American Heart Association


The CARS Study: Encouraging Results for Stroke Recovery with Cerebrolysin

Ilana Spokoyny, MD

Muresanu DF, Heiss WD, Hoemberg V, Bajenaru O, Popescu CD, Vester JC et al. Cerebrolysin and Recovery After Stroke (CARS): A Randomized, Placebo-Controlled, Double-Blind, Multicenter Trial. Stroke. 2016

The data on neuroprotectants has been quite discouraging so far. Often, an agent will prove effective at reducing stroke size or improving patient outcome in laboratory models of ischemia, but this effect does not always translate to clinical trials. The authors of the CARS study point out that this disconnect may be attributed to inappropriate animal models, and the simplistic design of human clinical trials which have not taken into account the complex parallel pathways which contribute to cerebral ischemia. Previous agents have targeted one pathophysiologic pathway, but the authors suggest that a multi-targeted therapy is necessary. Cerebrolysin, a porcine-derived neuropeptide combination, may in fact be an exception to the notion that neuroprotectants do not work, based on this phase II randomized controlled clinical trial conducted in Romania, Ukraine, and Poland.

Cerebrolysin has been previously shown to be effective in animal models, even when started up to 48 hours post-stroke. It has also been studied in several small clinical trials, and as a subgroup of a larger clinical trial, in which it was shown to improve outcome and reduce mortality after severe stroke. However, the effects did not persist over time, and had disappeared by day 90. In these previous trials, Cerebrolysin was given in the acute phase and for a short duration. The authors comment that the potential neurotrophic and neuroplastic effects may have been overlooked.

The CARS study compared arm motor recovery at 90 days among patients receiving Cerebrolysin or placebo. The trial included 205 patients between 18-80 years old, with supratentorial ischemic strokes at least 4 cc in volume, with baseline mRS 0-1, moderate or minimal aphasia, and minimal to severe arm weakness. The mean baseline NIHSS was 9.2. Patients were treated with IV Cerebrolysin or placebo daily for 21 days, beginning at 24-72 hours post-stroke. All patients also received early aggressive rehabilitation for 21 days, which was started within 72 hours of stroke onset and consisted of exercise 2 hours per day, five days per week. The patients then continued to exercise for 30 minutes per day, 3 days a week post-discharge.

The primary outcome was arm motor function, measured by the Action Research Arm Test score at 90 days. The ARAT score ranges from 0 (no function) to 57 (no limitation). Patients with post-stroke baseline score 0-50 were included. The primary outcome showed a large superiority of Cerebrolysin (increased ARAT in 92%, an average of 30.7 points) over placebo (increased ARAT in 84%, an average of 15.9 points). A good functional outcome (mRS 0-1) was seen in 42% of Cerebrolysin-treated patients compared with 15% of placebo-treated patients. The secondary outcome was a composite of twelve outcome scales, including gait velocity, fine motor function, ADL independence, aphasia, neglect, quality of life, cognition, and depression. The composite outcome showed a small superiority of Cerebrolysin. The safety of Cerebrolysin was equivalent to placebo. The most common adverse effects were UTI, depression, and cytolytic hepatitis in the Cerebrolysin group, and UTI, hypertension, and depression in the placebo group.

A larger-scale phase III randomized trial is needed to ensure that effects were not exaggerated by poor outcomes in the placebo group, small sample size, or the fact that both groups engaged in early and sustained rehabilitation therapy. However, this phase II trial is quite encouraging for the prospect of an effective neuroprotective and neuroplastic agent on the horizon.

Functional gain in stroke rehabilitation a predictor of long-term mortality

Peggy Nguyen, MD

Scrutinio D, Monitillo V, Guida P, Nardulli R, Multari V, Monitillo F, et al. Functional Gain After Inpatient Stroke Rehabilitation: Correlates and Impact on Long-Term Survival. Stroke. 2015

A common scenario vascular neurologists encounter are patients who ask us questions that run the gamut of: What’s going to happen after I leave the hospital or after I leave rehabilitation? The world of stroke has recently been focused on acute interventions at presentation and predictors of outcome acutely, but long-term, what are some of the things we can advise our patients? Here, the authors performed a cross-section study evaluating the association of stroke rehabilitation, as measured by improvement in functional independence motor (FIM) score on admission and discharge, with long-term mortality, as well as predictors of successful stroke rehabilitation.

