Recent Advances in Neurology 2017 DIFFICULT HEADACHE MANAGEMENT DECISIONS Difficult Headache Management • Challenges in headache diagnosis Decisions • Some common management impasses • New treatment options Morris Levin, MD Professor of Neurology, UCSF Director, UCSF Headache Center

INTERNATIONAL CLASSIFICATION Disclosures for Dr. Morris Levin OF HEADACHE DISORDERS 2013

Primary HA Consultant: 1. Supernus, Amgen, Allergan, Pernix 2. Tension-type HA 3. Cluster headaches relatives (TAC) Royalties: 4. Exertional and other headaches Secondary HA Oxford University Press, Anadem Publishing, 5. Posttraumatic Wiley Blackwell, Castle Connolly, Publ, 6. Vascular disease UCSF Office of Innovation 7. Abnormal ICP, Neoplasm 9. CNS infection 10. Metabolic disturbances Grants: 11. Cervicogenic, Eyes, Sinuses, Jaw American Headache Society 12. Psychiatric >200 HA types 13. Neuralgias

1 1. Migraine without aura 1.2 Migraine with aura Headache attacks lasting 4-72 h (untreated or ≥1 of the following fully reversible aura symptoms: unsuccessfully treated) 1. visual; 2. sensory; 3. speech and/or language; Headache has ≥2 of the following 4. motor ; 5. brainstem; 6. retinal 1. unilateral location ≥2 of the following 4 characteristics: 2. pulsating quality 1. ≥1 aura symptom spreads gradually over ≥5 min, 3. moderate or severe pain intensity and/or ≥2 symptoms occur in succession 4. aggravation by or causing avoidance of routine 2. each aura symptom 5-60 min physical activity ( eg , walking, climbing stairs) 3. ≥1 aura symptom is unilateral During headache ≥1 of the following: 4. aura accompanied or followed 1. nausea and/or vomiting in <60 min by headache 2. photophobia and phonophobia

Migraine with Aura ICHD III 1.3 Chronic migraine

With A. Headache (TTH-like and/or migraine-like) on ≥15 d/mo headache for >3 mo and fulfilling criteria B and C Migraine with B. In a patient who has had ≥5 attacks fulfilling criteria B-D typical aura for 1.1 Migraine without aura and/or criteria B and C for Migraine with Without headaches 1.2 Migraine with aura aura Migraine with ≥ brainstem C. On 8 d/mo for >3 mo fulfilling any of the following: aura 1. criteria C and D for 1.1 Migraine without aura 2. criteria B and C for 1.2 Migraine with aura Migraine with 3. believed by the patient to be migraine at onset and hemiplegia relieved by a or ergot derivative D.Not better accounted for by another ICHD-3 diagnosis Retinal migraine

2 Is Chronic migraine different Transformation : 2.5% per year than intermittent migraine? Risk increased by Imaging studies – PET, DTI - may begin to differentiate High HA frequency, high use of acute meds, poor success with acute tx, obesity, depression, asthma) Maniyar, FH et al. Functional imaging in Chronic Migraine. Curr Headache and Pain Reports, 2013. Increasing frequency of migraine attacks is associated with changes in key brainstem areas, basal ganglia and various cortical areas involved in pain. Episodic Chronic Migraine Migraine Schwedt, T, et al Headache 2015 Accurate subclassification of individuals into lower and higher frequency subgroups via measurements of cortical thickness (and other measurements in temporal pole, anterior cingulate cortex, superior temporal lobe, entorhinal cortex, medial orbital Bigal, ME., et al. "Acute migraine and evolution from episodic to chronic migraine: a frontal gyrus, and pars triangularis. Threshold = 15 days longitudinal population ‐based study." Headache 48.8 (2008): 1157-1168. Lipton, Richard B., et al. "Ineffective acute treatment of episodic migraine is associated with new-onset per month chronic migraine." Neurology 84.7 (2015): 688-695. Martin, Vincent T., et al. "Asthma is a risk factor for new onset chronic migraine: Results from the American migraine prevalence and prevention study." Headache (2016).

