Randolph S. Marshall

A Trial of Imaging Selection and Endovascular Treatment for Ischemic Stroke

BACKGROUND Whether brain imaging can identify patients who are most likely to benefit from therapies for acute ischemic stroke and whether endovascular thrombectomy improves clinical outcomes in such patients remains unclear. METHODS In this study, we randomly assigned patients within 8 hours after the onset of large-vessel, anterior-circulation strokes to undergo mechanical embolectomy (Merci Retriever or Penumbra System) or receive standard care. All patients underwent pretreatment computed tomography or magnetic resonance imaging of the brain. Randomization was stratified according to whether the patient had a favorable penumbral pattern (substantial salvageable tissue and small infarct core) or a nonpenumbral pattern (large core or small or absent penumbra). We assessed outcomes using the 90-day modified Rankin scale, ranging from 0 (no symptoms) to 6 (dead). RESULTS Among 118 eligible patients, the mean age was 65.5 years, the mean time to enrollment was 5.5 hours, and 58% had a favorable penumbral pattern. Revascularization in the embolectomy group was achieved in 67% of the patients. Ninety-day mortality was 21%, and the rate of symptomatic intracranial hemorrhage was 4%; neither rate differed across groups. Among all patients, mean scores on the modified Rankin scale did not differ between embolectomy and standard care (3.9 vs. 3.9, P=0.99). Embolectomy was not superior to standard care in patients with either a favorable penumbral pattern (mean score, 3.9 vs. 3.4; P=0.23) or a nonpenumbral pattern (mean score, 4.0 vs. 4.4; P=0.32). In the primary analysis of scores on the 90-day modified Rankin scale, there was no interaction between the pretreatment imaging pattern and treatment assignment (P=0.14). CONCLUSIONS A favorable penumbral pattern on neuroimaging did not identify patients who would differentially benefit from endovascular therapy for acute ischemic stroke, nor was embolectomy shown to be superior to standard care. (Funded by the National Institute of Neurological Disorders and Stroke; MR RESCUE ClinicalTrials.gov number, NCT00389467.).

Inter-individual Variability in the Capacity for Motor Recovery After Ischemic Stroke

Background. Motor recovery after stroke is predicted only moderately by clinical variables, implying that there is still a substantial amount of unexplained, biologically meaningful variability in recovery. Regression diagnostics can indicate whether this is associated simply with Gaussian error or instead with multiple subpopulations that vary in their relationships to the clinical variables. Objective. To perform regression diagnostics on a linear model for recovery versus clinical predictors. Methods. Forty-one patients with ischemic stroke were studied. Impairment was assessed using the upper extremity Fugl-Meyer Motor Score. Motor recovery was defined as the change in the upper extremity Fugl-Meyer Motor Score from 24 to 72 hours after stroke to 3 or 6 months later. The clinical predictors in the model were age, gender, infarct location (subcortical vs cortical), diffusion weighted imaging infarct volume, time to reassessment, and acute upper extremity Fugl-Meyer Motor Score. Regression diagnostics included a Kolmogorov-Smirnov test for Gaussian errors and a test for outliers using Studentized deleted residuals. Results. In the random sample, clinical variables explained only 47% of the variance in recovery. Among the patients with the most severe initial impairment, there was a set of regression outliers who recovered very poorly. With the outliers removed, explained variance in recovery increased to 89%, and recovery was well approximated by a proportional relationship with initial impairment (recovery ≅ 0.70 × initial impairment). Conclusions. Clinical variables only moderately predict motor recovery. Regression diagnostics demonstrated the existence of a subpopulation of outliers with severe initial impairment who show little recovery. When these outliers were removed, clinical variables were good predictors of recovery among the remaining patients, showing a tight proportional relationship to initial impairment.

Stroke, cognitive deficits, and rehabilitation: still an incomplete picture

Cognitive impairment after stroke is common and can cause disability with major impacts on quality of life and independence. There are also indirect effects of cognitive impairment on functional recovery after stroke through reduced participation in rehabilitation and poor adherence to treatment guidelines. In this article, we attempt to establish the following: • whether there is a distinct profile of cognitive impairment after stroke; • whether the type of cognitive deficit can be associated with the features of stroke-related damage; and • whether interventions can improve poststroke cognitive performance. There is not a consistent profile of cognitive deficits in stroke, though slowed information processing and executive dysfunction tend to predominate. Our understanding of structure-function relationships has been advanced using imaging techniques such as lesion mapping and will be further enhanced through better characterization of damage to functional networks and identification of subtle white matter abnormalities. Effective cognitive rehabilitation approaches have been reported for focal cortical deficits such as neglect and aphasia, but treatments for more diffusely represented cognitive impairment remain elusive. In the future, the hope is that different techniques that have been shown to promote neural plasticity (e.g., exercise, brain stimulation, and pharmacological agents) can be applied to improve the cognitive function of stroke survivors.

