnecessary; (5) forcing in-person care without appropriate PPE; (6) the risk of exposure to asymptomatic individuals as it relates to opening clinics; (7) media gag orders; (8) pay and benefit reductions; (9) spreading of misinformation about the COVID-19 pandemic; and (10) workload expectations. The 11th scenario addresses HCPs' psychological and physical reactions to this challenging and prolonged stressful situation. We close by discussing the need for support and compassion at this difficult and unpredictable time and by offering suggestions to foster resilience and feelings of self-efficacy among HCPs.

Retrospective Chart Review of Intravenous Valproate Sodium as a Preventive Treatment for Patients With Chronic Migraine.

OBJECTIVE: This is a small pilot study to evaluate the effectiveness of an intravenous (IV) valproate sodium therapy protocol for migraine prevention in a population of patients with chronic migraine refractory to multiple preventive medications. BACKGROUND: Valproate sodium is an anti-epileptic and mood stabilizer that has been shown to prevent migraine when used daily in oral form. The specific mechanism of action in migraine is unknown, but it may be related to suppressing inflammation and increasing brain Gamma-aminobutyric acid levels. It also may relate to its ability to suppress cortical spreading depression. Multiple studies have suggested that valproic acid and its derivatives may inhibit Calcitonin gene-related peptide. In the present work, we undertook a small pilot study to evaluate the effectiveness of an IV valproate sodium therapy for migraine prevention in a population of patients with chronic migraine refractory to multiple preventive medications. METHODS: Fourteen adult patients with chronic migraine were admitted for a 4-day course of IV valproate sodium. Patients received 250 mg of valproate sodium over a standard infusion time of 60 minutes every 8 hours. Most patients received 9 doses over the 4-day course of treatment. One patient had to discontinue after 1 dose of 250-mg valproate sodium, as this patient experienced an increase in his previous symptoms of nausea, vomiting, and vertigo with his first dose. To avoid positive selection bias, we evaluated the first admission for valproate IV therapy in patients with multiple admissions; there was 1 patient with 2 admissions and 1 with 3 admissions for IV valproate sodium. Of note - all admission outcomes for these patients were similar. Headache diaries were reviewed from 1 month before, during, and approximately 2 months after their admission. STATISTICAL ANALYSES: Due to the observational nature of the study and small sample size, we did not think that quantitative statistical analysis would add more meaning to this pilot study. Formal quantitative statistical analysis was not performed in this study and descriptive statistical analysis was used due to this being a pilot proof of concept study. Physician clinical judgment in combination with patient reports were used to assign a dichotomous conclusion on clinical improvement for each patient. In the future, we plan to create a larger study, including additional treatment groups for control, such as IV Dihydroergotamine or IV Chlorpromazine, in order to quantify improvement of symptoms. RESULTS: A total of 9 out of 13 (69%) patients had an improvement in their headache post-admission and reported a reduction in headache frequency, intensity, and/or use of acute medications 4-6 weeks following their admissions. A total of 5 out of 13 (38%) patients also reported an improvement in headache intensity during the 4-day period of inpatient admission. The other 8 out of 13 (62%) patients reported stable headache pattern. One patient had feelings of restlessness, which improved with prolongation of infusion time to 120 minutes. CONCLUSION: These results indicate that this repetitive dosing valproate sodium protocol is a safe and well-tolerated intervention for the treatment of chronic migraine resistant to oral medications. Given the promising outcomes on patient headache improvement with this small pilot study, studies to confirm this benefit in a larger cohort of chronic migraine patients are warranted, preferable with the addition of a blinded control group for comparison.

Exacerbation of headache during dihydroergotamine for chronic migraine does not alter outcome.

OBJECTIVE: To evaluate whether headache exacerbation associated with IV dihydroergotamine (DHE) infusion predicts medium-term headache outcome in patients with chronic migraine. METHODS: This was a retrospective chart review study of the UCSF Headache Center's use of IV DHE for chronic migraine from 2008 to 2012. Medium-term headache outcome was assessed at 6-week follow-up. Univariate and multivariate logistic regression models were used to assess for predictors of outcome. RESULTS: Patients with chronic migraine (n = 274) were treated with a course of IV DHE. Of 214 with 6-week follow-up, 78% had medium-term headache benefit. In a univariate logistic regression model, headache exacerbation with DHE was associated with lower odds of a positive medium-term headache outcome (odds ratio [OR] 0.43, 95% confidence interval [CI] 0.20-0.91). However, in the multivariate logistic regression model, headache exacerbation was no longer an independent predictor of treatment outcome (OR 0.65, 95% CI 0.28-1.51). Factors that independently predicted outcome were nausea (OR 0.12, 95% CI 0.02-1.00, p = 0.05), age (OR 1.68 for each decade increase in age, 95% CI 1.24-2.28), and medication overuse (OR 0.42, 95% CI 0.18-0.97). CONCLUSIONS: After controlling for nausea and other factors, headache exacerbation with DHE infusions is not an independent predictor of poor headache outcome and clinicians should not interpret its presence as a reason to stop treatment. The focus of management should be on controlling nausea as it is the most important modifiable factor in achieving a good headache outcome with an inpatient course of IV DHE for chronic migraine.