UCSF Neurology a welcoming place! Migraine Headache clinical classification. Secondary infection hemorrhage trauma tumour CSF pressure change

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1 28 UCSF Neurology a welcoming place! Recent Advances in Neurology Ritz-Carlton Hotel, San Francisco 13 February 28 Professor Peter J. Goadsby Department of Neurology Headache clinical classification Age Specific Prevalence in the United States Primary Tension-type headache 3. Trigeminal autonomic cephalgias 3.1 Cluster headache 3.2 Paroxsymal hemicrania 3.3 SUNCT 4. Other Headaches 4.1 Primary Stabbing 4.2 Cough Headache 4.3 Exertional headache 4.4 Sex headache 4.5 Hypnic headache 4.6 Primary Thunderclap Headache 4.7 Hemicrania continua Secondary infection hemorrhage trauma tumour CSF pressure change (Cephalalgia 24;24:1-16) % patients >6 (Lipton et al., Headache 21; 41: ) 7 female male

2 International Headache Society Migrene Vanligvis episodisk hodepine (4-72 timer) med visse kjennetegn (& ingen annen årsak): Minst 2 av- ensidig pulserende Moderat til alvorlig Forverrelse ved aktivitet Minst en av- kvalme/brekninger foto/fonofobia Attacks The Attacks & the Disorder Premonitory symptoms Pain unilateral throbbing movement worse Nausea Sensory sensitivity photophobia phonophobia osmophobia Aura Disorder Repeated attacks < days/month: Episodic days/month: Chronic Family history Triggers (biology) Sleep: missing/excess Food: skipping meals Chemical: alcohol or nitroglycerin Weather Sensory: light, smells Hormonal Stress- relaxation (after International Headache Society, 1988) Accounting for the Disorder Genetics Triggering Attack Premonitory symptoms Aura Pain Moderate/severe Unilateral Throbbing Aggravation with movement Associated symptoms Nausea Photophobia Phonophobia Genetics of Familial Hemiplegic - an ionopathy FHM-I CACNA1A: P/Q voltage-gated Ca 2+ channel chr 19 Ophoff et al. Cell 1996; 87:543 FHM-III SCN1A: Voltage-gated Na + channel chr 2 Dichgans et al., Lancet 25;366:371 FHM-II ATP1A2: Na + /K + ATPase chr 1q23 De Fusco et al. Nat Gen 23;33:192 FHM-IV?: 2

3 Accounting for the Disorder Genetics Triggering Attack Premonitory symptoms Aura Pain Moderate/severe Unilateral Throbbing Aggravation with movement Associated symptoms Nausea Photophobia Phonophobia Orexins and Primary Headache Orexin A and B are hypothalamic neuropeptides that bind to two G-protein coupled receptors termed: OX 1 and OX 2. Involved in feeding, sleep/wake cycle, hormone regulation and have been linked to the modulation of nociceptive processing Benjamin et al., Neurobiol Dis 24 Trigeminovascular nociceptive modulation by orexins Trigeminovascular effects of orexins MMA: middle meningeal artery Holland et al., JPET 25;3:138 Holland et al., Eur J Neurosci 26;24: Orexin A and B differentially modulate nociceptive dural input to the trigeminal nucleus caudalis following microinjection into the posterior hypothalamus (Bartsch et al., Pain 24;19: 367) % baseline change # time (min) % baseline change # # # # # Orexin A 3 µgkg -1 Orexin A 3 µgkg -1 & SB mgkg -1 Vehicle Control Orexin A 5 µgkg time (min) 3

4 and the pons Accounting for the Disorder Nitroglycerin-triggered Spontaneous Bahra et al Lancet 21;357: Afridi et al. Arch Neurol 25;62, Genetics Triggering Attack Premonitory symptoms Aura Pain Moderate/severe Unilateral Throbbing Aggravation with movement Associated symptoms Nausea Photophobia Phonophobia When does migraine start? Are there Phases of a Attack? 1 (Giffin et al., Neurology 23; 6:935-94) VAS rating of state of health premonitory headache Time (hours) %change internal carotid tiredness stiff neck yawn polyuria premonitory headache postdrome hunger (Giffin et al., Neurology 23;6:935-94) thirst emotional 4

