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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).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.Tertiary care multispecialty medical center.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.None.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.There was a significant relationship between VM and cVEMP and oVEMP test outcomes.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.

The discovery of glutamate (Glu) is more than 100 years old, dating from when Ikeda isolated this natural amino acid from seaweed broth. Discoveries of neurotransmitter function, the role of Glu as a neurotransmitter, and Glu receptors and receptor types and functions followed over the subsequent century. To date, it is well established that Glu is the major neurotransmitter in the mammalian brain, and it participates in a myriad of functions in brain physiology and pathophysiology; migraine is no exception.

International Headache Society Clinical Trials Subcommittee members: Peer Tfelt-Hansen (chairman) (Denmark), Julio Pascual (vice-chairman) (Spain), Nabih Ramadan (vice-chairman) (USA), Carl Dahlof (Sweden), Domenico D’Amico (Italy), Hans-Christopher Diener (Germany), Jakob Moller Hansen (secretary) (Denmark), Michel Lanteri-Minet (France), Elisabeth Loder (USA), Douglas McCrory (USA), Sandra Plancade (France) and Todd Schwedt (USA)

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.

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.

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.

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.

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. Methods.—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

In the decade since the introduction of sumatriptan on the market, second- and third-generation triptans have been advanced with the goal of reducing side effects while maintaining or improving efficacy. While these efforts have yielded relatively minor changes to the sumatriptan molecule, the new triptans enhance the ability of clinicians to individualize therapy. More recent strategies focus on novel neuronal targets for acute migraine treatments without the liability of adverse cardiovascular effects. Current research is focusing on calcitonin gene-related peptide antagonists, glutamate modulators, selective serotonin 1F or 1D agonists, and adenosine type 1 agonists. Clinical data on these approaches are emerging and seem encouraging. However, these potential therapies are in an early stage of development, and to date, none has reached phase III clinical research.

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.

Background: Current evidence-based acute treatments of cluster headache are limited to oxygen inhalation and subcutaneous sumatriptan. Intranasal sumatriptan is a new formulation with better tolerability than the subcutaneous route. Two open-label studies suggested efficacy of intranasal sumatriptan in cluster headache.Methods: In a double-blind placebo-controlled randomized trial, patients with episodic or chronic cluster headache whose attacks lasted at least 45 minutes each treated one attack with 20 mg sumatriptan nasal spray and another one, at least 24 hours later, with matching placebo. They scored their headache on a five-point scale (very severe, severe, moderate, mild, or none) at 5, 10, 15, 20, and 30 minutes. The primary outcome measure was headache response (a decrease in pain from very severe, severe, or moderate to mild or none) at 30 minutes. Secondary outcome measures included pain-free rates, relief of associated symptoms, and rates of adverse events. Multilevel multivariate analysis was used for statistical analysis.Results: Five study centers enrolled 118 patients in whom 154 attacks were treated: 77 with sumatriptan and 77 with placebo. The responder rates at 30 minutes were 57% for sumatriptan and 26% for placebo (p = 0.002). Pain-free rates at 30 minutes were 47% for sumatriptan and 18% for placebo (p = 0.003). Sumatriptan was also superior to placebo considering initial response, meaningful relief, and relief of associated symptoms. There were no serious adverse events.Conclusion: Sumatriptan nasal spray is effective and well tolerated in the acute treatment of cluster headache attacks of at least 45 minutes’ duration.

Specific efficacy criteria were defined by the International Headache Society for controlled clinical trials on acute migraine. They are derived from the pain profile and the timing of rescue medication intake. We present a methodology to improve the analysis of such trials. Instead of analysing each endpoint separately, we model the joint distribution and derive success rates in any criteria as predictions. We use cumulative regression models for each response at a time and a multivariate normal copula to model the dependence between responses. Parameters are estimated using maximum likelihood. Benefits of the method include a reduction in the number of tests performed and an increase in their power. The method is well suited to dose-response trials from which predictions can he used to select doses and optimize the design of subsequent trials. More generally, our method permits a very flexible modelling of longitudinal series of ordinal data. Copyright (C) 2003 John Wiley Sons Ltd.

