A placebo controlled, randomized clinical trial of galcanezumab for vestibular migraine: The INVESTMENT study.

OBJECTIVE: To study if galcanezumab is effective for vestibular migraine (VM). BACKGROUND: There are currently no placebo-controlled trials showing that treatment is effective for VM. Therefore, we performed the first placebo controlled, randomized clinical trial of a calcitonin gene-related peptide-targeted monoclonal antibody for VM. METHODS: This was a single site, prospective, double-blind placebo controlled randomized clinical trial. Key inclusion criteria were as follows: participants aged 18-75 years with a diagnosis of VM or probable VM per Barany Society criteria. The primary outcome was change in VM-PATHI (Vestibular Migraine Patient Assessment Tool and Handicap Inventory) score, and secondary outcomes included change in DHI (Dizziness Handicap Inventory) score, and count of definite dizzy days (DDDs). Participants were randomized 1:1 to 3 months of treatment with galcanezumab or placebo via subcutaneous injection with a pre-filled syringe, 240 mg the first month, and 120 mg for the second and third months. RESULTS: Forty participants were randomized, and 38 participants were in the modified intent to treat analysis. VM-PATHI score was reduced 5.1 points (95% confidence interval [CI] -13.0 to 2.7) for placebo (N = 21), and 14.8 points (95% CI -23.0 to -6.5) for galcanezumab (N = 17), a difference of -9.6 (95% CI -20.7 to 1.5, p = 0.044). DHI dropped 8.3 points in the placebo arm (95% CI -15.0 to 1.6), and 22.0 points in the galcanezumab arm (95% CI -31.9 to -12.1), a difference of -13.7 (95% CI -20.4 to -8.5, p = 0.018). The count of DDDs per month dropped from 18 days (standard deviation [SD] 7.6) in the baseline month to 12.5 days (SD 11.2) in month 4 for those in the placebo arm, and from 17.9 days (SD 7.9) in the baseline month to 6.6 days (SD 7.3) in month 4 for those in the galcanezumab arm, a difference of -5.7 days (95% CI -10.7 to -0.7, p = 0.026). No serious adverse events were observed. CONCLUSIONS: In this pilot study, galcanezumab was effective in treating VM.

Classification and Diagnosis of Primary Headache Disorders.

Proper diagnosis is the key to successful management of headache disorders. Separating secondary causes from primary headache disorders is a necessary first step, followed by further refinement within these broader categories. For research into the physiological and pathophysiological underpinnings of headache disorders, distinguishing headache types and subtypes is even more crucial. Thus, classification of headache types is required in clinical work and research in headache medicine. This article will provide an overview of the guiding philosophy behind the International Classification of Headache Disorders, a guide to its use in diagnosing primary headache disorders, and a review of important diagnostic features of the primary headaches.

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.

Optimism, Pessimism, and Migraine: A Cross-Sectional, Population-Based Study.

BACKGROUND: Optimism and pessimism are related to several mental health and brain disorders, are significant predictors of physical and psychological health outcomes, and implicated as psychosocial determinants of the pain experience. Despite this promising evidence, limited information is available on optimism and pessimism in headache disorders. OBJECTIVE: To evaluate the influence of optimism and pessimism in meeting criteria for migraine and related disability in a population-based sample. METHODS: This is an observational, cross-sectional study. The sample population was selected through a stratified, multi-stage area probability sample of households, as used by the last Brazilian Census. A validated questionnaire eliciting data on demographics, headache features, migraine-related disability, depression (PHQ-9), anxiety (GAD-7), optimism, and pessimism (life orientation test - revised) was administered to people with migraine and headache-free control participants from the general population in São Paulo, Brazil via trained interviewers. Six hundred individuals were contacted. The odds for having migraine/no headache diagnosis were calculated by binary logistic regression, and ordinal regression was performed to check associations between migraine-related disability and optimism. RESULTS: A total of 302 individuals (mean ± SD age: 39.7 ± 12.7; BMI: 26.5 ± 5.9) met inclusion criteria and were included, 140 controls (with no history of headache disorders) and 162 people meeting criteria for migraine (29 with chronic migraine, that is, 15 or more headache days/month). People with migraine were less optimistic and more pessimistic than controls, and endorsed higher levels of anxious and depressive symptoms. Pessimism (OR 95% CI = 1.16 [1.05-1.28], P = .005) and anxiety (OR 95% CI = 1.19 [1.10-1.29], P < .001) were predictors of meeting criteria for migraine, while optimism (ß 95% CI = -0.915 [-1.643, -0.188], P = .01) was inversely associated with migraine-related disability. CONCLUSIONS: Optimism and pessimism are associated with migraine and migraine-related disability. These concepts should be further explored in people with migraine with regard to their potential influences on clinical research outcomes and treatments.

