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The Etiology and Diagnosis of Status Epilepticus
Epilepsy & Behavior 2, 311–317 (2001) doi:10.1006/ebeh.2001.0195, available online at http://www.idealibrary.com on
REVIEW The Etiology and Diagnosis of Status Epilepticus W. O. Tatum IV,* ,1 J. A. French, † S. R. Benbadis,* ,‡ and P. W. Kaplan § *Tampa General Hospital Epilepsy Center, Department of Neurology, and ‡Department of Neurosurgery, University of South Florida, Tampa Florida; †Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania; and §Department of Neurology, Johns Hopkins University, Baltimore, Maryland Received January 18, 2001; revised April 20, 2001; accepted for publication April 30, 2001
Status epilepticus (SE) is a common, serious, potentially life-threatening, neurologic emergency characterized by prolonged seizure activity. Generalized convulsive status epilepticus (GCSE) is the most widely recognized form of SE. Direct consequences of convulsive movements from SE can result in injury to the body and brain. Nonconvulsive status epilepticus (NCSE) is underrecognized, with controversy surrounding the consequences and treatment. High mortality rates with GCSE have been noted in the past. New treatments for SE are emerging with new parenteral drug formulations as well as new agents for refractory SE, offering an opportunity to improve outcome. Special drug delivery systems, drug combinations, and neuroprotective agents that prevent the subsequent development of epilepsy may soon emerge as future options for treating SE. © 2001 Academic Press Key Words: status epilepticus; seizures; emergency; brain; injury; convulsive; nonconvulsive; causes; outcome; treatment.
INTRODUCTION
a practical standpoint, however, treatment must be considered by 5–10 minutes, or when at least two seizures have occurred back-to-back without an intervening return to consciousness, because of the concern for causing irreversible neuronal injury.
Status epilepticus (SE) was described as early as 600 –700 bc in ancient Babylon (1). The annual frequency of SE in the United States is estimated to be between 126,000 and 195,000 events, with up to 42,000 deaths yearly, though the incidence may be higher due to underreporting (2, 3). Current annual costs probably exceed $4 billion to identify and treat cases with subsequent hospitalization (4). Definitions of SE have varied (5, 6). Strictly defined, SE represents more than 30 minutes of continuous seizure activity, or two or more sequential seizures without full recovery between seizures (7). Initial definitions of 30 minutes were used due to the substantial mortality associated with seizure prolongation, although more recent opinions have suggested using shorter periods (4, 8). From
CHARACTERISTICS Generalized convulsive SE (GCSE) is the most commonly identified form of SE. While any seizure type may evolve into SE, morbidity and mortality are most critical with GCSE. GCSE may involve tonic– clonic seizures. Continuous or intermittent tonic with or without clonic movements occur that may be symmetrical or asymmetrical with loss of consciousness. Descriptions have referred to GCSE when overt motor movement is seen. Subtle GCSE has been described (9) when minimal motor movement is restricted to continuous, rhythmic motor movements or twitches that can be seen to involve the eyes, eyelids, face, jaw,
1 To whom all correspondence should be addressed at c/o 13801 Bruce B. Downs Boulevard, No. 401, Tampa, FL 33613. Fax: (813) 971-6951. E-mail: [email protected].
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312 trunk, or extremity during stupor or coma. Such “subtle” forms of SE involve electrographic seizures with minimal clinical signs. Overt GCSE may evolve to subtle seizure activity by decreasing rostral– caudal vertical transmission of cortical electrical impulses that stimulate muscle movement. In this way, an “electromechanical dissociation” is paralleled by a series of changes that occur on the electroencephalogram (EEG). Discrete electrographic seizures eventually merge and become continuous ictal discharges that then become punctuated with intermittent suppressions prior to the late phases which on EEG reveal periodic epileptiform discharges on a suppressed background (10). Myoclonic seizures involving SE occur in two separate entities. Myoclonic SE in primary generalized epilepsy manifests as bilateral massive myoclonus at irregular intervals or in clusters usually with intact consciousness and polyspike waves on EEG. It has a good prognosis. Status myoclonus is not strictly speaking myoclonic SE but is more common and occurs after severe hypoxic–ischemic insult. Rapid, brief bilateral often asymmetric asynchronous low-amplitude jerks or contractions of axial or appendicular musculature may be stimulus-sensitive, and are accompanied by EEG epileptic discharges during evaluation of GCSE. Status epilepticus may also be nonconvulsive SE (NCSE). The clinical features consist of changes in behavior, memory, affect, or level of consciousness, often with alteration in body tone and fine facial or limb tremors followed by amnesia. NCSE is underdiagnosed (11), and may be confused with primary psychiatric or behavioral disorders (12). Another condition often confused for NCSE is coma with EEG epileptiform activity or electrographic seizures (13), an entity with various substrates, correlates, and outcomes. NCSE represents an “epileptic twilight state” and may be categorized into complex partial SE and absence SE (spike-wave) forms frequently best delineated using EEG. Typical absence SE does not appear to be associated with serious morbidity or mortality; however, complex partial status has been associated with controversy regarding permanent neurologic damage, similar to GCSE. Some authors suggest a causative association with serious morbidity and mortality (14), with neuronal damage arising from epileptiform activity acting synergistically with the acute symptomatic cause of SE (15). Others refute the effect of NCSE itself as causing cognitive or neurologic impairments, attributing the morbidity to the underlying cause rather than the effects of NCSE (16). Electrographic seizures in coma have been noted to persist in Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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14% of patients following control of GCSE at a time when overt tonic– clonic movements have disappeared (17). Other SE syndromes exist. Electrical status epilepticus during sleep (ESES) reflects an electrographic pattern consisting of almost continuous spike-wave discharges in slow-wave sleep. Clinical conditions with electrical status epilepticus in sleep (ESES) include “continuous spikes and waves during slow wave sleep” and the Landau–Kleffner syndrome and may present with neuropsychiatric and cognitive dysfunction in association with ESES (18, 19) often with a steady decline, although the course may be variable.
