Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.

Efns guía para el status epiléptico


Published on

Published in: Health & Medicine, Education
  • Login to see the comments

  • Be the first to like this

Efns guía para el status epiléptico

  1. 1. European Journal of Neurology 2010, 17: 348–355 doi:10.1111/j.1468-1331.2009.02917.xEFNS GUIDELINES/CME ARTICLEEFNS guideline on the management of status epilepticus in adultsH. Meierkorda, P. Boonb, B. Engelsenc,d, K. Gockee, S. Shorvonf, P. Tinuperg and M. Holtkamph ¨a Institute of Neurophysiology, Charite´ – Universita¨tsmedizin Berlin, Berlin, Germany; bDepartment of Neurology, Ghent University Hospital,Ghent, Belgium; cDepartment of Neurology, Haukeland University Hospital, Bergen; dDepartment of Clinical Medicine, University of Bergen,Bergen, Norway; eDeutsche Epilepsievereinigung e.V., Berlin, Germany; fInstitute of Neurology, University College London, London, UK;g Department of Neurological Sciences, University of Bologna, Bologna, Italy; and hDepartment of Neurology, Charite´ – Universita¨tsmedizinBerlin, Berlin, GermanyKeywords: The objective of the current article was to review the literature and discuss the degreecomplex partial status of evidence for various treatment strategies for status epilepticus (SE) in adults. Weepilepticus, generalised searched MEDLINE and EMBASE for relevant literature from 1966 to January 2005convulsive status epilepti- and in the current updated version all pertinent publications from January 2005 tocus, refractory status January 2009. Furthermore, the Cochrane Central Register of Controlled Trialsepilepticus, subtle status (CENTRAL) was sought. Recommendations are based on this literature and on ourepilepticus, treatment judgement of the relevance of the references to the subject. Recommendations were reached by informative consensus approach. Where there was a lack of evidence butReceived 29 July 2009 consensus was clear, we have stated our opinion as good practice points. The preferredAccepted 13 November 2009 treatment pathway for generalised convulsive status epilepticus (GCSE) is intravenous (i.v.) administration of 4–8 mg lorazepam or 10 mg diazepam directly followed by 18 mg/kg phenytoin. If seizures continue more than 10 min after first injection, an- other 4 mg lorazepam or 10 mg diazepam is recommended. Refractory GCSE is treated by anaesthetic doses of barbiturates, midazolam or propofol; the anaesthetics are titrated against an electroencephalogram burst suppression pattern for at least 24 h. The initial therapy of non-convulsive SE depends on type and cause. Complex partial SE is initially treated in the same manner as GCSE. However, if it turns out to be refractory, further non-anaesthetising i.v. substances such levetiracetam, pheno- barbital or valproic acid should be given instead of anaesthetics. In subtle SE, in most patients, i.v. anaesthesia is required. exceptionally high incidence is probably because of theBackground predominance of non-white individuals in the study population that are at a significantly higher risk toIncidence, mortality and morbidity develop SE. Mortality and morbidity rates of SE areGeneralised convulsive (GCSE) and non-convulsive heavily influenced by the underlying aetiology, patientsÕstatus epilepticus (NCSE) are important neurological age and clinical seizure form. Therefore, patient fatalityconditions potentially associated with significant mor- in different studies is quite heterogeneous ranging fromtality and morbidity rates. In Europe, annual incidence 3% to 33% [1–7]. In a recent large US sample includingrates of GCSE range from 3.6 to 6.6 per 100 000 and of more than 11 000 patients, predictors of in-hospitalNCSE from 2.6 to 7.8 per 100 000 [1–3]. A prospective mortality were old age, mechanical ventilation, cere-study from the US demonstrated an incidence rate brovascular disease, female sex and a higher comor-including all forms of SE of 41 per 100 000 [4]. This bidity index [7]. In particular, mortality rates of NCSE after profound brain damage are high and usually be-Correspondence: Hartmut Meierkord, Department of Neurophysiol- cause of the injury itself [6]. ´ogy, Charite – Universitatsmedizin Berlin, Tucholskystrasse 2, 10117 ¨Berlin, Germany (tel.: +49 30 450 52 82 30; fax: There is general agreement that immediate and+49 30 450 52 89 62; e-mail: effective treatment is required. Prospective data indicate that first-line anticonvulsants like benzodiazepines andThis is a Continuing Medical Education article, and can be found withcorresponding questions on the Internet at phenytoin fail to terminate SE in 35–45% of patientsSContinuing-Medical-Education-online.301.0.html. Certificates for [8]. SE continuing after such failure is termed refractorycorrectly answering the questions will be issued by the EFNS. status epilepticus (RSE) and represents an even more Ó 2009 The Author(s)348 Journal compilation Ó 2009 EFNS
