Safety and efficacy of prophylactic levetiracetam for prevention of epileptic seizures in the acute phase of intracerebral haemorrhage (PEACH): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The incidence of early seizures (occurring within 7 days of stroke onset) after intracerebral haemorrhage reaches 30% when subclinical seizures are diagnosed by continuous EEG. Early seizures might be associated with haematoma expansion and worse neurological outcomes. Current guidelines do not recommend prophylactic antiseizure treatment in this setting. We aimed to assess whether prophylactic levetiracetam would reduce the risk of acute seizures in patients with intracerebral haemorrhage. METHODS: The double-blind, randomised, placebo-controlled, phase 3 PEACH trial was conducted at three stroke units in France. Patients (aged 18 years or older) who presented with a non-traumatic intracerebral haemorrhage within 24 h after onset were randomly assigned (1:1) to levetiracetam (intravenous 500 mg every 12 h) or matching placebo. Randomisation was done with a web-based system and stratified by centre and National Institutes of Health Stroke Scale (NIHSS) score at baseline. Treatment was continued for 6 weeks. Continuous EEG was started within 24 h after inclusion and recorded over 48 h. The primary endpoint was the occurrence of at least one clinical seizure within 72 h of inclusion or at least one electrographic seizure recorded on continuous EEG, analysed in the modified intention-to-treat population, which comprised all patients who were randomly assigned to treatment and who had a continuous EEG performed. This trial was registered at ClinicalTrials.gov, NCT02631759, and is now closed. Recruitment was prematurely stopped after 48% of the recruitment target was reached due to a low recruitment rate and cessation of funding. FINDINGS: Between June 1, 2017, and April 14, 2020, 50 patients with mild-to-moderate severity intracerebral haemorrhage were included: 24 were assigned to levetiracetam and 26 to placebo. During the first 72 h, a clinical or electrographic seizure was observed in three (16%) of 19 patients in the levetiracetam group versus ten (43%) of 23 patients in the placebo group (odds ratio 0·16, 95% CI 0·03-0·94, p=0·043). All seizures in the first 72 h were electrographic seizures only. No difference in depression or anxiety reporting was observed between the groups at 1 month or 3 months. Depression was recorded in three (13%) patients who received levetiracetam versus four (15%) patients who received placebo, and anxiety was reported for two (8%) patients versus one (4%) patient. The most common treatment-emergent adverse events in the levetiracetam group versus the placebo group were headache (nine [39%] vs six [24%]), pain (three [13%] vs ten [40%]), and falls (seven [30%] vs four [16%]). The most frequent serious adverse events were neurological deterioration due to the intracerebral haemorrhage (one [4%] vs four [16%]) and severe pneumonia (two [9%] vs two [8%]). No treatment-related death was reported in either group. INTERPRETATION: Levetiracetam might be effective in preventing acute seizures in intracerebral haemorrhage. Larger studies are needed to determine whether seizure prophylaxis improves functional outcome in patients with intracerebral haemorrhage. FUNDING: French Ministry of Health.

Temporal trends in reperfusion therapy for patients with acute ischemic stroke.

OBJECTIVES: To analyze the temporal trends in thrombolysis rates after implementation of a regional emergency network for acute ischemic stroke (AIS). METHODS: We conducted a retrospective study based on a prospective multicenter observational registry. The AIS benefited from reperfusion therapy included in 1 of the 5 primary stroke units or 1 comprehensive stroke center and 37 emergency departments were included using a standardized case report form. The population covers 3 million inhabitants. RESULTS: In total, 32,319 AIS was reported in the regional hospitalization database of which 2215 thrombolyzed AIS patients were included in the registry and enrolled in this study. The annual incidence rate of thrombolysis continuously and significantly increased from 2010 to 2018 (10.2% to 17.3%, P-trend = 0.0013). The follow-up of the onset-to-door and the door-to-needle delays over the study period showed stable rates, as did the all-cause mortality rate at 3-months (13.2%). CONCLUSION: Although access to stroke thrombolysis has increased linearly since 2010, the 3-month functional outcome has not evolved as favorably. Further efforts must focus on reducing hospital delays.

Prediction of Early Neurological Deterioration in Individuals With Minor Stroke and Large Vessel Occlusion Intended for Intravenous Thrombolysis Alone.

