今日の臨床サポート

痙攣重積発作

著者: 柴田 護 東京歯科大学市川総合病院神経内科

監修: 永山正雄 国際医療福祉大学大学院医学研究科 脳神経内科学

著者校正済:2021/09/22
現在監修レビュー中
参考ガイドライン:
  1. 日本神経学会:てんかん診療ガイドライン2018
  1. 一般社団法人 日本蘇生協議会:JRC蘇生ガイドライン2020
患者向け説明資料

概要・推奨   

  1. 低酸素血症(SaO2<90%)、10分以上持続する痙攣発作を認める際は気道確保を行うことが推奨される(推奨度1)。
  1. 全身痙攣が持続あるいは反復している例、眼前ですでに全身痙攣している例をみた場合は全身痙攣重積状態(GCSE)と考え、ただちに呼吸・循環管理、抗てんかん薬投与、原因精査を行うことが推奨される(推奨度1O)。
  1. 全身痙攣重積状態に対する第1選択薬として、日本ではジアゼパム(セルシン)静注が強く推奨される。呼吸抑制、血圧低下に注意しつつ、通常5~10mgを2分以上かけて投与することが推奨され、必要に応じて3〜4時間ごとに計20mgまで反復することが可能である(推奨度1S)。
  1. 全身痙攣重積状態に対して、ジアゼパム(セルシン)投与5~10分後にホスフェニトイン(ホストイン)静注 (22.5 mg/kg, 150 mg/分以下)あるいはフェノバルビタール(ノーベルバール)静注(15~20 mg/kg, 100 mg/分以下)を併用することが推奨される(推奨度1S)。ホスフェニトインはフェニトインの副作用を軽減する目的で開発され、フェニトインと無作為試験で有効性に差は確認されなかった。レベチラセタム(イーケプラ)静注(1000~3000 mg, 2~5mg/kg/分)はホスフェニトインとフェノバルビタールと同等の効果を示す[1]
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要とな
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧には
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。
  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となりま
薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
柴田 護 : 講演料(日本イーライリリー)[2021年]
監修:永山正雄 : 未申告[2021年]

  1. 痙攣重積発作の治療法や管理法の大枠に変化はないが、近年レベチラセタム静注の有効性が示されている。ただし、わが国ではレベチラセタム静注は「てんかん重積状態」に対して承認されていない。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. Neurocritical Care Societyの定義(2012)によれば、てんかん重積発作(status epilepticus、SE)は「発作が5分以上続くか、または、短い発作でも反復し、その間の意識の回復のないもの」とされる。超難治性痙攣重積状態(superrefractory status epilepticus)とは「全身麻酔開始後24時間以上続く、または繰り返すてんかん重積状態を指し、麻酔の減量、または中止に伴っててんかん重積状態が再発する状態も含む」と定義されている[2]
  1. これまで、持続時間については30分とすることが多かった。しかし持続時間を「治療を開始すべき時間」として短い持続時間を設定している報告も多く、一定の見解はない。
病歴・診察のポイント  
病歴のポイント:
  1. 主に家族などの発作目撃者から病歴や発作状況を確認する。

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文献 

著者: Yuyi Feng, Yueyue Chen, Yaqin Jia, Zhe Wang, Xiaoyu Wang, Lili Jiang, Chunzhi Ai, Wei Li, Yong Liu
雑誌名: Seizure. 2021 Jul 13;91:339-345. doi: 10.1016/j.seizure.2021.07.012. Epub 2021 Jul 13.
Abstract/Text OBJECTIVES: To assess the efficiency and safety profiles of levetiracetam and (fos)phenytoin (phenytoin or fosphenytoin) for second-line treatment of seizures by performing a meta-analysis of RCTs.
METHODS: We systematically searched PubMed, Embase, Cochrane, FDA.gov, and ClinicalTrials.gov for RCTs (published before July 31, 2020; no language restrictions). Two independent reviewers screened abstracts and titles against inclusion and exclusion criteria published previously in the PROSPERO: CRD42020202736. Eleven studies fulfilled the established criteria. We assessed pooled data by using a random-effects model. Quality analysis was performed by using version 2 of the Cochrane risk-of-bias tool (RoB 2). RevMan v.5.3 was used to perform statistical analyses, and publication bias (egger's test) was assessed with Stata MP v.14.0.
RESULTS: Levetiracetam was similar to (fos)phenytoin in seizure termination rate (risk ratio [RR] 0.94; 95% CI 0.87 to 1.01), time of seizure termination (mean difference [MD] 0.44; -0.60 to 1.49), and drug resistance ([RR] 1.12, 0.86 to 1.45). The safety outcome showed a significant statistical difference between fosphenytoin group and levetiracetam group ([RR] 1.44, 1.14 to 1.81), while there was no significant difference observed between phenytoin treatment and levetiracetam treatment ([RR] 1.26, 0.99 to 1.60).
CONCLUSION: Levetiracetam was similar to (fos)phenytoin in cessation rate convulsive status epilepticus, and drug resistance, while it was superior (fos)phenytoin in pooled safety outcome. Further exploration is still needed as to whether it is the first choice for second-line drugs.

