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Status Epilepticus
Status Epilepticus DM Treiman, Barrow Neurological Institute at Phoenix Children’s Hospital, Phoenix, AZ, USA r 2014 Elsevier Inc. All rights reserved.
Introduction
Etiology
The term status epilepticus (SE) has several definitions. Clinicians diagnose SE when epileptic seizures are repeated in rapid succession without full recovery between the seizures or there is continuous seizure activity that lasts longer than that in single seizures and does not exhibit the typical evolution of behavioral and electroencephalographic (EEG) features characteristic of single seizures. Thus, two or more seizures without full recovery of neurological function between the seizures defines SE for treatment purposes. However, epidemiological studies of SE usually require 30 min of continuous or repeated seizures without full recovery between the seizures for inclusion. There have been several recent proposals to lower the duration of continuous or repetitive seizure activity required to classify seizure activity as SE from 30 min to as few as 10 or even 5 min. However, such debates are not necessary if there is recognition that physiologically SE is a state in which changes in neuronal function (e.g., slowing on EEG, postictal confusion, and focal postictal paralysis) caused by an epileptic seizure are still present when another seizure occurs, so the patient or experimental animal is in a continuous epileptic state regardless of the duration of the seizure activity. Such changes accumulate if SE persists, which may account for the progression to refractoriness to treatment and increased consequences of prolonged SE.
There are many causes of SE. The most common are head trauma, tumor, cerebrovascular insults, and central nervous system (CNS) infection. Medication change or antiepileptic drug noncompliance is a common cause of SE in patients with established epilepsy. In children, chronic epilepsy, febrile seizures, CNS infection, and metabolic disease are the most common causes of SE; recurrent episodes occur most often in neurologically abnormal children. Recent reports have suggested that anti-N-methyl-D-aspartate (NMDA) receptor encephalitis may account for some cases of prolonged, medically refractory, generalized convulsive SE (GCSE) previously considered cryptogenic.
History SE was first described in a Babylonian medical text approximately 2500 years ago, but little was written about status subsequently until the nineteenth century when Calmeil introduced the term SE in 1825. Extensive clinical descriptions were provided in the late nineteenth and early twentieth centuries by Bourneville, Trousseau, and Clark and Prout. The modern study of SE started with the Marseilles Conference in 1964. International conferences were subsequently held in 1980, 1997, 2007, 2009, and 2011.
Epidemiology The incidence of SE is reported to be between 10 and 20/105 in Caucasians in developed countries, but an ascertainment and age-adjusted incidence of 61/105 was reported in Richmond, Virginia, where there is a large African-American population. This suggests a likely worldwide incidence of approximately 3 million per year, but adequate epidemiological data are not available to determine the worldwide incidence accurately determine the worldwide incidence. The incidence of SE is much higher in the very young (o1 year: 135–156/105) and the elderly over 65 (14.6–86/105).