3. Trigeminal autonomic 3. Trigeminal autonomic cephalalgias (TACs) cephalalgias (TACs) 3.1 Cluster headache 3.1 Cluster headache 3.2 Paroxysmal hemicrania 3.2 Paroxysmal hemicrania 3.3 Short-lasting unilateral 3.3 Short-lasting unilateral neuralgiform headache. neuralgiform headache. 3.4 Hemicrania continua 3.4 Hemicrania continua

a) conjunctival injection and/or lacrimation; b) nasal All are unilateral, and Allcongestion are unilateral, and/or rhinorrhoea; and c) eyelid edema; d) accompanied by cranial autonomic sx accompaniedforehead and facial by cranialsweating; autonomic e) forehead sx and facial flushing; f) sensation of fullness in the ear; g) miosis and/or ptosis

3 TAC’s: 4. Other primary headaches

• Duration decreases with name length Exertional headaches Cough headache Exercise headache Orgasmic headache HC Pre-orgasmic headache Thunderclap headache Years Cluster HA related to stimulation 15-180 min Paroxysmal Short-lasting HA attributed to cold stimulus Hemicrania unilateral External compression headache 2-30 min neuralgiform Epicranias headaches Nummular HA 1-600 sec Epicrania fugax Stabbing Headache Other HAs Hypnic HA NDPH

New daily persistent headache The secondary headaches (NDPH) 5. Headache attributed to trauma or injury to the head A. Persistent headache fulfilling criteria B and C and/or neck B. Distinct and clearly-remembered onset , with pain 6. Headache attributed to cranial or cervical vascular becoming continuous and unremitting within 24 h disorder C. Present for >3 mo 7. Headache attributed to non-vascular intracranial disorder 8. Headache attributed to a substance or its withdrawal 9. Headache attributed to infection 10. Headache attributed to disorder of homoeostasis 11. Headache or facial pain attributed to disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth 12. Headache attributed to psychiatric disorder

4 Headache attributed to traumatic The secondary headaches injury to the head 5. Headache attributed to trauma or injury to the head and/or neck • If persistent, a key component of the post-concussive 6. Headache attributed to cranial or cervical vascular syndrome disorder • Can resemble other headache types including migraine 7. Headache attributed to non-vascular intracranial • Resistant to treatment disorder e.g. mass • Divided by causative mild or severe head injury 8. Headache attributed to a substance or its withdrawal 9. Headache attributed to infection 10. Headache attributed to disorder of homoeostasis 11. Headache or facial pain attributed to disorder of cranium, neck, eyes, ears, nose, sinuses, teeth , mouth 12. Headache attributed to psychiatric disorder

Mild Head Trauma: Headaches due to vascular disorders Definition • Stroke • Hemorrhage • Arteritis • Cerebral venous thrombosis • Reversible cerebral vasoconstriction synd Injury to • AVM • Aneurysm someone • Post endarterectomy else's' head • CADASIL • MELAS

5 Headaches due to vascular Intracranial Hypertension disorders Incidence of IIH 1/100,000

In obese young women as high as 20/100,000

Best treatment – weight loss if overweight Clues to tx: Headache worse in recumbent, pulsatile tinnitus, papilledema Cerebral Venous Thrombosis RCVS CSF pressure >250 mm CSF

IIH – Pseudotumor Cerebri IIH – Pseudotumor Cerebri

Papilledema Bilat enlarged blind spots Optical coherence tomography

Nerve fiber layer outside nl range Normal

6 IMAGING CLUES TO SIH Intracranial Hypotension

HA MUCH worse upon arising Antecedent LP, surgery, barotrauma Subdural CSF pressure <60 mm CSF collections Brain sag Goal – Find the sight of leak and perform Dural enhancement targeted blood patch

DIAGNOSING SIH DIAGNOSING SIH

Tools: • Spinal gad enhanced MR T1 with fat suppression • MRI myelography • CT myelography • Radioisotope cysternography

