Management of Status Epilepticus, Refractory Status Epilepticus, and Super-refractory Status Epilepticus.pdf

Management of Status REVIEW ARTICLE  Epilepticus, Refractory...

Management of Status REVIEW ARTICLE  Epilepticus, Refractory C O N T I N UU M A U D I O I NT E R V I E W A V A I L A B L E ONLINE Status Epilepticus, and Super-refractory Status CITE AS: Epilepticus CONTINUUM (MINNEAP MINN) 2022;28(2, EPILEPSY):559–602. By Eugen Trinka, MD, MSc, FRCP; Markus Leitinger, MD, MSc Address correspondence to Prof Eugen Trinka, Department of Neurology, Neurointensive Care, and Neurorehabilitation, Christian Doppler University Hospital, Paracelsus Medical ABSTRACT University, Ignaz Harrer Straße PURPOSE OF REVIEW: Status epilepticus is a serious condition caused by 79, A-5020 Salzburg, Austria, disorders and diseases that affect the central nervous system. In status [email protected]. epilepticus, hypersynchronous epileptic activity lasts longer than the usual RELATIONSHIP DISCLOSURE : duration of isolated self-limited seizures (time t1), which causes neuronal Dr Trinka has received personal compensation in the range of damage or alteration of neuronal networks at a certain time point (time t2), $500 to $4999 for serving as a depending on the type of and duration of status epilepticus. The Chief Executive Officer of successful management of status epilepticus includes both the early Neuroconsult Ges.m.b.H and for serving as a consultant for termination of seizure activity and the earliest possible identification of a Arvelle Therapeutics, Bial, causative etiology, which may require independent acute treatment. In Biogen, Boehringer Ingelheim nonconvulsive status epilepticus, patients present only with subtle clinical International GmbH, Eisai Co, Ltd, Ever Pharma, signs or even without any visible clinical manifestations. In these cases, GlaxoSmithKline plc, GW EEG allows for the assessment of cerebral function and identification of Pharmaceuticals plc, LivaNova PLC, Marinus Pharmaceuticals, patterns in need of urgent treatment. Inc, Medtronic, NewBridge Pharmaceuticals, Novartis AG, RECENT FINDINGS:In 2015, the International League Against Epilepsy Sandoz International GmbH, Sanofi, Sunovion Pharmaceuticals proposed a new definition and classification of status epilepticus, Inc, Takeda Pharmaceutical encompassing four axes: symptomatology, etiology, EEG, and age. Various Company Limited, and UCB, Inc, validation studies determined the practical usefulness of EEG criteria and has received research support from the Austrian to identify nonconvulsive status epilepticus. The American Clinical Science Fund (FWF), Bayer AG, Neurophysiology Society has incorporated these criteria into their Biogen, Eisai Co, Ltd, the most recent critical care EEG terminology in 2021. Etiology, age, European Union, GlaxoSmithKline plc, Novartis AG, symptomatology, and the metabolic demand associated with an increasing Oesterreichische Nationalbank, duration of status epilepticus are the most important determinants of Red Bull, and UCB, Inc. Dr Leitinger reports no disclosure. prognosis. The consequences of status epilepticus can be visualized in vivo by MRI studies. UNLABELED USE OF PRODUCTS/INVESTIGATIONAL SUMMARY: The current knowledge about status epilepticus allows for a more USE DISCLOSURE: Drs Trinka and Leitinger discuss reliable diagnosis, earlier treatment, and improved cerebral imaging of its the unlabeled/investigational consequences. Outcome prediction is a soft tool for estimating the need use of antiseizure medications for the treatment of status for intensive care resources. epilepticus. © 2022 American Academy of Neurology. CONTINUUMJOURNAL.COM 559 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS INTRODUCTION S tatus epilepticus, particularly in its most severe form of presentation, tonic-clonic (convulsive) status epilepticus, is a neurologic emergency that needs to be promptly recognized and treated to reduce morbidity and mortality.1-5 The outcome of status epilepticus depends on etiology, age, symptomatology, and duration of status epilepticus,6-11 and patients benefit from carefully chosen but rapidly administered efficacious antiseizure medication and appropriate management of status epilepticus.12-14 Over the past decades, the timelines for the definition of status epilepticus have been progressively shortened. Eventually, the Commission of Classification and Terminology of the International League Against Epilepsy (ILAE) and the Commission on Epidemiology proposed the following definition: Status epilepticus is a condition resulting either from the failure of the mechanisms responsible for seizure termination or from the initiation of mechanisms, which lead to abnormally prolonged seizures (after time point t1). It is a condition, which can have long-term consequences (after time point t2), including neuronal death, neuronal injury, and alteration of neuronal networks, depending on the type and duration of seizures.1 This definition of status epilepticus gives clear guidance as to when emergency treatment must be considered. In general, time point t1 is the time at which seizures usually do not stop spontaneously anymore, and hence, treatment should be initiated, which is at 5 minutes for bilateral tonic-clonic (convulsive) status epilepticus and at 10 minutes for focal status with or without impairment of consciousness and absences (TABLE 12-1). Time point t2 marks the time at which neuronal damage or self-perpetuating alteration of neuronal networks may begin and indicates that status epilepticus should be controlled at the latest by that time (ie, 30 minutes in the case of bilateral tonic-clonic status epilepticus) (TABLE 12-1). Although these times t1 and especially t2 were set by the task force based on expert opinion and clinical judgment, clinical evidence supporting these timelines is increasing.15-19 TABLE 12-1 The Operational Definition of Time t1 and Time t2a Type of status epilepticus Time t1 Time t2 Seizure activity does not stop spontaneously Seizure activity may cause long-term with a high probability, therefore, time t1 is sequelae, therefore, time t2 is the time at the time at which emergency treatment of which treatment should be successful to status epilepticus should be started prevent long-term consequences Bilateral tonic-clonic status 5 minutes 30 minutes epilepticus Focal status epilepticus with and 10 minutes 60 minutes without impairment of consciousness, absences a Modified with permission from Trinka E, et al, Epilepsia.1 © 2015 International League Against Epilepsy. 560 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  The current pathophysiologic concepts of status epilepticus are beyond the scope of this article (more information can be found in previously published reviews20-23), but so far, the pathomechanisms including γ-aminobutyric acid–mediated (GABA-ergic) failure and glutamatergic hyperactivity are the basis for the staged treatment approach that is recommended today: rapid first- line administration of benzodiazepines IV or via alternative routes immediately after diagnosing status epilepticus (stage 1), followed by IV antiseizure medications (stage 2, FIGURE 12-1).3,24 Anesthetic drugs to induce therapeutic coma are the mainstay of therapy in later stages (stages 3 and 4, or refractory and super-refractory status epilepticus). In addition, critical care management and other treatment options such as immune therapies,25,26 dietary treatments,27,28 and neurostimulation provide important additional treatments.29,30 The clinical evidence is good for the earlier treatment stages, but refractory status epilepticus and super-refractory status epilepticus can still be considered an “evidence-free area.”31 This article does not follow the traditional scholarly approach but instead reviews status epilepticus as a process, spanning from the initial onset of symptoms to the application of continuous EEG in the neurologic intensive care unit (FIGURE 12-2). After some introductory information on