Headache & Migraine Brian J. Piper, Ph.D., M.S.                October 23, 2012
Goals• Describe differences in symptomology  between migraines, cluster headaches, and  tension-type headaches.• List the ...
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5503a6.htm
Importance   • WHO ranks migraine among world’s most     debilitating chronic illnesses   • 3rd most common reason for ER ...
Migraine Terminology  • migraineurs: person who experiences migraines  • aura: collection of symptoms that may precede or ...
George Cruikshank: The Head Ache (1819)2:20: http://www.mayoclinic.com/health/migraine-aura/MM00659
International Headache Society Migraine Criteria      • Migraine with aura (classic migraine)        – At least 2 attacks ...
Epidemiology: American Migraine     Prevalence & Prevention Study• Mailed Survey to 257K, response by 163K (64.9%) who  ar...
Epidemiology: American Migraine     Prevalence & Prevention Study• Mailed Survey to 257K, response by 163K (64.9%) who  ar...
Epidemiology: American Migraine         Prevalence & Prevention Study • Mailed Survey to 257K, response by 163K (64.9%) wh...
Pathophysiology• limited animal models• theory: genetic (50% heritable) & neurovascular• 2 min: http://www.youtube.com/wat...
Neural Substrates of Migraine • 1) meningeal vessels • 2) trigeminal: opthalmic nerve (V1)
Neural Substrates of Migraine•   1) meningeal vessels•   2) trigeminal: opthalmic nerve (V1)•   3) pons (input from other ...
Neural Substrates of MigraineGoadsby et al. (2002). New England Journal of Medicine, 346(4), 257-270.
5-HT1B: vasoconstriction      5-HT1D: peripheral neuronal inhibitionGoadsby et al. (2002). New England Journal of Medicine...
Brainstem Activation During Migraine                                               Posterior• 43 year old man with history...
Migraine Across Countries (Twins)Mulder et al. (2003). Twin Research, 6(5), 422-431.
Genetic Contribution to MigraineMulder et al. (2003). Twin Research, 6(5), 422-431.
Environmental Factorsstresshead and neck infectionhead trauma/surgeryHormone changesaged cheesedairyred winenutss...
Cluster Headache    • unilateral pain    • unilateral other:         – ptosis         – miosis         – rhinorrhoea    • ...
Hypothalamic & Insular Activation             During Cluster Headache    • 9 patients with a history of cluster completed ...
Episodic Tension-type Headache                  (TTH)A. Number of days with such headache < 180/year (<15/month)B. Headach...
DSubstrates of TTH                    V                        Dorsal Horn: sensory                        Ventral Horn: m...
Tension-type Headache or Migraine                              Mild                        Moderate                       ...
Comparison• Frequency: TTH > Migraine > Cluster• Pain:• Sex Ratio: F > M      F>M         M>F
Summary  • Headache and migraine are common but    under-appreciated.  • Migraine & headache pathophysiology is an    acti...
Medication Overuse Headache• Occurrence of rebound headache following  long-term treatment• Identification may take months...
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Pathophysiology: Migraine & Headache

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This presentation was given to first year pharmacy students as a part of course on a medical physiology and pathophysiology.

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  • Christopher Robin Milne, the son of A. A. Milne (author of Winnie-the-Pooh ) and the person on whom Christopher Robin was based, lived with myasthenia gravis for many years (1920-1996).
  • The National Health Interview Survey (NHIS) is an annual, cross-sectional survey intended to provide nationally-representative estimates on a wide range of health status and utilization measures among the nonmilitary, noninstitutionalized population of the United States.
  • A recent survey by the World Health Organization (WHO) rates severe migraine, along with quadriplegia, psychosis, and dementia, as one of the most disabling chronic disorders.
  • Basilar type aura can include temporary blindness, which is one reason they can be quite terrifying. They are believed to originate in the brainstem.Phonophobia:  a fear of sounds, noise, and one&apos;s own voicePhotophobia: an abnormal sensitivity to or intolerance of light
  • The trigeminal nerve (CN5) is a nerve responsible for sensation in the face and certain motor functions such as biting, chewing, and swallowing. It is the largest of the cranial nerves. Its name (&quot;trigeminal&quot; = tri- or three, and -geminus or twin, or thrice twinned) derives from the fact that each trigeminal nerve, one on each side of the pons, has three major branches: the ophthalmic nerve (V1), the maxillary nerve (V2), and the mandibular nerve (V3). 
  • Pons receives input from locus ceruleus &amp; raphe.