Improvement in Aphasia Scores After Stroke Is Well Predicted by Initial Severity

Background and Purpose— Most improvement from poststroke aphasia occurs within the first 3 months, but there remains unexplained variability in recovery. Recently, we reported a strong correlation between initial impairment and change scores in motor recovery at 90 days. We wanted to determine whether aphasia recovery (defined as a change from baseline to 90 days) shows a comparably strong correlation and whether the relation was similar to that in motor recovery. Methods— Twenty-one stroke patients had aphasia scores on the Western Aphasia Battery (WAB) obtained on stroke admission (WABinitial) and at 90 days (WAB3 mo). The relation between actual change (&Dgr;) scores (defined as WAB3 mo− WABinitial) and WABinitial was calculated in multiple-regression analysis. Results— Regression analysis demonstrated that WABinitial was highly correlated with &Dgr;WAB (R2=0.81, P<0.001) and that, in addition, the relation between WABinitial and &Dgr;WAB was proportional, such that patients recovered 0.73 of maximal potential recovery (WABmaximum−WABinitial). Conclusions— We show that, like motor recovery, there is a highly predictable relation between aphasia recovery and initial impairment, which is also proportional in nature. The comparability of recovery from motor and language impairment suggests that common mechanisms may govern reduction of poststroke neurologic impairment across different functional domains and that they could be the focus of therapeutic intervention.

Urgent endovascular revascularization for symptomatic intracranial atherosclerotic stenosis

Background: Endovascular revascularization for intracranial atherosclerotic stenoses is being increasingly performed at major medical centers and has been reported to be technically feasible and safe. The authors report their experience with patients who underwent such a procedure for impending stroke and neurologic instability. Method: All 18 patients (21 intracranial lesions) treated between 1997 and 2002 at the authors’ institution with endovascular revascularization were retrospectively reviewed. Each patient had failed maximal medical therapy and was thought to be at high risk for an imminent stroke. Results: Endovascular revascularization was performed on eight distal internal carotid artery lesions, six middle cerebral artery lesions, four intracranial vertebral artery lesions, and three basilar artery lesions. Recanalization was complete in 5 arteries (Thrombolysis in Myocardial Infarction [TIMI] Grade III), partial in 14 arteries (TIMI Grade II), and complete occlusion (TIMI 0) developed in 1 artery. In a patient with a tight basilar stenosis, no angioplasty could be performed because of the inability to cross the stenosis with the guidewire. Major periprocedural complications occurred in 9 (50%) patients: intracranial hemorrhage in 3 (17%), disabling ischemic stroke in 2 (11%), and major extracranial hemorrhage in 4 (22%). Three patients died: one from intracerebral hemorrhage and two from cardiorespiratory failure. Conclusions: Endovascular revascularization of intracranial vessels is technically feasible and may be performed successfully. However, periprocedural complication and fatality rates in neurologically unstable patients are high. The results suggest that patient selection, procedure timing, and periprocedural medical management are critical factors to reduce periprocedural morbidity and mortality.

Variability in language recovery after first-time stroke

Background: Predicting aphasia recovery after stroke has been difficult due to substantial variability in outcomes. Few studies have characterised the nature and extent of recovery, beginning with baselines at 24–72 hours after stroke onset. Aim: To characterise the course of language recovery after first-time stroke. Methods: Using our Performance and Recovery in Stroke Study (PARIS) database, we evaluated consecutive first-time stroke patients with aphasia and diffusion-weighted-image-positive lesions on admission and at 90 days. Results: Twenty-two of 91 patients had language disorders. Initial syndrome scores were positively correlated with 90-day scores (r = 0.60) and negatively correlated with the change in score from baseline to follow-up (r = −0.66). Neither lesion size, age nor education correlated with initial syndrome severity or with performance at 90 days. Level of education was not associated with degree of recovery. A multiple regression model that combined lesion size, age and initial syndrome was significant (p = 0.03) but only explained 29% of the variance. Patients with severe deficits at baseline in individual language domains could recover, improve to a less severe deficit or not improve at all. Conclusion: There was significant variability in language recovery after first-time stroke, even in more severe, initial syndromes. Traditional predictors of post-stroke language outcomes did not reliably predict function at 90 days. These data suggest that other factors that account for functional stroke recovery have not yet been identified.