definitions, classifications, epidemiology, and treatment principles, the article follows a patient’s pathway through the treatment stages and focuses on the practicalities, supported by scientific evidence wherever possible. FIGURE 12-1 Clinical course of convulsive status epilepticus and its therapeutic implications. IM = intramuscular; IN = intranasal; IV = intravenous; SE = status epilepticus. Modified with permission from Trinka E, et al, Drugs 2015.3 © The Authors. CONTINUUMJOURNAL.COM 561 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS FIGURE 12-2 The process of management of status epilepticus. The red triangles represent two examples of etiologies (eg, encephalitis or stroke). The boxes to their right represent an example of the course of status epilepticus starting with aphasic status evolving to focal motor status, convulsive symptomatology, and nonconvulsive status epilepticus, first with nonprominent jerks that later cease. The status epilepticus is termed convulsive status because of the appearance of bilateral tonic-clonic symptomatology at any time along the course. Therefore, it is important to note all the different stages in the report. ASM = antiseizure medication; BTC = bilateral tonic-clonic; EEG = electroencephalography; ICU = intensive care unit; NCSE-c = nonconvulsive status epilepticus in coma; SE = status epilepticus. DEFINITION AND CLASSIFICATION The recent definition of time criteria by the ILAE was an important step toward diagnostic standardization.1 The ILAE classification distinguishes between status epilepticus without prominent motor phenomena (synonymous term: nonconvulsive status epilepticus) and status epilepticus with prominent motor phenomena including bilateral tonic-clonic status epilepticus (ie, convulsive status epilepticus) and focal, myoclonic, tonic, and hyperkinetic status epilepticus (FIGURE 12-3 and TABLE 12-1).1 Clinical symptomatology may change over the time course of one status epilepticus episode, which is called evolution of symptomatology (FIGURE 12-2).7 This evolution of symptomatology has an impact on outcomes with convulsive status epilepticus with only convulsive symptomatology (“convulsive status epilepticus only”) having a better outcome than the sequence nonconvulsive status epilepticus evolving to convulsive status epilepticus (“nonconvulsive status epilepticus → convulsive status epilepticus”), which is even better than convulsive status epilepticus evolving to nonconvulsive status epilepticus (“convulsive status epilepticus → nonconvulsive status epilepticus”).7 The symptomatology that came later in the evolution determined the outcome.7 However, the terminology rates only the most prominent motor phenomenon, that is, the term convulsive status epilepticus applies to each form of status epilepticus including bilateral tonic-clonic symptomatology in any position along 562 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 12-3 The classification of status epilepticus (SE) by the International League Against Epilepsy. Data from Trinka E, et al, Epilepsia.1 the symptomatic sequence and in any combination with other symptomatology.1 Concerning the level of consciousness, the distinction between “nonconvulsive status epilepticus in coma” and “nonconvulsive status epilepticus without coma” puts a great emphasis on the presence of coma. However, in a retrospective study, the outcomes differed between the groups “nonconvulsive status epilepticus awake with or without reduced cognition” and “nonconvulsive status epilepticus with somnolence, stupor, and coma.”7 Thus, a thorough assessment of the evolution of the symptomatology, including the level of impairment of consciousness, is critical.1,7,32 Recent work has independently confirmed the association between symptomatology type and various outcomes. Clusters of subtypes of status epilepticus with etiologies, EEG patterns, and degrees of impairment that have a poorer outcome than others have been described.10,11 In clinical practice, the terms refractory status epilepticus and super-refractory status epilepticus have been established. They are defined by an international consensus group as follows24: u Refractory status epilepticus: status epilepticus persisting despite administration of at least two appropriately selected and dosed parenteral medications including a benzodiazepine. No specific seizure duration is required. u Super-refractory status epilepticus: status epilepticus persisting at least 24 hours after onset of anesthesia, either without interruption despite appropriate treatment with anesthesia, recurring while on appropriate anesthetic treatment, or recurring after withdrawal of anesthesia and requiring anesthetic reintroduction. “Anesthesia” includes commonly used agents such as midazolam, propofol, pentobarbital, thiopental, ketamine, and others, so long as they are used at anesthetic doses. CONTINUUMJOURNAL.COM 563 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS EPIDEMIOLOGY The epidemiology of status epilepticus is influenced by the time criterion used to define status epilepticus (5 minutes versus 10 minutes versus 30 minutes), the inclusion of only first episodes of status epilepticus, and the inclusion of people with preexisting epilepsy.33 Case ascertainment is also important because different results can be expected depending on how patient cases are identified, be it by detailed chart review or solely using the International Statistical Classification of Diseases and Related Health Problems (ICD).33 Other factors, which are necessary to consider in epidemiologic studies of status epilepticus are the inclusion of both adults and children as two mutually independent high-risk groups, the definition of age of adulthood, the percentage of very old patients as a high-incidence subgroup within the adult group, the prevailing etiologies in the study area, and the shape of the population pyramid of the reference population to which the data were adjusted.33 A population-based study from Austria used the 2015 ILAE criteria for status epilepticus and found an incidence of all types of status epilepticus in adults of 36.1 per 100,000 per year (95% confidence interval [CI], 26.2 to 48.5) and for nonconvulsive status epilepticus of 12.1 per 100,000 per year (95% CI, 6.8 to 20.0).7 The incidence of refractory status epilepticus was 7.2 per 100,000 adults per year (95% CI, 3.3 to 13.8), which included all status epilepticus episodes refractory to one benzodiazepine and one other antiseizure medication.7 Super- refractory status epilepticus occurred with an incidence of 1.2 per 100,000 per year (95% CI, 0.1 to 5.1).7 Population-based studies from Finland revealed similar incidence rates, using a slightly different case ascertainment strategy. The incidence of intensive care unit (ICU)-treated and anesthesia-treated refractory status epilepticus was 3.0 per 100,000 per year (95% CI, 2.4 to 3.8) and of super- refractory status epilepticus 0.6 per 100,000 per year (95% CI, 0.4 to 1.0).34-36 A German population-based study of children (0 to 18 years), detailed a slightly lower incidence with a crude status epilepticus incidence of 17.6 per 100,000 per year.37 The incidence of refractory status epilepticus was 3.9 per 100,000 per year, and super-refractory status epilepticus 2.3 per 100,000 per year. Super-refractory status epilepticus incidence peaked in the 0- to 1-year-old age subgroup, accounting for 48.3% of all pediatric super-refractory status epilepticus admissions.37 Studies using older definitions of status epilepticus reported lower incidence rates: In the United States, the Rochester, Minnesota, study revealed an incidence of 18.3 per 100,000 total population,38 which increased from 8.0 per 100,000 in 1935 to 1944 to 18.1 per 1,000,000 in 1975 to 1984.33,39 ICD-code based epidemiologic studies may underestimate the incidence of status epilepticus if status was not coded in the primary diagnostic position.33,40-42 However, these studies may also overestimate the incidence because ICD-based studies cannot distinguish first