Copyright © 2021 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
PMID 34284302  Seizure. 2021 Jul 13;91:339-345. doi: 10.1016/j.seizure・・・
著者: Simon Shorvon, Monica Ferlisi
雑誌名: Brain. 2011 Oct;134(Pt 10):2802-18. doi: 10.1093/brain/awr215. Epub 2011 Sep 13.
Abstract/Text Super-refractory status epilepticus is defined as status epilepticus that continues or recurs 24 h or more after the onset of anaesthetic therapy, including those cases where status epilepticus recurs on the reduction or withdrawal of anaesthesia. It is an uncommon but important clinical problem with high mortality and morbidity rates. This article reviews the treatment approaches. There are no controlled or randomized studies, and so therapy has to be based on clinical reports and opinion. The published world literature on the following treatments was critically evaluated: anaesthetic agents, anti-epileptic drugs, magnesium infusion, pyridoxine, steroids and immunotherapy, ketogenic diet, hypothermia, emergency resective neurosurgery and multiple subpial transection, transcranial magnetic stimulation, vagal nerve stimulation, deep brain stimulation, electroconvulsive therapy, drainage of the cerebrospinal fluid and other older drug therapies. The importance of treating the identifying cause is stressed. A protocol and flowchart for managing super-refractory status epilepticus is suggested. In view of the small number of published reports, there is an urgent need for the establishment of a database of outcomes of individual therapies.

PMID 21914716  Brain. 2011 Oct;134(Pt 10):2802-18. doi: 10.1093/brain/・・・
著者: P Gelisse, P Thomas, N Engrand, V Navarro, A Crespel
雑誌名: Rev Neurol (Paris). 2009 Apr;165(4):398-403. doi: 10.1016/j.neurol.2009.01.032. Epub 2009 Mar 10.
Abstract/Text Electroencephalography is a useful tool in the diagnosis and management of status epilepticus (SE) and it can also give prognostic information. It can help to confirm that an episode of SE has ended. It can identify the patients who have unsuspected subclinical seizures. There is a wide range of presentations of SE. Nearly all types of seizures have the potential of occurring in a repeated or continuous form. The polymorphic EEG patterns in SE reflect this wide variety. But controversial patterns also exist in the form of periodic epileptiform discharges. While some authors considered these patterns to be interictal or postictal, others postulate that these patterns are ictal. In these cases, clinical features are very important in order to conclude. Generalized convulsive SE is a medical emergency and the EEG is not necessary to make a diagnosis. Convulsive generalized SE requires immediate treatment and in this case, EEG is used in guiding treatment especially in refractory SE that may evolve into subtle SE. In non-convulsive SE, diagnosis is not obvious on the basis of clinical signs and symptoms alone and the diagnosis must be confirmed by urgent EEG. EEG can also be used to distinguish SE from psychogenic seizures, movement disorders and in patients who have causes of persistent loss of consciousness (metabolic encephalopathy, postanoxic encephalopathy). This article proposes a protocol for the use of the EEG in SE, guidelines and simple vocabulary for a good interpretation and comprehension of the EEG.

PMID 19278701  Rev Neurol (Paris). 2009 Apr;165(4):398-403. doi: 10.10・・・
著者: R Jaitly, J A Sgro, A R Towne, D Ko, R J DeLorenzo
雑誌名: J Clin Neurophysiol. 1997 Jul;14(4):326-34.
Abstract/Text Despite the significant morbidity and mortality associated with status epilepticus (SE), little is known about changes in cortical function that occur after SE. We evaluated cortical function after clinical SE using continuous EEG monitoring lasting at least 24 h in 180 patients admitted to the Medical College of Virginia Hospitals (MCVH). The major EEG patterns observed after SE were a normal record, burst suppression, after SE ictal discharge (ASIDs), periodic lateralizing epileptiform discharges (PLEDs), attenuation, focal and generalized slowing, and epileptiform discharges. Normalization of the EEG after SE was highly correlated with good outcome. The presence of burst suppression and ASIDs was highly statistically significantly associated with mortality. PLEDs were also highly correlated with mortality, but not to the same degree as burst suppression and ASIDs. In addition, these EEG patterns were still significantly correlated with morbidity and mortality when we controlled for etiology using multivariate logistic statistical analysis. Persistent ictal activity was observed in many patients despite control of clinical seizure activity, indicating the importance of EEG monitoring to determine treatment patterns after clinical seizure activity in SE is controlled. The results indicate that certain EEG patterns (normalization of the EEG, ASIDs, burst suppression and PLEDs) are useful predictors of outcome in SE in addition to etiology. EEG monitoring after control of clinical SE is important to guide treatment of SE and is a useful technique for evaluating prognosis.

