Syringomyelia, a cyst in the spinal cord, causes progressive paralysis in affected patients, including patients in childhood and early adulthood. Because the mechanism underlying the development and progression of syringomyelia has been unknown, there are a variety of current therapies, including surgery to open the spinal cord and the placement of drainage systems into the spinal cord. Understanding the mechanism causing syringomyelia may permit the identification of treatment that is more effective and less invasive. The purpose of this study is to establish the mechanism(s) of the progression of syringomyelia. A clinical study elucidating the basis of syringomyelia associated with the Chiari I malformation was completed in which the mechanism was shown, paradoxically, to be one that is outside the spinal cord by the following mechanism. The cerebellar tonsils and the brainstem act on a partially enclosed spinal subarachnoid space to generate enlarged cervical subarachnoid CSF pressure waves. These waves compress the spinal cord from without, not from within, as had previously been considered to occur, to propel the syrinx fluid downward with each heartbeat. Syrinx progression occurs as a consequence. Craniocervical decompression and duroplasty improved CSF flow at the foramen magnum. Successful surgery, by a procedure that does not invade the nervous system, eliminated the anatomic cause of the excess pressure waves and resulted in consistent resolution of syringomyelia. The demonstration of this mechanism should result in less invasive surgery and more effective treatment for this form of progressive paralysis. In a related study (Protocol 92-N-0226), we are continuing to evaluate and treat subjects with Chiari I-type syringomyelia but who have had unsuccessful surgery elsewhere. In these subjects we have found that previous surgery failed because it did not relieve the obstruction of the cerebrospinal pathways at the foramen magnum that resulted in enlarged cervical subarachnoid CSF pressure waves. Surgical revision of the previous craniocervical decompression and duroplasty has been effective in opening CSF pathways, reducing CSF pressure waves, and resolving syringomyelia. In another clinical study (Protocol 01-N-0085) we are studying primary spinal syringomyelia, a type of syringomyelia not associated with Chiari I malformation. A preliminary finding is that obstruction of the spinal subarachnoid space in primary spinal syringomyelia is associated with enlarged CSF pressure waves superior to the obstruction. Successful surgery for primary spinal syringomyelia opens CSF pathways, reduces CSF pressure waves to normal, and resolves syringomyelia, as had successful surgery in our studies of Chiari I-type syringomyelia. This association suggests that primary spinal syringomyelia and Chiari I-type syringomyelia arise from a similar mechanism. The process by which the Chiari I malformation develops is unknown. Ectopia of the cerebellar tonsils, which is the defining characteristic of the Chiari I malformation, may result because the posterior fossa does not develop to a normal size and is too small to accommodate a cerebellum of normal size. In a clinical study of families with multiple members affected by the Chiari I malformation (Protocol 00-N-0089), we are using MRI scans of the brain to evaluate for Chiari I malformation and to measure the size of the osseous structures and volume of the posterior fossa. After phenotyping family members as being affected or unaffected by these traits, we collect DNA specimens from them for genotyping. Genotyping has recently been completed at the Center for Inherited Disease Research and linkage analysis will be performed over the next few months. Finding a genetic locus for the Chiari I malformation would lead to a better understanding of the etiology of the Chiari I malformation, which may lead to ways to prevent its development. Clinical and laboratory investigation of central nervous system vascular disorders: Delayed cerebral vasospasm is the most common cause of death or disability in patients with subarachnoid hemorrhage who survive to reach the hospital. We have investigated the mechanism of delayed vasospasm and examined new approaches for therapy of it. We have demonstrated the presence of nitric oxide synthase-based dysfunction of the endothelium in a primate model of vasospasm. To further our understanding pathophysiology of vasospasm after SAH we studied the mechanism of endothelial dysfunction in vitro examining the influence of oxidized bilirubin products (BOXes) on production of ADMA and the effect of inhibitors of ADMA production. Unfortunately, Probucol an inhibitor of ADMA production in vitro did affect ADMA levels in plasma nor prevent vasospasm in a primate model as it did not penetrate blood-brain barrier. We plan to examine the levels of ADMA in CSF of patients after aneurysmal SAH. Treatment of cerebral vasospasm after subarachnoid hemorrhage. On the basis of our recent observation that nitrite acts as NO donor, we have shown that intravenous long-lasting infusion of sodium nitrite prevents vasospasm after subarachnoid hemorrhage in primates. A clinical protocol to study intravenous nitrite infusion in normal volunteers to establish its safety and effective dose has been submitted to the IRB. With the use of thrombolytic therapy for ischemic stroke, reperfusion injury has become an important issue, as it appears to underlie the risks associated with delayed treatment. We have shown that an intracarotid infusion of proliNO (a Nitric Oxide donor) a) quenches oxygen free radical production and b) reduces the volume of brain infarction in a rat model of global transient cerebral ischemia. Furthermore, in acute experiments with the rat model, we observed a significant decrease of stroke volume after intracarotid infusion of proliNO or an oxygen free radical scavenger Tempol. We continue to study influences of the NO donor in the in vitro experiments to further our understanding of mechanism(s) of cellular protection against ischemia.
Showing the most recent 10 out of 34 publications
