1. HEADACHE Andrew Charles, M.D. Professor
Director, Headache Research and Treatment Program
David Geffen School of Medicine at UCLA

2. COMMON TYPES OF HEADACHES
PRIMARY HEADACHES
MIGRAINE
TENSION TYPE
CLUSTER HEADACHE AND OTHER TRIGEMINAL AUTONOMIC CEPHALGIAS
SECONDARY HEADACHES
Headaches due to infection
Headaches due to vascular causes
Headaches due to tumors
Etc., etc.

3. MIGRAINE: Prevalence and Impact
LIFETIME CUMULATIVE INCIDENCE
43% of women
18% of men
Stewart et al., Cephalagia, 2008
5% of women have headache more than 15 days per month – Migraine likely represents a significant component for these patients.
The majority of patients with migraine have not received an appropriate diagnosis, and are not receiving appropriate therapy

4. HEADACHE MIGRAINE – A MULTISYMPTOM COMPLEX AURA PATHOPHYSIOLOGICAL
SENSORY SYMPTOMS
LANGUAGE SYMPTOMS
VISUAL SYMPTOMS
MOTOR
DYSFUNCTION
COGNITIVE
PATHOPHYSIOLOGICAL
MECHANISMS
FATIGUE,
MOOD CHANGE
YAWNING,
POLYURIA
NAUSEA,
VOMITING
DIZZINESS,
VERTIGO
HEADACHE

5. CHANGING CONCEPTS OF MIGRAINE PATHOGENESIS
MIGRAINE IS A DISORDER OF BRAIN EXCITABILITY
VASODILATION MAY OCCUR AS PART OF THE DISORDER, BUT IS NOT REQUIRED FOR MIGRAINE PAIN

6. Penfield W. A contribution to the mechanism of intracranial pain
Penfield W. A contribution to the mechanism of intracranial pain. Assoc Res Nerv Ment Dis. 1935;15:
Ray BS, Wolff HG. Experimental studies in headache: Pain-sensitive structures of the head and their significance in headache. Arch Surg. 1940;41:

7. Issues with Studies of Ray and Wolff, Penfield
Stimulation of vessels was focal external stimulation or mechanical dilation
There is no evidence that physiological relaxation of smooth muscle and resultant dilation can cause pain
Multiple areas of brain that could evoke pain were not stimulated:
Cingulate cortex
Brainstem – Stimulation or lesions in brainstem can cause migraine

8. Nitric oxide donors PDE inhibitors Histamine CGRP
Vasoactive Drugs Cause Migraine After Significant Delay (hours), Not Correlated with Vasodilation
Nitric oxide donors
PDE inhibitors
Histamine
CGRP
Schoonman, et al. Migraine headache is not associated with cerebral or meningeal vasodilatation--a 3T magnetic resonance angiography study. Brain 131, , 2008.
Kruus, et al. Migraine can be induced by sildenafil without changes in middle cerebral artery diameter. Brain. 26: , 2003.
Rahman et al., Vasoactive intestinal peptide causes marked cerebral vasodilation but does not induce migraine. Cephalalgia. 28, , 2008.

9. Alternative Mechanisms of “ Vascular” Drugs
-blockers
Inhibit neuronal adrenergic signaling
Calcium channel blockers
Inhibit neuronal calcium channels
Caffeine
Neuronal/glial adenosine receptor antagonist
Ergotamines
Modulate central 5-HT receptors
Triptans
Activate neuronal 5-HT1 receptors in brainstem and thalamus

10. CORTICAL “WAVES” IN MIGRAINE WITH AURA
Olesen, et al. 1981
Hadjikhani et al., 2001
So by now we see that events c temporal, spatial, blood flow characteristics of CSD appear to occur in migraine pts, correlate with aura sx.
Bereczki et al., 2008
Cao et al., 1999

11. …AND MIGRAINE WITHOUT AURA
Woods et al., 1994
Denuelle et al., 2008
Before sumatriptan
2 to 4 h after the attack onset
After sumatriptan
4 to 6 h after the attack onset
Chalaupka, 2008

12. The image on this slide is a PET scan from one individual in the Weiller et. al. study. The red area or locus of activity is located in the brain stem. The authors of this study identified the raphe nuclei, the locus ceruleus, and the peri-aqueductal gray as brain stem regions that are selectively activated during a migraine attack. These regions are thought to be involved in the generation of headache pain.
Reference: Weiller C, May A, Limmroth V, et. al. Brain stem activation in spontaneous human migraine attacks. Nat Med. 1995;1:

