The drug treatment of status epilepticus in Europe: Consensus document from a workshop at the first London Colloquium on Status Epilepticus
2008; Wiley; Volume: 49; Issue: 7 Linguagem: Inglês
10.1111/j.1528-1167.2008.01706_3.x
ISSN1528-1167
AutoresSimon Shorvon, Michel Baulac, J. Helen Cross, Eugen Trinka, Matthew C. Walker,
Tópico(s)Drug Transport and Resistance Mechanisms
ResumoThis document summarizes the conclusions of a workshop of European clinicians held in conjunction with the first London Colloquium on Status Epilepticus, in April 2007. The purpose of the workshop was to outline options for treatment of the various forms of status epilepticus (SE) and to identify regulatory and medical aspects which require action, in the European context. The document provides: (1) suggestions for action to improve knowledge and practice in relation to SE (shaded in gray) and (2) options for treatment of various forms of SE (shaded in green). This document was approved by the Commission on European Affairs of the International League Against Epilepsy (ILAE). This is not a guideline document, but summarizes treatment options in an area characterized by a lack of randomized controlled trials or indeed other large studies. The various forms of SE are a significant health problem and often need urgent expert therapy to optimize outcome. The availability of intravenous antiepileptic drugs (AEDS) used in this condition, and their licensing status, varies across European countries, and this variation is to the detriment of patients (Annex 1). There is widespread use of nonlicensed drugs, which is unsatisfactory, and in some areas the treatment and protocols vary substantially without rational basis between centers and even within centers. It is unrealistic to expect randomized controlled trials (RCTs) to be performed in the near future in this area. This is because the major pharmaceutical companies are unlikely to engage in the sponsorship of such studies, given the high risk involved in treating convulsive SE, the nature of the drugs involved, and the low frequency of the condition. In addition, the European regulations in their current form for undertaking studies in the emergency situation in patients unable to give consent pose serious obstacles for future research in this area. SE is defined for the purposes of this document as epileptic activity continuing for 30 minutes or more. The classification of SE used in this document is given in Table 1. At the workshop, four specific areas were considered. The workshop suggested that the following measures might be adopted to improve epilepsy care in Europe. These were endorsed by the ILAE Commission on European Affairs (CEA) and it is hoped that these can be considered by other European agencies and professional bodies—including the Task Force in Europe for Drug Development in the Young (TEDDY), ILAE Commission on Pediatrics, European Pediatric Neurology Society, European Federation of Neurological Societies, and societies in other relevant specialties (i.e., intensivists). The regulatory issues should be presented by these (and other relevant bodies) to the European regulatory agencies for discussion and action. There is a need to document and to harmonize drug availability across Europe, as it is clear that the provision of medicines in different countries varies considerably; this reduces choice and is to the detriment of patients. The following suggestions for harmonizing and optimizing therapy are made: A list of currently licensed drugs for SE should be prepared (a first draft is at the end of this document—Annex 1. This list demonstrates the variability and inadequacy of current licensing). A list of drugs which are recommended for inclusion in European formularies for SE should be prepared (as a preliminary consideration, the workshop considered this should include: fosphenytoin, lorazepam, midazolam, phenytoin, phenobarbital, and valproate). National authorities should be approached with the approved list to ensure that these are included in national formularies. All countries should have clear guidelines sanctioned by the national ILAE chapter, and other professional bodies, for the optimal treatment of SE. A major issue of concern is that many of the effective drugs for SE are not licensed for this indication. The question of using the "Orphan Drug" legislation for certain agents has been raised, but SE has been considered too common to be considered an orphan condition. The current European Medicines Agency (EMEA) guideline for the approval of AEDs fails to mention intravenous (IV) formulations, and this is to be revised in 2007. It is also noted that too low an IV dosage of phenytoin is recommended in some regulatory documents. It was suggested