今日の臨床サポート 今日の臨床サポート

著者: 北川一夫 東京女子医科大学医学部脳神経内科

監修: 永山正雄 国際医療福祉大学医学部・成田病院 脳神経内科、集中治療部

著者校正/監修レビュー済:2023/01/11
参考ガイドライン:
  1. 日本脳卒中学会:脳卒中治療ガイドライン2021
患者向け説明資料

改訂のポイント:
  1. 片麻痺を伴う患者を含め脳梗塞超急性期の血栓回収療法のエビデンスが確立し、発症24時間以内の脳主幹動脈閉塞を伴う脳梗塞では、神経画像検査を駆使し適応患者を選別し血栓回収療法を行うことが推奨されるようになった。

概要・推奨   

  1. 片麻痺を数分以上生じた一過性脳虚血発作の患者には、発症数日以内であれば脳MRI検査(拡散強調画像)を24時間以内に施行することが勧められる(推奨度1)
  1. 片麻痺が突然発症し、脳CT検査を施行し脳出血が除外されれば、脳梗塞急性期と判断し発症後4.5時間以内であれば適用基準を遵守して血栓溶解薬(アルテプラーゼ)を投与することが推奨される(推奨度1また発症6時間以内の脳主幹動脈閉塞症例ではアルテプラーゼ静注療法を含む内科治療に追加して機械的血栓回収療法を開始することが推奨される(推奨度1)発症6時間以後の症例で脳主幹動脈閉塞症例では神経徴候と画像診断に基づく治療適応判定を行い16時間以内に血栓回収療法を開始することが勧められる(推奨度1。また16~24時間以内に同療法を開始することは妥当である(推奨度2
  1. 脳卒中の初発症候の半数以上は片麻痺である。片麻痺が突然発症した場合、脳卒中発症を第一に考えて検査、治療を勧めるのが妥当である(推奨度2)
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病態・疫学・診察 

疫学情報・病態・注意事項  
  1. 片麻痺とは、一側性にみられる上下肢の運動麻痺のことである。突然発症する片麻痺は、脳卒中の典型的な症状であり、脳卒中の初発症状の約70%は片麻痺である。
  1. 片麻痺は、錐体路に病変を生ずる疾患でみられる症状であり、脳卒中以外にも炎症性脳疾患、中枢神経感染症、脳腫瘍、脱髄性疾患、頚椎・頚髄疾患でも生じ、原因疾患は多岐にわたる。
  1. 一側上下肢に限局するのか、顔面を含むのか、深部腱反射亢進・低下、病的反射出現の有無、感覚障害、言語障害、視野障害など、他の神経症状、徴候の合併の有無を検索することは、病変の局在を知るうえで重要な手かがりになる。
  1. 突然片麻痺が発症した場合、神経救急疾患、特に脳卒中急性期を念頭に置き、迅速に一般検査、脳画像診断を施行し診断を行い、治療を開始する必要がある。特に脳梗塞発症後4.5時間以内の場合は血栓溶解療法の適応を、発症24時間以内で脳主幹動脈閉塞症例では血栓回収療法の適応を迅速に決定する必要がある。
問診・診察のポイント  
 
 
  1. 片麻痺が突然発症した場合は脳卒中を第一に考える。問診のポイントは、発症様式と筋力低下の部位であり、発症が比較的亜急性に生じた場合は免疫性、腫瘍性、脱髄性脳疾患を念頭に置く。

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文献 

G Leijon, J Boivie
Central post-stroke pain--a controlled trial of amitriptyline and carbamazepine.
Pain. 1989 Jan;36(1):27-36.
Abstract/Text A double-blind, 3-phase, cross-over, placebo-controlled trial of the pain-relieving effect of amitriptyline and carbamazepine was carried out in 15 patients with central post-stroke pain (CPSP) but without signs of depression. Treatment was given, in randomized order, for periods of 4 weeks, separated by 1 week wash-out. The final doses were 75 and 800 mg/day, respectively, for amitriptyline and carbamazepine. The treatment effects were assessed by daily ratings of pain intensity on a 10-step verbal scale and at the end of each treatment period by a global rating of the analgesic effect on a 5-step verbal scale. For the assessment of depression the Comprehensive Psychopathological Rating Scale (CPRS) was used. Amitriptyline produced a statistically significant reduction of pain when compared to placebo. According to the global rating, 10 of the 15 patients were responders to this drug. The effect could already be noticed during the second treatment week and it appeared to be correlated to the plasma concentration, since the median total ami- and nortriptyline concentrations were 497 and 247 nmol/l, respectively, for responders and non-responders. The early onset, together with the fact that the patients were not depressed, nor did they obtain reduced scores on ratings of depressive symptoms and signs, provides strong support for the conclusion that the pain relief was not caused by an antidepressive effect. Five of the 14 patients treated with carbamazepine reported some pain relief, but the effect did not reach statistical significance when compared to placebo. No correlation was found between effect and plasma concentration. In general, the patients tolerated the planned final dose of amitriptyline well. No final dose reduction was necessary. Carbamazepine caused more side effects and the final dose had to be reduced in 4 patients. However, only 1 patient had to be taken off medication, on day 25, due to drug interaction.

PMID 2465530
K Vestergaard, G Andersen, H Gottrup, B T Kristensen, T S Jensen
Lamotrigine for central poststroke pain: a randomized controlled trial.
Neurology. 2001 Jan 23;56(2):184-90.
Abstract/Text OBJECTIVE: Central poststroke pain (CPSP) is usually difficult to treat. Amitriptyline, the only oral preparation shown to be effective in a randomized controlled trial, is often associated with a range of side effects related to the many mechanisms of actions of tricyclic antidepressants. We investigated the effect of lamotrigine, a drug that reduces neuronal hyperexcitability, on poststroke pain.
METHODS: Thirty consecutive patients with CPSP (median age 59 years, range 37 to 77; median pain duration 2.0 years, range 0.3 to 12) from two centers participated in a randomized, double-blind, placebo-controlled cross-over study. The study consisted of two 8-week treatment periods separated by 2 weeks of wash-out. The primary endpoint was the median value of the mean daily pain score during the last week of treatment while treated with 200 mg/d lamotrigine. Secondary endpoints were median pain scores while on lamotrigine 25 mg/d, 50 mg/d, and 100 mg/d; a global pain score; assessment of evoked pain; areas of spontaneous pain; and allodynia/dysesthesia.
RESULTS: Lamotrigine 200 mg/d reduced the median pain score to 5, compared to 7 during placebo (p = 0.01) in the intent-to-treat population of 27 patients. No significant effect was obtained at lower doses. Twelve patients (44%) responded to the treatment. There was a uniform tendency to reduction of all secondary outcome measures, but lamotrigine only had significant effects on some of the secondary outcome measures. Lamotrigine was well tolerated with few and transient side effects. Two mild rashes occurred during lamotrigine treatment, one causing withdrawal from study.
CONCLUSIONS: Oral lamotrigine 200 mg daily is a well tolerated and moderately effective treatment for central poststroke pain. Lamotrigine may be an alternative to tricyclic antidepressants in the treatment of CPSP.

