Problems and Controversies in Status Epilepticus
Problems and Controversies in Status Epilepticus
There are approximately 200,000 cases of SE in the USA each year, and at least 3 million cases worldwide. In the USA and other first world countries, the initial treatment is almost always an iv. benzodiazepine, usually lorazepam, sometimes followed by phenytoin. In the VA Cooperative Trial, which compared the efficacy of lorazepam, phenobarbital, diazepam followed by phenytoin and phenytoin alone in the initial treatment of generalized convulsive SE, lorazepam was effective at stopping generalized convulsive SE 65% of the time, and the addition of phenytoin resulted in cessation of 7% more. Thus, from these data approximately 30% of generalized convulsive SE is refractory to initial optimal treatment. Overall in that study SE persisted after treatment with two drugs in 38% of the patients. In much of the world, most AEDs for iv. administration are not readily available and patients frequently present after prolonged SE. Thus the proportion of people with SE who progress to medically refractory SE is almost certainly much higher than 30–40%, although the true proportion is not known. From these figures, it can be estimated that there are approximately 60,000 cases of refractory SE in the USA each year and perhaps 1.5 million cases throughout the world. Because mortality of refractory SE within 30 days of the episode of SE is approximately 65%, this translates to 40,000 deaths per year in the USA and 1 million or more worldwide from refractory SE. A comparison with the morbidity and mortality of other common neurological conditions places these figures in perspective. There are approximately 10,000 new cases of multiple sclerosis in the USA each year, a current prevalence of a little under 400,000, and an annual mortality of less than 3000. The prevalence of Parkinson's disease in the USA is approximately 450,000 and age-matched relative risk for mortality is between 1.5 and 3. Among neurological disorders, only stroke exceeds the mortality of SE each year in the USA.
The underlying etiology of the episode of SE is the major determinant of mortality when treatment is optimal, as reviewed above, but the lack of aggressive treatment in our opinion contributes substantially to mortality, especially in refractory SE cases, even in the first world, and certainly leads to prolonged, and thus increasingly refractory, SE. In a pediatric study by Chin and colleagues in North London (UK), for each minute delay between the onset of generalized convulsive SE and arrival to the hospital emergency department there was a 5% cumulative increased risk that generalized convulsive SE would last more than 60 min. In the VA study, the first treatment had a far better chance of success than the second or third, regardless of the drug (55 vs 7 vs 2%). Animal data also make it clear that aggressive early treatment is more successful in experimental SE. The later in the course of experimental SE animals are treated with benzodiazepine with or without another drug, the poorer the response. Studies by Goodkin and Naylor suggest this is due to progressive internalization of GABA receptors on postsynaptic membranes, although there may be also a decrease in available synaptic GABA. Chen and Wasterlain have also suggested an increase in excitatory receptors on the postsynaptic membrane during the course of experimental SE. Neuronal damage becomes progressively severe during experimental SE and there is a profound effect on learning and memory in late SE. These data, combined with multiple reports of increasing refractoriness to treatment and poor outcome in prolonged generalized convulsive SE make it imperative to treat at least this form of SE (whether it presents as overt, subtle or electrical generalized convulsive SE) rapidly and aggressively to increase the probability of seizure control and decrease the negative consequences of prolonged SE. Even with aggressive treatment some patients will experience significant morbidity or die as the result of the underlying etiology causing the episode of SE. What is tragic, however, is when a patient suffers unnecessary morbidity or death that could have been prevented with aggressive treatment. Table 1 summarizes the arguments for and against aggressive treatment of SE. There are also data that suggest significant consequences of prolonged complex partial SE but there is still considerable controversy as to how aggressive treatment of complex partial SE should be.
Box 2 presents a treatment protocol we have found useful in the management of early and late generalized convulsive SE. It is also applicable to the treatment of complex partial SE. The first two steps can be utilized in the management of simple partial SE, but we do not recommend induction of coma in an awake patient, but rather suggest aggressive treatment of simple partial SE with nonsedating drugs. Absence SE is usually responsive to iv. benzodiazepine administration, but if not, iv. valproate or LEV are appropriate as the next treatment.
There is considerable interest in understanding the underlying pathophysiology of SE, including what happens to prevent the rapid termination of a single seizure so it that progresses to SE, the details of the molecular events at neuronal synapses that lead to refractoriness to treatment, and the way that ongoing seizure activity leads to neuronal damage and death, cognitive impairment and long-term epilepsy if seizure activity is prolonged during unsuccessfully treated SE. It is likely that over the next 5 or pershaps 10 years, answers to these questions will be found and there will be an even stronger rationale for aggressive treatment of SE.
