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Paul Shanahan

The Changing Face of Migraine. Paul Shanahan. Headache Group The National Hospital for Neurology and Neurosurgery London UK Hallpike Symposium 18 th February 2011. Migraine: A disabling disorder.

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Paul Shanahan

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  1. The Changing Face of Migraine Paul Shanahan Headache Group The National Hospital for Neurology and Neurosurgery London UK Hallpike Symposium 18th February 2011

  2. Migraine: A disabling disorder • Characterised by recurrent attacks of moderate to severe headache, associated with some or all of: • Nausea/vomiting • Photophobia, phonophobia, osmophobia • Sensitivity to movement • Fatigue, impaired concentration • 25-30% of patients have aura • WHO rates a day with severe migraine as being as disabling as a day with quadriplegia, psychosis or dementia • Estimated to cost UK economy approximately £2.5bn per annum

  3. Migraine: A universal disorder • Prevalence of migraine is 10-15% • 2-3% of the population have chronic migraine • Population based studies show remarkable consistency around the world • Spain 12.6%(Matías-Guiuet al, 2010) • Croatia 11.3% (Vukovićet al, 2010) • Brazil 15.2% (Queirozet al, 2009) • Japan 8.4% (Sakai and Igarashi, 1997) • Women three time more commonly affect than men • Commonest cause of disabling headache

  4. Migraine: A timeless disorder • Descriptions of troublesome headaches can be found throughout history • If you are always wondering if you’ve got a headache • or are feeling giddy, and blaming your philosophical • studies for it, you will always be prevented from • exercising and proving your talents. • - Plato Republic 4th Century BC

  5. A Brief History of Migraine 350 BC Headache occurs “according as the patient be more or less burdened with superfluous humours” Aristotle 200 AD Term “Hemicrania” introduced by Galen 1200 Opium and vinegar solutions 1783 Tisso describes migraine as supraorbital neuralgia, as distinct from common headache, and “provoked by reflexes from the stomach, gallbladder or uterus” 1778 Fothergill coins the term “Fortification spectra”

  6. A Brief History of Migraine 1780s Erasmus Darwin recommends centrifugation 1873Liveing writes first monograph on migraine “On Megrim, Sick Headache and Some Allied Disorders: A contribution to the Pathology of Nerve-Storms” 1888Gowers recommends the “Gowers mixture” - a solution of 1% nitroglycerin in alcohol 1894 Ergot reported by Thomson and Campbell to be useful for migraine 1917 Ergotamine first isolated by Stoll

  7. Migraine: Theories and treatments 1925 Rothlin first describes subcutaneous use of ergotamine for migraine 1934 First controlled studies of ergotamine tartrate 1937 Wolff and Graham demonstrate vasoconstrictive effects of ergotamine 1941Lashley details the progression of his visual aura and estimates a cortical process spreading at 3 mm/min 1943Dihydroergotamine (DHE) synthesised 1944Leao describes cortical spreading depression in rabbit, cat and pigeon brain 1945 DHE used to treat migraine

  8. Wolff’s Vascular Hypothesis Hyperperfusion Normal CBF Hypo- perfusion Aura Headache 2 6 8 10 12 4 Hours after angiography

  9. Cortical Spreading Depression Cortical spreading depression (CSD) in rabbits as reported by Leao in 1944. The speed of this CSD was later calculated by Bures to be 3 mm/min.

  10. Migraine: Theories and treatments 1959 Milner: ‘...attention should be drawn to the striking similarity between the time courses of scintillating scotomas and Leao’s spreading depression because, if there is a true correspondence between these phenomena, there is hope that some of the work done on spreading depression can be brought to bear on the problem of migraine’ 1971 First study of CBF in migraine with aura

  11. Testing the Vascular Hypothesis • 1971 O’ Brien carries out Xe133 CBF study • Inhalational, 18 patients studied • 1 scintillation counter per side • 23% reduction in hemispheric blood flow during aura phase • 8% increase during headache phase • No difference between hemispheres • Inhalational technique does not distinguish between intracranial and extracranial blood flow

  12. Testing the Vascular Hypothesis • 1981 Olesen carries out Xe133 CBF study • Carotid injection, 6 patients studied • 254 detectors, 1cm resolution • 3 developed inital hyperaemia • Oligaemia developed in all patients during aura phase • Oligaemia spread slowly anteriorly, across vascular territories, at 2mm/min, and in 4 cases was present when headache developed • “Vasospastic model too simplistic”

  13. Linking CSD and Vascular Change • 1982 Lauritzen investigates CBF during CSD in rats • Demonstrated an initial hyperaemia (218%) associated with wave of excitation • Wave of oligaemia accompanied CSD • So… • What is the relationship between: • Altered neuronal activity • Altered vascular tone • and symptoms?

