`Lippincott Williams & Wilkins, Philadelphia
`0 International League Against Epilepsy
`
`Special Article
`It’s Time to Revise the Definition of Status Epilepticus
`
`Daniel H. Lowenstein, *Thomas Bleck, and ?Robert L. Macdonald
`Department of Neurology and Anatomyj University ($ California-San Francisco, San Francisco, Californiu; Wepurtment of
`Neurology, University of Virginia Medical Center, Charlottesville, Virginia; and )‘Department of Neurology, University of
`Michigan, Ann Arbor, Michigan, U.S.A.
`Generalized, tonic-clonic status epilepticus is well
`Much of the confusion with status epilepticus is that
`recognized as a common neurologic emergency requir-
`the “official” definition by the ILAE lacks a specific
`ing prompt treatment. The diagnosis is usually not diffi-
`duration of seizure activity. Most authors of reviews or
`cult, other than for patients with prolonged seizures, who
`research reports in the modern era choose precise tem-
`often develop increasingly subtle clinical features (1,2).
`poral criteria, but these criteria lack uniformity. Until
`There also appears to be a consensus among physicians
`recently, the most popular duration of seizures qualifying
`regarding treatment (3). Nonetheless, there is a major,
`as status epilepticus has been 30 min (for examples, see
`persistent dilemma regarding status epilepticus: its defi-
`references 3 and 10-12). The rationale for this duration,
`when stated, has generally been that 30 min represents a
`nition. Discussions concerning the precise definition of
`status epilepticus all too often result in agreement that
`time during which ongoing seizures can lead to neuronal
`current “textbook” definitions are either imprecise, at
`injury in certain animal models. Nonetheless, in the past
`odds with clinical practice, or both. Here we propose a
`few years, some clinicians suggested the duration of sei-
`revised system for defining status epilepticus that ad-
`zures qualifying as status epilepticus should be shorter.
`In a review article in 1991, Bleck (13) defined status
`dresses these problems.
`References to status epilepticus prior to the mid- 19th
`epilepticus as continuous or repeated seizures lasting >20
`century focused on cases in which seizures lasted many
`min. Furthermore, the recently completed, prospective
`hours to days (4). In 1904, Clark and Prout (5) defined
`VA Cooperative Trail on Treatment of Generalized Con-
`status epilepticus as a state in which seizures occur so
`vulsive Status Epilepticus used a duration of 10 min as
`frequently that ‘‘the coma and exhaustion are continuous
`inclusion criterion for status epilepticus ( 14).
`between the seizures.” In his general textbook of neu-
`The essential problem in the evolution of these defi-
`rology published in 1940, Kinnier Wilson (6) referred to
`nitions has been the limited understanding of the basic,
`status epilepticus as the severest form of seizures in
`pathophysiological mechanisms underlying status epi-
`which “the post-convulsive sleep of one attack is cut
`lepticus, as well as the variations in the clinical pheno-
`short by development of the next.” Aspects of these
`type. Resolution of this problem will require consider-
`definitions were mirrored in the first International Clas-
`ably more time and effort. In the meantime, we propose
`sification of Epileptic Seizures that was developed in
`that the definition of generalized, convulsive status epi-
`1964 by the International League Against Epilepsy
`lepticus be revised to incorporate the very practical con-
`(ILAE). Status epilepticus was defined as the situation in
`siderations of patient management. To do this, our
`which “a seizure persists for a sufficient length of time
`scheme delineates two distinct definitions: an operational
`or is repeated frequently enough to produce a fixed and
`definition and a mechanistic definition.
`enduring epileptic condition” (7). The same definition
`was retained in the revised classification published in
`1970 (8), and it was modified slightly in 1981 to refer to
`the situation in which “a seizure persists for a sufficient
`length of time or is repeated frequently enough that re-
`covery between attacks does not occur” (9).
`
`OPERATIONAL DEFINITION
`Generalized, convulsive status epilepticus in adults
`and older children (>5 years old) refers to a5 min of (a)
`continuous seizures or (0) two or more discrete seizures
`between which there is incomplete recovery of con-
`sciousness. This definition is in contrast to serial sei-
`zures, in which there are two or more seizures over a
`relatively brief period (i.e., minutes to many hours), but
`the patient regains consciousness between the seizures.
`
`Accepted
`Address correspondence and reprint requests to Dr. D. H.
`Lowenstein at Department of Neurology, Box 01 14, UCSF School of
`Medicine, 505 Parnassus Avenue, San Francisco, CA 94143-01 14,
`U.S.A.
`
`120
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`Given the unique forms of prolonged seizures in young
`children and infants, especially seizures associated with
`fever, a longer time frame than 5 min (e.g., 10-15 min)
`is suggested for this younger group. However, in contrast
`to the availability of data on seizure durations in adults
`(see the following), there is a paucity of similar infor-
`mation from young children. We are therefore unable to
`find a logical basis for providing an operational defini-
`tion for status epilepticus in this younger group at this
`time.
