Nonspecific oral medications versus anti-calcitonin gene-related peptide monoclonal antibodies for migraine: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To compare calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) versus nonspecific oral migraine preventives (NOEPs). BACKGROUND: Insurers mandate step therapy with NOEPs before approving CGRP mAbs. METHODS: Databases were searched for class I or II randomized controlled trials (RCTs) comparing CGRP mAbs or NOEPs versus placebo for migraine prevention in adults. The primary outcome measure was monthly migraine days (MMD) or moderate to severe headache days. RESULTS: Twelve RCTs for CGRP mAbs, 5 RCTs for topiramate, and 3 RCTs for divalproex were included in the meta-analysis. There was high certainty that CGRP mAbs are more effective than placebo, with weighted mean difference (WMD; 95% confidence interval) of -1.64 (-1.99 to -1.28) MMD, which is compatible with small effect size (Cohen's d -0.25 [-0.34 to -0.16]). Certainty of evidence that topiramate or divalproex is more effective than placebo was very low and low, respectively (WMD -1.45 [-1.52 to -1.38] and -1.65 [-2.30 to -1.00], respectively; Cohen's d -1.25 [-2.47 to -0.03] and -0.48 [-0.67 to -0.29], respectively). Trial sequential analysis showed that information size was adequate and that CGRP mAbs had clear benefit versus placebo. Network meta-analysis showed no statistically significant difference between CGRP mAbs and topiramate (WMD -0.19 [-0.56 to 0.17]) or divalproex (0.01 [-0.73 to 0.75]). No significant difference was seen between topiramate or divalproex (0.21 [-0.45 to 0.86]). CONCLUSIONS: There is high certainty that CGRP mAbs are more effective than placebo, but the effect size is small. When feasible, CGRP mAbs may be prescribed as first-line preventives; topiramate or divalproex could be as effective but are less well tolerated. The findings of this study support the recently published 2024 position of the American Headache Society on the use of CGRP mAbs as the first-line treatment.

Alopecia as an emerging adverse event to CGRP monoclonal antibodies: Cases Series, evaluation of FAERS, and literature review.

BACKGROUND: Alopecia is associated with erenumab post-marketing, but no cases have been described. METHODS: We describe two patients that reported temporary hair loss and review the FDA Adverse Event Reporting System (FAERS). RESULTS: The first patient experienced alopecia within three months of starting erenumab, which did not improve with ongoing use or transition to fremanezumab. The second patient reported alopecia within two weeks of starting erenumab, which continued after transition to galcanezumab; months later, there was also recurrent hair loss within one month of starting fremanzeumab. According to FAERS (last accessed 18 August 2022), alopecia was reported most with erenumab (1158), followed by galcanezumab (554), fremanezumab (175), eptinezumab (23), rimegepant (26), ubrogepant (4), and atogepant (3). CONCLUSION: Most events were reported in women and non-serious. The potential mechanism of alopecia with drugs targeting calcitonin gene-related peptide or its receptor possibly includes disruptions in the microvascular circulation and other homeostatic mechanisms.

Post-vaccination headache reporting: Trends according to the Vaccine Adverse Events Reporting System.