Importance: The best reperfusion strategy in patients with acute minor stroke and large vessel occlusion (LVO) is unknown. Accurately predicting early neurological deterioration of presumed ischemic origin (ENDi) following intravenous thrombolysis (IVT) in this population may help to select candidates for immediate transfer for additional thrombectomy. Objective: To develop and validate an easily applicable predictive score of ENDi following IVT in patients with minor stroke and LVO. Design, Setting, and Participants: This multicentric retrospective cohort included 729 consecutive patients with minor stroke (National Institutes of Health Stroke Scale [NIHSS] score of 5 or less) and LVO (basilar artery, internal carotid artery, first [M1] or second [M2] segment of middle cerebral artery) intended for IVT alone in 45 French stroke centers, ie, including those who eventually received rescue thrombectomy because of ENDi. For external validation, another cohort of 347 patients with similar inclusion criteria was collected from 9 additional centers. Data were collected from January 2018 to September 2019. Main Outcomes and Measures: ENDi, defined as 4 or more points' deterioration on NIHSS score within the first 24 hours without parenchymal hemorrhage on follow-up imaging or another identified cause. Results: Of the 729 patients in the derivation cohort, 335 (46.0%) were male, and the mean (SD) age was 70 (15) years; of the 347 patients in the validation cohort, 190 (54.8%) were male, and the mean (SD) age was 69 (15) years. In the derivation cohort, the median (interquartile range) NIHSS score was 3 (1-4), and the occlusion site was the internal carotid artery in 97 patients (13.3%), M1 in 207 (28.4%), M2 in 395 (54.2%), and basilar artery in 30 (4.1%). ENDi occurred in 88 patients (12.1%; 95% CI, 9.7-14.4) and was strongly associated with poorer 3-month outcomes, even in patients who underwent rescue thrombectomy. In multivariable analysis, a more proximal occlusion site and a longer thrombus were independently associated with ENDi. A 4-point score derived from these variables-1 point for thrombus length and 3 points for occlusion site-showed good discriminative power for ENDi (C statistic = 0.76; 95% CI, 0.70-0.82) and was successfully validated in the validation cohort (ENDi rate, 11.0% [38 of 347]; C statistic = 0.78; 95% CI, 0.70-0.86). In both cohorts, ENDi probability was approximately 3%, 7%, 20%, and 35% for scores of 0, 1, 2 and 3 to 4, respectively. Conclusions and Relevance: The substantial ENDi rates observed in these cohorts highlights the current debate regarding whether to directly transfer patients with IVT-treated minor stroke and LVO for additional thrombectomy. Based on the strong associations observed, an easily applicable score for ENDi risk prediction that may assist decision-making was derived and externally validated.

Cyclosporine in acute ischemic stroke.

OBJECTIVES: We examined whether IV administration of cyclosporine in combination with thrombolysis might reduce cerebral infarct size. METHODS: Patients aged 18 to 85 years, presenting with an anterior-circulation stroke and eligible for thrombolytic therapy, were enrolled in this multicenter, single-blinded, controlled trial. Fifteen minutes after randomization, patients received either an IV bolus injection of 2.0 mg/kg cyclosporine (Sandimmune, Novartis) or placebo. The primary endpoint was infarct volume on MRI at 30 days. Secondary endpoints included infarct volume according to the site (proximal/distal) of arterial occlusion and recanalization after thrombolysis. RESULTS: From October 2009 to July 2013, 127 patients were enrolled. The primary endpoint was assessed in 110 of 127 patients. The reduction of infarct volume in the cyclosporine compared with the control group was overall not significant (21.8 mL [interquartile range, IQR 5.1, 69.2 mL] vs 28.8 mL [IQR 7.7, 95.0 mL], respectively; p = 0.18). However, in patients with proximal occlusion and effective recanalization, infarct volume was significantly reduced in the cyclosporine compared with the control group (14.9 mL [IQR 1.3, 23.2 mL] vs 48.3 mL [IQR 34.5, 118.2 mL], respectively; p = 0.009). CONCLUSIONS: Cyclosporine was generally not effective in reducing infarct size. However, a smaller infarct size was observed in patients with proximal cerebral artery occlusion and efficient recanalization. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in patients with an acute anterior-circulation stroke, thrombolysis plus IV cyclosporine does not significantly decrease 30-day MRI infarct volume compared with thrombolysis alone.

Thrombolysis for Acute Minor Stroke: Outcome and Barriers to Management. Results from the RESUVAL Stroke Network.