Neuroimaging in Stroke Recovery: A Position Paper from the First International Workshop on Neuroimaging and Stroke Recovery

Baron, Jean-Claude*Black, Sandra E.Butler, Andrew J.Carey, JamesChollet, FrancoisCohen, Leonardo G.*Corbetta, MaurizioCramer, Steven C.*Dobkin, Bruce H.*Frackowiak, RichardHeiss, W.D.Johansen-Berg, Heidi*Krakauer, John W.Lazar, Ronald M.Lennihan, Laura L.Loubinoux, Isabelle*Marshall, Randolph S.*Matthews, PaulMohr, J.P.Nelles, GereonPascual-Leone, AlvaroPomeroy, ValerieRijntjes, MichelRossini, Paolo MariaRothwell, John C.Seitz, Rudiger J.Small, Steven L.Sunderland, AlanWard, N.S.*Weiller, CorneliusWise, Richard J.S.IntroductionThe First International Workshop on Neuroimagingand Stroke Recovery was convened in February, 2004 inNew York City. The purpose of the workshop was to de-scribe the state of the field with regard to technical andanalytical methods, to discuss the use of complementaryimaging modalities, and to assess the current potential toapply functional neuroimaging to the development of ratio-nal treatment strategies for enhanced stroke recovery.Presented herein is a summary statement of topics dis-cussed at the workshop. These included (i) the clinical rel-evance of functional imaging changes after stroke for themotor and language systems; (ii) the technical challengesfaced in moving towards establishing functional neuro-imaging as a clinically useful tool; (iii) the contributions ofneurophysiological probes such as transcranial magnet-ic stimulation (TMS) to improve understanding of themechanisms underlying brain reorganization after stroke;and (iv) the potential role of neuroimaging in the assess-ment and development of rational pharmacological andbehavioral therapies.Clinical RelevanceFunctional recovery commonly occurs in survivingstroke patients in the weeks and months following theinjury. There is evidence from animal models that cere-bral reorganization underlies at least some of this recov-ery and it is hoped that an understanding of the neuro-physiological processes underlying this reorganization inthe human brain will lead to a rational approach to thetreatment of impairment. In animal models, focal braindamage triggers a number of changes at the molecular, cel-lular, and systems level, some of which alter the potentialfor cerebral reorganization and consequent functionalrecovery. Although the same techniques are not availableto study the working human brain, functional brain imag-ing has provided insights into how the human brainresponds to focal injury.

Improvement After Constraint-Induced Movement Therapy Recovery of Normal Motor Control or Task-Specific Compensation?

Background. Constraint-induced movement therapy (CIMT) has proven effective in increasing functional use of the affected arm in patients with chronic stroke. The mechanism of CIMT is not well understood. Objective. To demonstrate, in a proof-of-concept study, the feasibility of using kinematic measures in conjunction with clinical outcome measures to better understand the mechanism of recovery in chronic stroke patients with mild to moderate motor impairments who undergo CIMT. Methods. A total of 10 patients with chronic stroke were enrolled in a modified CIMT protocol over 2 weeks. Treatment response was assessed with the Action Research Arm Test (ARAT), the Upper-Extremity Fugl-Meyer score (FM-UE), and kinematic analysis of visually guided arm and wrist movements. All assessments were performed twice before the therapeutic intervention and once afterward. Results. There was a clinically meaningful improvement in ARAT from the second pre-CIMT session to the post-CIMT session compared with the change between the 2 pre-CIMT sessions. In contrast, FM-UE and kinematic measures showed no meaningful improvements. Conclusions. Functional improvement in the affected arm after CIMT in patients with chronic stroke appears to be mediated through compensatory strategies rather than a decrease in impairment or return to more normal motor control. We suggest that future large-scale studies of new interventions for neurorehabilitation track performance using kinematic analyses as well as clinical scales.

Early imaging correlates of subsequent motor recovery after stroke

To determine whether functional magnetic resonance imaging activation obtained in the first few days after stroke correlates with subsequent motor recovery.

Interhemispheric transfer of language in patients with left frontal cerebral arteriovenous malformation.

Cerebral arteriovenous malformations (AVMs) are frequently evaluated before therapeutic embolization by superselective injection of anesthetics into individual arterial branches so as to determine whether permanent occlusion would affect eloquent function. In Experiment 1, we used this adaptation of the Wada procedure to study three right-handed adult patients with left frontal cerebral AVMs by injecting vessels in Wernickes and Brocas areas, respectively, and assessing language functions. The results showed that superselective testing in the inferior division of the left MCA in all three patients produced a dense Wernickes aphasia. Injections into the left frontal regions, however, resulted in right paresis in all patients, but no language deficits including no loss of fluency. In Experiment 2, Patient 2 underwent fMRI activation for spontaneous word-list generation using multi-slice echo planar BOLD techniques at 1.5 Tesla. A voxel-by-voxel comparison of rest vs activation for each task was performed with a Z-score threshold of 2.5 SD for activated voxels. There was activation in the right hemisphere in the insula, frontal operculum pars opercularis, and inferior frontal gyrus, an area homologous to Brocas area in the left hemisphere. There was also activation in the left hemisphere in the Rolandic region, but language function was unaffected during Wada testing in this area. These data suggested that features of expressive language were no longer controlled by the left frontal lobe where the AVM was located, and provided new evidence for interhemispheric re-organization under conditions of chronic neurovascular disease.