SCIENCE TIMES
Brain Plasticity After Stroke: The Potential Role of Memantine
S
troke is the fourth leading cause of death and a major cause of long-term disability in the United States.1 Notably, ischemic strokes constitute the majority (87%) of all types of stroke. Although the role of medical therapy for acute ischemic strokes is well documented in the literature, treatment strategies are limited. To date, intravenous tissue-type plasminogen activator is the only pharmacological treatment shown to improve outcome when given to select patients within a few hours after stroke, and beyond this time period, conservative treatment and secondary prevention have been the standard of care.2 Furthermore, although acute medical and surgical interventions, including craniectomy in select patients, and aggressive rehabilitation may improve outcomes, disability rates remain unacceptably high. In light of this, previous human studies have attempted to prevent neuronal death beyond the infarct core boundaries, but results have been discouraging. Yet, animal and clinical data have shown that brain cells demonstrate extensive plasticity after stroke.3 Strategies aimed at enhancing this plasticity have been the subject of intense interest. In particular, memantine, a noncompetitive N-methyl-D-aspartate antagonist, has
received considerable attention from the scientific community and has been examined as a potential neuroprotective agent. With this in mind, López-Valdés et al4 developed an animal model with the aim to evaluate the role of memantine in recovery from stroke. Their article was published in the June 2014 issue of Stroke. The authors selected a group of male mice (n ¼ 82) to induce focal ischemia. Mice underwent injection of 200 mL of 10 mg/mL Rose Bengal solution, followed by photothrombosis with 2-mm-diameter irradiation positioned 1.5 mm lateral from the bregma. Two hours later, they were randomly treated with memantine (30 mg/ kg per day in 2% sucrose solution) or 2% sucrose vehicle for 28 days and allocated to 1 type of follow-up experiment (behavioral testing, sensory mapping, histology, or Western blot). Mice in the behavioral testing group underwent a cylinder test to determine a forelimb preference by counting limb contacts and obtaining the index for preference. They also underwent a grid-walking test to determine the number of normal steps and foot faults. In the sensory mapping experiment, optical intrinsic signal imaging was performed 7 days before and 7, 14, 21, and 28 days after focal ischemia through electric stimulation to the forepaw and hindpaw with subdermal needle electrodes and recording reflectance through the skull. A stimulus response . 50% of maximum response was used to quantify functional maps. Histological examinations were performed by perfusing mice, 7 or 28 days after photothrom-
bosis, with 0.9% NaCl and 4% paraformaldehyde in phosphate-buffered saline. Frozen sections were prepared to quantify infarct volumes with Nissl stain and to perform bright-field immunohistochemistry with rabbit anti–glial fibrillary acidic protein, rat anti–platelet endothelial cell adhesion molecule-1, and mouse anti–neuronal antigen. Finally, Western Blot was performed to quantify molecular expression using anti–vascular endothelial growth factor, anti–glial-derived neurotrophic factor, anti–brain-derived neurotrophic factor, anti–tyrosine kinase B, and anti–phospho-tyrosine kinase B antibodies. The authors found that infarct size was similar in memantine- and vehicle-treated mice. Photothrombosis affected the primary motor cortex, as well as forepaw and, more severely, hindpaw sensory cortexes. Neuronal density, as revealed by the neuronal antigen stain, was similar between the 2 groups. However, compared with the vehicletreated mice, memantine treatment was associated with significant behavioral improvement that was more pronounced for the forepaw at 28 days after stroke. For instance, the cylinder test revealed a gradual recovery of the impaired forelimb, whereas the grid-walking test showed a greater reduction in forepaw foot faults. Sensory mapping showed a slow increase in activation areas for the forepaw and hindpaw in both groups of mice; however, this increase was more significant for the forepaw in memantine-treated mice at 28 days after stroke. On immunohistochemistry, compared with the vehicle-treated group, the memantine-treated
Figure. Significant recovery of forepaw sensory maps with memantine treatment. A, forepaw (FP) and hindpaw (HP) sensory maps in representative vehicle (Veh)- and memantine (MEM)–treated animals. B, area of activation for the forepaw and hindpaw. There was a significant increase in forepaw, but not hindpaw, activation area at 28 days after treatment in memantine-compared with vehicle-treated animals. Reprinted with permissions from López-Valdés HE, Clarkson AN, Ao Y, et al. Memantine Enhances Recovery From Stroke; Stroke. 2014; 45: 2093-2100.