  2. 2. Management of status epilepticus in adults 349difficult clinical problem. Drug treatment approaches in more, the Cochrane Central Register of Controlledthis situation are based on prospective observational Trials (CENTRAL) was sought. Finally, the websites ofstudies, retrospective series, case reports and expert the World Health Organisation (WHO), the Interna-opinions. The goal of this article is to summarise pub- tional League against Epilepsy (ILAE) and the Ameri-lished treatment options for GCSE and NCSE. Post- can Academy of Neurology (AAN) were explored toanoxic myoclonus is not considered in this guideline look for additional information.because there is no agreement regarding its epilepticnature. The focus of this article is on initial and critical Evaluation of published literaturecare management of SE in adults, and children are notconsidered. The evidence for therapeutic interventions (Class I–IV) and the rating of recommendations (Level A–C) were classified by using the definitions previously reported [14].MechanismsThe basic processes generating SE may be seen as a Methods for reaching consensusfailure of the normal mechanisms that terminate sei-zures. Reduced inhibition and persistent excessive A proposed guideline with specific recommendationsexcitation create interactions that produce and sustain was drafted for circulation to all panel members. Eachongoing seizure activity. During prolonged seizure panellist studied and commented in writing on eachactivity, dynamic changes in gamma-aminobutyric acid successive guideline draft, revised to progressively(GABA)A and N-methyl-D-aspartate (NMDA) receptor accommodate the panel consensus. Where there was afunction are seen that have been termed Ôreceptor traf- lack of evidence but consensus was clear, we have statedfickingÕ [9]. Ongoing seizure activity results in gradual our opinion as good practice points (GPP). In a furtherreduction of GABAA receptors at the synaptic mem- step, the draft of the guideline was circulated to allbrane following receptor internalisation into endocy- members of the EFNS scientific committee for theirtotic vesicles and subsequent degradation [10]. This comments. These have been incorporated into theprocess results in erosion of endogenous GABAergic current version of the guideline.inhibition giving rise to sustained epileptic activity.Loss of post-synaptic GABAA receptors is a relevant Definitionspathophysiological factor on the way to progressivepharmacoresistance of drugs such as benzodiazepines, The time that has to evolve to define ongoing epilepticbarbiturates and propofol. In contrast, during ongoing activity as Ôstatus epilepticusÕ is as yet not generallyepileptic activity, NMDA receptors are progressively agreed upon. The Commission on Classification andtransported to the synaptic membrane, resulting in Terminology of the ILAE defines SE as Ôa seizure [that]increasing numbers of excitatory NMDA receptors per persists for a sufficient length of time or is repeatedsynapse [11]. This process facilitates neuronal excit- frequently enough that recovery between attacks doesability and consecutively sustained SE. On the other not occurÕ [15]. Experimental studies have shown irre-hand, the enhanced expression of glutamate receptors versible neuronal damage after about 30 min ofmay present a useful target in the pharmacological continuing epileptic activity [16]. Therefore, this timemanagement of advanced stages of SE. Absence SE window has been adopted by the majority of authorswith 3-Hz spike-wave discharges is induced by excessive [1,2,17]. On the other hand, some clinical data indicateinhibition [12]. This form of SE does not lead to the that spontaneous cessation of generalised convulsiveneuronal injury seen with excessive excitation [13]. seizures is unlikely after 5 min [18,19] and therefore acute treatment with anticonvulsants is required. Con- sequently, Lowenstein et al. [20] have proposed anSearch strategy operational definition of SE that is based on a durationOne member of the Task Force Panel (HM) searched of 5 min. Currently, clinical studies are based on 5 minavailable published reports from 1966 to 2005 and for [21], 10 min [8,22] or 30 min [2,23] of ongoing epilepticthe purpose of the current updated version from 2005 to activity to define SE. The diagnosis of NCSE is based2009 using the database MEDLINE and EMBASE on changes in behaviour and/or mental processes from(last search in January 2009). The search was limited to baseline associated with continuous epileptiform dis-papers published in English. The subject term Ôstatus charges in the electroencephalogram (EEG) [24]. ThereepilepticusÕ was combined with the terms Ôcontrolled is currently no generally accepted duration of electro-clinical trialÕ, Ôrandomised controlled trialÕ, Ômulticentre clinical alterations incorporated in the diagnosticstudyÕ, meta analysisÕ and Ôcross over studyÕ. Further- criteria of NCSE.Ó 2009 The Author(s)Journal compilation Ó 2009 EFNS European Journal of Neurology 17, 348–355