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: (i) clearly defined objectives; (ii) a well-characterised study population, identified using well-validated diagnostic tools; (iii) proper randomisation and blinding; (iv) inclusion of a placebo arm, with proper balancing of patients receiving placebo and those receiving active drug; (v) adequate study power; and (vi) appropriate statistical methods. Roth narallel and crossover studies may be suitable in clinical trials of antimipraine 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.

The introduction of sumatriptan, a selective 5-HT(1B/1D) agonist, for the treatment of migraine sparked a new era of drug research in this field. Many novel targets have since been developed, and tested in the clinic. The promise of these approaches is to deliver an anti-migraine compound with the optimal efficacy and safety profile. In this chapter, blind alleys in anti-migraine development are discussed. The failing soldiers have included the NK-1 antagonists, some second-generation 5-HT(1B/1D) agonists, CP-122,288, 4991W93, the neurosteroid ganaxolone, selective 5-HT(1F) (LY334370) and 5-HT(1D) agonists (PNU-142,633), and the endothelin-1 antagonist bosentan. Some of these promising targets failed to demonstrate clinical efficacy, while others were stopped for preclinical toxicity.

Previous studies demonstrated that zolmitriptan at doses of 1 to 25 mg was highly effective in treating acute migraine attacks. The 2.5-mg dose had a favorable therapeutic effect with high efficacy and good tolerability. The objective of this study was to further evaluate the efficacy of a single 2.5-mg dose of zolmitriptan (Zomig, formerly known as 311C90) for acute treatment of a single moderate or severe migraine attack. The study was a randomized, double-blind, placebo-controlled clinical trial. Female and male patients, 12 to 65 years old, with migraine (with or without aura) for ≥1 year, one to six migraines per month, and age at onset < 50 years were included; 327 patients were screened and randomized to receive either zolmitriptan (n = 219) or placebo (n = 108). Patients treated a single moderate or severe migraine headache with 2.5 mg zolmitriptan or placebo and recorded clinical efficacy and adverse events on a diary form. Headache response at 2 hours was 62% for zolmitripan compared with 36% for placebo(p < 0.001); at 4 hours, headche response was 70% with zolmitriptan and 37% with placebo (p < 0.001). Headache recurrence in patients treated with 2.5 mg zolmitriptan was 22% (versus placebo 30%). The headache response at 4 hours, pain-free rate, and response rate of nonheadache symptoms favored zolmitriptan over placebo. No serious adverse events were associated with zolmitriptan treatment. A 2.5-mg dose of zolmitriptan is clinically effective and well tolerated for the acute treatment of migraine.

Headache is a common symptom of HN-1 infection. The majority of HIV-related headaches are due to serious complications of the disease such as meningitis or CNS mass lesions. Clinical presentations of benign and serious headaches in patients with HIV-1 infection often overlap. Therefore, patients with HIV-1 infection, regardless of the disease stage, should undergo thorough investigations when they present with headache.

Over the past 15 years there has been enormous scientific and clinical progress in the field of headache. New and more effective treatments have emerged as migraine science has been translated into clinical practice. Despite the progress, not all patients respond to available treatments, and individual patients respond differentially for different attacks. Improving the outcomes of migraine patients requires further progress in using available knowledge to develop new treatments and novel combinations of existing treatments. The scientific foundation and opportunity for the future of acute migraine therapy provide the basis of this supplement. Migraine is a primary episodic headache disorder characterized by a cascade of events that involve various combinations of neurologic, gastrointestinal, and autonomic changes. Headache is probably caused by activation of meningeal and blood vessel nociceptors combined with an alteration in central pain modulation. Headache and its associated neurovascular changes are subserved by the trigeminal system. A link also exists between the migraine aura and headache. Cortical spreading depression (CSD) activates trigeminovascular afferents, causing a long-lasting increase in middle meningeal arterial blood flow and polypeptide release within the dura mater.1 Reflex connections to the cranial parasympathetics form the trigeminoautonomic reflex. Activation of the cranial parasympathetics leads to release of vasoactive intestinal polypeptide (VIP) and to vasodilatation. Trigeminal sensory neurons contain substance P (SP), calcitonin gene-related peptide (CGRP), and neurokinin A.2 Stimulation of the trigeminal sensory neurons causes the release of SP and CGRP from sensory C-fiber terminals3 and the start of neurogenic inflammation,4 suggested by one study to occur in humans.5 The neuropeptides interact with the blood vessel wall, producing dilatation, plasma protein extravasation (PPE), …

