levetiracetam and Cerebral-Hemorrhage

Spontaneous intracerebral haemorrhage (ICH) is associated with high mortality and high morbidity, including seizures. Seizure prophylaxis is "not recommended" by the American Stroke Association, but practice variation still exists due to inconclusive data. We performed a meta-analysis to assess the current relevant literature to determine the efficacy of seizure prophylaxis following ICH.. We performed searches of PubMed, Scopus, and Embase up to September 15, 2020. We included observational and randomized controlled studies reporting seizure prophylaxis and occurrence in adults with ICH. Outcomes were seizures, as defined by the authors, within 14 days of ICH and at the longest point of follow-up. We used random-effects models to estimate the odds ratios (ORs) for seizure prophylaxis and outcomes. The PROSPERO registration was CRD42019140493.. We included 8 studies (2852 patients) in our analysis. The mean (± standard deviation) age of the pooled patients was 65 (±4) years; 39 % (± 5%) were female. Seizure prophylaxis did not prevent seizures at the longest follow-up time (OR 0.708, 95 % CI 0.438-1.143, p = 0.158, I2 = 34 %). This result was confirmed in subgroup analyses using categorical variables and in meta-regressions using continuous variables. Additionally, seizure prophylaxis was not associated with preventing early seizures, defined as < 14 days of ICH (OR 0.66, 95 % CI 0.21-2.08, p = 0.48, I2 = 35 %).. Seizure prophylaxis following ICH was not associated with seizure prevention in adults. Most included studies were observational. Further randomized controlled trials examining the efficacy of seizure prophylaxis in high-risk patients and different types of antiepileptic drugs are needed.

Topics: Aged; Anticonvulsants; Cerebral Hemorrhage; Female; Humans; Levetiracetam; Male; Middle Aged; Phenytoin; Piracetam; Seizures

Frequency of clinical seizures may be as high as 16% in patients with spontaneous intracerebral hemorrhage (ICH). Current guidelines recommend against antiepileptic drug (AED) prophylaxis, but this recommendation is based on older trials, and the effect of newer AEDs is uncertain. The aim of this review was to study effects of AEDs on seizure occurrence and outcome in patients with spontaneous ICH.. We searched key databases using combinations of the following terms: "levetiracetam," "prophylaxis," "ICH," "intracerebral hemorrhage," "intraparenchymal hemorrhage." Selected studies were reviewed for level of evidence and overall quality of data using Grading of Recommendations, Assessment, Development and Evaluations criteria. A meta-analysis was performed to evaluate seizure prevention, functional outcome, and mortality in patients with seizure prophylaxis compared with no prophylaxis following spontaneous ICH.. Seven articles met inclusion criteria and were graded level III studies. Administration of AEDs was not associated with reduced seizure risk (odds ratio 1.14, 95% confidence interval 0.47-2.77, P = 0.77). There was an association between AED prophylaxis and poor functional outcome (odds ratio 1.65, 95% confidence interval 1.17-2.31, P = 0.004) but not mortality (odds ratio 1.04, 95% confidence interval 0.62-1.72, P = 0.89). The overall quality of evidence using Grading of Recommendations, Assessment, Development and Evaluations criteria was low.. This systematic review and meta-analysis including recent studies focusing on newer AEDs supports the 2015 guidelines regarding AED use in spontaneous ICH. There are some important caveats, including a possible confounding association between AED use and higher ICH score and the overall poor quality of the available data. A randomized clinical trial may be helpful.

Topics: Anticonvulsants; Cerebral Hemorrhage; Humans; Levetiracetam; Phenytoin; Piracetam; Seizures

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.. 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.. 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.. 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.. French Ministry of Health.

Topics: Cerebral Hemorrhage; Epilepsy; Humans; Levetiracetam; Seizures; Stroke; Treatment Outcome; United States