Encyclopedia of the Neurological Sciences, Volume 4
Classification The classification of SE has been the subject of debate. Henri Gastaut, who drafted the first International Classification of Epileptic Seizures, suggested that there are as many types of SE as there are types of epileptic seizures, and he thought that classification of SE should be based on the International Classification. In his view, any seizure that lasts long enough or recurs frequently enough is a type of SE. Others have proposed more elaborate classifications in order to include epileptic syndromes characterized by repeated prolonged seizure activity, such as the childhood syndromes of electrical SE of slowwave sleep and Landau–Klefner syndrome. The following are the major types of SE: GCSE (either primarily or secondarily generalized tonic–clonic SE), complex partial SE (CPSE), simple partial SE, and absence SE. GCSE is the most common and most life-threatening type of SE. It accounts for approximately 70% of all cases of SE. It usually presents as repeated brief, time-limited convulsions, without recovery to full alertness and normal mental function between seizures. However, if the seizures are not stopped quickly, there is an evolution of the seizure activity from overt to subtle convulsive activity, such as subtle twitches of the fingers, face, or abdominal muscles and/or nystagmoid jerks of the eyes, and eventually to complete cessation of motor activity. There is also an evolution through a predictable series of EEG patterns, a progressive decline in responsiveness to antiepileptic drugs, and a progressive increase in the extent and intensity of neuronal damage. The terms overt, subtle, and electrical GCSE (which refer to the extent of the clinical convulsions) have been applied to these early and late presentations of GCSE. CPSE is much less common than GCSE but is recognized much more frequently than previously. CPSE presents as an ‘epileptic twilight state’ in which the patient is awake but only partially responsive to external stimuli and has no memory of the episode. Frequently, there is cycling between partial responsiveness and unresponsiveness. Absence SE (spike–wave
doi:10.1016/B978-0-12-385157-4.00302-X
297
298
Status Epilepticus
stupor) has similar clinical features but can be distinguished from CPSE by the occurrence of paroxysmal, bilaterally symmetrical, generalized 3 cycles per second spike–wave discharges, although sometimes the bifrontal spike–wave patterns seen in CPSE may be difficult to distinguish from generalized spike–wave discharges. There is controversy regarding the term nonconvulsive SE (NCSE). Some suggest NCSE is best reserved for absence SE and CPSE but many authors now use this term to refer to subtle or electrical GCSE in severely encephalopathic patients. Simple partial SE (SPSE) refers to repetitive motor or sensory seizure activity that occurs without any alteration of consciousness because the seizure activity remains confined to one cerebral hemisphere. The clinical features of the motor or sensory seizure activity are dependent on the area of the cortex from which the seizures start. A special case of SPSE is epilepsia partialis continua, in which focal motor seizure activity without alteration of consciousness continues for days to weeks or longer.
scalp. In GCSE, there is a predictable sequence of progressive EEG changes if SE is untreated or inadequately treated, and ictal activity continues. Initially, there are discrete electrographic seizures, which coincide with generalized convulsions and have the typical evolution of single generalized tonic–clonic seizures. Over time, the ictal discharges begin to merge together to produce a waxing and waning pattern, which is followed by continuous, generally monomorphic, ictal discharges that may persist for some time. Eventually, the continuous seizure activity is punctuated by periods of relative flattening, which become longer as the ictal discharges become shorter, until finally periodic epileptiform discharges on a relatively flat background develop as the last EEG pattern in this evolution. There is controversy regarding the interpretation of periodic epileptiform discharges, and some authors have considered these injury patterns, rather than an expression of ongoing seizure activity.
Pathophysiology Electroencephalography of Status Epilepticus Repetitive or continuous ictal discharges are seen in scalp recordings of all types of SE, except sometimes during simple partial SE when the area of ongoing seizure activity is so small that the ictal discharges are attenuated by meninges, skull, and
Table 1
SE occurs when there is a failure of the mechanisms (e.g., activation of Na þ –K þ ATPase, acidification of the extracellular fluid, blockade of NMDA channels, activation of K þ conductances, and release of k opioids or neuropeptide Y) that terminate a single seizure and normally produce a refractory period before another seizure can occur. Failure of such
Treatment protocol for generalized convulsive status epilepticus
Time (min)
Protocol
0