CAUSES The causes of GCSE and NCSE are legion. Remote symptomatic, acute symptomatic, and idiopathic etiologies for SE are evenly distributed (20), with a structural basis being more likely to be discovered the more rigorous the search. Status epilepticus is very common in patients with epilepsy. Epilepsy is the strongest single risk factor for GCSE; however, young age, genetic predisposition, and an acquired brain injury are other important risks (21). About 15–20% of persons with epilepsy have a history of at least one episode of SE, and 15% present with SE (7, 20). In a prospective, population-based study (3), low antiepileptic drug levels in patients with epilepsy was the most common etiology, followed by remote brain insult and stroke. Almost 50% of adult cases of SE were caused by acute or remote cerebrovascular disease. Anoxia, hemorrhage/stroke, and tumor were common causes in adults, while in the pediatric group, fever (52%) was the most common concomitant factor, followed by remote brain insult and low antiepileptic drug (AED) levels. Low AED levels still constituted the largest identifiable etiology. SE is most common in young children. Approximately 40% of children developing status are less than 2 years of age (22). At this age, epilepsy is usually not present at the time of SE, and a febrile illness is the initiating event. Febrile illness, hypoxic–ischemic encephalopathies, and CNS infections are frequent causes in children. Recurrence is greatest (40 – 60%) in children with acute or chronic brain insults and rare (5%) in idiopathic causes or febrile status (23). In older children, preexisting epilepsy is present and low AED levels remain a common cause.
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MECHANISMS Initiation The principal means of generating SE is by failure of the normal mechanisms that terminate seizures. Fundamentally, persistent excessive excitation and failed inhibition have complex interactions that engender ongoing seizure activity. Excessive activation of excitatory amino acids via glutamate analogues has been noted to prolong seizures (24), impairing the usual mechanism by which seizures terminate. However, ␥-aminobutyric acid (GABA) antagonists may also provoke SE in experimental models with agents such as picrotoxin and bicuculline. Dynamic changes in GABA-A receptor function as seizures become prolonged may occur, resulting in receptor insensitivity during hyperexcitable states (25). Other neurotransmitters important for the initiation and maintenance of SE include adenosine, acetylcholine, and nitric oxide. Absence SE with 3-Hz spike-wave discharges are induced by excessive inhibition (21, 25). Modulated by GABA-B-mediated hyperpolarization through activation of thalamic T-type calcium channels, this form of SE does not lead to the neuronal injury seen with excessive excitation (21).
Injury Brain injury that is present after SE has been suggested to reflect the effects of CNS damage causing SE, the direct injury from electrical discharges during SE, and the associated systemic consequences incurred. As GCSE evolves, major systemic derangements occur, including hypoglycemia, hyperthermia, hypoxia, and acidosis that exacerbate neuronal injury (26). These changes may predispose to cardiac arrhythmias, pulmonary edema, aspiration, respiratory failure, or renal failure, and ultimately cardiovascular collapse, especially in conjunction with drug treatment (27). Hyperthermia with excessive muscle activity is present in up to 83% of patients with GCSE (28) and, with other systemic alterations, may be responsible in part for the resultant widespread neuronal loss and reactive gliosis in the neocortex, amygdala– hippocampus, dorsomedial thalamic nuclei, and, less frequently, the Purkinje cell layer of the cerebellum that characteristically occur with SE (29 –31). However, injury to neurons within 60 minutes may occur despite correction of systemic parameters and compensated cellular energy demands (27–30), with similar patterns of injury seen in those patients without preexisting
epilepsy (31). Neuronal injury probably occurs as a consequence of continued excessive excitatory amino acid release and not only from the excessive demands imposed by repetitive neuronal firing (32). Glutamate mediates most of the excitation through interaction with the N-methyl-d-aspartate receptor (NMDA) (33), facilitating intracellular calcium influx and subsequent acute and apoptotic cell death (21). Intracellular calcium activates enzymatic degradation of intracellular components, resulting in mitochondrial dysfunction, cellular energy failure, and necrotic cell death in SE, similar to the mechanisms seen with cerebral ischemia (33). Programmed cell death (apoptosis) may occur with SE by activation of immediate early genes that code for endonucleases that cleave the cells’ DNA into fragments. These mechanisms of delayed cell death are most applicable to regions of the brain where NMDA receptors are concentrated, such as in the hippocampus.