  • Migraine involves dysfunction of brain-stem pathways that normally modulate sensory input. The key pathways for the pain are the trigeminovascular input from the meningeal vessels, which passes through the trigeminal ganglion and synapses on second order neurons in the trigeminocervical complex. These neurons, in turn, project through the quintothalamic tract, and after decussating in the brain stem, form synapses with neurons in the thalamus. There is a reflex connection between neurons in the pons in the superior salivatory nucleus, which results in a cranial parasympathetic outflow that is mediated through the pterygopalatine, otic, and carotid ganglia. This trigeminal–autonomic reflex is present in normal persons34and is expressed most strongly in patientswith trigeminal–autonomic cephalgias, such as cluster headache and paroxysmal hemicrania; it may be active in migraine.Brain imaging studies suggest that important modulation of the trigeminovascular nociceptive input comes from the dorsal raphenucleus, locus ceruleus, and nucleus raphe magnus.
  • Glyceryltrinitrate (GTN) is an alternative name for the chemical nitroglycerin, which has been used to treat angina and heart failure since at least 1870.
  • Approximately half of people with migraine report a + family history (parent). Middle dot = mean, L &amp; R are 95% confidence interval.
  • Total twin sample = 29,717. Heritability overall = 40%!
  • Peter Goadsby, MD, a researcher on this subject said “Cluster headache is probably the worst pain that humans experience. I know that’s quite a strong remark to make, but if you ask a cluster headache patient if they’ve had a worse experience, they’ll universally say they haven&apos;t. Women with cluster headache will tell you that an attack is worse than giving birth. … Many cluster headache sufferers have committed suicide, leading to the nickname &quot;suicide headaches&quot; for cluster headaches”. Cluster headaches often occur at the same time of day each day and are typically brief (15 to 180 min).
  • Participants reported that the symptoms of nitro induced headache and the drug free one were equivalent. There was no evidence of activation of the brain stem (unlike with migraines)!Left: gray matter of hypothalamus. This is on the same side (ipsilateral) as the headache pain. Right: bilateral insula.The insula is a relay of sensory information into the limbic system and is known to play an important part in the regulation of autonomic responses.
  • These headaches were previously known by many terms such as psychogenic headache, stress headache, psychomyogenic headache, or muscle contraction headache. 
  • Males outnumber females from 5:1 or 3.5:1 for cluster headaches.
  • Pathophysiology: Migraine & Headache

    1. 1. Headache & Migraine Brian J. Piper, Ph.D., M.S. October 23, 2012
    2. 2. Goals• Describe differences in symptomology between migraines, cluster headaches, and tension-type headaches.• List the vascular and neural substrates of migraine/headaches.
    3. 3. http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5503a6.htm
    4. 4. Importance • WHO ranks migraine among world’s most debilitating chronic illnesses • 3rd most common reason for ER visits (U.S.) • ≈$13 billion/year in lost productivity (U.S.) • underdiagnosed & undertreatedMenken et al. (2000). Archives of Neurology, 57(3), 418-420.
    5. 5. Migraine Terminology • migraineurs: person who experiences migraines • aura: collection of symptoms that may precede or co-occur; typically visual, lasts less than 1 hour – positive features • scintillations: a rapidly oscillating pattern of visual distortions • photopsia: perception of flashes of light • teichopsia: spot of flickering light – negative features • scotoma: an area of diminished vision within the visual field • hemianopsia: blindness in half of the visual field, may involve one or both eyes – hemiplegic aura: occurring on one side of body – basilar type aura: aura is localized to the brainstemDiPiro et al. (2008). Pharmacotherapy: A Pathophysiologic Approach. p. 1008.