that: The ILAE CEA, TEDDY, European Federation of Neurological Sciences (EFNS), and other bodies] should register support for ongoing discussions with the regulatory authorities to facilitate the approval and licensing of appropriate drugs used in the emergency control of seizures (for instance, such drugs as IV or buccal midazolam, IV lorazepam, IV valproate, IV levetiracetam, and IV propofol). The ILAE CEA, which is a contact group of the EMEA, should provide input to the EMEA regarding IV formulations and doses. Other bodies should be encouraged also to provide input. The ILAE CEA should stimulate clinical trails in this area and also encourage EMEA to define design features for clinical trials that would meet regulatory standards. The ILAE CEA should advise regulatory authorities on the relevant and feasible clinical end points that would meet regulatory standards. A major issue in clinical trials concerns the recent European regulations concerning protection of subjects who are unable to give consent [this applies for instance to an unconscious patient presenting at an accident and emergency (A&E) with SE]. Recent tightening of European regulations has, on the face of it, made it extremely difficult to conduct clinical trials in SE. There may be national mechanisms for mitigating the rules for appropriate trials, but there is considerable uncertainty in this area. It was suggested that: ILAE CEA should make representations to clarify and improve the regulations regarding consent for clinical trials in SE. It should contact colleagues in other therapeutic areas with similar difficulties (i.e., stroke or head injury). SE is one area in which multicenter collaboration would be highly appropriate, given the relatively low frequency of some forms and the importance of the condition. It is suggested that the ILAE CEA should support the formation of: A European Registry collecting observational information, recording every off-label use, improving the care standards (based on the similar registries in existence for Fabry's disease and EURAP). Multicenter clinical trials to identify new improved therapies, particularly in stage 2 and stage 3 of tonic-clonic SE and in less common forms. There was general agreement on a general framework for the treatment of generalized tonic–clonic SE, although it was recognized that the clinical evidence on which to base drug choice in stages 2 and 3 of the condition is very weak. The following recommendations for a general treatment protocol are made: All units should have a written protocol for the therapy of convulsive SE. These should be agreed with colleagues in other disciplines and may be hospital-specific. Cardiorespiratory function should be continuously monitored if IV therapy is being given. The protocol should be staged with a clear structured time frame (Table 2 gives an example of a widely used staged protocol). General emergency management is essential. Support of cardiovascular function, which is often compromised, is vital, as well as the identification and treatment of other complications (Table 3). General measures should be instituted along with drug therapy (details are outside the scope of this article). Investigations to determine the cause of SE must be carried out without delay of initial treatment. Intravenous (IV) therapy is preferred where facilities for resuscitation are available, but should not generally be started in situations where facilities for resuscitation do not exist (i.e., out-of-hospital). In these situations, emergency therapy using alternative routes of administration should be used (i.e., intranasal midazolam, buccal midazolam, or rectal diazepam). There is good RCT evidence in early status (stage 1) that the early and rapidly instituted use of benzodiazepines (in sufficient dose) is the preferred treatment (Table 4). There is at least one RCT and metaanalysis that conclude that lorazepam is slightly superior to diazepam. Treatment with benzodiazepine can be repeated on a second occasion after 5–10 min if necessary. If benzodiazepine treatment fails to control seizures, the patient should be considered to be in the stage of established SE (stage 2), and this requires the rapid institution of IV antiepileptic drugs. Phenytoin or phenobarbital are commonly used, although alternative drugs exist (Table 5). If treatment in the stage of established SE fails to control seizures, the patient should be considered to enter the stage of refractory SE (stage 3), and general anesthesia should be instituted as soon as possible (Table 6). It is not appropriate to cycle through alternative treatments in the stage of established status and delay anesthetic treatment unless there are unavoidable resource difficulties. The anesthesia