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.

Migraine is a prevalent condition worldwide. It has far-reaching individual and societal economic impact. Almost all migraineurs (95%) take medications for headache relief and the majority use over-the-counter (OTC) medications. OTC drugs are readily accessible, affordable and effective. These medications are commonly used without the advice of a healthcare professional, hence the potential for negative health outcomes due to improper use. To avoid these problems and their potentially harmful consequences (e.g. toxicity, adverse effects), major efforts should be directed towards educating the public about migraine and its treatment, including the appropriate use of OTC medications.

We have reported previously that the 25-item Headache Disability Inventory has good internal consistency reliability, robust long-term (2 month) test-retest stability, and good construct validity. We conducted further investigations to evaluate the short-term (1 week) test-retest reliability and spouse perceptions of patients' self-perceived headache disability. The short-term test-retest reliability of the Headache Disability Inventory was excellent. Additionally, the spouse and patients' perceptions of the patient's headache disability generally were congruent, although we observed instances where the differences were marked.

Nonpharmacological therapy of primary headache conditions including chronic daily headache (CDH) is not well-studied. Barton and Blanchard report on their experience with intensive self-regulatory treatment in a cohort of patients with CDH. This negative trial provides preliminary observations that need further investigations in controlled, adequately powered clinical study.

Headache is a common, although under-emphasized, feature of ischemic cerebrovascular disease. In this review, we summarize the literature on the clinical features of headache in ischemic cerebrovascular disease (Part I) and elaborate upon the underlying mechanisms of the head pain (Part II-December issue).

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).

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 Cmax, tmax, AUC0-6, AUC0-48, AUC0-inf, and t1/2 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 (tmax∼12 minutes) DHE concentrations achieved after 4 actuations (∼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 AUC0-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.

To compare systemic delivery of ergotamine tartrate (ET) via a breath-synchronized, plume-control inhaler (BSPCI) (Tempo ET) with a sublingual ergot preparation and a commercial inhaler.Study 1 determined plasma ET concentrations in seven healthy subjects after administration of ET by a 2 mg tablet (Lingraine) and a BSPCI delivering 258 microg of ET. Study 2 determined plasma ET concentrations in 16 healthy subjects after administration via an ET metered dose inhaler (ME) (Medihaler) delivering 2052 microg of ET and a BSPCI delivering 129 microg of ET. Gamma scintigraphy with (99m)Tc validation was used to quantify lung deposition.For both studies, ET C(max) was higher with the BSPCI (study 1: sublingual ET 134 pg/mL at 37 min; BSPCI 3743 pg/mL at 3 min; study 2: metered-dose inhaler 1109 pg/mL at 4 min; BSPCI 1210 pg/mL at 2.5 min). Mean dose normalized AUC was several-fold higher with the BSPCI compared with sublingual ET and ME dosing. Lung deposition of ET with the BSPCI was 33.5, 8.9, 11.4, and 13.2% for whole, central, intermediate, and peripheral lung, respectively, with a 1.5 peripheral : central ratio.Based on these open-label studies, the BSPCI allows rapid delivery of potentially therapeutic plasma concentrations of ET at approximately 1/15th the dose of comparators.

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.

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.4946TA) 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.

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.