PMID 11160953
P Wiffen, S Collins, H McQuay, D Carroll, A Jadad, A Moore
Anticonvulsant drugs for acute and chronic pain.
Cochrane Database Syst Rev. 2005 Jul 20;(3):CD001133. doi: 10.1002/14651858.CD001133.pub2. Epub 2005 Jul 20.
Abstract/Text BACKGROUND: Anticonvulsant drugs have been used in the management of pain since the 1960s. The clinical impression is that they are useful for chronic neuropathic pain, especially when the pain is lancinating or burning. Readers are referred to reviews of carbamazepine and gabapentin in the Cochrane Library which replace the information on those drugs in this review. Other drugs remain unchanged at present in this review
OBJECTIVES: To evaluate the analgesic effectiveness and adverse effects of anticonvulsant drugs for pain management in clinical practice . Migraine and headache studies are excluded in this revision.
SEARCH STRATEGY: Randomised trials of anticonvulsants in acute, chronic or cancer pain were identified by MEDLINE (1966-1999), EMBASE (1994-1999), SIGLE (1980-1999) and the Cochrane Controlled Trials Register (CENTRAL/CCTR) (Cochrane Library Issue 3, 1999). In addition, 41 medical journals were hand searched. Additional reports were identified from the reference list of the retrieved papers, and by contacting investigators. Date of most recent search: September 1999.
SELECTION CRITERIA: Randomised trials reporting the analgesic effects of anticonvulsant drugs in patients, with subjective pain assessment as either the primary or a secondary outcome.
DATA COLLECTION AND ANALYSIS: Data were extracted by two independent reviewers, and trials were quality scored. Numbers-needed-to-treat (NNTs) were calculated from dichotomous data for effectiveness, adverse effects and drug-related study withdrawal, for individual studies and for pooled data.
MAIN RESULTS: Twenty-three trials of six anticonvulsants were considered eligible (1,074 patients). The only placebo-controlled study in acute pain found no analgesic effect of sodium valproate. Three placebo-controlled studies of carbamazepine in trigeminal neuralgia had a combined NNT (95% confidence interval (CI)) for effectiveness of 2.5 (CI 2.0-3.4). A single placebo-controlled trial of gabapentin in post-herpetic neuralgia had an NNT of 3.2 (CI 2.4-5.0). For diabetic neuropathy NNTs for effectiveness were as follows: (one RCT for each drug) carbamazepine 2.3 (CI 1.6-3.8), gabapentin 3.8 (CI 2.4-8.7) and phenytoin 2.1 (CI 1.5-3.6).Numbers-needed-to-harm (NNHs) were calculated where possible by combining studies for each drug entity irrespective of the condition treated. The results were, for minor harm, carbamazepine 3.7 (CI 2.4-7.8), gabapentin 2.5 (CI 2.0-3.2), phenytoin 3.2 (CI 2.1-6.3). NNHs for major harm were not statistically significant for any drug compared with placebo. Phenytoin had no effect in irritable bowel syndrome, and carbamazepine little effect in post-stroke pain. Clonazepam was effective in one study of temporomandibular joint dysfunction.
AUTHORS' CONCLUSIONS: Although anticonvulsants are used widely in chronic pain surprisingly few trials show analgesic effectiveness. Only one studied considered cancer pain. There is no evidence that anticonvulsants are effective for acute pain. In chronic pain syndromes other than trigeminal neuralgia, anticonvulsants should be withheld until other interventions have been tried. While gabapentin is increasingly being used for neuropathic pain the evidence would suggest that it is not superior to carbamazepine.

PMID 16034857
X Lataste, M Emre, C Davis, L Groves
Comparative profile of tizanidine in the management of spasticity.
Neurology. 1994 Nov;44(11 Suppl 9):S53-9.
Abstract/Text The therapeutic profile of a new antispastic drug cannot be defined solely on the basis of placebo-controlled studies. Its potential advantages must be evaluated in comparison with existing drugs. This review compares the efficacy and tolerability of tizanidine, a newer muscle relaxant, with that of baclofen and diazepam, the most widely used antispastic agents, for a variety of diagnoses and target symptoms associated with spasticity. More than 20 double-blind, comparative studies were conducted between 1977 and 1987. These included a total of 777 patients suffering from spasticity of various causes. The collected clinical data have been integrated into a combined analysis. Tizanidine emerges from this comparison as a valuable drug in the treatment of spasticity related to cerebral and spinal disorders.

PMID 7970011
J M Gracies, P Nance, E Elovic, J McGuire, D M Simpson
Traditional pharmacological treatments for spasticity. Part II: General and regional treatments.
Muscle Nerve Suppl. 1997;6:S92-120.
Abstract/Text Systemic pharmacologic treatments may be indicated in conditions in which the distribution of muscle overactivity is diffuse. Antispastic drugs act in the CNS either by suppression of excitation (glutamate) enhancement of inhibition (GABA, glycine), or a combination of the two. Only four drugs are currently approved by the US FDA as antispactic agents: baclofen, diazepam, dantrolene sodium, and tizanidine. However, there are a number of other drugs available with proven antispastic action. This chapter reviews the pharmacology, physiology of action, dosage, and results from controlled clinical trials on side effects, efficacy, and indications for 21 drugs in several categories. Categories reviewed include agents acting through the GABAergic system (baclofen, benzodiazepines, piracetam, progabide); drugs affecting ion flux (dantrolene sodium, lamotrigine, riluzole; drugs acting on monoamines (tizanidine, clonidine, thymoxamine, beta blockers, and cyproheptadine); drugs acting on excitatory amino acids (orphenadrine citrate); cannabinoids; inhibitory neuromediators; and other miscellaneous agents. The technique, advantages and limitations of intrathecal administration of baclofen, morphine, and midazolam are reviewed. Two consistent limitations appear throughout the controlled studies reviewed: the lack of quantitative and sensitive functional assessment and the lack of comparative trials between different agents. In the majority of trials in which meaningful functional assessment was included, the study drug failed to improve function, even though the antispastic action was significant. Placebo-controlled trials of virtually all major centrally acting antispastic agents have shown that sedation, reduction of global performance, and muscle weakness are frequent side effects. It appears preferable to use centrally acting drugs such as baclofen, tizanidine, and diazepam in spasticity of spinal origin (spinal cord injury and multiple sclerosis), whereas dantrolene sodium, due to its primarily peripheral mechanism of action, may be preferable in spasticity of cerebral origin (stroke and traumatic brain injury) where sensitivity to sedating effects is generally higher. Intrathecal administration of antispastic drugs has been used mainly in cases of muscle overactivity occurring primarily in the lower limbs in nonambulatory, severely disabled patients but new indications may emerge in spasticity of cerebral origin. Intrathecal therapy is an invasive procedure involving long-term implantation of a foreign device, and the potential disadvantages must be weighed against the level of disability in each patient and the resistance to other forms of antispastic therapy. In all forms of treatment of muscle overactivity, one must distinguish between two different goals of therapy: improvement of active function and improvement of hygiene and comfort. The risk of global performance reduction associated with general or regional administration of antispastic drugs may be more acceptable when the primary goal of therapy is hygiene and comfort than when active function is a priority.

PMID 9826984
Karen L Furie, Scott E Kasner, Robert J Adams, Gregory W Albers, Ruth L Bush, Susan C Fagan, Jonathan L Halperin, S Claiborne Johnston, Irene Katzan, Walter N Kernan, Pamela H Mitchell, Bruce Ovbiagele, Yuko Y Palesch, Ralph L Sacco, Lee H Schwamm, Sylvia Wassertheil-Smoller, Tanya N Turan, Deidre Wentworth, American Heart Association Stroke Council, Council on Cardiovascular Nursing, Council on Clinical Cardiology, and Interdisciplinary Council on Quality of Care and Outcomes Research
Guidelines for the prevention of stroke in patients with stroke or transient ischemic attack: a guideline for healthcare professionals from the american heart association/american stroke association.
Stroke. 2011 Jan;42(1):227-76. doi: 10.1161/STR.0b013e3181f7d043. Epub 2010 Oct 21.
Abstract/Text The aim of this updated statement is to provide comprehensive and timely evidence-based recommendations on the prevention of ischemic stroke among survivors of ischemic stroke or transient ischemic attack. Evidence-based recommendations are included for the control of risk factors, interventional approaches for atherosclerotic disease, antithrombotic treatments for cardioembolism, and the use of antiplatelet agents for noncardioembolic stroke. Further recommendations are provided for the prevention of recurrent stroke in a variety of other specific circumstances, including arterial dissections; patent foramen ovale; hyperhomocysteinemia; hypercoagulable states; sickle cell disease; cerebral venous sinus thrombosis; stroke among women, particularly with regard to pregnancy and the use of postmenopausal hormones; the use of anticoagulation after cerebral hemorrhage; and special approaches to the implementation of guidelines and their use in high-risk populations.

