Peter Goadsby, MBBS: If you look at the plasma CSF [cerebrospinal fluid] ratios, you see that the IgG [immunoglobulin G] is about 1000, but concentration is in the blood. You’ll also see that there’s a range. And there are, where this is being measured, a distribution of about 1 in 300 within the CSF of IgG, that you would inject in the periphery. I agree that most of it doesn’t get there, but I don’t know how much is enough. I know for a fact that there’s a variation in the absorption. I think we ought to keep on the table the possibility that some part of the enormous variation we’re seeing in the clinical outcomes may have something to do, among other things, with distribution. I don’t think the last word has been written, however.

Stephen Silberstein, MD: What about the aura that occurs in the brain?  

Stewart Tepper, MD: From a neurology standpoint in practice, it’s always worth emphasizing that aura does not clinically accompany every attack of migraine or occur in every patient. It probably only occurs in between 20% and 30% of patients.

I want to go back to what David said about the glutamatergic common final pathway that appears in a lot of what we know about the genetics of migraine—that there is too much glutamate in the synapse and not enough glutamate taken back up; it’s a pump failure with respect to glutamate, which is more readily available post-synaptically. What we know about aura is that the portal to aura is the primary activation of the NMDA [N-methyl-D-aspartate] glutamate receptor.

In fact, CGRPs [calcitonin gene-related peptides] do have a role in enabling the NMDA glutamate receptor at the cortical level. It is interesting to think about future targets with respect to aura in terms of having antiglutamate effects. We frequently use, for example, magnesium, which plugs the NMDA glutamate receptor. We use partial NMDA glutamate antagonists such as memantine [Namenda] and dextromethorphan [DayQuil] to work on aura. What’s most interesting to me about the monoclonal antibodies has been what appears to be equal effectiveness in preventing migraine with and without aura. That suggests again that migraine may be migraine, and there may be more commonalities than we initially thought.

Stephen Silberstein, MD: It’s exciting that people have made a monoclonal antibody against the NMDA receptor. They then looked at the protein sequence of the epitope and created a small peptide that goes to the NMDA receptor, blocks it, and goes through the blood-brain barrier; this is in clinical trials. Now for depression, it’s extraordinarily interesting to see if that blocks the aura and proves your hypothesis.

When we grew up a thousand years ago, migraine was a vascular disorder; the aura was due to vasoconstriction, and the headache was due to reactive vasodilation. Now that’s gone. We’ve invented the trigeminal vascular system believing it would be an interaction between the nerves and the blood vessel. The trigeminal vascular system actually interacts with the brain. It may turn out you cannot have migraine pain without the trigeminal vascular system, and you cannot have migraine pain if the brain’s not properly filled. So I think it’s not A versus B—it’s both; they’re systems that interact with each other, and it’s the defective interaction of the system that results in migraine.