status epilepticus episodes from recurring ones.33 All studies on the incidence of status epilepticus found a prominent increase with age. A 2019 study reported an age- and sex-adjusted incidence rate in older adults of 79.9 (95% CI, 53.4 to 114.8) per 100,000 adults (89.6 [95% CI, 54.0 to 139.7] in older women and 67.6 [95% CI, 32.3 to 124.7] in older men) with an associated case fatality of 22.5% (95% CI, 16.4% to 29.9%) (27.8% [95% CI 19.9% to 37.5%] in women and 12.0% [95% CI 5.3% to 24.2%] in men) (FIGURE 12-4).7 A systematic review analyzed the time trends of in-hospital mortality or 30-day case fatality expressed as proportional mortality. Sixty-one studies from 564 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  KEY POINTS The outcome of status epilepticus depends on etiology, age, symptomatology, and duration of status epilepticus. At time t1, the diagnosis of status epilepticus is established and therapy is started. At time t2, treatment should be successful in preventing neuronal damage. For convulsive (bilateral tonic-clonic) status epilepticus, time t1 is 5 minutes. For focal status epilepticus with or without FIGURE 12-4 impairment of Age-related increase in the incidence of status epilepticus (SE) in older adults. Error bars consciousness, time t1 is indicate 95% confidence intervals. 10 minutes. CSE = convulsive status epilepticus; NCSE = nonconvulsive status epilepticus; SE-PM = status epilepticus with prominent motor phenomena. Unsuccessful therapy Modified with permission from Leitinger M, et al, Epilepsia.7 © 2019 The Authors. with a benzodiazepine and one antiseizure medication defines refractory status epilepticus. high-income countries found mortality rates of 15.9% (95% CI, 12.7% to 19.2%) for adults and 3.6% (95% CI, 2.0% to 5.2%) for children.43 Mortality was 17.3% The management of (95% CI, 9.8% to 24.7%) for refractory status epilepticus.43 In another review status epilepticus should be on the epidemiology of status epilepticus, case fatalities ranged in-hospital from viewed as a process. 5.0% to 24.4% and at 30 days from 4.6% to 39%.33 Mortality in status epilepticus The changing is seen as a result of ongoing epileptic activity with its increased metabolic symptomatology within one demand and its deleterious consequences on neuronal networks and nerve tissue, episode of status but also, and even more significantly, because of the etiology of the status epilepticus is called epilepticus.6,43,44 evolution of symptomatology; the status epilepticus symptomatology CAUSES OF STATUS EPILEPTICUS that comes later determines Etiology varies largely with geography. Infectious diseases are common causes in outcomes. lower-income countries whereas cerebrovascular and degenerative cerebral The epidemiology of etiologies prevail in higher-income countries.45 Metabolic etiologies and status epilepticus is nonadherence to medication occur in both regions.45 The ILAE classified the determined by several etiology of status epilepticus into acute, remote, progressive, defined electroclinical factors. syndromes, and unknown etiology (ie, cryptogenic).1 However, the assignment into these categories appears heterogeneous among the various studies (TABLE 12-2).33 The etiology of status epilepticus can be divided From a practical perspective, it is advisable to distinguish common causes, into symptomatic (acute, which usually can be identified in the first hours, from the uncommon and rare remote, progressive, and causes, which need an intensive workup to start appropriate treatment.9,45,62,63 electroclinical syndromes) Common and easily recognized causes of status epilepticus include and cryptogenic. CONTINUUMJOURNAL.COM 565 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS TABLE 12-2 Population-based Studies of Adults With Status Epilepticus of Different Etiologiesa History of Acute Remote Defined Febrile Case First epilepsy, symptomatic, symptomatic, Progressive, electroclinical Cryptogenic, status,b fatality, author % % % % syndrome, % % % % Logroscino39 Not 53.8c 46.2c Excluded 24d available (NA) Hesdorffer38 46 50.3 19.6 8.5 13.6 8 NA Dham40 1.8-7 NA NA NA NA NA NA 9.2 46,47 DeLorenzo 42 NA 24 NA NA NA NA 22d Wu41 NA NA NA NA NA NA NA 10.7 42 Betjemann NA NA NA NA NA NA NA NA Jallon48 32.8 50.8 26.2 23.0 6.6 49 Coeytaux 43 62.7 18.6 9.8 2.9 5.8 NA 7.6 Knake50 33e >33f 62.7f 12.0g NA 8.7 0 9.3d Vignatelli51 39 34h 34 11 7 0 39d Vignatelli52 40.7 29.6i 25.9 11.1 NA 7.4 0 7d Govoni53 40 25.0 45.0 15 15 NA 5 Strzelczyk54 44.6 24.8 Not reported NR NR 4.3 NR 14.8 (NR) Leitinger7,j 40.7 36.2 46.6 14.0 1.4 1.8 0 16.3 55 Rodin 43.9 26.8 48.8 7.3 NA 17.1 0 24.4 Kantanen36 17.5 41.6 45.3 12.4 NA 10.9 0 9.0d Nazerian56,j 57.6 68.7 37.8 27.3 NA 6.1 0 13.1 Ong57 NA NA NA NA NA NA NA 8.8 58 Tiamkao NA NA NA NA NA NA 0 8.4 Tiamkao59 1.2 NA NA NA NA NA 0 12.0 60 g Bhalla 0 35.4 44.6 3.1 NA 16.9 NA 18.5 Bergin61 60.6k 43.3 43.6 5.2 3.5 17.7 21.0 4.6d a Reprinted with permission from Leitinger M, et al, Epilepsy Behav.33 © 2019 The Authors. b Only in children. c 1975-1984. d Case fatality at 30 days, otherwise in hospital. e Primary service area. f In most cases, more than one factor. Percentages were calculated from 150 patients with status epilepticus and also included patients outside the primary service area. g Tumors. h Multifactorial: additional 14%. i Multifactorial: additional 25.9%. j Proposal for definition and classification of status epilepticus by the International League Against Epilepsy in 2015. k Calculated per status epilepticus episodes and not per patients. 566 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. cerebrovascular disorders, brain trauma, infections, alcohol- and drug-related, KEY POINTS and low antiseizure medication levels in patients with epilepsy (FIGURE 12-5). Rare causes of status Uncommon causes fall into five categories62: epilepticus include immunologically mediated u Immunologically mediated disorders (TABLE 12-3) disorders, mitochondrial diseases, uncommon u Mitochondrial diseases (Rahman64,65 provides a comprehensive review) (TABLE 12-4) infective disorders, genetic u Uncommon infective disorders (TABLE 12-5) disorders, and drugs or toxins. u Genetic disorders u Drugs or toxins Status epilepticus and acute stroke share many features (eg, time is brain, Other rare causes exist, which have to be considered early in the diagnostic the onset is often not workup because they are reversible or treatable in many cases (TABLE 12-6). witnessed, and both need a structured diagnostic and therapeutic approach). STATUS EPILEPTICUS AT THE SCENE (OUT OF THE HOSPITAL AND IN THE HOSPITAL) Although the hospital setting seems to be quite different from situations occurring in family or caregiver environments, they share important relevant features. In both settings, the onset of status epilepticus may not be witnessed and the patient is often found seizing. Similar to stroke, the time of “last seen well” is taken as a substitute to estimate the time already elapsed since onset. This time is crucial both for the effects of status epilepticus but also if acute treatment of the underlying etiology is mandatory: “time is brain.”12 From the perspective of risk management, the first critical information transfer occurs between the witnesses and emergency medical services (EMS), comparable to the observations communicated between the nurses and patients without status FIGURE 12-5 Common and easily recognized causes of status epilepticus (SE). Reprinted with permission from Trinka E, et al, Epilepsia.62 © 2012 International League Against Epilepsy. AED = antiepileptic drug; Cardiovasc. = cardiovascular; CNS = central nervous system. CONTINUUMJOURNAL.COM 567 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS epilepticus and the in-hospital emergency team (FIGURE 12-2). For optimal documentation, EMS already uses proven and tested standard protocols.66 In the hospital, status epilepticus checklists help document information from the earliest moments including when emergency medications were given in the emergency department