Robert J. DeLorenzo

Prevalence of nonconvulsive status epilepticus in comatose patients

Background: Nonconvulsive status epilepticus (NCSE) is a form of status epilepticus (SE) that is an often unrecognized cause of coma. Objective: To evaluate the presence of NCSE in comatose patients with no clinical signs of seizure activity. Methods: A total of 236 patients with coma and no overt clinical seizure activity were monitored with EEG as part of their coma evaluation. This study was conducted during our prospective evaluation of SE, where it has been validated that we identify over 95% of all SE cases at the Medical College of Virginia Hospitals. Only cases that were found to have no clinical signs of SE were included in this study. Results: EEG demonstrated that 8% of these patients met the criteria for the diagnosis of NCSE. The study included an age range from 1 month to 87 years. Conclusions: This large-scale EEG evaluation of comatose patients without clinical signs of seizure activity found that NCSE is an under-recognized cause of coma, occurring in 8% of all comatose patients without signs of seizure activity. EEG should be included in the routine evaluation of comatose patients even if clinical seizure activity is not apparent.

Determinants of Mortality in Status Epilepticus

Summary: Using univariate and multivariate regression analysis, we studied seizure duration, seizure type, age, etiologies, other clinical features, and mortality among 253 adults with status epilepticus (SE) admitted to the Medical College of Virginia. Cerebral vascular disease and discontinuation of antiepileptic drugs (AEDs) were the most prominent causes of SE, each accounting for ∼22% of all patients in the series. The other principle etiologies were alcohol withdrawal, idiopathic, anoxia, metabolic disorders, hemorrhage, infection, tumor, drug overdose, and trauma. When the patients were divided into two groups, the group with SE lasting < 1 h had a lower mortality as compared with seizure duration ≥ 1 h. Low mortality rates were noted in alcohol and AED discontinuation etiologies. Anoxia and increasing age were significantly correlated with higher mortality. The mortality rates of partial and generalized SE were not significantly different. Race and sex did not affect mortality significantly. Our findings represent the first multivariate analysis of predictive indicators of mortality in SE and demonstrate that specific factors influence mortality rate in SE.

Persistent nonconvulsive status epilepticus after the control of convulsive status epilepticus

Summary: Purpose: Convulsive status epilepticus (CSE) is a major medical and neurological emergency that is associated with significant morbidity and mortality. Despite this high morbidity and mortality, most acute care facilities in the United States cannot evaluate patients with EEG monitoring during or immediately after SE. The present study was initiated to determine whether control of CSE by standard treatment protocols was sufficient to terminate electrographic seizures.

Epidemiology of status epilepticus.

Summary: This study presents a review of the epidemiology of status epilepticus (SE) in Richmond, Virginia, U.S.A. The data summarize some of the first population‐based information on the natural presentation of SE in a controlled community setting. SE occurred with an absolute incidence rate of 41 patients per 100,000 residents per year in Richmond. The frequency of total SE occurrences was 50 patients per 100,000 residents per year. Overall mortality in this population was 22%. Absolute incidence and occurrences of SE in this population were shown to be underestimates due to the inability, for multiple reasons, to document all cases of SE. Based on the Richmond data, the number of SE cases, frequencies of occurrence, and deaths per year occurring in the United States were estimated to be 102,000‐152,000, 125,000‐195,000, and 22,000‐42,000, respectively. In Richmond, nonwhites had a much higher incidence of SE than did whites. Partial SE was the most common form of seizure initiating SE. Age and etiology were also found to contribute to mortality. Infants <1 year of age had the highest incidence of SE, but the elderly population represented the largest number of SE cases. This study provides a review of the first prospective, population‐based, epidemiological data on SE and shows that SE is a major medical and neurological emergency in both academic and community hospital settings.

Cellular Actions of Topiramate: Blockade of Kainate-Evoked Inward Currents in Cultured Hippocampal Neurons

Purpose: This study was undertaken to evaluate the effects of topiramate (TPM) on excitatory amino acid‐evoked currents.

Status epilepticus in children, adults, and the elderly.

Summary: Status epilepticus (SE) is a major neurological and medical emergency associated with a high morbidity and mortality. Retrospective and prospective studies from the Medical College of Virginia Epilepsy Research Center have been utilized to investigate several clinical and epidemiological factors associated with SE. Univariate and multivariate logistic regression analysis of predictive indicators in patients with SE indicated that seizure duration, certain specific etiologies, and age were predictors of mortality. Sex, race, and certain other etiologies were not found to be factors that significantly affect mortality. These findings demonstrate that specific indicators are important in predicting mortality in SE. Preliminary prospective epidemiological data from Richmond, Virginia suggested that more than 250,000 cases of SE may occur annually in the United States with a mortality greater than 55,000 individuals. Studies comparing community and university hospitals in Richmond indicate that the mortality and clinical variables associated with SE in these two hospital populations are essentially identical. Further investigations employing prospective population‐based studies are essential in evaluating the epidemiology and mortality of SE.