PMID 20966421
J Donald Easton, Jeffrey L Saver, Gregory W Albers, Mark J Alberts, Seemant Chaturvedi, Edward Feldmann, Thomas S Hatsukami, Randall T Higashida, S Claiborne Johnston, Chelsea S Kidwell, Helmi L Lutsep, Elaine Miller, Ralph L Sacco, American Heart Association, American Stroke Association Stroke Council, Council on Cardiovascular Surgery and Anesthesia, Council on Cardiovascular Radiology and Intervention, Council on Cardiovascular Nursing, Interdisciplinary Council on Peripheral Vascular Disease
Definition and evaluation of transient ischemic attack: a scientific statement for healthcare professionals from the American Heart Association/American Stroke Association Stroke Council; Council on Cardiovascular Surgery and Anesthesia; Council on Cardiovascular Radiology and Intervention; Council on Cardiovascular Nursing; and the Interdisciplinary Council on Peripheral Vascular Disease. The American Academy of Neurology affirms the value of this statement as an educational tool for neurologists.
Stroke. 2009 Jun;40(6):2276-93. doi: 10.1161/STROKEAHA.108.192218. Epub 2009 May 7.
Abstract/Text This scientific statement is intended for use by physicians and allied health personnel caring for patients with transient ischemic attacks. Formal evidence review included a structured literature search of Medline from 1990 to June 2007 and data synthesis employing evidence tables, meta-analyses, and pooled analysis of individual patient-level data. The review supported endorsement of the following, tissue-based definition of transient ischemic attack (TIA): a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia, without acute infarction. Patients with TIAs are at high risk of early stroke, and their risk may be stratified by clinical scale, vessel imaging, and diffusion magnetic resonance imaging. Diagnostic recommendations include: TIA patients should undergo neuroimaging evaluation within 24 hours of symptom onset, preferably with magnetic resonance imaging, including diffusion sequences; noninvasive imaging of the cervical vessels should be performed and noninvasive imaging of intracranial vessels is reasonable; electrocardiography should occur as soon as possible after TIA and prolonged cardiac monitoring and echocardiography are reasonable in patients in whom the vascular etiology is not yet identified; routine blood tests are reasonable; and it is reasonable to hospitalize patients with TIA if they present within 72 hours and have an ABCD(2) score >or=3, indicating high risk of early recurrence, or the evaluation cannot be rapidly completed on an outpatient basis.

PMID 19423857
M F Giles, G W Albers, P Amarenco, E M Arsava, A W Asimos, H Ay, D Calvet, S B Coutts, B L Cucchiara, A M Demchuk, S C Johnston, P J Kelly, A S Kim, J Labreuche, P C Lavallee, J-L Mas, A Merwick, J M Olivot, F Purroy, W D Rosamond, R Sciolla, P M Rothwell
Early stroke risk and ABCD2 score performance in tissue- vs time-defined TIA: a multicenter study.
Neurology. 2011 Sep 27;77(13):1222-8. doi: 10.1212/WNL.0b013e3182309f91. Epub 2011 Aug 24.
Abstract/Text OBJECTIVES: Stroke risk immediately after TIA defined by time-based criteria is high, and prognostic scores (ABCD2 and ABCD3-I) have been developed to assist management. The American Stroke Association has proposed changing the criteria for the distinction between TIA and stroke from time-based to tissue-based. Research using these definitions is lacking. In a multicenter observational cohort study, we have investigated prognosis and performance of the ABCD2 score in TIA, subcategorized as tissue-positive or tissue-negative on diffusion-weighted imaging (DWI) or CT imaging according to the newly proposed criteria.
METHODS: Twelve centers provided data on ABCD2 scores, DWI or CT brain imaging, and follow-up in cohorts of patients with TIA diagnosed by time-based criteria. Stroke rates at 7 and 90 days were studied in relation to tissue-positive or tissue-negative subcategorization, according to the presence or absence of brain infarction. The predictive power of the ABCD2 score was determined using area under receiver operator characteristic curve (AUC) analyses.
RESULTS: A total of 4,574 patients were included. Among DWI patients (n = 3,206), recurrent stroke rates at 7 days were 7.1%(95% confidence interval 5.5-9.1) after tissue-positive and 0.4% (0.2-0.7) after tissue-negative events (p diff < 0.0001). Corresponding rates in CT-imaged patients were 12.8% (9.3-17.4) and 3.0% (2.0-4.2), respectively (p diff < 0.0001). The ABCD2 score had predictive value in tissue-positive and tissue-negative events (AUC = 0.68 [95% confidence interval 0.63-0.73] and 0.73 [0.67-0.80], respectively; p sig < 0.0001 for both results, p diff = 0.17). Tissue-positive events with low ABCD2 scores and tissue-negative events with high ABCD2 scores had similar stroke risks, especially after a 90-day follow-up.
CONCLUSIONS: Our findings support the concept of a tissue-based definition of TIA and stroke, at least on prognostic grounds.

PMID 21865578
Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group.
N Engl J Med. 1995 Dec 14;333(24):1581-7. doi: 10.1056/NEJM199512143332401.
Abstract/Text BACKGROUND: Thrombolytic therapy for acute ischemic stroke has been approached cautiously because there were high rates of intracerebral hemorrhage in early clinical trials. We performed a randomized, double-blind trial of intravenous recombinant tissue plasminogen activator (t-PA) for ischemic stroke after recent pilot studies suggested that t-PA was beneficial when treatment was begun within three hours of the onset of stroke.
METHODS: The trial had two parts. Part 1 (in which 291 patients were enrolled) tested whether t-PA had clinical activity, as indicated by an improvement of 4 points over base-line values in the score of the National Institutes of Health stroke scale (NIHSS) or the resolution of the neurologic deficit within 24 hours of the onset of stroke. Part 2 (in which 333 patients were enrolled) used a global test statistic to assess clinical outcome at three months, according to scores on the Barthel index, modified Rankin scale, Glasgow outcome scale, and NIHSS:
RESULTS: In part 1, there was no significant difference between the group given t-PA and that given placebo in the percentages of patients with neurologic improvement at 24 hours, although a benefit was observed for the t-PA group at three months for all four outcome measures. In part 2, the long-term clinical benefit of t-PA predicted by the results of part 1 was confirmed (global odds ratio for a favorable outcome, 1.7; 95 percent confidence interval, 1.2 to 2.6). As compared with patients given placebo, patients treated with t-PA were at least 30 percent more likely to have minimal or no disability at three months on the assessment scales. Symptomatic intracerebral hemorrhage within 36 hours after the onset of stroke occurred in 6.4 percent of patients given t-PA but only 0.6 percent of patients given placebo (P < 0.001). Mortality at three months was 17 percent in the t-PA group and 21 percent in the placebo group (P = 0.30).
CONCLUSIONS: Despite an increased incidence of symptomatic intracerebral hemorrhage, treatment with intravenous t-PA within three hours of the onset of ischemic stroke improved clinical outcome at three months.