PMID 9337142  J Clin Neurophysiol. 1997 Jul;14(4):326-34.
著者: Aidan Neligan, Simon D Shorvon
雑誌名: Arch Neurol. 2010 Aug;67(8):931-40. doi: 10.1001/archneurol.2010.169.
Abstract/Text We conducted a systematic review of all studies of status epilepticus (SE) with more than 30 patients published between January 1, 1990, and December 31, 2008, to determine the frequencies of the common underlying causes and the extent to which the underlying causes affect the prognosis of an episode of SE. The frequencies of underlying causes vary among studies and show marked geographic differences, but in most studies, the most common underlying causes were cerebrovascular disease and low antiepileptic drug levels. A relatively good prognosis of SE is found when the underlying cause is associated with low antiepileptic drug levels or alcohol abuse, and a relatively poor outcome occurs when the underlying cause is cerebrovascular disease, particularly in the case of SE due to acute cerebral anoxia, but in most conditions, the reported prognosis is variable. Also, when SE occurs in the context of an acute cerebral insult, such as cerebral infection or cerebrovascular disease, the prognosis of the acute cerebral event is worsened.

PMID 20697043  Arch Neurol. 2010 Aug;67(8):931-40. doi: 10.1001/archne・・・
著者: Mohamad Koubeissi, Amer Alshekhlee
雑誌名: Neurology. 2007 Aug 28;69(9):886-93. doi: 10.1212/01.wnl.0000269791.96189.70.
Abstract/Text OBJECTIVE: To evaluate the in-hospital mortality associated with generalized convulsive status epilepticus (GCSE), and predictors of death in a large US cohort.
METHODS: We identified our cohort from the National Inpatient Sample for the years 2000 through 2004 by searching the International Classification of Diseases, Ninth Revision, code for GCSE. We excluded patients with partial status epilepticus, and assessed whether associated diagnoses including brain tumors, CNS infections, stroke, hypoxic-ischemic brain injury, metabolic derangements, and respiratory failure predicted mortality. We used logistic regression models to identify predictors of death.
RESULTS: Eleven thousand five hundred eighty patients were included in this analysis. The mean age of the patients was 39 +/- 25.6 years, and the median duration of stay was 3 days. Male sex (53.4%) and white race (42.4%) were predominant. Overall in-hospital mortality was 399 in 11,580 (3.45%). Age was a significant predictor of death. Mortality tripled in those who received mechanical ventilation compared with those who did not (7.43% vs 2.22%, odds ratio [OR] 2.79, 95% CI 2.18 to 3.59). Other predictors of mortality included hypoxic-ischemic brain injury (OR 9.85, 95% CI 6.63 to 14.6), cerebrovascular diseases (OR 2.08, 95% CI 1.13 to 3.82), female sex (OR 1.34, 95% CI 1.04 to 1.73), and higher comorbidity index (OR 6.79, 95% CI 4.27 to 10.8).
CONCLUSION: Overall in-hospital mortality from generalized convulsive status epilepticus is low, but remarkably increases in those treated with mechanical ventilation. Other predictors of mortality include older age, female sex, hypoxic-ischemic brain injury, and higher comorbidity index.

PMID 17724291  Neurology. 2007 Aug 28;69(9):886-93. doi: 10.1212/01.wn・・・
著者: N B Fountain
雑誌名: Epilepsia. 2000;41 Suppl 2:S23-30.
Abstract/Text Status epilepticus is common and associated with significant mortality and complications. It affects approximately 50 patients per 100,000 population annually and recurs in >13%. History of epilepsy is the strongest single risk factor for generalized convulsive status epilepticus. More than 15% of patients with epilepsy have at least one episode of status epilepticus and low antiepileptic drug levels are a potentially modifiable risk factor. Other risks include young age, genetic predisposition, and acquired brain insults. Fever is a very common risk in children, as is stroke in adults. Mortality rates are 15% to 20% in adults and 3% to 15% in children. Acute complications result from hyperthermia, pulmonary edema, cardiac arrhythmias, and cardiovascular collapse. Long-term complications include epilepsy (20% to 40%), encephalopathy (6% to 15%), and focal neurologic deficits (9% to 11%). Neuronal injury leading to temporal lobe epilepsy is probably mediated by excess excitation via activation of the N-methyl-D-aspartate (NMDA) subtype of glutamate receptors and consequent elevated intracellular calcium that causes acute necrosis and delayed apoptotic cell death. Some forms of nonconvulsive status epilepticus may also lead to neuronal injury by this mechanism, but others may not. Based on clinical and experimental observations, complex partial status epilepticus is more likely to result in neuronal injury similar to generalized convulsive status epilepticus. Absence status epilepticus is much less likely to result in neuronal injury, and complications because it may be mediated primarily through excess inhibition. Future research strategies to prevent complications of status epilepticus include the study of new drugs (including NMDA antagonists, new drug delivery systems, and drug combinations) to stop seizure activity and prevent acute and delayed neuronal injury that leads to the development of epilepsy.