MR myelogram demonstrating myeloceles and leak

7 DIAGNOSING SIH -overuse headache (MOH)

Radioisotope Cisternography in SIH A.Headache occurring on ≥15 d/mo in a patient • Early bladder tracer with a pre-existing headache disorder • Paraspinal tracer B. Regular overuse for >3 mo of one or more drugs that can be taken for acute and/or symptomatic treatment of headache C. Not better accounted for by another ICHD-3 diagnosis

• Overuse is >2d/week usage • But overuse does not imply MOH

Secondary Headaches - Secondary Headaches - When to look for them When to look for them

RED FLAGS IN HA RED FLAGS IN HA

New or Change in pattern Onset in middle age or later Effort induced or Positional Change Febrile or Systemic illness - AIDS, Cancer Change in personality or cognition Sick Neurological findings Focal

8 CHALLENGING HA MANAGEMENT TREATING IN PATIENTS WITH SITUATIONS VASCULAR DISEASE OR RISK FACTORS

• Treating migraines in patients with vascular Case – disease or risk factors 72 year old woman with longstanding • Managing migraine in pregnancy migraine, HLD, borderline DM and a • Managing medication overuse headache lacunar stroke seen on MRI. She is using • Treating intractable cluster headache 1-2x per week. • New daily persistent headache • Migrainous vertigo • ED approach to treatment of acute severe headache

Levin UCSF Levin UCSF

TREATING MIGRAINES IN PATIENTS WITH TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS VASCULAR DISEASE OR RISK FACTORS

• Migraine usually begins in early adulthood but • Roberto et al - systematic review of observational not always; migraine often persists into old age – data of use of : 3-10% of elderly have migraine. (Fasted growing • “…intense consumption of may be demographic) associated with an increased risk of serious • Triptans are mildly vasoconstrictive and if risks are ischemic complications. As for triptans, available high, should probably be avoided. But often risks studies do not suggest strong CV safety issues”. are exaggerated. • Risk factor stratification based on Framingham study data using gender, Total Chol, HDL, DM,

HTN, and tobacco is more logical. Roberto, G., Raschi, E., Piccinni, et al. (2014). Adverse cardiovascular events associated with triptans and ergotamines for treatment of migraine. Cephalalgia 2014

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9 TREATING MIGRAINES IN PATIENTS WITH TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS VASCULAR DISEASE OR RISK FACTORS

Alternatives to triptans include • Use of triptans in “basilar migraine” (migraine • NSAIDs and acetaminophen which can become more useful as pts age with brainstem aura), and hemiplegic migraine (migraine with motor aura – contraindicated? • Magnesium 200 mg • • Short acting barbiturate butalbital – caution in Mathew, PG., et al. "A retrospective analysis of elderly triptan and DHE use for basilar and hemiplegic • Occipital nerve blocks migraine." Headache: 56.5 (2016): 841-848. – no incidents • Low dose opioids – hydrocodone 5 mg • • Neuroleptics – metoclopramide 10 mg, Also - no clear evidence that BM and HM carry prochlorperazine 25 mg an actual elevated risk for vascular events • Hydroxyzine 25-50 mg compared with migraine with aura.

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TREATING MIGRAINES IN PATIENTS WITH VASCULAR DISEASE OR RISK FACTORS STRUCTURAL BRAIN LESIONS IN MIGRAINE

• Migraine is associated with increased risk of Migraine particularly in women is stroke, and possibly with increased risk for associated with an increased risk of cardiovascular disease brain lesions, mostly in white matter • Migraine with aura is associated with an (1,2,3) increased risk of ischemic stroke (OR approx. 3) These tend to increase although can • (Mig without aura – 1.8x) disappear (more likely in low frequency headaches) (4) • Risk is particularly increased in women, especially women using oral contraceptives, peripartum period, younger than 45 • 1. Kruit, MC et al. JAMA 2004;291:427 Especially in smokers 2. Kruit, MC et al. Brain 2005;128:2068 3. Scher, AI et al. JAMA 2009;301:2563 4. Erdélyi-Bótor, S et al Headache 2015;55:55-70 .