OUTCOMES SE is recognized as an emergency because of the correlation of increasing duration of SE with increasing morbidity and mortality. Outcome is also related to age, etiology, and seizure duration, though the predominant factor affecting outcome is etiology (32). A younger age is a favorable factor in outcome (35). Etiologies including acute symptomatic disturbances of the CNS, especially with anoxia and stroke, are not only more difficult to treat, there is greater morbidity and mortality, especially in the elderly (36). Patients with epilepsy with SE as a result of withdrawal or low AED levels respond better to treatment (4). Status myoclonus following hypoxia carries an especially poor prognosis and calls for less aggressive treatment in refractory cases because of the generally futile effects of such treatment on outcome (37). Such a symptomatic cause may influence the response to treatment in a negative way. Duration of SE for more than 1 hour has also been shown to represent an extremely important risk factor imparting poor outcome (36). Simple partial SE and epilepsia partialis continua (when motor cortex is involved) are often resistant to AED treatment, have been recognized to be more common than NCSE or GCSE (2), and impose less immediate consequences. Acute morbidity associated with GCSE is influenced by the effects of coexistent coma. After terminating GCSE, a persistent encephalopathy occurs in 6 –15% (28, 38). CPSE has similarly been associated with Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
314 memory loss and cognitive deficits (14). However, of the many patients with complex partial SE, perhaps as many as 15% of patients with complex partial seizures (39), few have convincingly shown lasting cognitive changes (40). Perhaps one reason for the absence of identified neurologic sequelae has been the lack of formal neuropsychological evaluations in patients prior to the onset of NCSE which can be compared following an episode of SE. One small study (41) included impaired outcome in 7 of 10 patients where the immediate causes of NCSE could in themselves reflect an apparent permanent sequelae. Another series (38) of 5 patients with complex partial SE matched with control patients without complex partial SE showed no significant decline. NCSE may alter mental status and contribute to the development of infection, deep vein thrombosis, and decubitus ulcers among others. Focal neurologic deficits are noted in 9 –11% of patients with SE (21). With regard to GCSE, it is generally agreed that absence SE causes no discernable cognitive sequelae. Overall, children typically recover to a significantly greater degree than adults. Epilepsy may develop in approximately 20% of patients after SE (21). However, it is difficult to discern whether SE is the first “seizure” in the course of epilepsy, or the result. Estimates of survival after GCSE have improved from earlier reports which suggest mortality rates as high as 50% (36). At present, the mortality rate is approximately 20% in adults (32) and has remained relatively stable. The cause of death is usually the etiology that precipitates GCSE; however, a smaller number of patients may succumb to the effects of systemic deterioration. When hypoxia is associated with SE, death rates up to 60 –70% are reported, while alcohol and low AED levels are associated with the lowest mortality (36). Overall, GCSE was associated with a 19% mortality, which fell to 2.6% when prolonged seizures ceased within 29 minutes (42). Furthermore, mortality from SE is greater when seizure activity is continuous as opposed to intermittent, and increases with increasing duration (36). No difference has been demonstrated between the mortality of partial-onset and generalized-onset SE (36). Similarly, the mortality rates of GCSE and “subtle” SE were similar despite the difference in observed motor activity (9). Children and the elderly are most likely to develop SE. Children are more resilient, with mortality rates that climb proportionately as age increases. In one prospective study, mortality was 3% for the pediatric age group, 13% for young adults, and 38% in the elderly (3). Non-tonic– clonic status epilepticus remains quite Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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heterogenous in presentation and outcome (43), yet, depending on underlying illness and depth of coma, mortality rates have reached as high as 52% in critically ill elderly patients (44). With generalized nonconvulsive SE, absence SE carries no discernable cognitive morbidity or mortality, as mentioned previously. The detectable morbidity of complex partial SE in minimally confused patients who are ambulatory is probably less than 1% (40). Identifiable decline in activities of daily living or social integration was absent in one small study. The poor outcome of comatose patients with intercurrent electrographic seizures is high (4, 26, 36), with morbidity and mortality that are difficult to separate from the multisystem failure and neurologic insults that initially caused SE (40).
DIAGNOSIS The diagnosis of SE for treatment purposes often begins within 5–10 minutes, rarely allowing a 30minute period to elapse to meet the strict diagnosis of SE (4, 7, 8). More recent work suggests that since most seizures last less than 2 minutes, seizures lasting more than 10 minutes are at significant risk of extending beyond 29 minutes (42). Therefore, any seizures longer than 10 minutes should be treated as SE as previously suggested (4, 8). We suggest that this should allow revision of the criteria for a diagnosis of SE to include any seizure of 10 minutes in duration. Urgency exists for seizures that persist or recur over 30 minutes without recovery of consciousness; these merit immediate attention as well as confirmation of the epileptic origin (45). Vital signs are rapidly stabilized and hyperthermia is addressed. Historical elements that include epilepsy, drugs, alcohol, recent infections, trauma, cranial surgeries, any known brain abnormality, and a directed physical examination will guide appropriate management. Venous blood should be obtained within the first 5 minutes to analyze electrolytes, liver function tests, glucose, complete blood count, AED levels, and other drug levels or screens if applicable (7). Special monitoring for cardiac rhythm, arterial blood gas determination, urinalysis, and other special laboratory testing supplement the routine assessment. Computed tomography of the brain is usually the initial study performed to detect a structural lesion. Lumbar puncture is performed for cerebrospinal fluid analysis when CNS infection or subarachnoid hemorrhage is suspected. An electroencephalogram (EEG) is obtained as soon as possible in patients with altered
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mental status. GCSE typically is readily recognized and does not require an immediate EEG. However, EEG evaluation after cessation of convulsions is essential, particularly if the patient remains without improvement in mental status. Despite resolution of convulsive SE, up to 48% of patients have been noted to continue to demonstrate electrographic seizures, 14% without overt clinical signs (17). When an epileptic substrate is in question such as with toxic-metabolic encephalopathies or psychogenic SE (45, 46), or if NCSE with continuous or frequently recurring seizures manifests as a confusional state or encephalopathy, EEG confirmation is necessary (12, 45– 47). Emergency EEG is needed to confirm the clinical diagnosis. Despite the appearance of GCSE, 70 – 80% have focal EEG features (48). The evolution of EEG in GCSE was discussed earlier (10). The EEG of focal SE may vary and take several forms from discrete electrographic seizures to continuous focal epileptiform discharges (49). The complexity and variety of epileptiform patterns that occur with NCSE have been the subject of attention (11). Single-photon-emission computed tomography may also be useful in stable patients to clarify the ictal nature of the EEG when the clinical behavior is atypical or to define simple partial SE when scalp EEG findings are nondiagnostic (50, 51). SPECT may demonstrate regional cerebral hyperperfusion when CPSE presents as isolated confusion (52). With NCSE, the diagnosis is often inferred due to alteration in behavioral or cognitive baseline with concurrent EEG evidence of seizure activity with improved behavior and/or EEG pattern following antiepileptic drug treatment. Unfortunately, there is no universal agreement as to what constitutes seizure activity nor a period defined for the time to resolution. Periodic patterns including periodic lateralized epileptiform discharges (PLEDs), and triphasic waves may present a particular challenge (48, 53). Furthermore, there may be a gradual return to baseline over one or more days (54), though in some patients a rapid clinical response to intravenous benzodiazepines and EEG normalization may suggest confusion was the manifestation of NCSE (55).