  3. 3. 350 H. Meierkord et al. NCSE includes the subtypes of absence status, com- lorazepam after the first administration and three afterplex partial and subtle SE. Absence SE with 3-Hz spike- the second whilst three episodes did not respond. Withwave discharges is a benign type of NCSE, in most diazepam, 14 episodes responded to the first adminis-cases of which a small intravenous (i.v.) dose of lo- tration and two to the second whilst four episodes didrazepam or diazepam will terminate the event. There- not respond. In a recent randomised open study, first-fore, absence SE is not further considered in this article. line anticonvulsant treatment of GCSE with 30 mg/kgComplex partial status epilepticus (CPSE) represents valproic acid in 35 patients has been compared tothe most frequent type and accounts for almost every 18 mg/kg phenytoin in another 33 patients [32] (Classsecond case of all forms of SE [2]. Subtle SE evolves III). Valproic acid terminated SE in 66% of patients,from previously overt GCSE and is characterised by whilst phenytoin was successful in 42% (p = 0.046).coma and ongoing electrographic seizure activity Unfortunately, this study was underpowered giving risewithout any or with only subtle convulsive movements to cautious interpretation of the results. Also, the study[8]. Therefore, subtle SE is a form of NCSE that was not limited to adults, but also included a significantdevelops from GCSE if the latter has been treated number of children and adolescents in whom SE usuallyinsufficiently or has not been treated at all. is less difficult to terminate. Another randomised open An appropriate definition of refractory SE also is still study on first-line treatment of SE compared valproicmissing. The failure of two [22,25] or three [26,27] an- acid in 18 patients to phenytoin in nine patients usingticonvulsants has been suggested in combination with a the same doses as in the latter earlier mentioned studyminimal duration of the condition of 1 h [22,28,29] or [33] (Class III). Valproic acid (72%) was found to be as2 h [25,30] or regardless of the time that has elapsed successful as phenytoin (78%). Unfortunately, thissince onset [23,26]. study too did not yield data of major relevance for the treatment with first-line substances, because it also was underpowered and included patients with GCSE andResults CPSE, each of which is known to be associated with a different prognosis.Literature and data on treatmentInitial treatment of GCSE Initial treatment of CPSEHigh level evidence for the initial pharmacological Currently, there are no studies available focussingtreatment of GCSE has been given in some randomised exclusively on the initial anticonvulsant treatment ofcontrolled trials (RCTs) that are indicated below. In CPSE. Some trials included patients with CPSE but did384 patients with GCSE, i.v. administration of 0.1 mg/ not specify the success rate of anticonvulsant drugs inkg lorazepam was successful in 64.9% of patients, this form of SE [33,34].15 mg/kg phenobarbital in 58.2% of patients and0.15 mg/kg diazepam directly followed by 18 mg/kg Initial treatment of subtle SEphenytoin in 55.8% of patients, the efficacy of these The pharmacological treatment of subtle SE has beenanticonvulsants was not significantly different [8] (Class addressed in a RCT with 134 patients [8] (Class I). TheI). The same trial has shown that in pairwise compari- i.v. administration of lorazepam (0.1 mg/kg), diazepamson, initial monotherapy with 18 mg/kg phenytoin is (0.15 mg/kg) followed by phenytoin (18 mg/kg), phe-significantly less effective than administration of lo- nobarbital (18 mg/kg) and phenytoin (18 mg/kg) ter-razepam. Another RCT has focussed on the pre-hos- minated SE in 8–24% of patients, only. Success ratespital treatment of GCSE performed by paramedics [21] were not significantly different between the drugs or(Class I). A total of 205 patients were administered ei- drug combinations tested. However, key criterion forther 2 mg of i.v. lorazepam, 5 mg of i.v. diazepam or study entry was the evidence of subtle SE at the time ofplacebo, the injection of identical doses of benzodiaze- evaluation, regardless of prior treatment. Though notpines was repeated when seizures continued for more further specified, it can be assumed that in some ofthan 4 min. Lorazepam terminated SE in 59.1% of the patients, anticonvulsants have been administeredpatients and was as effective as diazepam (42.6%). Both before.drugs were significantly superior to the administrationof placebo (21.1%). An earlier RCT on 81 episodes of Side effects of initial treatment of SEall clinical forms of SE compared i.v. administration of Safety issues of the common initial anticonvulsants4 mg lorazepam versus 10 mg diazepam which were have been compared in patients with overt GCSE asrepeated when seizures continued or recurred after well as in patients with subtle SE [8] (Class I). In overt10 min [31] (Class II). In episodes of GCSE with or GCSE, hypoventilation was observed in 10–17% ofwithout focal onset (n = 39), 13 episodes responded to patients, hypotension in 26–34% and cardiac arrhyth- Ó 2009 The Author(s) Journal compilation Ó 2009 EFNS European Journal of Neurology 17, 348–355
