Recent Advances in Neurology 2019 Disclosures for Dr. Morris Levin

New Treatments for Consultant: Lilly, Amgen, Allergan, Alder, Teva, Upsher-Smith, Xoc, : When to Biohaven Royalties: Oxford University Press, Anadem Publishing, Wiley Blackwell, Expand Your Castle Connolly Publ, UCSF Office of Innovation Research and Grants: Armamentarium Scientific Review Board Chair – Theranica; Grants from American Headache Society, Miles for Migraine Morris Levin, MD Professor of Neurology, UCSF Some trade names will be used for devices, and in addition to generic Director, UCSF Headache Center names for some for completeness.

NEW TREATMENTS FOR MIGRAINE DO WE NEED NEW INTERVENTIONS IN MIGRAINE? • Abortive migraine tx’s relieve pain in 60% • Current state of success pts (in 2 h) and eradicate pain completely • Best pharmacological treatment for migraine in only 30% prevention, and new additions • Prophylactic migraine therapy reduces HA • Best acute treatment of migraine and coming freq by 50% in only 20-40% of patients additions • Abortive tx of cluster headache works • Neuromodulation in migraine about 75% of the time in 15 min (pain free • New ideas in refractory cluster headaches in 50%) • Proph tx of cluster reduce HA freq by 50% in 70% of patients

Levin UCSF

1 CHRONIC MIGRAINE TREATMENT MIGRAINE TREATMENT FAILURE FAILURE WITH OVERUSE

• 34 year old teacher reports throbbing, • 45 year old executive with a history of occasional frontotemporal headaches since her twenties. menstrual and other migrainous attacks in her They improved during her pregnancy 3 years late teens; began having frequent HAs in 30s, ago but frequency has increased to about 2x initially infrequent, now nearly daily leading her weekly, accompanied by nausea and often to use butalbital-acetaminophen-caffeine preceded by dramatic visual auras including tablets (Fioricet ®) 2-6 tablets most days, near loss of vision, and mental fog. frequent NSAIDs, occasional hydrocodone (Norco®) and other OTC meds. • Preventive medications – “all make me sick” and seem to have become • Triptans have not helped, nor have a number of much less effective. prophylactic medications. • She is missing many days at work • “I only take enough medication to function!”

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CLUSTER HEADACHE TREATMENT FAILURE ACUTE MIGRAINE TREATMENT • 50 year old fireman began having bouts of hour- long R sided “horrible” headaches in his late 20’s diagnosed as cluster headaches. Cycle intervals used to be about 2 years but he has had 2 • NSAIDS cycles already this year. • Antiemetic neuroleptics • used to help, but no longer seems to. • Hydroxyzine Lithium was not tolerated. He finds oxygen useless. • Opioids • He is using microdoses of LSD with some • Butalbital benefit. by injection used to bring relief, but not recently • Ergots • Triptans

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2 Acute Migraine - Tx options Acute Migraine - Tx options Specific: Non-specific Triptans – Serotonin 1b and 1d receptor agonists Naproxen sodium Alleve 550 mg po Sumatriptan Imitrex 6mg IM, 20 NS, 50-100 po Indomethacin Indocin 50 po, pr Amerge 2.5 po Ketorolac Toradol 30-60 mg IM Maxalt 10 mg po Promethazine Phenergan 5 mg IM, IV Zomig 2.5-5 mg po, 2.5/5 NS Prochlorperazine Compazine 5-10 mg IV, IM Axert 12.5 mg po Chlorpromazine Thorazine 10-25 mg IV, IM Frova 2.5 mg po Hydromorphone Dilaudid 1-2 mg IV Relpax 40-80 mg po Morphine 5-10mg IM, 2-5 IV Ergot derivatives – Broad serotonin receptor agonists Depacon 500 mg Mg Sulfate 1 g DHE-50 1 mg IV, IM Hydroxyzine Vistaril 25-50 mg q8h prn Migranal 2 mgNS

Triptans – most generic, cost

Ineffective in 20-25% Patients

Dural arteries

V Nucleus Triptans

3 Common AE’s and Contraindications

AEs: Contraindications  Tingling Hemiplegic or “basilar Mig”  Warmth Uncontrolled hypertension Concomitant use of MAOi  Flushing Use within 24 hrs of an ergot  Chest discomfort Pregnancy category C  Dizziness Vascular disease  somnolence “That’s just great. I create the perfect antidote  HA recurrence for migraine and all you can do is criticize.”

