1 / 50

Migraine Pathophysiology An Update

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.

base
Télécharger la présentation

Migraine Pathophysiology An Update

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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)

More Related