1. Migraine is a common neurological disorder affecting approximately 12-16% of the population globally. Prevalence is higher in women and decreases with age. 2. Diagnosis is based on patient history meeting International Headache Society criteria for migraine attacks including pulsating pain, photophobia, phonophobia, and nausea. 3. "Red flags" such as new onset headache after age 50, focal neurological symptoms, or systemic symptoms require further evaluation to rule out secondary causes. Imaging and lumbar puncture may be needed in some cases.

1. Treating Migraines Professor Yasser Metwally www.yassermetwally.com

3. Prevalence of migraine by sex and age 30 25 20 15 10 5 0 20 30 40 50 60 70 80 100 Migraine prevalence (%) Age (years) Lipton and Stewart (1993) The American Migraine Study ( n =2479 migraine sufferers) Females Males

8. Clinical features of migraine Sleepy Anorexia nausea Vomiting yawning Phonophobia Photophobia Phonophobia Photophobia Osmophobia Osmophobia Vomiting Deep sleep Headache III IV Headache Resolution Blau (1992) I II Normal Prodromes Aura Normal Appetite Awake/sleep Light tolerance Smell Noise Fluid balance Craving Tired yawning Heightened perception Fluid retention V Postdromes Normal Limited Light tolerance Noise Smell Fluid balance Tired Feeling high or low Diuresis Appetite Awake/sleep food tolerance Normal

11. IMPORTANT DIAGNOSTIC CONSIDERATIONS Recurring moderate to severe headache is migraine until proven otherwise 15% of patients have a neurological aura IHS criteria do not require GI symptoms Vomiting occurs in < 1/3 of patients 41% of migraine patients report bilateral pain 50% of the time, pain is non-pulsating Russell MB, et al. Cephalalgia . 1996. Pryse-Phillips WEM, et al. Can Med Assoc J . 1997. No single criterion necessary nor sufficient for diagnosis

13. MIGRAINE WITH AURA (FORMERLY “CLASSIC” MIGRAINE) Visual > sensory > motor, language, brainstem Gradual evolution: 5–20 minutes (<60 minutes) May or may not be associated with headache Complex array of symptoms reflecting focal cortical or brainstem dysfunction International Headache Society. Cephalalgia. 1988;8;(suppl 7):1-96.

14. MIGRAINE AURA “Cheiro-oral”

15. Fortification Spectrum

17. Alice in Wonderland

18. REASONS FOR MISDIAGNOSIS OF MIGRAINE AS TTH OR SINUS Sinus Up to 50% of migraine patients report their headaches are influenced by weather 45% of migraine patients report attack related ‘sinus’ symptoms including lacrimation, rhinorrhea, nasal congestion Tension-Type Headache 75% of migraine patients report posterior neck pain/tightness/stiffness during attacks Stress/anxiety frequent migraine trigger Migraine is bilateral in up to 40% of patients Raskin NH. Headache. 2nd ed. 1988; Barbanti P, et.al. Cephalalgia. 2001; Kaniecki R. Cephalalgia . 2001. Migraine is a referred pain syndrome (V1, C1-C3)

19. Differential diagnosis of primary headaches Dubose et al (1995); Goadsby (1999); Marks and Rapoport (1997) Family history Yes Sex More females Onset Variable Location Usually unilateral in adults Character/severity Pulsatile Throbbing Frequency/ 2–72 h/attack duration 1 attack/year to >8 per month Associated Visual aura symptoms Phonophobia Photophobia Pallor Nausea/vomiting Clinical feature Migraine No More males During sleep Behind/around one eye Excruciating/ sharp Steady 15–90 min/attack 1–8 attacks/day for 3–16 weeks 1–2 bouts/year Sweating Facial flushing Nasal congestion Ptosis Lacrimation Conjunctival injection Pupillary changes Cluster headache Yes More females Under stress Bilateral in band around head Dull Persistent Tightening/pressing 30 min to 7 days 3–4 attacks/week to 1–2 attacks/year Mild photophobia Mild phonophobia Anorexia Tension headache