OBJECTIVE: To assess the characteristics and associated disability of headache as an adverse event following vaccination. BACKGROUND: According to clinical trials and post-licensure surveillance, headache is a common symptom of vaccines, yet systematic investigations of post-licensure reports of this adverse event are lacking. METHODS: This was a retrospective database analysis study. We searched the Vaccine Adverse Events Reporting System (VAERS) database completed from July 1990 to June 2020 (a 30-year period prior to the start of COVID-19 pandemic) to identify reports of headache. We evaluated epidemiological features, including event characteristics, patient demographics, and vaccine type. RESULTS: In those aged 3 years or older, headache was the fifth most reported adverse symptom, present in 8.1% (43,218/536,120) of all reports. Of headache reports, 96.3% (41,635/43,218) included the code "headache" not further specified. Migraine was coded in 1973 cases, although almost one-third (12,467/41,808; 29.8%) of headache reports without a migraine code mention nausea or vomiting. The onset of symptoms was within 1 day of vaccination in over two-thirds of cases. The majority of reports were classified as not serious; about one-third involved emergency room or office visits. Of the 43,218 total headache reports, only a minority involved hospitalizations (2624; 6.1%) or permanent disability (1091; 2.5%), females accounted for 68.9% (29,771) and males for 29.5% (12,725), patients aged 6 to 59 years represented 67.3% (29,112), and over one-third of cases were reported after herpes zoster (8665; 20.1%) and influenza (6748; 15.6%) vaccinations. CONCLUSION: In a national surveillance system, headache was a commonly reported post-vaccination adverse event; a small subset of reports was considered serious. The development of standardized vaccine-related case definitions could be useful for better evaluating headache as an adverse event during vaccine development, and may reduce vaccine hesitancy especially in headache-prone individuals.

Increased stroke severity and mortality in patients with SARS-CoV-2 infection: An analysis from the N3C database.

BACKGROUND: Studies from early in the COVID-19 pandemic showed that patients with ischemic stroke and concurrent SARS-CoV-2 infection had increased stroke severity. We aimed to test the hypothesis that this association persisted throughout the first year of the pandemic and that a similar increase in stroke severity was present in patients with hemorrhagic stroke. METHODS: Using the National Institute of Health National COVID Cohort Collaborative (N3C) database, we identified a cohort of patients with stroke hospitalized in the United States between March 1, 2020 and February 28, 2021. We propensity score matched patients with concurrent stroke and SARS-COV-2 infection and available NIH Stroke Scale (NIHSS) scores to all other patients with stroke in a 1:3 ratio. Nearest neighbor matching with a caliper of 0.25 was used for most factors and exact matching was used for race/ethnicity and site. We modeled stroke severity as measured by admission NIHSS and the outcomes of death and length of stay. We also explored the temporal relationship between time of SARS-COV-2 diagnosis and incidence of stroke. RESULTS: Our query identified 43,295 patients hospitalized with ischemic stroke (5765 with SARS-COV-2, 37,530 without) and 18,107 patients hospitalized with hemorrhagic stroke (2114 with SARS-COV-2, 15,993 without). Analysis of our propensity matched cohort revealed that stroke patients with concurrent SARS-COV-2 had increased NIHSS (Ischemic stroke: IRR=1.43, 95% CI:1.33-1.52, p<0.001; hemorrhagic stroke: IRR=1.20, 95% CI:1.08-1.33, p<0.001), length of stay (Ischemic stroke: estimate = 1.48, 95% CI: 1.37, 1.61, p<0.001; hemorrhagic stroke: estimate = 1.25, 95% CI: 1.06, 1.47, p=0.007) and higher odds of death (Ischemic stroke: OR 2.19, 95% CI: 1.79-2.68, p<0.001; hemorrhagic stroke: OR 2.19, 95% CI: 1.79-2.68, p<0.001). We observed the highest incidence of stroke diagnosis on the same day as SARS-COV-2 diagnosis with a logarithmic decline in counts. CONCLUSION: This retrospective observational analysis suggests that stroke severity in patients with concurrent SARS-COV-2 was increased throughout the first year of the pandemic.

Advocacy for Migraine Relief: Strategic Planning to Eliminate the Burden.

PURPOSE OF REVIEW: The goal of this article is to describe migraine advocacy as an essential means to advance the field of headache medicine. Special attention is spent outlining advocacy initiatives and priorities. RECENT FINDINGS: There is little written about "migraine advocacy" in the literature. However, organizational and expert priorities include advocating for policies that improve systems of care, telemedicine, education, research, and public initiatives that reduce health disparities and the stigma of migraine. This summary includes the latest advocacy efforts to support policies that may improve migraine care, strengthen the field of headache medicine, and eliminate the burden of migraine.