  4. 4. Management of status epilepticus in adults 351mias in 2–7%. These side effects were more frequent in Two surveys amongst critical care neurologists andsubtle SE and ranged between 3% and 59% of patients. epileptologists from Europe and the United States haveDistribution of side effects was not significantly differ- been performed. In the American study, there was noent in patients treated with lorazepam, diazepam fol- agreement as to how to proceed in pharmacologicallowed by phenytoin, phenobarbital and phenytoin in treatment of GCSE after failure of benzodiazepines andovert and subtle SE. Out-of-hospital administration of phenytoin or fosphenytoin: more than 80% would notbenzodiazepines compared to placebo did not result in directly proceed to an anaesthetic (43% administermore complications such as arterial hypotension, car- phenobarbital and 16% valproic acid), whilst 19%diac arrhythmias or respiratory depression requiring would directly administer anaesthetic [40] (Class IV).intervention [21] (Class I). These side effects occurred in However, this survey did not include the management10.6% of patients treated with lorazepam, 10.3% of refractory CPSE. The European survey revealed thattreated with diazepam and 22.5% given placebo. after failure of benzodiazepines and phenytoin, two- thirds of the participants would administer in bothRefractory GCSE and NCSE GCSE and CPSE another non-anaesthetising anticon-The rationale for treating refractory SE with anaesthe- vulsant, the majority preferred phenobarbital. Imme-tising anticonvulsants is to prevent both severe acute diate administration of an anaesthetic was preferred bysystemic and long-term neuronal consequences. Acute 35% in GCSE and by 16% in CPSE [41] (Class IV).systemic complications such as pulmonary oedema and – Three-fourths of the experts did not administer anaes-potentially fatal – cardiac arrhythmias may occur early in thetics in refractory CPSE at all, whilst all did at somethe course of GCSE [35] but are rarely seen in CPSE. In time point in GCSE. Administration of anaestheticshumans, the correlation of duration of SE with neuronal was withheld in CPSE: more than 60% of the partici-damage is not known. In contrast, in experimental ani- pants administer anaesthetics not earlier than 60 minmal models, prolonged electrographic seizure activity after onset of status compared to only 21% of partici-results in brain damage [36,37]. It is unclear to what ex- pants waiting that long in GCSE.tent these findings can be translated to the human situ-ation. But it is for this reason that most authorities Further non-anaesthetising anticonvulsantsrecommend prompt and aggressive treatment using Though phenobarbital has been assessed in the initialgeneral anaesthesia if initial therapy has not controlled anticonvulsant treatment [8] of SE, sufficient data on theSE within 1–2 h. However, there are no studies com- efficacy of this substance after failure of benzodiazepinesparing anaesthetic therapy with continuing non-anaes- and phenytoin/fosphenytoin are missing. Doses ofthetising anticonvulsants. The therapeutic decision is 20 mg/kg infused at a rate of 30–50 mg/min are used.based on the type of SE, age, comorbidity and prognostic The role of i.v. valproic acid in the treatment of RSEissues. This is of special relevance in patients with CPSE is yet to be defined. Valproic acid is a non-sedatingbecause the risks of anaesthesia (e.g. arterial hypoten- substance that has not caused hypotension or respira-sion, gastroparesis and immunosuppression) may be tory suppression and has been reported to be effective ingreater than the risks of ongoing non-convulsive epileptic generalised convulsive and complex partial RSE [42]activity [38]. In view of the lack of controlled studies, the (Class IV). In a randomised open study, SE refractorydecision on further treatment is based on a few retro- to diazepam administered in adequate doses was treatedspective studies and expert opinions. Retrospective with valproic acid (20 mg/kg) or phenytoin (20 mg/kg)studies have analysed the further treatment options after in 50 patients each [43] (Class III). Treatment successfailure of initial anticonvulsants [22]. It should be noted was 88% and 84%, respectively. The clinical forms ofthat treatment pathways were naturally influenced by SE that were included into the study are not reported,multiple variables such as aetiology, age and comorbid- and approximately 30% of patients were younger thanity. In 26 episodes of RSE, after failure of first- and sec- 18 years. In a retrospective study that included 63 pa-ond-line drugs, 23 episodes were treated with a third-line tients with previously untreated or refractory GCSE,drug that was non-anaesthetising in all but one case. In overall efficacy rates of 63% were reported, valproictwelve of these episodes, seizures were controlled, but acid was even more successful in RSE [44] (Class IV).eleven patients needed further more aggressive treatment Loading doses of 25–45 mg/kg at infusion rates of up to[22] (Class IV). In another study, RSE was terminated by 6 mg/kg/min have been suggested [45] (Class IV), andfurther non-anaesthetising anticonvulsants in 18 of 35 favourable tolerance of rapid administration rangingepisodes [39] (Class IV). However, data in both studies from 200 to 500 mg/min was reported [44] (Class IV).did not differentiate between GCSE and CPSE. Levetiracetam is a second-generation antiepileptic In view of the very few clinical studies, further drug with proven oral efficacy in epilepsies withavailable evidence has to be based on expertsÕ opinions. generalised and/or partial seizures. The substance isÓ 2009 The Author(s)Journal compilation Ó 2009 EFNS European Journal of Neurology 17, 348–355