13. Hypothalamic Activation in Migraine
(Denuelle et al., Headache, 2007)

14. Sensory, Cognitive, Motor Symptoms
MIGRAINE – A MULTISYMPTOM COMPLEX
PAIN
Sensory, Cognitive, Motor Symptoms
VISUAL SYMPTOMS
Cortical
Activation
Brainstem
Activation
Nausea/Vomiting
VESTIBULAR SYMPTOMS
PAIN

15. MIGRAINE SHOULD BE IN DIFFERENTIAL DIAGNOSIS OF ANY EPISODIC NEUROLOGICAL DISORDER

16. Do most headache patients need an imaging study of the brain?

17. “I’ll want to get a few tests on you, just to cover my ass”

18. When Don’t You Need to Get a Scan?
Patient with established history of episodic headache
Current headache is consistent with previous headaches or is consistent with different manifestation of a primary headache.
Normal neurological exam

19. When You Do Need to Get a Scan
Extremely abrupt onset of headache
Persistent unremitting headache
New onset of headache in patient over age of 50
Fever
Papilledema
Abnormal neurological examination

20. General Approach to The Headache Patient
Make a diagnosis (or challenge the diagnosis that a patient has already been given)
Identify and change exacerbating environmental factors and medications
Establish regimen for acute therapy of headache
Determine if preventive therapy is appropriate

21. IHS CRITERIA FOR MIGRAINE WITHOUT AURA
At least 5 attacks fulfulling the following:
Headaches lasting 4 to 72 hours
During headache, at least one of the following:
Nausea and/or vomiting
Photophobia and phonophobia
At least 2 of the following criteria
Unilateral location
Pulsating quality
Moderate or severe intensity
Aggravated by physical activity

22. Simplified Diagnostic Criteria: ID Migraine
Light sensitivity with headache
Nausea with headache
Decreased ability to function with headache
Any 2 out of 3 = Migraine
Migraine should be the default diagnosis for any headache that is brought to the attention of a health care provider

23. Migraine: Other Features
Perimenstrual timing
Stereotypical prodromal symptoms
Characteristic triggers
Abatement with sleep
Childhood precursors (motion sickness, somnambulism, episodic vomiting, episodic vertigo)
Osmophobia
Diarrhea during attack

24. Landmark: How Likely Is it That “Headache” Is Migraine?
In a prospective, open-label study of 1203 patients with episodic headache
94% (of 377 evaluable patients) had migraine or probable migraine
25% with migraine were not diagnosed by their physician
Headaches had a severe impact (HIT–6 score 64)
Probable migraine (n=67)
18%
Migraine (n=288)
76%
Episodic tension-type (n=11) 3%
The Landmark Study evaluated the diagnosis of patients consulting their primary care physicians with headache, and was conducted in 128 practices (93% primary care) in 15 countries. This prospective, open-label study included patients (aged 18–65 years) who consulted their physician with headache as a primary or secondary complaint. Patients were excluded if they had chronic daily headache or if they had a known or suspected secondary headache disorder. A total of 1203 patients were included.
During the screening visit, patients self-reported a headache diagnosis, and were then assigned a headache diagnosis by their physician following his or her usual practice. Patients with a physician diagnosis of migraine or non-migraine primary headache completed diaries to record headache symptoms for 3 months or 6 attacks, whichever occurred first. Members of an expert panel (Carl Dahlöf, Sweden; Andrew Dowson, UK; and Lawrence Newman and Stewart Tepper, US), who were unaware of the physician diagnosis, then used the diary data to assign a headache diagnosis according to IHS criteria.
The expert panel reviewed diary data for 448 patients (306 with a new physician diagnosis of migraine and 142 with a diagnosis of non-migraine primary headache). Of these, 377 diaries were evaluable for making a headache diagnosis.
Of the 377 patients, 355 (94%) were assigned a diagnosis of migraine (76%) or probable migraine (18%) by the expert panel.
The Landmark Study found that if a patient presents to their physician with complaint of headache, there is a 94% likelihood it is migraine or migrainous headache.
Unclassifiable (n=11) 3%
Adapted from Tepper SJ et al. Headache. 2004;44:856–864.