NEW FORMS OF TRIPTANS AND New Acute Migraine ERGOT Options • Sumatriptan nasal Onzetra®

• Inhaled DHE (not yet approved)

• Needle microarray zolmitriptan patch

Kellerman DJ, et al. Rapid systemic delivery of zolmitriptan using an Levin UCSF adhesive dermally applied microarray. Pain management. 2017 7:559-67.

4 A new class – Serotonin 1F A new class of (not-)triptans – receptor blockers - Serotonin 1F receptor Kuca, et al. Lasmiditan is an effective acute treatment for migraine: A phase 3 RCT. Neurology 2018 agonists - lasmiditan Methods - 1856 adult patients with migraine were randomized (1:1:1) to a double-blind dose of oral lasmiditan 200 mg, lasmiditan 100 mg, or placebo for their next migraine attack • Lasmiditan, the first “ditan”, has clear proof of within 4 hours of onset. principle in 2 studies, and 1 phase 3 study • It is non-vasoconstrictive Results - Of the 1,856 patients who treated an attack, 77.9% had ≥1 cardiovascular risk factors in addition to migraine. Compared • Can serve as an option for patients with with placebo, more patients dosed with lasmiditan 200 mg were cardiovascular and cerebrovascular disease. free of headache pain at 2 hours after dosing, 32.2% vs 15.3%; (similar with lasmiditan 100 mg.) Adverse events were mostly mild or moderate in intensity – Dizziness 16%, Paresthesia 8%, Somnolence 5%, Nausea 5%, Fatigue 3%, Lethargy 2%

Calcitonin gene related peptide Oxytocin Nasal Spray (CGRP) receptor antagonists  The “Love Hormone” – peptide hormone synth in hypothal released by post pituitary  , – abandoned because of liver enzyme elevations  Can be absorbed in nasal mucosa by trigeminal afferents  , uborgepant – being studied  Available at compounding pharmacies  Lipton et al - Rimegepant 75 mg, an oral calcitonin gene-  7.5 U/0.1 ml spray, quantity 5 ml (max 10/d; 10 related peptide antagonist, for the acute treatment of migraine: Two phase 3, double-blind, randomized, placebo- ml per mo) controlled trials. CEPHALALGIA 2018  Being promoted also for autism, anxiety, wt loss

2 Hour Rimegepant Placebo  Virtually 0 AEs

Endpoint (N=669) (N=682) Difference p-value

Pain Freedom 21.2% 10.9% 10.3% < 0.0001 Yeomans DC, Angst MS, William HF, Jacobs DI, inventors; Leland Stanford Junior Freedom from University, HealthPartners Research Foundation, TRIGEMINA Inc, assignee. 1 MBS 35.1% 26.8% 8.3% 0.0009 Methods for treatment of headaches by administration of oxytocin. United States 1. Most Bothersome Symptom of Photophobia, Phonophobia or Nausea patent US 8,252,745. 2012 Aug 28.

5 PROPHYLACTIC TREATMENT OF Ketamine Nasal MIGRAINE  NMDA receptor antagonist; induces general anesthesia and dissociative state  Available at compounding pharmacies  Rx: 100 mg/cc, compound for sprays of 0.1 ml each – 2 sprays in each nostril up to q12 hours  Also being promoted for depression  Potential AEs – drowsy/dreamlike, nausea, dizziness, blurred vision

Carr DB, Goudas LC, Denman WT, Brookoff D, Staats PS, Brennen L, Green G, Albin R, Hamilton D, Rogers MC, Firestone L. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double- blind, placebo-controlled, crossover study. Pain. 2004 108:17-27. Levin UCSF