Establish the diagnosis by observing one additional seizure in a patient with recent seizures or impaired consciousness or by observing continuous behavioral and/or electrical seizure activity for 410 min. Start EEG as soon as possible, but do not delay treatment unless EEG verification of the diagnosis is necessary. Establish intravenous (IV) catheter with normal saline (dextrose solutions may precipitate phenytoin); with fosphenytoin, either dextrose or saline is acceptable. Draw blood for serum chemistry, hematological values, and antiepileptic drug concentrations. Check for hypoglycemia by finger stick. If hypoglycemia is present administer 100 mg of thiamine (if indicated) followed by 50 ml of 50% dextrose by direct push into the IV line. Administer lorazepam (0.1 mg/kg) by IV push (o2 mg/min). If status continues, start fosphenytoin (20 mg/kg PE) by fast IV push (up to 150 mg PE/min) directly into the IV port nearest to the patient; if only phenytoin is available, give by slow IV push (o50 mg/min); with either preparation, monitor blood pressure and electrocardiogram during infusion. If status continues after 20 mg PE/kg fosphenytoin (or 20 mg/kg phenytoin), administer an additional 5 mg/kg and, if necessary, another 5 mg/kg, to a maximum dose of 30 mg/kg. If status persists, support respiration by endotracheal intubation; give phenobarbital (20 mg/kg) by IV push (o100 mg/min) or, preferably, start barbiturate coma: Give pentobarbital (5–15 mg/kg) slowly as an initial IV dose to suppress all epileptiform activity and continue 0.5–5 mg/kg/h to maintain suppression; slow infusion rate periodically to determine cessation of seizure activity; monitor blood pressure, electrocardiogram, and respiratory function. If unable to suppress all epileptiform activity, change to continuous infusion of propofol (1 mg/kg given over 5 min, then 2–4 mg/kg/h; adjust to 1–15 mg/kg/h) or use midazolam (0.2 mg/kg bolus injection, followed by infusion of 0.05–0.5 mg/kg/h). Maintain full suppression of epileptiform activity (not a burst-suppression pattern) for 48–72 h before beginning to slow the infusion rate. Before beginning withdrawal of IV anesthesia, adjust phenytoin serum concentration to 30 mg/ml and load phenobarbital to achieve 100–150 mg/ml serum concentration. Alternatively, or in addition, load with valproate, 30 mg/kg, to achieve 120 mg/ml or levetiracetam, 50 mg/kg, or lacosamide, 10 mg/kg. Maintain these serum levels/doses as the anesthetic agent is slowed. If epileptiform activity returns during lightening of the induced coma, increase the infusion rate of the anesthetic agent (pentobarbital, propofol, or midazolam) to suppress all epileptiform activity for another 48–72 h before attempting anesthesia withdrawal again. Repeat as many times as necessary. Do not give up. Patients have recovered consciousness and useful existence after 42 months of coma.
5
10 25
60
460
Abbreviation: PE, Phenytoin equivalents. Source: Adapted with permission from Treiman DM (2009) Convulsive status epilepticus. In: Wheless JW, Willmore LJ, and Brumback RA (eds.) Advanced Therapy in Epilepsy, pp. 144–151. Shelton, CT: People’s Medical Publishing House.
Status Epilepticus
seizure-stopping mechanisms, or the occurrence of a strong excitatory stimulus, may result in repeated or prolonged seizures. A variety of acute neurological insults either lower seizure threshold or result in excessive excitation or inhibitory failure. Once status occurs, regardless of the precipitating cause, several mechanisms contribute to continuing seizure activity, including alterations in calcium- and calmodulin-dependent kinase II activity, increases in substance P, impairment of g-aminobutyric acid (GABA)-mediated inhibition, or altered GABAA receptor function due to structural rearrangement in the subunit composition of the GABAA receptor. Internalization of postsynaptic GABAA receptors and externalization of glutamate receptors in late SE have recently been recognized as a partial explanation for progressive resistance to treatment as SE progresses.
Management The initial management of SE is similar to that of other medical emergencies: Adequate airway, breathing, and circulation must be ensured. Then pharmacological therapy is started. A recent study demonstrated the utility of prehospital emergency treatment by paramedics using intravenous diazepam or lorazepam, and another recent prehospital treatment study found intramuscular midazolam to be at least as effective as intravenous lorazepam. In hospital management, most neurologists initiate treatment of all types of SE with intravenous administration of a benzodiazepine. Lorazepam is the most common benzodiazepine used, although diazepam, midazolam, or clonazepam (widely used in Europe) is also sometimes the initial drug. Lorazepam was the treatment most often effective at stopping GCSE in the only large head-tohead, blinded, randomized comparison of drug regimens used in the management of GCSE. Most neurologists follow benzodiazepine administration with fosphenytoin to provide long-term protection against the recurrence of SE, although several studies have shown lorazepam (but not diazepam or midazolam) to have a prolonged effective duration of action against SE. If SE is refractory to the initial two treatments, phenobarbital may be given next, although there is an increasing tendency to start intravenous general anesthesia at this stage. Intravenous general anesthesia is induced by continuous infusion of pentobarbital, midazolam, propofol, or sometimes diazepam or lorazepam. Management of refractory SE is done with continuous EEG monitoring in order to verify cessation of all seizure activity. Table 1 outlines a widely used treatment regimen for GCSE.
