David S. Liebeskind

Trends in Acute Ischemic Stroke Trials Through the 20th Century

Background and Purpose— The advent of controlled clinical trials revolutionized clinical medicine over the course of the 20th century. The objective of this study was to quantitatively characterize developments in clinical trial methodology over time in the field of acute ischemic stroke. Methods— All controlled trials targeting acute ischemic stroke with a final report in English were identified through MEDLINE and international trial registries. Data regarding trial design, implementation, and results were extracted. A formal 100-point scale was used to rate trial quality. Results— A total of 178 controlled acute stroke trials were identified, encompassing 73 949 patients. Eighty-eight trials involved neuroprotective agents, 59 rheological/antithrombotic agents, 26 agents with both neuroprotective and rheological/antithrombotic effects, and 5 a nonpharmacological intervention. Only 3 trials met conventional criteria for a positive outcome. Between the 1950s and 1990s, the number of trials per decade increased from 3 to 99, and mean trial sample size increased from 38 (median, 26) to 661 (median, 113). During 1980–1999, median time window allowed for enrollment decreased per half decade from 48 to 12 hours. Reported pharmaceutical sponsorship increased substantially over time, from 38% before 1970 to 68% in the 1990s. Trial quality improved substantially from a median score of 12 in the 1950s to 72 in the 1990s. Conclusions— Accelerating trends in acute stroke controlled trials include growth in number, sample size, and quality, and reduction in entry time window. These changes reflect an increased understanding of the pathophysiology of acute stroke, the imperative for treatment initiation within a critical time window, and more sophisticated trial design.

Utility of the NIH Stroke Scale as a Predictor of Hospital Disposition

Background and Purpose— Early identification of stroke patients in need of rehabilitation or long-term nursing facility (NF) care may promote more efficient use of health care resources and lead to better outcomes. The NIH Stroke Scale (NIHSS) is an attractive candidate predictor of disposition because it is widely used, is easily learned, and can be performed rapidly on admission. Methods— We present a retrospective study of stroke patients admitted within 24 hours of symptom onset to a university hospital from March through June 2000. Medical records were reviewed for demographic information, stroke type, prestroke living arrangement and independence, initial NIHSS, and medical complications during hospitalization. Results— Among 94 patients evaluated during the study period, 59% were discharged home, 30% to rehabilitation, and 11% to NF. In multivariate analyses, disposition was associated only with initial NIHSS. For each 1-point increase in NIHSS, the likelihood of going home was significantly reduced (odds ratio, 0.79; 95% CI, 0.70 to 0.89, P <0.001). Categorization of NIHSS was also predictive of disposition, with NIHSS ≤5 being most strongly associated with discharge home, NIHSS 6 to 13 with rehabilitation, and NIHSS >13 with NF (P <0.001). Although no other baseline characteristics predicted disposition, major medical complications during hospitalization tended to reduce the odds of going home (odds ratio, 0.30; 95% CI, 0.08 to 1.0, P =0.07). Conclusion— The NIHSS predicts postacute care disposition among stroke patients. Predicting disposition on the first day of admission may facilitate the time-consuming and costly process of securing a bed at rehabilitation or NF, and perhaps decrease unnecessary length of stay in acute care settings.

Late secondary ischemic injury in patients receiving intraarterial thrombolysis

Although animal models have demonstrated that late secondary cerebral injury after arterial occlusion and subsequent recanalization may limit the benefit of reperfusion therapy, this phenomenon has not been well characterized in humans. Diffusion‐perfusion magnetic resonance imaging studies were performed before treatment, early after treatment, and at day 7 in patients undergoing vessel recanalization with intraarterial thrombolytics. Among 18 patients studied, mean age was 71 (range, 27–94), and median entry National Institutes of Health Stroke Scale score was 13 (range, 6–25). Early after recanalization, partial or complete normalization of diffusion imaging abnormalities occurred in 8 of 18 (44%) patients. Among the eight patients with early diffusion imaging reversal, late secondary injury by day 7 occurred in 5 (63%), and sustained normalization of all reversed tissue occurred in 3 (38%). Pretreatment apparent diffusion coefficient values were lowest in regions experiencing no reversal (mean apparent diffusion coefficient, 608μm2/sec), intermediate in regions with reversal and secondary decline (617μm2/sec), and highest in regions with sustained reversal (663μm2/sec). There was a trend toward less improvement in neurological deficit in patients with secondary injury versus patients with sustained reversal. In the future, late secondary tissue injury may become an important therapeutic target for postreperfusion neuroprotective therapies, with treatment efficacy monitored by serial diffusion magnetic resonance imaging.

