Transcript No Slide Title

MIGRAINE AURA
NEW INSIGHTS
AND
PERSISTENT QUESTIONS
Andrew Charles, M.D.
Professor
Director, Headache Research and Treatment Program
David Geffen School of Medicine at UCLA
MIGRAINE – A MULTISYMPTOM COMPLEX
AURA
LANGUAGE SYMPTOMS
MOTOR
DYSFUNCTION
PATHOPHYSIOLOGICAL
MECHANISMS
YAWNING,
POLYURIA
ICHD Classification of Migraine
With Aura
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 CLINCIAL FEATURES
OF MIGRAINE WITH VS. WITHOUT AURA
• 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.
MIGRAINE WITH AURA HAS
GREATER ASSOCIATION WITH:
•
•
•
•
•
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.
HOWEVER….
• 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,)
CORTICAL “WAVES” IN MIGRAINE WITH AURA
Olesen, et al. 1981
Hadjikhani et al., 2001
Bereczki et al., 2008
Cao et al., 1999
PET STUDY SHOWS SPREADING OLIGEMIA IN
MIGRAINE PATIENT WITHOUT AURA
Woods RP, Iacoboni M, Mazziotta JC.. N Engl J Med. 1994;331:1689-92.
…AND MIGRAINE WITHOUT AURA
Woods et al., 1994
Before sumatriptan
2 to 4 h after the attack onset
After sumatriptan
4 to 6 h after the attack onset
Chalaupka, 2008
Denuelle et al., 2008
• 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
Activation of the ipsilateral pons in patients with right-sided attacks (n = 8, A) and left-sided
attacks (n = 8, B)
Afridi, S. K. et al. Brain 2005 128:932-939;
Hypothalamic Activation in Migraine
(Denuelle et al., Headache, 2007)
MIGRAINE – A MULTISYMPTOM COMPLEX
AURA
LANGUAGE SYMPTOMS
Cortical
Activation
MOTOR
DYSFUNCTION
Hypothalamic
Activation
Brainstem
Activation
YAWNING,
POLYURIA
CSD evoked by KCl pulse --- rat cortex. 5 minute recording
OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION
• Allows visualization of parenchymal and vascular signals
over large area with local electrophysiological recording
• Induction thresholds can be reliably established
CSD evoked by KCl pulse --- mouse cortex. 5 minute recording
OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION -DIGITAL SUBTRACTION IMAGE
K.C. Brennan
Recording of CSD in the injured human cortex over a period of 40 min
Fabricius, M. et al. Brain 2006 129:778-790;.
SPREADING DEPRESSION IN HUMANS WITH BRAIN
INJURY PLAYS A ROLE IN PROGRESSION OF INJURY
ISSUES WITH CLASSICAL CORTICAL
SPREADING DEPRESSION IN MIGRAINE
• 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
VASCULAR EVENTS IN CORTICAL
ARTERIOLES WITH CSD
–INITIAL DILATION
• Conducted With Intrinsic Velocity
Ahead of CSD
–SUBSEQUENT CONSTRICTION
–EVENTUAL DILATION OR SUSTAINED
CONSTRICTION – MAY DEPEND ON
METABOLIC STATE
CSD evoked by KCl pulse --- mouse cortex. 5 minute recording
INTRINSIC VASCULAR CONDUCTION WITH CSD
Brennan et al., J. Neurophys, 2007
VASCULAR CELLS RELEASE DIFFUSIBLE MESSENGERS
THAT MAY INFLUENCE ACTIVITY OF NEIGHBORING
NEURONS AND GLIAL CELLS
Spontaneous CSD in setting of hypoxia – profound vasoconstriction
K.C. Brennan
ARTERIOLAR DILATION PROPAGATES AHEAD
OF PARENCHYMAL CHANGES OF CSD
COULD VASCULAR SIGNALING PLAY AN ACTIVE ROLE IN
CORTICAL WAVES?
“It seems well to consider, therefore, that, however brought about,
vascular changes may precede and condition the cortical depression”.
Leao, J. Neurophys, 1945
HUMAN ASTROCYTE WITH BLOOD VESSEL AND NEURONS
Maiken Nedergaard
Calcium wave evoked by mechanical stimulation in glial culture. Real Time
Astrocytes are capable of widespread intercellular
signaling via propagated waves of increased intracellular
calcium
ASTROCYTE CALCIUM WAVES
• 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
Multifocal Astrocyte
Calcium Waves in Cortical
Slice
Multifocal CSD Evoked by
KCl Crystal In Vivo
CORTICAL WAVES MAY BE REPETITIVE,
MULTIFOCAL EVENTS
FHM Mutations
Neurons
Na+/K+ ATPase
P/Q Ca2+
Channel
K+
GLUTAMATE
Nav1 Na+ Channel
Adenosine
ATP
CGRP
Astrocytes
Nitric Oxide
Endothelin
Eicosanoids
ATP
Adenosine
Vascular cells
K+
PROPENSITY FOR CSD IS INCREASED
BY:
• 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.
MEDICATIONS THAT INHIBIT CORTICAL
EXCITABILITY PREVENT MIGRAINE WITH
AND WITHOUT AURA
• 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
MIGRAINE – A MULTISYMPTOM COMPLEX
AURA
LANGUAGE SYMPTOMS
Cortical
Activation
MOTOR
DYSFUNCTION
Hypothalamic
Activation
Brainstem
Activation
YAWNING,
POLYURIA
Acknowledgements
• 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