Morbidity, Mortality, and Prognosis Before the development of effective antistatus drugs, most patients with prolonged convulsive SE died during or shortly after the episode. However, even with effective treatment, the prognosis for survival at 30 days after the episode is
299
poor. Morbidity 30 days after an episode of overt GCSE is approximately 20% in most series, and was 65% 30 days after subtle GCSE in a large US Department of Veterans Affairs study. When GCSE is treated effectively, mortality is usually due to the underlying cause of the episode of SE. In patients who survive and recover fully, most are left with chronic epilepsy, even if they had no history of epilepsy before the episode of SE. If SE is not treated effectively, there is the potential for permanent neuronal damage, especially if seizure activity is prolonged. Neuronal damage in patients dying soon after an episode of SE and in experimental animals is most often seen in Sommer’s sector (prosubiculum and area CA1) of the hippocampus, layers 3, 5, and 6 of the cerebral cortex, the Purkinje cells of the cerebellum, the thalamus and basal ganglia, and the hypothalamus.
See also: Antiepileptic Drug Therapy. Cell Death. Domoic Acid. Epilepsy; Antiepileptic Drug Profiles. Epilepsy; Basic Mechanisms. Epilepsy; Drug Treatment Principles. Epilepsy; Experimental Models. Epilepsy; Overview. Epilepsy Pathology. Epilepsy Treatment Strategies. Epileptic Seizures. Epileptic Syndromes and Diseases. Epileptogenesis. GABAA Receptor Channels; Properties and Regulation. Neurotransmitter Receptors. Neurotransmitters; Overview. Organophosphates and Carbamates
Further Reading Alldredge BK, Gelb AM, Isaacs SM, et al. (2001) A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. New England Journal of Medicine 345: 631–637. Avanzini G, Treiman DM, and Engel J (2008) Experimental models of partial seizures and status epilepticus. In: Engel J Jr, and Pedley TA (eds.) Epilepsy: A Comprehensive Textbook, 2nd edn., pp. 415–444. Philadelphia: Lippincott Williams & Wilkins. Drislane FW (ed.) (2005) Status Epilepticus: A Clinical Perspective. Totowa, NJ: Humana Press. Gastaut H, Roger J, and Lob H (1967) Les e´tats de mal e´pileptiques. Paris: Masson. Kaplan P and Drislane F (eds.) (2008) Nonconvulsive Status Epilepticus. New York: Demos Medical Publishing. Shorvon S (1994) Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge: Cambridge University Press. Silbergleit R, Durkalski V, Lowenstein D, et al. (2011) Intramuscular versus intravenous therapy for prehospital status epilepticus. New England Journal of Medicine 366: 591–600. Treiman DM (1995) Electroclinical features of status epilepticus. Journal of Clinical Neurophysiology 12: 343–362. Treiman DM (2008) Generalized convulsive status epilepticus. In: Engel J Jr, and Pedley TA (eds.) Epilepsy: A Comprehensive Textbook, 2nd edn., pp. 665–676. Philadelphia: Lippincott Williams & Wilkins. Treiman DM (2009) Convulsive status epilepticus. In: Wheless JW, Willmore LJ, and Brumback RA (eds.) Advanced Therapy in Epilepsy, pp. 144–151. Shelton, CT: People’s Medical Publishing House. Treiman DM, Meyers PD, Walton NY, et al. (1998) A comparison of four treatments for generalized convulsive status epilepticus. New England Journal of Medicine 339: 792–798. Wasterlain CL and Treiman DM (eds.) (2006) Status Epilepticus: Mechanisms and Management. Boston: MIT Press.