  5. 5. 352 H. Meierkord et al.non-sedating and has almost no interactions with other further boluses of 1–2 mg/kg were given until a burstdrugs. In 2006, its i.v. formulation has been introduced suppression EEG pattern was achieved [52] (Class IV).into the market. Retrospective data describe treatment Thereafter, an infusion of 4 mg/kg/h was initiated,success in at least benzodiazepine-refractory SE in 16 of however, the maintenance of a continuing burst sup-18 episodes with loading doses of i.v. levetiracetam pression pattern was difficult to achieve and requiredbetween 250 and 1500 mg [46] (Class IV). A recent incremental doses of propofol with a median maximumprospective observational study reported termination of infusion rate of 9.5 mg/kg/h. The anaesthetic was ta-10 of 11 episodes of various clinical forms of SE with pered after 12 h of satisfactory burst suppression, andi.v. levetiracetam administered in a dose of 2500 mg in epileptic seizures re-occurred in three patients. Arterial5 min [47] (Class IV). In both studies, adverse effects of hypotension was treated with fluid resuscitation in alli.v. levetiracetam were negligible. patients, and seven patients received norepinephrine. Lacosamide has been licensed in Europe and the A systematic review of drug therapy for RSE includingUnited States in autumn 2008 as oral and i.v. formu- barbiturates, midazolam and propofol assessed andlation for the adjunctive treatment of partial epilepsies. compared data on 193 patients from 28 retrospectiveThe pharmacokinetic profile is interesting for the trials [53] (Class IV). Pentobarbital was more effectivetreatment of SE as well, however, so far there has been than either propofol or midazolam in preventing break-only one report on its efficacy in a patient with non- through seizures (12% vs. 42%). However, in mostconvulsive predominantly aphasic SE [48]. studies, barbiturates were titrated against an EEG burst Both levetiracetam and lacosamide are not licensed suppression pattern whilst midazolam and propofol werefor the treatment of SE. administered to obtain EEG seizure cessation. Accord- ingly, side effects such as arterial hypotension were sig-Anaesthetising anticonvulsants nificantly more frequently seen with pentobarbitalMost authorities recommend administration of anaes- compared to midazolam and propofol (77% vs. 34%).thetic agents to a depth of anaesthesia which produces a Overall mortality was 48% but there was no associationburst suppression pattern in the EEG [41] (Class IV) or between drug selection and the risk of death. A retro-an isoelectric EEG [49]. Studies are needed in this area, spective study assessed treatment aggressiveness onas these issues give rise to ethically highly problematic prognosis revealing that outcome was independent of thedecisions. specific coma-inducing agent used [54] (Class IV). Barbiturates, propofol and midazolam are commonly The earlier mentioned progressive loss of GABAAused in refractory SE [41] but it is extremely difficult to receptors with ongoing seizure activity limits the efficacyachieve bust suppressions with midazolam (Class IV). of anticonvulsants with predominantly GABAergicThere have been no RCT comparing these treatment mechanisms of action. In advanced stages of SE whenoptions. These substances have been assessed in pro- NMDA receptors are increasingly expressed, specificspective observational studies. Thiopental anaesthesia antagonists may be good candidates to be administered.was induced in 10 patients with an initial bolus of 5 mg/ Ketamine has been described in some case reports andkg and additional boluses of 1–2 mg/kg to achieve patient series to terminate SE after failure of GABAergicburst suppressions [50]. Thereafter, the infusion rate anticonvulsants [55–57] (Class IV).was started at 5 mg/kg/h and had to be increased toa median of 7 mg/kg/h to maintain burst suppression. RecommendationsIn no patient, epileptic seizure activity re-occurredfollowing tapering of thiopental. Mean arterial pressure The use of an in-house protocol for the general man-decreased in all patients and required catecholamines in agement and specific pharmacological treatment of SEfour. Nine patients were treated with antibiotics be- is highly recommended (GPP) to provide the highestcause of infection indicating that high-dose thiopental quality of care.anaesthesia may be immunosuppressive. Midazolamanaesthesia was induced in 19 patients with a bolus of General initial management0.2 mg/kg followed by continuous infusion at a startingrate of 1 lg/kg/min [51] (Class IV). Infusion rate was General management approaches in generalised con-increased to a median of 8 lg/kg/min to control clinical vulsive, complex partial, and subtle SE should include:seizures. Seizure activity was terminated in all but one assessment and control of the airways and of ventila-patient, and no patient developed haemodynamically tion, arterial blood gas monitoring to see if there isrelevant arterial hypotension or other important medi- metabolic acidosis and hypoxia requiring immediatecal side effects. Propofol anaesthesia was induced in 10 treatment through airway management and supple-consecutive patients with a bolus of 2–3 mg/kg, and mental oxygen, ECG and blood pressure monitoring. Ó 2009 The Author(s) Journal compilation Ó 2009 EFNS European Journal of Neurology 17, 348–355