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

This article reviews the overall pathophysiology of migraine and identifies specific pathways and potential targets for the acute treatment of migraine. This will include a review of our current understanding of the primary sites of action of commonly used antimigraine therapies, including triptans, analgesics (opioids, barbiturates, and narcotics), anti-inflammatories (NSAIDs, COX-2 inhibitors), and potential future treatments. The article closes with the suggestion that targeting multiple migraine mechanisms may enhance the effectiveness of antimigraine treatment compared to traditional monotherapeutic approaches. Over the past 25 years the field of migraine research has witnessed an explosion of information on the understanding of the pathophysiology and mechanisms involved in the disorder. Advances in molecular biology, genomic science, and imaging techniques have helped to better define pathways involved in the migraine process. Head pain is generated when pain-sensitive intracranial structures are stimulated. These include vascular, meningeal, and neural elements. The circle of Willis and proximal cerebral arteries, middle meningeal, superficial, and trochlear arteries, superior sagittal sinus, and sylvian veins are all vascular pain structures.1,2 Neuronal structures that mediate head pain include the trigeminal, glossopharyngeal, and vagus cranial nerves. Finally, the cranial meninges, and especially the perivascular components of the dura, are important sources of headache. Pain signals are transmitted from the nociceptive structures, mostly via A-δ- and C-fibers that contain glutamate and neuropeptides such as calcitonin gene-related peptide (CGRP), substance P (SP), and neurokinin A (NKA). Cat studies indicate that the middle meningeal artery nociceptive fibers travel through the ophthalmic branch of the trigeminal nerve to the projection area of the ipsilateral ganglion. On the other hand, fibers from the dura of the middle cranial fossa travel to the mandibular projection area of the ipsilateral trigeminal ganglion. From the first relay in the trigeminal ganglion, fibers project centrally to synapse on secondary sensory neurons …

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.

Background and Purpose Low pulsatility signals (LPS) on transcranial Doppler ultrasonography are detected (1) with arteriovenous malformations, (2) distal to hemodynamically significant stenosis, and (3) in venous structures. We describe focal LPS in the territory of the internal carotid artery siphon that do not represent any of the above conditions. Methods We performed retrospective and prospective reviews of transcranial Doppler studies on 3225 patients over 5 years. Clinical and radiological data of all patients with focal LPS were extracted. LPS was defined as a focal signal identified through the orbital windows with a low pulsatility index ( Results Sixteen LPS (mean flow velocity [mean±SD], 62±11 cm/s; pulsatility index [mean±SD], 0.41±0.08; depth range, 46 to 72 mm) from 15 patients (mean±SD age, 45±15 years; 4 men, 11 women) were identified. LPS flow direction was away from the probe in 13 cases and toward it in 3. Presenting symptoms included headache, focal neurological deficits, dizziness, and pulsatile tinnitus. All patients had cranial MRI (MRI and MR angiography in 11). Three patients underwent conventional cerebral angiography. Arteriovenous malformations or significant arterial stenoses were not detected on any study. Conclusions A focal signal from the internal carotid artery siphon region with low pulsatility index and normal mean flow velocity, identified in the absence of other transcranial Doppler abnormalities, is not related to an arteriovenous malformation or proximal arterial stenosis. LPS, as defined, are not of venous origin since mean flow velocity was in the arterial range. LPS are likely related to prominent venous flow in the cavernous sinus secondary to unusually strong pulsation of the intracavernous internal carotid artery.

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. Abbreviations: CDP = computerized dynamic posturography; ENG = electronystagmography; MRI = magnetic resonance imaging; SOT = sensory organization test; T2WI = T2 weighted image; TE = echo time; TR = repetition time; VOR = vestibulo-ocular reflex; VS = velocity storage

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.

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.