`Our rationale for the revised, operational definition in
`adults is based on the following three points:
`1. Defining status epilepticus based on the theoretic
`onset of neuronal injury, as done in the past, is of
`questionable value because the relation between
`status epilepticus and neuronal injury in humans is
`complex and influenced by various factors besides
`duration of seizure activity. The seminal work in
`the 1970s by Meldrum et al. (15) established that
`seizures lasting >82 rnin in unanesthesized baboons
`could cause irreversible brain injury. However, five
`animals in status epilepticus for 50-1 20 min had no
`obvious brain injury. Not surprisingly, numerous
`clinical studies suggested a relation between sei-
`zure duration and patient mortality (16-18). How-
`ever, acute mortality in status epilepticus is usually
`due to systemic derangements that are directly and
`indirectly related to persistent seizures, not neuro-
`nal injury per se. Furthermore, various reports sug-
`gested that the etiology of status epilepticus may be
`an extremely important determinant of short-term
`outcome and response to therapy, leading to even
`more variability in defining the time at which irre-
`versible brain injury occurs (17-19). Although it is
`often not considered in definitions of status epilep-
`ticus, age is also an important determinant of out-
`come, further confounding the development of a
`definition of status epilepticus that has general ap-
`plication (1 8).
`2. The typical, generalized tonic-clonic seizure
`(GTCS) in adults appears to last >5 rnin relatively
`rarely. Gastaut and Broughton (20) studied the
`clinical phenomenology of GTCS in thousands of
`patients, and observed that the tonic phase lasted
`1-20 s, the clonic phase lasted -30 s, and the
`“postictal tonic contraction” lasted a few seconds
`to 4 min. Another study found that the mean dura-
`tion of secondarily generalized GTCSs was 53 s
`(21). More recently, in a careful video-EEG analy-
`sis of 120 secondarily GTCSs in 47 hospitalized
`patients, Theodore et al. (22) reported that the mean
`duration of GTCSs was 62 s, with a range of 16-
`108 s. These latter two studies were concerned with
`a selected group of patients (those with medically
`
`intractable partial seizures), so the results are not
`necessarily applicable to all GTCSs. Nonetheless,
`these observations, combined with data from clini-
`cal studies of status epilepticus, suggest that
`GTCSs in adults that do not terminate within 5 rnin
`may vary considerably in duration and last from
`many minutes to several hours. The biologic dif-
`ferences between adult patients with typical GTCSs
`lasting at most a few minutes and patients who
`have seizures lasting >5 rnin are unknown. In
`young children and infants, there is relatively little
`known about the durations of typical “single” sei-
`zures and prolonged seizures. As in adults, the fac-
`tors that govern the duration of seizures in young
`children are poorly understood.
`3. Perhaps most important, patients with convulsions
`that persist beyond the duration of a typical GTCS
`should be treated acutely with antiepileptic drugs
`(AEDs), as long as complications of therapy can be
`safely managed. This approach is consistent with
`common, clinical practice. When faced with a pa-
`tient who is having continuous seizures, it is un-
`reasonable to wait 30 or even 15 min before initi-
`ating therapy. Similarly, a patient in a postictal
`coma who has a second GTCS would be treated
`acutely. Patients who are experiencing GTCSs at
`the time of arrival in the emergency department are
`treated promptly, regardless of the prior duration of
`seizures. All of these practices are based on empiric
`observations that patients with persistent seizures
`of any duration are potentially at greater risk for
`cardiorespiratory problems. It also is obvious that
`assessment and management of these patients is
`much less complicated when the seizures are
`stopped. Simplified management is a primary rea-
`son for the increased use of AED therapy by para-
`medics in the pre-hospital setting. Paramedics who
`are called to treat patients with seizures in the pre-
`hospital setting often initiate therapy if the patient
`continues to have seizures at the time of paramedic
`arrival. In the ongoing “Pre-hospital Treatment of
`Status Epilepticus” (PHTSE) study in San Francis-
`co, the working definition of status epilepticus sets
`the duration of seizures as >5 rnin to match local
`practice (23).
`MECHANISTIC DEFINITION
`Generalized, convulsive status epilepticus refers to a
`condition in which there is a failure of the “normal”
`factors that serve to terminate a typical GTCS. This defi-
`nition can now be considered a basic research definition
`because our knowledge of the mechanisms governing
`seizure cessation remains incomplete. These mechanisms
`presumably involve abnormal persistence of seizure-
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`Eplepsia, Vol. 40, No. I , 1999
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`AQUESTIVE EXHIBIT 1102 Page 0002
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`122
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`D. H. LOWENSTEIN ET AL.
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`induced factors, a delay in the expression of factors that
`suppress seizures, or both. Once the factors responsible
`for seizure termination are fully understood, it will be
`possible to focus efforts on analyzing the evolving “sei-
`zure state” of a patient based on fundamental, patho-
`physiological properties. Ultimately, this definition
`should supplant the operational definition proposed, be-
`cause a precise assessment of seizure pathophysiology in
`a patient will guide both aspects of clinical assessment
`and treatment decisions.