20. WORRISOME HEADACHE RED FLAGS “SNOOP” O lder: new onset and progressive headache, especially in middle-age >50 (giant cell arteritis) S ystemic symptoms (fever, weight loss) or S econdary risk factors (HIV, systemic cancer) N eurologic symptoms or abnormal signs (confusion, impaired alertness, or consciousness) O nset: sudden, abrupt, or split-second P revious headache history: first headache or different (change in attack frequency, severity, or clinical features)

22. EVALUATION STRATEGIES Red Flags” “ Investigate the Atypical and the

23. SUDDEN ONSET HEADACHE Primary Secondary SAH Pituitary apoplexy Venous sinus thrombosis Arterial dissection Meningoencephalitis Acute hydrocephalus Acute hypertension Spontaneous intracranial hypotension Idiopathic thunderclap headache (TCH) Exertional headache Cough headache Sexual headache deBruijn, SF, et al. Lancet . 1996; Lancet . 1998.

24. LUMBAR PUNCTURE Headache associated with fever, confusion, meningism, or seizures Thunderclap headache with negative CT head Subacute progressive headache High or low CSF pressure suspected (even if papilledema is absent) The first unusually severe headache Evans RE, Rozen TD, Adelman JU. In: Wolff’s Headache And Other Head Pain . 2001.

25. SENSITIVITY OF CT SCAN IN SUBARACHNOID HEMORRHAGE (SAH) van Gijn J, van Dongen KJ. Neuroradiology . 1982. Kassell NF et al. J Neurosurg. 1990. TIME AFTER HEADACHE ONSET PROBABILITY (%) DAY 0 95 DAY 3 80 1 WEEK 50 2 WEEKS 30 3 WEEKS ~0

28. MR AND CONVENTIONAL ANGIOGRAPHY MR Angiography Angiography Acute SAH Arterial dissection CNS vasculitis Aneurysm (>5 mm) Arterial dissection Venous thrombosis (MR venography) AV malformation Leclerc X et al. Neuroradiology . 1999.

30. CEREBRAL VENOUS SINUS THROMBOSIS Bousser MG et al. In: Wolff’s Headache And Other Head Pain . 2001 .

31. Sleepers Awake!! Treatment

32. STRATEGIES FOR MIGRAINE TREATMENT Preemptive treatment Migraine trigger time-limited and predictable Preventive Treatment Decrease in migraine frequency warranted Acute treatment To stop pain and prevent progression Silberstein SD. Cephalalgia . 1997.

33. ACUTE MIGRAINE TREATMENT Discuss problems that arise in the acute management of migraine Evaluate the general principles of treatment Review the clinical evidence for acute treatment alternatives Present an approach for selecting and sequencing acute therapies Objectives

37. MIGRAINE TRIGGERS Diet Hormonal changes Head trauma Stress and anxiety Sleep deprivation or excess Environmental factors Physical exertion

42. Trigeminovascular model of migraine Efferent Adapted from Goadsby and Olesen (1996) Dura mater Afferent Trigeminal ganglion Peptide releasing neurones Dura mater Efferent Trigeminal nerve Afferent Blood vessels Efferent CGRP/SP release Dilatation Cranium

43. Mechanisms for treatment CGRP NK SP 5-HT 1F 5-HT 1D 5-HT 1B Blood vessel Trigeminal nerve Adapted from Goadsby (1997) CGRP calcitonin gene related peptide NK neurokinin A SP substance P triptan CONSTRICTION INHIBITION

46. ROUTES OF ADMINISTRATION Suppositories: antiemetics, ergots, opioids Oral therapies: most medications Nasal sprays: sumatriptan, DHE, butorphanol, zolmitriptan Injectable (SL, IM, IV) sumatriptan, DHE, injectable NSAIDs, opioids, neuroleptics

47. FORMULATION: ONSET Increasing Speed Parenteral Oral Tablet SL IN PR IM/SC IV

51. Headache responses continue to improve over time after eletriptan dosing Time course for headache response 0 20 40 60 80 100 0 1 2 3 4 Time post dose (h) n =563 Pfizer, data on file % Patients with response Placebo 20 mg eletriptan 40 mg eletriptan Study 314 ** P <0.05 vs placebo for all doses 80 mg eletriptan ** ** **

52. ACUTE TREATMENT PRINCIPLES Early intervention Use correct dose and formulation Use a maximum of 2 – 3 days/week     Use preventive therapy in selected patients  stratified care Silberstein SD. Neurology . 2000; Lipton RB, et al. JAMA . 2000.