or on the ward (TABLE 12-7 and FIGURE 12-6).67 In the past years, several efficacious antiseizure medications have been developed, which are suitable for out-of-hospital administration via alternative routes. Historically, rectal diazepam was the first non-IV drug available for emergency use.68 Midazolam is a water-soluble benzodiazepine, which may be administered by different routes: IV, IM, buccal, and intranasal. Thus, it is ideally suited for early out-of-hospital treatment by caregivers and paramedic personnel. The efficacy and safety of non-IV midazolam were compared with rectal diazepam in a meta-analysis including 19 studies with 1933 seizures in 1602 patients (some trials included patients with more than one seizure).69 For seizure cessation, non-IV midazolam was as effective as diazepam (any route) (relative risk, 1.03; 95% CI, 0.98 to 1.08).69 No difference in adverse effects was found between non-IV midazolam and diazepam by any route (relative risk, 0.87; 95% CI, 0.50 to 1.50).69 Buccal midazolam was more effective than rectal diazepam in terminating status epilepticus (relative risk, 1.78; 95% CI, 1.11 to 2.85).69 The time interval between arrival and seizure cessation was significantly shorter with non-IV midazolam by any route than with diazepam by any route (mean difference, -3.67 minutes; 95% TABLE 12-3 Examples of Immunologic Disorders Causing Status Epilepticusa ◆ Paraneoplastic encephalitis ◆ Steroid-responsive encephalopathy with associated autoimmune thyroiditis (SREAT) ◆ Autoimmune thyroiditis ◆ Anti–N-methyl-D-aspartate (NMDA)-receptor encephalitis ◆ Anti–leucine-rich, glioma inactivated 1 (LGI1) encephalitis ◆ Anti–α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-receptor encephalitis ◆ Anti–γ-aminobutyric acid (GABA)-receptor encephalitis ◆ Rasmussen syndrome ◆ Cerebral lupus erythematosus ◆ Adult-onset Still disease ◆ Anti–glutamic acid decarboxylase (GAD) antibody–associated encephalitis ◆ Goodpasture syndrome ◆ Multiple sclerosis ◆ Thrombotic thrombocytopenic purpura ◆ Antibody-negative limbic encephalitis ◆ Ulcerative colitis ◆ Behçet syndrome ◆ Celiac disease a Reprinted with permission from Trinka E, et al, Epilepsia.62 © 2012 Wiley Periodicals, Inc. 568 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. CI, -5.98 to -1.36); a similar result was found for the time from arrival to drug administration (mean difference, -3.56 minutes; 95% CI, -5.00 to -2.11).69 Based on these findings and another common reference network meta- analysis,70 buccal or intranasal midazolam can be regarded as the first-choice treatment for out-of-hospital repetitive seizures or status epilepticus.3 However, this first-line non-IV treatment will not stop status epilepticus in around 20% to 30% of cases,71 which requires rapid admission to an emergency department. STATUS EPILEPTICUS IN THE EMERGENCY DEPARTMENT On arrival to the emergency department (FIGURE 12-7), the management of status epilepticus requires parallel work on different domains such as (1) standardized information transfer from EMS to the emergency department team (TABLE 12-7 and FIGURE 12-6), (2) acute stabilization and monitoring of vital signs (FIGURE 12-7), (3) rapid identification of etiologies with independently essential acute treatment (TABLE 12-8), and (4) start or continuation of status epilepticus treatment (FIGURE 12-8, TABLE 12-9, TABLE 12-10, and CASE 12-1).72-75 The “time is brain” principle is most crucial in status epilepticus with prominent motor phenomena, especially convulsive status epilepticus. Symptomatic treatments with antiseizure medications must be applied rapidly and, if needed, escalated toward anesthetics to prevent severe metabolic derangements and long-term consequences after time point t2.2-4,73-76 The risks of treatment have to be weighed against the benefits of early seizure termination. The evidence is good for benzodiazepine administration in stage 1 (early status epilepticus), and the safety and efficacy of IV lorazepam, diazepam, clonazepam, or IM midazolam seem to have clinical equipoise.69,70,73,77 Each antiseizure medication has advantages and disadvantages (TABLE 12-9),3 which need to be considered in the emergency department, especially, when confronted with a patient with one, or several, comorbidities or specific situations (TABLE 12-10). This is even more the case when status epilepticus cannot be controlled by initial benzodiazepines and patients move to benzodiazepine-refractory status epilepticus, in which IV treatment with antiseizure medications is needed. A 2019 landmark article78 and two other high-class clinical trials79,80 could not find a statistical difference in efficacy and tolerability among levetiracetam, fosphenytoin, and valproic acid. Seizures will be controlled in about 50% of patients with any of these antiseizure medications. A recent network meta-analysis including five randomized controlled trials involving 349 patients compared valproate (20 mg/kg to 30 mg/kg), Examples of Mitochondrial Diseases Causing Status Epilepticusa TABLE 12-4 ◆ Alpers disease ◆ Occipital lobe epilepsy/mitochondrial spinocerebellar ataxia and epilepsy (MSCAE) ◆ Mitochondrial encephalopathy, lactic acidosis, and strokelike episodes (MELAS) ◆ Leigh syndrome ◆ Myoclonic encephalopathy with ragged red fibers (MERRF) ◆ Neuropathy, ataxia, and retinitis pigmentosa (NARP) a Reprinted with permission from Trinka E, et al, Epilepsia.62 © 2012 Wiley Periodicals, Inc. CONTINUUMJOURNAL.COM 569 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS phenytoin (20 mg/kg), diazepam (0.2 mg/kg, then 4 mg/h), phenobarbital (20 mg/kg, then 100 mg every 6 h), lacosamide (400 mg), and levetiracetam (20 mg/kg) in benzodiazepine-resistant status epilepticus (stage 2).81 Phenobarbital was superior to phenytoin, valproate, diazepam, levetiracetam, and lacosamide with respect to status epilepticus cessation and performed better concerning seizure freedom at 24 hours than valproate, diazepam, and lacosamide. According to this analysis, phenobarbital had the greatest probability of achieving status epilepticus control and seizure freedom at 24 hours, whereas valproate and lacosamide ranked best in terms of safety outcomes.81,82 The problem in a real-world setting, which cannot be overestimated, is underdosing. In a registry study of 1049 patients, bolus doses of the first TABLE 12-5 Uncommon Infectious Diseases Causing Status Epilepticusa Atypical bacterial infections ◆ Bartonella/catscratch disease ◆ Coxiella burnetii (Q fever) ◆ Neurosyphilis ◆ Scrub typhus ◆ Shigellosis ◆ Mycoplasma pneumoniae ◆ Chlamydophila psittaci Viral infections ◆ Human immunodeficiency virus (HIV) and HIV-related infections ◆ West Nile encephalitis ◆ JC virus (progressive multifocal leukoencephalopathy) ◆ Parvovirus B19 ◆ Varicella zoster virus encephalitis ◆ Subacute sclerosing panencephalitis ◆ Measles encephalitis ◆ Rubella encephalitis ◆ Rous sarcoma virus–associated status epilepticus ◆ Polioencephalomyelitis ◆ St. Louis encephalitis Prion disease ◆ Creutzfeldt-Jakob disease Other infections ◆ Paragonimiasis ◆ Mucormycosis ◆ Paracoccidioidomycosis a Reprinted with permission from Trinka E, et al, Epilepsia.62 © 2012 Wiley Periodicals, Inc. 570 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. treatment step were lower than recommended by current guidelines in 76% of convulsive status epilepticus.83 As a result of underdosing, 70% of patients were still in status epilepticus 1 hour after initiating treatment, compared with randomized controlled trials in which benzodiazepines terminated status epilepticus in at least 60% with the initial treatment during stage 1. It can be expected that the same proportion is also underdosed in benzodiazepine- refractory status epilepticus, but data on this critical issue are missing. In the nonconvulsive forms of status epilepticus, therapy may include two or more antiseizure medications to prevent escalation to IV anesthetics in an ICU, with the aim of minimizing the burden of treatment in patients who will be difficult to wean