  14. Pathophysiology of Migraine • Numerous hypotheses advanced: • Peripheral mechanisms • Vascular hypothesis • Neurogenic inflammation Central mechanism • Cortical spreading depression triggered trigeminovascularactivation • Neurovascular hypothesis

  15. Neurogenic Inflammation Model • Stimulation of craniovascularnociceptive nerve endings or the trigeminal ganglion produces inflammation of the dura mater and extracranial tissues but not of the brain • Neurogenic inflammation caused by antidromic activation of the sensory nerve fibres • Neuropeptide release – CGRP, Substance P, Neuropeptide K • Neurogenic inflammation sensitises nerve fibres (peripheral sensitisation) that then respond to previously innocuous stimuli

  16. Perception of pain The Neurovascular Hypothesis Nociceptive system Somatosensory cortex Thalamus Endogenous Antinociceptive System Hypothalamus Brainstem nuclei Parasympathetic outflow Trigeminal sensoryfibres Trigeminal nucleus caudalis Meningealvessels Superior salivatory nucleus

  17. Functional Neuroimaging of Primary Headaches CSD-triggered Trigeminovascular Activation? Visually-triggered Migraine BOLD-fMRI Study Meninges Cortical Spreading Depression Trigeminal nerve Sphenopalatine ganglion Trigeminal ganglion Pain Cao et al, Arch Neurol 1999; Cao et al, Neurology 2002 Superior salivatory nucleus BOLD signal changes in brainstem before occipital cortex signal changes (consistent with CSD) or onset of visual symptoms Trigeminal nucleus Adapted from Iadecola C. Nat Med 2002; Bolay H et al. Nat Med. 2002.

  18. Serotonin and Migraine • Several lines of indirect evidence suggest a link between serotonin and migraine • Urinary excretion of 5-hydroxyindoleacetic acid increased • Platelet 5-HT drops • 5-HT depletion can induce a migraine attack and intravenous 5-HT can abort an attack

  19. TARGETS FOR TRIPTANS

  20. Selective 5HT1F Receptor Agonists • Receptors expressed in trigeminal nucleus caudalis and trigeminal ganglion • Potent inhibition in neurogenic inflammation model • Dose dependent inhibition of c-fos expression in TNC neurons • Lack of contractile effect in human cerebral arteries and rabbit saphenous vein

  21. 37 amino acid peptide Potent endogenous vasodilator Expressed extensively in central and peripheral neural structures involved in headache syndromes: Perivascular nerve endings Trigeminal ganglion Trigeminal nucleus caudalis Brainstem aminergic nuclei Cortex • Calcitonin Gene Related Peptide (CGRP)

  22. CGRP and HeadacheANIMAL STUDIES Electrical stimulation of trigeminal ganglion in cats releases CGRP (and SP) in the cranial circulation Electrical stimulation Sagittal sinus in cat releases CGRP (and VIP) CGRP 5HT1B CGRP+5HT1B CGRP co-localizes with 5HT1B/1Dreceptors in rat trigeminal ganglion Triptans suppress CGRP release Zagami et al, Neuropeptides 1990; Goadsby et al, Ann Neurol 1988; Ma et al, EJN 2001

  23. CGRP and Headache HUMAN STUDIES CGRP elevated during migraine attack * * Elevated CGRP returns to normal when migraine attack treated with triptans * p < 0.05 CGRP infusion causes a delayed migrainous headache in migraine subjects Goadsby, Ann Neurol. 1990; Goadsby, Headache 1994; Lassen, Cephalalgia 2002

  24. Randomised, double-blind, controlled, parallel-group phase III study of Telcagepant in Migraine Sustained Pain Freedom at 2- to 48-Hours Post-dose ***, # *** Response Rate, % (95% CI) *, # n=347 n=333 n=342 n=324 *p<0.05, ***p<0.001 vs. placebo; #p<0.05 vs. Zolmitriptan. Ho TW et al. Lancet. 2008;372:2115-2223.

  25. Mechanism of Action ofExisting Preventive Drugs used in Migraine • Poorly understood • Inhibition of CSD? • Chronic daily administration of migraine prophylactic drugs dose-dependently suppressed CSD frequency by 40 to 80% • Target the pain neuromatrix • Neuronal activity in the afferent sensory pathway • The activity of the higher-order modulatory circuits

  26. Glutamate in Migraine • Migraineurs have elevated levels of CSF glutamate • CSF glutamate levels correlate with headache scores • Headache pain-relay structures (trigeminal ganglion, trigeminocervical complex, thalamus) contain glutamate positive neurons • Animal studies demonstrate increased levels of glutamate in TNC following stimulation of dural structures and trigeminal nerve • Majority of glutamatergicneurons in the trigeminal ganglia carry 5-HT 1B/D/F receptors which can modulate glutamate release

  27. Treatments for Migraine

  28. The Current Face of Migraine • A complex disorder, primarily neuronal but involving bidirectional interactions between peripheral nerve, central pain circuitry and vasculature • Numerous therapeutic targets • Better understanding of mechanisms is leading to more targeted treatments

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