Equity and Disparities in Diagnosis, Management, and Research of Post-Traumatic Headache.

PURPOSE OF REVIEW: There are notable health disparities and inequities in individuals with traumatic brain injury (TBI) and concussion by race, ethnicity, gender, socioeconomic status, and geography. This review will evaluate these disparities and inequities and assess the social determinants of health that drive outcomes for post-traumatic headache. Interventions for achieving this are also discussed. RECENT FINDINGS: Significant disparities and inequities exist in TBI and concussion among people of different races, socioeconomic status, and geographic locations. Migraine is a common symptom post-concussion, for which disparities and social determinants of health are also discussed. Overall, multi-level interventions to reduce these disparities and inequities are reviewed for post-traumatic headache but require further investigation. Interventions are needed to reduce disparities and inequities including public health initiatives, improvements in clinical care, diversity/inclusion training, and research efforts. As literature expands, we can form guidance to identify solutions for eliminating disparities in care of diverse populations.

Headache After Vaccination: An Update on Recent Clinical Trials and Real-World Reporting.

PURPOSE OF REVIEW: The aim of this review is to characterize headache as a vaccine adverse event (VAE) in clinical trials. RECENT FINDINGS: Of the recent phase III vaccine RCTs (non-COVID-19), 53 studies reported on headache (13 infectious agents). The median rate (interquartile range) of headache was 15.6% (IQR: 9.6-37.6%). Of these, 24.5% of the RCTs reported headache greater in the vaccine group compared to the placebo/control group. In the herpes zoster vaccination trials, headache was more common in all active groups: median rate 33.9% (IQR: 29.7-40.5%) as compared to placebo: median rate 17.7% (IQR: 15.4-23.8%). Influenza and HPV vaccination trials were the 2nd and 3rd most common to have headache as a VAE. Of the 6 widely distributed COVID-19 vaccinations, median rate of post-vaccination headache was 39% (IQR: 28-50%). Headache is a common VAE in vaccine trials. Standardized grading methods, predictors of persistence, and treatment regimens are warranted.

Reversible Lesion of the Corpus Callosum in a Patient With Migraine With Aura: A Case Study.

OBJECTIVE: To describe a patient with migraine with aura (MWA) who was found to have a reversible lesion of the corpus callosum. BACKGROUND: Reversible lesions of the splenium of the corpus callosum are well-described clinical-radiographic phenomena, which have been associated with a wide array of disease states, including epilepsy, demyelinating disease, infection, and metabolic derangements. There have been few case reports in the literature to date of these lesions associated with migraine headache. DESIGN/METHODS: A case report. RESULTS: A 41 year-old female with a history of migraine with visual aura presented with headache associated with left-sided sensorimotor deficits. Routine laboratory tests were within normal limits. An electroencephlogram was also normal. Magnetic resonance imaging (MRI) of the brain with and without contrast revealed areas of restricted diffusion in the splenium and the genu of the corpus callosum. The patient's symptoms resolved after 2 days. A follow-up MRI 2 days after the onset of symptoms revealed resolution of the callosal lesions. The patient was diagnosed clinically with migraine with prolonged aura. CONCLUSION: MWA may be associated with reversible lesions of the corpus callosum.

Migraine Care Challenges and Strategies in US Uninsured and Underinsured Adults: A Narrative Review, Part 2.