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10 MANAGING MIGRAINE IN PREGNANCY STRUCTURAL BRAIN LESIONS IN MIGRAINE

Management of WML’s in migraine • Most proph meds contraindicated in patients pregnancy, including botulinum toxin If asymptomatic – no workup • Case – May follow imaging... • 29 year old with migraine since her late teens is now having more frequent and more severe HAs with nausea and vomiting in her nd 2 trimester.

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MANAGING MIGRAINE IN PREGNANCY MANAGING MIGRAINE IN PREGNANCY

Medication FDA category TERIS risk rating • First steps – • Rule out preechlampsia, gestational HTN, gestational diabetes, cerebral venous Acetaminophen B No risk

thrombosis, reversible cerebral rd vasoconstrictive syndrome Ibuprofen cB (D in 3 Trimester) Minimal rd • Follow BP, UA, Glu Naproxen cB (D in 3 Trimester) Undetermined • CVT usually produces persistent severe HA Oxycodone cB (D near term) often with increased ICP or focal signs or both – Magnesium B Unlikely • MRV without gad & LP – will also help to R/O Metoclopramide B Unlikely RCVS st C in 1 trimester; nd rd Prednisone ? 2 /3 trimesters Minimal

Levin UCSF Promethazine C None

11 1438050943351_bob1.png MANAGING MIGRAINE IN PREGNANCY MANAGING MIGRAINE IN PREGNANCY

• Triptans are contraindicated in pregnancy – • Magnesium becoming controversial – but very few reports of defects or other issues • Fetal calcium depletion – small but real risk • Nezvalová-Henriksen, K, Spigset, O, and Hedvig • Respiratory distress in newborn – very small risk Nordeng, H. "Triptan safety during pregnancy: a Norwegian population registry study." European journal of epidemiology 28.9 (2013): 759-769. • Herbal supplements also risky – •  found no associations between triptan use Butterbur, Feverfew not safe during pregnancy and congenital malformations. Second trimester use was associated with postpartum haemorrhage (adjusted OR 1.5)

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Non medicinal Tx MANAGING MIGRAINE IN PREGNANCY • Occipital and other nerve blocks – Lidocaine Lifestyle adjustment and Bupivicaine category C, Ropivicaine B • Avoidance of triggers Evidence is anecdotal but some small studies support its efficacy Exercise Sleep regulation Relaxation techniques Biofeedback, yoga meditation, hypnotherapy Manual therapies Acupuncture Suproaorbital Greater and Lesser Auriculotemporal supratrochlear occipital

12 MANAGING MEDICATION OVERUSE MANAGING MEDICATION OVERUSE HEADACHE HEADACHE • Case – • Mechanisms are unclear but consensus holds • 45 year old executive began having HAs in that use of analgesic or abortive headache 30s, initially infrequent, now nearly daily medications >2x a week tends to worsen leading her to use butalbital- migraine frequency and severity acetaminophen-caffeine tablets (Fioricet ®) • Reducing the use of medications will tend to 2-6 tablets most days, frequent NSAIDs, further worsen headaches, leading to an occasional hydrocodone (Norco®) and impasse. other OTC meds. • Physical and psychological dependency may be • Triptans have not helped, nor have a number occurring simultaneously of prophylactic medications. • Allowing MOH to continue seems to be “I am not addicted! I only take associated with conversion of migraine to enough medication to function!” chronic migraine

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MANAGING MEDICATION OVERUSE MANAGING MEDICATION OVERUSE HEADACHE HEADACHE

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

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13 MANAGING MEDICATION OVERUSE HEADACHE DOES OVERUSE OF TRIPTAN MEDICATION REALLY CAUSE MOH? Preemptive treatment of withdrawal • Opioids – .1 mg – titrate dose to sx • Yes. • Barbiturates – lorazepam .5-1 mg on a • Katsarava, Z, et al. Clinical features of schedule titrated to sx withdrawal headache following overuse of • triptans and other headache drugs Neurology Triptans – DHE, NSAIDs 2001 57: 1694-1698

• Pathophysiology of medication overuse headache: Insights and hypotheses from preclinical studies Cephalalgia 2011 31:851-860 • Triptan overuse in the Dutch general population: A nationwide pharmaco-epidemiology database analysis in 6.7 million people Cephalalgia 2011 31: 943-952

