SEMINARS I N NEUROLOGY-VOLUME
10, N O . 4 DECEMBER 1990
Status Epilepticus: Concepts in Diagnosis and Treatment
Status epilepticus (SE), or prolonged seizures, represents a serious medical and neurologic emergency. SE has been defined through the International Classification of Epileptic Seizures as a seizure lasting for more than 30 minutes or intermittent seizures lasting for more than 30 minutes from which the patient does not regain consciousness.' This definition applies to any seizure type. Thus, any seizure that lasts for more than 30 minutes must be classified as SE. The first major step in treating SE is making the correct diagnosis.' It is essential that the length of all seizures be determined as accurately as possible. This is the only way that the definition or diagnosis of SE can be regularly made. T h e most dramatic and familiar type of SE is generalized tonic-clonic. This type of SE was previously described as persistent grand ma1 seizures. It is difficult not to make this diagnosis correctly, since the generalized tonic-clonic seizures usually continue indefinitely until treatment is initiated. Other types of SE can be more difficult to diagnose, especially generalized absence SE or partial complex SE. Because of the significant mortality and morbidity associated with SE and its common occurrence, it is essential that the clinician be familiar with this condition.
MAKING THE DIAGNOSIS Seizures are usually self-limiting and vary in duration from approximately a few seconds to several minutes. Seizures are common medical phenomena that occur in as high as 2% of children and 1% of the adult population."." Generalized tonic-
clonic seizures (grand ma1 seizures) are readily identified by the physician and are less difficult to diagnose. However, more subtle types of seizure disorders may be more difficult to recognize. All seizure types are usually self-limiting. However, when a seizure of any type does not stop on its own, the transition between a single seizure and SE begins. This transition between an individual seizure and continuous seizure activity must be recognized. In earlier literature it was not clear how long the transition from a seizure to SE should take. In more recent years, a clear and precise definition of SE has been developed through the International Classification of Epileptic Seizures. T h e establishment of and agreement on this international definition, previously cited, have made the diagnosis of SE more specific. T h e first step in treating SE is to make the correct diagnosis. As opposed to many self-limiting seizure conditions, SE does not have a benign prognosis. Delaying the diagnosis of SE puts the patient at risk for increased associated mortality and morbidity. The most common error in diagnosing SE often occurs when the patient presents to the emergency room. By the time the physician arrives at the bedside, the patient may have been stabilized or have been under treatment by ambulance or emergency room staff for a prolonged period of time. If a careful history including the duration of seizures en route to the hospital and in the emergency room is not obtained, the diagnosis of SE may be missed. This error is a common problem in diagnosing SE. Because of the significant morbidity and mortality associated with SE, patients need
Professor and Chairman of Neurology, Professor, Departments of Pharmacology and Biochemistry, Director, Molecular Neuroscience Research Facility Neurologist-in-Chief, Medical College of Virginia Hospitals Reprint requests: Dr. DeLorenzo, Department of Neurology, Medical College of' Virginia, P.O. Box 599, MCV Station, Richmond, VA 23298-0599 Copyright O 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 100 16. All rights reserved.
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Robert J . DeLorenzo, M.D., Ph.D., M.P.H.
STATUS EPILEPTICUS-DELORENZO Table 1. Diagnostic Types of Status Epilepticus Generalized status epilepticus 1. Generalized tonic-clonic status epilepticus (grand mal) 2. Generalized tonic status epilepticus 3. Generalized clonic status epilepticus 4. Generalized myoclonic status epilepticus 5. Generalized absence status epilepticus (petit mal) Partial status epilepticus 1. Simple partial status epilepticus 2. Complex partial status epilepticus Nonepileptic status epilepticus 1. Pseudo (hysterical) status epilepticus 2. Decorticate or decerebrate posturing
associated with a higher percentage of' morbidity .~ patients will have a partial or and m ~ r t a l i t ySome focal onset with secondary generalization, but most patients will present with generalized tonic-clonic symptoms. T h e generalized tonic-clonic movements associated with this condition when lasting for more than 30 minutes can produce significant trauma to the patient through repeated movements of the body. Respiratory arrest, hyperthermia, and acidosis are also major problems associated with this type of SE.
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to be followed and watched carefully following- the cessation of seizures. Diagnosis of SE often depends therefore on obtaining a careful and detailed history of the type and duration of' seizure activity. Appropriate questioning of the family, the ambulance or emergency vehicle transport personnel, hospital nurses, and emergency room staff is essential. Another more subtle problem in diagnosis occurs when subclinical seizures produce symptoms that are not readily associated with a seizure disorder. Thus, patients who present with prolonged alterations in the mental status examination or alterations in state of consciousness must be considered potential candidates for a diagnosis of subclinical SE. T h e electroencephalogram (EEG) is an essential part of diagnosis in any patient with altered mental status. These patients will often have a normal computerized tomographic (CT) or magnetic resonance imaging (MRI) scan, but a dramatically abnormal EEG. The types of subtle seizure disorders described further in this text should be well understood.
TYPES OF STATUS EPILEPTICUS T h e most common and well-recognized type of SE is tonic-clonic or convulsive SE. Generalized tonic-clonic SE was previously described as grand ma1 SE. This condition is associated with a high morbidity and mortality. In addition to this wellrecognized form of SE, any seizure type can develop into SE. T h e International Classification of' Epileptic Seizures can be used as a guide for diagnosing SE. By obtaining a careful seizure history and observing the patient during the episode of SE, the type of seizure phenomena can be readily d i ~ c e r n e d In . ~ addition to using the International Classification of Epileptic Seizures, three broad groupings are often employed to characterize SE: (1) Convulsive SE-primarily generalized tonicclonic seizures; (2) nonconvulsive SE-most commonly associated with generalized absence (petit ma1 status) or complex partial SE; and (3) nonepileptic seizures-primarily representative of hysterical (pseudo) seizures or decerebration and decortication. T h e following description can be used as a general guide to diagnosing the different types of SE (Table 1).
Generalized Tonic Status Epilepticus Tonic SE is not commonly observed clinically and is most often seen in children with the Lennox-Gastaut syndrome. T h e ictal motor activity seen with tonic SE may be almost imperceptible in some cases, making the EEG identification of this condition essential. Tonic SE is often associated with EEG findings consisting of generalized electrodecremental activity or bursts of recruiting epileptiform rhythms.
Generalized Clonic Status Epilepticus Clonic SE is another rare condition and is usually seen only in infants and children. It is characterized by bilateral low-amplitude jerking, often asymmetrical and asynchronous. T h e EEG demonstrates bilateral bursts of high amplitude delta activity with intermixed spikes in most situations.
Generalized Myoclonic Status Epilepticus GENERALIZED STATUS EPZLEPTZCUS
Generalized Tonic-Clonic Status Epilepticus Generalized tonic-clonic SE is the most com. ~ is also mon form seen in large clinical ~ e r i e s It
Myoclonic SE occurs in children presenting with bilateral myoclonus with preserved consciousness. It also occurs in children and adults secondary to acute or subacute brain disorders such as anoxia, hypoxia, renal or liver encephalopathy, viral
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Generalized Absence Status Epilepticus Generalized absence seizures can present with a clouding of consciousness or a fuguelike state. Another term for this condition is the continuous twilight state. These symptoms are accompanied by generalized 3 Hz spike-wave discharges in either closely spaced bursts o r uninterrupted activity lasting for 30 minutes or longer. Generalized absence SE is the most common form of nonconvulsive SE. This is an important condition to recognize because it is treatable. It can produce a long-term alteration of memory or consciousness. Generalized absence status is also associated with a significant morbidity and mortality, although this type of SE usually has a better prognosis than generalized tonic-clonic SE. It is much more common in children and adolescents, but it can be seen in adults. Any patient who presents with an altered level of consciousness or a fuguelike state should be evaluated with an EEG.
PARTIAL STATUS EPILEPTZCUS
Simple Partial Status Epilepticus Simple partial SE represents a continuous partial (focal) seizure without secondary generalization, which may be motor, somatosensory, autonomic, dysphasic, psychic, o r combinations of these types. Patients are diagnosed as having simple partial SE when they have evidence of focal epileptiform activity associated with clinical manifestations lasting continuously for 30 minutes or longer. Somatomotor SE is most commonly seen. Focal cortical lesions in the motor or sensory cortex can produce seizure activity that lasts for long periods of time. Thus, a twitching arm can be produced by a contralateral seizure focus firing in the motor cortex of the arm. This type of SE is widely seen following brain injuries or tumors. Simple somatomotor SE is most commonly seen with seizure activity in an extremity or facial muscles. In these types of seizures, loss of consciousness is unusual, although secondary generalization can occur. Secondary generalization is less common than might be expected, and why generalization is not more common with this type of persistent simple partial seizure condition is unknown.