25. Landmark: Patient and Physician Diagnoses
In a prospective, open-label study of 1203 patients with episodic headache
Patient
If patient self-reports migraine, 99.5% chance migraine or probable migraine
If patient self-reports non-migraine, 86% chance migraine or probable migraine
Physician
If physician diagnoses migraine, 98% chance migraine or probable migraine
If physician diagnoses non-migraine, 82% chance migraine or probable migraine
Of the 206 patients in the Landmark study who self-reported migraine at the screening visit, almost all (99.5%) were confirmed as having migraine or probable migraine by the expert panel (88% migraine, 11.5% probable migraine). No patient who self-reported migraine was subsequently diagnosed with episodic tension-type headache. Of the 272 patients who were given a new diagnosis of migraine by their physician, 98% were diagnosed with migraine or probable migraine by the expert panel. Therefore, a patient or a physician diagnosis of migraine is likely to be accurate, according to this study.
However, if the patient or the physician diagnosed non-migraine, there was a high probability that the patient actually had migraine. Of the 148 patients who self-reported non-migraine headache, 86% were diagnosed by the expert panel with migraine or probable migraine. Likewise, of the 105 patients diagnosed by their physicians as having non-migraine headache, 82% were assigned a diagnosis of migraine or probable migraine by the expert panel.
A self-report or physician diagnosis of migraine was almost always correct. On the other hand, a self-report or physician diagnosis of non-migraine was almost always later found out to be migraine.
It may be helpful to provide such tools as migraine diaries for patients, and request them to fill it out over several migraine attacks before asking the patient to return to the clinic. During this followup visit, the physician can review the diary and refer to the I.H.S. diagnostic criteria in order to help reach a final diagnosis.
Self-report or physician diagnosis of migraine was almost always correct
Self-report or physician diagnosis of non-migraine was almost always later found out to be migraine
Adapted from Tepper SJ et al. Headache. 2004;44:856–864.

26. MIGRAINES ARE OFTEN MISDIAGNOSED
SINUS HEADACHES
SIMILAR DISTRIBUTION OF PAIN
MIGRAINES CAN BE SEASONAL
DECONGESTANTS CAN “TAKE THE EDGE OFF” OF MIGRAINE
WITHDRAWAL FROM DECONGESTANTS CAN PRECIPITATE MIGRAINES

27. “SINUS HEADACHE”

28. OTHER COMMON MIGRAINE MISDIAGNOSES
TENSION HEADACHE/CERVICOGENIC HEADACHE
NECK PAIN IS A SYMPTOM OF MIGRAINE
MIGRAINE COMMONLY ASSOCIATED WITH NECK PAIN
NECK PAIN MAY OCCUR BEFORE, DURING, OR AFTER HEADACHE

29. ARE THERE MIGRAINE TRIGGERS?

31. COMMON HEADACHE TRIGGERS
IRREGULAR MEALS
IRREGULAR CAFFEINE, CHOCOLATE, NUTS, BANANAS, ETC.
IRREGULAR SLEEP (PARTICULARLY EXCESSIVE SLEEP)
STRESS OR “LET-DOWN” FROM STRESS
AIR TRAVEL, CHANGE IN BAROMETRIC PRESSURE
MENSTRUAL PERIOD

32. THE MIGRAINE LIFESTYLE
CONSISTENCY
TIMING OF MEALS, BALANCE OF DIET –- Don’t skip meals, mix of different food groups
SLEEP --- Don’t oversleep or undersleep
CAFFEINE – “Minimum daily dose” of caffeine on a daily basis
EXERCISE – The more aerobic exercise the better

33. MEDICATIONS THAT MAY MAKE MIGRAINES WORSE
ORAL CONTRACEPTIVES
HORMONE REPLACEMENT
SSRI ANTIDEPRESSANTS
STEROIDS (TAPERING)
DECONGESTANTS
SHORT ACTING SEDATIVES (e.g. Ambien (?)
BONE DENSITY MEDICATIONS (?)
BOTOX

34. AMPP DATA (Bigal et al., Neurology 2008)
FREQUENT OPIOID OR BARBITURATE (BUTALBITAL) USE IS A RISK FACTOR FOR MIGRAINE PROGRESSION
GROWING EVIDENCE THAT OVERUSE OF ANALGESIC MEDICATIONS LEADS TO WORSENING OF MIGRAINE
AMPP DATA (Bigal et al., Neurology 2008)
Frequent use of opioids or butalbital (more than 8 days/month) is a risk factor for progression to chronic migraine
Triptan use is neutral for progression
Nonsteroidal use is protective