    6. 6. George Cruikshank: The Head Ache (1819)2:20: http://www.mayoclinic.com/health/migraine-aura/MM00659
    7. 7. International Headache Society Migraine Criteria • Migraine with aura (classic migraine) – At least 2 attacks – Aura fulfills criteria for typical aura, hemiplegic aura, or basilar type aura – Not attributed to another disorder • Migraine without aura – At least 5 attacks – Headache lasts 4 to 72 hours (untreated or successfully treated) – Headache has at least 2 characteristics • Unilateral location, pulsating quality, or moderate or severe intensity – Aggravation by or avoidance of routine physical activity (walking, climbing stairs) – During headache, at least one of the following: • Nausea, vomiting, or both • Photophobia and phonophobia – Not attributed to another disorderhttp://ihs-classification.org/en/02_klassifikation/02_teil1/01.00.00_migraine.html
    8. 8. Epidemiology: American Migraine Prevalence & Prevention Study• Mailed Survey to 257K, response by 163K (64.9%) who are representative of U.S. population• Migaine: IHS criteria, Chronic Migraine: >15 days/month over 3 months
    9. 9. Epidemiology: American Migraine Prevalence & Prevention Study• Mailed Survey to 257K, response by 163K (64.9%) who are representative of U.S. population• Migraine: IHS criteria, Chronic Migraine: >15 days/month over 3 months
    10. 10. Epidemiology: American Migraine Prevalence & Prevention Study • Mailed Survey to 257K, response by 163K (64.9%) who are representative of U.S. population • Migraine: IHS criteria, Chronic Migraine: >15 days/month over 3 months • Demographic Correlates – Age (18-49) – Sex (Female) – SES: >$90K = 0.52; <$22K = 2.71; 5.2 fold! • Primary versus Secondary (tumor, infection, stroke)Buse et al. (2012-in press). Headache. doi: 10.1111/j.1526-4610.2012.02223.x
    11. 11. Pathophysiology• limited animal models• theory: genetic (50% heritable) & neurovascular• 2 min: http://www.youtube.com/watch?v=yZr9Joe85wg• orthodromic: electrical potential following typical direction (soma to axon)• antidromic: electrical potential traveling in the reverse direction (axon to soma)
    12. 12. Neural Substrates of Migraine • 1) meningeal vessels • 2) trigeminal: opthalmic nerve (V1)
    13. 13. Neural Substrates of Migraine• 1) meningeal vessels• 2) trigeminal: opthalmic nerve (V1)• 3) pons (input from other structures)• 4) facial nerve
    14. 14. Neural Substrates of MigraineGoadsby et al. (2002). New England Journal of Medicine, 346(4), 257-270.
    15. 15. 5-HT1B: vasoconstriction 5-HT1D: peripheral neuronal inhibitionGoadsby et al. (2002). New England Journal of Medicine, 346(4), 257-270.
    16. 16. Brainstem Activation During Migraine Posterior• 43 year old man with history of migraine without aura• Positron Emission Tomography completed at rest and following nitroglycerin AnteriorBahra et al. (2001). Lancet, 357, 1016-1017.
    17. 17. Migraine Across Countries (Twins)Mulder et al. (2003). Twin Research, 6(5), 422-431.
    18. 18. Genetic Contribution to MigraineMulder et al. (2003). Twin Research, 6(5), 422-431.
    19. 19. Environmental Factorsstresshead and neck infectionhead trauma/surgeryHormone changesaged cheesedairyred winenutsshellfishcaffeine withdrawalvasodilatorsperfumes/strong odorsirregular diet/sleeplight
    20. 20. Cluster Headache • unilateral pain • unilateral other: – ptosis – miosis – rhinorrhoea • circadian • males > females • brief ( < 3 hours) • rareDodick et al. (2001). Cluster headache. Cephalagia, 20(9), 787-803.http://ihs-classification.org/en/02_klassifikation/02_teil1/03.01.00_cluster.html
    21. 21. Hypothalamic & Insular Activation During Cluster Headache • 9 patients with a history of cluster completed PET for regional cerebral blood flow at rest & following nitroglycerinMay et al. (1998). Lancet, 352(9124), 275-278.
    22. 22. Episodic Tension-type Headache (TTH)A. Number of days with such headache < 180/year (<15/month)B. Headache lasting from 30 minutes to 7 daysC. At least 2 of the following: • Pressing/tightening (non-pulsating) quality • Mild or moderate intensity (may inhibit, but does not prohibit activities) • Bilateral location • No aggravation by walking stairs or similar routine physical activityD. Both of the following: • No nausea or vomiting (anorexia may occur) • Photophobia and phonophobia are absent, or one but not the other is presentE. At least 10 previous headache episodes fulfilling these criteriaF. No evidence of organic disease
    23. 23. DSubstrates of TTH V Dorsal Horn: sensory Ventral Horn: motor
    24. 24. Tension-type Headache or Migraine Mild Moderate Severe Aura Unilateral Vomiting Bilateral Photophobia Aggravated by Activity Nausea Throbbing Pressure Tension-Type Migraine
    25. 25. Comparison• Frequency: TTH > Migraine > Cluster• Pain:• Sex Ratio: F > M F>M M>F
    26. 26. Summary • Headache and migraine are common but under-appreciated. • Migraine & headache pathophysiology is an active, but far from complete, area of research.0 to 1.5 min (skip ad): http://www.youtube.com/watch?v=eJZMnXG_Yw0
    27. 27. Medication Overuse Headache• Occurrence of rebound headache following long-term treatment• Identification may take months, may involve transition to prophylactic treatment (e.g. SSRI)Smith & Stonerman (2004). Drugs, 64(22), 2503-2514.

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