TREATMENT SE is a life-threatening neurologic emergency requiring prompt treatment. Treatment should first include aggressive intervention and rapid termination of SE. The intensity of treatment should reflect the risk to an individual patient relative to the effects of SE balanced with
315 the untoward effects of treatment on respiration and cardiovascular integrity. Intravenous therapy is the first route of administration, though intramuscular and rectal administration of benzodiazepines has been used (56 – 58). The Veterans Administration (VA) cooperative trial demonstrated intravenous lorazepam to be the quickest effective treatment for GCSE when compared with phenobarbital, diazepam/phenytoin, and phenytoin alone, with a success rate of 64.9% when used as the initial treatment (59). The recommended treatment for GCSE is therefore to begin with lorazepam (8). No differences among treatments were seen in “subtle” SE or with respect to recurrence during the subsequent 12-hour period. The aggregate response rate to a second drug was 7.0%, and to a third drug, 2.3% (59). As a second-line treatment, fosphenytoin or phenytoin is still recommended if SE is not controlled within 5–7 minutes (8). Fosphenytoin is better tolerated, with less adverse reactions and quicker delivery capabilities (8, 57). Patients with continued SE despite lorazepam and fosphenytoin have been subsequently treated with phenobarbital (7), though the results of the VA study indicate that this approach is unlikely to result in rapid termination (59). Intravenous valproate is now available, with a role in the treatment of SE that is yet to be defined. Valproate is a nonsedating AED that has not caused hypotension or respiratory suppression and has been used successfully in GNSE (60), as well as in critically ill unstable patients, without adverse effects on cardiovascular parameters (61). High-dose phenobarbital in children and pentobarbital in adults have been employed in the management of SE when it appears refractory to conventional therapy (62). High-dose barbiturates, high-dose benzodiazepines, and propofol are used when SE is refractory to at least two agents (8). Most of the experience with refractory SE has been with pentobarbital. Continuous EEG monitoring is necessary in conjunction with ICU support and mechanical ventilation to verify elimination of seizure activity. Burst suppression has been a goal, although the clinical necessity has not been established (8). High-dose benzodiazepines including midazolam and lorazepam have also been used (62– 64). The major disadvantage is tachyphylaxis after 24 – 48 hours. Propofol is a unique GABA-A agonist with very potent anticonvulsant activity that must not be rapidly discontinued (65, 66). Intravenous valproate has been used in pediatric epilepsy patients with refractory SE (67). In absence or idiopathic myoclonic SE, carbamazepine or phenytoin may provoke generalized SE (68) and earlier substitution with valproate may be successful (69). Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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FUTURE TREATMENT The future treatment of SE will involve newer treatments beyond merely seizure suppression. N-Methyld-aspartate anatagonists may reduce the electrophysiologic consequences of epileptiform depolarization, and also may prevent the cascade of acute and delayed cell injury (21). Neuroprotection beyond seizure cessation has been evaluated with a short-term anesthetic agent, ketamine (70). Further evaluation in humans is required, though a combination approach using agents such as a GABA agonist (i.e., lorazepam) with an NMDA antagonist may be a way to both stop SE in addition to preventing neuronal injury. Additionally, agents such as free radical scavengers, nitric oxide, and adenosine modulators may also someday be used in a comprehensive approach to patients with SE (21, 23). The future brings hope and promise of new approaches for treating status epilepticus.
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ACKNOWLEDGMENT 19. The authors thank Ms. Kelly Porrey for her help with word processing of the manuscript. 20. 21.