Basic Considerations for the Use of Monoclonal Antibodies in Migraine.

BACKGROUND: Migraine impacts more than 36 million people in the United States and 1 billion people worldwide. Despite the increasing availability of acute and preventive therapies, there is still tremendous unmet need. Potential treatments in development include monoclonal antibodies (mAbs). Appropriate use of these "biologic" treatments will necessitate an understanding of the aspects that distinguish them from traditional medications. AIM: Many drug classes are prescribed for migraine treatment, but all have limitations. Recently, calcitonin gene-related peptide (CGRP) activity has shown a significant promise as a target for preventive therapy. In this review, we provide an overview of the potential role of CGRP mAbs in migraine, with a focus on their design, pharmacokinetics, safety, and immunogenicity. CONCLUSIONS: The CGRP mAbs are an innovative new therapy for migraine and address the need for effective and tolerable preventive options. MAbs, including those that target CGRP or its receptor, bind to a target with high specificity and affinity and lead to few off-target adverse effects, although mechanism-based adverse reactions may occur. Unlike other therapeutic antibodies used to treat neurologic disease, CGRP mAbs do not have a target within the immune system and have been designed to avoid altering the immune system. The safety and efficacy of mAbs against CGRP or its receptors are being investigated in clinical development programs, and the first of these therapies has received regulatory approval in the United States.

Procedural Headache Medicine in Neurology Residency Training: A Survey of US Program Directors.

OBJECTIVE: To survey neurology residency program directors (PDs) on trainee exposure, supervision, and credentialing in procedures widely utilized in headache medicine. BACKGROUND: Clinic-based procedures have assumed a prominent role in headache therapy. Headache fellows obtain procedural competence, but reliance on fellowship-trained neurologists cannot match the population eligible for treatments. The inclusion of educational modules and mechanisms for credentialing trainees pursuing procedural competence in residency curricula at individual programs is not known. METHODS: A web-based survey of US neurology residency PDs was designed by the American Headache Society (AHS) procedural special interest section in collaboration with AHS and American Academy of Neurology's Headache and Facial Pain section leadership. The survey addressed exposure, training, and credentialing in: (1) onabotulinumtoxinA (onabotA) injections, (2) extracranial peripheral nerve blocks (PNBs), and (3) trigger point injections (TPIs). RESULTS: Fifty-five PDs (42.6%) completed the survey. Compared to noncompleters, survey completers were more likely to feature headache fellowships at their institutions (38.2% vs 10.8%, P=0.0002). High exposure (onabotA=90.9%, PNBs=80.0%, TPIs=70.9%) usually featured hands-on patient instruction (66.2%) and lectures (55.7%). Supervised performance rates were high (onabotA=65.5%, PNBs=60.0%, TPIs=52.7%), usually in continuity clinic (60.0%) or headache elective (50.9%). Headache specialists (69.1%) or general neurology (32.7%) faculty most commonly trained residents. Formal credentialing was uncommon (16.4-18.2%), mostly by documenting supervised procedures (25.5%). Only 27.3% of programs permitted trainees to perform procedures independently. Most PDs felt procedural exposure (80.0-90.9%) and competence (50.9-56.4%) by all trainees was important. CONCLUSIONS: Resident exposure to procedures for headache is high, but credentialing mechanisms, while desired by most PDs, are not generally in place. Implementation of a credentialing process may ensure trainees enter practice with the ability to perform procedures safely and effectively.

Spinal rehabilitative exercise or manual treatment for the prevention of cervicogenic headache in adults.

This is the protocol for a review and there is no abstract. The objectives are as follows: To quantify and compare the short- and long-term effects of manual treatment and spinal rehabilitative exercise for cervicogenic headache, classified according to the International Headache Society's (IHS) diagnostic criteria, with an active or placebo/sham comparison or wait-list control.

Spinal rehabilitative exercise or manual treatment for the prevention of tension-type headache in adults.

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the short- and long-term effects of manual treatment and spinal rehabilitative exercise for the prevention of tension-type headache in adults.

Approach to the Workup and Management of Headache in the Emergency Department and Inpatient Settings.

