Craig Blackwell, MD
Ophthalmology

Santa Cruz, CA
Diplomate: American Board of Ophthalmology
Fellow: American Academy of Ophthalmology

Welcome to the Website of Craig Blackwell, MD

An Ophthalmology Practice in Santa Cruz, CA

Migraine II Mechanism

Historic Mechanism of Migraine

Historic mechanism of Migraine

Explained by Harold Wolff, this explanation is based on the pulsations of the temporal artery observed in some patients with migraine who, after taking Ergotamine, noticed the arterial pulsations and throbbing headache subsided. This scheme was not superceded until improved research tools became available in the 1980’s revealing a much more complicated process involving central nervous system effects.

Working on Current Mechanism of Migraine

Let us be clear at the outset that not all parts of this story are yet clearly understood or agreed upon. Current research is ongoing.

Two things happened to call the above classic model into question. (1) As accurate methods of measuring cerebral blood flow (CBF) became available it was increasingly clear that change in CBF during a migraine attack did not follow the expected pattern. That is, vasodilation and increased blood flow did not correlate with the time course of headache. (2) It was realized that the extent of the visual aura overlapped boundaries of arterial blood supply, therefore aura symptoms could not be caused by vessel constriction.

Cortical Spreading Depression

The first line of evidence for developing a new theory was based on a previous observation of a pattern of electrical activity on the surface of the brain called “cortical spreading depression,” CSD. This is like the passage of a thunderstorm over the prairie. The storm front arrives as a wave of increased electrical discharge that starts out at a particular spot and spreads gradually outward over the cortex, the surface of the brain. After the wave passes electrical activity in the area behind is significantly reduced. The speed and distribution of the change in electrical activity exactly maps the progression of the aura, which is easy to follow with the visual symptoms. This was mapped by one of the researchers who studied his own migraine symptoms.

Cortical Spreading Depression. A wave of intense electrical activity spreads across the surface of the brain traveling 3 to 6 mm per minute. The intense electrical activity at the leading edge likely causes the visual scintillations at the beginning of the aura. After the storm front passes it leaves an area of exhausted nerve cells with depressed electrical activity that are responsible for the missing or dark area of vision, the scotoma.

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Section of Skull and Cortex with Meninges and Blood Vessels

Meninges are the covering layers of the brain. The meninges and their associated blood vessels are among the few pain sensitive structures in the head.

  • Dura: Outer tough layer. Vessels from Meningeal Arteries.
  • Arachnoid: Middle “spidery” layer. Vessels from Cerebral Arteries supply cortex.
  • Pia: Inner layer. Closely covers the surface of the brain. Rich in vascular supply.

Sensory nerves from the blood vessels carry information to the Trigeminal Ganglion. Experimental stimulation of these vessels in humans produces migraine-like throbbing pain. Motor nerves going to the blood vessels control constriction and dilation.

Trigeminal Nerve as Mediator

Side View of Brain and Brain Stem Showing the Likely Route of Pain Mediation Dashed lines denote internal structures.

  • TNG-G: Trigeminal Nerve – Ganglion. (1st order neuron) Receives sensory input including from dural vessels.
  • TNG-NC: Trigeminal Nerve – Nucleus Caudalis. (2nd order neuron) Receives input from TGN-G and relays it to other brain stem nuclei and Thalamus.
  • Thal: Thalamus. (3rd order) Processing and relay to cortical centers.

The second line of evidence came from observing the Trigeminal Nerve (TGN) during an attack in humans and in experiments in animals. The TGN carries sensory input including pain from the face and meninges to the TGN Ganglion, then TGN Nucleus where it is relayed on to the Thalamus and sensory area of the brain.

It is now believed that an initial electrical event in the brain triggers the Trigeminal Nerve which is then responsible for mediating the pain in migraine. Exactly how that happens is under study.

Michael Moskowitz’s research has helped map the role of the TGN from peripheral vascular input from the meninges, to brainstem connections, to final output. It has led to the concept of neuronal inhibition as the method by which Triptans work. Peter Goadsby, in England, has found a role for a potent vasodilator in migraine, CGRP.

Tripans

The third finding, which was to be very significant for developing an effective treatment, was the discovery of the role of Serotonin (5-HydroxyTryptamine, 5-HT), a neurotransmitter with multiple actions in various sites throughout the body. The early link to migraine related to its ability to cause blood vessel constriction.

Researchers had measured reduced levels of Serotonin in migraine sufferers before an attack. That neatly led to the conclusion that a possible factor precipitating a migraine was a decrease in the level of Serotonin which allowed for vasodilation and pain.