PMID 7477192
Werner Hacke, Markku Kaste, Erich Bluhmki, Miroslav Brozman, Antoni Dávalos, Donata Guidetti, Vincent Larrue, Kennedy R Lees, Zakaria Medeghri, Thomas Machnig, Dietmar Schneider, Rüdiger von Kummer, Nils Wahlgren, Danilo Toni, ECASS Investigators
Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke.
N Engl J Med. 2008 Sep 25;359(13):1317-29. doi: 10.1056/NEJMoa0804656.
Abstract/Text BACKGROUND: Intravenous thrombolysis with alteplase is the only approved treatment for acute ischemic stroke, but its efficacy and safety when administered more than 3 hours after the onset of symptoms have not been established. We tested the efficacy and safety of alteplase administered between 3 and 4.5 hours after the onset of a stroke.
METHODS: After exclusion of patients with a brain hemorrhage or major infarction, as detected on a computed tomographic scan, we randomly assigned patients with acute ischemic stroke in a 1:1 double-blind fashion to receive treatment with intravenous alteplase (0.9 mg per kilogram of body weight) or placebo. The primary end point was disability at 90 days, dichotomized as a favorable outcome (a score of 0 or 1 on the modified Rankin scale, which has a range of 0 to 6, with 0 indicating no symptoms at all and 6 indicating death) or an unfavorable outcome (a score of 2 to 6 on the modified Rankin scale). The secondary end point was a global outcome analysis of four neurologic and disability scores combined. Safety end points included death, symptomatic intracranial hemorrhage, and other serious adverse events.
RESULTS: We enrolled a total of 821 patients in the study and randomly assigned 418 to the alteplase group and 403 to the placebo group. The median time for the administration of alteplase was 3 hours 59 minutes. More patients had a favorable outcome with alteplase than with placebo (52.4% vs. 45.2%; odds ratio, 1.34; 95% confidence interval [CI], 1.02 to 1.76; P=0.04). In the global analysis, the outcome was also improved with alteplase as compared with placebo (odds ratio, 1.28; 95% CI, 1.00 to 1.65; P<0.05). The incidence of intracranial hemorrhage was higher with alteplase than with placebo (for any intracranial hemorrhage, 27.0% vs. 17.6%; P=0.001; for symptomatic intracranial hemorrhage, 2.4% vs. 0.2%; P=0.008). Mortality did not differ significantly between the alteplase and placebo groups (7.7% and 8.4%, respectively; P=0.68). There was no significant difference in the rate of other serious adverse events.
CONCLUSIONS: As compared with placebo, intravenous alteplase administered between 3 and 4.5 hours after the onset of symptoms significantly improved clinical outcomes in patients with acute ischemic stroke; alteplase was more frequently associated with symptomatic intracranial hemorrhage. (ClinicalTrials.gov number, NCT00153036.)

2008 Massachusetts Medical Society
PMID 18815396
Takenori Yamaguchi, Etsuro Mori, Kazuo Minematsu, Jyoji Nakagawara, Kazuo Hashi, Isamu Saito, Yukito Shinohara, Japan Alteplase Clinical Trial (J-ACT) Group
Alteplase at 0.6 mg/kg for acute ischemic stroke within 3 hours of onset: Japan Alteplase Clinical Trial (J-ACT).
Stroke. 2006 Jul;37(7):1810-5. doi: 10.1161/01.STR.0000227191.01792.e3. Epub 2006 Jun 8.
Abstract/Text BACKGROUND AND PURPOSE: Based on previous studies comparing different recombinant tissue plasminogen activator (rt-PA) doses, we performed a clinical trial with 0.6 mg/kg, which is lower than the internationally approved dosage of 0.9 mg/kg, aiming to assess the efficacy and safety of alteplase in acute ischemic stroke for the Japanese.
METHODS: Our prospective, multicenter, single-arm, open-label trial was designed with a target sample size of 100 patients. The primary end points were the proportion of patients with a modified Rankin Scale (mRS) score of 0 to 1 at 3 months and the incidence of symptomatic intracranial hemorrhage (sICH) within 36 hours. Thresholds for these end points were determined by calculating 90% CIs of weighted averages derived from published reports. The protocol was defined according to the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA stroke study with slight modifications.
RESULTS: Among the 103 patients enrolled, 38 had an mRS of 0 to 1 at 3 months; this proportion (36.9%) exceeded the predetermined threshold of 33.9%. sICH within 36 hours occurred in 6 patients; this incidence (5.8%) was lower than the threshold of 9.6%.
CONCLUSIONS: In patients receiving 0.6 mg/kg alteplase, the outcome and the incidence of sICH were comparable to published data for 0.9 mg/kg. These findings indicate that alteplase, when administered at 0.6 mg/kg to Japanese patients, might offer a clinical efficacy and safety that are compatible with data reported in North America and the European Union for a 0.9 mg/kg dose.

PMID 16763187
Jyoji Nakagawara, Kazuo Minematsu, Yasushi Okada, Norio Tanahashi, Shinji Nagahiro, Etsuro Mori, Yukito Shinohara, Takenori Yamaguchi, J-MARS Investigators
Thrombolysis with 0.6 mg/kg intravenous alteplase for acute ischemic stroke in routine clinical practice: the Japan post-Marketing Alteplase Registration Study (J-MARS).
Stroke. 2010 Sep;41(9):1984-9. doi: 10.1161/STROKEAHA.110.589606. Epub 2010 Jul 22.
Abstract/Text BACKGROUND AND PURPOSE: In Japan, alteplase at 0.6 mg/kg was approved in October 2005 for use within 3 hours of stroke onset by the Ministry of Health, Labor and Welfare (MHLW). The aim of the Japan post-Marketing Alteplase Registration Study (J-MARS), which was requested by MHLW at the time of approval, was to assess the safety and efficacy of 0.6 mg/kg alteplase in routine clinical practice for the Japanese.
METHODS: A total of 7492 patients from 942 centers were enrolled in the J-MARS, an open-label, nonrandomized, observational study, from October 2005 to October 2007. Primary outcome measures were symptomatic intracranial hemorrhage (a deterioration in NIHSS score >or=4 from baseline) and favorable outcome (modified Rankin Scale score, 0-1) at 3 months after stroke onset.
RESULTS: The proportion of patients with symptomatic intracranial hemorrhage in 7492 patients (safety analysis) was 3.5% (95% confidence interval [CI], 3.1%-3.9%) within 36 hours and 4.4% (95% CI, 3.9%-4.9%) at 3 months. The overall mortality rate was 13.1% (95% CI, 12.4%-13.9%) and the proportion of patients with fatal symptomatic intracranial hemorrhage was 0.9% (95% CI, 0.7%-1.2%). The outcomes at 3 months were available for 4944 patients and the proportion of favorable outcome (efficacy analysis) was 33.1% (95% CI, 31.8%-34.4%). The subgroup analysis in patients between 18 and 80 years with a baseline NIHSS score <25 demonstrated that favorable outcome at 3 months was 39.0% (95% CI, 37.4%-40.6%).
CONCLUSIONS: These data suggest that 0.6 mg/kg intravenous alteplase within 3 hours of stroke onset could be safe and effective in routine clinical practice for the Japanese.