NMDA receptor activation during status epilepticus is required for the development of epilepsy.

NMDA receptor activation has been implicated in modulating seizure activity; however, its complete role in the development of epilepsy is unknown. The pilocarpine model of limbic epilepsy involves inducing status epilepticus (SE) with the subsequent development of spontaneous recurrent seizures (SRSs) and is widely accepted as a model of limbic epilepsy in humans. The pilocarpine model of epilepsy provides a tool for looking at the molecular signals triggered by SE that are responsible for the development of epilepsy. In this study, we wanted to examine the role of NMDA receptor activation on the development of epilepsy using the pilocarpine model. Pretreatment with the NMDA receptor antagonist MK-801 does not block the onset of SE in the pilocarpine model. Thus, we could compare animals that experience similar lengths of SE in the presence or absence of NMDA receptor activation. Animals treated with MK-801 (4 mg/kg) 20 min prior to pilocarpine (350 mg/kg) (MK-Pilo) were compared to the pilocarpine treated epileptic animals 3-8 weeks after the initial episode of SE. The pilocarpine-treated animals displayed both ictal activity and interictal spikes on EEG analysis, whereas MK-801-pilocarpine and control animals only exhibited normal background EEG patterns. In addition, MK-801-pilocarpine animals did not exhibit any SRSs, while pilocarpine-treated animals exhibited 4.8 +/- 1 seizures per 40 h. MK-801-pilocarpine animals did not demonstrate any decrease in pyramidal cell number in the CA1 subfield of the hippocampus, while pilocarpine animals averaged 15% decrease in cell number. In summary, the MK-801-pilocarpine animals exhibited a number of characteristics similar to control animals and were statistically significantly different from pilocarpine-treated animals. Thus, NMDA receptor inhibition by MK-801 prevented the development of epilepsy and interictal activity following SE. These results indicate that NMDA receptor activation is required for epileptogenesis following SE in this model of limbic epilepsy.

The use of topiramate in refractory status epilepticus

In cases of refractory status epilepticus (RSE) unresponsive to sequential trials of multiple agents, a suspension of topiramate administered via nasogastric tube was effective in aborting RSE, including one patient in a prolonged pentobarbital coma. Effective dosages ranged from 300 to 1,600 mg/d. Except for lethargy, no adverse events were reported.

Temperature modulation of ischemic neuronal death and inhibition of calcium/calmodulin-dependent protein kinase II in gerbils.

We used brief bilateral carotid artery occlusion in gerbils to examine the effects of temperature on ischemia-induced inhibition of calcium/calmodulin-dependent protein kinase II activity and neuronal death. In normothermic (36 degrees C) gerbils, ischemia induced a severe loss of hippocampal CA1 pyramidal neurons measured 7 days after ischemia (28.4 neurons/mm, n = 10; control density in 10 naive gerbils 262.1 neurons/mm) and a significant decrease in forebrain calcium/calmodulin-dependent protein kinase II autophosphorylation measured 2 hours after ischemia (12.9 fmol/min, n = 6; control phosphorylation in six naive gerbils 23.5 fmol/min). The effect of temperature on these indicators of ischemic damage was examined by adjusting intracerebral temperature before and during the ischemic insult. Hyperthermic (39 degrees C) gerbils showed almost complete loss of neurons in the CA1 region (3.0 neurons/mm, n = 11) and extension of neuronal death into the CA2, CA3, and CA4 regions. In addition, hyperthermia exacerbated ischemia-induced inhibition of calcium/calmodulin-dependent protein kinase II activity (4.2 fmol/min, n = 6). Hypothermia (32 degrees C) protected against ischemia-induced CA1 pyramidal cell damage (257.0 neurons/mm, n = 20) and inhibition of calcium/calmodulin-dependent protein kinase II activity (26.0 fmol/min, n = 6). Our results are consistent with the hypothesis that loss of calcium/calmodulin-dependent protein kinase II activity may be a critical event in the development of ischemia-induced cell death.

In Whom Does Status Epilepticus Occur: Age-Related Differences in Children

: Purpose: Status epilepticus (SE) is an uncommon but potentially life‐threatening seizure. It is most common in children. Little is known about the differences within the pediatric age group in terms of the type of patient seen with SE.