1010 consecutive patients admitted for stroke rehabilitation with an FIM score < 80 and a recent (< 90 day from onset) ischemic or hemorrhagic stroke were enrolled in the study. Variables identified as independent positive correlates of FIM gain were younger age, being married, lower NIHSS score at time of rehabilitation admission, decreased time from stroke onset to rehabilitation admission, and presence of aphasia. Over a median follow up of 6.17 years, 36.9% of the subjects died. Age, coronary heart disease, atrial fibrillation, total cholesterol, and FIM gain were found to be independently associated with mortality. After adjusting for mortality risk markers, FIM gain remained a predictor of long-term mortality risk.  

These study yielded some interesting results. The finding that FIM gain is a predictor of long-term mortality suggests that better functional improvement with rehabilitation decreases long-term mortality risk in stroke survivors. Of course, as the authors also point out, this association may also be confounded by the finding that younger age and lower NIHSS were associated with higher FIM gain; therefore, mortality may be a reflection of severity of stroke in an older population rather than rehabilitation, but this may still be helpful in how we counsel our patients as we transition them to rehabilitation. In addition, the finding that a higher FIM gain is associated with less time between stroke onset to rehabilitation is highly relevant and, again, not only helps us when counseling patients and their families, but may also aid in decision making at discharge.

By |October 16th, 2015|rehabilitation|1 Comment

Neuromuscular Electrical Stimulation for Post-Stroke Spasticity

Rizwan Kalani, MD  

Stein C, Fritsch CG, Robinson C, Sbruzzi G, and Méa Plentz RD. Effects of Electrical Stimulation in Spastic Muscles After Stroke: Systematic Review and Meta-Analysis of Randomized Controlled Trials. Stroke. 2015

Spasticity occurs in 20-30% of individuals with prior stroke. Common management strategies include administration of GABAergic agents (baclofen), ankle-foot orthotics, physical therapy, and tendon surgeries. Given inconsistent results from prior randomized controlled trials (RCTs), Stein et al did a systematic review and meta-analysis of studies evaluating the effect of neuromuscular electrical stimulation (NMES) on post-stroke spasticity.

The authors reviewed the literature for RCTs that assessed the effect of NMES (with or without additional therapeutic intervention) for spasticity after stroke. Studies evaluating at least three days of NMES, regardless of dosage, and applied to the upper or lower extremities, were included. Two independent reviewers selected the studies, extracted relevant data, and assessed for risk of bias. The primary outcome was spasticity (per the modified ashworth scale) and secondary outcome was range of motion (ROM) (by goniometer).

Of the 29 RCTs (with 940 subjects) that met the inclusion criteria for the systematic review, 14 were included in the meta-analysis (the other 15 had missing data and used other scales to assess spasticity). Most studies used NMES frequencies of 18-50 Hz and pulse duration from 0.1-0.3 seconds. NMES (alone or combined with other treatment) was associated with reduction in spasticity (-0.30, 95% CI: -0.58 – -0.03) compared to the control group. The 12 studies that combined NMES with another therapeutic modality for spasticity significantly reduced spasticity (-0.35, 95% CI: -0.63 – -0.07) whereas the two studies that evaluated NMES alone did not. Interestingly, reports that used NMES on the legs showed a significant reduction in spasticity (-0.78, 95% CI: -1.02 – -0.54) but those with NMES applied to the upper extremity did not. NMES (alone or with other intervention) was associated with an increase in ROM (2.87, 95% CI: 1.18-4.56). Again, when NMES was combined another modality, a significant increase in ROM was noted (2.73, 95% CI: 1.07-4.39); this did not hold true when NMES was used alone. Application to the leg and elbow improved ROM, whereas use on the wrist did not.

NMES combined with other therapeutic interventions improves spasticity and increases ROM after stroke. RCTs evaluated varied in the time the intervention was started after stroke, treatment duration, stimulation parameters used, degree of spasticity and functional deficit, as well as comparative treatments evaluated in certain studies; these factors may affect response to NMES. Establishing efficacy would be best assessed by a large, high-quality RCT. However, based on this analysis, it is worth considering this option in conjunction with a physiatrist and the patient.

FIM Motor Score Predictive of Good Outcome in Rehab

Duy Le, MD
It is often stated that lack of proof is not proof itself. Such is the case of rehabilitation after stroke. While there is no clear prospective randomized trial showing that rehabilitation is beneficial, by and large, consensus is that it is beneficial for patients. We spend tremendous resources screening and triaging patients to see who would be good acute rehabilitation candidates. But the large looming question still remains: Who actually gets better, and what are predictors of good outcomes at rehab?  

While there is much research left to do regarding rehabilitation post stroke, it’s also quite an exciting venture because there is so much left to learn. Previous work done on rehab post stroke have identified comorbid conditions, demographic information, social status, vocational status, functional limitations and stroke subtype as being predictive factors in outcome after inpatient rehab. However these reports are limited by small sample size and single center reviews.