Complex Partial Status Epilepticus Complex partial SE presents with a broad range of motor and behavioral symptomatology.7 One type of presentation of this syndrome is partial responsiveness or altered personality. Any patient who presents with an acute change in behavior without any evidence of underlying causes should receive an EEG. This presentation is important in the differential diagnosis of psychiatric disorders. Patients can present with semipurposeful automatism~, speech arrest, stereotypical automatisms or total unresponsiveness as a form of partial complex SE. T h e presentation of an acute confusional state or altered mental status should also be included in the differential of partial complex SE. EEG analysis is essential in making the diagnosis. This condition also responds dramatically to intravenous (IV) benzodiazepine therapy, with clearing of neurologic symptoms and resumption of more normal EEG activity. Aphasic SE is a recognized syndrome that is best described as an episode of aphasia that may last from hours to days, associated with persistent EEG findings8 Thus, any patient with persistent aphasia should receive an EEG to rule out this rare syndrome. This condition represents a treatable cause of aphasia. The acute presentation of aphasia with no other evidence of cerebrovascular disease should always raise the question of aphasic SE, which is a form of complex partial, nonconvulsive SE. NONEPZLEPTZC STATUS EPILEPTIC US
Nonepileptic SE is difficult to diagnose definitively. T h e true incidence of hysterical seizures is However, in refractory epinot well establi~hed.~ lepsy patients referred to major epilepsy centers, hysterical seizures comprise as high as 10% of the seizures. T h e term "pseudoseizures" is often used to describe these nonepileptic seizures. Pseudoseizures cannot be differentiated from generalized SE or other types of SE syndromes based on clinical observation alone. All patients must be treated as if they have a primary convulsive or nonconvulsive condition until more definitive diagnostic information can be obtained. T h e diagnosis of nonepileptic or pseudoseizures should be considered when the usual response to anticonvulsapt medications is not seen, or when it is difficult tb explain an intractable seizure disorder. T h e absence of EEG epileptic activity during the clinical symptomatology strongly suggests the diagnosis of pseudoseizures. However, surface EEG recordings may be normal or show
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and degenerative disorders. Myoclonic SE due to these metabolic or infectious conditions usually carries a grave p r ~ g n o s i s . ~
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STATUS EPILEPTICUS-DELORENZO
very subtle changes in patients with subcortical or limbic seizures. Pseudoseizures are difficult to diagnose and are a challenge even for the expert epileptologist. Decorticate or decerebrate posturing can be persistent and produce repetitive movements that can be mistaken for seizure activity. Thus, these persistent movements can mimic tonic-clonic or tonic SE. The history, circumstances, and clinical presentation of the case usually differentiate these patients from those with actual seizure activity. 'The EEG can also be helpful in making the differential diagnosis.
patients seen in most large series. Metabolic disorders also represent a major cause of SE, accounting for 10 to 15% of cases seen in most large series. Not all patients presenting with SE have a previous history of a seizure disorder. As shown in Table 2, approximately one fifth of patients who develop SE have a history of epilepsy. Thus, the majority of patients who present with SE d o not have a previous history of epilepsy. Several common medical and surgical conditions can cause SE. A majority of SE patients in a large metropolitan general hospital will present on non-neurologic services. Thus, all clinicians should be familiar with this serious medical and neurologic emergency.
ETIOLOGIES OF STATUS EPILEPTICUS
Table 2. Causes of Status Epilepticus in 280 Patients from the Medical College of Virginia Status Epilepticus Data Base Etiology
Percent
Withdrawal of anticonvulsants
21
Alcohol withdrawal
18
Anoxia Hypotension Cerebrovascular disease Hemorrhage Metabolic disorders
2 4
21 7
13
Infectious disorders
4
Tumors
3
Other
7
Mortality rates in SE in several large studies have varied. Over the last 20 years, several studies have accumulated more than 100 patients. T h e mortality rates have varied from 8 to 50%.4,5,10-18 The precise mortality rate is not the important issue. Even a mortality of 8 to 10% represents a significant death rate for any neurologic disease. These mortality data indicate that at least 1 of 10 patients who develop SE will die. Initial studies on the mortality of SE in children included a high mortality rate.14 However, more recent investigations have indicated that children have a lower morbidity and mortality than adults.ls At the present time, it is difficult to d o carefully controlled, validated studies on the incidence or prevalence of SE. Recent data from the Medical College of Virginia Status Epilepticus Database indicate, in a validated database, that the mortality rate of SE may approach as high as 20 to 30%, when all cases in the population are ascertained.Ig The associated high mortality of SE emphasizes the importance of treating this condition as a major medical and neurologic emergency. Since all of the large reported SE mortality figures have come from large academic medical centers, it is important to determine if similar mortality rates are seen in private hospital settings. Recent studies have demonstrated that the mortality rate of SE in a community population, and the community hospital population, parallels that of the major medical center.'"hese data suggest that the high mortality rate associated with SE is not a feature uniquely associated with a major medical center, but is major concern to physicians in practice in the community settings as well. There is clinical agreement that it is essential to initiate treatment for SE rapidly. Evidence is accumulating suggesting that early treatment, with
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MORTALITY IN STATUS EPILEPTICUS
Once the diagnosis of SE is made, the clinician must immediately consider the possible cause of the prolonged seizures. Treatment of SE, although directed at the control of the seizures, must also take into account the underlying etiology of' the SE. In some cases, these etiologies require aggressive treatment o r surgical intervention. Table 2 presents the etiologies of 280 adult cases of SE from the Medical College of Virginia Status Epilepticus D a t a b a ~ eThese .~ etiologies are typical of several other large st~dies.".'~." The causes of SE shown in 'Table 2 are divided into ten major groups: withdrawal of anticonvulsants, anoxia, hypotension, alcohol-related SE, metabolic disorders, infectious disorders, cerebrovascular disease, tumors, hemorrhage, and other. As can be seen from the data presented in Table 2, there are three major causes associated with SE: cerebrovascular disease, alcohol-related SE, and withdrawal of arlticonvulsant medications. Each of these categories represents about one fifth of' the
decrease of seizure duration, prevents significant morbidity and mortality in many cases. It is also essential to initiate treatment of serious, life-threatening neurologic or medical conditions that may underlie SE. In centers where effective treatment modalities are available with appropriate support personnel, it is rare that a patient dies during treatment o r during SE itself. Mortality from this condition is usually seen in the first week or two following the episode of SE. The cause of death and whether it is more related to SE itself or the underlying etiology of the SE has not been clearly elucidated at this time. Further studies to address this question may provide useful prognostic indicators for mortality and morbidity.
TREATMENT OF STATUS EPILEPTICUS Management and treatment of SE require a timely and organized treatment plan. It would be
V O L U M E 10, NUMBER 4 DECEMBER 1990
desirable to have a rigid protocol for the treatment of SE that requires little thought and can be initiated in a rapid and timely fashion. However, this is not always possible, since SE may vary in presentation and the patient's condition may have certain idiosyncratic aspects relating to reactions to drug therapy or clinical presentation. There are also differences between available emergency staff and support equipment from major medical centers to community hospitals. Taking these variations into account, a generalized treatment program for SE in adults and children has been developed at the Medical College of Virginia Status Epilepticus Research Center. This treatment plan was developed drawing on the available literature for treatment of SE, the experience at the university epilepsy center, and the experience from community hospitals in the Greater Richmond Metropolitan Area. It is suggested that this type of treatment plan be developed in each hospital or community setting and be reviewed as part of an ongoing quality assur-
Table 3. Status Epilepticus Treatment for Adults: Medical College of Virginia Hospitals Protocol* Steo
Time Frame of Procedure
Intervention
~p
1.
6.
400
- - -
0-5 minutes
Determination of SE. As soon as the diagnosis is made, institute monitoring of blood pressure, temperature, pulse, respiratory ECG and EEG, Insert oral airway and administer oxygen if necessary. Insert an intravenous catheter and draw venous blood for anticonvulsant levels, glucose, electrolytes, calcium, magnesium, blood urea nitrogen, and complete blood count. Draw arterial blood for arterial blood gases. Obtain urine for urinalysis and toxic screen if indicated. Nasotracheal suction if necessary is performed
6-9 minutes
An intravenous line is placed with normal saline containing vitamin B complex. A bolus of 50 ml of 50% glucose is given
10-30 minutes
Infuse IV lorazepam given at a rate of 2 mglmin (0.1 mglkg) to a maximum dose of 5 mg or alternatively administer IV diazepam given at a rate not to exceed 2 mglmin until seizures stop or to a total of 20 mg. This is followed by IV phenytoin, 20 mglkg at a rate no faster than 50 mglmin. If seizures not controlled, a repeat bolus of phenytoin at 10 mglkg can be given before proceeding to step 4. Monitor ECG and blood pressure
31-60 minutes
If seizures persist, elective endotracheal intubation is recommended before starting a bolus infusion of phenobarbital at a rate no faster than 100 mglmin until seizures stop or to a loading dose of 20 mglkg
1 hour
If control is still not achieved, other options include: a. Pentobarbital with an initial IV loading dose of 5 to 10 mglkg, with additional amounts given to produce a burst-suppression pattern on EEG. Maintenance of pentobarbital anesthesia is continued for approximately 4 hours by an infusion of 1-3 mglkglhr. After this time, the patients are checked for reappearance of seizure activity by decreasing the infusion rate. If clinical seizures and/or generalized EEG discharges persist, the procedure is repeated; if not, the pentobarbital is tapered over 12 to 24 hours b. Paraldehyde is given either by the intravenous (no longer available) or rectal route at a dose of 0.1 to 0.15 mllkg after being diluted in normal saline every 2 to 4 hours if necessary c. Diazepam (50 to 100 mg) is diluted in a solution of 500 ml 0.9% NaCl or D5W and run as a continuous infusion to achieve blood levels of 0.2 to 0.8 mglml. The IV solution is changed every 6 hours as advised by certain authors and short length IV tubing is used
60-80 minutes
If seizures are still not controlled, the anesthesia department is called and general anesthesia with halothane and neuromuscular blockade is begun
'Continuous EEG monitoring is recommended in the obtunded patient to assure that SE has not reoccurred. In the management of intractable status, a neurologist who has expertise in SE should be consulted and advice from a regional epilepsy center should be sought.