Introduction
Etiology
The term status epilepticus (SE) has several definitions. Clinicians diagnose SE when epileptic seizures are repeated in rapid succession without full recovery between the seizures or there is continuous seizure activity that lasts longer than that in single seizures and does not exhibit the typical evolution of behavioral and electroencephalographic (EEG) features characteristic of single seizures. Thus, two or more seizures without full recovery of neurological function between the seizures defines SE for treatment purposes. However, epidemiological studies of SE usually require 30 min of continuous or repeated seizures without full recovery between the seizures for inclusion. There have been several recent proposals to lower the duration of continuous or repetitive seizure activity required to classify seizure activity as SE from 30 min to as few as 10 or even 5 min. However, such debates are not necessary if there is recognition that physiologically SE is a state in which changes in neuronal function (e.g., slowing on EEG, postictal confusion, and focal postictal paralysis) caused by an epileptic seizure are still present when another seizure occurs, so the patient or experimental animal is in a continuous epileptic state regardless of the duration of the seizure activity. Such changes accumulate if SE persists, which may account for the progression to refractoriness to treatment and increased consequences of prolonged SE.
There are many causes of SE. The most common are head trauma, tumor, cerebrovascular insults, and central nervous system (CNS) infection. Medication change or antiepileptic drug noncompliance is a common cause of SE in patients with established epilepsy. In children, chronic epilepsy, febrile seizures, CNS infection, and metabolic disease are the most common causes of SE; recurrent episodes occur most often in neurologically abnormal children. Recent reports have suggested that anti-N-methyl-D-aspartate (NMDA) receptor encephalitis may account for some cases of prolonged, medically refractory, generalized convulsive SE (GCSE) previously considered cryptogenic.
History SE was first described in a Babylonian medical text approximately 2500 years ago, but little was written about status subsequently until the nineteenth century when Calmeil introduced the term SE in 1825. Extensive clinical descriptions were provided in the late nineteenth and early twentieth centuries by Bourneville, Trousseau, and Clark and Prout. The modern study of SE started with the Marseilles Conference in 1964. International conferences were subsequently held in 1980, 1997, 2007, 2009, and 2011.
Epidemiology The incidence of SE is reported to be between 10 and 20/105 in Caucasians in developed countries, but an ascertainment and age-adjusted incidence of 61/105 was reported in Richmond, Virginia, where there is a large African-American population. This suggests a likely worldwide incidence of approximately 3 million per year, but adequate epidemiological data are not available to determine the worldwide incidence accurately determine the worldwide incidence. The incidence of SE is much higher in the very young (o1 year: 135–156/105) and the elderly over 65 (14.6–86/105).
Encyclopedia of the Neurological Sciences, Volume 4
Classification The classification of SE has been the subject of debate. Henri Gastaut, who drafted the first International Classification of Epileptic Seizures, suggested that there are as many types of SE as there are types of epileptic seizures, and he thought that classification of SE should be based on the International Classification. In his view, any seizure that lasts long enough or recurs frequently enough is a type of SE. Others have proposed more elaborate classifications in order to include epileptic syndromes characterized by repeated prolonged seizure activity, such as the childhood syndromes of electrical SE of slowwave sleep and Landau–Klefner syndrome. The following are the major types of SE: GCSE (either primarily or secondarily generalized tonic–clonic SE), complex partial SE (CPSE), simple partial SE, and absence SE. GCSE is the most common and most life-threatening type of SE. It accounts for approximately 70% of all cases of SE. It usually presents as repeated brief, time-limited convulsions, without recovery to full alertness and normal mental function between seizures. However, if the seizures are not stopped quickly, there is an evolution of the seizure activity from overt to subtle convulsive activity, such as subtle twitches of the fingers, face, or abdominal muscles and/or nystagmoid jerks of the eyes, and eventually to complete cessation of motor activity. There