BACKGROUND: We evaluated the management, outcome and haemorrhagic risk in a cohort of ischaemic stroke patients with mild symptoms treated with intravenous tissue plasminogen activator (tPA) within the first 4.5 h. METHODS: We analysed data from a prospective stroke thrombolysis registry. A total of 1,043 patients received tPA between 2010 and 2014 in the 5 stroke units of the RESUVAL stroke network (Rhône Valley, France). Among them, 170 patients had a National Institute of Health Stroke Scale (NIHSS) score ≤4 (minor group: MG) before tPA and 873 patients had a NIHSS score >4. RESULTS: A high rate (77%) of excellent outcome (3-month-modified Rankin Scale score ≤1) was observed in the MG. No symptomatic intracerebral haemorrhage occurred and the rate of any haemorrhagic transformation was 5%. Fifty-four percent of the MG patients had visible arterial occlusion before tPA. Patients of the MG were less likely to be transported by Emergency Medical Services and to be directly admitted to the stroke unit or to imaging. Median delays from onset to admission, from admission to imaging and from onset to tPA were longer in the MG. CONCLUSION: Our data provided evidence of safety and suggested potential benefit of thrombolysis in patients with NIHSS score ≤4. A majority of these patients exhibited arterial occlusion before thrombolysis. Most often, patients with mild stroke are not given priority in terms of the mode of transport, direct admission to stroke unit and rapid imaging, resulting in an increased delay from onset to thrombolysis. Health system improvements are needed to provide all suspected stroke victims equal access to imaging and treatment on an emergency basis.

Audit report and systematic review of orolingual angioedema in post-acute stroke thrombolysis.

RATIONALE: Post-intravenous recombinant tissue plasminogen activator (r-tPA) orolingual angioedema (PIROLA), including the life-threatening form, is an underappreciated complication of ischaemic stroke treatment. AIMS: We present an audit report and a systematic review of published observational studies on PIROLA occurrence in acute ischaemic stroke patients. METHODS: Clinical files of patients treated in the stroke unit of Bourg-en-Bresse General Hospital (France) from January 2010 to December 2012 were reviewed, and MEDLINE (inception to May 2013) were searched and bibliographies/citations of retrieved articles examined for evidence of PIROLA. RESULTS: Of the 129 acute ischaemic stroke patients treated at Bourg-en-Bresse between 2010 and 2012, four patients, all receiving angiotensin converting enzyme inhibitor (ACEI), developed a PIROLA (cumulative incidence rate: 32‰). The complication started within an hour of receiving r-tPA and integrally resolved within 3-24 hours, with antihistamines/steroid treatment in two patients. The systematic review identified 27 studies, totalising with ours, over 9050 acute ischaemic stroke patients from 12 countries, among whom 100 (cumulative incidence rate: 17‰; 95% confidence intervals: 8-26), developed a PIROLA within 6-240 minutes of receiving r-tPA, 0-100% of them occurring among patients on ACEI. The complication was contralateral to the stroke location in 47% cases, ipsilateral in 14%, and bilateral in 39%; and resolved within 24 hours with treatment in 90%. No related death was recorded. CONCLUSIONS: About 17‰ acute ischaemic stroke patients receiving r-tPA develop PIROLA, occurring essentially among those on concomitant ACEI. PIROLA occurrence should be actively monitored, particularly within the first few hours as some may require urgent lifesaving procedures.

Ethical issues of informed consent in acute stroke. Analysis of the modalities of consent in 56 patients enrolled in urgent therapeutic trials.

BACKGROUND: Many patients may be mentally incompetent or physically unable to give informed consent at the acute stage of stroke. Accordingly, we aimed to investigate the modalities of informed consent in urgent therapeutic stroke trials, the awareness of patients and relatives regarding stroke clinical trials and the impact of decision making on patients and relatives. METHODS: We present a study of 56 acute ischemic stroke patients who were randomized in 4 trials (2 trials testing neuroprotective agents, 1 testing thrombolysis and 1 testing antithrombotic agents). A standardized questionnaire was used to assess the modalities of informed consent in this setting. RESULTS: The mean age was 67.1 (SD 12.6) years. The mean baseline Scandinavian Stroke Scale (SSS) score was 23.8 (SD 10.5). Only 13 patients (23% of cases) gave consent while relatives gave consent for 43 patients (77%). The main reason for not getting consent from the patient was aphasia in 29 patients (67.4%). Multiple logistic regression analysis showed that the two independent factors influencing the ability to give consent are age and baseline neurological deficit as assessed by the SSS score. Concerning the psychological impact of consent, none of the 10 patients who answered our questionnaire declared feeling uncomfortable when giving consent, while 7 out of the 13 relatives who could be reached declared they felt uncomfortable, mainly because of the psychological stress induced by urgent decision making. CONCLUSIONS: Our study emphasizes the specific ethical difficulties of informed consent in the setting of acute stroke research. Only a minority of patients are able to give consent at the acute stage. Increasing age and neurological deficit are independent predictors of inability to give consent. Thus, the responsibility for consent usually relies on relatives with potential inaccuracy of decision concerning the patient's wish or even conflict of interest. Further evaluation of the psychological impact of decision on relatives is needed in this setting of acute stroke.