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SEMINARS I N NEUROLOGY
STATUS EPILEPI'ICUS-DELORENZO
Stea 1.
6.
Status Epilepticus Treatment for Pediatrics: Medical College of Virginia Hospitals Protocol Time Frame of Procedure
Intervention't
0-5 minutes
Determination of SE. As soon as the diagnosis is made, institute monitoring of temperature, blood pressure, pulse, respiratory ECG and EEG, Insert oral airway and administer oxygen if necessary. Insert an intravenous catheter and draw venous blood for anticonvulsant levels, glucose (check Dextrostik), electrolytes, calcium, blood urea nitrogen, and complete blood count. Draw arterial blood for arterial blood gases. Treat elevated temperature with rectal antipyretics (acetaminophen). Frequent suction
6-9 minutes
An intravenous line is placed with normal saline. A bolus of 2 cclkg 50% glucose is given
10-30 minutes
Initial treatment consists of an infusion of IV lorazepam given at a rate of 1-2 mglmin (0.1 mglkg) to a maximum dose of 5 mg. This is followed by IV phenytoin at 18-20 mgl kg infused at a rate no faster than 1 mglkgimin or 50 mgimin. Monitor ECG and blood pressure
31-60 minutes
If seizures persist, administer a bolus infusion of phenobarbital at a rate no faster than 50 mgimin until seizures stop or to a loading dose of 20 mg/kg
1 hour
If control is still not achieved, other options include: a. Diazepam 50 mg is diluted in a solution of 250 ml 0.9% NaCl or D5W and run as a continuous infusion at 1 cclkglhr (2 mglkglhr) to achieve blood levels of 0.2 to 0.8 mglml. The IV solution is changed every 6 hours as advised by certain authors and short length IV tubing is used b. Pentobarbital with an initial IV loading dose of 5 mglkg with additional amounts given to produce a burst-suppression pattern on EEG. Maintenance of pentobarbital anesthesia is continued for approximately 4 hours by an infusion of 1-3 mglkglhr. After this time, the patients are checked for reappearance of seizure activity by decreasing the infusion rate. If clinical seizures or generalized EEG discharge persist, the procedure is repeated; if not, the pentobarbital is tapered over 12 to 24 hours
60-80 minutes
If seizures are still not controlled, the anesthesia department is called and general anesthesia with halothane and neuromuscular blockade is begun
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Table 4.
*Continuous EEG monitoring is recommended in the obtunded patient to assure that SE has not reoccurred. In the management of intractable status, a neurologist who has expertise in SE should be consulted and advice from a regional epilepsy center should be sought. Lumbar puncture should be done as soon as possible, especially in the febrile child or infant younger than 1 year. tFor infants with a history of neonatal seizures, infantile spasms, or early-onset seizures, pyridoxine 100 mg IV should be given while under EEG monitoring to diagnose and treat the rare B, dependency patient with seizures.
ance program. The treatment protocols shown for adults in Table 3 and children in Table 4 were developed at the Medical College of Virginia Epilepsy Center. These treatment plans can be utilized directly or form the basis of developing a customized treatment program for each medical center. Since SE does not occur as frequently as other major medical emergencies, such as myocardial infarction, stroke, or trauma, having a protocol readily available in the emergency room or on the hospital floors coordinates management among medical, nursing, and paramedical personnel. Placing the protocols prominently in these settings and reviewing them in ongoing quality assurance and risk management programs are essential in providing excellent care for the treatment of SE. The protocols shown in Tables 3 and 4 are primarily used for the treatment of generalized tonic-clonic SE. The following material details several important aspects of these treatment plans. TREATMENT OF STATUS EPZLEPTZCUS IN THE ADULT
The Medical College of VirginialVirginia Commonwealth University protocol for treating SE in
the adult is shown in Table 3. This treatment protocol represents a synthesis of clinical experience by university and community physicians in addition to drawing on the existing literature on treatment for SE.20-24It is primarily for treatment of generalized tonic-clonic SE, but can be used in the treatment of partial complex SE.
Making the Diagnosis The high mortality and morbidity associated with SE make it essential to first diagnose as quickly and as accurately as possible. Making the diagnosis quickly assures that the treatment protocol can be put into effect in a timely manner. Delay in making the diagnosis can put the patient at considerable risk for morbidity and mortality. Emergency room staff and hospital personnel must be alerted to this condition through routine in-service education programs that highlight the importance of recognizing seizures that last for more than 20 minutes as potential candidates for developing into SE. An appropriately trained
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SEMINARS IN NEUROLOGY
Stabilization of the Patient
402
As in any medical emergency, the patient should be stabilized medically and an intravenous (IV) line initiated. Many causes of SE can also produce significant cardiovascular and autonomic changes. Thus, the vital signs of the patient are essential in evaluating SE. The intravenous line is usually supported with normal saline, since this is the most common compatible IV solution for the administration of IV phenytoin. Supplementation with vitamin B complex can also be initiated. Other IV solutions can be considered, depending on the patient's medical condition, age, and the possibility of underlying hypertension. The decision tree recommended in Table 3 serves as a model for initially stabilizing the patient. EEG recording and C T scanning, as rapidly as possible, are also invaluable in determining the underlying etiology and making the electrophysiologic diagnosis of SE. C T scanning is essential in ruling out any mass lesions or other contraindications for lumbar puncture. Occasionally, patients will regain consciousness rapidly following generalized tonic-clonic SE. This is not common, since most patients will have at least a 30-minute to 2-hour postictal coma or lethargy. However, those patients who do awake more rapidly should also be observed carefully. Although the prognosis is usually better with rapid recovery, this has not been clearly ascertained statistically and at least 24 hours of observation are recommended for patients who have undergone seizures for more than 30 minutes. Patients recovering from SE should be hospitalized on a neurologic service or appropriate medical service. Patients who do not recover rapidly from the postictal state benefit from hospitalization in a neurologic or medical intensive care unit. Careful observation and recording of vital signs with simultaneous EEG recording are invaluable in avoiding complications.
Medical Treatment
The major anticonvulsant of first choice for treatment of SE at the Medical College of Virginia Hospitals is phenytoin. It is effective in controlling SE, often rapidly;22,23 it also has the advantage of not being highly sedative. In many patients, seizures will stop following loading with IV phenytoin. Treatment should begin as rapidly as possible after the diagnosis has been made. Initiation of therapy involves the use of 18 mglkg of phenytoin. The rate of infusion should not exceed 50 mglmin. Intravenous phenytoin preparations are not soluble in most IV solutions except for normal saline. It is imperative that phenytoin not be administered with 5% dextrose in water (D5W) or other IV solutions that will not maintain the solubility of this compound. Following phenytoin administration, if the patient stops having seizures, it is anticipated that the patient should wake up following the postictal phase of SE. The phenytoin itself should not produce any significant increase in the duration of coma. Because of this rapid distribution and effectiveness in treating SE, IV administration of phenytoin should be routinely available in hospital emergency rooms and on hospital floors, but it must be given carefully to any patient with compromised cardiac output. Cardiovascular complications caused by phenytoin affecting cardiac output and blood pressure can be significant if the accepted dose and rate of administration are not f~llowed.'~ Most healthy individuals tolerate the recommended phenytoin dosage and rate of administration. Significant side effects are rare and phenytoin is a safe and effective treatment for SE. Simultaneous electrocardiographic (ECG) and blood pressure monitoring, if available, is recommended whenever SE is being treated. It is especially advisable in elderly patients or in patients with a compromised cardiovascular condition. If a patient is sensitive to phenytoin and the heart rate or blood pressure decreases, the rate of administration can be decreased or infusion can be stopped. This usually results in a rapid reversal of the cardiovascular effects. Although phenytoin is the first choice as a major anticonvulsant in the treatment of SE, in most emergency rooms and hospital settings a benzodiazepine is usually administered as the initial treatment modality. Intravenous diazepam is the most common initial treatment for SE." When lorazepam is available, it is often given. Diazepam is given intravenously at a rate not to exceed 2 mglmin until the seizure stops or a total of 20 mg is administered. It is essential to follow the rate of administration of diazepam carefully, since idiosyncratic
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emergency vehicle staff person would arrive at an emergency room with a patient who has been having seizures for 20 minutes and immediately indicate that this patient is at high risk for developing SE. Appropriate neurologic o r medical consultation can be obtained immediately and the situation is already recognized as a potential emergency. It is also important to document clearly the duration of seizures in the emergency room or hospital chart. If the physician arrives after the seizures have already been controlled with treatment, the diagnosis of SE may be missed.