is also an evolution through a predictable series of EEG patterns, a progressive decline in responsiveness to antiepileptic drugs, and a progressive increase in the extent and intensity of neuronal damage. The terms overt, subtle, and electrical GCSE (which refer to the extent of the clinical convulsions) have been applied to these early and late presentations of GCSE. CPSE is much less common than GCSE but is recognized much more frequently than previously. CPSE presents as an ‘epileptic twilight state’ in which the patient is awake but only partially responsive to external stimuli and has no memory of the episode. Frequently, there is cycling between partial responsiveness and unresponsiveness. Absence SE (spike–wave
doi:10.1016/B978-0-12-385157-4.00302-X
297
298
Status Epilepticus
stupor) has similar clinical features but can be distinguished from CPSE by the occurrence of paroxysmal, bilaterally symmetrical, generalized 3 cycles per second spike–wave discharges, although sometimes the bifrontal spike–wave patterns seen in CPSE may be difficult to distinguish from generalized spike–wave discharges. There is controversy regarding the term nonconvulsive SE (NCSE). Some suggest NCSE is best reserved for absence SE and CPSE but many authors now use this term to refer to subtle or electrical GCSE in severely encephalopathic patients. Simple partial SE (SPSE) refers to repetitive motor or sensory seizure activity that occurs without any alteration of consciousness because the seizure activity remains confined to one cerebral hemisphere. The clinical features of the motor or sensory seizure activity are dependent on the area of the cortex from which the seizures start. A special case of SPSE is epilepsia partialis continua, in which focal motor seizure activity without alteration of consciousness continues for days to weeks or longer.
scalp. In GCSE, there is a predictable sequence of progressive EEG changes if SE is untreated or inadequately treated, and ictal activity continues. Initially, there are discrete electrographic seizures, which coincide with generalized convulsions and have the typical evolution of single generalized tonic–clonic seizures. Over time, the ictal discharges begin to merge together to produce a waxing and waning pattern, which is followed by continuous, generally monomorphic, ictal discharges that may persist for some time. Eventually, the continuous seizure activity is punctuated by periods of relative flattening, which become longer as the ictal discharges become shorter, until finally periodic epileptiform discharges on a relatively flat background develop as the last EEG pattern in this evolution. There is controversy regarding the interpretation of periodic epileptiform discharges, and some authors have considered these injury patterns, rather than an expression of ongoing seizure activity.
Pathophysiology Electroencephalography of Status Epilepticus Repetitive or continuous ictal discharges are seen in scalp recordings of all types of SE, except sometimes during simple partial SE when the area of ongoing seizure activity is so small that the ictal discharges are attenuated by meninges, skull, and
Table 1
SE occurs when there is a failure of the mechanisms (e.g., activation of Na þ –K þ ATPase, acidification of the extracellular fluid, blockade of NMDA channels, activation of K þ conductances, and release of k opioids or neuropeptide Y) that terminate a single seizure and normally produce a refractory period before another seizure can occur. Failure of such
Treatment protocol for generalized convulsive status epilepticus
Time (min)
Protocol
0
Establish the diagnosis by observing one additional seizure in a patient with recent seizures or impaired consciousness or by observing continuous behavioral and/or electrical seizure activity for 410 min. Start EEG as soon as possible, but do not delay treatment unless EEG verification of the diagnosis is necessary. Establish intravenous (IV) catheter with normal saline (dextrose solutions may precipitate phenytoin); with fosphenytoin, either dextrose or saline is acceptable. Draw blood for serum chemistry, hematological values, and antiepileptic drug concentrations. Check for hypoglycemia by finger stick. If hypoglycemia is present administer 100 mg of thiamine (if indicated) followed by 50 ml of 50% dextrose by direct push into the IV line. Administer lorazepam (0.1 mg/kg) by IV push (o2 mg/min). If status continues, start fosphenytoin (20 mg/kg PE) by fast IV push (up to 150 mg PE/min) directly into the IV port nearest to the patient; if only phenytoin is available, give by slow IV push (o50 mg/min); with either preparation, monitor blood pressure