A. At least 2 attacks fulfilling criteria B–D

A. At least 2 attacks fulfilling criteria B–D

• A. At least 2 attacks fulfilling criteria B–D

• B. Aura consisting of at least one of the following, but no motor weakness:

• 1. fully reversible visual symptoms including positive features (eg, flickering lights, spots or lines) and/or negative features (ie, loss of vision)

• 2. fully reversible sensory symptoms including positive features (ie, pins and needles) and/or negative features (ie, numbness)

• 3. fully reversible dysphasic speech disturbance

• C. At least two of the following:

• 1. homonymous visual symptoms and/or unilateral sensory symptoms

• 2. at least one aura symptom develops gradually over ≥5 minutes and/or different aura symptoms occur in succession over ≥5 minutes

• 3. each symptom lasts ≥5 and <60 minutes

• D. Headache fulfilling criteria B–D for 1.1 Migraine without aura begins during the aura or follows aura within 60 minutes

• E. Not attributed to another disorder

Different patterns of inheritance

• Different patterns of inheritance

• Different occurrence relative to menstrual cycle

• Higher incidence of allodynia in patients with aura

• Vibeke et al., Evidence of a genetic factor in migraine with aura: A population-based Danish twin study. Annals of Neurology. 1999;45:242-6.

• MacGregor E. Oestrogen and attacks of migraine with and without aura. The Lancet Neurology. 2004;3:354-61.

• Lipton RB, Bigal ME, Ashina S, Burstein R, Silberstein S, Reed ML, et al. Cutaneous allodynia in the migraine population. Ann Neurol. 2008;63:148-58.

STROKE

• STROKE

• PATENT FORAMEN OVALE

• CARDIOVASCULAR DISEASE IN WOMEN

• DEPRESSION

• ANXIETY, PANIC, PHOBIAS, SUICIDAL IDEATION

• Schwedt TJ, Demaerschalk BM, Dodick DW. Cephalalgia. 2008;28:531-40.

• Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener HC, Buring JE. Jama. 2006;296:283-91.

• Kurth T, Slomke MA, Kase CS, Cook NR, Lee IM, Gaziano JM, et al. Neurology. 2005;64:1020-6.

• Samaan Z, Farmer A, Craddock N, Jones L, Korszun A, Owen M, McGuffin P. The British Journal of Psychiatry. 2009;194:350-4.

VERY FEW MA PATIENTS HAVE AURA WITH 100% OF THEIR ATTACKS

• VERY FEW MA PATIENTS HAVE AURA WITH 100% OF THEIR ATTACKS

• MANY PATIENTS CLASSIFIED AS HAVING MIGRAINE WITHOUT AURA HAVE HAD 1 or 2 EPISODES WITH TYPICAL AURA

• CLINICAL SYMPTOMS MAY NOT MEET DEFINITION OF AURA (e.g. cognitive symptoms, timing relative to headache,)

UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS OF AURA MAY BE CLINICALLY SILENT

• UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS OF AURA MAY BE CLINICALLY SILENT

• ABSENCE OF AURA SYMPTOMS, PARTICULARLY THOSE STRICTLY DEFINED BY ICHD CRITERIA, DOES NOT MEAN THAT CORTICAL PHENOMENA ARE NOT OCCURRING

CLASSIC EEG FINDINGS OF CORTICAL SPREADING HAVE NOT BEEN OBSERVED IN MIGRAINE PATIENTS

• CLASSIC EEG FINDINGS OF CORTICAL SPREADING HAVE NOT BEEN OBSERVED IN MIGRAINE PATIENTS

• MOST PATIENTS DO NOT HAVE THE PROFOUND NEUROLOGICAL IMPAIRMENT ONE WOULD EXPECT WITH CLASSICAL CSD

• MIGRAINE MAY INVOLVE CORTICAL WAVES THAT ARE RELATED TO, BUT NOT IDENTICAL TO CSD OBSERVED IN ANIMAL MODELS

• DIFFERENT TYPES OF CORTICAL WAVES MAY INVOLVE DISTINCT CELLULAR MECHANISMS

INITIAL DILATION

• INITIAL DILATION
• Conducted With Intrinsic Velocity Ahead of CSD
• SUBSEQUENT CONSTRICTION
• EVENTUAL DILATION OR SUSTAINED CONSTRICTION – MAY DEPEND ON METABOLIC STATE

SLOWLY PROPAGATED WAVES EVOKED BY WIDE VARIETY OF STIMULI

• SLOWLY PROPAGATED WAVES EVOKED BY WIDE VARIETY OF STIMULI

• ASSOCIATED WITH ACTIVE RELEASE OF:

• ATP
• GLUTAMATE
• K+
• LACTATE
• PROSTANOIDS
• INTERLEUKINS

• CAPABLE OF ACTIVE MODULATION OF NEURONAL AND VASCULAR ACTIVITY

GENES -- Transgenic mice expressing FHM1 genes show increased propensity for CSD

• GENES -- Transgenic mice expressing FHM1 genes show increased propensity for CSD

• GENDER – Female mice have a reduced threshold for CSD

• HORMONES – Ovarian hormones reduce the threshold for CSD

• van den Maagdenberg AMJM, Pietrobon D, Pizzorusso T, Kaja S, Broos LAM, Cesetti T, et al. Neuron. 2004;41:701-10.

• Brennan KC, Romero-Reyes M, López Valdés HE, Arnold AP, Charles AC. Annals of Neurology. 2007;61:603-6.

• Eikermann-Haerter K, Dileköz E, Kudo C, Savitz SI, Waeber C, Baum MJ, et al. J Clin Invest. 2009;119:99-109.

Ayata et al., Annals of Neurology 2006.

• Ayata et al., Annals of Neurology 2006.

• Diverse pharmacological agents that are effective for migraine prevention suppress cortical spreading depression in rat.

• Memantine for migraine prevention??

• Identified as an inhibitor of CSD
• Initial clinical results encouraging (Charles, et al, Journal of Headache and Pain, 2007).

• Specific neuronal, astrocytic, and vascular cortical mechanisms may represent individual distinct targets for new acute and preventive therapies

UCLA Headache Research and Treatment Program

• UCLA Headache Research and Treatment Program

• K.C. Brennan
• Marcelo Romero Reyes
• Hector Lopez-Valdes

• Feldman Lab

• Mike Baca

• UCSF/HHMI

• Louis Ptáček
• Ying-Hui Fu
• Ying Xu
• Archana Shenoy

• University of Vermont

• Robert E. Shapiro

• Department of Neurology/Brain Mapping Center

• John Mazziotta
• Arthur Toga