MIGRAINE PROPHYLAXIS MIGRAINE PROPHYLAXIS CURRENT OPTIONS CURRENT OPTIONS

– 100-200 mg hs Anticonvulsants – topiramate 100-200 mg hs Beta blockers – 80 mg bid Beta blockers – propranolol 80 mg bid Cyclic antidep – 25-75 mg hs Cyclic antidep – nortriptyline 25-75 mg hs Calcium channel bl – amlodipine 2.5-10 mg/d Angiotensin receptor bl – candesartan 4-16 mg Memantine 10 mg bid

Noruzzadeh, R, et al. Memantine for prophylactic treatment or migraine w/o aura: a RDBPC study. Headache 2016, 56:95-103.

Levin UCSF

6 MIGRAINE PROPHYLAXIS RATIONALE FOR CGRP MODULATION IN MIGRAINE CURRENT OPTIONS

. CGRP levels elevated in migraineurs between attacks and during (even higher) At best, 50% pts are 50% . Triptans and Onabotulinum toxin block CGRP better release, thought to be a significant component of their mechanisms of action Multiple adverse effects . CGRP infusion induces migraine-like headache in Med-med interactions susceptible individuals Tachyphylaxis

“I feel so much better since I Buchanan T, et al. Expert Rev Neurotherapeutics 2004; Edvinsson L. Expet Opin Ther Targets 2003; stopped taking the pills you Buzzi MG, et al. Cephalalgia 1995; prescribed” Goadsby PJ, et al. Ann Neurol 1988; Edvinsson L, et al. J Auton Nerv Syst, 1998; Ashina M, et al. Pain 2000.

Levin UCSF

CGRP BLOCKADE MECHANISM OF ACTION IN MIGRAINE CGRP mAbs

• In the trigeminal ganglion, CGRP is expressed in C-fibers CGRP and and its receptor is expressed in Aδ-fibers; both are receptors involved in different aspects of pain perception, hence antagonism may be antinociceptive. • Blocking CGRP released antidromically by perivascular afferents may break the connection in the trigeminovascular network Dural • The trigeminal ganglion and dura are not behind the arteries blood–brain barrier; therefore, they are some of the most likely targets of gepants and mAbs in migraine V Nucleus Triptans

Levin UCSF

7 4 anti-CGRP MABs to prevent migraine CGRP MAbs – Routes and Doses

• Aimovig®(Amgen ) – Human anti GCRP receptor MAB target Antibody type Doses (mg) Route Ab – SC monthly; available since June 2018 receptor IgG2 70,140 SC • Ajovy® (Teva ) - humanized mAb anti CGRP erenumab (Amgen) Human ligand - SC monthly – delayed due to production issues – late 2018? ligand IgG4 120,240 SC • Emgality® (Lilly galcanezumab) – humanized mAb anti- (Lilly) humanized CGRP ligand - SC monthly; FDA decision late 2018 fremanezumab ligand IgG2 225,675 SC • ALD403 (Alder )– humanized mAb anti-CGRP (Teva) humanized ligand - IV q3mo; not yet submitted to the FDA for regulatory evaluation eptinezumab ligand IgG1 100,300 IV (Alder) humanized

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Response to mAb over time CGRP MAbs – Best evidence to date generally very positive at high dose

MAB target EM (12 wks) CM Route erenumab receptor P2 −3.4d v. −2.3 -6.6d v. -4.2d SC (Amgen) Human P3 -3.7 v. -1.8 galcanezumab ligand P2 -4.2 v. -3.0 -2.7 v. -4.8 SC (Lilly) humanized P3 -4.7 v. 2.8 -4.3 v. 2.3 fremanezumab ligand P2 -6.3 v. -3.5 -6.2 v. -4.2 SC (Teva) humanized P3 -3.7 v. -2.2 -5.0 v. -3.2

eptinezumab ligand P2 −5.6 v. −4.6 -8.2 v. -5.6 IV (Alder) humanized P3 -4.3 v. -3.8

