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Department of Neurology. Migraine Pathophysiology An Update. BASH Teaching Meeting Hull 22 January 2009. Professor Peter J. Goadsby Peter.Goadsby@headache.ucsf.edu. Migraine a systems disorder. ( after Goadsby et al ., NEJM 2002; 346:257-270). Migraine and the pons.

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Migraine Pathophysiology An Update


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    1. Department of Neurology Migraine PathophysiologyAn Update BASH Teaching Meeting Hull 22 January 2009 Professor Peter J. Goadsby Peter.Goadsby@headache.ucsf.edu

    2. Migrainea systems disorder (after Goadsby et al., NEJM 2002; 346:257-270)

    3. Migraine and the pons Nitroglycerin-triggered Spontaneous Bahra et al Lancet 2001;357:1016-1017 Afridi et al. Arch Neurol 2005;62,1270-1275

    4. Brainstem activations in right and left-sided headache with PET Left-sided headache Right-sided headache Afridi et al., Brain 2005; 128:932-939

    5. Premonitory symptoms Pain unilateral throbbing movement worse Nausea Sensory sensitivity photophobia phonophobia osmophobia Aura Repeated attacks < 15 days/month: Episodic ≥ 15 days/month: Chronic Family history Triggers (biology) Sleep: missing/excess Food: skipping meals Chemical: alcohol or nitroglycerin Weather Sensory: light, smells Hormonal Stress- relaxation MigraineThe Attacks & the Disorder Attacks Disorder “The simple headaches have the same characters, and occur under the same causal conditions of heredity &c, as those in which there are additional other sensory symptoms” Gowers 1893

    6. MigraineClassification

    7. Migraine Pathophysiolgy- Update • Genetics • Pain mechanisms • Treatment

    8. Genetics of Migraine Familial Hemiplegic Migraine- an ionopathy Ophoff et al. Cell 1996; 87:543 De Fusco et al. Nat Gen 2003;33:192 Dichgans et al., Lancet 2005;366:371 FHM-I CACNA1A: P/Q voltage-gated Ca2+ channel chr 19 FHM-II ATP1A2: Na+/K+ ATPase chr 1q23 FHM-III SCN1A: Voltage-gated Na+ channel chr 2 FHM-IV ?:

    9. Infarctions in the Migrainous Brain? 18Jan06 3Feb06 Rozen Cephalalgia 2007;27:557-560 Kruit et al., Brain 2005;128:2068

    10. Migraine aura Silberstein et al., Headache in Clinical Practice 2nd Ed 2002

    11. Secretin/Glucagon Superfamily Peptides and Migraine • VIP, vasoactive intestinal polypeptide; PACAP, pituitary adenylate cyclase activating peptide • Jansen-Olesen et al., Peptides 2004;25:2105 • Rahmann et al., Cephalalgia 2008;28:226 • Henrik et al., Brain 2009; in press

    12. Migraine Pathophysiolgy- Update • Genetics • Disease mechanisms • Premonitory symptoms • The neck • Allodynia • Medication overuse • Treatment

    13. When does migraine start? (Giffin et al., Neurology 2003; 60:935-940)

    14. Are there Phases of a Migraine Attack? % patients (Giffin et al., Neurology 2003;60:935-940)

    15. Dose-dependent dopaminergic modulation of trigeminocervical complex neurons MMA: middle meningeal artery D1 Dopamine NeuN D2 D2 Bergerot et al. Ann Neurol 2007;61:251-262

    16. A11 Neurons are Dopaminergic A11 neurons contain tyrosine hydroxylase (green) but not dopamine b-hydroxylase (red) Charbit et al.,

    17. A11 Stimulation is Anti-Nociceptive through a dopaminergic mechanism MMA MMA + A11 Charbit, Akerman & Goadsby

    18. A11 lesioning is Pro-Nociceptive MMA MMA + A11 lesion Charbi, Akerman & Goadsby

    19. Migraine Pathophysiolgy- Update • Genetics • Disease mechanisms • Premonitory symptoms • The neck • Allodynia • Medication overuse • Treatment

    20. Migraine and the NeckReferred Pain in the Trigeminocervical Complex (TCC) dura mater V ganglion } trigeminal nucleus TCC C1 Cervical input C2

    21. Neck and Headache Bartsch & Goadsby Current Pain and Headache Reports 2003;7:371-376

    22. Migraine Pathophysiolgy- Update • Genetics • Disease mechanisms • Premonitory symptoms • The neck • Allodynia • Medication overuse • Treatment