Seizures are a morbid complication of intracerebral hemorrhage (ICH) and increase the risk for herniation, status epilepticus, and worse patient outcomes. Prophylactic levetiracetam is administered to approximately 40% of patients with ICH. It is unclear which patients are consciously selected for treatment by physicians. We sought to determine how patients are selected for treatment with prophylactic levetiracetam after ICH.. We administered an adaptive conjoint analysis using decision making software to an NIH Stroke Trials Network Working Group. The adaptive conjoint analysis determines the most influential attributes for making a decision in an iterative, algorithm-driven process. We asked respondents which would most influence a decision to administer prophylactic levetiracetam. The attributes and their levels were taken from published phenotypes associated with prophylactic seizure medications and the likelihood of seizures after ICH: hematoma location (lobar or basal ganglia), hematoma volume (<=10 mL or >10 mL), level of consciousness (Glasgow Coma Scale 5-12 or Glasgow Coma Scale 13-15), age (<65 or ≥65 years), and race (White or Caucasian or Black/African American). The algorithm terminated when the attributes were ranked from most to least influential.. The study sample included 27 respondents who completed the adaptive conjoint analysis out of 42 who responded to the survey with a mean age of 43.4 ± 9.4 years. The attribute with the greatest weight was hematoma location (30%), followed by reduced level of consciousness (24%), hematoma volume (19%), race (14%), and age (13%). Ranks of attributes were different (P < .001).. The decision to administer prophylactic levetiracetam to patients with ICH is driven by lobar hematoma location and depressed level of consciousness. Future research on prophylactic seizure medication could focus on patients most likely to receive it.

Topics: Adult; Aged; Anticonvulsants; Attitude of Health Personnel; Cerebral Hemorrhage; Clinical Decision-Making; Decision Support Techniques; Drug Administration Schedule; Drug Utilization; Female; Health Care Surveys; Health Knowledge, Attitudes, Practice; Humans; Levetiracetam; Male; Middle Aged; Patient Selection; Practice Patterns, Physicians'; Predictive Value of Tests; Risk Assessment; Risk Factors; Seizures

Intracranial hemorrhage (ICH) is a devastating disease that induces hematoma formation with poor neuronal outcome. Levetiracetam (LEV) has been approval for epilepsy seizures. In a previous study, LEV exerted protective effects on cerebral ischemia models; however, the detail effects and the influence of LEV on ICH are still unknown. The aim of this study was to investigate whether oral administration of LEV (50 or 150 mg/kg) has protective effects on ICH injury using both in vivo and in vitro experiments. In in vivo experiments, we utilized ICH models induced by autologous blood (bICH) or collagenase (cICH) injection. Moreover, we established a neuronal injury model using SYSH5Y human neuroblastoma cell lines. In the bICH model, frequently oral administration of LEV attenuated both cerebral edema and neurological deficits. In addition, the expression levels of phosphorylation-extracellular signal‑related kinase (ERK) 1/2 and cleaved caspase-7 were increased after ICH, and LEV suppressed such alterations. In in vitro experiments, hematoma releasing factors, such as hemoglobin (Hb) and hemin, induced neuronal cell death, and LEV treatment attenuated neuronal injury in a dose-dependent manner. In the cICH model, neurological deficits induced by extensive hematoma formation were attenuated by LEV without affecting hematoma volume. Taken together, these findings suggested that LEV has protective effect on neurons after ICH injury. Therefore, LEV may not only be an efficacious therapeutic agent for seizures, but also for post-hemorrhagic stroke brain injury.

Topics: Animals; Anticonvulsants; Cerebral Hemorrhage; Disease Models, Animal; Humans; Intracranial Hemorrhages; Levetiracetam; Neuroprotective Agents

BACKGROUND Levetiracetam (LEV) is an antiepileptic drug that promotes recovery of neurological function by alleviating inflammatory reactions. However, it is not known whether it can improve secondary brain injury after intracerebral hemorrhage (ICH). The aim of this study was to determine whether LEV can reduce early inflammatory response after ICH in rats. MATERIAL AND METHODS An in vitro model of early inflammation was created by treating microglia cells with lipopolysaccharide (LPS). After exposure to various concentrations of LEV, the expression levels of NF-kappaB and STAT3 and inflammatory factors such as interleukin (IL)-1ß and tumor necrosis factor (TNF)-alpha in microglia were detected. In vivo, autologous blood was used to induce the rat ICH model. The effects of LEV on post-cerebral hemorrhagic inflammatory response were examined using neurobehavioral tests, FJC staining, brain water content testing, and analysis of protein expression levels of NF-kappaB, JAK2, STAT3, and inflammatory factors. RESULTS LEV treatment significantly reduced the expression of inflammatory factors and protein expression levels of NF-kappaB and STAT3 in LPS-treated microglia cells (P<0.05). In male Sprague-Dawley (SD) rats, LEV treatment markedly decreased the volume of hematoma and the number of degenerative neurons (P<0.05). It also improved the neurological function and relieved brain edema. The protein expression levels of NF-kappaB, JAK2, and STAT3 were significantly lower in the ICH+LEV group than in the control group (P<0.05). CONCLUSIONS Our study suggests that treatment with LEV alleviates early inflammatory responses induced by ICH. Mechanistically, LEV inhibited the JAK2-STAT3 signaling pathway and reduced neuronal injury around the hematoma, and ameliorated brain edema, all of which promoted recovery of nerve function after hemorrhage.