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Thomas P, Zifkin B, Migneco O, Lebrun C, Darcourt J, Andermann F. Nonconvulsive status epilepticus of frontal origin. Neurology 1999;52:1174 – 83. Benbadis SR, Tatum WO IV. Prevalence of nonconvulsive status epilepticus in comatose patients [letter]. Neurology 2000; 55:1421–3. Lee SI. Nonconvulsive status epilepticus: ictal confusion in later life. Arch Neurol 1985;42:778 – 81. Kaplan PW. Benzodiazepine-responsive confusion: is this NCSE? In: American Clinical Neurophysiology Society Meeting. Montreal, Canada, September 2000. Towne AR, DeLorenzo RJ. Use of intramuscular midazolam for status epilepticus. J Emerg Med 1999;17:323– 8. DeToledo JC, Ramsay RE. Fosphenytoin and phenytoin in patients with status epilepticus: improved tolerability versus increased cost. Drug Saf 2000;22:459 – 66. Cereghino JJ, Mitchell WG, Murphy J, Kriel RL, Rosenfeld WE, Trevathan E, and The North American Diastat Study Group. Treating repetitive seizures with a rectal diazepam formulation: a randomized study. Neurology 1998;51:1274 – 82. Treiman DM, Meyers PD, Walton NY, et al. A comparison of four treatments for generalized convulsive status epilepticus. N Engl J Med 1998;339:792– 8. Kaplan PW. Intravenous valproate treatment of generalized nonconvulsive status epilepticus. Clin Electroencephalogr 1999;30:1– 4. Sinha S, Naritoku DK. Intravenous valproate is well tolerated in unstable patients with SE. Neurology 2000;55:722– 4. Holmes GL, Riviello JJ Jr., Midazolam and pentobarbital for refractory status epilepticus. Pediatr Neurol 1999;20:259 – 64. Labar DR, Ali A, Root J. High-dose intravenous lorazepam for the treatment of refractory status epilepticus. Neurology 1994; 44:1400 –3. Hanley DF, Pozo M. Treatment of status epilepticus with midazolam in the critical care setting. Int J Clin Pract 2000;54: 30 –5. Brown LA, Levin GM. The role of propofol in refractory status epilepticus. Ann Pharmacother 1998;32:1053–9. Stecker MM, Kramer TH, Raps EC, O’Meeghan R, Dulaney E, Skaar DJ. Treatment of refractory status epilepticus with propofol: clinical and pharmacokinetic findings. Epilepsia 1998;39:18 –26. Uberall MA, Trollmann R, Wunsiedler U, Wenzel D. Intravenous valproate in pediatric epilepsy patients with refractory status epilepticus. Neurology 2000;54:2188 –9. Osorio I, Reed RC, Peltzer JN. Refractory idiopathic absence status epilepticus: a probable paradoxical effect of phenytoin and carbamazepine. Epilepsia 2000;41:887–94. Sheth RD, Gidal BE. Intravenous valproic acid for myoclonic status epilepticus. Neurology 2000;54:1201. Fujikawa DG. Neuroprotective effect of ketamine administered after status epilepticus onset. Epilepsia 1995;36:186 –95.
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REVIEW The Etiology and Diagnosis of Status Epilepticus W. O. Tatum IV,* ,1 J. A. French, † S. R. Benbadis,* ,‡ and P. W. Kaplan § *Tampa General Hospital Epilepsy Center, Department of Neurology, and ‡Department of Neurosurgery, University of South Florida, Tampa Florida; †Department of Neurology, University of Pennsylvania, Philadelphia, Pennsylvania; and §Department of Neurology, Johns Hopkins University, Baltimore, Maryland Received January 18, 2001; revised April 20, 2001; accepted for publication April 30, 2001
Status epilepticus (SE) is a common, serious, potentially life-threatening, neurologic emergency characterized by prolonged seizure activity. Generalized convulsive status epilepticus (GCSE) is the most widely recognized form of SE. Direct consequences of convulsive movements from SE can result in injury to the body and brain. Nonconvulsive status epilepticus (NCSE) is underrecognized, with controversy surrounding the consequences and treatment. High mortality rates with GCSE have been noted in the past. New treatments for SE are emerging with new parenteral drug formulations as well as new agents for refractory SE, offering an opportunity to improve outcome. Special drug delivery systems, drug combinations, and neuroprotective agents that prevent the subsequent development of epilepsy may soon emerge as future options for treating SE. © 2001 Academic Press Key Words: status epilepticus; seizures; emergency; brain; injury; convulsive; nonconvulsive; causes; outcome; treatment.
INTRODUCTION
a practical standpoint, however, treatment must be considered by 5–10 minutes, or when at least two seizures have occurred back-to-back without an intervening return to consciousness, because of the concern for causing irreversible neuronal injury.
Status epilepticus (SE) was described as early as 600 –700 bc in ancient Babylon (1). The annual frequency of SE in the United States is estimated to be between 126,000 and 195,000 events, with up to 42,000 deaths yearly, though the incidence may be higher due to underreporting (2, 3). Current annual costs probably exceed $4 billion to identify and treat cases with subsequent hospitalization (4). Definitions of SE have varied (5, 6). Strictly defined, SE represents more than 30 minutes of continuous seizure activity, or two or more sequential seizures without full recovery between seizures (7). Initial definitions of 30 minutes were used due to the substantial mortality associated with seizure prolongation, although more recent opinions have suggested using shorter periods (4, 8). From
CHARACTERISTICS Generalized convulsive SE (GCSE) is the most commonly identified form of SE. While any seizure type may evolve into SE, morbidity and mortality are most critical with GCSE. GCSE may involve tonic– clonic seizures. Continuous or intermittent tonic with or without clonic movements occur that may be symmetrical or asymmetrical with loss of consciousness. Descriptions have referred to GCSE when overt motor movement is seen. Subtle GCSE has been described (9) when minimal motor movement is restricted to continuous, rhythmic motor movements or twitches that can be seen to involve the eyes, eyelids, face, jaw,
1 To whom all correspondence should be addressed at c/o 13801 Bruce B. Downs Boulevard, No. 401, Tampa, FL 33613. Fax: (813) 971-6951. E-mail: [email protected].