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ever, a small percentage of the seizures may still be resistant to this treatment and further medical management will be indicated. At this point, it should be evident that these patients are severely compromised. The seizures will probably have persisted for more than an hour by this time. This population of patients represents an especially vulnerable group for developing morbidity or dying. A diazepam intravenous drip is effective for obtaining further control in SE. Diazepam, 50 to 100 mg, is diluted into 500 ml of 0.9% sodium chloride or D5W. This solution can be run as a continuous infusion to achieve a blood level ranging from 0.2 to 0.8 mglml. Continuous diazepam infusion must be administered with extreme caution. Diazepam can cause idiosyncratic respiratory arrest if infused too rapidly. This type of treatment is usually administered only in an intensive care unit setting with controlled IV administration. As already described, lorazepam infusion can also be utilized for further control in SE. However, this has not been widely utilized as a second-line anticonvulsant in refractory cases. Further evaluation of the effect of lorazepam in this setting is being investigated. Several additional regimens have been effective in eventually controlling SE following initial treatment with phenytoin and phenobarbital. A paraldehyde drip may be used. Paraldehyde is an effective anticonvulsant. However, it is no longer readily available in most hospital emergency rooms or inpatient settings. Paraldehyde can be administered rectally in a dose of 0.1 to 0.15 mglkg after being mixed 1: 1 with mineral oil. Rapid absorption of rectal paraldehyde provides effective anticonvulsant treatment in SE. Paraldehyde can be administered through a Foley catheter that has been inflated in the rectum to assure that the drug remains in contact with the rectal mucosa for absorption. Paraldehyde, however, is less Likely to be used in most clinical settings; it is unpopular because of its smell, its solubility problems, and its route of administration. Intravenous paraldehyde can also be administered, but this is more difficult and has complications. Pentobarbital anesthesia is also an effective treatment for further control of intractable SE." An initial IV loading dose of 5 mglkg of pentobarbital is given to produce a burst-suppression pattern on the EEG. Following this initial dose, pentobarbital anesthesia can be continued for as long as 3 hours by infusion of 1 to 3 mglkglhr. Intubation and respiratory support are essential. T h e paResistance to Treatment tient should also be continuously monitored with an EEG. If the seizure activity ceases with pentoThe majority of SE cases will be successfully barbital administration, it is usually advisable to treated with phenytoin and phenobarbital. How- wait 2 to 3 hours before tapering the pentobarbital.
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respiratory arrests can be precipitated by rapid administration. Lorazepam is administered at a rate of 2 mglmin to a dose of 1 mglkg and can be repeated at 10 to 15-minute intervals if the seizures persist.20 Benzodiazepine therapy for SE is often initiated first because benzodiazepines are readily available in most emergency room and hospital ward settings. At the initiation of a seizure, it is also not possible to determine if the patient will stop spontaneously or progress to SE. Intravenous diazepam is usually effective in treating a single seizure and is often initiated for this reason. If the seizures persist past 20 to 30 minutes and the diagnosis of SE is made, then major anticonvulsant therapy can be initiated. Diazepam treatment is short acting and an initial diazepam treatment is usually effective for only 10 to 20 minutes following the initial IV bolus. Thus, if other therapy is not available except for diazepam, its effect must be reenforced at regular intervals. Lorazepam has an advantage because its effects appear to be longer lasting with initial treatment. When seizures persist following the initial treatment with phenytoin or phenytoin plus a benzodiazepine, endotracheal intubation and initiation of phenobarbital infusion are recommended. Phenobarbital, which is a useful second anticonvulsant in the treatment of SE following phenytoin, is listed in some university hospital protocols as the first-line anticonvulsant. However, because of its sedative properties, it is used in our protocol as a second-line anticonvulsant. Phenobarbital is administered intravenously at a rate not to exceed 100 mglmin until the seizures stop or a loading dose of 20 mglkg has been reached. Phenobarbital is a potent anticonvulsant and, usually, when combined with phenytoin, is effective in stopping SE in the majority of cases. Because of its sedative properties and respiratory suppression, its use must be considered with caution; the availability of intubation and respiratory assistance is advisable whenever phenobarbital is administered at these doses. Patients loaded with phenobarbital at a dose of 20 mglkg will often remain sedated for at least 12 to 24 hours. This makes it much more difficult to evaluate the postictal state of the patient and the recovery related to the SE and its underlying cause. Patients who receive phenobarbital require more careful monitoring and observation following SE.
103
Careful EEG monitoring can document the recurrence of seizures, and more pentobarbital can be administered. Titration of seizure control with pentobarbital can be very useful in some intractable cases. In the very remote possibility that pentobarbital is not effective in controlling seizure activity, general anesthesia with halothane and neuromuscular blockade may be initiated with the assistance of an anesthesiologist. TREATMENT PROTOCOL FOR CHILDREN
The treatment protocol utilized for children at the Medical College of Virginia Hospital complex is summarized in Table 4. This treatment protocol is similar to the protocol used for adults, with some modifications. There is still more variability at the present time in the treatment of SE in children than in adults. However, over the last several years more consistency and agreement have developed among clinicians. The diagnosis and treatment of seizures in the neonatal period are extremely difficult, especially since seizures may be subtle and electrical SE may be present without associated movements or clinical features. Because neonatal seizures are a special problem, the SE protocol presented in Table 4 is applicable only to infants older than 6 months of age. The pediatric population also represents a special challenge in making an early diagnosis and initiating rapid treatment of SE. Young children have a significant difference in surface area to volume ratios in comparison with adults. Thus, there is often difficulty in managing fluid and the associated metabolic complications. SE can thus be associated with more difficult medical management problems in the child. T h e pediatrician must be especially diligent in stabilizing the patient. Following initial stabilization and establishment of the diagnosis of SE, anticonvulsant treatment is initiated. The Medical College of Virginia protocol utilizes intravenous lorazepam given at a rate of 1 to 2 mglmin to a maximum dose of 5 mg as the initial treatment. T h e appropriate loading dose is 0.1 mg/kg for this medication in children. Following intravenous lorazepam, phenytoin is initiated as the first-choice major anticonvulsant. Phenytoin is given at a dose of 18 to 20 mglkg, to a total dose of 20 mglkg. It cannot be given faster than 1 mglkg per minute. Continuous ECG monitoring is recommended during phenytoin treatment in the pediatric population also. Blood pressure monitoring, if available, is helpful. If the seizures are resistant to phenytoin treatment, initiation of phenobarbital therapy is the second
VOLUME 10, NUMBEK 4 DECEMBER 1990
choice for anticonvulsant treatment as described in Table 4. SE will be stopped in the majority of children with phenytoin and benzodiazepine or phenytoin and phenobarbital administration. Intractable SE is not common but occurs in the pediatric population somewhat more commonly than in adults. The treatment protocol shown in Table 4 recommends further treatment for intractable seizures similar to the adult protocol. Paraldehyde has been found to be especially useful in the treatment of intractable SE in children, although this medication is now difficult to obtain. Children or infants with a history of neonatal seizures, infantile spasms, or early-onset seizures should also receive intravenous pyridoxine (vitamin B,), 100 mg, given intravenously during the initial stabilization. Pyridoxine should be given while the EEG is being monitored to allow for the diagnosis of the rare B, deficiency-induced seizures. SE is a common medical emergency in children. However, recent studies indicate that the mortality rate in children treated rapidly and effectively is lower than in the adult population.lx Rapid treatment needs to be initiated to maintain this lower mortality. REFERENCES Delgado-Escueta AV, Wasterlain GC, Trieman DM, Porter RJ. Status epilepticus. New York: Raven Press, 1983 DeLorenzo KJ. Status epilepticus. In: Johnson KI',ed. Current therapy in neurological disease -3. Philadclphia: B.C. Decker, 1990;3:57-83 DeLorenzo RJ, Towne AR. Epilepsy. I n : Appel S H , e d . Current neurology. Chicago: Year Book Medical Publishers, 1989;9:27-76 Hauser A. Status epilepticus: frequency, etiology, a n d neurological sequelae. Adv Neurol 1983;34:3-14 Leppik IE. Status epilepticus. Neurol Clin 1986;4:63:443 Celesia (;G, Grigg MM, Ross E. Generalized status myoclonicus in acute anoxic and toxic-metabolic encephalopathies. Arch Neurol 1988;45:781-4 Treiman DM, Delgado-Escueta AV. Conlplex partial status epilepticus. Adv Neurol 1983;34:69-8 1 Hamilton N, Matthews T. Aphasia, the sole rnanifestatioti of status epilepticus. Neurology (NY) 1979;29:745-8 Toone R K , Roberts J . Status epilepticus. An uncommon hysterical conversion syndrome. J Nerv Ment Dis 1979; 167:548-52 Aminoff MJ, Simon RP. Status epilepticus: causes, clinical features and consequences in 98 patients. Am J Med 1980;69:657-66 Hunter RA. Status epilepticus: history, incidence and problems. Epilepsia 1959160; 1: 162-88 Rowan AJ, Scott DF. Major status epilepticus: a series of 42 patients. Acta Neurol Scarid 1970;46:573-84 J a n z D. Conditions and causes of status epilepticus. Epilepsia 196 1;2: 170-7 Aicardi J , Chevrie JJ. Convulsive status epilepticus in infants and children: a study of' 239 cases. Epilepsia 1970;11:187-97
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21.