Diffusion-perfusion MR evaluation of perihematomal injury in hyperacute intracerebral hemorrhage

Background: It has been suggested that a zone of perihematomal ischemia analogous to an ischemic penumbra exists in patients with primary intracerebral hemorrhage (ICH). Diffusion-perfusion MRI provides a novel means of assessing injury in perihematomal regions in patients with ICH. Objective: To characterize diffusion-perfusion MRI changes in the perihematomal region in patients with hyperacute intracerebral hemorrhage. Method: Twelve patients presenting with hyperacute, primary ICH undergoing CT scanning and diffusion-perfusion MRI within 6 hours of symptom onset were reviewed. An automated thresholding technique was used to identify decreased apparent diffusion coefficient (ADC) values in the perihematomal regions. Perfusion maps were examined for regions of relative hypo- or hyperperfusion. Results: Median baseline NIH Stroke Scale score was 17 (range, 6 to 28). Median hematoma volume was 13.3 mL (range, 3.0 to 74.8 mL). MRI detected the hematoma in all patients on echo-planar susceptibility-weighted imaging and in all seven patients imaged with gradient echo sequences. In six patients who underwent perfusion imaging, no focal defects were visualized on perfusion maps in tissues adjacent to the hematoma; however, five of six patients demonstrated diffuse ipsilateral hemispheric hypoperfusion. On diffusion imaging, perihematomal regions of decreased ADC values were identified in three of 12 patients. All three subsequently showed clinical and radiologic deterioration. Conclusions: A rim of perihematomal decreased ADC values was visualized in the hyperacute period in a subset of patients with ICH. The presence of a rim of decreased ADC outside the hematoma correlated with poor clinical outcome. Although perfusion maps did not demonstrate a focal zone of perihematomal decreased blood flow in any patient, most patients had ipsilateral hemispheric hypoperfusion.

Diffusion-perfusion MRI characterization of post-recanalization hyperperfusion in humans

Background: Animal and human studies have demonstrated that postischemic hyperperfusion may occur both early and late timepoints following acute cerebral ischemia. Objective: To use diffusion-perfusion MRI to characterize hyperperfusion in humans following intra-arterial thrombolysis. Methods: MRI were performed before treatment, several hours following vessel recanalization, and at day 7 in patients successfully recanalized with intra-arterial thrombolytics. Results: Hyperperfusion was visualized in 5 of 12 patients within several hours after recanalization (mean volume, 18 mL; range, 7 to 40 mL), and in 6 of 11 patients at day 7 (mean volume, 28 mL; range, 4 to 45 mL). Within the core region of hyperperfusion, mean cerebral blood flow was 2.1 times greater than in the contralateral homologous region at the early time point, and 3.1 times greater at day 7. Seventy-nine percent of voxels with hyperperfusion at day 7 demonstrated infarction at day 7, whereas only 36% of voxels (within the initial hypoperfusion region) not showing hyperperfusion at day 7 demonstrated infarction at day 7. Mean pretreatment apparent diffusion coefficient (ADC) and perfusion values were more impaired in voxels that subsequently developed hyperperfusion compared with other at-risk voxels (all p values < 0.0001). There were no significant differences in the degree of clinical improvement in patients with regions of hyperperfusion versus those without, although sample size limited power to detect group differences. Conclusions: Postischemic hyperperfusion, visualized with perfusion MRI in humans following recanalization by intra-arterial thrombolytic therapy, occurred in about 40% of patients within hours and in about 50% of patients at day 7. Hyperperfusion developed mainly in regions that went on to infarction. Compared with other abnormal regions, tissues that developed postischemic hyperperfusion had greater bioenergetic compromise in pretreatment apparent diffusion coefficient values and greater impairment in pretreatment blood flow measures.