PMID 10885737  Epilepsia. 2000;41 Suppl 2:S23-30.
著者: Jan Claassen, Lawrence J Hirsch, Ronald G Emerson, Stephan A Mayer
雑誌名: Epilepsia. 2002 Feb;43(2):146-53.
Abstract/Text BACKGROUND: New continuous infusion antiepileptic drugs (cIV-AEDs) offer alternatives to pentobarbital for the treatment of refractory status epilepticus (RSE). However, no prospective randomized studies have evaluated the treatment of RSE. This systematic review compares the efficacy of midazolam (MDL), propofol (PRO), and pentobarbital (PTB) for terminating seizures and improving outcome in RSE patients.
METHODS: We performed a literature search of studies describing the use of MDL, PRO, or PTB for the treatment of RSE published between January 1970 and September 2001, by using MEDLINE, OVID, and manually searched bibliographies. We included peer-reviewed studies of adult patients with SE refractory to at least two standard AEDs. Main outcome measures were the frequency of immediate treatment failure (clinical or electrographic seizures occurring 1 to 6 h after starting cIV-AED therapy) and mortality according to choice of agent and titration goal (cIV-AED titration to "seizure suppression" versus "EEG background suppression").
RESULTS: Twenty-eight studies describing a total of 193 patients fulfilled our selection criteria: MDL (n = 54), PRO (n = 33), and PTB (n = 106). Forty-eight percent of patients died, and mortality was not significantly associated with the choice of agent or titration goal. PTB was usually titrated to EEG background suppression by using intermittent EEG monitoring, whereas MDL and PRO were more often titrated to seizure suppression with continuous EEG monitoring. Compared with treatment with MDL or PRO, PTB treatment was associated with a lower frequency of short-term treatment failure (8 vs. 23%; p < 0.01), breakthrough seizures (12 vs. 42%; p < 0.001), and changes to a different cIV-AED (3 vs. 21%; p < 0.001), and a higher frequency of hypotension (systolic blood pressure <100 mm Hg; 77 vs. 34%; p < 0.001). Compared with seizure suppression (n = 59), titration of treatment to EEG background suppression (n = 87) was associated with a lower frequency of breakthrough seizures (4 vs. 53%; p < 0.001) and a higher frequency of hypotension (76 vs. 29%; p < 0.001).
CONCLUSIONS: Despite the inherent limitations of a systematic review, our results suggest that treatment with PTB, or any cIV-AED infusion to attain EEG background suppression, may be more effective than other strategies for treating RSE. However, these interventions also were associated with an increased frequency of hypotension, and no effect on mortality was seen. A prospective randomized trial comparing different agents and titration goals for RSE with obligatory continuous EEG monitoring is needed.

PMID 11903460  Epilepsia. 2002 Feb;43(2):146-53.
著者: R D Kilbride, A S Reynolds, J P Szaflarski, L J Hirsch
雑誌名: Neurocrit Care. 2013 Jun;18(3):374-85. doi: 10.1007/s12028-013-9823-4.
Abstract/Text BACKGROUND: To define the clinical profile and outcome of patients in prolonged refractory status epilepticus (PRSE), and investigate possible predictors of outcome.
METHODS: We reviewed 63 consecutive patients with PRSE cared for in the medical and neurointensive care units of three academic medical centers over a 9-year period. For this multi-center retrospective cohort study, PRSE was defined as SE that persisted despite at least 1 week of induced coma. Variables examined for their relationship to outcome included etiology, EEG, neuroimaging, and age.
RESULTS: Forty-two (66%) of 63 patients in PRSE survived to discharge from hospitalization. Fourteen (22%) patients had a good outcome (mRS ≤ 3) at last available follow up (at least 6 months post-PRSE). Of these, 6 (10%) individuals had no significant disability and were able to carry out all usual activities (mRS = 1). Normal neuroimaging and a reactive EEG at onset of PRSE were associated with good outcome. Good or excellent clinical outcomes were possible in patients in PRSE for up to 79 days, and in patients up to 69 years old.
CONCLUSIONS: Good outcome is not unusual in PRSE, including in some older patients, in a variety of diagnoses, and despite months of coma.