22. 23. 24.
study of lorazepam and diazepam in status epilepticus. JAMA 1983;249:1452-4 Rashkin MC, Youngs C, Penovich P. Pentobarbital treatment of refractory status epilepticus. Neurology (Cleve) 1987;37:500-2 Wilder BJ, Rarnsay E, Wilmore LJ, et al. Efficacy of intravenous phenytoin in the treatment of status epilepticus. Ann Neurol 1977; 1 : 5 11-8 Cranford RE, Leppik IE, Patrick B, et al. Intravenous phenytoin in acute treatment of seizures. Neurology (NY) 1979;29:1476-9 Louis S, Kutt H, McDowell F. l ' h e cardiocirculatory changes caused by intravenous Dilantin and its solvent. Am Heart J 1967;74:523-9
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15. Oxbury JM, Whitty CWM. T h e syndrome of isolated epileptic status. J. Neurol Neurosurg Psychiatry 197 1 ; 34: 182-4 16. Lennox WG. Epilepsy and related disorders. Boston: Little Brown, 1980: 1 17. Heintel H . Status epilepticus, etiology, clinical aspects a n d lethality. Stuttgart: Gustav Fischer Verlag, 1972 18. Maytal J , Shinnar S, Moshe SL, Alvarez LA. Low morbidity a n d mortality of status epilepticus in children. Pediatrics 1989;83:323-3 1 19. Towne AR, McGee FE, Mercer El., et al. Mortality in a community-based status epilepticus study. Neurology (Clcve) 1990;40(Suppl 1):299 20. Leppik IE, Derivan AT, Homan RW, et al. Double-blind
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Status Epilepticus: Concepts in Diagnosis and Treatment
Status epilepticus (SE), or prolonged seizures, represents a serious medical and neurologic emergency. SE has been defined through the International Classification of Epileptic Seizures as a seizure lasting for more than 30 minutes or intermittent seizures lasting for more than 30 minutes from which the patient does not regain consciousness.' This definition applies to any seizure type. Thus, any seizure that lasts for more than 30 minutes must be classified as SE. The first major step in treating SE is making the correct diagnosis.' It is essential that the length of all seizures be determined as accurately as possible. This is the only way that the definition or diagnosis of SE can be regularly made. T h e most dramatic and familiar type of SE is generalized tonic-clonic. This type of SE was previously described as persistent grand ma1 seizures. It is difficult not to make this diagnosis correctly, since the generalized tonic-clonic seizures usually continue indefinitely until treatment is initiated. Other types of SE can be more difficult to diagnose, especially generalized absence SE or partial complex SE. Because of the significant mortality and morbidity associated with SE and its common occurrence, it is essential that the clinician be familiar with this condition.
MAKING THE DIAGNOSIS Seizures are usually self-limiting and vary in duration from approximately a few seconds to several minutes. Seizures are common medical phenomena that occur in as high as 2% of children and 1% of the adult population."." Generalized tonic-
clonic seizures (grand ma1 seizures) are readily identified by the physician and are less difficult to diagnose. However, more subtle types of seizure disorders may be more difficult to recognize. All seizure types are usually self-limiting. However, when a seizure of any type does not stop on its own, the transition between a single seizure and SE begins. This transition between an individual seizure and continuous seizure activity must be recognized. In earlier literature it was not clear how long the transition from a seizure to SE should take. In more recent years, a clear and precise definition of SE has been developed through the International Classification of Epileptic Seizures. T h e establishment of and agreement on this international definition, previously cited, have made the diagnosis of SE more specific. T h e first step in treating SE is to make the correct diagnosis. As opposed to many self-limiting seizure conditions, SE does not have a benign prognosis. Delaying the diagnosis of SE puts the patient at risk for increased associated mortality and morbidity. The most common error in diagnosing SE often occurs when the patient presents to the emergency room. By the time the physician arrives at the bedside, the patient may have been stabilized or have been under treatment by ambulance or emergency room staff for a prolonged period of time. If a careful history including the duration of seizures en route to the hospital and in the emergency room is not obtained, the diagnosis of SE may be missed. This error is a common problem in diagnosing SE. Because of the significant morbidity and mortality associated with SE, patients need
Professor and Chairman of Neurology, Professor, Departments of Pharmacology and Biochemistry, Director, Molecular Neuroscience Research Facility Neurologist-in-Chief, Medical College of Virginia Hospitals Reprint requests: Dr. DeLorenzo, Department of Neurology, Medical College of' Virginia, P.O. Box 599, MCV Station, Richmond, VA 23298-0599 Copyright O 1990 by Thieme Medical Publishers, Inc., 381 Park Avenue South, New York, N Y 100 16. All rights reserved.
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Robert J . DeLorenzo, M.D., Ph.D., M.P.H.
STATUS EPILEPTICUS-DELORENZO Table 1. Diagnostic Types of Status Epilepticus Generalized status epilepticus 1. Generalized tonic-clonic status epilepticus (grand mal) 2. Generalized tonic status epilepticus 3. Generalized clonic status epilepticus 4. Generalized myoclonic status epilepticus 5. Generalized absence status epilepticus (petit mal) Partial status epilepticus 1. Simple partial status epilepticus 2. Complex partial status epilepticus Nonepileptic status epilepticus 1. Pseudo (hysterical) status epilepticus 2. Decorticate or decerebrate posturing
associated with a higher percentage of' morbidity .~ patients will have a partial or and m ~ r t a l i t ySome focal onset with secondary generalization, but most patients will present with generalized tonic-clonic symptoms. T h e generalized tonic-clonic movements associated with this condition when lasting for more than 30 minutes can produce significant trauma to the patient through repeated movements of the body. Respiratory arrest, hyperthermia, and acidosis are also major problems associated with this type of SE.
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to be followed and watched carefully following- the cessation of seizures. Diagnosis of SE often depends therefore on obtaining a careful and detailed history of the type and duration of' seizure activity. Appropriate questioning of the family, the ambulance or emergency vehicle transport personnel, hospital nurses, and emergency room staff is essential. Another more subtle problem in diagnosis occurs when subclinical seizures produce symptoms that are not readily associated with a seizure disorder. Thus, patients who present with prolonged alterations in the mental status examination or alterations in state of consciousness must be considered potential candidates for a diagnosis of subclinical SE. T h e electroencephalogram (EEG) is an essential part of diagnosis in any patient with altered mental status. These patients will often have a normal computerized tomographic (CT) or magnetic resonance imaging (MRI) scan, but a dramatically abnormal EEG. The types of subtle seizure disorders described further in this text should be well understood.
TYPES OF STATUS EPILEPTICUS T h e most common and well-recognized type of SE is tonic-clonic or convulsive SE. Generalized tonic-clonic SE was previously described as grand ma1 SE. This condition is associated with a high morbidity and mortality. In addition to this wellrecognized form of SE, any seizure type can develop into SE. T h e International Classification of' Epileptic Seizures can be used as a guide for diagnosing SE. By obtaining a careful seizure history and observing the patient during the episode of SE, the type of seizure phenomena can be readily d i ~ c e r n e d In . ~ addition to using the International Classification of Epileptic Seizures, three broad groupings are often employed to characterize SE: (1) Convulsive SE-primarily generalized tonicclonic seizures; (2) nonconvulsive SE-most commonly associated with generalized absence (petit ma1 status) or complex partial SE; and (3) nonepileptic seizures-primarily representative of hysterical (pseudo) seizures or decerebration and decortication. T h e following description can be used as a general guide to diagnosing the different types of SE (Table 1).
Generalized Tonic Status Epilepticus Tonic SE is not commonly observed clinically and is most often seen in children with the Lennox-Gastaut syndrome. T h e ictal motor activity seen with tonic SE may be almost imperceptible in some cases, making the EEG identification of this condition essential. Tonic SE is often associated with EEG findings consisting of generalized electrodecremental activity or bursts of recruiting epileptiform rhythms.
Generalized Clonic Status Epilepticus Clonic SE is another rare condition and is usually seen only in infants and children. It is characterized by bilateral low-amplitude jerking, often asymmetrical and asynchronous. T h e EEG demonstrates bilateral bursts of high amplitude delta activity with intermixed spikes in most situations.
Generalized Myoclonic Status Epilepticus GENERALIZED STATUS EPZLEPTZCUS
Generalized Tonic-Clonic Status Epilepticus Generalized tonic-clonic SE is the most com. ~ is also mon form seen in large clinical ~ e r i e s It
Myoclonic SE occurs in children presenting with bilateral myoclonus with preserved consciousness. It also occurs in children and adults secondary to acute or subacute brain disorders such as anoxia, hypoxia, renal or liver encephalopathy, viral
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Generalized Absence Status Epilepticus Generalized absence seizures can present with a clouding of consciousness or a fuguelike state. Another term for this condition is the continuous twilight state. These symptoms are accompanied by generalized 3 Hz spike-wave discharges in either closely spaced bursts o r uninterrupted activity lasting for 30 minutes or longer. Generalized absence SE is the most common form of nonconvulsive SE. This is an important condition to recognize because it is treatable. It can produce a long-term alteration of memory or consciousness. Generalized absence status is also associated with a significant morbidity and mortality, although this type of SE usually has a better prognosis than generalized tonic-clonic SE. It is much more common in children and adolescents, but it can be seen in adults. Any patient who presents with an altered level of consciousness or a fuguelike state should be evaluated with an EEG.
PARTIAL STATUS EPILEPTZCUS
Simple Partial Status Epilepticus Simple partial SE represents a continuous partial (focal) seizure without secondary generalization, which may be motor, somatosensory, autonomic, dysphasic, psychic, o r combinations of these types. Patients are diagnosed as having simple partial SE when they have evidence of focal epileptiform activity associated with clinical manifestations lasting continuously for 30 minutes or longer. Somatomotor SE is most commonly seen. Focal cortical lesions in the motor or sensory cortex can produce seizure activity that lasts for long periods of time. Thus, a twitching arm can be produced by a contralateral seizure focus firing in the motor cortex of the arm. This type of SE is widely seen following brain injuries or tumors. Simple somatomotor SE is most commonly seen with seizure activity in an extremity or facial muscles. In these types of seizures, loss of consciousness is unusual, although secondary generalization can occur. Secondary generalization is less common than might be expected, and why generalization is not more common with this type of persistent simple partial seizure condition is unknown.
