This project proposes to study hypothermia as a treatment of refractory status epilepticus (RSE). RSE is an increasingly common problem in VA Intensive Care Units. This may be due to improvement in life support systems and ICU technology, to increased availability of EEG recordings and increased recognition of """"""""subtle"""""""" status epilepticus (SE) and other factors. The results of treatment of RSE are very poor, with high mortality and morbidity. New treatments are needed. Deep hypothermia (200 C) is used clinically during cardiac surgery and neurosurgery. Moderate hypothermia (32-330 C) is used routinely in the treatment of neonatal hypoxic- ischemic encephalopathy, of post-cardiac arrest encephalopathy and of traumatic brain injury. Hypothermia has proved safe and effective in those conditions. It has also been shown to inhibit seizure activity. Yet, it is rarely used to treat RSE, and we lack a basic understanding of its indications and effectiveness in RSE. We will test the hypothesis that deep hypothermia reduces seizure activity in two models of experimental status epilepticus induced respectively by chemical (lithium and pilocarpine) or by electrical (perforant path) stimulation of the brain. We will compare deep and mild hypothermia, and will test different durations of mild hypothermia, to find out whether longer durations of mild hypothermia can be as effective in terminating RSE as short durations of deep hypothermia. We will compare two methods for delivering hypothermia: whole body cooling and head cooling (""""""""cool cap""""""""). For the same level of cooling of parietal cortex, we expect whole body cooling is more effective than the """"""""cool cap"""""""" method in terminating SE. Finally, we will study the effect of hypothermia treatment on the long-term consequences of RSE: neuronal injury, blood-brain barrier breakdown, cell-mediated inflammation, epileptogenesis and behavioral deficits. We expect hypothermia treatment to reduce all of these complications. At the end of this study, we expect to be able to define the depth, duration and method of hypothermia that is most effective in the treatment of experimental status epilepticus.

Public Health Relevance

Status Epilepticus (SE), a series of repetitive seizures without recovery of consciousness between seizures, is a common complication of epilepsy and of traumatic brain injury, the signature pathology of OEF/OIF. When SE does not respond to drugs (as did nearly half the patients in the In the VA Cooperative Study of SE), there is no alternative treatment, although extreme measure such as electroconvulsive shock or surgery have been attempted. Our preliminary data suggest that refractory SE (RSE) may respond to hypothermia, and we propose to investigate the parameters which make hypothermia successful in the treatment of RSE. We will study the depth of hypothermia, its optimal duration, its methodology (whole body hypothermia vs cool cap: hypothermia). If our preliminary data are confirmed, we will have an alternative treatment to offer Veterans who develop RSE as a result of TBI and other causes, and do not respond to traditional pharmacotherapy.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000273-05
Application #
8543421
Study Section
Neurobiology C (NURC)
Project Start
2009-04-01
Project End
2017-09-30
Budget Start
2013-10-01
Budget End
2014-09-30
Support Year
5
Fiscal Year
2014
Total Cost
Indirect Cost
Name
VA Greater Los Angels Healthcare System
Department
Type
DUNS #
066689118
City
Los Angeles
State
CA
Country
United States
Zip Code
90073
Torolira, Daniel; Suchomelova, Lucie; Wasterlain, Claude G et al. (2017) Phenobarbital and midazolam increase neonatal seizure-associated neuronal injury. Ann Neurol 82:115-120
Niquet, Jerome; Suchomelova, Lucie; Thompson, Kerry et al. (2017) Acute and long-term effects of brivaracetam and brivaracetam-diazepam combinations in an experimental model of status epilepticus. Epilepsia 58:1199-1207
Niquet, Jerome; Baldwin, Roger; Suchomelova, Lucie et al. (2017) Treatment of experimental status epilepticus with synergistic drug combinations. Epilepsia 58:e49-e53
Niquet, Jerome; Baldwin, Roger; Norman, Keith et al. (2017) Simultaneous triple therapy for the treatment of status epilepticus. Neurobiol Dis 104:41-49
Niquet, Jerome; Baldwin, Roger; Suchomelova, Lucie et al. (2016) Benzodiazepine-refractory status epilepticus: pathophysiology and principles of treatment. Ann N Y Acad Sci 1378:166-173
Torolira, Daniel; Suchomelova, Lucie; Wasterlain, Claude G et al. (2016) Widespread neuronal injury in a model of cholinergic status epilepticus in postnatal day 7 rat pups. Epilepsy Res 120:47-54
Niquet, Jerome; Baldwin, Roger; Norman, Keith et al. (2016) Midazolam-ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits. Epilepsia 57:1406-15
Niquet, Jerome; Gezalian, Michael; Baldwin, Roger et al. (2015) Neuroprotective effects of deep hypothermia in refractory status epilepticus. Ann Clin Transl Neurol 2:1105-15
Niquet, Jerome; Baldwin, Roger; Gezalian, Michael et al. (2015) Deep hypothermia for the treatment of refractory status epilepticus. Epilepsy Behav 49:313-7
Suchomelova, L; Lopez-Meraz, M L; Niquet, J et al. (2015) Hyperthermia aggravates status epilepticus-induced epileptogenesis and neuronal loss in immature rats. Neuroscience 305:209-24

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