    23. Allodynia and migraine • Allodynia • pain from non-noxious heat, cold or pressure • Incidence • …now and then extensive pain over the head may be accompanied by some general tenderness of the hairy scalp… • Two-thirds of 500 patients • Selby & Lance JNNP 1960;23:23-32 • 71% of 44 patients • Burstein et al., Ann Neurol 2000;47:614 • 63% of 16,573 • higher for frequency & BMI • Bigal et al., Neurology 2008;70:1525 • Site • Trigeminal • Cervical • Rest of body Burstein et al. Ann Neurol 2004;55:19

    24. “Act when Mild” StudyAllodynia did not predict outcome • - Randomised Double-Blind Placebo Controlled Parallel Group • - Allodynia surrogate: cutaneous sensitivity • Outcome • Patients treating at mild pain did better • The presence of allodynia did not determine outcome (Goadsby et al., Cephalalgia 2008; 28383-391)

    25. Migraine Pathophysiolgy- Update • Genetics • Disease mechanisms • Premonitory symptoms • The neck • Allodynia • Medication overuse • Treatment

    26. Medication Overuse and the evolution of chronic migraine • AMPP Sample- 16,339 • Progression to Chronic migraine in 2.5% over one year • Acetaminophen use does not predict risk • Predictors • Barbiturates at 5 day/month • Opioids at 10 days/month • Triptans at 13 days/month • NSAIDs are protective if used more than five days a month Bigal et al., Headache 2008;48:1157

    27. Migraine Pathophysiolgy- Update • Genetics • Disease mechanisms • Premonitory symptoms • The neck • Allodynia • Medication overuse • Treatment

    28. Trigeminovascular System & Migraine (Goadsby et al., NEJM 2002; 346:257-270)

    29. Acute Treatment of Migraine with Sumatriptan and Naproxen • Double-blind randomized parallel group single attack adult migraineurs Study I Study II Meta-analysis %patients n = 360 356 361 364 382 364 362 362 799 1751 Brandes et al., JAMA 2007;297:1443 SumaRT/Nap Ferrari et al., Lancet 2001;358:1668 sumatriptan

    30. Acute Treatment of Migraine with Sumatriptan and Naproxen • Double-blind randomized parallel group single attack adult migraineurs • AEs • Nausea • Somnolence • Dizziness • Paresthesia • Dyspepsia %patients n = 360 356 361 364 382 364 362 362 799 1751 Brandes et al., JAMA 2007;297:1443 SumaRT/Nap Ferrari et al., Lancet 2001;358:1668 sumatriptan

    31. Trigeminovascular System & Migraine 5-HT1D CGRP Hou et al., Brain Res 2001;909:112-120 (Goadsby et al., NEJM 2002; 346:257-270)

    32. Trigeminal ganglion stimulation increases CGRP in the cranial circulation * * * * Cat Human (pmol/l) (Goadsby, Edvinsson & Ekman Ann Neurol 1988;23:193)

    33. Superior sagittal sinus (SSS) stimulation in catNeuropeptide changes * (pmol/l) * (Zagami, Goadsby & Edvinsson, Neuropeptides 1990;16:69-74)

    34. Calcitonin Gene-Related Peptide (CGRP) and Migraine • CGRP is released in the cranial circulation in migraine1 • BIBN4096BS (olcegepant), a CGRP receptor antagonist, is effective in migraine2 * * (pmol/l) 1Goadsby et al., Ann Neurol 1990;28:183 2Olesen et al NEJM 2004;350:1104

    35. Gepants & the Calcitonin Receptor Family Ian Dickerson- www.urmc.rochester.edu/smd/cgrp • Calcitonin receptor-like receptor (CLR) • Calcitonin gene-related peptide (CGRP) binds to CLR when it is co-expressed with receptor activity modifying protein 1 (RAMP1); • Adrenomedullin (AM) binds to CLR when RAMP2 or RAMP3 expressed; • Intermedin (IM) binds to CLR when RAMP1 or RAMP3 are expressed. • Receptor component protein (RCP) for efficient signal transduction at CLR. • Calcitonin Receptor (CTR) • Calcitonin (CT) binds to the CTR; • Amylin binds to CTR in the presence of RAMP1, RAMP2, or RAMP3.