Complex Partial Status Epilepticus Complex partial SE presents with a broad range of motor and behavioral symptomatology.7 One type of presentation of this syndrome is partial responsiveness or altered personality. Any patient who presents with an acute change in behavior without any evidence of underlying causes should receive an EEG. This presentation is important in the differential diagnosis of psychiatric disorders. Patients can present with semipurposeful automatism~, speech arrest, stereotypical automatisms or total unresponsiveness as a form of partial complex SE. T h e presentation of an acute confusional state or altered mental status should also be included in the differential of partial complex SE. EEG analysis is essential in making the diagnosis. This condition also responds dramatically to intravenous (IV) benzodiazepine therapy, with clearing of neurologic symptoms and resumption of more normal EEG activity. Aphasic SE is a recognized syndrome that is best described as an episode of aphasia that may last from hours to days, associated with persistent EEG findings8 Thus, any patient with persistent aphasia should receive an EEG to rule out this rare syndrome. This condition represents a treatable cause of aphasia. The acute presentation of aphasia with no other evidence of cerebrovascular disease should always raise the question of aphasic SE, which is a form of complex partial, nonconvulsive SE. NONEPZLEPTZC STATUS EPILEPTIC US
Nonepileptic SE is difficult to diagnose definitively. T h e true incidence of hysterical seizures is However, in refractory epinot well establi~hed.~ lepsy patients referred to major epilepsy centers, hysterical seizures comprise as high as 10% of the seizures. T h e term "pseudoseizures" is often used to describe these nonepileptic seizures. Pseudoseizures cannot be differentiated from generalized SE or other types of SE syndromes based on clinical observation alone. All patients must be treated as if they have a primary convulsive or nonconvulsive condition until more definitive diagnostic information can be obtained. T h e diagnosis of nonepileptic or pseudoseizures should be considered when the usual response to anticonvulsapt medications is not seen, or when it is difficult tb explain an intractable seizure disorder. T h e absence of EEG epileptic activity during the clinical symptomatology strongly suggests the diagnosis of pseudoseizures. However, surface EEG recordings may be normal or show
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and degenerative disorders. Myoclonic SE due to these metabolic or infectious conditions usually carries a grave p r ~ g n o s i s . ~
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STATUS EPILEPTICUS-DELORENZO
very subtle changes in patients with subcortical or limbic seizures. Pseudoseizures are difficult to diagnose and are a challenge even for the expert epileptologist. Decorticate or decerebrate posturing can be persistent and produce repetitive movements that can be mistaken for seizure activity. Thus, these persistent movements can mimic tonic-clonic or tonic SE. The history, circumstances, and clinical presentation of the case usually differentiate these patients from those with actual seizure activity. 'The EEG can also be helpful in making the differential diagnosis.
patients seen in most large series. Metabolic disorders also represent a major cause of SE, accounting for 10 to 15% of cases seen in most large series. Not all patients presenting with SE have a previous history of a seizure disorder. As shown in Table 2, approximately one fifth of patients who develop SE have a history of epilepsy. Thus, the majority of patients who present with SE d o not have a previous history of epilepsy. Several common medical and surgical conditions can cause SE. A majority of SE patients in a large metropolitan general hospital will present on non-neurologic services. Thus, all clinicians should be familiar with this serious medical and neurologic emergency.
ETIOLOGIES OF STATUS EPILEPTICUS
Table 2. Causes of Status Epilepticus in 280 Patients from the Medical College of Virginia Status Epilepticus Data Base Etiology
Percent
Withdrawal of anticonvulsants
21
Alcohol withdrawal
18
Anoxia Hypotension Cerebrovascular disease Hemorrhage Metabolic disorders
2 4
21 7
13
Infectious disorders
4
Tumors
3
Other
7
Mortality rates in SE in several large studies have varied. Over the last 20 years, several studies have accumulated more than 100 patients. T h e mortality rates have varied from 8 to 50%.4,5,10-18 The precise mortality rate is not the important issue. Even a mortality of 8 to 10% represents a significant death rate for any neurologic disease. These mortality data indicate that at least 1 of 10 patients who develop SE will die. Initial studies on the mortality of SE in children included a high mortality rate.14 However, more recent investigations have indicated that children have a lower morbidity and mortality than adults.ls At the present time, it is difficult to d o carefully controlled, validated studies on the incidence or prevalence of SE. Recent data from the Medical College of Virginia Status Epilepticus Database indicate, in a validated database, that the mortality rate of SE may approach as high as 20 to 30%, when all cases in the population are ascertained.Ig The associated high mortality of SE emphasizes the importance of treating this condition as a major medical and neurologic emergency. Since all of the large reported SE mortality figures have come from large academic medical centers, it is important to determine if similar mortality rates are seen in private hospital settings. Recent studies have demonstrated that the mortality rate of SE in a community population, and the community hospital population, parallels that of the major medical center.'"hese data suggest that the high mortality rate associated with SE is not a feature uniquely associated with a major medical center, but is major concern to physicians in practice in the community settings as well. There is clinical agreement that it is essential to initiate treatment for SE rapidly. Evidence is accumulating suggesting that early treatment, with
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MORTALITY IN STATUS EPILEPTICUS
Once the diagnosis of SE is made, the clinician must immediately consider the possible cause of the prolonged seizures. Treatment of SE, although directed at the control of the seizures, must also take into account the underlying etiology of' the SE. In some cases, these etiologies require aggressive treatment o r surgical intervention. Table 2 presents the etiologies of 280 adult cases of SE from the Medical College of Virginia Status Epilepticus D a t a b a ~ eThese .~ etiologies are typical of several other large st~dies.".'~." The causes of SE shown in 'Table 2 are divided into ten major groups: withdrawal of anticonvulsants, anoxia, hypotension, alcohol-related SE, metabolic disorders, infectious disorders, cerebrovascular disease, tumors, hemorrhage, and other. As can be seen from the data presented in Table 2, there are three major causes associated with SE: cerebrovascular disease, alcohol-related SE, and withdrawal of arlticonvulsant medications. Each of these categories represents about one fifth of' the
decrease of seizure duration, prevents significant morbidity and mortality in many cases. It is also essential to initiate treatment of serious, life-threatening neurologic or medical conditions that may underlie SE. In centers where effective treatment modalities are available with appropriate support personnel, it is rare that a patient dies during treatment o r during SE itself. Mortality from this condition is usually seen in the first week or two following the episode of SE. The cause of death and whether it is more related to SE itself or the underlying etiology of the SE has not been clearly elucidated at this time. Further studies to address this question may provide useful prognostic indicators for mortality and morbidity.
TREATMENT OF STATUS EPILEPTICUS Management and treatment of SE require a timely and organized treatment plan. It would be
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desirable to have a rigid protocol for the treatment of SE that requires little thought and can be initiated in a rapid and timely fashion. However, this is not always possible, since SE may vary in presentation and the patient's condition may have certain idiosyncratic aspects relating to reactions to drug therapy or clinical presentation. There are also differences between available emergency staff and support equipment from major medical centers to community hospitals. Taking these variations into account, a generalized treatment program for SE in adults and children has been developed at the Medical College of Virginia Status Epilepticus Research Center. This treatment plan was developed drawing on the available literature for treatment of SE, the experience at the university epilepsy center, and the experience from community hospitals in the Greater Richmond Metropolitan Area. It is suggested that this type of treatment plan be developed in each hospital or community setting and be reviewed as part of an ongoing quality assur-
Table 3. Status Epilepticus Treatment for Adults: Medical College of Virginia Hospitals Protocol* Steo
Time Frame of Procedure
Intervention
~p
1.
6.
400
- - -
0-5 minutes
Determination of SE. As soon as the diagnosis is made, institute monitoring of blood pressure, temperature, pulse, respiratory ECG and EEG, Insert oral airway and administer oxygen if necessary. Insert an intravenous catheter and draw venous blood for anticonvulsant levels, glucose, electrolytes, calcium, magnesium, blood urea nitrogen, and complete blood count. Draw arterial blood for arterial blood gases. Obtain urine for urinalysis and toxic screen if indicated. Nasotracheal suction if necessary is performed
6-9 minutes
An intravenous line is placed with normal saline containing vitamin B complex. A bolus of 50 ml of 50% glucose is given
10-30 minutes
Infuse IV lorazepam given at a rate of 2 mglmin (0.1 mglkg) to a maximum dose of 5 mg or alternatively administer IV diazepam given at a rate not to exceed 2 mglmin until seizures stop or to a total of 20 mg. This is followed by IV phenytoin, 20 mglkg at a rate no faster than 50 mglmin. If seizures not controlled, a repeat bolus of phenytoin at 10 mglkg can be given before proceeding to step 4. Monitor ECG and blood pressure
31-60 minutes
If seizures persist, elective endotracheal intubation is recommended before starting a bolus infusion of phenobarbital at a rate no faster than 100 mglmin until seizures stop or to a loading dose of 20 mglkg
1 hour
If control is still not achieved, other options include: a. Pentobarbital with an initial IV loading dose of 5 to 10 mglkg, with additional amounts given to produce a burst-suppression pattern on EEG. Maintenance of pentobarbital anesthesia is continued for approximately 4 hours by an infusion of 1-3 mglkglhr. After this time, the patients are checked for reappearance of seizure activity by decreasing the infusion rate. If clinical seizures and/or generalized EEG discharges persist, the procedure is repeated; if not, the pentobarbital is tapered over 12 to 24 hours b. Paraldehyde is given either by the intravenous (no longer available) or rectal route at a dose of 0.1 to 0.15 mllkg after being diluted in normal saline every 2 to 4 hours if necessary c. Diazepam (50 to 100 mg) is diluted in a solution of 500 ml 0.9% NaCl or D5W and run as a continuous infusion to achieve blood levels of 0.2 to 0.8 mglml. The IV solution is changed every 6 hours as advised by certain authors and short length IV tubing is used
60-80 minutes
If seizures are still not controlled, the anesthesia department is called and general anesthesia with halothane and neuromuscular blockade is begun
'Continuous EEG monitoring is recommended in the obtunded patient to assure that SE has not reoccurred. In the management of intractable status, a neurologist who has expertise in SE should be consulted and advice from a regional epilepsy center should be sought.