53. STEP VS. STRATIFIED CARE Start Start A B C A B C

58. TREAT MIGRAINE WHEN PAIN IS MILD Retrospective analysis of 3 studies confirmed triptan treatment while pain is mild provided higher pain-free response at 2 h than ergotamine plus caffeine or aspirin plus metoclopramide, and reduced need for redosing Prospective rizatriptan study of 1919 patients confirms triptan effectiveness at all levels of pain but enhanced benefit if taken while pain is mild Post-hoc analysis of Spectrum study (26 patients) showed sumatriptan provided more effective relief with less recurrence when taken while pain was still mild Cady RK et al. Headache . 2000; Cady RK et al. Clin Ther . 2000; Hu XH et al. Headache . 2002.

59. TRIPTANS IN THE SPECTRUM OF MIGRAINE In patients with migraine, sumatriptan effectively treats all 3 types In patients with pure TTH, sumatriptan is not effective In migraine sufferers TTH, has a migraine-like mechanism, whereas pure TTH has a different mechanism Therefore, sumatriptan can effectively treat TTH in migraine sufferers, probably because it is a form of mild migraine Patients with disabling migraine have different headache types, including migraine, migrainous, and tension-type headache (TTH) Lipton et al. Headache. 2000; Cady RK et al. Cephalalgia. 1997.

62. SUMMARY OF ACUTE MIGRAINE MANAGEMENT Identify coexistent conditions that influence therapy Make a specific, credible diagnosis and communicate it Assess migraine severity and it’s impact on the patient Determine the patient’s preferences and needs (eg, fast relief, adverse effects tolerance) Develop a therapeutic partnership with realistic expectations Create plan based on migraine type and severity, as well as patient’s needs, preferences, and comorbidities Consider need for preventive treatment

66. Chronic Daily HA

68. MIGRAINE ADDITIONAL FEATURES Abatement with sleep Stereotyped premonitory symptoms Characteristic triggers Positive family history Childhood precursors (motion sickness, episodic vomiting, episodic vertigo) Osmophobia Predictable timing around menstruation (or ovulation) Pryse-Phillips WEM, et al. Can Med Assoc J . 1997.

69. UNDIAGNOSED MIGRAINE SUFFERERS OFTEN RECEIVE OTHER MEDICAL DIAGNOSES Lipton RB et al. Headache . 2001.

70. AURA: MIMICS AND SECONDARY CAUSES TIA Carotid artery dissection Venous sinus thrombosis Vasculitis Tumor Simple partial seizure AVM Bousser MG et al. In: Wolff’s Headache And Other Head Pain . 2001; Campbell JK, Sakai F. In: The Headaches . 2000; Silberstein SD, Lipton RB, Goadsby PJ. Headache in Clinical Practice . 2002.

71. LATE-LIFE MIGRAINE ACCOMPANIMENTS VS TIA Mild headache in 50% Progression from one accompaniment to another Repetition (  2 similar attacks) Duration 15 – 25 minutes Characteristic midlife flurry of attacks Build up of scintillations — “march” of paresthesias Fisher CM. Can J Neurol Sci . 1980; Silberstein SD, Saper JR, Freitag FG. In: Wolff’s Headache And Other Head Pain . 2001.

72. MIGRAINE AND STROKE Clinical manifestations of underlying disease (MELAS, CADASIL) Causal Comorbid Coexistent Bousser MG et al. In: Wolff’s Headache And Other Head Pain . 2001 .

73. CADASIL

74. CSF XANTHOCHROMIA AFTER SAH SPECTROPHOTOMETRY Vermeulen M et al. J Neurol Neurosurg Psychiatry . 1989. TIME AFTER HEMORRHAGE PROBABILITY (%) 12 HOURS 100 1 WEEK 100 2 WEEKS 100 3 WEEKS >70 4 WEEKS >40

75. Preventive Management of Migraine

76. GUIDELINES: WHEN TO USE PREVENTIVE MANAGEMENT Uncommon migraine conditions Acute medications contraindicated, ineffective, intolerable AEs, or overused Frequent headache (  2 attacks per week) Patient preference Cost considerations Silberstein SD et al. Wolff’s Headache And Other Head Pain . 2001. Migraine significantly interferes with patient’s daily routine, despite acute R x

