Lessons From the Laboratory: The Pathophysiology, and Consequences of Status Epilepticus

Abstract

Status epilepticus (SE) is the most common neurological emergency of childhood. Experimental models parallel several clinical features of SE including: (1) treatment is complicated by an increasing probability that benzodiazepines will fail with increasing seizure duration and (2) outcome varies with age and etiology. Studies using these models demonstrated that the activity-dependent trafficking of GABA A receptors contributes, in part, to the progressive decline in GABA-mediated inhibition and the failure of the benzodiazepines. Furthermore, laboratory studies have provided evidence that age and inciting stimulus interact to determine the neuronal circuits activated during SE (i.e. functional anatomy), and that differences in functional anatomy can partially account for variations in SE outcome. Future laboratory studies are likely to provide an additional understanding of the cellular and molecular mechanisms that underlie SE and its consequences. Such studies are necessary in the development of rational emergent therapy for SE and its long term outcomes.The majority of seizures stop spontaneously. However, when the mechanisms that terminate a seizure fail, the result is a prolonged, self-sustaining seizure that can be refractory to treatment. This condition, which has been termed status epilepticus (SE), represents the most common neurological emergency of childhood with an estimated incidence of 10-27/100,000/ year for children between the ages of 1 month and 15 years with the majority of episodes occurring in children <4 years. 1-5 Fortunately for many children, SE occurs without apparent consequences; however, for others, SE results in death or long term neurological dysfunction or potentially epilepsy1 , 6 -14The intent of translational research focused on the pathogenesis and long term outcome of SE is to gain a better understanding of the mechanisms that underlie this childhood emergency with the goal of reducing its associated mortality and morbidity to even lower levels. The ethical and practical limitations of performing such studies in children are well known. 15 Furthermore, current clinical techniques do not yet provide the resolution required to completely address questions at the cellular and molecular levels in human studies. Therefore, many questions regarding basic mechanisms are still best addressed using in vivo animal models that, for the Corresponding author: Howard P. Goodkin, MD PhD, Box 800394, Charlottesville, VA 22908, 434-924-8378 (office), 434-982-1726 (fax), hpg9v@virginia.edu. Disclosures: KR received support from the Epilepsy Foundation, SAZ receives support from the Epilepsy Foundation and NIH (NS063118). HPG receives support from the NIH (NS048413, NS067439) and has served as a consultant to MedImmune, Inc. within the last 3 years.Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, type...

Early metabolic responses to lithium/pilocarpine‐induced status epilepticus in rat brain

“…GABAergic receptors are postulated to be reduced by internalization, thereby causing a lack of inhibitory tone (Rajasekaran et al . ). In our hands, seizures were efficiently terminated by diazepam, a GABAergic agonist, indicating that GABAergic receptors were still functional after 90 min of SE; by ketamine, an NMDA receptor antagonist; but not by atropine, a muscarinic receptor antagonist.…”

“…Instead, seizures are now efficiently stopped by blockade of NMDA receptors, an indication that continuous seizures are sustained by glutamatergic (hyper) activation (Solberg and Belkin 1997). GABAergic receptors are postulated to be reduced by internalization, thereby causing a lack of inhibitory tone (Rajasekaran et al 2010). In our hands, seizures were efficiently terminated by diazepam, a GABAergic agonist, indicating that GABAergic receptors were still functional after 90 min of SE; by ketamine, an NMDA receptor antagonist; but not by atropine, a muscarinic receptor antagonist.…”

Expression of AMPA receptor subunits in hippocampus after status convulsion

“…This age-dependency could be due to differing amounts of hippocampal neuronal damage produced by seizures at different ages [1][2][3][4][5]. To determine if there was an early developmental resistance to seizure-induced hippocampal damage, we compared the effects of pilocarpineinduced SC on the hippocampus of immature (20-day-old) and adult rats.…”

“…Laboratory models of prolonged seizures and status epilepticus in developing animals have demonstrated an agedependent propensity for brain injury [1,2]. Children are more vulnerable to seizures and SC; however, adults are at a higher risk than children of late seizures and disability [3,4].…”

Status Epilepticus

“…The N-methyl-d-aspartate (NMDA) linked channels appear to be important in the pathogenesis of neuronal injury in SE [10]. Studies have shown that during SE, reduction in the GABA-mediated inhibition correlated with a reduction in the surface expression of the benzodiazepine-sensitive GABA A receptors but not the benzodiazepine-insensitive GABA A receptors [11][12][13][14]. This activity-dependent decrease in benzodiazepine-sensitive receptors is a potential mechanism to explain the failure of benzodiazepines to treat SE in its late stages.…”