Ocular and Cervical Vestibular Evoked Myogenic Potentials in Patients With Vestibular Migraine.

OBJECTIVE: To evaluate the relationship between normal and abnormal ocular vestibular evoked myogenic potentials (oVEMP) and cervical vestibular evoked myogenic potentials (cVEMP) in patients with and without vestibular migraine (VM). STUDY DESIGN: Retrospective review of oVEMP and cVEMP results in patients with vestibular disorders who were assessed clinically and completed vestibular function studies. Data were extracted from a deidentified RedCap Repository. SETTING: Tertiary care multispecialty medical center. PATIENTS: Subjects were 212 consecutive adults meeting prespecified inclusion criteria who were evaluated in the Balance Disorders Clinic at Vanderbilt University Medical Center between 2011 and 2017. Patients with bilaterally absent VEMPs were excluded from the study. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Proportions of subjects with or without VM in one of the following four test outcomes: normal cVEMP/normal oVEMP, abnormal cVEMP/abnormal oVEMP, abnormal cVEMP/normal oVEMP, and normal cVEMP/abnormal oVEMP. RESULTS: There was a significant relationship between VM and cVEMP and oVEMP test outcomes. CONCLUSION: Patients with VM are more likely than subjects with vestibular disorders other than migraine to exhibit normal cVEMP responses in the presence of unilaterally abnormal oVEMP responses. Such a VEMP pattern may be a biomarker of VM and further supports a possible pathophysiologic relationship between the utriculo-ocular reflex and VM.

Commentary on headache currents articles by Alhazzani and Goddeau.

Headache is a symptom of cerebrovascular disease, particularly the hemorrhagic type. Also, certain headache types, notably migraine with aura, predispose individuals to ischemic and perhaps hemorrhagic stroke. The relationship between migraine and cerebrovascular disease can be causal, coincidental or co-morbid.

Reduced adverse event profile of orally inhaled DHE (MAP0004) vs IV DHE: potential mechanism.

BACKGROUND: MAP0004 is a novel orally inhaled formulation of dihydroergotamine mesylate (DHE) currently in development that has been clinically observed to provide rapid ( approximately 10 minutes) therapeutic levels of DHE but with lower rates of adverse effects (dizziness, nausea, and paresthesia) compared with intravenous (IV) dosing. Receptor-based mechanistic studies were conducted to determine if differences between IV DHE and inhaled DHE (MAP0004) binding and functional activity were responsible for the improved adverse event profile. METHODS: Radioligand competitive binding assays were performed at adrenergic (alpha1 [non-specific], alpha2A, alpha2B, alpha2C, beta), dopaminergic (D; D(1), D(2), D(3)), and at serotonergic (5-HT; 5-HT(1A), 5-HT(1B), 5-HT(1D), 5-HT(2A), 5-HT(2C), 5-HT(3), 5-HT(4), 5-HT(5A), 5-HT(6), 5-HT(7)) receptors. Binding assays were also conducted for the major metabolite of DHE, 8'-hydroxy-DHE (8'-OH-DHE). Subsequent functional receptor assays were also performed at 5-HT(1B), 5-HT(1D), 5-HT(2A), 5-HT(2C), 5-HT(3), D(2), alpha1A, alpha2A, alpha2B, beta1, and beta2 and muscarinic receptors to ensure that observed receptor binding translated into potential functional response. RESULTS: For competitive binding studies, DHE demonstrated extensive activity at IV C(max) for all 5-HT receptors tested, except 5-HT(3) and 5-HT(4), and alpha1, alpha2A, alpha2B, alpha2C, and D(3) receptors. DHE concentrations used in the studies were equal to the peak plasma concentrations (C(max)) observed in human subjects following IV DHE 1.0 mg (the standard approved dose), and 2 and 4 inhalations MAP0004 which, respectively, produced systemic circulation levels of DHE equivalent to 0.44 mg and 0.88 mg administered IV. MAP0004 binding activity at the C(max) concentrations was lower than IV DHE and no binding was observed for the 8'-OH-DHE metabolite. However, MAP0004 preserved potent agonist action at key anti-migraine 5-HT(1B) and 5-HT(1D) receptors, even at the lower C(max )concentrations. Functional binding studies displayed similar results whereby IV DHE C(max) concentrations invoked strong agonist/antagonist responses, for instance at adrenergic and 5-HT(2C) receptors, which could have been responsible for dizziness. Conversely, at C(max) concentrations of MAP0004, inhaled DHE achieved a significantly lower response or no response at the adrenergic and 5-HT(2C) receptors. CONCLUSIONS: The mechanism by which nausea was experienced with IV DHE--yet not with MAP0004--was not associated with classic nausea pathways/targets (dopamine, 5-HT(3), or muscarinic receptors) or with peripheral action in the intestine via enterochromaffin cells. Importantly, the maximum DHE concentrations following MAP0004 administration were insufficient to interact with receptors implicated in cardiovascular (5-HT(2B) and beta(1)) and pulmonary effects (beta(2), adenosine, muscarinic, and leukotriene).