Neuroprotection for ischaemic stroke : An unattainable goal?

Neuroprotective therapies for acute ischaemic stroke have yet to be realised despite the determined efforts of basic science and clinical investigators. Progressive elucidation of the complex pathophysiology involved in the ischaemic cascade has led to the development of numerous candidate interventions. Preliminary efficacy in animal models has repeatedly resulted in frustration after extensive clinical testing. Failure in the translation of results from animal models to humans implicates potential limitations of the current drug development process. Reflection on prior studies suggests possible flaws at several stages. Incorporation of standardised guidelines for preclinical testing of putative neuroprotective therapies and modification of clinical trial design, methodology and reporting may improve chances for success. The future of neuroprotection for stroke remains bright in spite of previous disappointments.

FDG-PET findings in patients with suspected encephalitis.

Purpose: Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) may be used to establish a diagnosis of encephalitis, yet prior descriptions are mainly limited to small case reports. We explore the role of FDG-PET in the diagnostic evaluation of encephalitis. Methods: Brain FDG-PET was acquired in a consecutive case series of 10 cases of suspected encephalitis over a 5-year-period. Cases with positive Lyme serology were excluded. Two expert reviewers graded the FDG-PET studies in blinded fashion with respect to the clinical history. Retrospective review of the clinical history and examination, laboratory findings, electroencephalogram (EEG), and magnetic resonance imaging (MRI) studies was performed. A diagnosis of encephalitis was based on a combination of the clinical and diagnostic examination findings in each case. Results: Encephalitis was diagnosed in 6 of 10 cases. FDG-PET hypermetabolism was demonstrated in 5 cases of encephalitis, most frequently involving the medial temporal lobes. Multifocal hypometabolism was noted in at least 2 regions in all 6 cases of encephalitis, with at least 4 regions of hypometabolism noted in 5 of 6 cases. Nonencephalitis cases revealed hypermetabolism in only 1 of 4 cases, ascribed to status epilepticus. Hypometabolism was evident in all nonencephalitis cases. Conclusion: Encephalitis frequently manifests as FDG-PET hypermetabolism, but focal hypometabolism can also be observed. Seizure activity must be excluded as a possible cause of hypermetabolism in patients suspected of having encephalitis. Because other conditions that can cause hypometabolism may mimic encephalitis clinically, FDG-PET is more likely to serve as an adjunct to lumbar puncture, EEG, and clinical findings rather than a primary diagnostic tool in the management of patients suspected of having encephalitis.

Modified National Institutes of Health Stroke Scale Can Be Estimated From Medical Records

Background and Purpose— The 15-item National Institutes of Health Stroke Scale (NIHSS) is a quantitative measure of stroke-related neurological deficit with established reliability and validity for use in clinical research. An abridged 11-item modified NIHSS (mNIHSS) has been described that simplifies or eliminates redundant and less reliable items. We aimed to determine whether the mNIHSS could be accurately abstracted from medical records to facilitate retrospective research. Methods— We selected 39 patient records for which NIHSS scores were formally measured. Handwritten notes from medical records were abstracted, and NIHSS item scores were estimated by 5 raters blinded to actual scores. Estimated scores were compared among raters and with actual measured scores. Results— Interrater reliability for total NIHSS on admission and discharge was excellent, with intraclass correlation coefficients (ICCs) of 0.85 and 0.79, respectively. However, ICCs for 2 items (facial palsy and dysarthria) were poor (<0.40). Interrater reliability for total mNIHSS was slightly greater, with ICCs of 0.87 and 0.89 on admission and discharge, respectively. None of the 11 mNIHSS items had poor reliability, 4 were moderate (ICC, 0.40 to 0.75), and 7 were excellent (ICC >0.75). Sixty-two percent of estimated total NIHSS scores were within 2 points of actual scores and 91% were within 5 points, whereas 70% of estimated total mNIHSS scores were within 2 points and 95% were within 5 points. Conclusions— The mNIHSS can be estimated from medical records with a high degree of reliability and validity. In retrospective assessment of stroke severity, the mNIHSS performs better than the standard NIHSS and may be easier to use because it has fewer and simpler items.