OBJECTIVE: To review the challenges and potential solutions in treatment options for quality migraine care in adult patients who are under or uninsured. BACKGROUND: The Affordable Care Act has improved access to health care for many; however, those who are underserved continue to face treatment disparities and have inadequate access to appropriate migraine management. METHODS: This manuscript is the second of a 2-part narrative review which was performed after a series of discussions within the Underserved Populations in Headache Medicine Special Interest Section meetings of the American Headache Society. Literature was reviewed for key concepts underpinning conceptual boundaries and a broad overview of the subject matter. Published guidelines, state-specific Medicaid websites, headache quality measurement sets, literature review, and expert opinion were used to tailor suggested treatment options and therapeutic strategies. In this second part of our narrative review, we explored migraine care strategies and considerations for underserved and vulnerable adult populations with migraine. RESULTS: Although common, migraine remains untreated, particularly among those of low socioeconomic status. Low socioeconomic status may play an important role in the disease progression, prescription of hazardous medications such as opioids, outcomes, and quality of life of patients with migraine and other headache disorders. There are some evidence-based and guideline supported treatment options available at low cost that include prescription medications and supplements, though approved devices are costly. Resources available online and simple nonpharmacological strategies may be particularly useful in the underserved migraine population. CONCLUSIONS: We identified and discussed migraine treatment barriers that affect underserved populations in the US and summarized practical, cost-effective strategies to surmount them. However, more research is needed to identify the best cost-effective measures for migraine management in underserved and vulnerable patients who are uninsured or underinsured.

Migraine Care Challenges and Strategies in US Uninsured and Underinsured Adults: A Narrative Review, Part 1.

OBJECTIVE: To review the scope of the problem facing individuals with migraine who are under- or uninsured. In this first of a 2-part narrative review, we will explore migraine epidemiology and the challenges that face this vulnerable population. BACKGROUND: Implementation of the Affordable Care Act has improved access to health care for many individuals who were previously uninsured, but there are many, particularly those of certain demographics, who are at high risk for worse outcomes. METHODS: A narrative review was performed after a series of discussions within the Underserved Populations in Headache Medicine Special Interest Section meetings of the American Headache Society. Literature was reviewed for key concepts underpinning conceptual boundaries and a broad overview of the subject matter. Published guidelines, state-specific Medicaid websites, headache quality measurement set, literature review, and expert opinion were used to tailor suggested treatment options and therapeutic strategies. RESULTS: Migraine is common, yet remains underdiagnosed and associated with worse outcomes among those of under-represented backgrounds and those who are underinsured or uninsured. Low socioeconomics may play an important role in the disease progression, characteristics, outcome, and quality of life of patients with migraine and other headache disorders. Other barriers to optimal care include time constraints, lack of access to specialty providers, transportation, and financial limitations. CONCLUSION: There are many barriers and challenges that affect people with migraine who are underinsured or uninsured, particularly those of under-represented racial backgrounds and of lower socioeconomic status.

Despite Variations, Evidence Provides Clear Road Map for Adult Patients Presenting with Acute Migraine.

Although there is solid evidence to support how patients presenting with migraine headaches should be treated in the ED, studies show there is wide variation in the care that these patients receive. To reduce this variation, experts have unveiled guidelines based on a review of 68 randomized, controlled trials that looked at 28 injectable migraine medications. Investigators did not present any A-level, or "must offer," recommendations, but four medications received B-level, or "should offer," recommendations. The authors advised that intravenous metoclopramide and prochlorperazine, as well as subcutaneous sumatriptan, should be offered as a first-line treatment to adults who present to the ED with an acute migraine. Investigators also advised that dexamethasone should be offered to these patients to prevent their acute headache from recurring over the short term. Researchers noted that injectable morphine and hydromorphone should be avoided as a first-line therapy.

The utility of radioisotope cisternography in low CSF/volume syndromes compared to myelography.