Topics: Animals; Cerebral Hemorrhage; Inflammation; Janus Kinase 2; Levetiracetam; Male; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Signal Transduction; STAT3 Transcription Factor

The role of prophylactic antiepileptic drugs (AEDs) in preventing seizures and/or improving the outcomes after intracerebral hemorrhage (ICH) has remained controversial. The current guidelines have recommended against AED prophylaxis. However, these recommendations were based on older studies that had primarily used phenytoin as the AED of choice. Newer medications, such as levetiracetam, have yet to be extensively studied.. We performed a retrospective review of patients with ICH from 2010 to 2015. The patient demographic data, seizure data, and outcomes were collected. The results were analyzed using descriptive statistics, binary logistic regression, and quantile regression. The primary outcome was seizure incidence.. A total of 360 patients with a median age of 70 years had met the inclusion criteria. Of the 360 patients, 30 (8.3%) had had recorded seizure events, 54% were men, and 81% had a history of hypertension. The median admission National Institutes of Health stroke scale (NIHSS) score was 7 (interquartile range [IQR], 14), and the median discharge NIHSS score was 5.0 (IQR, 13). The median hematoma size was 7.1 mL (IQR, 13 mL), and 143 patients (40%) had had cortical involvement. Of the 360 patients, 273 (76%) had received prophylaxis and 87 (24%) had not. After adjustment for the admission NIHSS and the presence of cortical involvement, the rate of new seizure events after ICH remained significantly lower for the patients who had received AED prophylaxis (adjusted odds ratio, 0.28; 95% confidence interval, 0.11-0.71; P = 0.008).. The administration of, predominantly, levetiracetam for AED prophylaxis after ICH reduced the odds of new seizure events, independently of the admission NIHSS score and the presence of cortical involvement.

Topics: Aged; Anticonvulsants; Cerebral Hemorrhage; Female; Humans; Incidence; Levetiracetam; Male; Middle Aged; Retrospective Studies; Seizures

Prophylactic levetiracetam is currently used in ~40% of patients with intracerebral hemorrhage, and the potential impact of levetircetam on health-related quality of life is unknown. We tested the hypothesis that prophylactic levetiracetam is independently associated with differences in cognitive function health-related quality of life.. Patients with intracerebral hemorrhage were enrolled in a prospective cohort study. We performed mixed models for T-scores of health-related quality of life, referenced to the U.S. population at 50 ± 10, accounting for severity of injury and time to follow-up.. Academic medical center.. One-hundred forty-two survivors of intracerebral hemorrhage.. None.. T-scores of Neuro-Quality of Life Cognitive Function v2.0 was the primary outcome, whereas Neuro-Quality of Life Mobility v1.0 and modified Rankin Scale (a global functional scale) were secondary measures. We prospectively documented if prophylactic levetiracetam was administered and retrieved administration data from the electronic health record. Patients who received prophylactic levetiracetam had worse cognitive function health-related quality of life (T-score 5.1 points lower; p = 0.01) after adjustment for age (p = 0.3), National Institutes of Health Stroke Scale (p < 0.000001), lobar hematoma (p = 0.9), and time of assessment; statistical models controlling for prophylactic levetiracetam and the Intracerebral Hemorrhage Score, a global measure of intracerebral hemorrhage severity, yielded similar results. Lower T-scores of cognitive function health-related quality of life at 3 months were correlated with more total levetiracetam dosage (p = 0.01) and more administered doses of levetiracetam in the hospital (p = 0.03). Patients who received prophylactic levetiracetam were more likely to have a lobar hematoma (27/38 vs 19/104; p < 0.001), undergo electroencephalography monitoring (15/38 vs 21/104; p = 0.02), but not more likely to have clinical seizures (4/38 vs 7/104; p = 0.5). Levetiracetam was not independently associated with the modified Rankin Scale scores or mobility health-related quality of life (p > 0.1).. Prophylactic levetiracetam was independently associated with lower cognitive function health-related quality of life at follow-up after intracerebral hemorrhage.