from the respirator because of comorbidities (TABLE 12-10).84-88 Similarly, the cause of status epilepticus has to be identified rapidly and treated accordingly. Other Causes of Status Epilepticusa TABLE 12-6 Iatrogenic ◆ Electroconvulsive therapy ◆ Temporal lobectomy and other neurosurgery ◆ Insertion of intracranial electrode ◆ Ventriculoperitoneal shunt ◆ Blood transfusion ◆ Carotid angioplasty and stenting ◆ Deep-brain stimulation Other medical conditions and epilepsy syndromes ◆ Hypertension-induced posterior reversible encephalopathy syndrome ◆ Panayiotopoulos syndrome ◆ Thyroid disease ◆ Pyridoxine-dependent seizure ◆ Neuroleptic malignant syndrome ◆ Cobalamin deficiency ◆ Amyloid angiopathy ◆ Folinic acid–responsive seizures ◆ Renal artery stenosis ◆ Pituitary apoplexy ◆ Renal artery dissection ◆ Hypomelanosis of Ito ◆ Cerebral palsy ◆ Hemophagocytic lymphohistiocytosis ◆ Anhidrotic ectodermal dysplasia ◆ Methemoglobinemia a Modified with permission from Trinka E, et al, Epilepsia.62 © 2012 Wiley Periodicals, Inc. CONTINUUMJOURNAL.COM 571 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS Nonepileptic psychogenic events are an important mimic of status epilepticus, which may receive potentially harmful medication when mistaken for drug- resistant status epilepticus.89 It has been shown that patients with nonepileptic psychogenic events show a paradoxical increase of activity with increasing benzodiazepine doses and often end up in ICUs with central venous access.90 Early recognition and appropriate treatment are needed to prevent harm to these patients. Psychogenic nonepileptic events may be distinguished from epileptic seizures by several criteria such as speed of onset, absence of tongue biting, the state of the eyelids during the event, skin color, duration of convulsion, speed of postictal reorientation, and absence of postictal stertorous breathing.91 STATUS EPILEPTICUS IN THE INTENSIVE CARE UNIT The ICU offers the right environment to escalate treatments while monitoring patients’ cardiorespiratory and brain functions. The key clinical questions are the following: u Is the patient still in status epilepticus on admission to the ICU? u What is the cause of status epilepticus? u Did the treatment successfully and persistently terminate status epilepticus? u Did status epilepticus–related brain damage take place? TABLE 12-7 Admission to the Hospital: A Critical Interface for Information Transfer Information Relevance Last seen well, time of onset, and any Relevant for cerebral ischemia as differential diagnosis and potential etiology of full recovery in between status epileptius, time criteria for status epilepticus, and cluster of seizures Initial symptoms and signs Clues to etiology and cerebral symptomatogenic zone Preceding or concomitant symptoms Vomiting as a hint for increased cerebral pressure or cause of aspiration; cough (vomiting, cough, ear pain, fever, rash) indicative of pneumonia as a trigger or complication (aspiration); ear pain for pneumococcal infection, fever for cerebral or systemic infection; rash for systemic illness, thrombocytopenia, and coagulopathy Any bilateral tonic-clonic Determines a convulsive status epilepticus, patient may be in subtle status symptomatology epilepticus on admission Any nonprominent motor Minor jerks in fingers, toes, abdominal muscles, perioral or periorbicular region; symptomatology recurrent spontaneous pupillary dilatation and constriction; gaze deviation away from cerebral lesion; nystagmus Reactivity to speech or tactile stimuli Speed of deterioration of alertness and consciousness gives clue to etiology, before admission allows estimation of Glasgow Coma Scale Witness’s report and telephone number Clues to acute etiologies, time of onset, and symptomatic evolution of status epilepticus Amount and time of medication applied Prevents overdosing of first-line drugs and delay in escalation of status by physicians at the scene and by treatment, allows for body weight–adapted dosing, time frame allows for emergency medical services pharmacokinetic estimations Neurologic examination on admission Sometimes very brief because of the need to urgently manage neurologic and related medical issues but essential for further comparisons (improvement/ deterioration) 572 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  KEY POINTS Acute etiologies of status epilepticus may need a specific emergency treatment (eg, ischemic stroke). The main reason for unsuccessful treatment of status epilepticus is underdosing. FIGURE 12-6 Documentation of status epilepticus (SE) on patient admission or on the ward in the hospital. CT = computed tomography; CTA = computed tomography angiography; DZP = diazepam; EEG = electroencephalogram; FOS = fosphenytoin; L = left; Lab = laboratory; LCM = lacosamide; LEV = levetiracetam; LZP = lorazepam; MDZ = midazolam; MRA = magnetic resonance angiography; MRI = magnetic resonance imaging; R = right; Tox = toxicology; VPA = valproate. Modified with permission from Leitinger M, et al, Epilepsy Behav.67 © 2015 The Authors. CONTINUUMJOURNAL.COM 573 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS FIGURE 12-7 Strategic thoughts on the initial management of status epilepticus on admission or identification in the hospital. CT = computed tomography; ECG = electrocardiogram; EMS = emergency medical services; FLAIR = fluid- attenuated inversion recovery; MRI = magnetic resonance imaging; TOF-MR = time-of-flight magnetic resonance. Patients with successfully treated status epilepticus usually gradually regain their previous level of consciousness within a few minutes or hours, but this may take longer in older patients. The distinction between the postictal state and ongoing nonconvulsive status epilepticus remains difficult on clinical judgment alone.92 Additional investigations are needed to clarify and clearly assign the clinical phenomenology.1,32 In particular, if no sign of improvement is seen, it can be uncertain whether the patient is in nonconvulsive status epilepticus or not. An EEG is essential in all those patients without clinical signs of subtle jerks, gaze deviation, or hippus.93 Of note, many severely affected patients will demonstrate substantial changes on EEG, but clearly not every highly pathologic EEG qualifies as status epilepticus.32,93,94 The Salzburg nonconvulsive status epilepticus diagnostic criteria provide an essential standardized approach to prevent overdiagnosis in EEGs severely affected solely by the underlying condition. At this point, sound clinical, electrophysiologic, and radiologic judgment is of significant importance. The concept of the “electro-paraclinical gap” (ie, the phenomenon that the changes in EEG exceed what can be expected from clinical, laboratory, and imaging data) can help with decision making. Based on the relationship among epileptic brain dysfunction, structural brain damage, and impairment of consciousness (FIGURE 12-10)32 in the different forms of status epilepticus, the paraclinical data (imaging, laboratory, and toxicologic investigations) are further integrated into this scheme to assess the electro- paraclinical gap. If the underlying pathology, for instance acute renal failure, is the cause of the stereotyped EEG patterns, there seems to be no additional seizure burden which could be reversed with intensive antiseizure treatment 574 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. (CASE 12-2). Thus, no electro-paraclinical gap is present, and consequently, aggressive treatment should be avoided. The treatment should be aimed toward the underlying renal failure (CASE 12-2). If the EEG changes exceed what can be expected from imaging, laboratory, and toxicology findings, this indicates a significant electro-paraclinical gap caused by the seizure burden so that nonconvulsive status epilepticus should be suspected and consequent treatment with antiseizure medication should be initiated or continued at the earliest possible time (CASE 12-3). The refinement of diagnostic criteria for nonconvulsive status