Objective The objective of this report is to compare computed tomography (CT) and magnetic resonance (MR) myelography with radioisotope cisternography (RC) for detection of spinal cerebrospinal (CSF) leaks. Methods We retrospectively reviewed 12 spontaneous intracranial hypotension (SIH) patients; CT and RC were performed simultaneously. Three patients had MR myelography. Results CT and/or MR myelography identified CSF leaks in four of 12 patients. RC detected spinal leaks in all three patients confirmed by CT myelography; RC identified the CSF leak location in two of three cases, and these were due to osteophytic spicules and/or discs. RC showed only enlarged perineural activity. Only intrathecal gadolinium MR myelography clearly identified a slow leak from a perineural cyst. In eight remaining cases, the leak site was unknown; however, two of these showed indirect signs of CSF leak on RC. CSF slow leaks from perineural cysts were the most common presumed etiology; and the cysts were best visualized on myelography. Conclusion RC is comparable to CT myelography but has spatial limitations and should be limited to atypical cases.

Hypertension and Migraine in the Northern Manhattan Study.

OBJECTIVE: To investigate the association between migraine and hypertension in the Northern Manhattan Study (NOMAS), a multiethnic community-based sample. DESIGN: Cross-sectional cohort study. PARTICIPANTS: 1338 NOMAS participants (mean age 68.1 ± 9.6 years, 37% male, 15% non-Hispanic White, 19% non-Hispanic Black, 67% Hispanic). SETTING: Northern Manhattan community. INTERVENTION: Participants were assessed for migraine symptoms using a self-report questionnaire based on criteria from the International Classification of Headache Disorders. Hypertension was defined as blood pressure ≥140/90 mm Hg, the patient's self-reported hypertension, or use of anti-hypertensive medications. Duration (≤9 years vs >9 years) and control (BP<140/90) of hypertension were examined. We estimated the association between hypertension and migraine (overall and with/without aura) using logistic regression, adjusting for sociodemographic and vascular risk factors. RESULTS: The majority of participants (80%) had no migraine, 6% had migraine with aura, and 15% had migraine without aura. Hypertension was present in 76% of the study population (7% had controlled hypertension ≤9 years duration, 5% controlled hypertension >9 years duration, 41% uncontrolled hypertension ≤9 years duration, 23% uncontrolled hypertension >9 years duration). Hypertension was associated with migraine (OR: 1.76, 95% CI: 1.21-2.54), both with and without aura. This association was particularly apparent for those with uncontrolled and long duration hypertension. CONCLUSION: Hypertension, particularly uncontrolled and of long duration, is associated with migraine, both with and without aura, in a predominantly Hispanic community-based cohort.

The premonitory phase of migraine--what can we learn from it?

This review aims to understand the prevalence of premonitory symptoms in migraine, postulate their mechanisms, and compare these with functional imaging studies. A thorough literature review was conducted using PubMed for prevalence studies of premonitory symptoms in migraine and functional imaging studies in the premonitory phase. The majority of studies have been retrospective reporting a prevalence of 7-88% for premonitory symptoms in migraine. Only one study has investigated premonitory symptoms prospectively and used preselected patients with recognized premonitory symptoms. The majority of patients were able to predict correctly the onset of migraine headache. Only one functional imaging study has been conducted in the premonitory phase that showed activation of posterolateral hypothalamus, midbrain tegmental area and substantia nigra, periaqueductal gray, dorsal pons, and various cortical areas including occipital, temporal, and prefrontal cortex. Subgroup analysis of patients with photophobia more than without photophobia in the premonitory phase showed activation of the occipital cortex. Comparison of patients with nausea more than without nausea in the premonitory phase showed activation in upper dorsal medulla and periaqueductal gray. Premonitory symptoms are common in migraine, although the true prevalence cannot be stated with certainty in the absence of prospective studies in unselected patients. Hypothalamic involvement can explain many of the premonitory symptoms. Activation of the the brainstem structures and hypothalamus before pain suggests a pivotal role of these structures in the pathogenesis of migraine. Hypersensitivity to light and occurrence of nausea in migraine is associated with activation of central brain structures involved in these pathways, and this can occur in the absence of pain.

Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks.