not infrequently needs to be continued for days or weeks. EEG monitoring is essential during anesthesia for refractory SE. At all stages, the patients who have been administered parenteral medication must be continuously observed by a competent person to monitor cardiorespiratory function. In SE, due to drug withdrawal/reduction (in patients with preexisting epilepsy) the withdrawn drug should be reinstituted immediately by the intravenous route if possible, and this will usually in itself result in the resolution of the SE. In cases of SE in the postoperative neurosurgical setting, early intubation and anesthesia should be considered in view of the special risks. It was recognized that treatment failures are often the result of: Underdosing at the stage of established SE. Neglecting maintenance therapy. Emergency therapy with lorazepam, phenytoin, or phenobarbital will have an effect for up to 12 hours, and if maintenance antiepileptic therapy has not been adequately introduced within this period, relapse of the SE is common. Misdiagnosis, and particularly confusion with psychogenic nonepileptic status or drug-induced or metabolic encephalopathy. Failure to identify and treat the underlying etiology of the SE or the secondary complications (Table 3). It was also recognized that a number of factors influence the choice of AED used in status. These factors include: comorbidity, age, and epilepsy syndrome. There is general agreement that initial treatment should be with benzodiazepines. This should be given via the IV route wherever possible (usually in hospital settings), but out-of-hospital treatments with alternative modes of administration are better than delaying therapy. The options for AED therapy include: Out-of-hospital treatment: Non-IV therapy is recommended where facilities for resuscitation do not exist. The usual chosen options are the use of rectal diazepam, buccal midazolam, or intranasal midazolam. There is one well-conducted RCT that favors buccal midazolam over rectal diazepam.In out-of hospital situations where facilities for resuscitation and cardiorespiratory monitoring exists, IV treatment can be started (see no.2). In-hospital treatment (and in other special settings where facilities for resuscitation exist): Use of IV therapy is recommended. Diazepam, lorazepam, and clonazepam can be used, and several trials have favored lorazepam. Therapy in this stage has been traditionally with IV phenytoin or IV phenobarbital, although there is considerable recent uncontrolled evidence suggesting that IV valproate is be a good alternative to these traditional therapies. There is also promising uncontrolled evidence suggesting that IV levetiracetam may be a good alternative mode of therapy. The options for AED therapy include: The use of either: phenytoin, fosphenytoin, phenobarbital, valproate, or levetiracetam. There are several RCTs showing that phenytoin and phenobarbital have equivalent efficacy. There is an RCT showing that fosphenytoin has superior tolerability compared to phenytoin in the setting of acute seizures (but not SE). Treatment with general anesthesia requires the full panoply of intensive therapy unit (ITU) facilities and ideally also continuous or at least intermittent/repeated electroencephalography (EEG) monitoring. The options for anesthetic drug treatment include: Midazolam, propofol, or thiopental (pentobarbital) are the most commonly used, although there are no RCT comparing outcome. Other anesthetic options, less commonly used, include ketamine and the inhalational anesthetics. Hypothermia may improve outcome. It should be considered in ITU settings if available. The treatment options depend on the type of nonconvulsive SE (NCSE). This requires urgent therapy and can be started out of hospital. The options for treatment include: An oral benzodiazepine, such as lorazepam, clobazam, diazepam, or midazolam is first-line therapy and should be given as soon as possible (out-of-hospital if necessary). If this does not resolve the condition, IV therapy should be given, but this requires hospitalization and preferably EEG monitoring. The usual initial IV therapy is with low dose diazepam or lorazepam. In the cases in which IV benzodiazepines are not effective, there is open trial evidence that suggests that IV valproate or levetiracetam can be effective. Out-of-hospital treatment is not recommended except in exceptional circumstances—for instance in patients with partial epilepsy and EEG confirmed prior episodes presenting with identical symptoms. In this situation, out-of-hospital treatment with oral, buccal, nasal, or rectal benzodiazepine treatment can be given. Where there is diagnostic uncertainty and/or management concerns, admission is required. The following