  6. 6. Management of status epilepticus in adults 353Other measures include i.v. glucose and thiamine as doses of midazolam, propofol or barbiturates becauserequired, emergency measurement of antiepileptic drug of the progressive risk of brain and systemic damage.levels, electrolytes and magnesium, a full haematologi- Because of poor evidence, we can not recommendcal screen and measures of hepatic and renal function. which of the anaesthetic substances should be the drugThe cause of the status should be identified urgently of choice.and may require treatment in its own right (GPP). Depending on the anaesthetic used in the individual in-house protocol, we recommend titration against an EEG burst suppression pattern with propofol andInitial pharmacological treatment for GCSE and NCSE barbiturates. If midazolam is given, seizure suppressionIn GCSE, the preferred treatment pathway is i.v. is recommended. This goal should be maintained for atadministration of 0.1 mg/kg lorazepam (Level A rat- least 24 h. Simultaneously, initiation of the chronicing). Depending on the patientÕs general medical con- medication, the patient will be treated with in futuredition, the clinician may decide to start treatment at a should be initiated (GPP).lower dose of 4 mg and repeat this dose if SE is notterminated within 10 min (Level B rating). A single shot Barbituratesof 4 mg lorazepam has proven to be sufficient in more Thiopental is started with a bolus of 3–5 mg/kg,than 80% of patients with successfully treated SE. If i.v. then further boluses of 1–2 mg/kg every 2–3 minlorazepam is not available (e.g. in France), 10 mg until seizures are controlled, thereafter continuousdiazepam directly followed by 18 mg/kg phenytoin or infusion at a rate of 3–7 mg/kg/h (GPP). Pento-equivalent fosphenytoin may be given instead (Level A barbital (the first metabolite of thiopental) israting). Phenytoin should be loaded rapidly with an marketed in the United States as the alternativeinfusion rate at 50 mg/min, this regimen is as safe as to thiopental and is given as a bolus dose ofanticonvulsant treatment using other drugs (Level A 5–15 mg/kg over 1 h followed by an infusion ofrating). However, it should be kept in mind that length 0.5–1 mg/kg/h, increasing if necessary to 1–3 mg/kg/hof infusion time for diazepam followed by phenytoin is (GPP).about 40 min compared to the 5 min for administrationof lorazepam. If possible, pre-hospital treatment is Midazolamrecommended, and in GCSE, i.v. administration of Effective initial i.v. doses of midazolam are a 0.2 mg/kg2 mg lorazepam is as effective as 5 mg diazepam (Level bolus, followed by continuous infusion at rates ofA rating). Out-of-hospital, i.v. administration of ben- 0.05–0.4 mg/kg/h (GPP).zodiazepines in GCSE is as safe as placebo treatment(Level A rating). So far, available studies have not Propofolconvincingly demonstrated a good-enough efficacy of Initial i.v. bolus of 2–3 mg/kg should be administeredvalproic acid to be included in the group of first-line followed by further boluses at 1–2 mg/kg until seizuresubstances for the treatment of generalised convulsive control, then continuous infusion at 4–10 mg/kg/hor other clinical forms of SE. CPSE should be treated (GPP).initially in the same way as GCSE (GPP). Subtle SEevolving from previously overt GCSE in most patients In cases of elderly patients in whom intubation andwill already have been treated with anticonvulsants. In artificial ventilation would not be justified, further non-the rare patients with previously untreated subtle SE, anaesthetising anticonvulsants may be tried (see below)the initial anticonvulsant treatment should be identical (GPP).to that of overt GCSE (GPP). Pharmacological treatment for refractory complexGeneral management of RSE partial SEGCSE that does not respond to initial anticonvulsant In complex partial SE, the time that has elapsed untilsubstances needs to be treated on an intensive care unit termination of status is less critical compared to GCSE.(GPP). Thus, general anaesthesia because of its possible severe complications should be postponed and further non- anaesthetising anticonvulsants may be tried before.Pharmacological treatment for refractory generalised Because of poor evidence and lack of any head-to-headconvulsive and subtle SE comparison studies, we can not recommend which ofIn generalised convulsive and subtle SE, we suggest to the non-anaesthetising anticonvulsants should be theproceed immediately to the infusion of anaesthetic drug of choice (GPP).Ó 2009 The Author(s)Journal compilation Ó 2009 EFNS European Journal of Neurology 17, 348–355
