Medically Intractable Epilepsy

Martin E. Weinand, MD
Section of Neurosurgery

My research activity is primarily concerned with medically intractable epilepsy. I have also produced research in collaboration with other neuroscientists in the areas of clinical neurosurgery and blood-brain-barrier pathophysiology. Among the most significant of these works was a study of long-term cortical cerebral blood flow in temporal lobe epilepsy. This clinical project showed that progressive hypoperfusion of the epileptic temporal lobe correlates with increased epileptogenicity (i.e. increased seizure frequency). It was discovered and reported that the relationship between epileptic (CBFe) and nonepileptic (CBFn) cortical cerebral blood flow is the inverse of normal (i.e. CBFe and CBFn are correlated in a negative, linear fashion). It was concluded that because cerebral blood flow alterations precede electrocorticographic seizure activity, vasomotor changes may produce electrical and clinical seizure onset. This work was separately peer-reviewed by the official on-line and print journals of the American Association of Neurological Surgeons. Subsequently, my research into cerebral blood flow (CBF) abnormalities in epilepsy emphasized the role of nonepileptic CBF in temporal lobe seizures.

My next major clinical study supported the hypothesis that human temporal lobe epileptogenicity (i.e. seizure frequency) depends on perfusion of nonepileptic cortex. Increasing nonepileptic CBF was shown to be associated with increased seizure frequency. It was theorized that this may be due to a redistribution of CBF from epileptic to nonepileptic cortex. It was concluded that future therapeutic strategies designed to reduce nonepileptic cortical perfusion should produce reduction in temporal lobe epileptogenicity. This paper was published in the official journal of the International Pathophysiology Society.

After concluding studies of epileptic and nonepileptic cortical perfusion, I focused my research activities on developing mathematical models of temporal lobe epilepsy. This research produced the Vascular Steal Model of temporal lobe epileptogenicity. The model suggested that a small CBF redistribution from non-epileptic to epileptic cortex should produce substantial reduction in temporal lobe seizure frequency in association with prolongation of the electrocorticographic interhemispheric propagation time (IHPT). The hypothesis of this mathematical model that IHPT, a clinical correlate of epileptogenicity, depended upon cerebral perfusion was confirmed with a subsequent clinical study. Long-term combined subdural EEG and CBF monitoring showed that IHPT was a nonlinear function of nonepileptic cortical cerebral blood flow. It was suggested that, in temporal lobe epilepsy, nonepileptic cortical hypoperfusion may represent a protective mechanism for delaying seizure interhemispheric propagation. It was concluded that since IHPT decreased exponentially with increasing CBFn then small increases in CBFn should substantially reduce IHPT and increase epileptogenicity.

Other recent major research accomplishments have included the identification of three electrocorticographic factors associated with temporal lobe epileptogenicity, the discovery that time from electrocorticographic to clinical seizure onset is prognostic for seizure-free outcome following temporal lobectomy, confirmation that temporal lobe epileptogenicity depends upon cerebral blood flow changes preceding seizure onset, and the delineation of age related demographic factors which are predictive of success in temporal lobe epilepsy surgery. A mathematical model has been derived for internal time processing in temporal lobe epilepsy, which may improve understanding of such interesting clinical phenomena as the antedating of conscious perceptions. Further clinical research in epilepsy has emphasized hemispheric neuropsychological dysfunction detected during the intracarotid sodium amobarbital test. Evidence has been discovered for the integration of perceptual and mnemenic dysfunction based on the association between sensory auras and left hemispheric memory impairment. It has also been shown that the severity of left hemispatial neglect is related to the degree of right hemispheric dysfunction.

Based upon research interest in cerebral perfusion, my basic neuroscience activity has emphasized study of the human cerebral microvasculature. In basic research on cerebral endothelial structure and pathophysiology, I have collaborated with neuroscientists at the University of California, Los Angeles (UCLA), University of Nebraska, Omaha, and Long Island Jewish Medical Center, Hyde Park, New York. In accordance with the University of Arizona Human Subject's Committee approved protocol, a novel human blood-brain barrier (BBB) model has been constructed from temporal lobe endothelial cells obtained during epilepsy surgery. Using this model, it has been suggested that microglial activation alone and/or through its interactions with astrocytes induces beta-chemokine-mediated monocyte BBB migration in human immunodeficiency virus (HIV)-1-associated dementia (HAD)13; a major mechanism for the transendothelial migration of monocytes during HIV encephalitis is the immune activation associated with viral infection of the central nervous system14; chemokine receptors are differentially expressed on brain and coronary endothelia and could play a role in endothelial migration and repair15; tumor necrosis factor (TNF)-alpha opens a BBB paracellular route for HIV-1 penetration into the brain16; amyloid-beta induces chemokine secretion and monocyte migration across the blood-brain barrier model and could add to the inflammatory destruction of the brain in Alzheimer's disease; and scatter factor promotes motility of human glioma and neuromicrovascular endothelial cells.

In the past 6 years, my current and former neurosurgery fellows and one medical student have been recognized as my co-authors in research with eleven citations. The quality of clinical care, including post-operative outcome, of my epilepsy patients has been enhanced by clinical research improving selection of epilepsy surgery candidates. I shall continue to explore the pathophysiology of temporal lobe epilepsy with emphasis on discovering new prognostic factors predictive of success in epilepsy surgery. I will continue to matintain strong, productive collaborative relationships with basic neuroscientists exploring the human blood-brain barrier and endothelia to improve understanding of central nervous system pathophysiology.