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Stea 1.
6.
Status Epilepticus Treatment for Pediatrics: Medical College of Virginia Hospitals Protocol Time Frame of Procedure
Intervention't
0-5 minutes
Determination of SE. As soon as the diagnosis is made, institute monitoring of temperature, blood pressure, pulse, respiratory ECG and EEG, Insert oral airway and administer oxygen if necessary. Insert an intravenous catheter and draw venous blood for anticonvulsant levels, glucose (check Dextrostik), electrolytes, calcium, blood urea nitrogen, and complete blood count. Draw arterial blood for arterial blood gases. Treat elevated temperature with rectal antipyretics (acetaminophen). Frequent suction
6-9 minutes
An intravenous line is placed with normal saline. A bolus of 2 cclkg 50% glucose is given
10-30 minutes
Initial treatment consists of an infusion of IV lorazepam given at a rate of 1-2 mglmin (0.1 mglkg) to a maximum dose of 5 mg. This is followed by IV phenytoin at 18-20 mgl kg infused at a rate no faster than 1 mglkgimin or 50 mgimin. Monitor ECG and blood pressure
31-60 minutes
If seizures persist, administer a bolus infusion of phenobarbital at a rate no faster than 50 mgimin until seizures stop or to a loading dose of 20 mg/kg
1 hour
If control is still not achieved, other options include: a. Diazepam 50 mg is diluted in a solution of 250 ml 0.9% NaCl or D5W and run as a continuous infusion at 1 cclkglhr (2 mglkglhr) to achieve blood levels of 0.2 to 0.8 mglml. The IV solution is changed every 6 hours as advised by certain authors and short length IV tubing is used b. Pentobarbital with an initial IV loading dose of 5 mglkg with additional amounts given to produce a burst-suppression pattern on EEG. Maintenance of pentobarbital anesthesia is continued for approximately 4 hours by an infusion of 1-3 mglkglhr. After this time, the patients are checked for reappearance of seizure activity by decreasing the infusion rate. If clinical seizures or generalized EEG discharge persist, the procedure is repeated; if not, the pentobarbital is tapered over 12 to 24 hours
60-80 minutes
If seizures are still not controlled, the anesthesia department is called and general anesthesia with halothane and neuromuscular blockade is begun
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Table 4.
*Continuous EEG monitoring is recommended in the obtunded patient to assure that SE has not reoccurred. In the management of intractable status, a neurologist who has expertise in SE should be consulted and advice from a regional epilepsy center should be sought. Lumbar puncture should be done as soon as possible, especially in the febrile child or infant younger than 1 year. tFor infants with a history of neonatal seizures, infantile spasms, or early-onset seizures, pyridoxine 100 mg IV should be given while under EEG monitoring to diagnose and treat the rare B, dependency patient with seizures.
ance program. The treatment protocols shown for adults in Table 3 and children in Table 4 were developed at the Medical College of Virginia Epilepsy Center. These treatment plans can be utilized directly or form the basis of developing a customized treatment program for each medical center. Since SE does not occur as frequently as other major medical emergencies, such as myocardial infarction, stroke, or trauma, having a protocol readily available in the emergency room or on the hospital floors coordinates management among medical, nursing, and paramedical personnel. Placing the protocols prominently in these settings and reviewing them in ongoing quality assurance and risk management programs are essential in providing excellent care for the treatment of SE. The protocols shown in Tables 3 and 4 are primarily used for the treatment of generalized tonic-clonic SE. The following material details several important aspects of these treatment plans. TREATMENT OF STATUS EPZLEPTZCUS IN THE ADULT
The Medical College of VirginialVirginia Commonwealth University protocol for treating SE in
the adult is shown in Table 3. This treatment protocol represents a synthesis of clinical experience by university and community physicians in addition to drawing on the existing literature on treatment for SE.20-24It is primarily for treatment of generalized tonic-clonic SE, but can be used in the treatment of partial complex SE.
Making the Diagnosis The high mortality and morbidity associated with SE make it essential to first diagnose as quickly and as accurately as possible. Making the diagnosis quickly assures that the treatment protocol can be put into effect in a timely manner. Delay in making the diagnosis can put the patient at considerable risk for morbidity and mortality. Emergency room staff and hospital personnel must be alerted to this condition through routine in-service education programs that highlight the importance of recognizing seizures that last for more than 20 minutes as potential candidates for developing into SE. An appropriately trained
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Stabilization of the Patient
402
As in any medical emergency, the patient should be stabilized medically and an intravenous (IV) line initiated. Many causes of SE can also produce significant cardiovascular and autonomic changes. Thus, the vital signs of the patient are essential in evaluating SE. The intravenous line is usually supported with normal saline, since this is the most common compatible IV solution for the administration of IV phenytoin. Supplementation with vitamin B complex can also be initiated. Other IV solutions can be considered, depending on the patient's medical condition, age, and the possibility of underlying hypertension. The decision tree recommended in Table 3 serves as a model for initially stabilizing the patient. EEG recording and C T scanning, as rapidly as possible, are also invaluable in determining the underlying etiology and making the electrophysiologic diagnosis of SE. C T scanning is essential in ruling out any mass lesions or other contraindications for lumbar puncture. Occasionally, patients will regain consciousness rapidly following generalized tonic-clonic SE. This is not common, since most patients will have at least a 30-minute to 2-hour postictal coma or lethargy. However, those patients who do awake more rapidly should also be observed carefully. Although the prognosis is usually better with rapid recovery, this has not been clearly ascertained statistically and at least 24 hours of observation are recommended for patients who have undergone seizures for more than 30 minutes. Patients recovering from SE should be hospitalized on a neurologic service or appropriate medical service. Patients who do not recover rapidly from the postictal state benefit from hospitalization in a neurologic or medical intensive care unit. Careful observation and recording of vital signs with simultaneous EEG recording are invaluable in avoiding complications.
Medical Treatment
The major anticonvulsant of first choice for treatment of SE at the Medical College of Virginia Hospitals is phenytoin. It is effective in controlling SE, often rapidly;22,23 it also has the advantage of not being highly sedative. In many patients, seizures will stop following loading with IV phenytoin. Treatment should begin as rapidly as possible after the diagnosis has been made. Initiation of therapy involves the use of 18 mglkg of phenytoin. The rate of infusion should not exceed 50 mglmin. Intravenous phenytoin preparations are not soluble in most IV solutions except for normal saline. It is imperative that phenytoin not be administered with 5% dextrose in water (D5W) or other IV solutions that will not maintain the solubility of this compound. Following phenytoin administration, if the patient stops having seizures, it is anticipated that the patient should wake up following the postictal phase of SE. The phenytoin itself should not produce any significant increase in the duration of coma. Because of this rapid distribution and effectiveness in treating SE, IV administration of phenytoin should be routinely available in hospital emergency rooms and on hospital floors, but it must be given carefully to any patient with compromised cardiac output. Cardiovascular complications caused by phenytoin affecting cardiac output and blood pressure can be significant if the accepted dose and rate of administration are not f~llowed.'~ Most healthy individuals tolerate the recommended phenytoin dosage and rate of administration. Significant side effects are rare and phenytoin is a safe and effective treatment for SE. Simultaneous electrocardiographic (ECG) and blood pressure monitoring, if available, is recommended whenever SE is being treated. It is especially advisable in elderly patients or in patients with a compromised cardiovascular condition. If a patient is sensitive to phenytoin and the heart rate or blood pressure decreases, the rate of administration can be decreased or infusion can be stopped. This usually results in a rapid reversal of the cardiovascular effects. Although phenytoin is the first choice as a major anticonvulsant in the treatment of SE, in most emergency rooms and hospital settings a benzodiazepine is usually administered as the initial treatment modality. Intravenous diazepam is the most common initial treatment for SE." When lorazepam is available, it is often given. Diazepam is given intravenously at a rate not to exceed 2 mglmin until the seizure stops or a total of 20 mg is administered. It is essential to follow the rate of administration of diazepam carefully, since idiosyncratic
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emergency vehicle staff person would arrive at an emergency room with a patient who has been having seizures for 20 minutes and immediately indicate that this patient is at high risk for developing SE. Appropriate neurologic o r medical consultation can be obtained immediately and the situation is already recognized as a potential emergency. It is also important to document clearly the duration of seizures in the emergency room or hospital chart. If the physician arrives after the seizures have already been controlled with treatment, the diagnosis of SE may be missed.
