Diagnosing and treating episodic migraine

D A N I S H H E A D A C H E C E N T E R Danish Headache Center Disclosures Diagnosing and treating episodic migraine M.A. is a consultant or scientific adviser for Allergan, Alder, Amgen, ATI, Bayer and Chordate, and principal investigator for pathway M-1 ATI and AMG 334 20120178 trials Messoud Ashina, MD, PhD Glostrup Hospital, the Capital Region of Denmark Diagnosis and management of migraine Migraine attack Headache Migraine with aura Migraine without aura Aura Time Premonitory phase Headache phase Resolution Postmonitory phase Ashina 2014 5-60 min MIGRAINE WITH AURA Fully reversible visual and sensory symptoms Migraine with aura 1

MIGRAINE WITHOUT AURA 93% 4% AURA AURA Free interval HEADACHE HEADACHE At least two of the following characteristics: HEADACHE 4-72 h At least one of the following: 3% AURA AURA HEADACHE 1. Unilateral location 2. Pulsating quality 3. Moderate or severe intensity 4. Aggravation by routine physical activities 1. Nausea and/or vomiting 2. Photophobia and phonophobia Russell and Olesen, Brain 1996 Diagnosis No specific blood tests or brain scans currently exist to diagnose migraines Useless! What triggers migraines? Management of migraine 2

Management of migraine Reference programme of the Danish Headache Society, 2010 Has been sent to all neurologists and GP s in DK Patient education Non-pharmacological Acute Pharmacological Prophylactic pharmacological Provoking factors Protecting factors Stress Hormones Alcohol Medicine Sleep deprivation Food, skipping meals Smoking Weather, bright light Unphysiological body positions Provoking factors Protecting factors Regular sleep Regular meals Regular exercise Provoking factors Protecting factors Migraine management Acute Bendtsen et al. J Head Pain 2012 3

Acute Sumatriptan 50-100 mg Sumatriptan 100 mg + Naproxen 500 mg Nasal 20 mg; Supp 25 mg; Inj 6 mg; Sumavel Dosepro Acute Eletriptan 40-80 mg Rizatriptan disintegrating 5-10 mg Zolmitriptan 2.5 mg, Rapimelt 2.5 mg, Nasal 2.5-5 mg Almotriptan 12.5 mg Naratriptan 2.5-5 mg Frovatriptan 2.5 mg Bendtsen et al. J Head Pain 2012 Triptans (oral): Comparison of efficacy Education at the time of triptan prescribing: patient expectations Pain free in 2-4 hours or pain Early versus late treatment 24-hour sustained pain-free or relapse rates Side effects Medication overuse headache*** Migraine management Who should be treated? 2-3 severe attacks per month in spite of optimal non-pharmacological treatment Prophylactic optimal pharmacological acute treatment no medication-overuse 4

Which drugs to choose? Previous treatments Sufficient dose? Sufficient duration? Concomitant medication overuse? Consider co-morbidity E.g. depression, overweight, cardiac problems Danish Headache Center Preventive treatment Antihypertensive Anticonvulsants Antidepressants Other Metoprolol (100-200mg) Lisinopril (10-20 mg) Candersartan16-32 mg) Topiramate (100-150 mg) Valproate (1000-1500 mg) Amitriptyline (10-70 mg) Mirtazapine (15-30 mg) Flunarizine (10-20 mg) Pizotifen (3-4,5 mg) When is prophylactic treatment a success? Frequency or intensity reduced by at least 50% Acceptable adverse effects Monitor with calendar Prophylactic treatment Information Start low, go slow Sufficient dose and duration Follow-up Monitor with calendar Treat for up to 3 months Taper off every 6-12 months Follow EFNS Guidelines 5

Summary Optimize non-pharmacological management Optimize acute pharmacological treatment Consider short term prophylaxis (menstrual migraine) Begin with pharmacological prophylaxis according to guidelines for episodic migraine Treat medication overuse D A N I S H H E A D A C H E C E N T E R Danish Headache Center Migraine is a vascular disorder Migraine is a vascular disorder Messoud Ashina, MD, PhD Glostrup Hospital, the Capital Region of Denmark C Galen AD 129 c. 200/c. 216 Suggested that throbbing pain originated from blood vessels D Thomas Willis 1621 1675 Proposed the first vascular hypothesis of migraine Relationship of cerebrovascular cells with neurons, glia, and perivascular nerves. Aura and vascular mechanisms? Headache and vascular mechanisms? Migraine and vascular dysfunction? Girouard H, and Iadecola C J Appl Physiol 2006;100:328-335 2006 by American Physiological Society 6

Wolff's vascular theory of migraine with aura Migraine aura and cortical spreading depression rcbf with Xenon 133 and 254 channels Aura is due to constriction of cerebral vessels Head pain is due to the dilation of pain sensitive cerebral vessels C D Speed of hypoperfusion = 2-3 mm/min Aura Headache Olesen et al. Ann Neurol 1981 rcbf, aura* and headache How can aura/csd generate head pain? * normal rcbf during migraine without aura Hyperperfusion Hypoperfusion 2-3 mm/min Normal CBF Aura Headache 2 4 6 8 10 12 Hours Olesen et al. Ann Neurol 1981; Olesen et al. Ann Neurol 1990 Vascular changes during CSD Migraine headache Where does it hurt? Bolay et al. Nature Medicine 2002 7

