The Science of MigraineBrian M. Plato, DONorton Headache and Concussion CenterNorton Neuroscience Institute
A Common Problem• 45 million Americans with headache disorders• 30 million Americans with migraine, the mostcommon disabling form of headache• 12% of the US population has migraine• 18% of women, 6% of men are affected bymigraine
One Year Prevalence of MigraineLipton R B et al. Neurology 2007;68:343-349
Migraine is more common thandiabetes and asthma combined!1%7%6%7%13%0% 5% 10% 15% 20%MigraineOsteoarthritisDiabetesAsthmaRheumatoidArthritis
Commonly Mis- / Un-DiagnosedDiagnosed MigraineUndiagnosedMigraine39%61% 52%48%19891999Lipton et al., 2001American Migraine Study II
A Costly Problem• Chronic headache disorders are among thetop 20 causes of disability in the US accordingto the World Health Organization (WHO)• 4% of Americans experience 4 hours ofheadaches per day, at least 15 days per month• Headache disorders are responsible for morethan $31B in economic costs in the USannually
Diagnosis of Migraine Without Aura• No single feature required or sufficient for diagnosis• Characteristics (2/4)– Unilateral (40% bilateral or generalized)– Throbbing (50% non-pulsating)– Moderate-severe intensity (~20% mild)– Pain worsened by exertion (>95%)• Associated symptoms (1/2)– Nausea (86% – 95%) or vomiting (47% – 62%)– Photophobia (82% – 95%), phonophobia (61% – 98%)Russell MB et al. Cephalalgia. 1996.Pryse-Phillips WEM et al. Can Med Assoc J. 1997.
Additional Features of Migraine• Predictable timing around menstruation andovulation• Stereotyped prodromal symptoms• Characteristic triggers• Improves with sleep (more effective in young pts)• Positive family history• Childhood precursors (cyclic vomiting, abdominal“migraine”, episodic vertigo, probably motionsickness)• Osmophobia (smell sensitivity)
“I have sinus headaches”Eross E, Dodick D, Eross M. The sinus, allergy and migraine study (SAMS)86% Migraine3% Sinus related headachePatients self diagnosing “sinus headaches”
What Causes Migraine?• The Vascular Theory• Blood vessels constricting (aura)Followed by• Blood vessels dilating
The Vascular Theory• Does not explain prodrome• Not supported by blood flow studies• There are effective nonvascular drugs, such asNSAIDs• Most patients do not have aura• THIS IS NOT CORRECT
The Neurovascular Theory• Referred pain from dura mater and bloodvessels• Peripheral Neural Processing• Central Neural Processing
Pain Perceiving Structures Inside the SkullThe most important structures that register pain in the head are the large cranial vessels,proximal cerebral vessels and dural arteries and the large veins and venous sinuses
A More Sensitive BrainPain control mechanisms are partially defective in migraine patients
Wang, Schoenen. Cephalalgia. 1998.People with migraine process visual and auditory stimulation differently that peoplewithout migraine. In this example with repeated stimulation non-migraine patientshave decreased response with repeated stimulation whereas migraine patients havean increased response.
Migraine Aura• A reversible focal neurological deficit– Most commonly visual• Cortical spreading depression– Think a wave of activity moving across the brainfollowed by decreased activity– The part of the brain inactivated causes theneurological deficit• Occipital lobes = vision
Spreading Depression of LeãoEEG activity is suppressed and moves in a wave, correlates with symptoms
Neuropeptides• Cranial levels of both substance P andcalcitonin gene-related peptide (CGRP) areincreased by stimulation of the trigeminalganglion in humans• In migraine CGRP is elevated in externaljugular vein blood, whereas substance P is not• CGRP infusions can trigger headache andmigraine
A Growing Snowball• Trigeminal nerve and its blood supply(neurovascular)– Release of neuropeptides• CGRP• Substance P• 5-HT (serotonin) --> “triptans”• Nitric oxide– Vasodilatation (CGRP) leads to further activation, and theprocess spreads– Brainstem, thalamus, cortex become activated leading to“central sensitization”• Amplified pain signaling in the central nervous system– Allodynia: pain due to a non-noxious stimulant
Cutaneous AllodyniaMigraineurs develop increasedsensitivity to stimuli as a result ofincreased nerve excitability80% of migraine patients hadcutaneous allodynia during attacksNon painful stimuli perceived aspainfulAfter allodynia occurs, triptans loseeffectiveness
Burstein R, et al. Brain. 2000.1-PeripheralTrigeminal Sensitization2-Central TrigeminalSensitization3-Forehead Allodynia4-ExtracephalicAllodynia
Allodynia is a risk factor fordeveloping chronic migraine
Earliest Possible Treatment to StopMigraine Progression and ChronificationInheritedthreshold fortrigeminalactivationTriggers orstressorsEpisodicmigraineIneffectivepaincontrolMedicationoveruseIncreasedheadachefrequencyChronicmigraineGraphic adapted from: Calhoun AH. In: Headache Newsletter: American Headache SocietyCommittee for Headache Education; Veteran’s Day, 2010.
Medication Overuse Headache• Headache present on ≥15 days/month• Regular overuse for ≥3 months of one or more drugsthat can be taken for acute and/or symptomatictreatment of headache• Headache has developed or markedly worsenedduring medication overuse• Headache resolves or reverts to its previous patternwithin 2 months after discontinuation of overusedmedication
Chronification of MigraineMedication Overuse HeadacheThe Cleveland Clinic Manual of Headache Therapy p. 156Bigal ME, et al. Headache. 2008;48:1157-1168.Bigal ME, et al. Pain. 2009;142:179-182.
TriptansSelective agonists (activators) of serotoninblocking the release of other inflammatorychemicals during a migraine attackTriptans work here
Triptans• Prevent release of neuropeptides• Once enough activation has occurred theprocess of central sensitization begins– Manifested by allodynia– Remember 15% vs. 93% chance of success
NSAIDs• Ketorolac infusion has been shown to reversecentral sensitization• IV ketorolac is not practical in the outpatientsetting• Ibuprofen, naproxen, diclofenac
DHE• Can also reverse central sensitization• More side effects• A little less convenient to give in the homesetting
Summary• Hyperexcitable brain: more susceptible totriggers• Aura: spreading excitation and depression• Throbbing head pain: trigeminal inflammation• Allodynia: common, important and due tocentral sensitization
Learn More at Headache School• Women and Headaches• June 13 • 6 to 7:30 p.m.• Biofeedback and stressmanagement• July 11 • 6 to 7:30 p.m.• Headache related to injury• August 8 • 6 to 7:30 p.m.• What is a migraine aura?• September 12 • 6 to 7:30p.m.• Alternative headachetreatments• October 17 • 6 to 7:30 p.m.