5 Dose-dependent dopaminergic modulation of trigeminocervical complex neurons MMA: middle meningeal artery Dopamine and the Trigeminocervical complex A11 Stimulation Charbit et al., Cephalalgia 27;27:65 mt A11 3v D 1 Dopamine NeuN A11 Lesion D 2 mt A11 3v D 2 Bergerot et al. Ann Neurol 27;61:251 Total cells fired Total cells fired A11 Stimulation is Anti-Nociceptive through a dopaminergic mechanism Time (sec) MMA MMA + A11 Percentage of baseline firing Time (sec) Baseline response n = 14 MMA Noxious pinch Innocuous brush n = 13 n = 12 n = 5 n = 5 n = 5 A11 A mins 5-4 mins post i.v. post iv D2 antagonist D2 antagonist Charbit et al., Cephalalgia 27;27:65 n = 5 n = 5 n = 5 n = 6 n = 6 n = 6 Baseline response Total cells fired Total cells fired A11 lesioning is Pro-Nociceptive MMA Time (sec) MMA + A11 lesion Time ( sec ) Percentage of baseline firing 16 MMA noxious pinch innocuous brush Sham (n = 5) Lesion A11 (n = 8) Sham (n = 5) 5-4mins post lesion A11 or control Charbit et al., Cephalalgia 27;27:65 Lesion A11 (n = 8) Sham (n = 5) Lesion A11 (n = 8) Baseline response 5

6 Accounting for the Disorder aura Genetics Triggering Attack Premonitory symptoms Aura Pain Moderate/severe Unilateral Throbbing Aggravation with movement Associated symptoms Nausea Photophobia Phonophobia Silberstein et al., Headache in Clinical Practice 2nd Ed 22 Infarctions in the Migrainous Brain? PFO Closure- MIST-I 18Jan6 3Feb6 % Elimination of attacks Primary endpoint PFO closure does not eliminate headache 4 5 sham n = closure Kruit et al., Brain 25;128:268 Rozen Cephalalgia 27;27: Dowson et al., Late-Breaking Abstract AAN San Diego 26 6

7 % Elimination of attacks PFO Closure- MIST-I Primary endpoint PFO closure does not eliminate headache Dowson et al., Late-Breaking Abstract AAN San Diego 26 4 sham closure n = Accounting for the Disorder Genetics Triggering Attack Premonitory symptoms Aura Pain Moderate/severe Unilateral Throbbing Aggravation with movement Associated symptoms Nausea Photophobia Phonophobia The tentorial nerve is a branch of V 1 Trigeminovascular System & (Feindel et al., Neurology 196;1:555) (Goadsby et al., NEJM 22; 346:257-27) 7

8 (pmol/l) Trigeminal ganglion stimulation increases CGRP in the cranial circulation control VG stimulation CGRP Substance P CGRP Substance P Cat Human (Goadsby, Edvinsson & Ekman Ann Neurol 1988;23:193) (pmol/l) Calcitonin Gene-Related Peptide (CGRP) and CGRP is released in the cranial circulation in migraine 1 BIBN496BS a CGRP receptor antagonist is effective in migraine 2 CGRP Sub P control MWA MWOA Goadsby et al., Ann Neurol 199;28:183 2 Olesen et al NEJM 24;35: HA response placebo BIBN496BS 2.5mg 12 Aes 25 %patients Triptans, NSAIDS & CGRP receptor antagonists in acute migraine Double-blind randomized parallel group single attack adult migraineurs Pain Free at 2 hours Placebo 9 25 Brandes et al. JAMA 27;297: n = Nx SRT Trx 3 6 R1 S1 Ho et al., Neurology 27; 9 3 Ferrari et al., Lancet 21;358:1668 %patients Triptans, NSAIDS & CGRP receptor antagonists in acute migraine Double-blind randomized parallel group single attack adult migraineurs Sustained Pain Free at 24 hours 8 Placebo n = Nx SRT Trx 3 6 R1 S1 Brandes et al. JAMA 27;297: Ho et al., Neurology 27; 7 19 Ferrari et al., Lancet 21;358:1668 8