Expert Commentary & Five-year View
There are approximately 200,000 cases of SE in the USA each year, and at least 3 million cases worldwide. In the USA and other first world countries, the initial treatment is almost always an iv. benzodiazepine, usually lorazepam, sometimes followed by phenytoin. In the VA Cooperative Trial, which compared the efficacy of lorazepam, phenobarbital, diazepam followed by phenytoin and phenytoin alone in the initial treatment of generalized convulsive SE, lorazepam was effective at stopping generalized convulsive SE 65% of the time, and the addition of phenytoin resulted in cessation of 7% more. Thus, from these data approximately 30% of generalized convulsive SE is refractory to initial optimal treatment. Overall in that study SE persisted after treatment with two drugs in 38% of the patients. In much of the world, most AEDs for iv. administration are not readily available and patients frequently present after prolonged SE. Thus the proportion of people with SE who progress to medically refractory SE is almost certainly much higher than 30–40%, although the true proportion is not known. From these figures, it can be estimated that there are approximately 60,000 cases of refractory SE in the USA each year and perhaps 1.5 million cases throughout the world. Because mortality of refractory SE within 30 days of the episode of SE is approximately 65%, this translates to 40,000 deaths per year in the USA and 1 million or more worldwide from refractory SE. A comparison with the morbidity and mortality of other common neurological conditions places these figures in perspective. There are approximately 10,000 new cases of multiple sclerosis in the USA each year, a current prevalence of a little under 400,000, and an annual mortality of less than 3000. The prevalence of Parkinson's disease in the USA is approximately 450,000 and age-matched relative risk for mortality is between 1.5 and 3. Among neurological disorders, only stroke exceeds the mortality of SE each year in the USA.
The underlying etiology of the episode of SE is the major determinant of mortality when treatment is optimal, as reviewed above, but the lack of aggressive treatment in our opinion contributes substantially to mortality, especially in refractory SE cases, even in the first world, and certainly leads to prolonged, and thus increasingly refractory, SE. In a pediatric study by Chin and colleagues in North London (UK), for each minute delay between the onset of generalized convulsive SE and arrival to the hospital emergency department there was a 5% cumulative increased risk that generalized convulsive SE would last more than 60 min. In the VA study, the first treatment had a far better chance of success than the second or third, regardless of the drug (55 vs 7 vs 2%). Animal data also make it clear that aggressive early treatment is more successful in experimental SE. The later in the course of experimental SE animals are treated with benzodiazepine with or without another drug, the poorer the response. Studies by Goodkin and Naylor suggest this is due to progressive internalization of GABA receptors on postsynaptic membranes, although there may be also a decrease in available synaptic GABA. Chen and Wasterlain have also suggested an increase in excitatory receptors on the postsynaptic membrane during the course of experimental SE. Neuronal damage becomes progressively severe during experimental SE and there is a profound effect on learning and memory in late SE. These data, combined with multiple reports of increasing refractoriness to treatment and poor outcome in prolonged generalized convulsive SE make it imperative to treat at least this form of SE (whether it presents as overt, subtle or electrical generalized convulsive SE) rapidly and aggressively to increase the probability of seizure control and decrease the negative consequences of prolonged SE. Even with aggressive treatment some patients will experience significant morbidity or die as the result of the underlying etiology causing the episode of SE. What is tragic, however, is when a patient suffers unnecessary morbidity or death that could have been prevented with aggressive treatment. Table 1 summarizes the arguments for and against aggressive treatment of SE. There are also data that suggest significant consequences of prolonged complex partial SE but there is still considerable controversy as to how aggressive treatment of complex partial SE should be.
Box 2 presents a treatment protocol we have found useful in the management of early and late generalized convulsive SE. It is also applicable to the treatment of complex partial SE. The first two steps can be utilized in the management of simple partial SE, but we do not recommend induction of coma in an awake patient, but rather suggest aggressive treatment of simple partial SE with nonsedating drugs. Absence SE is usually responsive to iv. benzodiazepine administration, but if not, iv. valproate or LEV are appropriate as the next treatment.
There is considerable interest in understanding the underlying pathophysiology of SE, including what happens to prevent the rapid termination of a single seizure so it that progresses to SE, the details of the molecular events at neuronal synapses that lead to refractoriness to treatment, and the way that ongoing seizure activity leads to neuronal damage and death, cognitive impairment and long-term epilepsy if seizure activity is prolonged during unsuccessfully treated SE. It is likely that over the next 5 or pershaps 10 years, answers to these questions will be found and there will be an even stronger rationale for aggressive treatment of SE.
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