PMID 20651262
Jonathan Emberson, Kennedy R Lees, Patrick Lyden, Lisa Blackwell, Gregory Albers, Erich Bluhmki, Thomas Brott, Geoff Cohen, Stephen Davis, Geoffrey Donnan, James Grotta, George Howard, Markku Kaste, Masatoshi Koga, Ruediger von Kummer, Maarten Lansberg, Richard I Lindley, Gordon Murray, Jean Marc Olivot, Mark Parsons, Barbara Tilley, Danilo Toni, Kazunori Toyoda, Nils Wahlgren, Joanna Wardlaw, William Whiteley, Gregory J del Zoppo, Colin Baigent, Peter Sandercock, Werner Hacke, Stroke Thrombolysis Trialists' Collaborative Group
Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials.
Lancet. 2014 Nov 29;384(9958):1929-35. doi: 10.1016/S0140-6736(14)60584-5. Epub 2014 Aug 5.
Abstract/Text BACKGROUND: Alteplase is effective for treatment of acute ischaemic stroke but debate continues about its use after longer times since stroke onset, in older patients, and among patients who have had the least or most severe strokes. We assessed the role of these factors in affecting good stroke outcome in patients given alteplase.
METHODS: We did a pre-specified meta-analysis of individual patient data from 6756 patients in nine randomised trials comparing alteplase with placebo or open control. We included all completed randomised phase 3 trials of intravenous alteplase for treatment of acute ischaemic stroke for which data were available. Retrospective checks confirmed that no eligible trials had been omitted. We defined a good stroke outcome as no significant disability at 3-6 months, defined by a modified Rankin Score of 0 or 1. Additional outcomes included symptomatic intracranial haemorrhage (defined by type 2 parenchymal haemorrhage within 7 days and, separately, by the SITS-MOST definition of parenchymal type 2 haemorrhage within 36 h), fatal intracranial haemorrhage within 7 days, and 90-day mortality.
FINDINGS: Alteplase increased the odds of a good stroke outcome, with earlier treatment associated with bigger proportional benefit. Treatment within 3·0 h resulted in a good outcome for 259 (32·9%) of 787 patients who received alteplase versus 176 (23·1%) of 762 who received control (OR 1·75, 95% CI 1·35-2·27); delay of greater than 3·0 h, up to 4·5 h, resulted in good outcome for 485 (35·3%) of 1375 versus 432 (30·1%) of 1437 (OR 1·26, 95% CI 1·05-1·51); and delay of more than 4·5 h resulted in good outcome for 401 (32·6%) of 1229 versus 357 (30·6%) of 1166 (OR 1·15, 95% CI 0·95-1·40). Proportional treatment benefits were similar irrespective of age or stroke severity. Alteplase significantly increased the odds of symptomatic intracranial haemorrhage (type 2 parenchymal haemorrhage definition 231 [6·8%] of 3391 vs 44 [1·3%] of 3365, OR 5·55, 95% CI 4·01-7·70, p<0·0001; SITS-MOST definition 124 [3·7%] vs 19 [0·6%], OR 6·67, 95% CI 4·11-10·84, p<0·0001) and of fatal intracranial haemorrhage within 7 days (91 [2·7%] vs 13 [0·4%]; OR 7·14, 95% CI 3·98-12·79, p<0·0001). The relative increase in fatal intracranial haemorrhage from alteplase was similar irrespective of treatment delay, age, or stroke severity, but the absolute excess risk attributable to alteplase was bigger among patients who had more severe strokes. There was no excess in other early causes of death and no significant effect on later causes of death. Consequently, mortality at 90 days was 608 (17·9%) in the alteplase group versus 556 (16·5%) in the control group (hazard ratio 1·11, 95% CI 0·99-1·25, p=0·07). Taken together, therefore, despite an average absolute increased risk of early death from intracranial haemorrhage of about 2%, by 3-6 months this risk was offset by an average absolute increase in disability-free survival of about 10% for patients treated within 3·0 h and about 5% for patients treated after 3·0 h, up to 4·5 h.
INTERPRETATION: Irrespective of age or stroke severity, and despite an increased risk of fatal intracranial haemorrhage during the first few days after treatment, alteplase significantly improves the overall odds of a good stroke outcome when delivered within 4·5 h of stroke onset, with earlier treatment associated with bigger proportional benefits.
FUNDING: UK Medical Research Council, British Heart Foundation, University of Glasgow, University of Edinburgh.

Copyright © 2014 Emberson et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd. All rights reserved.
PMID 25106063
Olvert A Berkhemer, Puck S S Fransen, Debbie Beumer, Lucie A van den Berg, Hester F Lingsma, Albert J Yoo, Wouter J Schonewille, Jan Albert Vos, Paul J Nederkoorn, Marieke J H Wermer, Marianne A A van Walderveen, Julie Staals, Jeannette Hofmeijer, Jacques A van Oostayen, Geert J Lycklama à Nijeholt, Jelis Boiten, Patrick A Brouwer, Bart J Emmer, Sebastiaan F de Bruijn, Lukas C van Dijk, L Jaap Kappelle, Rob H Lo, Ewoud J van Dijk, Joost de Vries, Paul L M de Kort, Willem Jan J van Rooij, Jan S P van den Berg, Boudewijn A A M van Hasselt, Leo A M Aerden, René J Dallinga, Marieke C Visser, Joseph C J Bot, Patrick C Vroomen, Omid Eshghi, Tobien H C M L Schreuder, Roel J J Heijboer, Koos Keizer, Alexander V Tielbeek, Heleen M den Hertog, Dick G Gerrits, Renske M van den Berg-Vos, Giorgos B Karas, Ewout W Steyerberg, H Zwenneke Flach, Henk A Marquering, Marieke E S Sprengers, Sjoerd F M Jenniskens, Ludo F M Beenen, René van den Berg, Peter J Koudstaal, Wim H van Zwam, Yvo B W E M Roos, Aad van der Lugt, Robert J van Oostenbrugge, Charles B L M Majoie, Diederik W J Dippel, MR CLEAN Investigators
A randomized trial of intraarterial treatment for acute ischemic stroke.
N Engl J Med. 2015 Jan 1;372(1):11-20. doi: 10.1056/NEJMoa1411587. Epub 2014 Dec 17.
Abstract/Text BACKGROUND: In patients with acute ischemic stroke caused by a proximal intracranial arterial occlusion, intraarterial treatment is highly effective for emergency revascularization. However, proof of a beneficial effect on functional outcome is lacking.
METHODS: We randomly assigned eligible patients to either intraarterial treatment plus usual care or usual care alone. Eligible patients had a proximal arterial occlusion in the anterior cerebral circulation that was confirmed on vessel imaging and that could be treated intraarterially within 6 hours after symptom onset. The primary outcome was the modified Rankin scale score at 90 days; this categorical scale measures functional outcome, with scores ranging from 0 (no symptoms) to 6 (death). The treatment effect was estimated with ordinal logistic regression as a common odds ratio, adjusted for prespecified prognostic factors. The adjusted common odds ratio measured the likelihood that intraarterial treatment would lead to lower modified Rankin scores, as compared with usual care alone (shift analysis).
RESULTS: We enrolled 500 patients at 16 medical centers in The Netherlands (233 assigned to intraarterial treatment and 267 to usual care alone). The mean age was 65 years (range, 23 to 96), and 445 patients (89.0%) were treated with intravenous alteplase before randomization. Retrievable stents were used in 190 of the 233 patients (81.5%) assigned to intraarterial treatment. The adjusted common odds ratio was 1.67 (95% confidence interval [CI], 1.21 to 2.30). There was an absolute difference of 13.5 percentage points (95% CI, 5.9 to 21.2) in the rate of functional independence (modified Rankin score, 0 to 2) in favor of the intervention (32.6% vs. 19.1%). There were no significant differences in mortality or the occurrence of symptomatic intracerebral hemorrhage.
CONCLUSIONS: In patients with acute ischemic stroke caused by a proximal intracranial occlusion of the anterior circulation, intraarterial treatment administered within 6 hours after stroke onset was effective and safe. (Funded by the Dutch Heart Foundation and others; MR CLEAN Netherlands Trial Registry number, NTR1804, and Current Controlled Trials number, ISRCTN10888758.).