9 Trigeminocervical nociceptive transmission is blocked by anti-migraine compounds Trigeminovascular System & Firing rate (Hz) -per one second bin HT 1B/1D agonists Saline HCA Zolmitriptan Ergo Saline HCA Suma time (seconds) Storer and Goadsby, Brain 1997; 12:2171 Firing rate (Hz) 8 L-glutamate 6 na, 1 s pulses CGRP receptor blockers 2 time (seconds) BIBN na Storer et al., Brit J Pharmacol 24; 142:1171 (Goadsby et al., NEJM 22; 346:257-27) Fos activation after superior sagittal sinus stimulation in the cat Neck and Headache TNC C1 C2 C3 (Kaube et al., Brain Research 629:95;1993) Bartsch & Goadsby Current Pain and Headache Reports 23;7:

10 Trigeminocervical complex and Headache Treatment of mild pain in acute migraine with a triptan- No relationship to cutaneous sensitivity Two double-blind randomized parallel group single attack adult migraineurs 1 Placebo-1 Rizatriptan-1 Placebo-2 Rizatriptan-2 8 (Bartsch & Goadsby Brain 22;125:1496-9) %patients n = Overall Sensitvity+ Sensitivity- Cady et al., Cephalalgia 27;27:5-16 and the Neck Referred Pain in the Trigeminocervical Complex (TCC) Chronic Patients treated with Occipital Nerve Stimulation dura mater Cervical input V ganglion trigeminal nucleus C 1 C 2 }TCC Eight patients all with history of episodic migraine All with + days/month HA with N/Photo/Phono/Mvt (+) Five: trauma-triggered change Three: no trauma All responded to Occipital Nerve Stimulation (Matharu et al., Brain 24;127:22-23) 1

11 Effect of ONS on Chronic Effect of ONS on Chronic P+ P+ P- (Matharu et al., Brain 24;127:22-23) (Matharu et al., Brain 24;127:22-23) Effect of ONS on Chronic (Matharu et al., Brain 24;127:22-23) P+ P- % Reduction in headache days placebo Topiramate in Chronic topiramate 1mg/day 23.2 n = Diener et al., Cephalalgia 27;27: Silberstein et al., Headache 26;46:838 P <

12 How long does the effect of a preventive last? Topiramate PROMPT Study Accounting for the Disorder Reduction in migraine days yrs, baseline one month- 8.9 attacks/month Six month open label Rx, then randomised to placebo or topiramate for six months Open Baseline Placebo withdrawal Month six Month six n = Diener et al., Lancet Neurol 27;6:4, P < topiramate 5-2 mg placebo Genetics Triggering Attack Premonitory symptoms Aura Pain Moderate/severe Unilateral Throbbing Aggravation with movement Associated symptoms Nausea Photophobia Phonophobia Lesions in the Brainstem Produce Periaqueductal Grey & Goadsby Cephalalgia 22;22:17 Obermann et al. Cephalalgia 26;26:763 1 A Nat Med 1995;1: Cephalalgia 22;22: % of control 75 5 J Anat 21;197:29 B Tracey et al. J Neurosci 22;22: baseline PAG stim. recovery Knight & Goadsby Neurosci 21;16:

13 Ergots, Triptans, P/Q Ca 2+ channels and the PAG Ergot & triptan receptors are located in crucial sub-cortical modulatory areas Mean±SEM change in TNC Aδ activity after PAG agatoxin, n=18 WDR, n=16; NS, n=2 Triptans and Trigeminal Processing: Necessarily an action in the trigeminal nucleus? Naratriptan injected into the vlpag inhibits dural inputs but has no effect on facial input Face- thermal stimulation Dura mater 14 Ann Neurol 1991;21:91-94 % change agatoxin Cephalalgia 1997;17:3 time in minutes Knight et al., J Neurosci 22; (RC213):1-6 (Bartsch et al., Ann Neurol 24; 56: ) Ergots, Triptans, P/Q Ca 2+ channels and the PAG Ergot, triptan & CGRP receptors are located in crucial subcortical modulatory areas and the pons Nitroglycerin-triggered Spontaneous Ann Neurol 1991;21:91-94 Cephalalgia 1997;17:3 Ma et al., Neuroscience 23;12: Bahra et al Lancet 21;357: Afridi et al. Arch Neurol 25;62,

