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.

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.

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.

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.

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.

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.

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.

Future pharmacologic targets for acute and preventive treatments of migraine.

Advances in investigative research (e.g., functional magnetic resonance imaging) have made it possible to study putative migraine processes and better understand the pathophysiology of the disorder. Consequently, the apparent opposing vascular and neuronal theories of migraine are now reconciled into a neurovascular hypothesis that pieces together migrainous events and allows us to better target such events in the hope of providing safe and effective therapies. Parallel discoveries in the fields of pharmacology, physiology, genetics and other biomedical disciplines will lead to the development of optimal migraine therapeutics. Such discoveries have already yielded some major enhancement in acute migraine treatment with the development of sumatriptan (Imitrex, GlaxoSmithKline) and other triptans and the trajectory is likely to be exponential. Novel targets, such as calcitonin gene-related peptide antagonists and inhibitors of excitatory glutamatergic receptors, are leading the pack but many other promising targets are in development. The post-sumatriptan decades will witness treatment strategies that will improve the therapeutic index of acute therapies and others which will effectively and safely prevent migraine attacks.

The link between glutamate and migraine.

Migraine pain-relay centers, including the trigeminal ganglion, trigeminal nucleus caudalis, and thalamus, contain glutamate-positive neurons, and glutamate activates the trigeminal nucleus caudalis. Glutamate is implicated in cortical spreading depression, trigeminovascular activation, and central sensitization. Glutamate receptor-subtype antagonists are effective in preclinical models of migraine, and in the clinic. These preclinical and clinical observations argue for a strong link between migraine and the glutamatergic system, a link that is important to further characterize in an effort to better understand migraine mechanisms and deliver effective therapies.

Assessing the efficacy of drugs for the acute treatment of migraine: issues in clinical trial design.

Clinical trials of therapies for acute migraine attacks have evolved over the years from open-label, small observational studies to highly structured randomised, controlled trials. The International Headache Society Committee on Clinical Trials in Migraine developed a tool to guide in designing scientifically sound trials. The proof of effect is best achieved in a clinical trial with: clearly defined objectives;a well-characterised study population, identified using well-validated diagnostic tools;proper randomisation and blinding;inclusion of a placebo arm, with proper balancing of patients receiving placebo and those receiving active drug;adequate study power; and appropriate statistical methods. Both parallel and crossover studies may be suitable in clinical trials of antimigraine agents, although the latter are a better choice in patient preference and bioequivalence studies. Although various efficacy measures are used to assess treatment effect, the 2-hour pain free rate (total resolution of pain within 2 hours after an initial moderate to severe headache) is preferred because it is clinically relevant and is relatively 'placebo-insensitive'. Various migraine surveys have indicated that a rapid onset of therapeutic effect is a highly desirable attribute of an antimigraine drug. Therefore, accurate measurements of treatment effect before 2 hours are becoming increasingly emphasised. Consistency of effect across multiple attacks adds to the understanding of the therapeutic efficacy of a test drug. Finally, preference and satisfaction studies allow us to assess patients' global impression of a particular treatment, weighing the positive effects on pain and associated symptoms of migraine against potential adverse effects.