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312 trunk, or extremity during stupor or coma. Such “subtle” forms of SE involve electrographic seizures with minimal clinical signs. Overt GCSE may evolve to subtle seizure activity by decreasing rostral– caudal vertical transmission of cortical electrical impulses that stimulate muscle movement. In this way, an “electromechanical dissociation” is paralleled by a series of changes that occur on the electroencephalogram (EEG). Discrete electrographic seizures eventually merge and become continuous ictal discharges that then become punctuated with intermittent suppressions prior to the late phases which on EEG reveal periodic epileptiform discharges on a suppressed background (10). Myoclonic seizures involving SE occur in two separate entities. Myoclonic SE in primary generalized epilepsy manifests as bilateral massive myoclonus at irregular intervals or in clusters usually with intact consciousness and polyspike waves on EEG. It has a good prognosis. Status myoclonus is not strictly speaking myoclonic SE but is more common and occurs after severe hypoxic–ischemic insult. Rapid, brief bilateral often asymmetric asynchronous low-amplitude jerks or contractions of axial or appendicular musculature may be stimulus-sensitive, and are accompanied by EEG epileptic discharges during evaluation of GCSE. Status epilepticus may also be nonconvulsive SE (NCSE). The clinical features consist of changes in behavior, memory, affect, or level of consciousness, often with alteration in body tone and fine facial or limb tremors followed by amnesia. NCSE is underdiagnosed (11), and may be confused with primary psychiatric or behavioral disorders (12). Another condition often confused for NCSE is coma with EEG epileptiform activity or electrographic seizures (13), an entity with various substrates, correlates, and outcomes. NCSE represents an “epileptic twilight state” and may be categorized into complex partial SE and absence SE (spike-wave) forms frequently best delineated using EEG. Typical absence SE does not appear to be associated with serious morbidity or mortality; however, complex partial status has been associated with controversy regarding permanent neurologic damage, similar to GCSE. Some authors suggest a causative association with serious morbidity and mortality (14), with neuronal damage arising from epileptiform activity acting synergistically with the acute symptomatic cause of SE (15). Others refute the effect of NCSE itself as causing cognitive or neurologic impairments, attributing the morbidity to the underlying cause rather than the effects of NCSE (16). Electrographic seizures in coma have been noted to persist in Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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14% of patients following control of GCSE at a time when overt tonic– clonic movements have disappeared (17). Other SE syndromes exist. Electrical status epilepticus during sleep (ESES) reflects an electrographic pattern consisting of almost continuous spike-wave discharges in slow-wave sleep. Clinical conditions with electrical status epilepticus in sleep (ESES) include “continuous spikes and waves during slow wave sleep” and the Landau–Kleffner syndrome and may present with neuropsychiatric and cognitive dysfunction in association with ESES (18, 19) often with a steady decline, although the course may be variable.
CAUSES The causes of GCSE and NCSE are legion. Remote symptomatic, acute symptomatic, and idiopathic etiologies for SE are evenly distributed (20), with a structural basis being more likely to be discovered the more rigorous the search. Status epilepticus is very common in patients with epilepsy. Epilepsy is the strongest single risk factor for GCSE; however, young age, genetic predisposition, and an acquired brain injury are other important risks (21). About 15–20% of persons with epilepsy have a history of at least one episode of SE, and 15% present with SE (7, 20). In a prospective, population-based study (3), low antiepileptic drug levels in patients with epilepsy was the most common etiology, followed by remote brain insult and stroke. Almost 50% of adult cases of SE were caused by acute or remote cerebrovascular disease. Anoxia, hemorrhage/stroke, and tumor were common causes in adults, while in the pediatric group, fever (52%) was the most common concomitant factor, followed by remote brain insult and low antiepileptic drug (AED) levels. Low AED levels still constituted the largest identifiable etiology. SE is most common in young children. Approximately 40% of children developing status are less than 2 years of age (22). At this age, epilepsy is usually not present at the time of SE, and a febrile illness is the initiating event. Febrile illness, hypoxic–ischemic encephalopathies, and CNS infections are frequent causes in children. Recurrence is greatest (40 – 60%) in children with acute or chronic brain insults and rare (5%) in idiopathic causes or febrile status (23). In older children, preexisting epilepsy is present and low AED levels remain a common cause.
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MECHANISMS Initiation The principal means of generating SE is by failure of the normal mechanisms that terminate seizures. Fundamentally, persistent excessive excitation and failed inhibition have complex interactions that engender ongoing seizure activity. Excessive activation of excitatory amino acids via glutamate analogues has been noted to prolong seizures (24), impairing the usual mechanism by which seizures terminate. However, ␥-aminobutyric acid (GABA) antagonists may also provoke SE in experimental models with agents such as picrotoxin and bicuculline. Dynamic changes in GABA-A receptor function as seizures become prolonged may occur, resulting in receptor insensitivity during hyperexcitable states (25). Other neurotransmitters important for the initiation and maintenance of SE include adenosine, acetylcholine, and nitric oxide. Absence SE with 3-Hz spike-wave discharges are induced by excessive inhibition (21, 25). Modulated by GABA-B-mediated hyperpolarization through activation of thalamic T-type calcium channels, this form of SE does not lead to the neuronal injury seen with excessive excitation (21).
Injury Brain injury that is present after SE has been suggested to reflect the effects of CNS damage causing SE, the direct injury from electrical discharges during SE, and the associated systemic consequences incurred. As GCSE evolves, major systemic derangements occur, including hypoglycemia, hyperthermia, hypoxia, and acidosis that exacerbate neuronal injury (26). These changes may predispose to cardiac arrhythmias, pulmonary edema, aspiration, respiratory failure, or renal failure, and ultimately cardiovascular collapse, especially in conjunction with drug treatment (27). Hyperthermia with excessive muscle activity is present in up to 83% of patients with GCSE (28) and, with other systemic alterations, may be responsible in part for the resultant widespread neuronal loss and reactive gliosis in the neocortex, amygdala– hippocampus, dorsomedial thalamic nuclei, and, less frequently, the Purkinje cell layer of the cerebellum that characteristically occur with SE (29 –31). However, injury to neurons within 60 minutes may occur despite correction of systemic parameters and compensated cellular energy demands (27–30), with similar patterns of injury seen in those patients without preexisting
epilepsy (31). Neuronal injury probably occurs as a consequence of continued excessive excitatory amino acid release and not only from the excessive demands imposed by repetitive neuronal firing (32). Glutamate mediates most of the excitation through interaction with the N-methyl-d-aspartate receptor (NMDA) (33), facilitating intracellular calcium influx and subsequent acute and apoptotic cell death (21). Intracellular calcium activates enzymatic degradation of intracellular components, resulting in mitochondrial dysfunction, cellular energy failure, and necrotic cell death in SE, similar to the mechanisms seen with cerebral ischemia (33). Programmed cell death (apoptosis) may occur with SE by activation of immediate early genes that code for endonucleases that cleave the cells’ DNA into fragments. These mechanisms of delayed cell death are most applicable to regions of the brain where NMDA receptors are concentrated, such as in the hippocampus.