PMID 23479069  Neurocrit Care. 2013 Jun;18(3):374-85. doi: 10.1007/s12・・・
著者: B K Alldredge, A M Gelb, S M Isaacs, M D Corry, F Allen, S Ulrich, M D Gottwald, N O'Neil, J M Neuhaus, M R Segal, D H Lowenstein
雑誌名: N Engl J Med. 2001 Aug 30;345(9):631-7. doi: 10.1056/NEJMoa002141.
Abstract/Text BACKGROUND: It is uncertain whether the administration of benzodiazepines by paramedics is an effective and safe treatment for out-of-hospital status epilepticus.
METHODS: We conducted a randomized, double-blind trial to evaluate intravenous benzodiazepines administered by paramedics for the treatment of out-of-hospital status epilepticus. Adults with prolonged (lasting five minutes or more) or repetitive generalized convulsive seizures received intravenous diazepam (5 mg), lorazepam (2 mg), or placebo. An identical second injection was given if needed.
RESULTS: Of the 205 patients enrolled, 66 received lorazepam, 68 received diazepam, and 71 received placebo. Status epilepticus had been terminated on arrival at the emergency department in more patients treated with lorazepam (59.1 percent) or diazepam (42.6 percent) than patients given placebo (21.1 percent) (P=0.001). After adjustment for covariates, the odds ratio for termination of status epilepticus by the time of arrival in the lorazepam group as compared with the placebo group was 4.8 (95 percent confidence interval, 1.9 to 13.0). The odds ratio was 1.9 (95 percent confidence interval, 0.8 to 4.4) in the lorazepam group as compared with the diazepam group and 2.3 (95 percent confidence interval, 1.0 to 5.9) in the diazepam group as compared with the placebo group. The rates of respiratory or circulatory complications (indicated by bag valve-mask ventilation or an attempt at intubation, hypotension, or cardiac dysrhythmia) after the study treatment was administered were 10.6 percent for the lorazepam group, 10.3 percent for the diazepam group, and 22.5 percent for the placebo group (P=0.08).
CONCLUSIONS: Benzodiazepines are safe and effective when administered by paramedics for out-of-hospital status epilepticus in adults. Lorazepam is likely to be a better therapy than diazepam.

PMID 11547716  N Engl J Med. 2001 Aug 30;345(9):631-7. doi: 10.1056/NE・・・
著者: I E Leppik, A T Derivan, R W Homan, J Walker, R E Ramsay, B Patrick
雑誌名: JAMA. 1983 Mar 18;249(11):1452-4.
Abstract/Text Lorazepam was compared with diazepam for the treatment of status epilepticus in a double-blind, randomized trial. Seventy-eight patients with 81 episodes were enrolled. Patients received one or two doses of either 4 mg of lorazepam or 10 mg of diazepam intravenously. Seizures were controlled in 89% of the episodes treated with lorazepam and in 76% treated with diazepam. The times for onset of action of the medications did not differ significantly. Adverse effects occurred in 13% of the lorazepam-treated patients and in 12% of the diazepam-treated patients. Respiratory depression and arrest, the most frequent adverse effects, were treated symptomatically; no adverse sequelae were noted.

PMID 6131148  JAMA. 1983 Mar 18;249(11):1452-4.
著者: Simon Shorvon, Michel Baulac, Helen Cross, Eugen Trinka, Matthew Walker, TaskForce on Status Epilepticus of the ILAE Commission for European Affairs
雑誌名: Epilepsia. 2008 Jul;49(7):1277-85. doi: 10.1111/j.1528-1167.2008.01706_3.x.
Abstract/Text
PMID 18638280  Epilepsia. 2008 Jul;49(7):1277-85. doi: 10.1111/j.1528-・・・
著者: Iván Sánchez Fernández, Tobias Loddenkemper
雑誌名: Expert Opin Pharmacother. 2015 Mar;16(4):487-500. doi: 10.1517/14656566.2015.997212. Epub 2015 Jan 27.
Abstract/Text INTRODUCTION: Convulsive status epilepticus (SE) is one of the most frequent and severe neurological emergencies in both adults and children. A timely administration of appropriate antiepileptic drugs (AEDs) can stop seizures early and markedly improve outcome.
AREAS COVERED: The main treatment strategies for SE are reviewed with an emphasis on initial treatments. The established first-line treatment consists of benzodiazepines, most frequently intravenous lorazepam. Benzodiazepines that do not require intravenous administration like intranasal midazolam or intramuscular midazolam are becoming more popular because of easier administration in the field. Other benzodiazepines may also be effective. After treatment with benzodiazepines, treatment with fosphenytoin and phenobarbital is usually recommended. Other intravenously available AEDs, such as valproate and levetiracetam, may be as effective and safe as fosphenytoin and phenobarbital, have a faster infusion time and better pharmacokinetic profile. The rationale behind the need for an early treatment of SE is discussed. The real-time delays of AED administration in clinical practice are described.
EXPERT OPINION: There is limited evidence to support what the best initial benzodiazepine or the best non-benzodiazepine AED is. Recent and developing multicenter trials are evaluating the best treatment options and will likely modify the recommended treatment choices in SE in the near future. Additionally, more research is needed to understand how different treatment options modify prognosis in SE. Timely implementation of care protocols to minimize treatment delays is crucial.