Brown et al. attempt to up the ante by evaluating the Uniform Data System for Medical Rehabilitation (UDSMR) which contains data collected from the Inpatient Rehabilitation Patient Assessment Instrument (IRF-PAI). They evaluate patients with a diagnosis of stroke from 2005 to 2007. Patients were included if they were older than 18 years of age and were admitted for rehabilitation from an acute care facility. Patients were excluded if they were not living at home prior to acute hospitalization, or had interruption of their rehab stay. 

This study finds that the admission Functional Independence Measurement (FIM) score is the best predictor of patients doing well post rehabilitation (i.e., being discharged home and having a higher change in FIM score from admission to discharge). The FIM score is broken into components; a motor and cognitive portion. It was found that the motor component has a high predictive value of good outcome. 

Weaknesses of this study stem from the inherent nature of a retrospective review. The bias of patient selection for acute rehab itself likely contributes to the outcome of this study. Take for example that the FIM motor component is more predictive of outcomes and that the cognitive portion is not as predictive. Most patients who are selected to attend acute rehab usually have good cognition with ability to participate. Thus, the patient spectrum of poor cognition was not truly evaluated for predictive outcome. Of note, prior reported predictors such as pre-existing medical condition and stroke related comorbid conditions did not substantially contribute poor outcome in this study. Nonetheless, this study still makes strides in the rehabilitation research due to the large sample size on which to draw conclusions. This is a good launching point and a strong data base to continue extrapolating more answers. Again, much work still needs to be done in the realm of research to see what factors influence good outcomes; as this will be crucial to optimize rehabilitation care.

Cautious Hope in the form of Cutesamine

Rajbeer Singh Sangha, MD

Urfer R, Moebius HJ, Skoloudik D, Santamarina E, Sato W, Mita S, and Muir KW. Phase II Trial of the Sigma-1 Receptor Agonist Cutamesine (SA4503) for Recovery Enhancement After Acute Ischemic Stroke. Stroke. 2014

While therapy for acute ischemic stroke has made many advances in the past two decades, enhancement of functional recovery during the sub-acute and chronic phases of stroke represents a major therapeutic goal and one that remains elusive thus far. Current theory based on pre-clinical in vivo models suggests that a time-limited window of neuroplasticity exists following neuronal injury. One of the mechanisms is via the sigma-1 receptor chaperone protein (Sig-1R) mediated functional recovery in a model of neuronal plasticity.  Cutamesine (1-(3,4-dimethoxyphenethyl)-4-(3-phenylpropyl) piperazine dihydrochloride, SA4503), is an orally available, central nervous system active, selective agonist of the Sig-1R. During previous studies, it has shown that use of this compound had enhanced functional recovery in rat models when treatment commenced 48 hours after stroke and continued for one month, without affecting infarct size. The authors of this study conducted a phase II clinical trial of cutamesine in which they examined the safety and preliminary efficacy of this compound in ischemic stroke patients.

60 patients were randomized between 48 and 72 hours post-stroke to receive cutamesine at 1 mg/day, 3 mg/day, or placebo for 28 days. Effects on safety and function were assessed at baseline, at end of treatment (Day 28) and at end of follow-up (Day 56). No significant effect was observed on the primary efficacy measure (change in NIHSS from baseline to day 56), or modified Rankin Scale and Barthel Index scores. Further Post-hoc analysis of moderately and severely affected patients (baseline NIHSS ≥7 and ≥10) showed greater NIHSS improvements in the 3 mg/day cutamesine group compared to placebo (p=0.034 and p=0.038, respectively). A trend also was noted towards a higher proportion of the cutesamine group being able to complete a 10m timed walk when compared to the placebo group. The nature and frequency of adverse events were as expected from the medical history of enrolled subjects and mostly reflect sequelae of the recent stroke.

Clinical trials thus far investigating the effects of compounds that may enhance functional recovery following stroke have had disappointing results. Cerebrolysin is a compound that comes to mind that also did not show significant improvements in functional recovery.  While the power is limited with only 60 subjects enrolled in the study, Cutesamine does show encouraging results in the post hoc analysis that moderately and severely affected patients did better than their placebo counterparts and this is an avenue for hope. The authors also allude to this in their article and one of the limitations in the study was the controlling of the rehab therapies for the patients going forward. While they do mention that further studies need to investigate cutesamine’s effect on the moderate to severely affected stroke group of patients, it should also be recommended that patient self-reported functional outcomes be utilized as a tool to assess the effects of this compound going forward. Use of the Neuro-QOL may provide a more sensitive and specific analysis of cognitive improvements in these patients.