Influence of pretreatment MRI parameters on clinical outcome, recanalization and infarct size in 49 stroke patients treated by intravenous tissue plasminogen activator.

We hypothesized that pretreatment magnetic resonance imaging (MRI) parameters might predict clinical outcome, recanalization and final infarct size in acute ischemic stroke patients treated by intravenous recombinant tissue plasminogen activator (rt-PA). MRI was performed prior to thrombolysis and at day 1 with the following sequences: magnetic resonance angiography (MRA), T2*-gradient echo (GE) imaging, diffusion-weighted imaging (DWI) and perfusion-weighted imaging (PWI). Final infarct size was assessed at day 60 by T2-weighted imaging (T2-WI). The National Institutes of Health Stroke Scale (NIHSS) score was assessed prior to rt-PA therapy and the modified Rankin Scale (m-RS) score was assessed at day 60. A poor outcome was defined as a day 60 m-RS score >2. Univariate and multivariate logistic regression analyses were used to identify the predictors of clinical outcome, recanalization and infarct size. Forty-nine patients fulfilled the inclusion criteria. Baseline NIHSS score was the best independent indicator of clinical outcome (p=0.002). A worse clinical outcome was observed in patients with tandem internal carotid artery (ICA)+middle cerebral artery (MCA) occlusion versus other sites of arterial occlusion (p=0.009), and in patients with larger pretreatment PWI (p=0.001) and DWI (p=0.01) lesion volumes. Two factors predict a low rate of recanalization: a proximal site of arterial occlusion (p=0.02) and a delayed time to peak (TTP) on pretreatment PWI (p=0.05). The final infarct size was correlated with pretreatment DWI lesion volume (p=0.025). Recanalization was associated with a lower final infarct size (p=0.003). In conclusion, a severe baseline NIHSS score, a critical level of pretreatment DWI/PWI parameters and a proximal site of occlusion are predictive of a worse outcome after IV rt-PA for acute ischemic stroke.

Magnetic resonance imaging: significance of early ischemic changes on computed tomography.

UNLABELLED: The significance of early ischemic changes (EICs) on CT remains controversial. MRI may provide relevant information in patients with EICs. METHODS: EICs were assessed in patients with acute ischemic stroke. MRI was promptly performed at presentation after CT and repeated on day 1. The relationship between EICs and MRI parameters was assessed with one-way ANOVA for analysis of continuous variables and by the chi2 test for the analysis of variables with a binary outcome. RESULTS: Fourty-eight patients underwent CT and MR imaging before treatment with recombinant tissue plasminogen activator (age: 63 +/- 14 years). EICs were graded as absent in 28 patients, <33% in 15 patients, and >33% of the middle cerebral artery (MCA) territory in 5 patients. NIHSS score was higher in patients with EICs that covered more than one third of the MCA territory (19 +/- 3) compared to those without EICs (12 +/- 5; p = 0.04). Patients who had major EICs had a larger acute lesion volume in diffusion-weighted imaging (DWI; 140 +/- 78 cm3) compared to those without EICs (33 +/- 51 cm3, p < 0.0001). Regional cerebral blood flow, regional cerebral blood volume, time to peak and mean transit time values were not significantly different in the study groups. CONCLUSION: EICs reflect mainly a larger DWI lesion.

Early fibrinogen degradation coagulopathy is predictive of parenchymal hematomas in cerebral rt-PA thrombolysis: a study of 157 cases.