35. ACUTE THERAPIES TRIPTANS – Selective 5HT 1b 1d agonists
SUMATRIPTAN (IMITREX TABLETS, NASAL SPRAY, INJECTION), SUMATRIPTAN NAPROXEN COMBINATION
RIZATRIPTAN (MAXALT “MELTABS”, TABLETS)
NARATRIPTAN (AMERGE TABLETS)
ZOLMITRIPTAN (ZOMIG)
ALMOTRIPTAN (AXERT)
FROVATRIPTAN (FROVA)
ELETRIPTAN (RELPAX)
DHE NASAL SPRAY (MIGRANAL), INJECTION
NSAIDS
METACLOPRAMIDE

36. TRIPTAN NEWS
TRIPTANS ARE NOW AVAILABLE WIDELY WITHOUT A PRESCRIPTION IN EUROPE.
SUMATRIPTAN WILL SOON BE AVAILABLE AS A GENERIC IN MULTIPLE PREPARATIONS.
SUMATRIPTAN/NAPROXEN COMBINATION TABLET (TREXIMET) IS NOW AVAILABLE.

37. EVIDENCE-BASED NON-PRESCRIPTION APPROACHES TO MIGRAINE
Magnesium ( mg. per day)
Riboflavin (400 mg. per day)
CoQ10 ( mg. per day)
Melatonin (3 mg. qhs)
Petasites (Butterbur 75 mg. BID)

38. THERAPEUTIC OPTIONS FOR MIGRAINE PROPHYLAXIS
BETA BLOCKERS
TRICYCLICS
CALCIUM CHANNEL BLOCKERS
VALPROIC ACID (Depakote)
TOPIRAMATE (Topamax)
?? MEMANTINE

39. MEMANTINE FOR MIGRAINE PREVENTION?
Activity dependent blocker of NMDA receptors
Identified as a blocker of CSD in rodents
Appears to be effective as a migraine preventive therapy for significant percentage of patients with frequent migraine who had failed other preventive therapies
It is generally very well tolerated
Well designed studies are warranted
Peeters et al., JPET, 2007
Charles, et al., Journal of Headache and Pain, 2007
Bigal et al., Headache, 2008

40. MIGRAINE AND PREGNANCY
THE SIGNIFICANT MAJORITY OF WOMEN HAVE AN IMPROVEMENT IN MIGRAINE FREQUENCY DURING THE 2nd and 3rd TRIMESTERS OF PREGNANCY
THERE IS NO CONSENSUS OR EVIDENCED BASED APPROACH TO TREATMENT OF HEADACHE DURING PREGNANCY
REGULAR SMALL AMOUNTS OF CAFFEINE, MAGNESIUM SUPPLEMENTATION ARE REASONABLE NON-PRESCRIPTION ALTERNATIVES
THE ONLY ADVERSE EVENT THAT HAS BEEN IDENTIFIED WITH TRIPTANS AND PREGNANCY IS A SLIGHTLY INCREASED RISK OF PREMATURE DELIVERY….i.e. OK TO USE TRIPTANS IN SEVERE CASES

41. NEW THERAPIES ON THE HORIZON
ACUTE THERAPIES
CGRP Antagonist – Initial placebo controlled trials look very promising.
Transcranial magnetic stimulation
Inhaled ergotamines
PREVENTIVE THERAPIES
PFO Closure – Multiple closure devices in clinical trials
Memantine – Initial uncontrolled results are promising
Occiptial nerve stimulation
Tonabersat

42. TAKE HOME MESSAGES
MIGRAINE IS A COMPLEX DISORDER OF BRAIN EXCITABILITY AND NOT SIMPLY A “VASCULAR HEADACHE”
MIGRAINE IS EXTRAORDINARILY COMMON AND UNDERDIAGNOSED.
THE MAJORITY OF MIGRAINE PATIENTS CAN BE EFFECTIVELY AND SAFELY TREATED WITH AN ORGANIZED PLAN OF LIFESTYLE MANAGEMENT , ACUTE THERAPY, AND PREVENTIVE THERAPY IF NEEDED
PROMISING NEW THERAPIES ARE ON THE HORIZON