treatment suggestions are made: Urgent EEG is recommended wherever possible. A review by an experienced neurologist is important to avoid diagnostic error. In patients with epilepsy in whom complex partial SE is strongly suspected and in whom no other cause is identified, oral or IV antiepileptic drugs should be given (the route of administration depends on the severity of the condition). Options include: IV valproate, benzodiazepine (preferably lorazepam 4 mg), or phenytoin/fosphenytoin. Wherever possible, this should be carried out with EEG monitoring. EEG is diagnostic and should be arranged as soon as possible. The choice of therapy will depend on age, comorbidity, level of consciousness, and etiology. This will also influence the intensity of treatment, and anesthesia (with intubation, ITU facilities, and continuous EEG monitoring) is needed in cases in which there is a severe life-threatening etiology. This condition is often the result of psychotropic drug withdrawal or is a late recurrence of idiopathic generalized epilepsy. The options for treatment include: Low dose IV benzodiazepine (i.e., lorazepam 1 mg) should be given, with EEG monitoring. IV therapy should only be given where resuscitation facilities are available. There may not be an immediate clinical response, and the dose can be repeated. In almost all cases, the SE can be controlled in this way. Long-term antiepileptic therapy is indicated if there are focal abnormalities on magnetic resonance imaging (MRI) or EEG, or if there are no identifiable provoking factors. This was considered separately during the workshop, and the following conclusions were arrived at: There is an almost universal consensus that a benzodiazepine should be used as a drug of choice in treatment of a prolonged seizure or in early SE in children (including febrile SE); the therapy follows similar lines to that in adults. Which benzodiazepine is likely to be country-dependent, but it is recommended that guidelines should be available in each country as to which one and what dose, and by which route it should be administered. It is important that prehospital treatment should be part of the guideline. There remains a likely gap however between recommendations and actual emergency treatment administered. This requires education, including what defines a prolonged seizure, what may be seen as continuing seizure activity, and also when to treat acute repetitive seizures. There is also a need for education regarding the recognition of acute symptomatic seizures and psychogenic seizures. It is suggested that: Treatment protocols for children should be available in all countries. A target is set of 80% of individuals to be treated appropriately. Educational initiatives should be put in place for diagnosis and treatment. Evidence on the relative advantages and disadvantages of different therapies in children is deficient. It is unlikely that pediatricians could be persuaded to use IV valproate in the de novo acute situation in view of the risk of unrecognized metabolic disease. In addition, there is enough evidence of extravasation injury with phenytoin use to feel fosphenytoin should be compared against phenobarbitone or levetiracetam. There is no evidence that any agent is more superior in efficacy over another—what is used in individual countries will depend on availability and tradition. There is a need formally to assess efficacy and safety. It is suggested that: An RCT is conducted, comparing what is optimal medication in children as in adults in established SE. As in adults, there is a clear need for protocol and audit with regard to when to proceed to anesthesia and which anesthetic to use. This will again depend on experience and tradition. There is also a need for statement with regard to EEG monitoring. It is suggested that: A protocol is prepared regarding the choice of anesthetic and EEG monitoring. The treatment depends on the type (see Table 1). NCSE in epileptic encephalopathies needs to be assessed in a syndrome-specific way. NCSE cannot be compared across syndromes. The outcome expected differs. The aim of therapy in Panayiotopoulos syndrome, Rett syndrome, electrical SE in slow wave sleep (ESES), Lennox-Gastaut syndrome, and Landau-Kleffner syndrome are quite different. There are no randomized trials in any of these forms of NCSE comparing treatment options. Universal guidance cannot therefore be given. It is suggested that: A "registry" should be compiled with single sheet data with regard to clinical presentation, behavioral questionnaire, EEG criteria, details of treatment, and follow-up data. This data could be collected and analyzed prior to next SE workshop, from which study or treatment recommendations could be discussed. It was recognized