Objectives.—To determine the preventive benefit of “medical oophorectomy” and transdermal estradiol in women with migraine. Background.—Epidemiological studies have demonstrated that declines in serum estrogen levels occurring during normal menstrual cycles can trigger headache in women with migraine. Prior to this study, no randomized controlled trials have evaluated whether minimizing these hormonal changes pharmacologically can prevent headache. Methods.—Twenty-one women with regular menstrual cycles and a diagnosis of migraine headache were enrolled. After a 2.5-month placebo run-in phase, all patients received a subcutaneous goserelin implant (a gonadotropin-releasing hormone agonist) to induce a medical oophorectomy. One month later, while continuing goserelin, participants were randomized to receive a transdermal patch containing 100 μg of estradiol-17β (gonadotropin-releasing hormone agonist/estradiol group, n = 9) or a placebo patch (gonadotropin-releasing hormone agonist/placebo group, n = 12) during a 2-month treatment phase. The primary outcome measure was the headache index, which was defined as the mean of pain severity ratings (0 to 10 scale) recorded three times per day by daily diary. Secondary outcome measures included headache disability, headache severity, headache frequency, and the percentage of headaches with a pain severity rating of 7 or greater. Results.—The headache index was significantly lower during the treatment period in the gonadotropin-releasing hormone agonist/estradiol group than in the gonadotropin-releasing hormone agonist/placebo group (P = .025). Similar improvements were observed in the gonadotropin-releasing hormone agonist/estradiol group for all secondary outcome measures with the exception of headache frequency, which was unchanged between the groups. Within the gonadotropin-releasing hormone agonist/estradiol group, there was a 33.7% reduction (95% confidence interval, −64.4 to −3.0) in the headache index during the treatment phase when compared with the placebo run-in phase; no difference was seen between those phases within the gonadotropin-releasing hormone agonist/placebo group. Conclusions.—Minimization of hormonal fluctuations with gonadotropin-releasing hormone agonist therapy alone is inadequate to prevent headache in women who are premenopausal with migraine. The addition of transdermal estradiol to existing gonadotropin-releasing hormone agonist therapy provides a modest preventive benefit.

In Chapter 14, blind alleys in acute anti-migraine drug development were discussed. In this chapter, future therapies are covered. There is growing interest and support for the use of CGRP antagonists, nitric oxide synthase inhibitors, and ionotropic glutamate receptor antagonists. The hope is to strike the balance of high efficacy with minimal to no safety concern and good tolerability. Some of the targets discussed in this chapter have been in early efficacy trials and others are in first human dose stages. Large-scale efficacy and safety trials are eagerly awaited.

Objective.—To compare gabapentin with placebo for use as a prophylactic agent in patients with migraine (with or without aura). Study Design and Treatment.—After screening, a 4-week, single-blind, placebo baseline period was followed by a 12-week, double-blind, treatment period. The 12-week treatment period consisted of a 4-week titration phase and an 8-week stable-dosing phase. During the 4-week titration phase, patients were started on one 300-mg capsule of gabapentin or matching placebo. Patients were titrated weekly from 900 mg/day (end of week 1) to 2400 mg/day (end of week 4) and had to be receiving a stable dose of study medication by the end of the titration period. Study medication was to be given on a three-times-a-day dosing regimen. Methods.—The study hypothesis was defined a priori as a lower 4-week migraine rate during the second stabilization period for the gabapentin-treated patients as compared with the placebo-treated patients. The analyses were performed with the 4-week migraine rate at baseline as a covariate and center as a blocking factor. Results.—At seven participating centers, 143 patients with migraine were randomized in a 2:1 ratio and received either gabapentin (n 5 98) or matching placebo (n 5 45). Thirty-three patients (24.1%) discontinued prematurely from the study, including 24 (24.5%) of 98 gabapentin-treated patients and 9 (20.0%) of 45 placebo-treated patients; the majority of patients discontinued due to adverse events (16 [16.3%] of 98 gabapentin-treated patients; 4 [8.9%] of 45 placebo-treated patients). Patients included in the analysis were evenly balanced for age, sex, race, weight, and height. The majority of these patients were white (80 [92.0%] of 87) and women (72 [82.8%] of 87), with a mean age of approximately 39.4 years and a history of migraine episodes for a mean of about 21 years. At the end of the 12-week treatment phase, the median 4-week migraine rate was 2.7 for the gabapentin-treated patients maintained on a stable dose of 2400 mg/day and 3.5 for the placebo-treated patients ( P 5 .006), compared with 4.2 and 4.1, respectively, during the baseline period. Additionally, 26 (46.4%) of 56 patients receiving a stable dose of 2400 mg/day gabapentin and 5 (16.1%) of 31 patients receiving placebo showed at least a 50% reduction in the 4-week migraine rate ( P 5 .008). The average number of days per 4 weeks with migraine was also statistically significant and favored gabapentin ( P 5 .006) during stabilization period 2. The median change in 4-week headache rate was statistically significant as well ( P 5 .013). The most frequently reported adverse events for both treatment groups were asthenia, dizziness, somnolence, and infection. Adverse events determined by the investigator to be associated with study drug resulted in patient withdrawal in 13 (13.3%) of 98 gabapentin-treated patients and 3 (6.7%) of 45 placebo-treated patients. Somnolence and dizziness accounted for many of the premature withdrawals among those taking gabapentin. Conclusion.—Gabapentin is an effective prophylactic agent for patients with migraine. In addition, gabapentin appears generally well tolerated with mild to moderate somnolence and dizziness.