and electrocardiogram during infusion. If status continues after 20 mg PE/kg fosphenytoin (or 20 mg/kg phenytoin), administer an additional 5 mg/kg and, if necessary, another 5 mg/kg, to a maximum dose of 30 mg/kg. If status persists, support respiration by endotracheal intubation; give phenobarbital (20 mg/kg) by IV push (o100 mg/min) or, preferably, start barbiturate coma: Give pentobarbital (5–15 mg/kg) slowly as an initial IV dose to suppress all epileptiform activity and continue 0.5–5 mg/kg/h to maintain suppression; slow infusion rate periodically to determine cessation of seizure activity; monitor blood pressure, electrocardiogram, and respiratory function. If unable to suppress all epileptiform activity, change to continuous infusion of propofol (1 mg/kg given over 5 min, then 2–4 mg/kg/h; adjust to 1–15 mg/kg/h) or use midazolam (0.2 mg/kg bolus injection, followed by infusion of 0.05–0.5 mg/kg/h). Maintain full suppression of epileptiform activity (not a burst-suppression pattern) for 48–72 h before beginning to slow the infusion rate. Before beginning withdrawal of IV anesthesia, adjust phenytoin serum concentration to 30 mg/ml and load phenobarbital to achieve 100–150 mg/ml serum concentration. Alternatively, or in addition, load with valproate, 30 mg/kg, to achieve 120 mg/ml or levetiracetam, 50 mg/kg, or lacosamide, 10 mg/kg. Maintain these serum levels/doses as the anesthetic agent is slowed. If epileptiform activity returns during lightening of the induced coma, increase the infusion rate of the anesthetic agent (pentobarbital, propofol, or midazolam) to suppress all epileptiform activity for another 48–72 h before attempting anesthesia withdrawal again. Repeat as many times as necessary. Do not give up. Patients have recovered consciousness and useful existence after 42 months of coma.
5
10 25
60
460
Abbreviation: PE, Phenytoin equivalents. Source: Adapted with permission from Treiman DM (2009) Convulsive status epilepticus. In: Wheless JW, Willmore LJ, and Brumback RA (eds.) Advanced Therapy in Epilepsy, pp. 144–151. Shelton, CT: People’s Medical Publishing House.
Status Epilepticus
seizure-stopping mechanisms, or the occurrence of a strong excitatory stimulus, may result in repeated or prolonged seizures. A variety of acute neurological insults either lower seizure threshold or result in excessive excitation or inhibitory failure. Once status occurs, regardless of the precipitating cause, several mechanisms contribute to continuing seizure activity, including alterations in calcium- and calmodulin-dependent kinase II activity, increases in substance P, impairment of g-aminobutyric acid (GABA)-mediated inhibition, or altered GABAA receptor function due to structural rearrangement in the subunit composition of the GABAA receptor. Internalization of postsynaptic GABAA receptors and externalization of glutamate receptors in late SE have recently been recognized as a partial explanation for progressive resistance to treatment as SE progresses.
Management The initial management of SE is similar to that of other medical emergencies: Adequate airway, breathing, and circulation must be ensured. Then pharmacological therapy is started. A recent study demonstrated the utility of prehospital emergency treatment by paramedics using intravenous diazepam or lorazepam, and another recent prehospital treatment study found intramuscular midazolam to be at least as effective as intravenous lorazepam. In hospital management, most neurologists initiate treatment of all types of SE with intravenous administration of a benzodiazepine. Lorazepam is the most common benzodiazepine used, although diazepam, midazolam, or clonazepam (widely used in Europe) is also sometimes the initial drug. Lorazepam was the treatment most often effective at stopping GCSE in the only large head-tohead, blinded, randomized comparison of drug regimens used in the management of GCSE. Most neurologists follow benzodiazepine administration with fosphenytoin to provide long-term protection against the recurrence of SE, although several studies have shown lorazepam (but not diazepam or midazolam) to have a prolonged effective duration of action against SE. If SE is refractory to the initial two treatments, phenobarbital may be given next, although there is an increasing tendency to start intravenous general anesthesia at this stage. Intravenous general anesthesia is induced by continuous infusion of pentobarbital, midazolam, propofol, or sometimes diazepam or lorazepam. Management of refractory SE is done with continuous EEG monitoring in order to verify cessation of all seizure activity. Table 1 outlines a widely used treatment regimen for GCSE.