Topics: Anticonvulsants; Cerebral Hemorrhage; Cognition; Cognitive Dysfunction; Female; Humans; Levetiracetam; Male; Middle Aged; Prospective Studies; Quality of Life; Seizures

Prophylactic anticonvulsants are routinely prescribed in the acute setting for intracerebral hemorrhage (ICH) patients, but some studies have reported an association with worse outcomes. We sought to characterize the prevalence and predictors of prophylactic anticonvulsant administration after ICH as well as guideline adherence. We also sought to determine whether prophylactic anticonvulsants were independently associated with poor outcome.. We performed a retrospective study of primary ICH in our two academic centers. We used a propensity matching approach to make treated and non-treated groups comparable. We conducted multiple logistic regression analysis to identify independent predictors of prophylactic anticonvulsant initiation and its association with poor outcome as measured by modified Rankin score.. We identified 610 patients with primary ICH, of whom 98 were started on prophylactic anticonvulsants. Levetiracetam (97%) was most commonly prescribed. Age (OR 0.97, 95% CI 0.95-0.99, p < .001), lobar location (OR 2.94, 95% CI 1.76-4.91, p < .001), higher initial National Institutes of Health Stroke Scale (NIHSS) score (OR 2.31, 95% CI 1.40-3.79, p = .001), craniotomy (OR 3.06, 95% CI 1.51-6.20, p = .002), and prior ICH (OR 2.36, 95% CI 1.10-5.07, p = .028) were independently associated with prophylactic anticonvulsant initiation. Prophylactic anticonvulsant use was not associated with worse functional outcome [modified Rankin score (mRS) 4-6] at hospital discharge or with increased case-fatality. There was no difference in prescribing patterns after 2010 guideline publication.. Levetiracetam was routinely prescribed following ICH and was not associated with worse outcomes. Future investigations should examine the effect of prophylactic levetiracetam on cost and neuropsychological outcomes as well as the role of continuous EEG in identifying subclinical seizures.

Topics: Adult; Aged; Aged, 80 and over; Anticonvulsants; Cerebral Hemorrhage; Drug Prescriptions; Female; Guideline Adherence; Humans; Levetiracetam; Male; Middle Aged; Outcome Assessment, Health Care; Piracetam; Prevalence; Retrospective Studies; Seizures

Prophylactic medications can be a source of preventable harm, potentially affecting large numbers of patients. Few data exist about how clinicians change prescribing practices in response to new data and revisions to guidelines about preventable harm from a prophylactic medication. We sought to determine the changes in prescribing practice of seizure medications for patients with intracerebral hemorrhage (ICH) across a metropolitan area before and after new outcomes data and revised prescribing guidelines were published.. We conducted an observational study using electronic medical record data from 4 academic medical centers in a large US metropolitan area.. A total of 3,422 patients with ICH, diagnosed between 2007 and 2012, were included. In 2009, after a publication found an association of phenytoin with higher odds of dependence or death, the use of phenytoin declined from 9.6% in 2009 to 2.2% in 2012 (p < 0.00001). Conversely, the use of levetiracetam more than doubled, from 15.1% in 2007 to 35% in 2012 (p < 0.00001). Use of levetiracetam varied among the 4 institutions from 6.7% to 29.8% (p < 0.00001).. New data that led to revised prescribing guidelines for prophylactic seizure medications for patients with ICH were temporally associated with a significant decrease in use of the medication, potentially reducing adverse outcomes. However, a corresponding increase in the use of an alternative medication, levetiracetam, occurred despite limited knowledge about its potential effects on outcomes. Future guideline changes should anticipate and address alternatives.

Topics: Adult; Aged; Anticonvulsants; Cerebral Hemorrhage; Cohort Studies; Craniotomy; Electronic Health Records; Female; Humans; Levetiracetam; Male; Middle Aged; Phenytoin; Piracetam; Seizures

Cardiac dysfunction occurring secondary to neurologic disease, termed neurogenic stunned myocardium, is an incompletely understood phenomenon that has been described after several distinct neurologic processes. We present a case of neurogenic stunned myocardium, discovered intraoperatively after anesthetic induction, in a patient who presented to our operating room with a recent intraparenchymal hemorrhage. We discuss the longitudinal cardiac functional course after neurogenic stunned myocardium. Finally, we discuss the pathophysiology of neurogenic stunned myocardium, as well as its implications for anesthesiologists caring for neurosurgical patients.

Topics: Adult; Anesthesia, General; Cerebral Hemorrhage; Emergency Service, Hospital; Heart; Hemangioma, Cavernous, Central Nervous System; Humans; Hypertension; Hypotension; Levetiracetam; Male; Methamphetamine; Myocardial Stunning; Nicardipine; Perioperative Period; Phenylephrine; Piracetam; Seizures; Substance-Related Disorders; Takotsubo Cardiomyopathy