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MANAGING INTRACTABLE CLUSTER MANAGING INTRACTABLE CLUSTER HEADACHE HEADACHE • Case – Traditional approach to CH • 48 year old accountant has had yearly cluster cycles since his 20s. This cycle began 2 months • Break cycle : Prednisone ago and has not responded to the usual • Prophylaxis: interventions  Calcium channel blockers –  Lithium Initial step: Establish diagnosis with certainty  Antiepileptics – • R/o hemicranias continua, intracranial pathology • Acute treatment (especially pituitary region neoplasms),  Oxygen 8-10 L/min sinus or ocular pathology, and chronic  Sumatriptan subcutaneous paroxysmal hemicranias

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14 MANAGING INTRACTABLE CLUSTER MANAGING INTRACTABLE CLUSTER HEADACHE HEADACHE

• Break cycle : Prednisone • Prophylaxis:  Verapamil – consider high dose – up to 480 mg and avoid SR  Antiepileptics - also high dose Valproate; Consider Lamotrigine, remembering to up- titrate the dose gradually • Acute treatment  Oxygen 8-10 L/min  25 L/min  Sumatriptan subcutaneous, IV  Occipital nerve blocks with steroid  Sphenopalatine ganglion blockade  Sphenopalatine ganglion stimulation Levin UCSF Levin UCSF

MANAGING INTRACTABLE CLUSTER NEW DAILY PERSISTENT HEADACHE HEADACHE • Case – • 25 year old grad student has unremitting headaches which she distinctly recalls having begin one day during a “flu” and have been essentially constant since then. The pain is diffuse, not associated with much nausea, photosensitivity or phonosensitivity, and there are no other features. Exam and MRI are normal.

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15 NEW DAILY PERSISTENT HEADACHE

• Definition – an unremitting headache that began at a clearly recalled time, unassociated with typical migraine features. • Perhaps not a homogeneous group – Postinfectious, posttraumatic, migrainous, etc – • Therefore treatment responses may vary. • Step 1 – exclude secondary causes – mass, inflammation, thrombosis, IIH, intracranial hypotension, etc. MRI, LP, Screening labs incl TSH, Lyme. • When NDPH confirmed – attempt migraine The way we treat NDPH here is proph; but often fails to divert your attention to something else Levin UCSF

CHOICES IN MIGRAINE CHOICES IN MIGRAINE PROPHYLAXIS – GOOD OPTIONS PROPHYLAXIS – GOOD 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 daily

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

16 OTHER CHOICES IN MIGRAINE NEW DAILY PERSISTENT HEADACHE PROPHYLAXIS • Botulinum toxin •  Inpatient DHE or chlorpromazine B2 • Nerve blockade  Magnesium, • Address MOH  Feverfew • Address depression Co Q 10 • Persistence Melatonin Ginger Boswellia

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MIGRAINOUS VERTIGO MIGRAINOUS VERTIGO AKA VESTIBULAR MIGRAINE AKA VESTIBULAR MIGRAINE Definition: • Case – • 39 year old teacher who had recurring • Current or previous history of migraine with or without headaches during her. They improved during her aura 2 pregnancies and she is now having only rare • One or more migraine features with at least 50% of headaches. She does not remember auras. the vestibular episodes • Over the past 3 years she has had many episodes of nausea and a sensation of being • Vestibular migraine affects up to 1% of the general pulled to the side along with some sensation of movement. These can last for hours. population* • 7% of patients in specialized dizziness clinics; • 9% of patients in HA Centers

*Neuhauser, et al. Migrainous vertigo: prevalence and impact on quality of life, Neurology 67 (2006), 1028–1033. Levin UCSF Levin UCSF

17 Migraine with Aura ICHD III DDX VESTIBULAR

With headache MIGRAINE Migraine with typical aura Without • Mal de Debarquement headaches • Benign Paroxysmal Vertigo of Childhood Migraine with Migraine with aura brainstem aura • Benign Positional Vertigo