BACKGROUND: Little is known about the coagulation factors as predictors of cerebral bleeding in rt-PA thrombolysis. The aim of this study was to determine what early coagulation parameters could predict early hemorrhagic lesions. METHODS: Consecutive patients were included in the Lyon rt-PA protocol. Early hematomas (within 24 hours), diagnosed on an anatomoradiological basis (symptomatic and not symptomatic) were considered for the study. Fibrinogen and fibrin(ogen) degradation products (FDP) were assessed at entry and at 2 and 24 hours after the beginning of thrombolysis. RESULTS: Of 157 patients, 11 had early parenchymal hematomas (7%), 31 had early hemorrhagic infarcts (19.7%), and 115 had no bleeding (73.2%). In logistic regression, FDP at 2 hours was the single predictor of parenchymal hematomas (OR: 2.5; CI: 1.09 to 5.8), whereas an increase of FDP >200 mg/L multiplied the odds of parenchymal hematoma by 4.95 (IC: 1.09 to 22.4). Early parenchymal hematomas were indicative of a poor prognosis at 3 months (P=0.001). CONCLUSIONS: Early parenchymal hematomas appear as both "malignant" and exclusively related to an explosive increase of FDP at 2 hours, ie, an early fibrinogen degradation coagulopathy (EFDC). All patients scheduled to rt-PA thrombolysis should have an assay of FDP 2 hours after the beginning of thrombolysis: patients with an established EFDC (FDP >200 mg/L) should be monitored specifically, with no antithrombotic drug during the first 72 hours. Patients with FDP >100 mg should share the same monitoring.

Thrombolysis for ischemic stroke in patients with old microbleeds on pretreatment MRI.

BACKGROUND: Old asymptomatic microbleeds (MBs) visualized on T2-weighted MRI are indicative of microangiopathy. They may be a marker of increased risk of intracerebral hemorrhage (ICH) following thrombolysis. However, data regarding this potential risk are limited. METHODS: A retrospective analysis of pretreatment T2-weighted MRI was performed in consecutive stroke patients who received intravenous tissue plasminogen activator (tPA). We aimed to assess the impact of MBs on the risk of cerebral bleeding. The frequency and location of MBs were assessed and compared with the location of ICH after thrombolysis. RESULTS: Forty-four patients were studied. MBs were present on pretreatment MRI in 8 cases (18.2%). At day 1, symptomatic ICH occurred in none of 8 patients with MBs versus 1 of 36 patients without (NS). At day 1, ICH occurred in 3 of 8 patients with MBs versus 10 of 36 patients without (NS). At day 7, symptomatic ICH occurred in 1 of 8 patients with MBs versus 2 of 36 patients without (NS). At day 7, ICH occurred in 5 of 8 patients with MBs versus 12 of 36 patients without (NS). No ICH occurred at the site of an MB. ICH occurred within the ischemic area in all patients who bled. CONCLUSIONS: Our study suggests that stroke patients with a small number of MBs on pretreatment MRI could be treated safely with thrombolysis. Larger prospective studies are needed to address the predictive value of detection of MBs with regard to the risk of tPA-induced ICH.

Early magnetic resonance imaging prediction of arterial recanalization and late infarct volume in acute carotid artery stroke.

In patients with acute ischemic stroke, early recanalization may save tissue at risk for ischemic infarction, thus resulting in smaller infarcts and better clinical outcome. The hypothesis that clinical and diffusion- and perfusion-weighted imaging (DWI, PWI) parameters may have a predictive value for early recanalization and final infarct size was assessed. Twenty-nine patients were prospectively enrolled and underwent sequential magnetic resonance imaging (1) within 6 hours from hemispheric stroke onset, before thrombolytic therapy; (2) at day 1; and (3) at day 60. Late infarct volume was assessed by T2 -weighted imaging. At each time, clinical status was assessed by the National Institutes of Health Stroke Scale (NIHSS). Twenty-eight patients had arterial occlusion at day 0 magnetic resonance angiography (MRA). They were classified into two groups according to day 1 MRA: recanalization (n = 18) versus persistent occlusion (n = 10). Any significant differences between these groups were assessed regarding (1) PWI and DWI abnormality volumes, (2) relative and absolute time-to-peak (TTP) and apparent diffusion coefficient within the lesion on DWI; and (3) day 60 lesion volume on T2 -weighted imaging. Univariate and multivariate logistic regression analysis showed that the most powerful predictive factors for recanalization were lower baseline NIHSS score and lower baseline absolute TTP within the lesion on DWI. The best predictors of late infarct size were day 0 lesion volume on DWI and day 1 recanalization. Early PWI and DWI studies and day 1 MRA provide relevant predictive information on stroke outcome.