Indices of Kidney Dysfunction and Discharge Outcomes in Hospitalized Stroke Patients without Known Renal Disease

Background: The utility of clinical measurements of impairments in glomerular barrier or filtration rate among hospitalized stroke patients without known chronic kidney disease (CKD) has not been well studied. We determined whether various indices of CKD would predict discharge outcomes in persons hospitalized with a recent ischemic stroke. Methods: Presence of proteinuria and estimated low glomerular filtration rate (GFR) <60 ml/min per 1.73 m2 on admission were assessed in consecutive ischemic stroke and transient ischemic attack patients admitted to a university hospital over 18 months, who had no history of CKD. The primary discharge outcomes assessed (among stroke patients only) were death or disability (modified Rankin Scale score ≥2) and being discharged home directly from hospital. Independent effects of CKD indices on the outcomes were evaluated using multivariable regression modeling. Results: Of 251 patients with recent ischemic cerebrovascular events, 198 ischemic stroke patients (79%), met the study criteria. In crude analyses, persons with proteinuria or low GFR were significantly more likely to die in the hospital (p < 0.05). After adjusting for confounders, proteinuria was independently linked with lower odds of going home directly from the hospital (OR = 0.38, 95% CI = 0.16–0.92) and poorer discharge functional status (OR = 3.19, 95% CI = 1.37–7.46), but low GFR was not independently related to either of these outcomes. Conclusions: Among hospitalized ischemic stroke patients without known CKD, presence of proteinuria on admission is independently associated with poorer discharge functional activity and lower likelihood of being discharged home directly. Low GFR was not related to either outcome in these patients without known CKD.

Impact of metabolic syndrome on distribution of cervicocephalic atherosclerosis: Data from a diverse race-ethnic group

BACKGROUND Vascular localization of symptomatic large artery atherosclerotic (LAA) stroke differs for unknown reasons by race-ethnicity. The metabolic syndrome (MetSD) is associated with higher atherosclerotic stroke risk and comprises abnormal risk factors that can vary by race. Thus, we investigated whether MetSD may contribute to race-ethnic differences in LAA stroke by examining the association of MetSD with symptomatic intra- and extracranial atherosclerosis among a diverse race-ethnic group. METHOD We analyzed data prospectively collected over a 4-year period on subjects with ischemic stroke/TIA. Independent vascular risk factor associations with intracranial and extracranial LAA vs. non-LAA mechanism were evaluated in two groups stratified by race-ethnicity; whites and non-whites (Hispanics, African-American, and Asian-American). RESULTS 1167 patients met study criteria. Intracranial LAA was more prevalent in non-whites vs. whites (20.4% vs. 9.6%, P<0.001), while extracranial LAA had a more frequent point value in whites compared to non-whites (10.7% vs. 7.5%, P=0.267). The presence of MetSD was more prevalent in both intracranial and extracranial LAA group than in non-LAA group: no significant differences were observed in the prevalence of MetSD between intra vs. extracranial LAA or whites vs. non-whites. However, with increasing numbers of abnormal metabolic components, whites were more likely to have experienced extracranial LAA, whereas non-whites were more likely to have experienced intracranial LAA. After adjusting for covariates, MetSD was associated with extracranial LAA in whites (OR, 1.98; 95% CI, 1.13-3.45), while there was a tendency that intracranial LAA was associated with MetSD in non-whites (OR, 1.80; 95% CI, 0.97-3.32). No association was found between MetSD and extracranial LAA in non-whites and between this syndrome with intracranial LAA in whites. CONCLUSIONS Our results showed that the impact of MetSD on the distribution of cervicocephalic atherosclerosis differed by race-ethnicity. This finding may in part explain the well-known differences in race-ethnic predilection to intracranial or extracranial atherosclerosis.