    36. CGRP receptor antagonists are effective in acute migraine • Double-blind randomized parallel group single attack adult migraineurs • Pain Free at 2 hours %patients n = 115 38 40 34 799 1751 300 600 R10 S100 Ho et al., Neurology 2008;70:1004 telcagepant Ferrari et al., Lancet 2001;358:1668 sumatriptan

    37. CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine • Double-blind parallel group randomised controlled trial • 2 Hour pain free (% patients) N = 348 333 354 345 553 1135 1219 Lancet 2009;372:2115Lancet 2001;358;1668

    38. CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine • Sustained pain free (SPF) at 24 and 48 hr (% patients) (Ho et al., Lancet 2009;372:2115)

    39. CGRP receptor antagonist telcagepant is effective in the treatment of acute migraine (% patients) ?Gepant-class AEs- dry mouth, fatigue (Headache 2008;48:S7-S8)

    40. Ergot Alkaloid (tetracylic ergolene) Family Tree CH3 H H

    41. Dural Plasma Protein Extravasation Plasma protein extravasation, CP122,288 and migraine Buzzi et al., Brain Res 1999;583:137 Rat Human %patients 70,000pmol/kg 100pmol/kg (Lee & Moskowitz Brain Res 1993;626:303) (Roon et al., Ann Neurol 2000;47:238-241 response at 2 hours)

    42. iNOS and the dura materiNOS protein co-localizes in macrophages after GTN treatment GTN Macrophages iNos Macrophages/iNOS Ctrl Reuter et al. Brain 2001;124:2490

    43. iNOS in the treatment of migraineGW274150* • Randomised, double-blind placebo-controlled • Migraine headache days base vs Rx • Prevention • Randomised, single-blind placebo-controlled adaptive design • Acute attacks • *NOS inhibition at 120mg > 80% 2 hr pain free n = 22 6 8 15 24 n= 111 37 36 Palmer at al., EHMTIC2008 Hoye et al., EHMTIC2008

    44. Ergot Alkaloid (tetracylic ergolene) Family Tree CH3 H H

    45. COL-144, 5-HT1F receptor agonist, in the acute treatment of migraine • Randomised, single-blind placebo-controlled adaptive design • Specific agonist- 500 fold less affinity at 5-HT1B/1D than 5-HT1F receptors • No detectable 5-HT1B receptor agonist activity in vivo, eg., rabbit saphenous vein 24 hr SPF 2 hr pain free 42 24 28 16 Reuter at al., EHMTIC2008

    46. Occipital nerve stimulation in chronic migraine ONSTIM • Double-blind randomized parallel group sham stimulation controlled study • Note- occipital pain, fail 2 preventives, exclude MOH NS % * ** n = 16 29 17 * Adverse event: lead migration in 24 % (Saper et al., AHS 2008 late-breaking) *P = 0.032; **P = 0.003

    47. Transcranial magnetic stimulation for Migraine • Randomised double-blind placebo controlled study • Include: 30% aura episodes, aura leads to headache 90% • Exclude: Prolonged aura, MOH • TMS- 0.9T for 180 ms; Sham- click and vibrate • Primary endpoint: 2 hr pain free plus non-inferiority for nausea/photo/phono • Blinding: Thought they got active, 67% Sham and 72% active * % Patients n = 82 82 (Lipton et al., AHS Late-breaking abstract)

    48. Botulinum Toxin and Headache after Aoki Cui et al., Pain 2004; 107: 125-133

    49. Botulinum Toxin and Headache • Chronic tension-type headache • No difference in frequency; n = 300 • Silberstein et al., Cephalalgia 2006;26:717 • Migraine (episodic) • No differences; n = 232 • Saper et al., J Neurol 2005; 252: II-58 • No differences; n = 495 • Relja et al., J Neurol 2005; 252: II-62. • Reduced frequency (?primary endpoint); n = 128 • Chankrachang et al., Cephalalgia 2005; 25: 992-993. • Chronic Daily Headache • No reduction in headache frequency; n = 702 • Silberstein et al., Mayo Clin Proc 2005; 80: 1126-37 • No reduction in headache free days; n = 355* • Mathew et al., Headache 2005; 45: 293-307 • Chronic Migraine • Reduced headache frequency on no other preventive (sub-group *) • Dodick et al., Headache 2005; 45: 315 • Two RCTs Positive for reduction in headache days (Press release)

    50. (after Goadsby et al., NEJM 2002; 346:257-270)