Wolff's experiments Focal headache induced by balloon dilation Distal MCA Mid MCA Proximal MCA MCA Middle cerebral artery Superficial temporal artery Middle meningeal artery Dalessio, 1980 Nichols et al. Stroke 1990 Spontaneous migraine pain associated with dilation Dilation of the MCA on the headache side (Friberg et al. Lancet 1991) Dilation of the MCA on the headache side (Thomsen et al. Cephalalgia 1995) Amin et al., Lancet Neurology 2013 ATTACK DAY vs. ATTACK-FREE DAY 14.4% 10.5% Sumatriptan 6 mg sc. No effect on the cerebral arteries Amin et al., Lancet Neurology 2013 8

Can vasodilators provoke migraine? Human model of migraine Nitroglycerin CGRP PACAP38 Cilostazol Sildenafil PGE 2 All provoke migraine! Ashina 2014 Is migraine associated with vascular diseases? CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) Migraine with aura is a common initial symptom in 20% to 40% of patients Abnormal accumulation of mutated NOTCH3 in vascular smooth-muscle cells both in cerebral and extracerebral vessels Meta-analysis the risk of ischaemic stroke The risk of ischaemic stroke was approximately doubled in migraine with aura The risk was further increased by being female, age less than 45 years, smoking, and oral contraceptive use No risk in in migraine without aura 9

Meta-analysis The meta-analysis of WMAs showed an association for MA (OR 1.68; 95% CI 1.07 2.65; p =0.03) but not for MO (OR 1.34; 95% CI 0.96 1.87; p =0.08) CAMERA-1: High prevalence of ILLs in the posterior circulation territory in MA and with attack frequency >1 per month, compared to MO and with attack frequency >1 per month and controls. Most ILLs were located in the cerebellum The association of ILLs was greater for MA (OR 1.44; 95% CI 1.02 2.03; p =0.04) than for MO, but no association was found for MA (p =0.52) and MO (p =0.08) compared to controls CAMERA-2: No increased risk of progression. The study showed no association between ILLs and cognitive function Bashir et al. Migraine is a neuro vascular disorder Zlokovic et al. Neurosurgery 1998 Findings on endothelial function: Endothelial dysfunction No difference in endothelial function Enhanced endothelial function Reports on arterial function: Suggest that functional properties of large arteries are altered Strong link between blood vessels and aura Strong link between perivascular neurons and headache Altered functional properties of large arteries and possibly endothelial function Vascular changes in migraine migraine cannot be understood without a clear understanding of the dynamic role of the blood vessel in its pathogenesis - K.C. Brennan and Andrew Charles Curr Opin Neurol 2010 10

D A N I S H H E A D A C H E C E N T E R From episodic to chronic migraine Treating chronic migraine Messoud Ashina, MD, PhD Danish Headache Center If the frequency of headaches increases, chronic migraine can develop Every year, between 2.5 and 4.6% of people with episodic migraine experience progression to chronic migraine Approximately the same proportion regress from chronic migraine to episodic migraine spontaneously 0-9 headache days/month 10-14 headache days/month 15 headache days/month Low frequency episodic migraine High frequency episodic migraine Chronic migraine Glostrup Hospital, the Capital Region of Denmark Lipton RB. Neurology 2009; Munakata J et al. Headache 2009 Natural History of Migraine Strategy Remission Evolution to symptom-free over prolonged period of time Migraine Modifiable risk factors Depression Anxiety Medication & caffeine overuse Sleep disorders Stressful life events Marriage Obesity Persistence Transformation Relative clinical stability and no markers of transformation Clinical transformation - Increases in attack frequency over time chronic migraine - Medication overuse headache Functional transformation - Changes in nociceptive thresholds (allodynia) - Changes in pain pathways Anatomic transformation -Grey matter abnormalities Genetics? Patient education Non-pharmacological treatment Acute pharmacological treatment Remember medication overuse headache! Prophylactic pharmacological treatment Modified from Bigal et al Neurology 2008 Patient education TEMPORAL PATTERNS OF HEADACHE Patient education: diary & calendar Use calendar to monitor Treatment effect Use of analgesics Migraine Chronic migraine 11

Headache frequency before and after detoxification in MOH (N= 651) Non-pharmacological therapies Headache days /month Highly significant effect on: Use of medication Pain intensity and duration Costs of health care Quality of life Depression and anxiety 78% reverted to episodic headache Widely used Evidence for efficacy? Guidelines? Tassorelli et ComoEstas study group Non-pharmacological management Non-pharmacological management EFNS guideline conclusions Non-drug management should always be considered Information, reassurance and identification of trigger factors may be rewarding EMG biofeedback has a documented effect Cognitive-behavioral therapy and relaxation training are most likely effective Physical therapy and acupuncture may be valuable Bendtsen et al., EJN 2010 Nicholson et al. Curr Treat Options Neurol. 2011 Psychological therapies Groups of 8 patients, nine sessions, 2 h each Efficacy on headache 1. Stress and tension, how to recognize and control 2. Biofeedback 3. Pain behavior, pain accept 4. Cognitive restructuring 5. Feelings, how to handle 6. Thoughts, avoid negative circles Neg. 5% None 51% Intensity Great 4% Some 40% Neg. 2% Frequency None 59% Great 7% Some 32% Neg. 1% None 54% Duration Great 2% Some 43% 7. Communication. Headache, relationships and social life 8. Problem solving methods 9. Summary, plan ahead Vinther et al. unpublished 12