PMID 25626010  Expert Opin Pharmacother. 2015 Mar;16(4):487-500. doi: ・・・
著者: Cynthia Harden, Torbjörn Tomson, David Gloss, Jeffrey Buchhalter, J Helen Cross, Elizabeth Donner, Jacqueline A French, Anthony Gil-Nagel, Dale C Hesdorffer, W Henry Smithson, Mark C Spitz, Thaddeus S Walczak, Josemir W Sander, Philippe Ryvlin
雑誌名: Neurology. 2017 Apr 25;88(17):1674-1680. doi: 10.1212/WNL.0000000000003685.
Abstract/Text OBJECTIVE: To determine the incidence rates of sudden unexpected death in epilepsy (SUDEP) in different epilepsy populations and address the question of whether risk factors for SUDEP have been identified.
METHODS: Systematic review of evidence; modified Grading Recommendations Assessment, Development, and Evaluation process for developing conclusions; recommendations developed by consensus.
RESULTS: Findings for incidence rates based on 12 Class I studies include the following: SUDEP risk in children with epilepsy (aged 0-17 years) is 0.22/1,000 patient-years (95% confidence interval [CI] 0.16-0.31) (moderate confidence in evidence). SUDEP risk increases in adults to 1.2/1,000 patient-years (95% CI 0.64-2.32) (low confidence in evidence). The major risk factor for SUDEP is the occurrence of generalized tonic-clonic seizures (GTCS); the SUDEP risk increases in association with increasing frequency of GTCS occurrence (high confidence in evidence).
RECOMMENDATIONS: Level B: Clinicians caring for young children with epilepsy should inform parents/guardians that in 1 year, SUDEP typically affects 1 in 4,500 children; therefore, 4,499 of 4,500 children will not be affected. Clinicians should inform adult patients with epilepsy that SUDEP typically affects 1 in 1,000 adults with epilepsy per year; therefore, annually 999 of 1,000 adults will not be affected. For persons with epilepsy who continue to experience GTCS, clinicians should continue to actively manage epilepsy therapies to reduce seizures and SUDEP risk while incorporating patient preferences and weighing the risks and benefits of any new approach. Clinicians should inform persons with epilepsy that seizure freedom, particularly freedom from GTCS, is strongly associated with decreased SUDEP risk.

© 2017 American Academy of Neurology.
PMID 28438841  Neurology. 2017 Apr 25;88(17):1674-1680. doi: 10.1212/W・・・
著者: K Prasad, K Al-Roomi, P R Krishnan, R Sequeira
雑誌名: Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003723. doi: 10.1002/14651858.CD003723.pub2. Epub 2005 Oct 19.
Abstract/Text BACKGROUND: Status epilepticus is a medical emergency associated with significant mortality and morbidity, which requires immediate and effective treatment.
OBJECTIVES: (1) To determine whether a particular anticonvulsant is more effective or safer to use in status epilepticus compared to another and compared to placebo.(2) To delineate reasons for disagreement in the literature regarding recommended treatment regimens and to highlight areas for future research.
SEARCH STRATEGY: We searched the following electronic databases using the highly sensitive search strategy for identifying published randomised controlled trials: (1) Cochrane Epilepsy Group Specialized Register (July 2005); (2) Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 2,2005); (3) MEDLINE (1966 - August 2004); (4) EMBASE (1966 - January 2003).
SELECTION CRITERIA: Randomised controlled trials of participants with premonitory, early, established or refractory status epilepticus using a truly random or quasi-random allocation of treatments were included.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed trial quality and extracted data.
MAIN RESULTS: Eleven studies with 2017 participants were included. Few studies used the same interventions. Diazepam was better than placebo in reducing the risk of non-cessation of seizures (RR 0.73, 95% CI 0.57 to 0.92), requirement for ventilatory support (RR 0.39, 95% CI 0.16 to 0.94) or continuation of status epilepticus requiring use of a different drug or general anaesthesia (RR 0.73, 95% CI 0.57 to 0.92). Lorazepam was better than placebo for risk of non-cessation of seizures (RR 0.52, 95% CI 0.38 to 0.71) and for risk of continuation of status epilepticus requiring a different drug or general anaesthesia (RR 0.52, 95% CI 0.38 to 0.71). Lorazepam was better than diazepam for reducing risk of non-cessation of seizures (RR 0.64, 95% CI 0.45 to 0.90) and had a lower risk for continuation of status epilepticus requiring a different drug or general anaesthesia (RR 0.63, 95% CI 0.45 to 0.88). Lorazepam was better than phenytoin for risk of non-cessation of seizures (RR 0.62, 95% CI 0.45 to 0.86). Diazepam (30 mg intrarectal gel) was better than a lower dose (20 mg intrarectal gel) in premonitory status epilepticus for the risk of seizure continuation (RR 0.39, 95% CI 0.18 to 0.86).
AUTHORS' CONCLUSIONS: Lorazepam is better than diazepam or phenytoin alone for cessation of seizures and carries a lower risk of continuation of status epilepticus requiring a different drug or general anaesthesia. Both lorazepam and diazepam are better than placebo for the same outcomes. In the treatment of premonitory seizures, diazepam 30 mg in an intrarectal gel is better than 20 mg for cessation of seizures without a statistically significant increase in adverse effects. Universally accepted definitions of premonitory, early, established and refractory status epilepticus are required.