that treatment is very dependent on (1) the etiology of the condition—this is fundamental, and where possible, treatment should be aimed at alleviating the etiology as a way of resolving the epilepsy; (2) the severity of the condition; (3) acute EPC requires a different approach to chronic EPC. In view of these variables, it has not been possible to devise simple guidelines for the treatment of EPC, which cover all clinical eventualities. Nevertheless, there is a fair degree of consensus on the various treatment options available. The options for management include the following points: In the acute phase, AEDs may be helpful, and any drug effective in chronic epilepsy may be tried. Even if the focal jerking can not be completely prevented, the antiepileptics have a vital role in preventing secondary generalization. There are no large series that can provide reliable information as to which drugs are required. In the chronic phase, the jerking may not respond to AED therapy even in high doses, but again antiepileptics have a role in minimizing symptoms and preventing secondary generalization. Steroids are sometimes given, but their effectiveness is not established, and their role is probably more in suppressing inflammatory etiologies rather than through a specifically antiepileptic action. Intravenous immunoglobulin (IVIG) and plasma exchange are now also recommended, and can be profoundly effective, but again their role is probably more in suppressing inflammatory etiologies rather than through a specifically antiepileptic action. Agreed protocols for treatment (dose, timing, duration) have not been formulated. Surgical therapy, including resective surgery, thalamic stimulation, and also transcranial magnetic stimulation (TMS), has been recommended in individual cases. Again, opinion differs as to its role. It is also suggested that: As the condition is rare and heterogeneous, an RCT is not feasible. In this situation, it is recommended that a European registry is developed with active surveillance in order to develop observational data on treatment outcome. This form of SE usually occurs in the context of severe brain injury as a result of anoxia (for instance after delayed resuscitation following cardiac arrest). The EEG may show periodic lateralized epileptiform discharges (PLEDs) or generalized periodic spiking (GPS), and the management of this is controversial. There are no well conducted randomized studies, and guidance is difficult to give. Options for management include: Anticonvulsant therapy with IV barbiturate, propofol, or other anesthetics to abolish the PLED pattern on the EEG. Cooling—this has been shown to improve outcome. AED therapy to control EEG changes suggesting evolving seizures. It is also recommended that: EEG monitoring is optimal in this situation, but in many centers this is not available. Intermittent EEG monitoring is a good alternative, but the use of a cerebral function monitor is not recommended. EEGs can be read online off-site if there are no available neurophysiologists. There is a tendency for anesthetic decisions not to account for neurological factors, to the detriment of patients and neurologists. Therefore, neurologists, as well as intensivists should be involved in the management of this and other forms of SE. Kadriye Agan; Berrin Aktekin; Ghassan Al-Hourani; Sumantoke Bagchi; Michel Baulac; Carla Bentes; Ketil Berg Olsen; Thomas Bleck; Frank Boesebeck; Francis Bolgert; Paul Bouma; Eylert Brodtkorb; Lai Choo Ong; Hannah Cock; Helen Cross; Sophie Demeret; Marita Englund; Kai Eriksson; Martha Feucht; Tangunu Fosi; Candan Gurses; Yvette Geerts; Deepak Gill; Jesper Gyllenborg; Edda Haberlandt; Georg Hagemann; Dimitri Hemelsoet; Hans Hoegenhaven; Olli Hõpplõ; Heike Juch; Mikko Kallela; Reetta Kalviainen; Peter Kaplan; Marija Knezevic Pogancev; Kristina Kullen; Sam Lhatoo; Alexandra Liava; Atle Lilleboe; Chiening Lo; Dora Lozsadi; Kristina Malmgren; Johannes Mathis; Hartmut Meierkord; Helene Meinild; Walter Merella; Gabriel Moddel; Lina Nashef; Vincent Navarro; Tomas Nezadal; Astrid Nustad; Cigdem Ozkara; Gerald Pahs; Birthe Pedersen; Emilio Perucca; Jose Pimentel; Tilman Polster; Alessandro Pozzero; Alexander Reinshagen; Konrad Rejdak; Willy Renier; Felix Rosenow; Andrea Rossetti; Stephan Ruegg; Kurt Schlachter; Friedhelm Schmitt; Frans Scholtes; Andreas Schulze-Bonhage; Simon Shorvon; Seppo Soinila; Vovo Szepielow; Inga Talvik; Somsak Tiamkao; Eugen Trinka; Assuncao Tuna; Gerard Van der Linden; Federico Vigevano; Philipp von Rosenstiel; Matthew Walker; Elizabeth Waterhouse; Peter Wolf; Tahir Yoldas. Conflict of interest: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. None of the authors has any conflicts of interest to disclose.
Referência(s)