epilepticus has been ongoing since the first criteria by Young and colleagues in 1996,95 with more precise criteria provided by Chong and Hirsch in 2005,96 a distinction between Common Acute Causes and Most Important Mimics of Status Epilepticus TABLE 12-8 and Their Treatment Approaches Clues from history (relatives, witnesses, Etiology of status epilepticus emergency medical services) Therapeutic approach Cerebral ischemia Sudden onset neurologic symptoms and Systemic thrombolysis, mechanical clot signs before seizure activity retrieval Parenchymal hemorrhage Sudden onset neurologic symptoms and Use clotting factors to reverse anticoagulation signs before seizure activity with warfarin or use idarucizumab or andexanet alfa to reverse oral direct inhibitors of activated coagulation factor X Bacterial meningitis Rapid deterioration of performance, fever, Dexamethasone, antibiotics altered mental status, Viral encephalitis Rapid deterioration of neurologic symptoms, For herpes simplex virus: acyclovir fever (optional), recent travel, skin changes Intoxication (prescribed Ongoing medication despite decreased Activated charcoal, antidote drugs, illicit drugs, renal function; drug abuse, contact with environmental toxins) industrial goods (eg, solvents, herbicides, insecticides, chemicals in workplace or spare time activity) Traumatic brain injury Lying beside ladder or bottom of stairs, skin Surgical evacuation of subdural or epidural lacerations hematoma, stabilization of concomitant fracture of cervical vertebrae Mimic of status epilepticus Psychogenic seizures Very irregular movements, changing side EEG normal or near normal: reduce staff, use and region of body abruptly without a calm reassuring talking “marchlike” propagation; waxing and If EEG is not available: allow 3 minutes for waning; overarching of trunk (arc de cercle); reevaluation of diagnosis of status epilepticus rapid head shaking; history of dissociative disorders or psychological trauma Cerebral hypoperfusion Reported palpitations or pain in the heart, Check adequate cardiocirculatory function (cardiocirculatory arrest) neck, arm, epigastrium; “blood pressure not (palpation of carotid or femoral pulses, measurable”; pale or cyanotic skin; flush monitoring of blood pressure and ECG) during reperfusion ECG = electrocardiogram; EEG = electroencephalogram. CONTINUUMJOURNAL.COM 575 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS FIGURE 12-8 Proposed algorithm for convulsive status epilepticus by the American Epilepsy Society.73,74 D12.5W = dextrose 12.5% in water; D25W = dextrose 25% in water; D50W = dextrose 50% in water; ECG = electrocardiogram; exam = examination; IV = intravenous; PE = phenytoin sodium equivalents. Reprinted with permission from the American Epilepsy Society.74 © 2021 American Epilepsy Society. with or without preexisting encephalopathy by Kaplan in 2007,97 and the Salzburg Consensus Criteria developed by an expert group at the fourth London-Innsbruck Colloquium on acute seizures and status epilepticus98 and published by Beniczky and colleagues in 2013.99 A critical view and the addition of clinical and paraclinical criteria and suggestions to standardize testing and gauging of the response to antiseizure medication were provided by Leitinger and colleagues in 2015.94,100 The Salzburg Consensus Criteria were validated retrospectively in a multicenter study with very good test performance characteristics101-103 and can be implemented in the ICU environment with 576 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. continuous EEG recordings.104-106 The American Clinical Neurophysiology KEY POINTS Society adopted the Salzburg Consensus Criteria into their most recent Standard The electro-paraclinical Critical Care EEG Terminology 2021 (FIGURE 12-13).107 FIGURE 12-14 shows a gap exists if the EEG findings synopsis that includes the integration of the established Salzburg Consensus cannot sufficiently be Criteria for EEG together with the essential pathways to diagnose nonconvulsive explained by imaging, status epilepticus (CASE 12-4).94,99,100,107 laboratory, or toxicologic investigations. The current set of criteria have several advantages. The main advantage is the clear characterization of several status epilepticus patterns and the ictal- The electro-paraclinical interictal continuum.107 However, a few notes of caution should be added. On gap is a useful tool to the one hand, clinicians may misinterpret the neurophysiologist’s diagnosis of diagnose nonconvulsive “possible status” as “status epilepticus” without critically reviewing the full status epilepticus and to increase specificity. clinical and paraclinical information (imaging, laboratory, toxicology) as to whether the diagnosis of nonconvulsive status epilepticus should be The Salzburg diagnostic confirmed or rejected (FIGURE 12-11 and FIGURE 12-14). On the other hand, EEG criteria for clinicians reading “ictal-interictal continuum” in the report may be satisfied nonconvulsive status epilepticus are part of the and not further investigate the patient with ictal MRI or ictal SPECT to recent American Clinical confirm status epilepticus (FIGURE 12-14). Because the terms ictal-interictal Neurophysiology Society continuum and possible electrographic status epilepticus are synonyms, the Standard Criteria for Critical authors of this article recommend using all available clinical, imaging, Care EEG Terminology. laboratory, and toxicologic information to understand as to what extent pathologic EEG patterns are the result of structural or metabolic derangements (concept for high specificity) (FIGURE 12-11, FIGURE 12-12, FIGURE 12-13, and FIGURE 12-14). Concerning the EEG or clinical response to IV administered antiseizure medication, no consensus has been reached as to which time points to test and which criteria define an EEG-based or clinical improvement.100 EEG improvement may occur if encephalopathic waves are treated with benzodiazepines.108,109 Further, evidence is growing that the metabolic demand is already increased at frequencies less than 2.5 Hz. This border zone is not yet well defined, in particular, concerning modulating factors aggravating or alleviating the metabolic burden associated with periodic discharges.1,110-115 Status epilepticus in neonates differ significantly from children and adults because of very dynamic maturation processes and the causes. Therefore, they are treated according to guidelines tailored to their specific needs.116 The further identification of the etiology goes in parallel with the stabilization of the patient, the interpretation of EEG, and the treatment response. Once treatment has been escalated to therapeutic coma with suppression of status activity, the relevant question “Did the treatment successfully and persistently abort status epilepticus?” has to be addressed again after a period of 24 to 48 hours. Here, the EEG gives guidance as to when weaning from the respirator can be safely performed.87 Despite the clarity of the Salzburg Consensus Criteria for EEG, several EEG patterns in the severely injured brain reflect disturbed function but not necessarily ongoing nonconvulsive status epilepticus; in other words, no electro-paraclinical gap is present (CASE 12-2).32,93,94,100,117,118 Continuous EEG provides the opportunity to monitor cerebral function without interruption and, therefore, to quantify the load of the various patterns, which is characterized as the “seizure burden.” Lalgudi Ganesan and Hahn119 provided a detailed review emphasizing the spatial extent of the brain involved and the temporal proximity of the status activity to the brain injury (known as temporal evolution of seizure burden). Seizure burden was analyzed in a more CONTINUUMJOURNAL.COM 577 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS detailed study of 50 patients with seizures in a total cohort of 402 patients diagnosed with subarachnoid hemorrhage.120 The seizure burden was defined as the duration, in hours, and a median length of 6 hours (interquartile range, 1 to 13 hours) was