Migraine with • Meniere’s Disease hemiplegia • Migraine with brainstem aura Retinal • Vestibular pathology migraine

Vestibular migraine

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CHRONIC VERTIGO MIGRAINOUS VERTIGO AKA VESTIBULAR MIGRAINE BPPV Meniere’s Vestib MdeD Migraine Positionality + + + Acute treatment Hearing loss + RCT 38% relief v 22% placebo prevented motion sickness in the VM Ear Fullness + + group better than placebo Tinnitus + + Photo/Phonoph + + Vestib testing +

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18 MIGRAINOUS VERTIGO MIGRAINOUS VERTIGO AKA VESTIBULAR MIGRAINE AKA VESTIBULAR MIGRAINE

Pharmacologic Prophylaxis – best evidence Other options: • • caffeine cessation, nortriptyline and topiramate • Propranolol • Vestibular rehabilitation • Lamotrigine • Even less evidence – though suggested - prophylaxis: benzodiazepines, cinnarizine, SSRIs, Lepcha A, et al. (2014) Flunarizine in the prophylaxis of migrainous vertigo: , dothiepin, acetazolamide, and a randomized controlled trial. Eur Arch Otorhinolaryngol 271:2931–2936 behavioral modification Van Ombergen A, et al. (2015) Vestibular migraine in an otolaryngology clinic: prevalence, associated symptoms, and prophylactic medication Mikulec AA, et al (2012) Evaluation of theefficacy of caffeine cessation, nortriptyline, and topiramate therapy in vestibular migraine and complex dizziness effectiveness. Otol Neurotol 36(1):133–138 of unknown etiology. Am J Otolaryngol 33:121–127 Bisdorff AR (2004) Treatment of migraine related vertigo with lamotrigine, Vitkovic J, et al (2013)Vestibular rehabilitation outcomes in patients with and an observational study. Bull Soc Sci Med Luxemb 2:103–108 without vestibular migraine. J Neurol 260:3039–3048

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MIGRAINOUS VERTIGO AKA VESTIBULAR MIGRAINE

Pharmacologic Symptomatic Tx

Anticholinergic Meclizine 12.5-25 mg po tid Scopalamine patch 1q3d Anti-DA Promethazine (phenergan) 12.5-25 mg po tid, 25 mg IM for acute attack “I went round and round with my neurologist about Sedative whether I have vestibular migraine” Diazepam 2-5 mg po tid prn

19 EMERGENCY DEPT APPROACH TO ED APPROACH TO ACUTE SEVERE HA ACUTE SEVERE HEADACHE STEP 1 - DDX

Case – • Intracerebral hemorrhage • Subarachnoid hemorrhage 52 year old man rapidly developed the • Pituitary Apoplexy worst headache of his life while hiking. 2 • Cerebral Venous Thrombosis hours later in the ED he is in a great deal of • Arterial Dissection pain. • CNS Vasculitis, RCVS He has had migraine headaches in the past. • Intracranial hypotension Exam is normal, but he complains of some • Primary Thunderclap Headache “neck stiffness” • Sex related Headache • Meningitis CT of the head is normal • Acute Sinusitis

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ED APPROACH TO ACUTE SEVERE HA R/O SAH, DISSECTION, INFECTION ED APPROACH TO ACUTE SEVERE HA

• 2-5% of SAH may be missed by CT Ketotolac15-60 mg IM, IV • LP may not finalize dx Chlorpromazine – 25 mg IV with Benadryl • In the 6 hours following subarachnoid [Opioids – avoid – particularly meperidine] hemorrhage, fluid may not be xanthochromic • Traumatic tap leads to uncertainty Triptans - sumatriptan injectable 6 mg Ergots – DHE – 1 mg IV with antinauseant Typical approach: • If CT is normal, LP should be done Other options: • If LP is not conclusive, or concerned about Valproate 250 mg IV dissection – head and neck vessel imaging Magnesium 1-4 g IV (CTA)