Armed with this model researchers set out to find a medication that would mimic the action of Serotonin as a vasoconstrictor. Extensive searching led to identification of Serotonin receptor sites in blood vessels throughout the body. To be useful the chemical they were looking for had to be specific enough that it would activate only receptors in the brain and not in peripheral blood vessels in order to avoid unwanted side effects. In 1984 researchers at Glaxo, lead by Patrick Humphrey, synthesized just such a compound, Sumatriptan (later sold as Imitrex). It became available to patients in Holland in 1991 and the US in 1993. The discovery of the family of Triptans was rated by the American Headache Society as the most important breakthrough in headache medicine in the last 50 years. (Headache 2008, 48;685-687 and Headache 2007, 47 [Suppl 1]:S10-S19 )

There is no doubt Triptans are effective in treating the pain of Migraine. It is an interesting coincidence that it was developed because of its action targeted as a vasoconstrictor agent. However, since the hypothesized cause for pain has changed from vasodilation to Trigeminal Nerve activity attention has turned to investigate alternative actions of Triptans and it is still not exactly clear where they act in migraines. Michael Moskowitz’s research has led to the concept of neuronal inhibition.

Treatments in Development

  • Triptans. Patrick Humphrey spent years investigating Serotonin which led to development of Triptans, the most successful migraine treatment to date. Because aspirin has been shown to block second order processing there is a Triptan-NSAID combination in trials
  • CGRP. Peter Goadsby and others, have found a role for another substance in migraine, CGRP, a potent vasodilator of dural and cranial vessels. Trials of CGRP blockers are underway showing a high rate of success which is particularly interesting because they have no vasoconstrictor activity.
  • Tonabersat, a new antiseizure mediation thought to block CSD, is in clinical trials.

Summary of Migraine Model

1- Susceptibility to Migraine is inherited. Current speculation suggests that probably comes from more than one defective ion pathway which may result in abnormal cortical sensitivity.

2- Serotonin levels fall in a migraine patient, possibly before the actual episode. Whether there is a causative relation is unclear.

3- The trigger, whatever it is, sets off Cortical Spreading Depression. If it is on the surface then it causes an aura. If there is no aura the electrical storm may still occur, but under the surface where is does not produce recognizable symptoms. Less that 30% of migraineurs experience aura.

4- The electrical discharge triggers the Trigeminal Nerve which mediates headache pain by a mechanism yet to be confirmed. It could be action on the pain centers of the brain or on meningeal blood vessels.

5- Triptan medications, like Sumatriptan, imitate Serotonin in suppressing the pain signals from the Trigeminal Nerve (peripheral at the dura and central at the TGN nucleus), thus relieving the headache. The vasoconstrictor effect cannot be excluded as possibly helpful.

6- The beneficial effect of CGRP blockers is going to force reexamination of the expected mechanism of headache.

This is as far as we go on solid ground. If you are interested in more details and proposed actual anatomic connections see the following:

Migraine Mechanism More Details, Bonus Material.

What is Missing?

  • Mechanism of susceptibility to migraine. Postulated to be inherited ion transport defect.
  • Trigger mechanism for CSD.
  • Explain conflicting findings about the role of Serotonin.
  • Common migraine doesn’t have aura while ocular migraine has no headache. Account for the several manifestations of migraine.
  • Cause of headache pain. Vasodilation, TNG activation and projection to higher centers, or abnormal sensitization of the cortex?

References

There are several review papers that provide excellent detailed information.

  1. Migraine, Current Understanding and Treatment. New England Journal of Medicine 2002.Vol.346, No.4,P.257-270. By Peter Goadsby, Richard Lipton and Michel Ferrari.
  2. Intrinsic Brain Activity Triggers Trigeminal Afferents. Nature Medicine 2002. Vol.8, No.2, P.136-142. Bolay et al, with senior author Michael Moscowitz. Available on line.
  3. CGRP Antagonist BIBN 4096 BS for the Acute Treatment of Migraine. New England Journal of Medicine, 2004; Vol 350. P. 1104-10. Available on line.
  4. Recent Advances in Understanding Migraine Mechanisms. Trends in Molecular Medicine, 2006, Vol. 13, No. 1, P. 39-44. By Peter Goadsby.
  5. Discovery of a new Drug Class for the Treatment of Migraine. Headache, 2007. Vol. 47, Suppl 1: S10-S19. By Patrick Humphrey.

The 50th anniversary issue of Headache contains several review articles of historical interest authored by the lead scientists. They are available on line.

  1. American Headache Through the Decades: 1950 to 2008. Headache, 2008. Vol. 48. P. 671-677. Authors include Seymour Diamond, MD.
  2. The Discovery and Development of the Triptans, a Major Therapeutic Breakthrough. Headache, 2008. Vol. 48. P.685-687. By Patrick Humphrey.
  3. Defining a Pathway to Discovery from Bench to Bedside: The Trigeminovascular System and Sensitization. Headache, 2008. Vol. 48. P.688-690. By Michael Moscowitz.

CBlackwell-Oct 2008