recorded. The seizure burden was shown to be significantly associated with an unfavorable functional and cognitive outcome at 3 months with a significant odds ratio for every hour of seizure.120 In a retrospective cohort of 23 patients with nonconvulsive status epilepticus out of 127 patients with continuous EEG with various acute and remote etiologies, mortality was 57%, with seizure duration being significantly associated with increased mortality with an hourly increased odds ratio (1.131/h, P=.0057) after multivariate logistic regression analysis.95 It must be emphasized that the approach of determining the burden (ie, exposure of the brain to a potentially toxic agent, in this case an electrically mediated metabolic derangement) differs substantially from pure association TABLE 12-9 Advantages and Disadvantages of Drugs Commonly Used in Early and Established Status Epilepticusa Drug Advantages Disadvantages Diazepam Rapid onset of action following IV Rapid redistribution responsible for short administration, non-IV formulation available duration of action; sedation, hypotension, (rectal), long-standing clinical experience in respiratory depression; risk of drug adults and children, efficacy and safety accumulation after repeated doses and evaluated in randomized controlled trials, infusion; risk of reaction at the injection site relatively inexpensive and widely available Lorazepam Rapid onset of action following IV Sedation, hypotension, respiratory depression; administration, longer effect (>24 hours) after risk of reaction at the injection site administration compared with diazepam, long- standing clinical experience in adults and children, efficacy and safety evaluated in randomized controlled trials, little risk of drug accumulation Midazolam Non-IV formulations available (buccal, Risk of seizure recurrence because of short intranasal, IM), rapid onset of action after duration of action; sedation, hypotension, administration by any route, efficacy and safety respiratory depression of all formulations evaluated in randomized controlled trials, administration is easy and rapid, better social acceptance than drugs administered rectally, little risk of drug accumulation Clonazepam Rapid onset of action following IV Lack of randomized controlled administration, longer effect after trials administration compared with diazepam, little risk of drug accumulation Phenobarbital Rapid onset of action following IV Sedation, hypotension, respiratory depression; administration, long-standing clinical risk of clinically significant drug interactions; risk experience in adults and children, efficacy and of reaction at the injection site safety evaluated in randomized controlled trials, inexpensive and widespread availability CONTINUED ON PAGE 579 578 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. studies as it paves the way for deep understanding and modeling of pathophysiologic processes.119 In particular, the correlation of seizure burden with MRI changes will provide evidence about the relative harm of various EEG patterns.15,16,121 However, the interplay of these factors is complex (FIGURE 12-16) and can be integrated into a model including structural damage and metabolic derangement, burden of status epilepticus, success of treatment, burden of treatment, functional reserve, severity of decompensation, and impact of burden (ie, the “impact of burden” model) (FIGURE 12-16). In short, the seizure burden adds to variable degrees of metabolic exhaustion and the structural damage caused by the underlying brain injury, which may result in functional decompensation leading to neuronal injury and neuronal death (FIGURE 12-16). The success of treatment may alleviate seizure burden. However, medical aggressiveness may pose a burden of treatment. In patients with large structural and metabolic reserves, the burdens of status epilepticus and its treatment will be CONTINUED FROM PAGE 578 Drug Advantages Disadvantages Phenytoin Long-standing clinical experience in adults and Rapid onset of action following IV children, efficacy and safety evaluated in administration, long-standing clinical randomized controlled trials, lack of sedation, experience in adults and children, efficacy and inexpensive (not fosphenytoin) and widespread safety evaluated in randomized controlled availability trials, low incidence of adverse events overall, good cardiovascular and respiratory tolerability, relatively inexpensive and widespread availability Valproate Rapid onset of action following IV Dizziness, thrombocytopenia, and mild administration, long-standing clinical hypotension (uncommon side effects); risk of experience in adults and children, efficacy and acute encephalopathy usually associated with safety evaluated in randomized controlled hepatic abnormalities or hyperammonemia; risk trials, low incidence of adverse events overall, of pancreatitis and liver failure good cardiovascular and respiratory tolerability, relatively inexpensive and widespread availability Levetiracetam Long-standing clinical experience in adults and Somnolence, sedation, agitation, and children, lack of drug interactions, low thrombocytopenia (uncommon side effects); incidence of adverse events overall, good relatively expensive cardiovascular and respiratory tolerability Lacosamide Rapid onset of action following IV Little clinical experience and lack of administration, low incidence of adverse events randomized controlled trials, risk of cardiac overall, good cardiovascular and respiratory arrhythmias tolerability a Reprinted with permission from Trinka E, et al, Expert Opin Pharmacother.75 © 2016 Taylor & Francis Group. CONTINUUMJOURNAL.COM 579 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS better compensated and, therefore, lead to increased patient survival than in those with only marginal reserves. This relationship heavily impacts the appropriate choice of study end point parameters. Functional or imaging outcomes are more suitable in patient cohorts with large reserves because mortality will demonstrate a floor effect and vice versa. In deeply sedated patients, various EEG patterns may arise spontaneously or as the result of stimulation, such as stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs).32,93,94,100,122 However, their pathogenetic role and the degree to which these patterns should be treated remain to be elucidated.123 The clinical assessment is limited in this context, and other methods to monitor brain functions are needed. The increased metabolic demand associated with ongoing or recurring seizure/status activity may be measured by multimodal monitoring, including perfusion measures with single-photon emission computed tomography (SPECT), perfusion CT, or perfusion MRI. Increased secondary hyperperfusion has been revealed by cerebral hexamethylpropyleneamine oxime (HMPAO)-SPECT.124-127 Lateralized periodic discharges (LPDs) faster than 2.0 Hz have been associated with a drop in partial pressure of oxygen in interstitial brain tissue,114 suggesting a failure to compensate the increased metabolic demand coming with the periodic discharges (FIGURE 12-16). MRI AND STATUS EPILEPTICUS MRI represents a useful technique to identify peri-ictal MRI abnormalities related to status epilepticus. Highly variable MRI alterations have been reported during or after status epilepticus, related to the underlying cause or the ongoing TABLE 12-10 Patient Groups and Specific Situations Where Special Consideration Is Needed When Initiating Treatment for Status Epilepticus Patient group/specific situation Caution Chronic obstructive pulmonary disease, Benzodiazepines may cause hypercapnia and respiratory depression, keep bronchial asthma intubation equipment and staff available Chronic heart failure, children Rapid administration of antiseizure medication may result in fluid overload and congestive heart failure Renal failure, hepatic failure Accumulation of previously administered antiseizure medication could contribute to compromised clinical condition Mitochondrial disorders in children and Valproic acid contraindicated adults Patients with low blood pressure on Risk of further drop in blood pressure with midazolam, phenytoin, propofol, admission and narcotics Suspicion of nonconvulsive status Wait for EEG if no clinical hints of nonconvulsive status epilepticus especially in epilepticus in comatose patients coma (intoxication, eg, with benzodiazepines, may be misinterpreted as nonconvulsive status epilepticus) No venous access readily available Consider buccal, nasal, and IM routes of administration; in selected cases, also intraosseous access (special equipment required) should be considered EEG = electroencephalogram. 