Edlow JA, Caplan LR. Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N Engl J Med Levin, M. "Approach to the Workup and Management of Headache in the 2000;342:29–36. Emergency Department and Inpatient Settings." Seminars in neurology . Vol. Ditta et al, Lumbar puncture and the diagnosis of CT negative subarachnoid haemorrhage: time for 35. No. 6. 2015. a new approach Br J of Neurosurgery 2013; 27:599-602 Levin UCSF

20 NEW DEVELOPMENTS IN DO WE NEED NEW MIGRAINE MANAGEMENT INTERVENTIONS IN MIGRAINE?

• Abortive migraine tx’s relieve pain in 60% pts (in 2 h) and eradicate pain completely in only 30% • Prophylactic migraine tx reduce HA freq by 50% in only 20-40% of patients • Abortive tx of cluster headache works about 75% of the time in 15 min (pain free in 50%) • Proph tx of cluster reduce HA freq by 50% in “I’m looking for something slightly more perfect” 70% of patients

NEW FORMS OF TRIPTANS NEW TREATMENT OPTIONS IN AND ERGOT HEADACHE • Sumatriptan nasal Onzetra® • New forms of triptans & other older meds • CGRP as a target • Monoclonal antibodies • Neurostimulation • Inhaled DHE

21 CALCITONIN GENE RELATED PEPTIDE A NEW CLASS OF TRIPTANS – – CGRP – A NEW TARGET IN SEROTONIN 1F RECEPTOR MIGRAINE BLOCKERS • Small molecule antagonists were • , the first “ditan”, has clear developed but not finalized due to proof of principle in 2 studies adverse effects • • It is nonvascular so safer Humanized and fully human monoclonal antibodies against CGRP and its receptor now in development

RATIONALE FOR CGRP MODULATION IN 4 MABS BEING DEVELOPED FOR MIGRAINE MONTHLY INJECTION TO PREVENT MIGRAINE  Released from trigeminovascular afferents • LY2951742 (Lilly ) – humanized  Causes perivascular plasma protein extravasation mAb anti-CGRP – aimed at preventing episodic and nociceptive pain migraine - SC monthly  CGRP levels elevated in migraineurs between • ALD403 (Alder )– humanized attacks and during (even higher) mAb anti-CGRP – aimed at preventing episodic  Triptans and Onabotulinum toxin block CGRP release migraine - IV q3mo   CGRP induces migraine-like headache in • TEV 48125 (Labrys LBR-101 Teva) - humanized susceptible individuals mAb aimed at preventive treatment of chronic  CGRP enhances transmission of pain signals in CNS migraine - SC monthly • AMG 334 (Amgen ) – Human anti GCRP receptor Ab – SC monthly Buchanan T, et al. Expert Rev Neurotherapeutics 2004; Edvinsson L. Expet Opin Ther Targets 2003; Buzzi MG, et al. Cephalalgia 1995; Goadsby PJ, et al. Ann Neurol 1988; Edvinsson L, et al. J Auton Nerv Syst , 1998; Ashina M, et al. Pain 2000.

22 CGRP MABS - EVIDENCE TO DATE NEUROSTIMULATION IN HA GENERALLY VERY POSITIVE AT HIGH DOSE Non-invasive MAB target EM (12 wks) CM Other

-4.2 d v -3.0 LY ligand humanized

−5.6d v −4.6 ALD ligand humanized TMS Supraorbital n stim −3.4 d−2.3 -6.6 v -4.2 d AMG receptor human -75h v -57 h Vagal n stim -6 d v -3.5 -67h v -37h TEV ligand humanized

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

23 THE UCSF HEADACHE CENTER

• Intractable migraine, cluster headaches, post-traumatic headaches and other unusual or difficult headache disorders • Outpatient treatment • Nerve blocks • Neurostimulation • Inpatient treatment • Telemedicine • Research “I think I have the placebo.”

INPATIENT TREATMENT OF Headache diagnosis and treatment REFRACTORY HEADACHES An interesting game

• Intravenous Dihydroergotamine (DHE) • Intravenous Chlorpromazine • Intravenous Lidocaine • Safe discontinuation of pain medications

24 UCSF HEADACHE MEDICINE

25