PMID 16235337  Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003723. d・・・
著者: Kameshwar Prasad, Pudukode R Krishnan, Khaldoon Al-Roomi, Reginald Sequeira
雑誌名: Br J Clin Pharmacol. 2007 Jun;63(6):640-7. doi: 10.1111/j.1365-2125.2007.02931.x. Epub 2007 Apr 18.
Abstract/Text AIMS: To determine whether a particular anticonvulsant is more effective or safer than another or placebo in patients with status epilepticus, and to summarize the available evidence from randomized controlled trials, and to highlight areas for future research in status epilepticus.
METHODS: Randomized controlled trials of participants with premonitory, early, established or refractory status epilepticus using a truly random or quasi-random allocation of treatments were included.
RESULTS: Eleven studies with 2017 participants met the inclusion criteria. Lorazepam was better than diazepam for reducing risk of seizure continuation [relative risk (RR) 0.64, 95% confidence interval (CI) 0.45, 0.90] and of requirement of a different drug or general anaesthesia (RR 0.63, 95% CI 0.45, 0.88) with no statistically significant difference in the risk of adverse effects. Lorazepam was better than phenytoin for risk of seizure continuation (RR 0.62, 95% CI 0.45, 0.86). Diazepam 30 mg intrarectal gel was better than 20 mg in premonitory status epilepticus for the risk of seizure continuation (RR 0.39, 95% CI 0.18, 0.86).
CONCLUSIONS: Lorazepam is better than diazepam or phenytoin alone for cessation of seizures and carries a lower risk of continuation of status epilepticus requiring a different drug or general anaesthesia. Both lorazepam and diazepam are better than placebo for the same outcomes. In the treatment of premonitory seizures, diazepam 30 mg intrarectal gel is better than 20 mg for cessation of seizures without a statistically significant increase in adverse effects. Universally accepted definitions of premonitory, early, established and refractory status epilepticus are required.

PMID 17439538  Br J Clin Pharmacol. 2007 Jun;63(6):640-7. doi: 10.1111・・・
著者: D M Treiman, P D Meyers, N Y Walton, J F Collins, C Colling, A J Rowan, A Handforth, E Faught, V P Calabrese, B M Uthman, R E Ramsay, M B Mamdani
雑誌名: N Engl J Med. 1998 Sep 17;339(12):792-8. doi: 10.1056/NEJM199809173391202.
Abstract/Text BACKGROUND AND METHODS: Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. We conducted a five-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg per kilogram of body weight) followed by phenytoin (18 mg per kilogram), lorazepam (0.1 mg per kilogram), phenobarbital (15 mg per kilogram), and phenytoin (18 mg per kilogram). Patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicated by coma and ictal discharges on the electroencephalogram, with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after the beginning of the drug infusion and there was no return of seizure activity during the next 40 minutes. Analyses were performed with data on only the 518 patients with verified generalized convulsive status epilepticus as well as with data on all 570 patients who were enrolled.
RESULTS: Three hundred eighty-four patients had a verified diagnosis of overt generalized convulsive status epilepticus. In this group, lorazepam was successful in 64.9 percent of those assigned to receive it, phenobarbital in 58.2 percent, diazepam plus phenytoin in 55.8 percent, and phenytoin in 43.6 percent (P=0.02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (P=0.002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7 to 24.2 percent). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (P=0.12) or among those with subtle status epilepticus (P=0.91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days.
CONCLUSIONS: As initial intravenous treatment for overt generalized convulsive status epilepticus, lorazepam is more effective than phenytoin. Although lorazepam is no more efficacious than phenobarbital or diazepam plus phenytoin, it is easier to use.