Efficacy of psychological therapies Chronic migraine: how to treat? expert opinion suggests that conventional preventive therapy for episodic migraine may also be useful. Vinther et al. unpublished Prophylactic treatment Efficacy and Safety of Topiramate for the Treatment of Chronic Migraine: A Randomized, Double Blind, Placebo Controlled Trial -blockers: Propranolol, Metoprolol, Atenol Anticonvulsants: Valproat, Topiramate Sandomigrin/pizotifen, Sibelium/Flunarizine Angiotensin II antagonist: Candesartan ACE- inhibitor: Lisinopril Amitriptyline Silberstein et al. Headache 2007 Mean change from baseline to monthly migraine days, intent-to-treat population., Placebo;, topiramate. P < 0.05; P < 0.01 vs. placebo. Topiramate in chronic migraine Critical issues Lots of side-effects Limited efficacy Copyright by International Headache Society Diener H et al. Cephalalgia 2007;27:814-823 13

OnabotulinumtoxinA for Treatment of Chronic Migraine: Pooled Results From the Double Blind, Randomized, Placebo Controlled Phases of the PREEMPT Clinical Program A total dose of botulinum toxin type A of 155 U was administered to 31 sites in seven head and neck muscles Dodick et al., Headache 2010 Occipital nerve stimulation in refractory chronic migraine ONS in refractory chronic migraine Number of Follow-up time Authors Results Side effects patients (months) 64% patients improved by Lead migration Popeney 2003 25 18.3 at least 50% Infection Matharu 2004 8 18 100% of patients improved Abdominal haematoma by at least 50% Lead migration RCTs Schwedt 2007 8 19 50% of patients improved Lead migration by at least 50% Lipton 2009 (A) 125 3 No difference vs. sham Infection Site pain Sensory symptoms Marchioretto 2010 (A) 34 12 Overall 56% frequency Light Saper 2011 66 3 39% of patients improved Lead migration by at least 50% Infection Reed 2011 (A) ONS-SNS 44 13 Overall 57% frequency Narouze 2011 (A) 12 13 Overall 81% frequency Slight lead migration D.Magis Linder 2011 (A) 13? ONS-SNS Silberstein 2012 157 3 Total 492 Overall 80% frequency (60% pain free) No difference with sham except for patients who Implant site pain achieved a 30% frequence ~53% improvement Magis Lancet Neurol 2012 updated ONS in refractory chronic migraine Number of Follow-up time Authors Results Side effects patients (months) 64% patients improved by Lead migration Popeney 2003 25 18.3 at least 50% Infection ONS in refractory chronic migraine St Jude study (N=157) Matharu 2004 8 18 100% of patients improved Abdominal haematoma by at least 50% Lead migration 50% of patients improved RCTs Schwedt 2007 8 19 Lead migration by at least 50% Infection NB: Prediction No difference Lipton 2009 (A) of 125 ONS outcome 3? Site pain vs. sham Sensory symptoms Neuropsychological Overall 56% frequency Marchioretto 2010 (A) 34 aspects: 12 anxiety and Light depression p=0.003 p=0.009 p=0.02 Follow-up = 3 months 39% of patients improved Lead migration at baseline Saper 2011 less 66 favorable 3 outcome by at least 50% (Notaro Infection Pain Physician 2014) Reed 2011 (A) Overall 57% frequency 44 13 Paresthesia ONS-SNS threshold (Slotti Cephalalgia 2014) Overall 81% frequency Narouze 2011 (A) 12 13 Slight lead migration D.Magis Linder 2011 (A) 13? ONS-SNS Silberstein 2012 157 3 Total 492 Overall 80% frequency (60% pain free) No difference with sham except for patients who Implant site pain achieved a 30% frequence ~53% improvement Magis et al. Lancet Neurol 2012 updated D.Magis Silberstein et al. Cephalalgia 2012 14

Electrode migration Ranges between 0 and 100%! Mobility of cervical region Electrode type Patients: intolerance to paresthesia, cable discomfort, muscular spasms Infection, cutaneous erosions ONS: adverse effects Battery depletion (high intensities): cost Headache side shift with unilateral ONS (Liège) Isolated autonomic attacks without pain in CH patients Bion microstimulator Summary Treat medication overuse first Optimize non-pharmacological management Optimize acute pharmacological treatment Consider short term prophylaxis (menstrual migraine) Begin with pharmacological prophylaxis according to guidelines for episodic migraine Consider Botox in chronic migraine if no response to at least 3 other prophylactics (including topiramate) D.Magis 85 15