PMID 25517348
Bruce C V Campbell, Peter J Mitchell, Timothy J Kleinig, Helen M Dewey, Leonid Churilov, Nawaf Yassi, Bernard Yan, Richard J Dowling, Mark W Parsons, Thomas J Oxley, Teddy Y Wu, Mark Brooks, Marion A Simpson, Ferdinand Miteff, Christopher R Levi, Martin Krause, Timothy J Harrington, Kenneth C Faulder, Brendan S Steinfort, Miriam Priglinger, Timothy Ang, Rebecca Scroop, P Alan Barber, Ben McGuinness, Tissa Wijeratne, Thanh G Phan, Winston Chong, Ronil V Chandra, Christopher F Bladin, Monica Badve, Henry Rice, Laetitia de Villiers, Henry Ma, Patricia M Desmond, Geoffrey A Donnan, Stephen M Davis, EXTEND-IA Investigators
Endovascular therapy for ischemic stroke with perfusion-imaging selection.
N Engl J Med. 2015 Mar 12;372(11):1009-18. doi: 10.1056/NEJMoa1414792. Epub 2015 Feb 11.
Abstract/Text BACKGROUND: Trials of endovascular therapy for ischemic stroke have produced variable results. We conducted this study to test whether more advanced imaging selection, recently developed devices, and earlier intervention improve outcomes.
METHODS: We randomly assigned patients with ischemic stroke who were receiving 0.9 mg of alteplase per kilogram of body weight less than 4.5 hours after the onset of ischemic stroke either to undergo endovascular thrombectomy with the Solitaire FR (Flow Restoration) stent retriever or to continue receiving alteplase alone. All the patients had occlusion of the internal carotid or middle cerebral artery and evidence of salvageable brain tissue and ischemic core of less than 70 ml on computed tomographic (CT) perfusion imaging. The coprimary outcomes were reperfusion at 24 hours and early neurologic improvement (≥8-point reduction on the National Institutes of Health Stroke Scale or a score of 0 or 1 at day 3). Secondary outcomes included the functional score on the modified Rankin scale at 90 days.
RESULTS: The trial was stopped early because of efficacy after 70 patients had undergone randomization (35 patients in each group). The percentage of ischemic territory that had undergone reperfusion at 24 hours was greater in the endovascular-therapy group than in the alteplase-only group (median, 100% vs. 37%; P<0.001). Endovascular therapy, initiated at a median of 210 minutes after the onset of stroke, increased early neurologic improvement at 3 days (80% vs. 37%, P=0.002) and improved the functional outcome at 90 days, with more patients achieving functional independence (score of 0 to 2 on the modified Rankin scale, 71% vs. 40%; P=0.01). There were no significant differences in rates of death or symptomatic intracerebral hemorrhage.
CONCLUSIONS: In patients with ischemic stroke with a proximal cerebral arterial occlusion and salvageable tissue on CT perfusion imaging, early thrombectomy with the Solitaire FR stent retriever, as compared with alteplase alone, improved reperfusion, early neurologic recovery, and functional outcome. (Funded by the Australian National Health and Medical Research Council and others; EXTEND-IA ClinicalTrials.gov number, NCT01492725, and Australian New Zealand Clinical Trials Registry number, ACTRN12611000969965.).

PMID 25671797
Mayank Goyal, Andrew M Demchuk, Bijoy K Menon, Muneer Eesa, Jeremy L Rempel, John Thornton, Daniel Roy, Tudor G Jovin, Robert A Willinsky, Biggya L Sapkota, Dar Dowlatshahi, Donald F Frei, Noreen R Kamal, Walter J Montanera, Alexandre Y Poppe, Karla J Ryckborst, Frank L Silver, Ashfaq Shuaib, Donatella Tampieri, David Williams, Oh Young Bang, Blaise W Baxter, Paul A Burns, Hana Choe, Ji-Hoe Heo, Christine A Holmstedt, Brian Jankowitz, Michael Kelly, Guillermo Linares, Jennifer L Mandzia, Jai Shankar, Sung-Il Sohn, Richard H Swartz, Philip A Barber, Shelagh B Coutts, Eric E Smith, William F Morrish, Alain Weill, Suresh Subramaniam, Alim P Mitha, John H Wong, Mark W Lowerison, Tolulope T Sajobi, Michael D Hill, ESCAPE Trial Investigators
Randomized assessment of rapid endovascular treatment of ischemic stroke.
N Engl J Med. 2015 Mar 12;372(11):1019-30. doi: 10.1056/NEJMoa1414905. Epub 2015 Feb 11.
Abstract/Text BACKGROUND: Among patients with a proximal vessel occlusion in the anterior circulation, 60 to 80% of patients die within 90 days after stroke onset or do not regain functional independence despite alteplase treatment. We evaluated rapid endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core, a proximal intracranial arterial occlusion, and moderate-to-good collateral circulation.
METHODS: We randomly assigned participants to receive standard care (control group) or standard care plus endovascular treatment with the use of available thrombectomy devices (intervention group). Patients with a proximal intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients with a large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography were excluded. Workflow times were measured against predetermined targets. The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. A proportional odds model was used to calculate the common odds ratio as a measure of the likelihood that the intervention would lead to lower scores on the modified Rankin scale than would control care (shift analysis).
RESULTS: The trial was stopped early because of efficacy. At 22 centers worldwide, 316 participants were enrolled, of whom 238 received intravenous alteplase (120 in the intervention group and 118 in the control group). In the intervention group, the median time from study CT of the head to first reperfusion was 84 minutes. The rate of functional independence (90-day modified Rankin score of 0 to 2) was increased with the intervention (53.0%, vs. 29.3% in the control group; P<0.001). The primary outcome favored the intervention (common odds ratio, 2.6; 95% confidence interval, 1.7 to 3.8; P<0.001), and the intervention was associated with reduced mortality (10.4%, vs. 19.0% in the control group; P=0.04). Symptomatic intracerebral hemorrhage occurred in 3.6% of participants in intervention group and 2.7% of participants in control group (P=0.75).
CONCLUSIONS: Among patients with acute ischemic stroke with a proximal vessel occlusion, a small infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality. (Funded by Covidien and others; ESCAPE ClinicalTrials.gov number, NCT01778335.).

PMID 25671798
Jeffrey L Saver, Mayank Goyal, Alain Bonafe, Hans-Christoph Diener, Elad I Levy, Vitor M Pereira, Gregory W Albers, Christophe Cognard, David J Cohen, Werner Hacke, Olav Jansen, Tudor G Jovin, Heinrich P Mattle, Raul G Nogueira, Adnan H Siddiqui, Dileep R Yavagal, Blaise W Baxter, Thomas G Devlin, Demetrius K Lopes, Vivek K Reddy, Richard du Mesnil de Rochemont, Oliver C Singer, Reza Jahan, SWIFT PRIME Investigators
Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke.
N Engl J Med. 2015 Jun 11;372(24):2285-95. doi: 10.1056/NEJMoa1415061. Epub 2015 Apr 17.
Abstract/Text BACKGROUND: Among patients with acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, less than 40% regain functional independence when treated with intravenous tissue plasminogen activator (t-PA) alone. Thrombectomy with the use of a stent retriever, in addition to intravenous t-PA, increases reperfusion rates and may improve long-term functional outcome.
METHODS: We randomly assigned eligible patients with stroke who were receiving or had received intravenous t-PA to continue with t-PA alone (control group) or to undergo endovascular thrombectomy with the use of a stent retriever within 6 hours after symptom onset (intervention group). Patients had confirmed occlusions in the proximal anterior intracranial circulation and an absence of large ischemic-core lesions. The primary outcome was the severity of global disability at 90 days, as assessed by means of the modified Rankin scale (with scores ranging from 0 [no symptoms] to 6 [death]).
RESULTS: The study was stopped early because of efficacy. At 39 centers, 196 patients underwent randomization (98 patients in each group). In the intervention group, the median time from qualifying imaging to groin puncture was 57 minutes, and the rate of substantial reperfusion at the end of the procedure was 88%. Thrombectomy with the stent retriever plus intravenous t-PA reduced disability at 90 days over the entire range of scores on the modified Rankin scale (P<0.001). The rate of functional independence (modified Rankin scale score, 0 to 2) was higher in the intervention group than in the control group (60% vs. 35%, P<0.001). There were no significant between-group differences in 90-day mortality (9% vs. 12%, P=0.50) or symptomatic intracranial hemorrhage (0% vs. 3%, P=0.12).
CONCLUSIONS: In patients receiving intravenous t-PA for acute ischemic stroke due to occlusions in the proximal anterior intracranial circulation, thrombectomy with a stent retriever within 6 hours after onset improved functional outcomes at 90 days. (Funded by Covidien; SWIFT PRIME ClinicalTrials.gov number, NCT01657461.).