OUTCOMES SE is recognized as an emergency because of the correlation of increasing duration of SE with increasing morbidity and mortality. Outcome is also related to age, etiology, and seizure duration, though the predominant factor affecting outcome is etiology (32). A younger age is a favorable factor in outcome (35). Etiologies including acute symptomatic disturbances of the CNS, especially with anoxia and stroke, are not only more difficult to treat, there is greater morbidity and mortality, especially in the elderly (36). Patients with epilepsy with SE as a result of withdrawal or low AED levels respond better to treatment (4). Status myoclonus following hypoxia carries an especially poor prognosis and calls for less aggressive treatment in refractory cases because of the generally futile effects of such treatment on outcome (37). Such a symptomatic cause may influence the response to treatment in a negative way. Duration of SE for more than 1 hour has also been shown to represent an extremely important risk factor imparting poor outcome (36). Simple partial SE and epilepsia partialis continua (when motor cortex is involved) are often resistant to AED treatment, have been recognized to be more common than NCSE or GCSE (2), and impose less immediate consequences. Acute morbidity associated with GCSE is influenced by the effects of coexistent coma. After terminating GCSE, a persistent encephalopathy occurs in 6 –15% (28, 38). CPSE has similarly been associated with Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
314 memory loss and cognitive deficits (14). However, of the many patients with complex partial SE, perhaps as many as 15% of patients with complex partial seizures (39), few have convincingly shown lasting cognitive changes (40). Perhaps one reason for the absence of identified neurologic sequelae has been the lack of formal neuropsychological evaluations in patients prior to the onset of NCSE which can be compared following an episode of SE. One small study (41) included impaired outcome in 7 of 10 patients where the immediate causes of NCSE could in themselves reflect an apparent permanent sequelae. Another series (38) of 5 patients with complex partial SE matched with control patients without complex partial SE showed no significant decline. NCSE may alter mental status and contribute to the development of infection, deep vein thrombosis, and decubitus ulcers among others. Focal neurologic deficits are noted in 9 –11% of patients with SE (21). With regard to GCSE, it is generally agreed that absence SE causes no discernable cognitive sequelae. Overall, children typically recover to a significantly greater degree than adults. Epilepsy may develop in approximately 20% of patients after SE (21). However, it is difficult to discern whether SE is the first “seizure” in the course of epilepsy, or the result. Estimates of survival after GCSE have improved from earlier reports which suggest mortality rates as high as 50% (36). At present, the mortality rate is approximately 20% in adults (32) and has remained relatively stable. The cause of death is usually the etiology that precipitates GCSE; however, a smaller number of patients may succumb to the effects of systemic deterioration. When hypoxia is associated with SE, death rates up to 60 –70% are reported, while alcohol and low AED levels are associated with the lowest mortality (36). Overall, GCSE was associated with a 19% mortality, which fell to 2.6% when prolonged seizures ceased within 29 minutes (42). Furthermore, mortality from SE is greater when seizure activity is continuous as opposed to intermittent, and increases with increasing duration (36). No difference has been demonstrated between the mortality of partial-onset and generalized-onset SE (36). Similarly, the mortality rates of GCSE and “subtle” SE were similar despite the difference in observed motor activity (9). Children and the elderly are most likely to develop SE. Children are more resilient, with mortality rates that climb proportionately as age increases. In one prospective study, mortality was 3% for the pediatric age group, 13% for young adults, and 38% in the elderly (3). Non-tonic– clonic status epilepticus remains quite Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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heterogenous in presentation and outcome (43), yet, depending on underlying illness and depth of coma, mortality rates have reached as high as 52% in critically ill elderly patients (44). With generalized nonconvulsive SE, absence SE carries no discernable cognitive morbidity or mortality, as mentioned previously. The detectable morbidity of complex partial SE in minimally confused patients who are ambulatory is probably less than 1% (40). Identifiable decline in activities of daily living or social integration was absent in one small study. The poor outcome of comatose patients with intercurrent electrographic seizures is high (4, 26, 36), with morbidity and mortality that are difficult to separate from the multisystem failure and neurologic insults that initially caused SE (40).