N18 | VOLUME 75 | NUMBER 4 | OCTOBER 2014
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
SCIENCE TIMES
mice exhibited decreased reactive astrocytosis and increased vascular density, which were reflected by a significant reduction in glial fibrillary acidic protein–expressing-cell area nearest to the ischemic region and an increase in platelet endothelial cell adhesion molecule-1 expression within 1.050 mm adjacent to the lesion border, respectively. Finally, Western blot examinations showed no difference in glial-derived neurotrophic factor and vascular endothelial growth factor expression between the vehicle- and memantine-treated mice; however, there was a significant increase in brain-derived neurotrophic factor and phospho-tyrosine kinase receptor expression near the infarct in memantinetreated mice, suggesting a possible function in peri-infarct recovery and plasticity. We commend López-Valdés et al on their work. The potential for memantine to improve functional outcome in neurological diseases associated with ischemic complications is intriguing. Many diseases seen by neurosurgeons have ischemia as part of their pathophysiology, including, but not limited to, subarachnoid hemorrhage, intracerebral hemorrhage, and embolic stroke from carotid stenosis. Additionally, ischemic injury is a potential complication related to neurosurgical interventions. For this reason, it is our hope that this study will stimulate the conduction of high-quality clinical trials to examine the role of memantine for these difficult clinical problems. Youssef J. Hamade, MD Samer G. Zammar, MD Najib E. El Tecle, MD, MS Northwestern University Chicago, Illinois Tarek Y. El Ahmadieh, MD University of Texas Southwestern Dallas, Texas Allan D. Nanney III, MD Bernard R. Bendok, MD, MS Northwestern University Chicago, Illinois
REFERENCES 1. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129(3):399-410. 2. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947. 3. Rossini PM, Dal Forno G. Neuronal post-stroke plasticity in the adult. Restor Neurol Neurosci. 2004;22 (3-5):193-206. 4. López-Valdés HE, Clarkson AN, Ao Y, et al. Memantine enhances recovery from stroke. Stroke. 2014;45 (7):2093-2100.
NEUROSURGERY
Long-term Outcomes of a Randomized Clinical Trial of Stenting vs Aggressive Medical Therapy for Intracranial Arterial Stenosis
S
troke is a leading cause of morbidity and mortality and the most significant source of disability in the United States. Patients with recent transient ischemic attacks or stroke and significant intracranial stenosis are at particularly high risk of recurrent stroke. Recent trials have demonstrated that although outcomes for stroke patients are improving with aggressive medical therapy,1-3 the overall long-term prognosis is poor. In the initial Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, patients with a recent transient ischemic attack or stroke attributed to stenosis of 70% to 99% of the diameter of a major intracranial artery were randomized to aggressive medical management alone or aggressive medical management plus percutaneous transluminal angioplasty and stenting (PTAS) with the Wingspan stent system (Stryker Neurovascular, Fremont, California; formerly Boston Scientific Neurovascular).3 Aggressive medical management includes antiplatelet therapy, intensive management of vascular risk factors, and lifestyle modification program. The primary end point was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. Enrollment was stopped after 451 patients underwent randomization because the 30-day rate of stroke or death was 5.8% in the medical cohort compared with 14.7% in the PTAS cohort. Only preliminary results were available for follow-up in these patients, which did not appear to demonstrate a difference in recurrent events. Recently, the final results of the SAMMPRIS trial were announced.4 During a median followup of 32.4 months, the primary end point was significantly higher in those receiving PTAS (23%) compared with those receiving aggressive medical therapy alone (15%). The cumulative probability of the primary end points was smaller in the medical group than in the PTAS group (P ¼ .03; Figure). Beyond 30 days, 10% of patients in the medical group and 10% of the 191 patients in the stenting group had a primary end point. Additionally, the occurrence of any
stroke was higher in the PTAS group (26%) compared with the medical cohort (19%), and major hemorrhage was seen in 13% of those in the PTAS group vs 4% in the medical management cohort. Thus, the early benefit of aggressive medical over PTAS was sustained for high-risk patients with intracranial arterial stenosis. Stroke rates in the medical therapy cohort were lower than expected, as demonstrated in recent trials.1-3 Compared with the Warfarin-Aspirin Symptomatic Intracranial Disease Trial (WASID), which had similar enrollment criteria,5 the stroke rates were much lower in the SAMMPRIS medical cohort. This may be partially explained by the fact that patients in WASID were treated with risk factor management and either warfarin or aspirin, but patients in SAMMPRIS were treated with aggressive risk factor management along with aspirin and clopidogrel for 90 days followed by aspirin alone. The number of patients attaining blood pressure and low-density lipoprotein control was much higher in the SAMMPRIS trial. This must be taken into account in plans for future stroke trials. Concerns have been raised that the aggressive medical therapy achieved in SAMMPRIS does not reflect current practice and may partially explain the significantly higher number of patients lost to follow-up in the medical therapy cohort. The question remains as to what the optimal therapy is in patients with repeated strokes despite best medical therapy in the setting of significant intracranial stenosis. It is unclear in the current trial how many patients in the interventional cohort had significant in-stent stenosis or thrombosis. A number of prior studies have raised concerns over the significant rates of in-stent stenosis and thrombosis associated with the Wingspan stent, which may be .30%.6 This is