Dynamic cerebral blood flow (CBF) studies using acetazolamide or hypercapnia as a vasodilatory challenge have attempted to evaluate intracranial hemodynamics. We report two patients with asymptomatic internal carotid artery occlusion in whom the vasodilatory stimulus was a single oral dose of antihypertensive medication (prazosin hydrochloride or enalapril maléate). In both patients, changes in regional CBF occurred that were larger than those seen in nine normal controls. One patient experienced an improvement in regional CBF with a reduction in probe pair asymmetry. In the other patient, who had bilateral carotid artery disease, a decrease in regional CBF in all 16 probes (mean decrease 12 percent) and an accentuation of the predose asymmetry were observed. Both patients remained asymptomatic throughout the study. Assessing these effects on cerebral circulation may help identify patients at risk for iatrogenic focal cerebral ischemia and provide information regarding the functional status of the cerebral vasculature.

Background and Purpose.-Headache is the most common neurologic symptom following minor closed head injury. There is often a lack of objective evidence supporting an organic basis of cerebral pathology in these cases. This pilot study considers the possibility of alterations in cerebral blood flow, indicating evidence of an organic disorder in posttraumatic headache. Methods.-Regional cerebral blood flow studies of 35 patients with chronic posttraumatic headache (PTH) (International Headache Society criteria), identified retrospectively from our cerebral blood flow data base, were compared with those of 49 nonheadache controls and 92 migraineurs (Ad Hoc Committee criteria). Regional cerebral blood flow (initial slope index method) was measured using the xenon Xe 133 inhalation technique. Results.-Compared to migraineurs and controls, and after adjusting for differences (analysis of covariance) in baseline variables such as blood pressure, hematocrit, and Pco 2 , patients with PTH had: (1) significantly lower mean initial slope indices (P

This chapter describes transcranial Doppler sonography (TCD) and stroke. TCD is a noninvasive bedside method used for the evaluation of intracranial cerebral hemodynamics and may provide rapid and reliable data regarding the cause of stroke. TCD is also used to assess the degree of arterial vasospasm, evaluate patients with suspected brain death, and assist in the diagnosis of arteriovenous malformation (AVM). Transcranial Doppler is commonly used to detect abnormalities in cerebral hemodynamics among patients with cerebrovascular diseases, although its clinical usefulness has not been universally accepted. The use of TCD is becoming routine in detecting intracranial arterial lesions. The sensitivity and specificity of TCD for stenosis of a particular vessel varies in different studies. Platelet thrombi, air emboli, or atheromatous materials can be recognized by the examiner with the characteristic sound that they produce during the TCD study. The preoperative detection of high-intensity transient signals with TCD may help identify subgroups of patients with symptomatic as well as asymptomatic high grade carotid artery stenosis, as well as the hemodynamic changes during carotid endarterectomy or cardiac bypass surgery. It is suggested that the use of contrast agents and the new generation TCD machines with B-mode capabilities may enhance the utility of the technique.