Safety and pharmacokinetics of dihydroergotamine mesylate administered via a Novel (Tempo) inhaler.

OBJECTIVE: We investigated the pulmonary absorption of dihydroergotamine (DHE) mesylate and compared the safety, pharmacokinetic, and metabolic profile of 4 different doses of orally inhaled DHE delivered by the Tempo Inhaler (MAP Pharmaceuticals Inc., Mountain View, CA, USA) with 1.0 mg intravenously (IV) administered DHE in 18 healthy subjects. METHODS: Safety was measured by monitoring adverse events, vital signs, electrocardiograms, spirometry, and changes in biochemical and hematological laboratory values. Liquid chromatography, tandem mass spectrometry was used to determine plasma DHE levels while C(max), t(max), AUC(0-6), AUC(0-48), AUC(0-inf), and t(1/2) of parent DHE and the major bioactive metabolite, 8'OH-DHE. Pharmacokinetic parameters and qualitative spectrograms for DHE and metabolites for all treatment groups were compared after inhaled DHE (MAP0004) and IV DHE 1.0 mg. Geometric means and 90% confidence intervals of log-transformed data were calculated and the ratio of means compared. RESULTS: Inhaled DHE resulted in rapid systemic absorption with pharmacokinetic parameters of both parent DHE and 8'OH-DHE similar to those achieved after a 3-minute IV infusion. Post-peak (t(max) approximately 12 minutes) DHE concentrations achieved after 4 actuations ( approximately 0.88 mg respirable dose) of MAP0004 were comparable to those detected after IV administration. The systemic exposure to DHE after 6 actuations of MAP0004 was slightly greater than that achieved after IV administration (geometric mean AUC(0-inf) ratio = 1.24). CONCLUSION: The 4-actuation delivery was well tolerated and provided systemic levels of DHE and 8'OH-DHE slightly lower than IV administration and predicted levels.

Current trends in migraine prophylaxis.

A variety of drugs from diverse pharmacological classes are in use for migraine prevention. Traditionally, they have been discovered by serendipity. Examples include beta-adrenergic blockers, anticonvulsants, tricyclic antidepressants, and serotonin receptor antagonists. The mechanisms of action of migraine preventive drugs are multiple but it is postulated that they converge on two targets: (1) inhibition of cortical excitation; (2) restoring nociceptive dysmodulation. The antiepileptic drugs (e.g., topiramate, valproate, gabapentin), calcium channel blockers such as verapamil, and inhibitors of cortical spreading depression are some examples of drugs that reduce neuronal hyperexcitability. On the other hand, modulators of the serotonergic and adrenergic systems and cholinergic enhancing drugs may restore descending nociceptive inhibition and play a role in migraine prevention. To date, Level 1 evidence and clinical experience favor the use of the antidepressant amitriptyline, the anticonvulsants divalproex and topiramate, and the beta-adrenergic blockers propranolol, timolol and metoprolol as first line migraine preventive drugs. The evidence for others (e.g., verapamil) is not as strong. Migraine preventive drugs have varying degrees of adverse effects, some of which could be limiting, and their efficacy should balanced with their risks of adverse effects, patients' expectations and desires, and compliance. It is hoped that future migraine preventive drugs target migraine mechanisms more specifically, which could well enhance the therapeutic index.

The novel p.L1649Q mutation in the SCN1A epilepsy gene is associated with familial hemiplegic migraine: genetic and functional studies. Mutation in brief #957. Online.

Familial hemiplegic migraine (FHM) is a severe subtype of migraine with hemiparesis during attacks. We scanned 10 families with FHM without mutations in the CACNA1A (FHM1) and ATP1A2 (FHM2) genes. We identified the novel p.L1649Q mutation (c.4946T>A) in Na(v)1.1 sodium channel gene SCN1A (FHM3) in a North American kindred with FHM without associated ataxia or epilepsy. Functional analysis of the mutation, introduced in the highly homologous human SCN5A, revealed markedly slowed inactivation and a two-fold faster recovery from fast inactivation predicting enhanced neuronal excitation. Our findings establish the role of neuronal Na(v)1.1 sodium channels in FHM and reinforce the involvement of ion channel dysfunction in the pathogenesis of this episodic brain disorder.

Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine. METHODS: This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events. RESULTS: The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8% of the topiramate group and 55.2% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P= .010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P= .032). Treatment-emergent adverse events occurred in 132 (82.5%) and 113 (70.2%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8%), upper respiratory tract infection (n = 22, 13.8%), and fatigue (n = 19, 11.9%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4%), fatigue (n = 16, 9.9%), and nausea (n = 13, 8.1%). Discontinuations due to adverse events occurred in 18 (10.9%) topiramate subjects and 10 (6.1%) placebo subjects. There were no serious adverse events or deaths. CONCLUSIONS: Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.

New and future migraine therapy.

Modern neuroscience advanced our understanding of putative migraine mechanisms, which led to improved therapeutics. Indeed, mechanism-based acute migraine therapy gained steam in the early 1990s after the introduction of the triptans (5-HT1B,D agonists). Post-triptans, novel targets such as calcitonin gene-related peptide (CGRP) antagonists, inhibitors of excitatory glutamatergic receptors, and nitric oxide synthase (NOS) inhibitors are leading the pack in this exploding field of discovery research. In contrast, novel therapeutic targets for migraine prevention are lacking despite a hugely unmet need. To date, migraine prophylactic drugs are advanced based on expanded indications for already approved pharmaceuticals (e.g., topiramate, valproate, propranolol, and timolol). An improved understanding of the predisposition to an attack, genomic discoveries, valid and reliable biomarkers and surrogates, and predictive preclinical models likely will unravel the neuronal substrates for central hyperexcitability and nociceptive dysmodulation, hopefully leading us to better mechanism-based targets for prevention, and ultimately yielding drugs with optimal therapeutic ratios or indices.

Classification of headache disorders.

Clinical diagnostic classifications are critical when clear biological markers are not available. Such is the case in many headache disorders and mental disorders. Also, it is crucial that the classification is widely accepted and utilized. A main goal of classification is to be a universal language for categorizing a disease or a set of disorders, establishing diagnostic criteria, and promoting unity in treatment. The International Headache Society published its first Classification of Headache Disorders in 1988 and its second edition in 2004. The first classification paved the way for a better understanding of the epidemiology, mechanisms, and treatment of headache disorders, and the second edition likely will magnify our knowledge. This article provides an overview of the classification system and outlines some of the major changes in the revised edition.

Prophylactic pharmacotherapy for migraine headaches.

Migraine therapeutics are pharmacological, including acute and preventive, nonpharmacological and/or both. Preventive pharmacological strategies serendipitously were discovered to be effective and include drugs from various pharmacological classes (e.g., beta-adrenergic blocker, anticonvulsant, tricyclic antidepressants, serotonin receptor antagonist). Converging level I evidence and clinical experience support the use of the antidepressant amitriptyline, the anticonvulsants divalproex and topiramate, and the beta-adrenergic blockers propranolol, timolol, and metoprolol in migraine prevention. Other options for migraine prophylaxis exist, but the level of evidence in support of their use is not as robust. All of these drugs have varying degrees of adverse effects, some of which can limit their use. Balancing potential efficacy with risk of adverse effects, addressing patients' expectations and desires, complying with management recommendations, adequate follow up, and accurate assessment of treatment goals are key to migraine prevention. Finally, future migraine-preventive drugs likely will target migraine mechanisms more specifically, which undoubtedly will enhance the therapeutic index.

Migraine headache prophylaxis: current options and advances on the horizon.

Migraine is increasingly recognized as a disorder of altered neuronal excitability, in part based on genetically mediated and environmentally modified aberrations of ionic exchange across the brain neuronal membrane. To this end, migraine pharmacotherapy aids in restoring the abnormally low threshold for neuronal excitation. Indeed, modulation of neuronal excitability is a common property of several established migraine preventive drugs such as propranolol, valproate, amitriptyline, and topiramate. Future migraine preventive pharmacologic therapies likely will aim at restoring the neuronal threshold for excitation by targeting such processes as cortical spreading depression and intracellular calcium influx. Also, strategies aimed at enhancing descending antinociceptive inhibition will yield effective antimigraine drugs.

Symptoms of premenstrual syndrome and their association with migraine headache.