  7. 7. 354 H. Meierkord et al.Phenobarbital Cooperative Study Group. N Engl J Med 1998; 339:Initial i.v. bolus of 20 mg/kg i.v. at an infusion rate of 792–798. 9. Chen JW, Wasterlain CG. Status epilepticus: pathophys-50 mg/min, administration of additional boluses re- iology and management in adults. Lancet Neurol 2006; 5:quires intensive care conditions (GPP). 246–256. 10. Naylor DE, Liu H, Wasterlain CG. Trafficking of GA-Valproic acid BA(A) receptors, loss of inhibition, and a mechanism forIntravenous bolus of 25–45 mg/kg infused at rates of up pharmacoresistance in status epilepticus. J Neurosci 2005; 25: 7724– 6 mg/kg/min (GPP). 11. Wasterlain C, Liu H, Mazarati A, Baldwin R. NMDA receptor trafficking during the transition from singleLevetiracetam seizures to status epilepticus. Ann Neurol 2002; 52Intravenous bolus of 1000–3000 mg administered over (Suppl. 1): 16.a period of 15 min (GPP). 12. Snead OC III. Basic mechanisms of generalized absence seizures. Ann Neurol 1995; 37: 146–157. 13. Fountain NB. Status epilepticus: risk factors and com- If the treatment regimen includes the administration plications. Epilepsia 2000; 41(Suppl. 2): S23–S30.of anaesthetics, the same protocol applies as described 14. Brainin M, Barnes M, Baron JC, et al. Guidance for thefor refractory GCSE. preparation of neurological management guidelines by EFNS scientific task forces – revised recommendations 2004. Eur J Neurol 2004; 11: 577–581.Conflicts of interest 15. Proposal for revised clinical and electroencephalographic classification of epileptic seizures. From the CommissionHM has declared no conflict of interest. PB has on Classification and Terminology of the Internationalreceived Editorial/Advisory board fees from Cyber- League Against Epilepsy. Epilepsia 1981; 22: 489–501.onics, Elsevier, Medtronic, Pfizer, Sanofi and UCB 16. Meldrum BS, Brierley JB. Prolonged epileptic seizures in primates. Ischemic cell change and its relation to ictaland SpeakerÕs fees from Cyberonics, Medtronic and physiological events. Arch Neurol 1973; 28: 10–17.UCB. BE has declared no conflict of interest. KG has 17. Shorvon S. Status Epilepticus: Its Clinical Features anddeclared no conflict of interest. SS has received Treatment in Children and Adults. Cambridge: CambridgeEditorial/Advisory board fees from UCB and University Press, 1994.SpeakerÕs fees from UCB. PT has declared no conflict 18. Theodore WH, Porter RJ, Albert P, et al. The secondarily generalized tonic–clonic seizure: a videotape analysis.of interest. MH has received SpeakerÕs fees from Neurology 1994; 44: 1403–1407.UCB. 19. Jenssen S, Gracely EJ, Sperling MR. How long do most seizures last? A systematic comparison of seizures re- corded in the epilepsy monitoring unit. Epilepsia 2006; 47:References 1499–1503.1. Coeytaux A, Jallon P, Galobardes B, Morabia A. Inci- 20. Lowenstein DH, Bleck T, Macdonald RL. ItÕs time to dence of status epilepticus in French-speaking Switzer- revise the definition of status epilepticus. Epilepsia 1999; land: (EPISTAR). Neurology 2000; 55: 693–697. 40: 120–122.2. Knake S, Rosenow F, Vescovi M, et al. Incidence of 21. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison status epilepticus in adults in Germany: a prospective, of lorazepam, diazepam, and placebo for the treatment of population-based study. Epilepsia 2001; 42: 714–718. out-of-hospital status epilepticus. N Engl J Med 2001; 345:3. Vignatelli L, Tonon C, DÕAlessandro R. Incidence and 631–637. short-term prognosis of status epilepticus in adults in 22. Mayer SA, Claassen J, Lokin J, Mendelsohn F, Dennis Bologna, Italy. Epilepsia 2003; 44: 964–968. LJ, Fitzsimmons BF. Refractory status epilepticus: fre-4. DeLorenzo RJ, Hauser WA, Towne AR, et al. A pro- quency, risk factors, and impact on outcome. Arch Neurol spective, population-based epidemiologic study of status 2002; 59: 205–210. epilepticus in Richmond, Virginia. Neurology 1996; 46: 23. AmericaÕs Working Group on Status Epilepticus. Treat- 1029–1035. ment of convulsive status epilepticus. Recommendations5. Wu YW, Shek DW, Garcia PA, Zhao S, Johnston SC. of the Epilepsy Foundation of AmericaÕs Working Group Incidence and mortality of generalized convulsive sta- on Status Epilepticus. JAMA 1993; 270: 854–859. [Previ- tus epilepticus in California. Neurology 2002; 58: 1070– ous guidelines or recommendations]. 1076. 24. Meierkord H, Holtkamp M. Non-convulsive status epi-6. Shneker BF, Fountain NB. Assessment of acute morbid- lepticus in adults: clinical forms and treatment. Lancet ity and mortality in nonconvulsive status epilepticus. Neurol 2007; 6: 329–339. Neurology 2003; 61: 1066–1073. 25. Prasad A, Worrall BB, Bertram EH, Bleck TP. Propofol7. Koubeissi M, Alshekhlee A. In-hospital mortality of and midazolam in the treatment of refractory status epi- generalized convulsive status epilepticus: a large US lepticus. Epilepsia 2001; 42: 380–386. sample. Neurology 2007; 69: 886–893. 26. Lowenstein DH, Alldredge BK. Status epilepticus. N Engl8. Treiman DM, Meyers PD, Walton NY, et al. A com- J Med 1998; 338: 970–976. parison of four treatments for generalized convulsive 27. Cascino GD. Generalized convulsive status epilepticus. status epilepticus. Veterans Affairs Status Epilepticus Mayo Clin Proc 1996; 71: 787–792. Ó 2009 The Author(s) Journal compilation Ó 2009 EFNS European Journal of Neurology 17, 348–355