The challenge of headache management in the hospital can be divided into the diagnostic and management issues encountered in the emergency department, and the issues involved in the inpatient management of chronic refractory headaches. The two endeavors are different but linked because of overlapping diagnostic and treatment options. In addition, the problem of the intractable acute headache encountered in the emergency department can evolve into inpatient care of the same patient who has failed to respond to acute treatment. Here the author presents an approach to the patient with severe acute headache in the emergency department and explores the options available for managing intractable headaches in the inpatient setting.

Opioids in headache.

Opioid analgesics have long been used to treat head pain of various types. This has been increasing to a significant degree over the past 25 years because of a trend for more liberal use of opioids in non-malignant pain. Opioid treatment for acute headache, as well as prophylactically for refractory chronic headache, is controversial. There are a number of adverse effects associated with acute and chronic opioid treatment. Tolerance, dependence, and addiction are prominent issues. This article attempts to analyze the benefits and disadvantages for opioids in the management of migraine and other headache disorders, relying on known properties of this class of medication as well as clinical data. It will mainly focus on 2 topics: the use of opioid medication for the acute treatment of migraine attacks and continuous prophylactic use for refractory chronic migraine.

Inhibition of ALDH2 by quercetin glucuronide suggests a new hypothesis to explain red wine headaches.

The consumption of red wine induces headaches in some subjects who can drink other alcoholic beverages without suffering. The cause for this effect has been attributed to a number of components, often the high level of phenolics in red wine, but a mechanism has been elusive. Some alcohol consumers exhibit flushing and experience headaches, and this is attributed to a dysfunctional ALDH2 variant, the enzyme that metabolizes acetaldehyde, allowing it to accumulate. Red wine contains much higher levels of quercetin and its glycosides than white wine or other alcoholic beverages. We show that quercetin-3-glucuronide, a typical circulating quercetin metabolite, inhibits ALDH2 with an IC50 of 9.6 µM. Consumption of red wine has been reported to result in comparable levels in circulation. Thus, we propose that quercetin-3-glucoronide, derived from the various forms of quercetin in red wines inhibits ALDH2, resulting in elevated acetaldehyde levels, and the subsequent appearance of headaches in susceptible subjects. Human-subject testing is needed to test this hypothesis.

Association of pessimism with cardiovascular events and all-cause mortality.

Poor psychological health is associated with Takotsubo cardiomyopathy, cardiac syndrome X, coronary microcirculatory dysfunction, peripheral artery disease, or spontaneous coronary artery dissection. Data regarding pessimism, cardiovascular disease (CVD) events and mortality and all-cause mortality remained inconclusive. This systematic review and meta-analysis aim to provide an overview of the association between pessimism, CVD outcomes and mortality. A systematic search of electronic databases was conducted from inception through July 2022 for studies evaluating pessimism and adverse outcomes. A total of 17 studies published between 1966 and July 2022 met our inclusion criteria, for a total of 232,533 individuals. Pooled hazard ratios were calculated in random-effects meta-analyses. Based on pooled analysis of adjusted HRs, pessimism was associated with adjusted HR of 1.13 (95% CI 1.07-1.19) for all-cause mortality with minimal heterogeneity (I2 = 28.5%). Based on pooled analysis of adjusted HRs, pessimism was associated with adjusted HR of 1.30 (95% CI 0.43-3.95) for CHD mortality, adjusted HR of 1.41 (95% CI 1.05-1.91) for CVD mortality, and adjusted HR of 1.43 (95% CI 0.64-3.16) for stroke. In conclusion, pessimism seems to be significantly associated with a higher risk for and poorer outcomes from CVD events than optimistic styles. There are genetic and other bases for these life approaches, but behavioral, cognitive and meditative interventions can modify patients' level of pessimism, hopefully leading to better medical outcomes. Testing this theory would yield highly useful and practical data for clinical care.

Herbal treatment of headache.

Herbal (botanical) therapy has been used as treatment for headache disorders for millennia. Botanical therapy can be divided into 3 categories: oral, topical, and "aromatherapy." In this article, the options in these categories and the evidence supporting their use are discussed. Unfortunately, evidence is sparse for most herbal treatments, in large part due to a paucity of funding for the type of studies needed to assess their efficacy. Butterbur and feverfew are the 2 herbal oral preparations best studied, and they seem to have real potential to help many patients with migraine and perhaps other headache types. Patients most appropriate for trials of herbal therapy include those who have been refractory to pharmaceutical and other modes of therapy, patients who have had intolerable side effects from pharmaceutical medications, and patients willing to participate in controlled comparative studies. As for mechanisms behind botanical treatments, the lack of funding for studying these agents will continue to retard progress in this area as well, but hopefully the future will bring more concentrated efforts in this field.