OBJECTIVES: To determine the association between the severity of premenstrual (PMS) symptoms and headache outcome measures during natural menstrual cycles and after medical oophorectomy. BACKGROUND: Premenstrual syndrome may occur in 64% of those with pure menstrual migraine and 33% of those with menstrually related migraine. Few past studies have examined the relationship between the severity of PMS symptoms and migraine headache. METHODS: Data were obtained from a 6.5-month randomized-controlled trial examining the role of medical oophorectomy in the prevention of migraine headache and later divided into two data sets for analysis purposes. The menstrual cycle data set was composed of data from three natural menstrual cycles obtained from 21 participants during lead-in and placebo run-in phases. Each menstrual cycle was subdivided into seven 3-day intervals based on urine hormone metabolites. The medical oophorectomy data set included data from a 2-month treatment period in which a medical oophorectomy was induced by gonadotropin-releasing hormone agonists (GnRHa) and participants were randomized to transdermal estradiol or a matching placebo (GnRHa/estradiol and GnRHa/placebo groups, respectively). All participants completed a daily diary recording the severity of PMS symptoms and headache outcome measures. The primary outcome measures were the PMS index (mean of the daily PMS severity scores) and the headache index (mean of the headache severity scores). Pearson correlation coefficients were used to assess the degree of association between the outcome measures. RESULTS: Menstrual Cycle Data Set.-The PMS index was significantly correlated with the headache index during native menstrual cycles (correlation coefficient of 0.47; P < .05) and during all seven intervals of the menstrual cycle (correlation coefficients of 0.39 to 0.65; all P values < .05). Medical Oophorectomy Data Set.-Correlation coefficients between the PMS and headache indices were 0.58 and 0.47 for the GnRHa/estradiol (n = 9) and GnRHa/placebo groups, respectively (P-values of <.05). CONCLUSIONS: Moderate correlations exist within female migraineurs between the severity of PMS symptoms and headache outcome measures throughout natural menstrual cycles as well as after medical oophorectomy. Our data would suggest that the presence and severity of headache might modulate PMS symptoms in female migraineurs.

Defining the relationship between ovarian hormones and migraine headache.

OBJECTIVE: (1) To determine whether the attack characteristics of migraine differ between different intervals of the menstrual cycle; (2) To ascertain whether the "rate of change,""magnitude of change," or "total burden" of urinary hormone metabolites correlates with headaches outcome measures during different intervals of the menstrual cycle. BACKGROUND: The mechanisms through which migraines are influenced by ovarian hormones remain unclear. No previous studies until now have identified "hormonally defined" time intervals within the female menstrual cycle and compared headache outcome measures among these intervals in female migraineurs. METHOD: Daily headache diary data were obtained from 21 female migraineurs during three native menstrual cycles. Daily urine samples were collected and later assayed for estrogen and progesterone metabolites. Seven 3-day time intervals were identified within each menstrual cycle based on urine hormone measurements. Primary (headache index) and secondary (disability index, headache severity, and headache frequency) outcome measures were compared between intervals using the mixed model approach. "Rates of change,""magnitude of change," and the "total burden" of ovarian hormones were estimated from urine hormone metabolites and correlated with headache outcome measures. RESULTS: The headache index was significantly different across different intervals of the menstrual cycle (P values <.001) and was higher during menstrual intervals (first 6 days of the menstrual cycle) than during mid-cycle and mid-luteal intervals (P < .002). Similarly, secondary outcome measures were highest during the menstrual intervals. "Higher burdens" of urinary progesterone metabolites were positively correlated with headache outcome measures during the luteal intervals of the menstrual cycle. "Rates of change" and the "magnitude of change" of urinary hormone metabolites did not correlate with headache outcome measures. CONCLUSIONS: Migraine headache is more severe, disabling, and frequent during the menstrual intervals of the female reproductive cycle than during mid-luteal or mid-cycle intervals. Progesterone metabolites may play a role in modulating migraine headaches during luteal intervals of the menstrual cycle.

Functional and anatomical correlates of impaired velocity storage.

Velocity storage (VS), a brainstem function, extends the low-frequency response of the vestibular system. To better understand VS mechanisms and characteristics in humans, we analyzed retrospectively functional measures of gait, electrophysiological measures of vestibular function, and imaging studies in an attempt to determine clinical, electrophysiological, and anatomical correlates of abnormalities in VS. Two cohorts of patients referred to our Risk of Falls Assessment Clinic participated in this investigation. Group 1 (control) patients demonstrated normal caloric and rotary chair tests. Group 2 patients with impaired velocity storage (experimentals) differed clinically from Group 1 only by demonstrating abnormal multifrequency vestibulocular reflex phase measures on rotational testing. Results showed that Group 2 patients had greater impairments in postural stability and gait than Group 1 patients. Additionally, 80% of patients in Group 2 and none in Group 1 showed pontine hyperintense lesions on MRI.

Sports-related headache.

Sports-related or sports-associated headaches are common. They can be benign as in primary exertional headache or may signal serious pathology as in headache associated with traumatic subdural hematoma. Specific sports activities are associated with unique headache conditions such as decompression sickness headache or high-altitude headache, which mountain climbers experience along with other symptoms of chronic mountain sickness. The management of sports-related headaches requires an adequate understanding of its underlying etiology with subsequent cause-directed treatment plan.

Prophylactic migraine therapy: mechanisms and evidence.

This article focuses on the scientific evidence for pharmacotherapy for migraine prevention. Non-pharmacologic approaches are not discussed. However, it is important to remember the complementary value of some of these strategies (eg, biofeedback) to migraine treatment.