1. Multi-mechanisms in Migraine
Recent Advances in Pathophysiology and Diagnosis
Frank O’Donnell D.O.

2. Migraine Presentation: Contents
Impact of migraine & what patients want from treatment
Pathophysiology – Migraine is a multimechanistic disease
In-depth look at the multiple mechanisms of disease at a cellular level
Inflammation
Vasodilation & edema
Activation of pain receptors
Peripheral & central sensitization
Referred pain
Summary animation
Resulting insights into diagnostic accuracy
To understand migraine, one must examine several factors. These include the impact of migraine and a patient’s desires for treatment. Also, one must understand the pathophysiology, in that migraine has multiple mechanisms. During this presentation, we will review in-depth the pathophysiology of migraine and discuss how inflammation, vasodilation, edema, pain receptor activation, and peripheral and central sensitization are all involved during an acute migraine attack. This will then be summarized through an animation video that presents the pathophysiology of a migraine attack- including what occurs before pain is felt by the patient.

3. Migraine Presentation: Key Points
Migraine is a multimechanistic disease
Several separate processes are involved leading up to the sensation of pain including:
Vasodilation
Inflammation
Edema
Nociception (activation of pain receptors)
Pain is experienced long after these mechanisms are in place
Peripheral and central neuronal sensitization lead to more refractory migraines
Current treatments may not adequately address all of these multiple mechanisms
Understanding the multiple presentations of migraine can improve diagnostic accuracy
The key points we will review explain how migraine is a multimechanistic disease including how several separate processes lead up to the sensation of pain. These processes include vasodilation, inflammation, edema, and activation of nociceptors (pain receptors). Important to note that initial pain is experienced by the patient long after initiation of these activities. The continued activation of these processes leads to peripheral and central neuronal sensitization which may result in more refractory migraines. At this time, current treatments may not adequately address all of these multiple mechanisms. In addition, acknowledging the multiple presentations of migraine can improve diagnostic accuracy.

4. Impact of Migraine & What Patients Want from Treatment

5. Prevalence: The Impact of Migraine
Currently 28 million migraine sufferers age 12+ in the United States
21 million females
7 million males
Migraine prevalence peaks in the age group
25% of women age suffer from migraine
1 in 4 households has at least 1 migraine sufferer
Migraine is a very common disorder. Data from the 1999 American Migraine Study II, a US population-based survey, demonstrate that the 1-year prevalence of migraine was 18.2% among females and 6.5% among males (or approximately 12% overall). Projected to the US population, these numbers translate to 28 million migraine sufferers (21 million females and 7 million males) ages 12 and older in the United States.
In both females and males, the prevalence of migraine peaks during the ages of 25 to 55 – that is, the most productive years of the life span.
Migraine touches the lives of practically everyone: 1 in 4 households in the United States has at least 1 migraine sufferer.
Reference
Lipton RB, Diamond S, Reed M, et al. Migraine diagnosis and treatment: results from the American Migraine Study II. Headache. 2001;41:
Lipton RB et al. Headache. 2001;41:

6. What Patients Want from Treatment
Top 5 patient treatment desires1
Have relief from pain
Avoid recurrences
Quick symptom relief
Minimal side effects
Return to normal activities
Current therapies fall short on patient satisfaction for these desires
25-35% non-responders in clinical trials
less then 2/3 of patients respond 3/3 attacks
Survey results show that, migraine patients desire to have pain relief, while avoiding recurrences. They want their treatment to deliver quick symptom relief with minimal side effects. Ultimately, patients desire to return to their normal activities. Current therapies, however, fall short on patient satisfaction for these desires.
Reference
Lipton RB and Stewart WF. Acute migraine therapy: Do doctors understand what patients with migraine want from therapy? Headache. 1999;39(Suppl 2):S20-S26.
Lipton, et al. Headache. 1999;39(Suppl 2):S20-S26.

7. Triptan non-responders
HA intense at baseline
Severe nausea and vomiting
Less autonomic signs
Less menstrual influence
Onset at early age
High body mass index
Increased anxiety

8. Why Patients Fail Not able to treat early
Low and inconsistent oral absorption
Unrecognized analgesic overuse
Medical and psychiatric co-morbidities
5HT receptor polymorphisms

9. Migraine Pathophysiology
A thorough understanding of migraine pathophysiology is helpful for the development of treatment innovations.