Development and Validation of VM-PATHI: Vestibular Migraine Patient Assessment Tool and Handicap Inventory.

OBJECTIVE: The aim of this article is to develop and validate a disease-specific, patient-reported outcome measure for vestibular migraine. SETTING: Tertiary care vestibular center. PATIENTS: Adult patients with definite or probable vestibular migraine per Barany Society Criteria. STUDY DESIGN: This was a prospective cohort study. VM-PATHI (Vestibular Migraine Patient Assessment Tool and Handicap Inventory) was developed with expert input, literature review, and patient feedback. VM-PATHI scores were compared between those with vestibular migraine and controls, across several time points, and to other dizziness and quality of life (QoL) measures. RESULTS: A 25-item questionnaire was developed. Cronbach's α was high at 0.92. Test-retest reliability was excellent (r = 0.90, p < 0.001). Scores were much higher in patients with vestibular migraine (mean 42.5, SD = 16.1) than control patients (mean = 9.6, SD = 8.5). VM-PATHI scores were responsive to treatment (p = 0.01). Scores were well correlated with general QoL, depression, and anxiety scores. Scores were also correlated with the Dizziness Handicap Inventory (r = 0.69). An exploratory factor analysis was performed, which revealed 6 distinct factors that corresponded well to different aspects of disease-related symptomatology. CONCLUSION: VM-PATHI is a valid, reliable, and responsive measure of disease severity in vestibular migraine.

Defining refractory migraine: results of the RHSIS Survey of American Headache Society members.

OBJECTIVES: To gauge consensus regarding a proposed definition for refractory migraine proposed by Refractory Headache Special Interest Section, and where its use would be most appropriate. BACKGROUND: Headache experts have long recognized that a subgroup of headache sufferers remains refractory to treatment. Although different groups have proposed criteria to define refractory migraine, the definition remains controversial. The Refractory Headache Special Interest Section of the American Headache Society developed a definition through a consensus process, assisted by a literature review and initial membership survey. DESIGN: A 12-item questionnaire was distributed at the American Headache Society meeting in 2007 during a platform session and at the Refractory Headache Special Interest Section symposium. The same questionnaire was subsequently sent to all American Headache Society members via e-mail. A total of 151 responses from AHS members form the basis of this report. The survey instrument was designed using Survey Monkey. Frequencies and percentages of the survey were used to describe survey responses. RESULTS: American Headache Society members agreed that a definition for refractory migraine is needed (91%) that it should be added to the International Classification of Headache Disorders-2 (86%), and that refractory forms of non-migraine headache disorders should be defined (87%). Responders believed a refractory migraine definition would be of greatest value in selecting patients for clinical drug trials. The current refractory migraine definition requires a diagnosis of migraine, interference with function or quality of life despite modification of lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy. The proposed criteria for the refractory migraine definition require failing 2 preventive medications to meet the threshold for failure. Although 42% of respondents agreed with the working definition of refractory migraine, 43% favored increasing the number to 3 (50%) or 4 (26%) preventive treatment failures. When respondents were asked if they felt that the proposed definition was appropriate to select patients for invasive procedures (patent foramen ovale repair or stimulators) only 44% agreed. CONCLUSIONS: There is a consensus for a need for a definition for refractory migraine and that it should be added to the International Classification of Headache Disorder-2. There was also general agreement by the responders that refractory forms of non-migraine headache disorders should be defined.

Refractory headache: classification and nomenclature.

There are a number of reasons to attempt to define and classify refractory headache disorders. Particularly important are the potential benefits in the areas of research, treatment, and medical cost reimbursement. There are challenges in attempting to classify refractory forms of headaches, including the lack of biological or other objective markers and a lack of consensus among practitioners as to what qualifies as refractoriness, or even if a separate category for refractory migraine and other refractory headaches needs to be established. A definition of refractory migraine has been proposed by Schulman et al in this issue ("Defining Refractory Migraine [RM] and Refractory Chronic Migraine [RCM]: Proposed Criteria for the Refractory Headache Special Interests Section of the American Headache Society"), which should be tested for validity and usefulness. It seems reasonable to consider adding this defined syndrome to the International Classification of Headache Disorders, second edition (ICHD-II). In this article, options for adding refractory headache syndromes to the ICHD are discussed with pros and cons for each. Two "best" options for adding the disorder "refractory migraine" to the ICHD are presented along with an illustrative case example.