Levin UCSF

8 CGRP MAbs – Best evidence to date CGRP MAbs - Evidence to date generally very positive at higher doses for EM MAB target 50% RR at 12 wks* Potential strengths are significant erenumab receptor 65% • highly target specific, so if no on-target AEs galcanezumab ligand 70% (75% RR – 34%) emerge, a very focused treatment • Appear more effective than current prophylactic fremanezumab ligand 48% meds – certainly for some patients (high 50% responder rates, impressive 75% responder rates) eptinezumab ligand 61% (75% RR – 30%) • long half life – infrequent dosing boosts compliance • Might work in MOH, cluster, PTTHA *50% responder rate – the % of patients who over a spec time period experienced half as many (or less) than usual # HA days • Rapid onset – determination of benefit quick

Levin UCSF Levin UCSF

Aimovig® (erenumab) Ajovy® (fremanezumab)

• Autoinjector • Syringe – to inject by nurse or self – 1.5 cc • 70 and 140 mg • 225 mg monthly or 675 mg (3 injections) quarterly • Monthly • Not an autoinjector • Latex in needle cover • Viscous – may take 10 sec to inject

Levin UCSF Levin UCSF

9 Emgality® (galcanezumab) Eptinezumab

• Autoinjector • Intravenous • 120 mg monthly (240 mg loading dose – 2 • 100 or 300 mg infusion injections) • quarterly

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Lingering questions about CGRP mAbs Which patients will respond? Will CGRP levels help to predict? • Where do they exert their effects? • Which patients will respond? • CGRP levels found to be elevated interictally in some • Are responses going to be as dramatic in real migraine sufferers* life (i.e. did the high placebo rate confound) • CGRP levels can predict a patient’s response to • Will CGRP levels or other biomarkers help to Botox.** predict response? • So can we select a subgroup of migraine pts who will • Are they really safe? respond REALLY well to CGRP MABs? • Will there be clinical differences between the 4 CGRP mAbs? *Cerruda-Morollon, E, et al. Interictal increase of CGRP levels in peripheral blood as • Will they be covered by insurance biomarker for chronic migraine. Neurology 2013, 81:1191-6. **Cerruda-Morollon, E, et al. CGRP and VIP as predictors of efficacy of Onabotulinumtoxin plans? type A in chronic migraine. Headache 2014, 54:987-95

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10 Are anti-CGRP antibodies really safe? CGRP and its receptors

Observed adverse effects in clinical use: . GCRP receptors found in neural, respiratory, endocrine, gastrointestinal, immune and • Injection site swelling cardiovascular tissues. • Constipation . CGRP is a potent vasodilator and is considered • Nausea (area postrema - medulla) important in cardiovascular regulation, response to • Fatigue, several cases of overwhelming ischemia, gastrointestinal physiology and wound debilitation (Hypothal-Pit axis?) healing. • Arthralgias . CGRP MABs seem not to pose cardio- or cerebrovasc • risk but not adequately studied in people with Rashes underlying vascular disease or risks. • (No elevation of hepatic enzymes)

MaassenVanDenBrink, A, et al. Wiping out CGRP: Potential cardiovascular risks. Trends in Pharmacological Sciences 37.9 (2016): 779-788. Levin UCSF

Erenumab – “real world Might exercise caution in prescribing cardiac risk study” anti-CGRP antibodies for patients with: • GI illnesses with reduced motility Cardiac safety – Erenumab and Angina trial: 89 cardiac • Patients at risk for cardio and cerebrovascular patients (36 had prev MIs) disease Endpoint – exercise time during treadmill not effected • Inflammatory diseases by pts pretreated with erenumab 140 mg IV; no diff in • Recent surgery or injuries secondary endpoints of exercise induced angina or ST • Pregnancy depression. • Children/adolescents (HPA)

Depre C, Antalik L, Starling A, Koren M, Eisele O, Kubo Y, Lenz RA, Mikol DD. A randomized, double-blind, placebo-controlled study to evaluate the effect of erenumab on exercise time during a treadmill test in patients with stable angina. Cephalalgia 2017 37:340-341 Levin UCSF