10. Migraine Activity May Start in the Cortex
The cerebral cortex is the outer layer of the brain, consisting of nerve cells and the pathways that connect them. This extensive gray matter mass is largely responsible for sensation, voluntary muscle movement, thought, reasoning, and higher brain functions such as memory.
Triggers Lead to Cortical Spreading Depression (CSD) – Click to Play CSD
Cortical hyperexcitability forms the basis of migraine susceptibility.1 The onset of migraine can be initiated by a variety of internal and external triggers, which may lead to cortical spreading depression.3 Cortical spreading depression is a wave of depolarization that propagates slowly across the cortex, depressing neuronal activity for a few minutes and transiently reducing cerebral blood flow.3
References
1. Welch M. et al. Brain Hyperexcitability: The basis for antiepileptic drugs and migraine prevention. [Review]. Headache Apr; 45 Suppl 1:S25-32.
2. Van den Maagdenberg AM et al. A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. Neuron Mar 4;41(5):
3. Lauritzen M. Pathophysiology of the migraine aura: the spreading depression theory. [Review]. Brain. 1994; 117:199–210.

11. CSD Stimulates Trigeminal Sensory Fibers (TSF)1
Trigeminal nerve fibers in the
meningeal blood vessel 2 3
Cortical spreading depression is further believed to stimulate the central nervous system and initiate a cascade of events, including the activation of trigeminal sensory fibers surrounding cerebral and meningeal blood vessels.1,2
References
1. Bolay H., Reuter U, Dunn AK, et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nature Medicine. 2001;8(2):
2. Williamson DJ, Hargreaves RJ. Neurogenic inflammation in the context of migraine. Microsc Res Tech. 2001;53(3):

12. Release of CGRP, substance P & Inflammatory Cytokines4 2 3 1 5 6
During activation of trigeminal sensory fibers surrounding cerebral and meningeal blood vessels, the stimulated nerve fibers release a variety of inflammatory and vasodilatory neuroactive substances, such as calcitonin gene related peptide (CGRP), substance P, NO, and cytokines.1,2
References
1. Bolay H., Reuter U, Dunn AK, et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nature Medicine. 2001;8(2):
2. Williamson DJ, Hargreaves RJ. Neurogenic inflammation in the context of migraine. Microsc Res Tech. 2001;53(3):

15. Arachidonic Cascade Results in Prostaglandins
Kinins facilitate the production of Cyclooxygenases
Cyclooxygenases convert arachidonic acid to prostaglandins 1 2 3
The release of the inflammatory neuroactive substances results in a secondary inflammatory response, which includes the production of prostaglandins through a conversion of arachidonic acid by cyclooxygenase.1
Reference
1. Woolf CJ. Pain: Moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140:

16. Vasodilation and Edema in Local Blood Vessels
CGRP and prostaglandins cause inflammation and vasodilation of cerebral and meningeal blood vessels as well as surrounding tissue
CGRP and the inflammation caused by prostaglandins in turn act upon local blood vessels causing vasodilation and edema.1
Reference
1. Waeber C, Moskowitz MA. Therapeutic implications of central and peripheral neurologic mechanisms in migraine. [Review]. Neurology Oct 28;61 (Suppl 4):S9-20.

18. Activation of Nociceptors
The inflammation and edema activate peripheral meningeal pain receptors called nociceptors
These responses activate peripheral meningeal pain receptors called nociceptors, which then transmit the signals to the trigeminal ganglion and centrally to the trigeminal nucleus caudalis (TNC).1,2
References
1. Silberstein SD. Cephalalgia. 2004; 24(suppl 2):2-7.
2. Bolay H et al. Nature Medicine. 2002;8:
Nociceptors transmit signals to the trigeminal ganglion and the TNC

20. Review: Anatomy of the Trigeminal Nerve
The three divisions of the trigeminal nerve come together in an area called the Gasserion ganglion (also the trigeminal ganglion). 
From there, the trigeminal nerve root continues back towards the side of the brain stem, and inserts into the pons. Within the brain stem, the signals traveling through the trigeminal nerve reach specialized clusters of neurons called the trigeminal nerve nucleus, or trigeminal nucleus cordalis (TNC). Information brought to the brain stem by the trigeminal nerve is then processed before being sent up to the thalamus and cerebral cortex, where a conscious perception of facial sensation is generated.