Prophylactic antiseizure drugs (PAD) are commonly prescribed for non-traumatic intracerebral hemorrhage (ICH) despite limited evidence for this indication. We sought to determine the current prescribing patterns of the use of a PAD for ICH.. A 36-item survey was distributed to physicians who manage ICH patients soliciting details of PAD prescription in their practice.. A total of 199 physicians responded to the survey, all of who manage 50 or more ICH patients per year. The respondents were neurologists (32%), neurosurgeons (11%), and intensivists (57%) in academia (69%) and private practice (31%). Prophylactic antiseizure drugs prescriptions used: never (33%), 1-33% (35%), 34-66% (14%), 67-99% (9%) of the time, or always (9%). Most respondents performed electroencephalographic and serum level monitoring in at least some patients. Levetiracetam was used most often (60%), followed by fosphenytoin (37%), for a usual duration of days (36%), weeks (47%), or months (17%). Prophylactic antiseizure drugs prescription varied by patient characteristics and physician specialty. Perception of physician community consensus regarding PAD use for ICH among respondents ranged from strongly (7%) or weakly (23%) against the practice, to a fairly equal division of opinion (41%), to weakly (27%) or strongly (4%) in favor of the practice.. We found variability of multiple aspects of the current prescribing patterns and opinions regarding the use of a PAD for ICH. This variability is likely secondary to insufficient data. Clinical equipoise exists for this issue, and controlled trials would be both justified and useful.

Topics: Anticonvulsants; Brain; Cerebral Hemorrhage; Drug Prescriptions; Drug Utilization; Electroencephalography; Humans; Levetiracetam; Phenytoin; Piracetam; Practice Patterns, Physicians'; Seizures; Surveys and Questionnaires

Cerebral cavernous malformations (CCM) are vascular malformations causing seizures and cerebral hemorrhages. They occur in sporadic and familial forms. Familial cases are associated with a high frequency of multiple lesions, which are less frequently associated with sporadic cases.. We report a 46-year-old woman presenting with epilepsy with multiple cerebral cavernomatosis on MRI. Because she had had a previous liver transplantation operation, and received immunosuppressants, she was not advised to have a brain operation. However, she had to be operated as a result of a bleeding in one of her cerebral cavernomas. The histologic diagnosis was cavernoma. She has been seizure free after the operation with levetiracetam therapy for the last 17 months. She had no positive family history for both epilepsy and cavernomatosis.. When multiple cerebral cavernomatosis are identified in a patient, a detailed neurologic family history should be sought despite the possibility of its being a sporadic case. Our main intention is to present a patient who is surgically controversial and to point out the importance of genetic heredity.

Topics: Adult; Anticonvulsants; Brain; Cerebral Hemorrhage; Chromosomes, Human, Pair 7; Epilepsy; Family Health; Female; Genetic Predisposition to Disease; Hemangioma, Cavernous, Central Nervous System; Humans; KRIT1 Protein; Levetiracetam; Magnetic Resonance Imaging; Male; Microtubule-Associated Proteins; Middle Aged; Mutation; Neoplasms, Multiple Primary; Neurosurgical Procedures; Piracetam; Proto-Oncogene Proteins; Tomography, X-Ray Computed; Treatment Outcome

Topics: Brain Ischemia; Cerebral Hemorrhage; Humans; Infarction; Levetiracetam; Male; Middle Aged; Nootropic Agents; Piracetam; Treatment Outcome; Tremor

Levetiracetam (LEV) is used in the setting of acute brain injury for seizure treatment or prophylaxis but its safety and efficacy in this setting is unknown.. We retrospectively analyzed the patterns of use and safety/efficacy of LEV in 379 patients treated in the neuroscience intensive care unit (NSICU). We extracted from the charts clinical data including diagnosis, AED therapy before and during stay in the NSICU, complications of treatment, length of stay, and clinical outcomes (improvement, Glasgow Coma Scale, and death). We analyzed the data using binary and ordered (multi-category) logistic regression.. Overall, our findings are that phenytoin used prior to the NSICU admission was frequently replaced with LEV monotherapy (P < 0.001). Patients treated with LEV monotherapy when compared to other AEDs had lower complication rates and shorter NSICU stays. Older patients and patients with brain tumors or strokes were preferentially treated with LEV for prevention and/or management of seizures (all P < or = 0.014).. The results of this study suggest that LEV is a frequently used AED in the setting of acute brain injury and that it may be a desirable alternative to phenytoin. Prospective studies evaluating the long-term safety, efficacy and outcomes of LEV in this setting are indicated.

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Anticonvulsants; Brain Diseases; Brain Neoplasms; Cerebral Hemorrhage; Comorbidity; Critical Illness; Epilepsy; Humans; Intensive Care Units; Length of Stay; Levetiracetam; Middle Aged; Piracetam; Retrospective Studies; Stroke; Treatment Outcome