MIGRAINE AURA NEW INSIGHTS AND PERSISTENT QUESTIONS

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MIGRAINE AURANEW INSIGHTS AND PERSISTENT
QUESTIONS
Andrew Charles, M.D. Professor Director, Headache
Research and Treatment Program David Geffen
School of Medicine at UCLA
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MIGRAINE A MULTISYMPTOM COMPLEX
AURA
PATHOPHYSIOLOGICAL MECHANISMS
HEADACHE
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ICHD Classification of Migraine With Aura

• A. At least 2 attacks fulfilling criteria BD
• 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 lt60 minutes
• D. Headache fulfilling criteria BD for 1.1
  Migraine without aura begins during the aura or
  follows aura within 60 minutes
• E. Not attributed to another disorder

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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. 199945242-6.
• MacGregor E. Oestrogen and attacks of migraine
  with and without aura. The Lancet Neurology.
  20043354-61.
• Lipton RB, Bigal ME, Ashina S, Burstein R,
  Silberstein S, Reed ML, et al. Cutaneous
  allodynia in the migraine population. Ann Neurol.
  200863148-58.

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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. 200828531-40.
• Kurth T, Gaziano JM, Cook NR, Logroscino G,
  Diener HC, Buring JE. Jama. 2006296283-91.
• Kurth T, Slomke MA, Kase CS, Cook NR, Lee IM,
  Gaziano JM, et al. Neurology. 2005641020-6.
• Samaan Z, Farmer A, Craddock N, Jones L, Korszun
  A, Owen M, McGuffin P. The British Journal of
  Psychiatry. 2009194350-4.

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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,)

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CORTICAL WAVES IN MIGRAINE WITH AURA
Olesen, et al. 1981
Hadjikhani et al., 2001
Bereczki et al., 2008
Cao et al., 1999
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PET STUDY SHOWS SPREADING OLIGEMIA IN MIGRAINE
PATIENT WITHOUT AURA
Woods RP, Iacoboni M, Mazziotta JC.. N Engl J
Med. 19943311689-92.
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AND MIGRAINE WITHOUT AURA
Woods et al., 1994
Chalaupka, 2008
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• 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

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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 128932-939
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Hypothalamic Activation in Migraine (Denuelle et
al., Headache, 2007)
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MIGRAINE A MULTISYMPTOM COMPLEX
AURA
SENSORY SYMPTOMS
VISUAL SYMPTOMS
LANGUAGE SYMPTOMS
Cortical Activation
MOTOR DYSFUNCTION
COGNITIVE DYSFUNCTION
Hypothalamic Activation
YAWNING, POLYURIA
FATIGUE, MOOD CHANGE
Brainstem Activation
NAUSEA, VOMITING
DIZZINESS, VERTIGO
HEADACHE
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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

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CSD evoked by KCl pulse --- mouse cortex. 5
minute recording

• OPTICAL IMAGING OF CORTICAL SPREADING DEPRESSION
  --
• DIGITAL SUBTRACTION IMAGE
• K.C. Brennan

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Recording of CSD in the injured human cortex over
a period of 40 min
Fabricius, M. et al. Brain 2006 129778-790.
SPREADING DEPRESSION IN HUMANS WITH BRAIN INJURY
PLAYS A ROLE IN PROGRESSION OF INJURY
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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

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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

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CSD evoked by KCl pulse --- mouse cortex. 5
minute recording
INTRINSIC VASCULAR CONDUCTION WITH CSD Brennan et
al., J. Neurophys, 2007
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VASCULAR CELLS RELEASE DIFFUSIBLE MESSENGERS THAT
MAY INFLUENCE ACTIVITY OF NEIGHBORING NEURONS
AND GLIAL CELLS
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Spontaneous CSD in setting of hypoxia profound
vasoconstriction
K.C. Brennan
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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
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HUMAN ASTROCYTE WITH BLOOD VESSEL AND
NEURONS Maiken Nedergaard
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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
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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

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Multifocal Astrocyte Calcium Waves in Cortical
Slice
Multifocal CSD Evoked by KCl Crystal In Vivo
CORTICAL WAVES MAY BE REPETITIVE, MULTIFOCAL
EVENTS
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Neurons
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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.
  200441701-10.
• Brennan KC, Romero-Reyes M, López Valdés HE,
  Arnold AP, Charles AC. Annals of Neurology.
  200761603-6.
• Eikermann-Haerter K, Dileköz E, Kudo C, Savitz
  SI, Waeber C, Baum MJ, et al. J Clin Invest.
  200911999-109.

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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

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MIGRAINE A MULTISYMPTOM COMPLEX
AURA
SENSORY SYMPTOMS
VISUAL SYMPTOMS
LANGUAGE SYMPTOMS
Cortical Activation
MOTOR DYSFUNCTION
COGNITIVE DYSFUNCTION
Hypothalamic Activation
YAWNING, POLYURIA
FATIGUE, MOOD CHANGE
Brainstem Activation
NAUSEA, VOMITING
DIZZINESS, VERTIGO
HEADACHE
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Acknowledgements

• UCLA Headache Research and Treatment Program
• K.C. Brennan
• Marcelo Romero Reyes
• Hector Lopez-Valdes
• Feldman Lab
• Mike Baca
• UCSF/HHMI
• Louis Ptácek
• Ying-Hui Fu
• Ying Xu
• Archana Shenoy
• University of Vermont
• Robert E. Shapiro
• Department of Neurology/Brain Mapping Center
• John Mazziotta
• Arthur Toga