22. TNC Transmits Pain Signals to Thalamus & Cerebral Cortex
Patient first experiences the sensation of pain
From the TNC the signals travel to higher brain centers, including the thalamus and cerebral cortex.1 When the signal reaches the cerebral cortex the patient first experiences the sensation of pain.2
References
1. Goadsby PJ. Silberstein SD, Lipton RB, Dalession DJ eds. Pathophysiology of Headache in Wolff’s Headache and Other Pain. 7th ed. Oxford: Oxford University Press; 2001:62.
2. Hargreaves RJ, Shepheard SL. Pathophysiology of migraine – new insights. Can J Neurol Sci. 1999;26(suppl3):S12-19.

23. Multiple Mechanism Prior to Pain Perception
Click to Play Animated Summary
Quick Review Multiple Mechanism in process prior to pain perception
Release of neuroactive substances
Initiation of arachidonic cascade
Vasodilatation and edema
Activation of nociceptors
Signals transmit centrally to TNC
Signals travel to higher brain centers, including the thalamus and cerebral cortex
Thus, the multiple mechanisms of migraine are set into motion prior to pain perception, beginning long before most patients take their medication.

24. Consequences of Sustained Pain Transmission
Continuous stimulation of the trigeminal ganglion
Activation of the TNC
Activation of the surrounding glial cells
Peripheral sensitization is a reduction in threshold and an increase in responsiveness of the peripheral nociceptors.1
Following peripheral sensitization, continuous stimulation of the trigeminal ganglion results in activation of the TNC and surrounding glial cells.2
References
1. Burstein R, Jakubowski M. Implications of multimechanism therapy: when to treat? [Review]. Neurology. 2005;644(10 Suppl 2):S16-20.
2. Bolay H, Reuter U, Dunn AK, et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nature Medicine. 2001;8(2):

26. Glial Cells
Glial cells are now thought to have neuronal modulatory activity
Glial cells, which surround neurons and were previously believed only to provide nutritional support, are now believed to also play a role in neuronal modulation.
Reference
Watkins LR, Milligan ED, Maier SF. Spinal cord glial: new players in pain. Pain ;93:

27. Glial Cells Release Prostaglandin
Independent of signals from trigeminal ganglion
Once activated, glial cells release prostaglandins. These prostaglandins are believed to contribute to the stimulation of the TNC independent of signals from the trigeminal ganglion.1,2
Reference
1. Watkins LR, Milligan ED, Maier SF. Glial activation: a driving force for pathological pain. TRENDS in Neuroscience. 2001;24(8):
2. Wiesler-Frank J, Maier S, Watkins LR, et al. Glial activation and pathological pain. Neurochemistry International. 2004;

28. Prolonged TNC Stimulation May Lead to Central Sensitization
Prolonged stimulation of the TNC results in continuous firing by the TNC independent of any signals coming from the periphery; this creates a self-sustaining loop called central sensitization.1 The presence of central sensitization is associated with more refractory, harder-to-treat migraines where a sustained pain-free response is harder to achieve.2
References
1. Woolf CJ. Pain: Moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med. 2004;140:
2. Levy D, Jakubowski M, Burstein R. Disruption of communication between peripheral and central trigeminovascular neurons mediates the antimigraine action of 5HT1B/1D receptor agonists. PNAS 2004;101(12):
Cutaneous allodynia is a marker for central sensitization, which when present during a migraine, may make the migraine episode more difficult to treat
A sustained pain-free response is harder to achieve

30. Symptoms of Central Sensitization
Combing hair
Pulling hair back (ponytail)
Shaving
Wearing eyeglasses
Wearing contact lenses
Wearing jewelry
Wearing snug clothing
Using a heavy blanket in bed
Allowing shower water to hit the face (“it feels like pins and needles”)
Resting the face on the pillow on the migraine side
Rubbing back of neck
Cooking (“the heat is too much”)
Breathing through the nose on cold days (“it burns”)
Patients often avoid 1 or more of the following activities because of cutaneous allodynia
References
Burstein R, Yarnitsky D, Goor-Aryeh I, Ransil BJ, Bajwa ZH. An association between migraine and cutaneous allodynia. Ann Neurol. 2000;47:
Burstein R, Cutrer MF, Yarnitsky D. The development of cutaneous allodynia during a migraine attack: Clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain. 2000;123:
Burstein R et al. Ann Neurol. 2000;47:
Burstein R et al. Brain. 2000;123:

31. TNC Activation Results in Referred Pain
Pain can be referred to any of three branches of the trigeminal and/or cervical nerves & thus pain can be perceived on one or both sides of the head, around the eyes or sinuses, and in the posterior area of the head and neck.
Activation of the TNC may also result in referral of pain to various locations along the trigeminocervical network including the 3 branches of the trigeminal nerve: ophthalmic branch (V1), the maxillary branch (V2), and the mandibular branch (V3) as well as the sensory nerves for the posterior head and neck (C2, C3, and C4).1
Pain may be perceived on one or both sides of the head, around the eyes or sinuses, and in the posterior area of the head and neck.
Reference
1. Messlinger K, Dostrovsky J, Strassman A. Anatomy and Physiology of Head Pain. In: The Headaches. 3rd ed. Lippincott, Williams, Wilkins; 2006.

32. Cranial Parasympathetic Activation
Activated TNC can stimulate superior salivatory nucleus causing parasympathetic activation
Parasympathetic activation can cause sinus-like symptoms during a migraine attack
Through connections with the superior salivatory nucleus, activation of the TNC may additionally cause reflex cranial parasympathetic activation.1,2 Cranial parasympathetic activation can result in sinus-like symptoms such as rhinorrhea, congestion and lacrimation.1,2
References
1. Bolay H., Reuter U, Dunn AK, et al. Intrinsic brain activity triggers trigeminal meningeal afferents in a migraine model. Nature Medicine. 2001;8(2):
2. Cady RK. Schreiber CP. Sinus headache or migraine? Considerations in making a differential diagnosis. Neurology. 58(9):1-9.
Need to quote Bolay

35. Multiple Mechanisms of Migraine
Cortical spreading depression
Vasodilation
Inflammation
Nociception
Peripheral sensitization
Central neuronal sensitization
Referred pain
Thus, the pathophysiology of migraine is now believed to involve multiple mechanisms such as cortical spreading depression, vasodilation, inflammation, nociception and peripheral as well as central neuronal sensitization.

36. Animation

37. Pathophysiology: Key Points
Migraine is a multimechanistic disease
Several separate processes are involved leading up to the sensation of pain including
Vasodilation
Inflammation
Edema
Nociception (pain receptors)
Pain sensation is experienced long after these mechanisms are in action
Multiple mechanisms must be addressed
Migraine is a multimechanistic disease and the pathophysiology involves several separate processes leading up to the sensation of pain. These include vasodilation, inflammation, edema, and nociception. Recall that pain sensation is experienced long after these mechanisms are already set into action and that these multiple mechanisms must be addressed to meet a patient’s needs.

38. Conclusions
There are 28 million migraine sufferers in the United States
Migraine is a multimechanistic disease
Vasodilation
Inflammation
Nociception
Peripheral sensitization
Central neuronal sensitization
Referred pain
Current therapies fall short on addressing all of these mechanisms
A thorough understanding of migraine pathophysiology may explain why many patients are misdiagnosed
As sinus headache: due to symptoms like sinus congestion, rhinorrhea and sinus pain
As tension headache: due to symptoms like non-throbbing bilateral, posterior head and/or neck pain
In summary, migraine remains underdiagnosed in the United States, where only about half of the 28 million migraineurs have been diagnosed. Migraine continues to be underdiagnosed both because of failure to recognize it and because of misdiagnosis of migraine as another headache type. Many of the undiagnosed migraineurs have been diagnosed with tension or sinus headache because of the presence of symptoms such as bilateral pain, non-throbbing pain, and posterior head and neck pain, in addition to the traditional symptoms of migraine. Studies show that these symptoms are common in migraine and may explain why migraine is sometimes misdiagnosed as tension headache.
In order to be treated effectively, headaches need to be diagnosed accurately. In migraine, achieving a pain-free outcome is the top treatment goal of patients.

40. Back Up Slides