11 OTHER CHOICES IN MIGRAINE MANAGING CHRONIC MIGRAINE PROPHYLAXIS Definition • Headache on at least15 days/month for B2 >3 months, in a pt known to have had Magnesium, migraine headaches Feverfew • Headaches on 8 days/month fulfill criteria for either Migraine without aura, Migraine Co Q 10 with aura or believed by the patient to be Melatonin migraine at onset and relieved by a Ginger triptan or ergot derivative Boswellia

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MANAGING MEDICATION OVERUSE MEDICATION OVERUSE HEADACHE HEADACHE Definition • Mechanisms are unclear but consensus holds • Headache occurring on 15 days/month in that use of analgesic or abortive headache a patient with a pre-existing (primary) medications >2x a week tends to worsen headache disorder migraine frequency and severity • Initially, reducing the use of medications will tend • Regular overuse (10 or 15 days per month to further worsen headaches depending on the agent) for >3 months of one or more drugs that can be taken • Physical and psychological dependency may be occurring simultaneously for acute headache • Allowing MOH to continue seems to be associated with conversion of migraine to chronic migraine

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12 MANAGING MEDICATION OVERUSE MANAGING MEDICATION OVERUSE HEADACHE HEADACHE

Analgesic hierarchy – Solution = “Bridge Therapy” • Opioids (hydrocodone, oxycodone) • Steroid “burst” – prednisone 60 mg x 4 days reducing over the next 6 days to 0 • • IV Dihydroergotamine x 5 d • Barbiturates (Fioricet®) • IV Chlorpromazine x 4-5 d • Caffeine containing combination meds Coupled with discontinuation of previous (Excedrin®) analgesics • Triptans Replacement with rescue meds which are less • NSAIDS, acetaminophen likely to cause MOH • Antihistiminics Preemptive treatment of withdrawal

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MANAGING MEDICATION OVERUSE MANAGING MEDICATION OVERUSE HEADACHE HEADACHE

Do “rebound” producing acute meds need to Do “rebound” producing acute meds need to be discontinued to achieve success? be discontinued to achieve success? • Compared complete stop of acute meds PCORI study: MOTS (medication overuse v. limited intake (no more than 2 d/week) treatment strategies) to compare dc with not- for 2 months dc of acute medication in comb with initiation or optimization of preventive tx. • @ 6 months 70% complete stop reverted to episodic headache; 42% of reduction group reverted to episodic HA • Both good but complete cessation better

Levin UCSF Levin UCSF

13 MANAGING MEDICATION OVERUSE MANAGING CHRONIC MIGRAINE HEADACHE • When the medication overuse has stopped, Preemptive treatment of withdrawal and headaches persist • Opioids – .1 mg – titrate dose to • Or when you question the existence of symptom relief medication overuse headache in the first • Barbiturates – lorazepam .5-1 mg on a place… schedule titrated to symptom relief • What are viable strategies? • Triptans – DHE, NSAIDs

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MANAGING CHRONIC MIGRAINE BOTULINUM TOXIN FOR CHRONIC MIGRAINE • Botulinum toxin • CGRP mAbs • Inpatient infusion protocols: DHE, Chlorpromazine, valproate, lidocaine • Nerve blockade • Address MO • Address depression

31 injections 5U each in forehead, temples, occiput, neck, trapezius – 155U (can increase to 195) Repeated every 3 mo AE’s – facial asymmetry, neck pain

