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 recently 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 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 duraplasty improved CSF flow at the foramen magnum in all patients. This, along with other observations made in the same study, indicated that successful treatment should not require entering the spinal cord al all. 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. 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. In a series of experiments, we have shown that two new approaches, a ferrous iron chelator and intracarotid infusion of a nitric oxide (NO) donor, reverse and prevent vasospasm after subarachnoid hemorrhage in primates. The intracarotid route of NO donor delivery was chosen after success with ICA delivery, but failure of intravenous infusion, of the NO donor to reverse or prevent vasospasm in primates. We are preparing a pilot clinical study of intracarotid infusion of the NO donor in humans for reversal/prevention of cerebral vasospasm after rupture of an aneurysm. Recently, we have shown in a primate model of SAH and in patients who had ruptured intracranial aneurysm a strong association of CSF levels of an endogenous nitric oxide inhibitor (ADMA) with the course of cerebral vasospasm after SAH. To further our understanding pathophysiology of vasospasm after SAH we study mechanism of endothelial dysfunction in vivo and the influence of oxidized bilirubin products (BOXes) on levels of ADMA and the effect of purported inhibitors of ADMA in vitro. 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. This effect was comparable to the use of a new oxygen free radical scavenger (stable nitroxide, Tempol). In the rabbit model, we observed a decrease of oxygen free radical levels in response to intracarotid infusion of proliNO at the time of r-tPA-induced reperfusion. We continue to study influences of the NO donor in in vitro and in vivo chronic experiments to further our understanding of mechanism(s) of cellular protection against ischemia that NO may be involved (for instance preconditioning to lethal ischemia).