PMID 25882376
Tudor G Jovin, Angel Chamorro, Erik Cobo, María A de Miquel, Carlos A Molina, Alex Rovira, Luis San Román, Joaquín Serena, Sonia Abilleira, Marc Ribó, Mònica Millán, Xabier Urra, Pere Cardona, Elena López-Cancio, Alejandro Tomasello, Carlos Castaño, Jordi Blasco, Lucía Aja, Laura Dorado, Helena Quesada, Marta Rubiera, María Hernandez-Pérez, Mayank Goyal, Andrew M Demchuk, Rüdiger von Kummer, Miquel Gallofré, Antoni Dávalos, REVASCAT Trial Investigators
Thrombectomy within 8 hours after symptom onset in ischemic stroke.
N Engl J Med. 2015 Jun 11;372(24):2296-306. doi: 10.1056/NEJMoa1503780. Epub 2015 Apr 17.
Abstract/Text BACKGROUND: We aimed to assess the safety and efficacy of thrombectomy for the treatment of stroke in a trial embedded within a population-based stroke reperfusion registry.
METHODS: During a 2-year period at four centers in Catalonia, Spain, we randomly assigned 206 patients who could be treated within 8 hours after the onset of symptoms of acute ischemic stroke to receive either medical therapy (including intravenous alteplase when eligible) and endovascular therapy with the Solitaire stent retriever (thrombectomy group) or medical therapy alone (control group). All patients had confirmed proximal anterior circulation occlusion and the absence of a large infarct on neuroimaging. In all study patients, the use of alteplase either did not achieve revascularization or was contraindicated. The primary outcome was the severity of global disability at 90 days, as measured on the modified Rankin scale (ranging from 0 [no symptoms] to 6 [death]). Although the maximum planned sample size was 690, enrollment was halted early because of loss of equipoise after positive results for thrombectomy were reported from other similar trials.
RESULTS: Thrombectomy reduced the severity of disability over the range of the modified Rankin scale (adjusted odds ratio for improvement of 1 point, 1.7; 95% confidence interval [CI], 1.05 to 2.8) and led to higher rates of functional independence (a score of 0 to 2) at 90 days (43.7% vs. 28.2%; adjusted odds ratio, 2.1; 95% CI, 1.1 to 4.0). At 90 days, the rates of symptomatic intracranial hemorrhage were 1.9% in both the thrombectomy group and the control group (P=1.00), and rates of death were 18.4% and 15.5%, respectively (P=0.60). Registry data indicated that only eight patients who met the eligibility criteria were treated outside the trial at participating hospitals.
CONCLUSIONS: Among patients with anterior circulation stroke who could be treated within 8 hours after symptom onset, stent retriever thrombectomy reduced the severity of post-stroke disability and increased the rate of functional independence. (Funded by Fundació Ictus Malaltia Vascular through an unrestricted grant from Covidien and others; REVASCAT ClinicalTrials.gov number, NCT01692379.).

PMID 25882510
Mayank Goyal, Bijoy K Menon, Wim H van Zwam, Diederik W J Dippel, Peter J Mitchell, Andrew M Demchuk, Antoni Dávalos, Charles B L M Majoie, Aad van der Lugt, Maria A de Miquel, Geoffrey A Donnan, Yvo B W E M Roos, Alain Bonafe, Reza Jahan, Hans-Christoph Diener, Lucie A van den Berg, Elad I Levy, Olvert A Berkhemer, Vitor M Pereira, Jeremy Rempel, Mònica Millán, Stephen M Davis, Daniel Roy, John Thornton, Luis San Román, Marc Ribó, Debbie Beumer, Bruce Stouch, Scott Brown, Bruce C V Campbell, Robert J van Oostenbrugge, Jeffrey L Saver, Michael D Hill, Tudor G Jovin, HERMES collaborators
Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials.
Lancet. 2016 Feb 18;. doi: 10.1016/S0140-6736(16)00163-X. Epub 2016 Feb 18.
Abstract/Text BACKGROUND: In 2015, five randomised trials showed efficacy of endovascular thrombectomy over standard medical care in patients with acute ischaemic stroke caused by occlusion of arteries of the proximal anterior circulation. In this meta-analysis we, the trial investigators, aimed to pool individual patient data from these trials to address remaining questions about whether the therapy is efficacious across the diverse populations included.
METHODS: We formed the HERMES collaboration to pool patient-level data from five trials (MR CLEAN, ESCAPE, REVASCAT, SWIFT PRIME, and EXTEND IA) done between December, 2010, and December, 2014. In these trials, patients with acute ischaemic stroke caused by occlusion of the proximal anterior artery circulation were randomly assigned to receive either endovascular thrombectomy within 12 h of symptom onset or standard care (control), with a primary outcome of reduced disability on the modified Rankin Scale (mRS) at 90 days. By direct access to the study databases, we extracted individual patient data that we used to assess the primary outcome of reduced disability on mRS at 90 days in the pooled population and examine heterogeneity of this treatment effect across prespecified subgroups. To account for between-trial variance we used mixed-effects modelling with random effects for parameters of interest. We then used mixed-effects ordinal logistic regression models to calculate common odds ratios (cOR) for the primary outcome in the whole population (shift analysis) and in subgroups after adjustment for age, sex, baseline stroke severity (National Institutes of Health Stroke Scale score), site of occlusion (internal carotid artery vs M1 segment of middle cerebral artery vs M2 segment of middle cerebral artery), intravenous alteplase (yes vs no), baseline Alberta Stroke Program Early CT score, and time from stroke onset to randomisation.
FINDINGS: We analysed individual data for 1287 patients (634 assigned to endovascular thrombectomy, 653 assigned to control). Endovascular thrombectomy led to significantly reduced disability at 90 days compared with control (adjusted cOR 2·49, 95% CI 1·76-3·53; p<0·0001). The number needed to treat with endovascular thrombectomy to reduce disability by at least one level on mRS for one patient was 2·6. Subgroup analysis of the primary endpoint showed no heterogeneity of treatment effect across prespecified subgroups for reduced disability (pinteraction=0·43). Effect sizes favouring endovascular thrombectomy over control were present in several strata of special interest, including in patients aged 80 years or older (cOR 3·68, 95% CI 1·95-6·92), those randomised more than 300 min after symptom onset (1·76, 1·05-2·97), and those not eligible for intravenous alteplase (2·43, 1·30-4·55). Mortality at 90 days and risk of parenchymal haematoma and symptomatic intracranial haemorrhage did not differ between populations.
INTERPRETATION: Endovascular thrombectomy is of benefit to most patients with acute ischaemic stroke caused by occlusion of the proximal anterior circulation, irrespective of patient characteristics or geographical location. These findings will have global implications on structuring systems of care to provide timely treatment to patients with acute ischaemic stroke due to large vessel occlusion.
FUNDING: Medtronic.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 26898852
脳卒中データバンク 2009. 小林祥泰編, 解析責任者 大櫛陽一, 中山書店.
Georgios Tsivgoulis, Andrei V Alexandrov, Jason Chang, Vijay K Sharma, Steven L Hoover, Annabelle Y Lao, Wei Liu, Elefterios Stamboulis, Anne W Alexandrov, Marc D Malkoff, James L Frey
Safety and outcomes of intravenous thrombolysis in stroke mimics: a 6-year, single-care center study and a pooled analysis of reported series.
Stroke. 2011 Jun;42(6):1771-4. doi: 10.1161/STROKEAHA.110.609339. Epub 2011 Apr 14.
Abstract/Text BACKGROUND AND PURPOSE: Efforts to increase the availability and shorten the time delivery of intravenous thrombolysis in patients with acute ischemic stroke carry the potential for tissue plasminogen activator administration in patients with diseases other than stroke, that is, stroke mimics (SMs). We aimed to determine safety and to describe outcomes of intravenous thrombolysis in SM.
METHODS: We retrospectively analyzed stroke registry data of consecutive acute ischemic stroke admissions treated with intravenous thrombolysis over a 6-year-period. The admission National Institutes of Health Stroke Scale score, vascular risk factors, ischemic lesions on brain MRI (routinely performed as part of diagnostic work-up), and discharge modified Rankin Scale scores were documented. Initial stroke diagnosis in the emergency department was compared with final discharge diagnosis. SM diagnosis was based on the absence of ischemic lesions on diffusion-weighted imaging sequences in addition to an alternate discharge diagnosis. Symptomatic intracranial hemorrhage was defined as brain imaging evidence of intracranial hemorrhage with clinical worsening by National Institutes of Health Stroke Scale score increase of ≥4 points.
RESULTS: Intravenous thrombolysis was administered in 539 patients with acute ischemic stroke (55% men; mean age, 66 ± 15 years). Misdiagnosis of acute ischemic stroke was documented in 56 cases (10.4%; 95% CI, 7.9% to 13.3%). Conversion disorder (26.8%), complicated migraine (19.6%), and seizures (19.6%) were the 3 most common final diagnoses in SM. SMs were younger (mean age, 56 ± 13 years) and had milder baseline stroke severity (median National Institutes of Health Stroke Scale, 6; interquartile range, 4) compared with patients with confirmed acute ischemic stroke (mean age, 67 ± 14 years; median National Institutes of Health Stroke Scale, 8; interquartile range, 10; P<0.001). There was no case of symptomatic intracranial hemorrhage in SMs (0%; 95% CI, 0% to 5.5%); 96% of SMs were functionally independent at hospital discharge (modified Rankin Scale, 0 to 1).
CONCLUSIONS: Our single-center data indicate favorable safety and outcomes of intravenous thrombolysis administered to SM.