  8. 8. Management of status epilepticus in adults 35528. Hanley DF, Kross JF. Use of midazolam in the treatment 42. Sinha S, Naritoku DK. Intravenous valproate is well of refractory status epilepticus. Clin Ther 1998; 20: tolerated in unstable patients with status epilepticus. 1093–1105. Neurology 2000; 55: 722–724.29. Shorvon S, Baulac M, Cross H, Trinka E, Walker M. The 43. Agarwal P, Kumar N, Chandra R, Gupta G, Antony AR, drug treatment of status epilepticus in Europe: consensus Garg N. Randomized study of intravenous valproate and document from a workshop at the first London phenytoin in status epilepticus. Seizure 2007; 16: 527–532. Colloquium on Status Epilepticus. Epilepsia 2008; 49: 44. Limdi NA, Shimpi AV, Faught E, Gomez CR, Burneo 1277–1285. [Previous guidelines or recommendations]. JG. Efficacy of rapid IV administration of valproic acid30. Stecker MM, Kramer TH, Raps EC, OÕMeeghan R, for status epilepticus. Neurology 2005; 64: 353–355. Dulaney E, Skaar DJ. Treatment of refractory status ep- 45. Venkataraman V, Wheless JW. Safety of rapid intrave- ilepticus with propofol: clinical and pharmacokinetic nous infusion of valproate loading doses in epilepsy pa- findings. Epilepsia 1998; 39: 18–26. tients. Epilepsy Res 1999; 35: 147–153.31. Leppik IE, Derivan AT, Homan RW, Walker J, Ramsay 46. Knake S, Gruener J, Hattemer K, et al. Intravenous lev- RE, Patrick B. Double-blind study of lorazepam etiracetam in the treatment of benzodiazepine refractory and diazepam in status epilepticus. JAMA 1983; 249: status epilepticus. J Neurol Neurosurg Psychiatry 2008; 79: 1452–1454. 588–589.32. Misra UK, Kalita J, Patel R. Sodium valproate vs phe- 47. Uges JW, van Huizen MD, Engelsman J, et al. Safety and nytoin in status epilepticus: a pilot study. Neurology 2006; pharmacokinetics of intravenous levetiracetam infusion as 67: 340–342. add-on in status epilepticus. Epilepsia 2008; 50: 415–421.33. Gilad R, Izkovitz N, Dabby R, et al. Treatment of status 48. Kellinghaus C, Berning S, Besselmann M. Intravenous epilepticus and acute repetitive seizures with i.v. valproic lacosamide as successful treatment for nonconvulsive acid vs phenytoin. Acta Neurol Scand 2008; 118: 296–300. status epilepticus after failure of first-line therapy. Epi-34. Peters CN, Pohlmann-Eden B. Intravenous valproate as lepsy Behav 2009; 14: 429–431. an innovative therapy in seizure emergency situations 49. Kaplan PW. Nonconvulsive status epilepticus. Neurology including status epilepticus – experience in 102 adult pa- 2003; 61: 1035–1036. tients. Seizure 2005; 14: 164–169. 50. Parviainen I, Uusaro A, Kalviainen R, Kaukanen E,35. Walton NY. Systemic effects of generalized convulsive Mervaala E, Ruokonen E. High-dose thiopental in the status epilepticus. Epilepsia 1993; 34(Suppl. 1): S54–S58. treatment of refractory status epilepticus in intensive care36. Holtkamp M, Matzen J, van Landeghem F, Buchheim K, unit. Neurology 2002; 59: 1249–1251. Meierkord H. Transient loss of inhibition precedes 51. Ulvi H, Yoldas T, Mungen B, Yigiter R. Continuous spontaneous seizures after experimental status epilepticus. infusion of midazolam in the treatment of refractory Neurobiol Dis 2005; 19: 162–170. generalized convulsive status epilepticus. Neurol Sci 2002;37. Walker MC, Perry H, Scaravilli F, Patsalos PN, Shorvon 23: 177–182. SD, Jefferys JG. Halothane as a neuroprotectant during 52. Parviainen I, Uusaro A, Kalviainen R, Mervaala E, Ru- constant stimulation of the perforant path. Epilepsia 1999; okonen E. Propofol in the treatment of refractory status 40: 359–364. epilepticus. Intensive Care Med 2006; 32: 1075–1079.38. Kaplan PW. No, some types of nonconvulsive status ep- 53. Claassen J, Hirsch LJ, Emerson RG, Mayer SA. Treat- ilepticus cause little permanent neurologic sequelae (or: ment of refractory status epilepticus with pentobarbital, ‘‘the cure may be worse than the disease’’). Clin Neuro- propofol, or midazolam: a systematic review. Epilepsia physiol 2000; 30: 377–382. 2002; 43: 146–153.39. Holtkamp M, Othman J, Buchheim K, Masuhr F, Schi- 54. Rossetti AO, Logroscino G, Bromfield EB. Refractory elke E, Meierkord H. A ‘‘malignant’’ variant of status status epilepticus: effect of treatment aggressiveness on epilepticus. Arch Neurol 2005; 62: 1428–1431. prognosis. Arch Neurol 2005; 62: 1698–1702.40. Claassen J, Hirsch LJ, Mayer SA. Treatment of status 55. Bleck TP, Quigg M, Nathan BR, Smith TL, Kapur J. epilepticus: a survey of neurologists. J Neurol Sci 2003; Electroencephalographic effects of ketamine treatment for 211: 37–41. refractory status epilepticus. Epilepsia 2002; 43(Suppl. 1):41. Holtkamp M, Masuhr F, Harms L, Einhaupl KM, Me- 282. ierkord H, Buchheim K. The management of refractory 56. Sheth RD, Gidal BE. Refractory status epilepticus: generalised convulsive and complex partial status epilep- response to ketamine. Neurology 1998; 51: 1765–1766. ticus in three European countries: a survey among epi- 57. Pruss H, Holtkamp M. Ketamine successfully terminates leptologists and critical care neurologists. J Neurol malignant status epilepticus. Epilepsy Res 2008; 82: Neurosurg Psychiatry 2003; 74: 1095–1099. 219–222.Ó 2009 The Author(s)Journal compilation Ó 2009 EFNS European Journal of Neurology 17, 348–355