Levin UCSF Levin UCSF

14 BOTULINUM TOXIN CGRP MABS IN CHRONIC DRAWBACKS MIGRAINE GENERALLY VERY POSITIVE AT HIGHER DOSES FOR EM • Cost • Inconvenience • Adverse facial MAB target 50% RR at 12 wks changes erenumab receptor 50% • Neck pain galcanezumab ligand 28% • Tachyphylaxis fremanezumab ligand 54%

eptinezumab ligand 75% RR = 31%

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NEUROSTIMULATION IN HA NALTREXONE LOW DOSE PROPHYLAXIS Non-invasive • Supraorbital n. stimulation Cefaly® • Opioid antagonist (like naloxone but longer acting) • Transcranial Magnetic stimulation TMS eNeura® • Not a controlled substance • Vagal nerve stimulation (VNS) Gammacore® • Distant electrical stim – Nerivio® • Recommended dose for chronic pain - 4.5 mg daily • Potential AEs – nausea, diarrhea, restlessness, achiness, anorexia – generally at much higher dose than this low Implanted dose protocol • Occipital • Supraorbital • Sphenopalatine - not FDA approved • Deep brain – not FDA approved

Morphine Naltrexone Levin UCSF Levin UCSF

15 NEUROSTIMULATION IN HA CEFALY® SUPRAORBITAL N ELECTRICAL Non-invasive STIMULATION IN MIGRAINE

Acute treatment 3 pulses wait 15mins, 3 more pulses. Max 24 stims/day Supraorbital n stim TMS Proph

Vagal n stim 4 pulses BID daily. Max 24 stims/day.

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CEFALY® SUPRAORBITAL N ELECTRICAL TMS FOR MIGRAINE STIMULATION IN MIGRAINE Acute Treatment • 3 pulses wait 15mins, 3 more pulses. RENTAL: $450/3mo for first 3 • Max 24 stims/day months, then $750 /3-months

Proph Treatment • 4 pulses BID daily. Max 24 stims/day.

16 TMS FOR MIGRAINE Distant electrical stim: “Nerivio Migra” Rationale – magnetic pulses disrupt cortical spreading depr. A wireless wearable battery-operated Acute treatment RCT – N=167, 39% pain free at 2h v. 22% with stimulation unit with a smartphone software application. The active device produces a sham device proprietary electrical signal comprising a Preventive treatment open label studies N=249 modulated symmetrical biphasic square pulse FDA approved in 2017 as “non-significant risk device for with a modulated frequency of 100-120 Hz, preventive and acute tx pulse width of 400 us, generating up to a maximum of 40 mA output current (adjusted by the participant).

Distant electrical stim: “Nerivio Migra” Primary endpoint – In a RCT, the control group used a sham pain relief at 2 hours post-treatment device which produced a signal with a pulse P<0.0001 Active frequency of ~0.083 Hz and pulse width of 40- 80.0% Sham 550 us, aimed to be perceptible, presumably 66.7 70.0% without inducing conditioned response. % 60.0% 38.8 50.0% % 40.0%

30.0%

20.0%

10.0% Percent of participants considered responders N=66 N=4 0.0% 0

17 Principle of operation of Nerivio Migra Secondary endpoints – pain free at 2 hours post-treatment Activating the continuous pain modulation (CPM) system P<0.005 Active 60.0% Sham (DNIC in animal models) – “Pain modulates pain”

50.0% 37.4% A descending pain modulating 40.0% system in the 30.0% 18.4% lower brainstem 20.0% In animals:

10.0% DNIC - diffuse noxious 0.0% Percent of participants considered responders inhibitory mITT N=37 N=19 control

EXTERNAL VAGAL NERVE EXTERNAL VAGAL NERVE STIMULATION STIMULATION MANAGING INTRACTABLE CLUSTER FOR ACUTE MIGRAINE HEADACHE

$575/mo Abortive for Episodic Cluster HA 3 stims on affected side, wait 3 min, then 3 more (Max 24 1 stim on each side/affect side, may repeat after 20 stim/day. Each stim is 2 min) min. If needed, may repeat again (a 3rd time) after Preventions for Chronic Cluster 2hrs from start of Tx . Max 24 stims/day. 3 Stims BID.