DIAGNOSIS The diagnosis of SE for treatment purposes often begins within 5–10 minutes, rarely allowing a 30minute period to elapse to meet the strict diagnosis of SE (4, 7, 8). More recent work suggests that since most seizures last less than 2 minutes, seizures lasting more than 10 minutes are at significant risk of extending beyond 29 minutes (42). Therefore, any seizures longer than 10 minutes should be treated as SE as previously suggested (4, 8). We suggest that this should allow revision of the criteria for a diagnosis of SE to include any seizure of 10 minutes in duration. Urgency exists for seizures that persist or recur over 30 minutes without recovery of consciousness; these merit immediate attention as well as confirmation of the epileptic origin (45). Vital signs are rapidly stabilized and hyperthermia is addressed. Historical elements that include epilepsy, drugs, alcohol, recent infections, trauma, cranial surgeries, any known brain abnormality, and a directed physical examination will guide appropriate management. Venous blood should be obtained within the first 5 minutes to analyze electrolytes, liver function tests, glucose, complete blood count, AED levels, and other drug levels or screens if applicable (7). Special monitoring for cardiac rhythm, arterial blood gas determination, urinalysis, and other special laboratory testing supplement the routine assessment. Computed tomography of the brain is usually the initial study performed to detect a structural lesion. Lumbar puncture is performed for cerebrospinal fluid analysis when CNS infection or subarachnoid hemorrhage is suspected. An electroencephalogram (EEG) is obtained as soon as possible in patients with altered
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mental status. GCSE typically is readily recognized and does not require an immediate EEG. However, EEG evaluation after cessation of convulsions is essential, particularly if the patient remains without improvement in mental status. Despite resolution of convulsive SE, up to 48% of patients have been noted to continue to demonstrate electrographic seizures, 14% without overt clinical signs (17). When an epileptic substrate is in question such as with toxic-metabolic encephalopathies or psychogenic SE (45, 46), or if NCSE with continuous or frequently recurring seizures manifests as a confusional state or encephalopathy, EEG confirmation is necessary (12, 45– 47). Emergency EEG is needed to confirm the clinical diagnosis. Despite the appearance of GCSE, 70 – 80% have focal EEG features (48). The evolution of EEG in GCSE was discussed earlier (10). The EEG of focal SE may vary and take several forms from discrete electrographic seizures to continuous focal epileptiform discharges (49). The complexity and variety of epileptiform patterns that occur with NCSE have been the subject of attention (11). Single-photon-emission computed tomography may also be useful in stable patients to clarify the ictal nature of the EEG when the clinical behavior is atypical or to define simple partial SE when scalp EEG findings are nondiagnostic (50, 51). SPECT may demonstrate regional cerebral hyperperfusion when CPSE presents as isolated confusion (52). With NCSE, the diagnosis is often inferred due to alteration in behavioral or cognitive baseline with concurrent EEG evidence of seizure activity with improved behavior and/or EEG pattern following antiepileptic drug treatment. Unfortunately, there is no universal agreement as to what constitutes seizure activity nor a period defined for the time to resolution. Periodic patterns including periodic lateralized epileptiform discharges (PLEDs), and triphasic waves may present a particular challenge (48, 53). Furthermore, there may be a gradual return to baseline over one or more days (54), though in some patients a rapid clinical response to intravenous benzodiazepines and EEG normalization may suggest confusion was the manifestation of NCSE (55).
TREATMENT SE is a life-threatening neurologic emergency requiring prompt treatment. Treatment should first include aggressive intervention and rapid termination of SE. The intensity of treatment should reflect the risk to an individual patient relative to the effects of SE balanced with
315 the untoward effects of treatment on respiration and cardiovascular integrity. Intravenous therapy is the first route of administration, though intramuscular and rectal administration of benzodiazepines has been used (56 – 58). The Veterans Administration (VA) cooperative trial demonstrated intravenous lorazepam to be the quickest effective treatment for GCSE when compared with phenobarbital, diazepam/phenytoin, and phenytoin alone, with a success rate of 64.9% when used as the initial treatment (59). The recommended treatment for GCSE is therefore to begin with lorazepam (8). No differences among treatments were seen in “subtle” SE or with respect to recurrence during the subsequent 12-hour period. The aggregate response rate to a second drug was 7.0%, and to a third drug, 2.3% (59). As a second-line treatment, fosphenytoin or phenytoin is still recommended if SE is not controlled within 5–7 minutes (8). Fosphenytoin is better tolerated, with less adverse reactions and quicker delivery capabilities (8, 57). Patients with continued SE despite lorazepam and fosphenytoin have been subsequently treated with phenobarbital (7), though the results of the VA study indicate that this approach is unlikely to result in rapid termination (59). Intravenous valproate is now available, with a role in the treatment of SE that is yet to be defined. Valproate is a nonsedating AED that has not caused hypotension or respiratory suppression and has been used successfully in GNSE (60), as well as in critically ill unstable patients, without adverse effects on cardiovascular parameters (61). High-dose phenobarbital in children and pentobarbital in adults have been employed in the management of SE when it appears refractory to conventional therapy (62). High-dose barbiturates, high-dose benzodiazepines, and propofol are used when SE is refractory to at least two agents (8). Most of the experience with refractory SE has been with pentobarbital. Continuous EEG monitoring is necessary in conjunction with ICU support and mechanical ventilation to verify elimination of seizure activity. Burst suppression has been a goal, although the clinical necessity has not been established (8). High-dose benzodiazepines including midazolam and lorazepam have also been used (62– 64). The major disadvantage is tachyphylaxis after 24 – 48 hours. Propofol is a unique GABA-A agonist with very potent anticonvulsant activity that must not be rapidly discontinued (65, 66). Intravenous valproate has been used in pediatric epilepsy patients with refractory SE (67). In absence or idiopathic myoclonic SE, carbamazepine or phenytoin may provoke generalized SE (68) and earlier substitution with valproate may be successful (69). Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.
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FUTURE TREATMENT The future treatment of SE will involve newer treatments beyond merely seizure suppression. N-Methyld-aspartate anatagonists may reduce the electrophysiologic consequences of epileptiform depolarization, and also may prevent the cascade of acute and delayed cell injury (21). Neuroprotection beyond seizure cessation has been evaluated with a short-term anesthetic agent, ketamine (70). Further evaluation in humans is required, though a combination approach using agents such as a GABA agonist (i.e., lorazepam) with an NMDA antagonist may be a way to both stop SE in addition to preventing neuronal injury. Additionally, agents such as free radical scavengers, nitric oxide, and adenosine modulators may also someday be used in a comprehensive approach to patients with SE (21, 23). The future brings hope and promise of new approaches for treating status epilepticus.
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ACKNOWLEDGMENT 19. The authors thank Ms. Kelly Porrey for her help with word processing of the manuscript. 20. 21.
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