580 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.  A 65-year-old man was transported to the emergency department by CASE 12-1 emergency medical services. At 4:00 PM, the control center notified the emergency department of the impending arrival of the patient with bilateral tonic-clonic seizure activity for 15 minutes. On the patient’s arrival at 4:15 pm, the physician in the emergency department filled out the checklist as shown in FIGURE 12-9. FIGURE 12-9 Strategy for the initial management of status epilepticus for the patient in CASE 12-1. BP = blood pressure; BTC = bilateral tonic-clinic; ECG = electrocardiogram; IV = intravenous; L = left; MCA = left middle cerebral artery; MRI = magnetic resonance imaging; R = right; SE = status epilepticus; STOPP = end of status, or status epilepticus successfully treated; TOF-MR = time-of-flight magnetic resonance. The key message of this example is that focusing on the treatment of status COMMENT epilepticus may result in missing the acute underlying etiology that needs a specific emergency treatment. Checklists such as that in FIGURE 12-6 help minimize in-time identification of coexisting emergencies and minimize focus error, which refers to a situation when the attention of the treating team is too focused on one detail, thereby overlooking other highly important deteriorations. This case provides a practical example of how the concept shown in FIGURE 12-7 can be applied in daily work. Some considerations need to be documented in a sheet, such as in FIGURE 12-6, whereas others are essential for differential diagnosis and patient management. Intramuscular or intraosseous application routes do not apply if sufficient venous access is available (grayed out text in FIGURE 12-9). CONTINUUMJOURNAL.COM 581 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. STATUS EPILEPTICUS FIGURE 12-10 Relationship of EEG changes and impairment of consciousness. NCSE = nonconvulsive status epilepticus; SE = status epilepticus Reprinted with permission from Bauer G, Trinka E, Epilepsia.32 © 2009 International League Against Epilepsy. seizure activity directly.15,16,121 The key information that can be derived from ictal MRI studies is twofold: First, cerebral hyperperfusion (conventional MRI perfusion with contrast dye or arterial spin labeling) directly reflects the increased metabolic demand of brain tissue due to ongoing ictal activity.128 Second, cytotoxic edema reflects neuronal damage, as expected to occur at time t2. Despite the undoubtful importance of MRI in identifying peri-ictal abnormalities, no large prospective series have been conducted. What is known so far? Thalamic diffusion restriction was found in 48% in a study of 62 patients with focal-onset status epilepticus who underwent an MRI during an episode of status epilepticus, of whom 75.9% showed involvement of the medial pulvinar.129 Temporal lobe status epilepticus was associated with thalamic diffusion- weighted imaging (DWI) changes in 60.6% compared with only 27.3% and 6.7% in status epilepticus in the parietal and frontal lobes, respectively.129 Arterial spin labeling was successfully applied to reveal hyperperfusion in several patients with nonconvulsive status epilepticus.130 In 60 patients with status epilepticus, DWI and T2-weighted abnormalities were highly associated with a poor outcome.131 In another study including 69 patients, the EEG of patients with status epilepticus with peri-ictal DWI restrictions was predominated by circumscribed “periodic lateralized discharges (PLEDs)” and by repetitive seizures.132 This association of LPDs was corroborated in a large series of 277 patients of whom 12% showed peri-ictal MRI changes.16 Arterial spin labeling demonstrates ictal hyperperfusion and can be positive even in patients who are DWI negative.128 SUPER-REFRACTORY STATUS EPILEPTICUS The majority of status epilepticus episodes can be successfully treated with a benzodiazepine and one or two antiseizure medications provided they were 582 APRIL 2022 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. given early in the course in an adequate dose.83 As soon as the combination KEY POINTS of one benzodiazepine and one antiseizure medication has failed, status The impact of the burden epilepticus is called refractory (FIGURE 12-1).24 Especially in convulsive status model integrates structural epilepticus, the application of anesthetics is inevitable.3,75,133,134 The persisting damage and metabolic need for anesthetics in super-refractory status epilepticus for at least 7 days derangement, the burden of determines a prolonged super-refractory status epilepticus whereas a refractory status epilepticus, the success and burden of status epilepticus of the same duration but without anesthetics is called prolonged treatment, and the impact of refractory status epilepticus. Although this categorization seems clinically useful, burden. the terms have not been used widely in the community yet (FIGURE 12-1).24 The time criteria were arbitrarily set with a focus on practicality and to allow for the The amount of structural selection of subgroups with status epilepticus that may share similar etiologies or and metabolic reserves determines the optimal end treatment strategies. In this respect, the term new-onset refractory status epilepticus point parameters in studies. (NORSE) proved very valuable. It specifies neither a specific etiology nor diagnosis but rather a clinical presentation that is used in patients with new-onset MRI is useful to refractory status epilepticus but without preexisting relevant neurologic demonstrate ictal hyperperfusion by arterial disorders including active epilepsy and without a clear acute or active structural, spin labeling in those with metabolic, or toxic cause.24 Febrile infection–related epilepsy syndrome (FIRES) status epilepticus. is considered a subcategory of NORSE. FIRES is applicable to any age and requires a prior febrile infection starting between 2 weeks and 24 hours before New-onset refractory status epilepticus (NORSE) the onset of refractory status epilepticus whereas the presence of fever at the is a form of a clinical onset of status epilepticus is not a defining criterion.24 Reports of meaningful presentation of refractory results of biopsy in patients with NORSE are sparse and include rabies; primary status epilepticus. angiitis of the central nervous system; lymphocytic infiltration with simian virus 40 (SV40) inclusion in oligodendrocytes; spongiform necrosis in limbic system Febrile infection–related epilepsy syndrome (FIRES) associated with autoantibodies against GD1a, GT1b, and GQ1b; herpes simplex denotes a condition in which virus with negative polymerase chain reaction (PCR); Candida with negative a febrile infection preceded culture; and acute disseminated encephalomyelitis (ADEM).135-139 In one case NORSE. series, gliosis without infiltration was found in seven children.140 In a series of 26 patients, 73% of patients with biopsy had an unknown and unidentified etiology (cryptogenic).139 In 50 individuals with FIRES, including 23 single probands and 27 patient-parent trios, no pathologies were found in established genes for neurodevelopmental disorders or epilepsy.141 Among adult patients without cryptogenic NORSE, the most often identified cause is autoimmune encephalitis, either nonparaneoplastic or paraneoplastic.142 Infections are the most pre