Morbidity, Mortality, and Prognosis Before the development of effective antistatus drugs, most patients with prolonged convulsive SE died during or shortly after the episode. However, even with effective treatment, the prognosis for survival at 30 days after the episode is
299
poor. Morbidity 30 days after an episode of overt GCSE is approximately 20% in most series, and was 65% 30 days after subtle GCSE in a large US Department of Veterans Affairs study. When GCSE is treated effectively, mortality is usually due to the underlying cause of the episode of SE. In patients who survive and recover fully, most are left with chronic epilepsy, even if they had no history of epilepsy before the episode of SE. If SE is not treated effectively, there is the potential for permanent neuronal damage, especially if seizure activity is prolonged. Neuronal damage in patients dying soon after an episode of SE and in experimental animals is most often seen in Sommer’s sector (prosubiculum and area CA1) of the hippocampus, layers 3, 5, and 6 of the cerebral cortex, the Purkinje cells of the cerebellum, the thalamus and basal ganglia, and the hypothalamus.
See also: Antiepileptic Drug Therapy. Cell Death. Domoic Acid. Epilepsy; Antiepileptic Drug Profiles. Epilepsy; Basic Mechanisms. Epilepsy; Drug Treatment Principles. Epilepsy; Experimental Models. Epilepsy; Overview. Epilepsy Pathology. Epilepsy Treatment Strategies. Epileptic Seizures. Epileptic Syndromes and Diseases. Epileptogenesis. GABAA Receptor Channels; Properties and Regulation. Neurotransmitter Receptors. Neurotransmitters; Overview. Organophosphates and Carbamates
Further Reading Alldredge BK, Gelb AM, Isaacs SM, et al. (2001) A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. New England Journal of Medicine 345: 631–637. Avanzini G, Treiman DM, and Engel J (2008) Experimental models of partial seizures and status epilepticus. In: Engel J Jr, and Pedley TA (eds.) Epilepsy: A Comprehensive Textbook, 2nd edn., pp. 415–444. Philadelphia: Lippincott Williams & Wilkins. Drislane FW (ed.) (2005) Status Epilepticus: A Clinical Perspective. Totowa, NJ: Humana Press. Gastaut H, Roger J, and Lob H (1967) Les e´tats de mal e´pileptiques. Paris: Masson. Kaplan P and Drislane F (eds.) (2008) Nonconvulsive Status Epilepticus. New York: Demos Medical Publishing. Shorvon S (1994) Status Epilepticus: Its Clinical Features and Treatment in Children and Adults. Cambridge: Cambridge University Press. Silbergleit R, Durkalski V, Lowenstein D, et al. (2011) Intramuscular versus intravenous therapy for prehospital status epilepticus. New England Journal of Medicine 366: 591–600. Treiman DM (1995) Electroclinical features of status epilepticus. Journal of Clinical Neurophysiology 12: 343–362. Treiman DM (2008) Generalized convulsive status epilepticus. In: Engel J Jr, and Pedley TA (eds.) Epilepsy: A Comprehensive Textbook, 2nd edn., pp. 665–676. Philadelphia: Lippincott Williams & Wilkins. Treiman DM (2009) Convulsive status epilepticus. In: Wheless JW, Willmore LJ, and Brumback RA (eds.) Advanced Therapy in Epilepsy, pp. 144–151. Shelton, CT: People’s Medical Publishing House. Treiman DM, Meyers PD, Walton NY, et al. (1998) A comparison of four treatments for generalized convulsive status epilepticus. New England Journal of Medicine 339: 792–798. Wasterlain CL and Treiman DM (eds.) (2006) Status Epilepticus: Mechanisms and Management. Boston: MIT Press.