77. GOALS OF PREVENTIVE TREATMENT Improve responsiveness to acute R x Improve function and decrease disability Silberstein SD et al. Headache in Clinical Practice . 2nd ed. 2002. Decrease attack frequency (by 50%), intensity, and duration

78. Migraine Prevention

81. GENERAL PRINCIPLES OF PREVENTIVE TREATMENT Assess Coexisting Conditions Be aware of drug interactions Do not use migraine drug if contraindicated for other condition Do not use drug for other condition that exacerbates migraine Special concern for women of childbearing potential Silberstein SD et al. Headache in Clinical Practice . 2nd ed. 2002. Select drug to treat both disorders

82. Comorbidities

85. PREVENTIVE TREATMENT: DRUG CHOICE COMORBID CONDITION DRUG EFFICACY* SIDE EFFECTS* RELATIVE CONTRAINDICATION RELATIVE INDICATION Anticonvulsants Divalproex 4+ 2+ Liver disease, bleeding disorders Mania, epilepsy, impulse control Topiramate 3+ 2+ Kidney stones Epilepsy, mania, neuropathic pain Gabapentin 2+ 2+ Epilepsy, neuropathic pain Antidepressants TCAs 4+ 2+ Mania, urinary retention, heart block Other pain disorders, depression, anxiety disorders, insomnia SSRIs 2+ 1+ Mania Depression, OCD MAOIs 2+ 4+ Unreliable patient Refractory depression Silberstein SD et al. Headache in Clinical Practice . 2nd ed. 2002. Gray RN et al. Drug Treatments for the Prevention of Migraine . 1999. *On a scale of 0 to 4

86. PREVENTIVE TREATMENT: DRUG CHOICE COMORBID CONDITION DRUG EFFICACY* SIDE EFFECTS* RELATIVE CONTRAINDICATION RELATIVE INDICATION Antiserotonin Methysergide 4+ 4+ Angina, PVD Orthostatic hypotension  -Blockers 4+ 2+ Asthma, depression, CHF, Raynaud’s disease, diabetes HTN, angina Calcium channel blockers Verapamil 2+ 1+ Constipation, hypotension Migraine with aura, HTN, angina, asthma Silberstein SD et al. Headache in Clinical Practice . 2nd ed. 2002. Gray RN et al. Drug Treatments for the Prevention of Migraine . 1999. *On a scale of 0 to 4

87. PREVENTIVE TREATMENT: DRUG CHOICE COMORBID CONDITION DRUG EFFICACY* SIDE EFFECTS* RELATIVE CONTRAINDICATION RELATIVE INDICATION NSAIDs Naproxen 2+ 2+ Ulcer disease, gastritis Arthritis, other pain disorders Other Riboflavin 2+ 1+ Preference for natural products Feverfew Botulinum Toxin A 2+ 2+ 2+ 1+ Myasthenia gravis Dystonia or Spasticity *On a scale of 0 to 4 Silberstein SD et al. Headache in Clinical Practice . 2nd ed. 2002. Gray RN et al. Drug Treatments for the Prevention of Migraine . 1999.

89. CAUTIONS IN ACUTE MEDICATION USE Silberstein SD. Cephalalgia . 1997. PREVENTIVE CAUTION CONTRAINDICATION Methysergide Ergots, Triptans MAOIs Sumatriptan (subcutaneous) and zolmitriptan Meperidine, Midrin, sumatriptan (po, IN) and rizatriptan Propranolol Rizatriptan NSAIDs Other NSAIDs or ASA Divalproex Butalbital

90. NONPHARMACOLOGIC TREATMENT: POTENTIAL INDICATIONS Poor tolerance, response, or contraindications to drug therapy Pregnancy, planned pregnancy, or nursing History of overuse Significant life stress or deficient stress-coping skills Goslin RE et al. Behavioral and Physical Treatments for Migraine Headache . 1999. Patient preference

91. SUMMARY OF PREVENTION Use preventive medications when needed Treat long enough Avoid acute medication overuse Take coexisting conditions into account Use drug with the best efficacy for individual patient