Our aim was identify brain areas involved in the premonitory phase of migraine using functional neuroimaging. To this end, we performed positron emission tomography scans with H2(15)O to measure cerebral blood flow as a marker of neuronal activity. We conducted positron emission tomography scans at baseline, in the premonitory phase without pain and during migraine headache in eight patients. We used glyceryl trinitrate (nitroglycerin) to trigger premonitory symptoms and migraine headache in patients with episodic migraine without aura who habitually experienced premonitory symptoms during spontaneous attacks. The main outcome was comparing the first premonitory scans in all patients to baseline scans in all patients. We found activations in the posterolateral hypothalamus, midbrain tegmental area, periaqueductal grey, dorsal pons and various cortical areas including occipital, temporal and prefrontal cortex. Brain activations, in particular of the hypothalamus, seen in the premonitory phase of glyceryl trinitrate-triggered migraine attacks can explain many of the premonitory symptoms and may provide some insight into why migraine is commonly activated by a change in homeostasis.

Migraine, white matter hyperintensities, and subclinical brain infarction in a diverse community: the northern Manhattan study.

BACKGROUND AND PURPOSE: Migraine with aura is a risk factor for ischemic stroke. The goals of this study are to examine the association between migraine and subclinical cerebrovascular damage in a race/ethnically diverse older population-based cohort study. METHODS: In the Northern Manhattan Study (NOMAS), we quantified subclinical brain infarctions and white matter hyperintensity volumes among participants with self-reported migraine, confirmed by the International Classification of Headache Disorders-2 criteria. RESULTS: Of 546 study participants with imaging and migraine data (41% men; mean age at MRI, 71±8 years; mostly Hispanic [65%]), those reporting migraine overall had double the odds of subclinical brain infarction (adjusted odds ratio, 2.1; 95% confidence interval, 1.0-4.2) when compared with those reporting no migraine, after adjusting for sociodemographics and vascular risk factors. No association was observed between migraine with or without aura and white matter hyperintensity volume. CONCLUSIONS: Migraine may be a risk factor for subclinical brain infarction. Prospective studies are needed in race/ethnically diverse populations.

Olfactory function in migraine both during and between attacks.

INTRODUCTION: People with migraine often report being osmophobic, both during and between acute migraine attacks. It is not clear, however, whether such reports are associated with changes in olfaction such as hyperosmia, as measured by psychophysical testing. In this case-control study we quantitatively assessed olfactory identification ability, which correlates with threshold tests of olfactory acuity, in patients with migraine at baseline (no headache), during migraine episodes, and after a treated attack and compared the test scores to those of matched control subjects. METHODS: Fifty episodic migraine subjects and 50 and sex- and age-matched controls without headache were tested. All completed the University of Pennsylvania Smell Identification Test (UPSIT), a standardized and well-validated olfactory test. RESULTS: At baseline, the UPSIT scores did not differ significantly between the migraine and control study groups (median paired score difference: -1, p = 0.18). During migraine attacks, a minority of migraine subjects (eight of 42) developed microsmia (i.e. lower test scores by at least four points), suggesting that, as compared to their matched controls, olfactory acuity was somewhat impaired during migraine attacks (p = 0.02). This difference was less pronounced and not statistically significant after a successfully treated attack (p = 0.15). DISCUSSION: People with episodic migraine were found to have similar olfactory function as age- and sex-matched controls, but a minority exhibit microsmia or hyposmia during acute attacks. The cause of this dysfunction is unknown, but could relate to autonomic symptoms, limbic system activation, or disorders of higher order sensory processing.

Insights and advances in post-traumatic headache: research considerations.

Despite the growing awareness of mild traumatic brain injury in military and civilian populations, understanding of the acute and chronic effects of concussion on central nervous system structure and function is limited. Even less is understood about the underpinnings of the cardinal postconcussive symptom, post-traumatic headache (PTH). Here, we review recent advances in PTH, with special emphasis on the migraine-like phenotype, the most disabling form. Considerations for future research in PTH are discussed, including diagnostic classification, and applications with advanced neuroimaging techniques, biomarkers, and treatments.