PMID 21493900
C M Fisher
Ataxic hemiparesis. A pathologic study.
Arch Neurol. 1978 Mar;35(3):126-8.
Abstract/Text Three stroke patients showed weakness and pyramidal signs on one side combined with a cerebellar-like ataxia on the same side. Pathologic study in each case showed an old infarct cavity in the basis pontis at the level of the junction of the upper one third and lower two thirds on the side opposite the neurologic deficit. The basilar artery was patent and the infarcts were probably the result of occlusion of penetrating arteries. This study demonstrates that a lesion of the basis pontis may be associated with a contralateral ataxia that is cerebellar in character. The designation ataxic hemiparesis is suggested for the syndrome.

PMID 629655
Jinsong Zhang, Yi Huan, Yunqiu Qian, Lijun Sun, Yali Ge
Multishot diffusion-weighted imaging features in spinal cord infarction.
J Spinal Disord Tech. 2005 Jun;18(3):277-82.
Abstract/Text OBJECTIVE: The purpose of this study was to use a multishot, navigator-corrected, echo-planar (EP) pulse sequence to perform clinical diffusion-weighted imaging (DWI), analyze the DWI findings in ischemic spinal cord lesions, and discuss the value of DW magnetic resonance imaging (MRI) in distinguishing infarction (especially in the subacute stage) from inflammatory diseases and tumors of the spinal cord.
METHODS: Six patients (two male, four female) with typical sudden onset of neurologic deficits caused by spinal cord ischemia were evaluated. There were no definite etiologies in these patients. Three cases occurred in the thoracolumbar region and three others occurred in the cervical cord. DWI was performed within 1-12 days after the initial neurologic symptoms by using a Philips Gyroscan 1.5 T MR system. Four patients had other scans including contrast-enhanced MRI and fluid-attenuated inversion recovery (FLAIR) scans. Two cases were followed up with MR images in 3 months. All the patients were imaged using a multishot, navigator-corrected, EP pulse sequence; apparent diffusion coefficient (ADC) values were calculated on the sagittal-oriented plane.
RESULTS: MR abnormalities were demonstrated on sagittal T2-weighted images with "patch-like" or "strip-like" hyperintensities (six of six) and spinal cord enlargement (five of six). Axial T2-weighted images showed bilateral (six of six) hyperintensities. In one patient, only the posterior spinal artery territory was involved. The spinal cord was mainly affected at the cervical (three of six) and thoracolumbar (three of six) regions. Two cases involved the conus medullaris (T10-L1). The intensity of lesion signals in DW images depended on how soon after the onset of illness the scan was carried out and whether hemorrhage had occurred. In this group of patients, ADC values of lesions ranged from 0.23 x 10(-3) to 0.47 x 10(-3) mm2/s (average value 0.36 +/- 0.10 x 10(-3) mm2/s), markedly lower than the values of normal parts (average value 0.89 +/- 0.08 x 10(-3) mm2/s). There were obviously significant differences between areas with lesions and normal regions (P < 0.01). All cases had better signal contrast in DW images than in T2-weighted images. Dynamic or repeated DWI examinations may help analyze the degree of injury and recovery. Most lesions (three of four) showed nonenhanced effects in the contrast-enhanced MRI except one lesion, which showed irregular slight enhancement. FLAIR images showed poor signal contrast between lesions and normal tissue and thus are not fit for displaying infarct lesions.
CONCLUSIONS: MRI is useful in detecting spinal cord infarction. DWI (especially multishot DWI) of the spinal cord may provide additional information for the assessment of ischemic changes and help improve in differentiating diagnosis.

PMID 15905774
多発性硬化症治療ガイドライン 監修 日本神経学会 日本神経免疫学会 日本神経治療学会 編集 「多発性硬化症治療ガイドライン」作成委員会 2010、p18-22、 医学書院.
日本神経感染症学会編:ヘルペス脳炎―診療ガイドラインに基づく診断基準と治療指針 中山書店 2007.
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、渡邉裕次、井ノ口岳洋、梅田将光および日本医科大学多摩永山病院 副薬剤部長 林太祐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。
※同効薬・小児・妊娠および授乳中の注意事項等は、海外の情報も掲載しており、日本の医療事情に適応しない場合があります。
※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、実際の保険適応の査定において保険適応及び保険適応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応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:
北川一夫 : 講演料(第一三共(株),協和キリン(株),興和(株))[2025年]
監修:永山正雄 : 特に申告事項無し[2025年]

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