`There are a number of benefits to this revised defini-
`tion scheme. First, it offers an operational definition that
`makes clinical sense. Most clinicians agree that pro-
`longed seizures are accompanied by an increased risk of
`complications, and that we should not wait 10 min or
`longer before instituting a treatment protocol for status
`epilepticus. Second, it highlights a potentially vital but as
`yet unknown pathophysiological distinction between the
`single GTCS in adults that appears typically to last S2-4
`min and more prolonged seizures. (Further studies on the
`clinical epidemiology of status epilepticus-in
`both
`adults and pediatric patients-will
`be vital to refine these
`temporal criteria.) Third, it serves as a more realistic
`definition for clinical studies of status epilepticus. This
`will become even more important as progress is made in
`the rapid diagnosis and treatment of patients with sei-
`zures in the prehospital setting. However, there may be a
`need for alternative clinical research definitions, having
`different specifications for duration of seizures or recov-
`ery of consciousness, tailored to a particular population
`of patients or clinical setting.
`REFERENCES
`Treiman D, DeGiorgio C, Salisbury S, Wickboldt C. Subtle gen-
`eralized convulsive status epilepticus. Epileppsia 1984;25:263.
`Lowenstein D, Aminoff M. Clinical and electroencephalographic
`features of status epilepticus in comatose patients. Neurology
`1989;42: 1004.
`Working Group on Status Epilepticus. Treatment of convulsive
`
`status epilepticus: recommendations of the Epilepsy Foundation of
`America’s Working Group on Status Epilepticus. JAMA 1993;270:
`854-9.
`Hunter R. Status epilepticus: history, incidence and problems. Epi-
`lepsia 1959/60; 1 : 162-88.
`Clark L, Prout T. Status epilepticus: a clinical and pathological
`study in epilepsy. Am J Zrzsaniry 1903/04;60:29 1-306.
`Wilson S. Neurofogy. Baltimore: Williams & Wilkins, 1940.
`Commission on Terminology of the International League Against
`Epilepsy. A proposed international classification of epileptic sei-
`zures. Epilepsiu 1964;5:297-306.
`Gastaut H. Clinical and electroencephalographic classification of
`epileptic seizures. Epilepsia 1970;ll: 102-13.
`Commission on Classification and Terminology of the Interna-
`tional League Against Epilepsy. Proposal for revised clinical and
`electroencephalographic classification of epileptic seizures. Epi-
`lepsia 1981 ;22:489-501.
`Celesia G. Modern concepts of status epilepticus. JAMA 1976;235:
`15714.
`Brodie M. Status epilepticus in adults. h n c e t IWO;336:55 1-2.
`Shepherd S. Management of status epilepticus. Emerg Med Clin
`North Am 1994;12:941-61.
`Bleck T. Convulsive disorders
`tus epilepticus. Clin Neurophar-
`rnucol 199 I ; 14: I9 1-8.
`Treiman D, Meyera P, Walton N, et al. A comparison of four
`treatments for generalized convulsive status epilepticus. Veterans
`Affairs Status Epilepticus Cooperative Study Group. N Engl J Med
`1998;339:792-8.
`Meldrum B, Brierley J. Prolonged epileptic seizures in primates:
`ischemic cell change and its relation to ictal physiological events.
`Arch Neurol 1973;28:10-7.
`Aminoff M, Simon R. Status epilepticus: causes, clinical features
`and consequences in 98 patients. Am J Med 1980;69:657-66.
`Lowenstein D, Alldredge B. Status epilepticus at an urban public
`hospital in the 1980s. Neurology 1993;43:483-8.
`Towne A, Pellock J, KO D, DeLorenzo R. Determinants of mor-
`tality in status epilepticus. Epilepsiu 1994;35:27-34.
`Cranford R, Leppik 1, Patrick B, et al. Intravenous phenytoin:
`clinical and pharniacokinetic aspects. Neuro/ogy 1978;28:874-80.
`Gastaut H, Broughton R. Epileptic seizures: clinical and elecrro-
`graphic,features, diagnosis and treatment. Springfield, IL: Charles
`C Thomas, 1972:25-90.
`Kramer R, Levisohn P. The duration of secondarily generalized
`tonic-clonic seizures [Abstract]. Epilepsia 1992;33(suppl 3):68.
`Theodore W, Porter R, Albert P, et al. The secondarily generalized
`tonic-clonic seizure: a videotape analysis. Neurology 1994;44:
`1403-7.
`Aildredge B, Gelb A, Isaacs M, et al. Evaluation of out-of-hospital
`therapy for status epilepticus [Abstract]. Epilepsia 1995;36(suppl
`4):44.
`
`4.
`5.
`6.
`7.
`
`8.
`9.
`
`10.
`1 I.
`12.
`13.
`14.
`
`15.
`
`16.
`17.
`18.
`19.
`20.
`
`21.
`22.
`
`23.
`
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