PMID 9738086  N Engl J Med. 1998 Sep 17;339(12):792-8. doi: 10.1056/N・・・
著者: Lelia Duley, David J Henderson-Smart, Godfrey Ja Walker, Doris Chou
雑誌名: Cochrane Database Syst Rev. 2010 Dec 8;(12):CD000127. doi: 10.1002/14651858.CD000127.pub2. Epub 2010 Dec 8.
Abstract/Text BACKGROUND: Eclampsia, the occurrence of a seizure in association with pre-eclampsia, remains a rare but serious complication of pregnancy. A number of different anticonvulsants are used to control eclamptic fits and to prevent further fits.
OBJECTIVES: The objective of this review was to assess the effects of magnesium sulphate compared with diazepam when used for the care of women with eclampsia. Magnesium sulphate is compared with phenytoin and with lytic cocktail in other Cochrane reviews.
SEARCH STRATEGY: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 September 2010) and CENTRAL (2010, Issue 3).
SELECTION CRITERIA: Randomised trials comparing magnesium sulphate (intravenous or intramuscular administration) with diazepam for women with a clinical diagnosis of eclampsia.
DATA COLLECTION AND ANALYSIS: Two authors assessed and extracted data independently.
MAIN RESULTS: We have included seven trials, involving 1396 women. Three trials (1030 women) were good quality. Magnesium sulphate was associated with a reduction in maternal death (seven trials;1396 women; risk ratio (RR) 0.59, 95% confidence interval (CI) 0.38 to 0.92) and recurrence of seizures (seven trials;1390 women; RR 0.43, 95% CI 0.33 to 0.55) compared to diazepam. There were no clear differences in other measures of maternal morbidity.There was no clear difference in perinatal mortality (four trials; 788 infants; RR 1.04, 95% CI 0.81 to 1.34) or neonatal mortality (four trials; 759 infants; RR 1.18, 95% CI 0.75 to 1.84). In the magnesium sulphate group, fewer liveborn babies had an Apgar score less than seven at one minute (two trials; 597 babies; RR 0.75, 95% CI 0.65 to 0.87) or at five minutes (RR 0.70, 95% CI 0.54 to 0.90), and fewer appeared to need intubation at the place of birth (two trials; 591 infants; RR 0.67, 95% CI 0.45 to 1.00). There was no difference in admission to a special care nursery (four trials; 834 infants; RR 0.91, 95% CI 0.79 to 1.05), but fewer babies in the magnesium sulphate group had a length of stay more than seven days (three trials 631 babies; RR 0.66, 95% CI 0.46 to 0.96).
AUTHORS' CONCLUSIONS: Magnesium sulphate for women with eclampsia reduces the risk ratio of maternal death and of recurrence of seizures, compared with diazepam.

PMID 21154341  Cochrane Database Syst Rev. 2010 Dec 8;(12):CD000127. d・・・
著者:
雑誌名: JAMA. 1993 Aug 18;270(7):854-9.
Abstract/Text Convulsive status epilepticus is an emergency that is associated with high morbidity and mortality. The outcome largely depends on etiology, but prompt and appropriate pharmacological therapy can reduce morbidity and mortality. Etiology varies in children and adults and reflects the distribution of disease in these age groups. Antiepileptic drug administration should be initiated whenever a seizure has lasted 10 minutes. Immediate concerns include supporting respiration, maintaining blood pressure, gaining intravenous access, and identifying and treating the underlying cause. Initial therapeutic and diagnostic measures are conducted simultaneously. The goal of therapy is rapid termination of clinical and electrical seizure activity; the longer a seizure continues, the greater the likelihood of an adverse outcome. Several drug protocols now in use will terminate status epilepticus. Common to all patients is the need for a clear plan, prompt administration of appropriate drugs in adequate doses, and attention to the possibility of apnea, hypoventilation, or other metabolic abnormalities.

PMID 8340986  JAMA. 1993 Aug 18;270(7):854-9.
著者: Jikke-Mien F Niermeijer, Cuno S P M Uiterwaal, Cees A Van Donselaar
雑誌名: J Neurol. 2003 Oct;250(10):1237-40. doi: 10.1007/s00415-003-0180-7.
Abstract/Text INTRODUCTION: Several guidelines recommend the use of propofol for the treatment of refractory status epilepticus. An increased mortality rate in high dose, long-term treatment with propofol in adult patients was published recently. This prompted us to assess the literature on the scientific evidence for the efficacy and safety of propofol in the treatment of refractory status epilepticus.
METHODS: Medline was searched and the three authors independently reviewed all Medline abstracts for selection of papers.
RESULTS: We included 22 articles with original data on the use of propofol in refractory status epilepticus. Randomised clinical trials were lacking. Two non-randomised studies compared propofol with barbiturates and midazolam respectively. Both studies reported a higher risk of mortality for propofol. In addition, case reports and case series on the use of propofol as anaesthetic or sedative in children and adults reported several lethal cases.
CONCLUSIONS: Serious doubts may be raised on the safety of propofol in the treatment of refractory status epilepticus. The two non-randomised studies and several case reports show an increased risk of mortality. Guidelines should not recommend the use of propofol as a routine treatment in refractory status epilepticus before a proper randomised trial has been performed.

PMID 14586609  J Neurol. 2003 Oct;250(10):1237-40. doi: 10.1007/s00415・・・

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