14 Brainstem activations in right and left-sided headache with PET Left-sided headache Right-sided headache dura mater Vg pterygopalatine ganglion trigeminal nucleus Afridi et al., Brain 25; 128: C 2 nausea Trigeminal Autonomic Cephalalgias trigeminal-autonomic activation facilitated by the brain y = -12 Cluster headache Paroxysmal hemicrania SUNCT dura mater dura mater Vg V ganglion SSN pterygopalatine ganglion trigeminal nucleus pterygopalatine ganglion C1 trigeminal nucleus C 2 nausea C2 14

15 Better Management of Aim for the Sky Brain areas implicated in Primary Headache 28 dorsal pons posterior hypothalamus ventrolateral midbrain Ipsilateral Cluster Headache Ipsilateral Paroxysmal hemicrania Contralateral Contralateral SUNCT Bilateral Hemicrania continua Ipsilateral Contralateral Ipsilateral Botulinum Toxin and Headache Botulinum Toxin and Headache after Aoki Cui et al., Pain 24; 17: χ Chronic tension-type headache No difference in frequency; n = 3 Silberstein et al., Cephalalgia 26;26: in press χ (episodic) No differences; n = 232 Saper et al., J Neurol 25; 252: II-58 No differences; n = 495 Relja et al., J Neurol 25; 252: II-62. Reduced frequency (?primary endpoint); n = 128 Chankrachang et al., Cephalalgia 25; 25: χ Chronic Daily Headache No reduction in headache frequency; n = 72 Silberstein et al., Mayo Clin Proc 25; 8: No reduction in headache free days; n = 355 Mathew et al., Headache 25; 45: ? Chronic Reduced headache frequency on no other preventive (sub-group ) Dodick et al., Headache 25; 45: 3-24 Further studies in progress

16 Pain score 5 baseline Rx Brain Zapper - TMS for Open label- high and low stimulation primary endpoint: unclear 3.3 n = 42 NS 2.5 (Clarke et al., J Headache Pain 26:7: ) %patients Preventive Treatment of Candasartan Double-blind randomized cross-over study (ITT n = 57) Candasartan 16mg daily vs placebo Primary endpoint: 5 headache days reduced in active (P <.1) 2 32 Placebo 27 5% responders- headache days Aes (Tronvik et al., JAMA 23;289:65-69) Candasartan 26 NS P =.1 Patent Foramen Ovale MIST-I Randomised, double-blind placebo controlled, multi-center Surgical sham (n = 73) and Closure (n = 74) Patients - with aura (twice in their life!) - Refractory migraine (failed two preventives!) Endpoints- assessed over 3 months (+3 for healing) - Primary: Cessation of attacks - Secondary - Efficacy- 6 - Safety 2 - Failure 8 - Tertiary - 3 Dowson et al., Headache Care 25;2: ISRCTN % 5% responders Vitamin B2 vs PFO closure No significant effect on reported secondary endpoint after Bonferroni correction assuming only two tested placebo Riboflavin 4mg/day 59 1 N = sham closure Schoenen et al., Neurology 1998;5:466 Dowson et al., AAN NS 42 16

17 PFO closure- MIST-I: Serious AEs 18 FDG PET in Medication Overuse- a role for the orbitofrontal cortex? Implant Tamponade Pericardial effusion Retroperitoneal bleed Atrial fibrillation Chest pain Sham - Incision site bleed - Anemia - Nose bleed - Brainstem stroke Conclusion 1. The MIST-I study was negative 2. PFO closure is not risk free 3. There is no role for PFO closure in migraine outside clinical trials 4. Primun non nocere is it ethical to continue these studies without further information? Before withdrawal - Hypometabolic: bilateral thalamus, orbitofrontal cortex (OFC), anterior cingulate gyrus, insula/ventral striatum and right inferior parietal lobule; - Hypermetabolic: cerebellar vermis. After withdrawal - All dysmetabolic areas recovered except the OFC - OFC hypometabolism due to eight patients overusing combination analgesics and/or an ergotamine-caffeine preparation. (Coppola et al., Brain :98-13) Habituation of the Nociception-Specific Blink Reflex in migraineurs and their relatives (Di Clemente et al., Brain 27 13:765-77) 17