We wished to determine in asymptomatic hypertensive patients with > or = 70% stenosis of an internal carotid artery the change in regional cerebral blood flow (rCBF) produced by ramipril and enalapril and to evaluate the influence of age on drug-induced changes in rCBF. In a prospective, randomized, single-blind, placebo-controlled investigation, using the 133Xenon inhalation technique, we assessed baseline rCBF in 15 patients (9 men and 6 women aged 60-79 years) after a 24-h antihypertensive drug-free period. All patients then received a single 5-mg oral dose of ramipril, enalapril, or placebo. rCBF was reassessed 2 h postdose. There was no significant change in the median rCBF in any of the three treatment groups. Neither did we observe any lateralization of BF to any specific cerebral region in any of the three groups. There were no observed or patient-reported adverse events (AE). Single 5-mg oral doses of either ramipril or enalapril did not decrease CBF significantly in asymptomatic hypertensive patients with > or = 70% stenosis of an internal carotid artery and are probably safe starting doses in such patients. In addition, this effect was not modified by age.

Extremes of intracranial pressure commonly cause headache. Benign intracranial hypertension is a rare syndrome of increased intracranial pressure manifesting as headache, intracranial noises, transient visual obscuration, and palsy of the sixth cranial nerve. Endocrine disorders such as obesity and hypoparathyroidism, hypervitaminosis A, tetracycline use and thyroid replacement are probable causes of benign intracranial hypertension. In the majority of cases, however, it is idiopathic. Benign intracranial hypertension is though to be caused by cerebral edema, high cerebrospinal fluid outflow resistance and high cerebral venous pressure, or a combination of the three. The management of benign intracranial hypertension includes, symptomatic headache relief, removal of offending risk factor(s), and medical or surgical reduction of intracranial pressure. Spontaneous intracranial hypotension is more rare than benign intracranial hypertension. Postural headache (worse in the upright position) is the hallmark of spontaneous intracranial hypotension. Typically, the cerebrospinal fluid pressure is less than 60 mm H2O. Diminished cerebrospinal fluid production, hyperabsorption, and leak are postulated mechanisms of spontaneous intracranial hypotension. Empirical treatment includes bed rest, administration of caffeine, corticosteroids or mineralocorticoids, epidural blood patch, and epidural saline infusion.

The evidence for disordered mitochondrial oxidative phosphorylation and reduced intracellular free magnesium in brain and body tissue of migraine sufferers both between and during an attack is reviewed. We propose that between attacks these metabolic shifts cause instability of neuronal function which enhances the susceptibility of brain to develop a migraine attack.

In order to study the frequency and characteristics of post-angiography headache, we interviewed 45 consecutive patients (mean age +/- SD = 57 +/- 15 years; M/F = 15/30) who underwent transfemoral cerebral angiography for: ischemic cerebrovascular disease (n = 33); suspected arteriovenous malformations (n = 4; one confirmed); suspected cerebral aneurysm (n = 5; two confirmed); and arterial dissection (n = 3; one confirmed and one was a follow-up study of a previously demonstrated dissection). Postangiography headache developed in 15 (33%) patients, 125 +/- 99 min after the completion of the study. It was unilateral in nine (60%) patients, homolateral to the usual side of migraine headache in two or three migraineurs, and pulsating in six (40%). Nausea, vomiting, photophobia, and phonophobia accompanied postangiography headache in 20%, 7%, 33%, and 20% respectively. Postangiography headache fulfilled the International Headache Society criteria for migraine without aura (except for the number of attacks) in 27% of patients. Patients with and those without postangiography headache were comparable in mean age, sex, and indication for angiography. Fifty-three percent (8/15) of patients with postangiography headache and 23% (7/30) of the non postangiography headache group reported prior recurrent headaches (P = 0.047, likelihood ratio chi-square). Postangiography headache has the characteristics of delayed arterial pain which may be related to a catheter-induced or contrast dye-induced release of vasoactive substances, notably nitric oxide and serotonin.