Goadsby PJ, de Coo IF, Silver N, Tyagi A, Ahmed F, Gaul C, Jensen RH, Diener HC, Solbach K, Straube A, Liebler E. Non-invasive vagus nerve stimulation for the acute treatment of episodic and chronic cluster headache: A randomized, double-blind, sham- controlled ACT2 study. Cephalalgia. 2017 Jan 1:0333102417744362. Gaul C, Diener HC, Silver N, Magis D, Reuter U, Andersson A, Liebler EJ, Straube A, PREVA Study Group. Non-invasive vagus nerve stimulation for PREVention and Acute treatment of chronic cluster headache (PREVA): A randomised controlled study. Cephalalgia. 2016 May;36(6):534-46. Levin UCSF Levin UCSF

18 NEURAL STIMULATION MANAGING INTRACTABLE CLUSTER invasive HEADACHE Sphenopalatine ganglion stimulation

GON

DBS

SPG Jürgens TP, Barloese M, May A, Láinez JM, Schoenen J, Gaul C, Goodman AM, Caparso A, Jensen RH. Long-term effectiveness of sphenopalatine ganglion stimulation for cluster headache. Cephalalgia. 2017 Apr;37(5):423-34. Significantly reduces numbers of cluster headaches in refractory patients.

Levin UCSF

NEURAL STIMULATION Key Challenge in Studying invasive Neuromodulation in Headache • Placebo response rate high in migraine studies Supraorbital Supraorbital and occipital – 30% in adults and higher in pediatric population • Stimulation devices impart high placebo effect • Sham treatment very difficult to hide, therefore blinding almost impossible

19 MANAGING INTRACTABLE CLUSTER HEADACHE Sphenopalatine ganglion block

“I think I have the placebo.” 1-2cc 2% Lidocaine Levin UCSF

MANAGING INTRACTABLE CLUSTER MIGRAINE TREATMENT FAILURE HEADACHE • 34 year old teacher reports throbbing, frontotemporal Occipital Nerve blockade headaches since her twenties. They improved during her pregnancy 3 years ago but frequency has increased to about 2x weekly, accompanied by nausea and often preceded by dramatic visual auras including near loss of vision, and mental fog. • Preventive medications – “all make me sick” and triptans seem to have become much less effective. • She is missing many days at work

Frequent migraine CGRP mAb TMS at time of aura 1% lidocaine, .25% bupivacaine, triamcinolone 40 mg/cc (4%) -- In 2:2:1 ratio (so generally 20 mg triamcinolone) Levin UCSF

20 CHRONIC MIGRAINE TREATMENT CLUSTER HEADACHE TREATMENT FAILURE FAILURE WITH MEDICATION OVERUSE • 50 year old fireman began having bouts of hour-long • 45 year old executive with a history of occasional R sided “horrible” headaches in his late 20’s menstrual and other migrainous attacks in her late diagnosed as cluster headaches. Cycle intervals teens; began having frequent HAs in 30s, initially used to be about 2 years but he has had 2 cycles infrequent, now nearly daily leading her to use already this year. butalbital-acetaminophen-caffeine tablets (Fioricet ®) 2-6 tablets most days, frequent NSAIDs, occasional • Verapamil used to help, but no longer seems to. hydrocodone (Norco®) and other OTC meds. Lithium was not tolerated. He finds oxygen useless. • Triptans have not helped, nor have a number of • He is using microdoses of LSD with some benefit. prophylactic medications. “I am not addicted! I only Sumatriptan by injection used to bring relief, but not take enough medication to function!” recently Episodic Cluster • Chronic migraine, MOH VNS at time of HA • Reduce analgesics SPG blockade • CGRP mAb, Botox CGRP mAb Levin UCSF Levin UCSF

THE UCSF HEADACHE INPATIENT TREATMENT OF CENTER REFRACTORY HEADACHES • Intractable migraine, cluster headaches, • Intravenous Dihydroergotamine (DHE) post-traumatic headaches and other complex or refractory headache disorders • Intravenous Chlorpromazine • Outpatient treatment incl CGRP mAbs • Intravenous Divalproex • Nerve blocks, botulinum tox • Safe discontinuation of pain medications • Neurostimulation • Inpatient treatment • Telemedicine • Research

21 THE END - THANKS

Saturday, February 23, 2019

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