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STATUS EPILEPTICUS-DELORENZO
ever, a small percentage of the seizures may still be resistant to this treatment and further medical management will be indicated. At this point, it should be evident that these patients are severely compromised. The seizures will probably have persisted for more than an hour by this time. This population of patients represents an especially vulnerable group for developing morbidity or dying. A diazepam intravenous drip is effective for obtaining further control in SE. Diazepam, 50 to 100 mg, is diluted into 500 ml of 0.9% sodium chloride or D5W. This solution can be run as a continuous infusion to achieve a blood level ranging from 0.2 to 0.8 mglml. Continuous diazepam infusion must be administered with extreme caution. Diazepam can cause idiosyncratic respiratory arrest if infused too rapidly. This type of treatment is usually administered only in an intensive care unit setting with controlled IV administration. As already described, lorazepam infusion can also be utilized for further control in SE. However, this has not been widely utilized as a second-line anticonvulsant in refractory cases. Further evaluation of the effect of lorazepam in this setting is being investigated. Several additional regimens have been effective in eventually controlling SE following initial treatment with phenytoin and phenobarbital. A paraldehyde drip may be used. Paraldehyde is an effective anticonvulsant. However, it is no longer readily available in most hospital emergency rooms or inpatient settings. Paraldehyde can be administered rectally in a dose of 0.1 to 0.15 mglkg after being mixed 1: 1 with mineral oil. Rapid absorption of rectal paraldehyde provides effective anticonvulsant treatment in SE. Paraldehyde can be administered through a Foley catheter that has been inflated in the rectum to assure that the drug remains in contact with the rectal mucosa for absorption. Paraldehyde, however, is less Likely to be used in most clinical settings; it is unpopular because of its smell, its solubility problems, and its route of administration. Intravenous paraldehyde can also be administered, but this is more difficult and has complications. Pentobarbital anesthesia is also an effective treatment for further control of intractable SE." An initial IV loading dose of 5 mglkg of pentobarbital is given to produce a burst-suppression pattern on the EEG. Following this initial dose, pentobarbital anesthesia can be continued for as long as 3 hours by infusion of 1 to 3 mglkglhr. Intubation and respiratory support are essential. T h e paResistance to Treatment tient should also be continuously monitored with an EEG. If the seizure activity ceases with pentoThe majority of SE cases will be successfully barbital administration, it is usually advisable to treated with phenytoin and phenobarbital. How- wait 2 to 3 hours before tapering the pentobarbital.
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respiratory arrests can be precipitated by rapid administration. Lorazepam is administered at a rate of 2 mglmin to a dose of 1 mglkg and can be repeated at 10 to 15-minute intervals if the seizures persist.20 Benzodiazepine therapy for SE is often initiated first because benzodiazepines are readily available in most emergency room and hospital ward settings. At the initiation of a seizure, it is also not possible to determine if the patient will stop spontaneously or progress to SE. Intravenous diazepam is usually effective in treating a single seizure and is often initiated for this reason. If the seizures persist past 20 to 30 minutes and the diagnosis of SE is made, then major anticonvulsant therapy can be initiated. Diazepam treatment is short acting and an initial diazepam treatment is usually effective for only 10 to 20 minutes following the initial IV bolus. Thus, if other therapy is not available except for diazepam, its effect must be reenforced at regular intervals. Lorazepam has an advantage because its effects appear to be longer lasting with initial treatment. When seizures persist following the initial treatment with phenytoin or phenytoin plus a benzodiazepine, endotracheal intubation and initiation of phenobarbital infusion are recommended. Phenobarbital, which is a useful second anticonvulsant in the treatment of SE following phenytoin, is listed in some university hospital protocols as the first-line anticonvulsant. However, because of its sedative properties, it is used in our protocol as a second-line anticonvulsant. Phenobarbital is administered intravenously at a rate not to exceed 100 mglmin until the seizures stop or a loading dose of 20 mglkg has been reached. Phenobarbital is a potent anticonvulsant and, usually, when combined with phenytoin, is effective in stopping SE in the majority of cases. Because of its sedative properties and respiratory suppression, its use must be considered with caution; the availability of intubation and respiratory assistance is advisable whenever phenobarbital is administered at these doses. Patients loaded with phenobarbital at a dose of 20 mglkg will often remain sedated for at least 12 to 24 hours. This makes it much more difficult to evaluate the postictal state of the patient and the recovery related to the SE and its underlying cause. Patients who receive phenobarbital require more careful monitoring and observation following SE.
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Careful EEG monitoring can document the recurrence of seizures, and more pentobarbital can be administered. Titration of seizure control with pentobarbital can be very useful in some intractable cases. In the very remote possibility that pentobarbital is not effective in controlling seizure activity, general anesthesia with halothane and neuromuscular blockade may be initiated with the assistance of an anesthesiologist. TREATMENT PROTOCOL FOR CHILDREN
The treatment protocol utilized for children at the Medical College of Virginia Hospital complex is summarized in Table 4. This treatment protocol is similar to the protocol used for adults, with some modifications. There is still more variability at the present time in the treatment of SE in children than in adults. However, over the last several years more consistency and agreement have developed among clinicians. The diagnosis and treatment of seizures in the neonatal period are extremely difficult, especially since seizures may be subtle and electrical SE may be present without associated movements or clinical features. Because neonatal seizures are a special problem, the SE protocol presented in Table 4 is applicable only to infants older than 6 months of age. The pediatric population also represents a special challenge in making an early diagnosis and initiating rapid treatment of SE. Young children have a significant difference in surface area to volume ratios in comparison with adults. Thus, there is often difficulty in managing fluid and the associated metabolic complications. SE can thus be associated with more difficult medical management problems in the child. T h e pediatrician must be especially diligent in stabilizing the patient. Following initial stabilization and establishment of the diagnosis of SE, anticonvulsant treatment is initiated. The Medical College of Virginia protocol utilizes intravenous lorazepam given at a rate of 1 to 2 mglmin to a maximum dose of 5 mg as the initial treatment. T h e appropriate loading dose is 0.1 mg/kg for this medication in children. Following intravenous lorazepam, phenytoin is initiated as the first-choice major anticonvulsant. Phenytoin is given at a dose of 18 to 20 mglkg, to a total dose of 20 mglkg. It cannot be given faster than 1 mglkg per minute. Continuous ECG monitoring is recommended during phenytoin treatment in the pediatric population also. Blood pressure monitoring, if available, is helpful. If the seizures are resistant to phenytoin treatment, initiation of phenobarbital therapy is the second
VOLUME 10, NUMBEK 4 DECEMBER 1990
choice for anticonvulsant treatment as described in Table 4. SE will be stopped in the majority of children with phenytoin and benzodiazepine or phenytoin and phenobarbital administration. Intractable SE is not common but occurs in the pediatric population somewhat more commonly than in adults. The treatment protocol shown in Table 4 recommends further treatment for intractable seizures similar to the adult protocol. Paraldehyde has been found to be especially useful in the treatment of intractable SE in children, although this medication is now difficult to obtain. Children or infants with a history of neonatal seizures, infantile spasms, or early-onset seizures should also receive intravenous pyridoxine (vitamin B,), 100 mg, given intravenously during the initial stabilization. Pyridoxine should be given while the EEG is being monitored to allow for the diagnosis of the rare B, deficiency-induced seizures. SE is a common medical emergency in children. However, recent studies indicate that the mortality rate in children treated rapidly and effectively is lower than in the adult population.lx Rapid treatment needs to be initiated to maintain this lower mortality. REFERENCES Delgado-Escueta AV, Wasterlain GC, Trieman DM, Porter RJ. Status epilepticus. New York: Raven Press, 1983 DeLorenzo KJ. Status epilepticus. In: Johnson KI',ed. Current therapy in neurological disease -3. Philadclphia: B.C. Decker, 1990;3:57-83 DeLorenzo RJ, Towne AR. Epilepsy. I n : Appel S H , e d . Current neurology. Chicago: Year Book Medical Publishers, 1989;9:27-76 Hauser A. Status epilepticus: frequency, etiology, a n d neurological sequelae. Adv Neurol 1983;34:3-14 Leppik IE. Status epilepticus. Neurol Clin 1986;4:63:443 Celesia (;G, Grigg MM, Ross E. Generalized status myoclonicus in acute anoxic and toxic-metabolic encephalopathies. Arch Neurol 1988;45:781-4 Treiman DM, Delgado-Escueta AV. Conlplex partial status epilepticus. Adv Neurol 1983;34:69-8 1 Hamilton N, Matthews T. Aphasia, the sole rnanifestatioti of status epilepticus. Neurology (NY) 1979;29:745-8 Toone R K , Roberts J . Status epilepticus. An uncommon hysterical conversion syndrome. J Nerv Ment Dis 1979; 167:548-52 Aminoff MJ, Simon RP. Status epilepticus: causes, clinical features and consequences in 98 patients. Am J Med 1980;69:657-66 Hunter RA. Status epilepticus: history, incidence and problems. Epilepsia 1959160; 1: 162-88 Rowan AJ, Scott DF. Major status epilepticus: a series of 42 patients. Acta Neurol Scarid 1970;46:573-84 J a n z D. Conditions and causes of status epilepticus. Epilepsia 196 1;2: 170-7 Aicardi J , Chevrie JJ. Convulsive status epilepticus in infants and children: a study of' 239 cases. Epilepsia 1970;11:187-97
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