Treating Chiari With A Prescription?

July 31, 2007 - In the first article I wrote for this newsletter in February 2006, I discussed what it would take going forward into the future to develop a drug for treating Chiari. In that article, I stressed the importance of understanding the pathogenesis of the disease and suggested that two possible approaches existed. The first approach suggested was to understand the origin of the anatomical malformation and then to design a pharmacological intervention to prevent its genesis. The second approach was to understand the small anatomical changes that apparently occur with or near the malformation later in life that results in the emergence of symptoms and then to design a pharmacological approach to inhibit those changes. I want to go back to the future now in this article to review the progress against these strategies which has occurred in the last year and a half. Specifically, I will discuss two landmark presentations connected to these approaches which were given at this year's Conquer Chiari symposium that took place at the University of Illinois, Chicago, on June 2nd.

In my February 2006 article, I talked about the theory of differential growth rates between the skull and brain as well as the theory of differential pressures between the skull and spinal column in the developing fetus. The theory of differential growth rates implies that the skull begins to grow first but fails to grow to its full volume forcing the growing hindbrain to protrude into the spinal canal. The theory of differential pressures implies that fetal spinal tissue fails to close completely resulting in a pressure gradient that essentially sucks the hindbrain into upper spinal column. Both of these theories are based on anatomical observations upon the autopsies of developing human fetuses and animal embryos. These anatomical observation data sets were the best available data but data that none the less can be misleading as longitudinal tissue development data is inter-subject and intra-subject dependent. In other words, anatomical development data at one week comes from one subject while anatomical development data at 2 weeks comes from a different subject and assumptions have to be made as to what tissue develops or differentiates into new tissue. The problem is akin to tadpole development. Supposed we lived in the distant future where frogs have long since been extinct but we had access to fossils. We would see different types of fossils. We would have a set of fossils that looked like fish and we would see some that are small and some that are larger. We would also have a set of fossils that appear to be lizard-like with tails and feet and some of these would be small and others larger. We would also have a set of fossils that appear to be frogs and some would be small and others larger. Given these fossil sets and our absence of direct knowledge or experience at watching tadpoles develop into frogs, we would likely conclude that we have three different animals - small fish that grow into larger fish, small lizards that grow into larger lizards, and small frogs that grow into larger frogs. However, we would be wrong. We would fail to recognize that the small tadpoles that look like small fish actually evolve or transform over time into frogs because we would not have a complete longitudinal data set for a single developing subject.

At the June symposium, Dr. Georgy Koentges of the University of Warwick, presented findings on the stem cell origin of structures of the neck and shoulders in vertebrates using a modern genetic labeling technique. Dr. Koentges showed that the long time held belief that the Chiari malformation was a result of a defect in the development of mesoderm is probably not true and that it is more likely a defect in the development of cells in the dorsal segment of the post-otic neurocrest close to the nervous system.

So what does this mean or imply? It means that our previous understanding for the development and differentiation of fetal tissue leading to a Chiari malformation is probably wrong, illustrating once again the weakness in data derived at different points in time and from different subjects. The good news however is that we know more specifically what fetal tissues develop into a Chiari malformation and with that information techniques are available to trace the path back all the way to a specific defect in the DNA. While this will take a few more years, it is likely to be a reality in the future and with this knowledge we will then be able to determine how this genetic defect occurs and if something can be done to prevent it.

In February of 2006, I also talked about developing a drug to inhibit anatomical changes leading to the emergence of symptoms. The first step in this process is to determine what anatomical changes occur that lead to symptoms. I suggested several theories such as thickening of the dural band, the formation of intradural adhesions, and cranial/spinal settling. However, before these changes can be determined, we must first be able to find a sign or signal that can be objectively measured which reliably differentiates between Chiari patients with and without symptoms. To date, anatomical MRI has failed to achieve this. In February 2006, I mentioned Cine MRI as a diagnostic variant to anatomical MRI. However, it too has failed to reliably distinguish between patients with and without symptoms. More recently however, and as presented at the symposium in June by Drs. Terry Lichtor and Noam Alperin of the University of Illinois, Chicago, a refinement of Cine MRI can be used to measure a parameter called dural compliance. This is a ratio in the change of volume to the change in pressure. When I first heard this over a year ago, it made no sense to me because the volume of the skull is fixed and can not change. However, that is not exactly true. While the skull is fixed, there is some room between the dura and skull. At any one point the available volume is small, but the additive effect around the entire surface of the dura is considerable. At any rate, preliminary measures presented on dural compliance show great promise in the technique's ability to distinguish between symptomatic and asymptomatic patients. An important implication of this work is that a new theory is introduced which is one that has to do with the elasticity of the dura tissue itself. It could be that the dura stiffens with age and this stiffening together with compromised flow at the foramen magnum may be the combination required to give rise to symptoms. Additional studies are now planned with government funding to refine this exciting technique. Once in place, a much needed screen will be available to identify patient groups for further more specialized imaging techniques which may lead to identifying the small anatomical changes that give rise to symptoms. Again, it will be a few years before these anatomical changes can be identified, but once they are we can begin to think about approaches to intervene in their genesis.

We certainly have a long way to go but we have also made terrific progress in just 18 months. Again, I encourage readers to consider making a donation to the Conquer Chiari research fund which provided support for the MRI compliance work and is now providing support to Dr. Koentges. Further, I encourage all readers to view the proceedings of the symposium and to ask their doctors to view it. Perhaps our biggest challenge is to first increase awareness of Chiari and destroy many of the myths about it in the medical community as a variant of normal without clinical consequences.

Ed. Note: The opinions expressed above are solely those of the author. They do not represent the opinions of the editor, publisher, or this publication. Mr. D'Alonzo is not a medical doctor and does not give medical advice. Anyone with a medical problem is strongly encouraged to seek professional medical care.