significantly higher than the rates for alternative intracranial stents used for other pathologies.7 Currently, the Wingspan stent is the only stent approved by the US Food and Drug Administration (under a humanitarian device exemption) for use in patients with atherosclerotic intracranial arterial stenosis. Limitations of the Wingspan stent include the necessity of angioplasty with a separate balloon before stent deployment followed by a microwire exchange for stent placement. Balloon-mounted stents commonly used in coronary angioplasty may have lower rates of in-stent stenosis and thrombosis and can be quickly deployed with a rapid exchange system without the use of a microwire exchange. Select series of patients with intracranial arterial stenosis experiencing repeated strokes after initiation of best medical therapy suggest that this may be a beneficial alternative.8 This may also be a favorable therapeutic option in patients who cannot achieve the
VOLUME 75 | NUMBER 4 | OCTOBER 2014 | N19
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
Brain Plasticity After Stroke: The Potential Role of Memantine
S
troke is the fourth leading cause of death and a major cause of long-term disability in the United States.1 Notably, ischemic strokes constitute the majority (87%) of all types of stroke. Although the role of medical therapy for acute ischemic strokes is well documented in the literature, treatment strategies are limited. To date, intravenous tissue-type plasminogen activator is the only pharmacological treatment shown to improve outcome when given to select patients within a few hours after stroke, and beyond this time period, conservative treatment and secondary prevention have been the standard of care.2 Furthermore, although acute medical and surgical interventions, including craniectomy in select patients, and aggressive rehabilitation may improve outcomes, disability rates remain unacceptably high. In light of this, previous human studies have attempted to prevent neuronal death beyond the infarct core boundaries, but results have been discouraging. Yet, animal and clinical data have shown that brain cells demonstrate extensive plasticity after stroke.3 Strategies aimed at enhancing this plasticity have been the subject of intense interest. In particular, memantine, a noncompetitive N-methyl-D-aspartate antagonist, has
received considerable attention from the scientific community and has been examined as a potential neuroprotective agent. With this in mind, López-Valdés et al4 developed an animal model with the aim to evaluate the role of memantine in recovery from stroke. Their article was published in the June 2014 issue of Stroke. The authors selected a group of male mice (n ¼ 82) to induce focal ischemia. Mice underwent injection of 200 mL of 10 mg/mL Rose Bengal solution, followed by photothrombosis with 2-mm-diameter irradiation positioned 1.5 mm lateral from the bregma. Two hours later, they were randomly treated with memantine (30 mg/ kg per day in 2% sucrose solution) or 2% sucrose vehicle for 28 days and allocated to 1 type of follow-up experiment (behavioral testing, sensory mapping, histology, or Western blot). Mice in the behavioral testing group underwent a cylinder test to determine a forelimb preference by counting limb contacts and obtaining the index for preference. They also underwent a grid-walking test to determine the number of normal steps and foot faults. In the sensory mapping experiment, optical intrinsic signal imaging was performed 7 days before and 7, 14, 21, and 28 days after focal ischemia through electric stimulation to the forepaw and hindpaw with subdermal needle electrodes and recording reflectance through the skull. A stimulus response . 50% of maximum response was used to quantify functional maps. Histological examinations were performed by perfusing mice, 7 or 28 days after photothrom-
bosis, with 0.9% NaCl and 4% paraformaldehyde in phosphate-buffered saline. Frozen sections were prepared to quantify infarct volumes with Nissl stain and to perform bright-field immunohistochemistry with rabbit anti–glial fibrillary acidic protein, rat anti–platelet endothelial cell adhesion molecule-1, and mouse anti–neuronal antigen. Finally, Western Blot was performed to quantify molecular expression using anti–vascular endothelial growth factor, anti–glial-derived neurotrophic factor, anti–brain-derived neurotrophic factor, anti–tyrosine kinase B, and anti–phospho-tyrosine kinase B antibodies. The authors found that infarct size was similar in memantine- and vehicle-treated mice. Photothrombosis affected the primary motor cortex, as well as forepaw and, more severely, hindpaw sensory cortexes. Neuronal density, as revealed by the neuronal antigen stain, was similar between the 2 groups. However, compared with the vehicletreated mice, memantine treatment was associated with significant behavioral improvement that was more pronounced for the forepaw at 28 days after stroke. For instance, the cylinder test revealed a gradual recovery of the impaired forelimb, whereas the grid-walking test showed a greater reduction in forepaw foot faults. Sensory mapping showed a slow increase in activation areas for the forepaw and hindpaw in both groups of mice; however, this increase was more significant for the forepaw in memantine-treated mice at 28 days after stroke. On immunohistochemistry, compared with the vehicle-treated group, the memantine-treated
Figure. Significant recovery of forepaw sensory maps with memantine treatment. A, forepaw (FP) and hindpaw (HP) sensory maps in representative vehicle (Veh)- and memantine (MEM)–treated animals. B, area of activation for the forepaw and hindpaw. There was a significant increase in forepaw, but not hindpaw, activation area at 28 days after treatment in memantine-compared with vehicle-treated animals. Reprinted with permissions from López-Valdés HE, Clarkson AN, Ao Y, et al. Memantine Enhances Recovery From Stroke; Stroke. 2014; 45: 2093-2100.
N18 | VOLUME 75 | NUMBER 4 | OCTOBER 2014
www.neurosurgery-online.com
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
SCIENCE TIMES
mice exhibited decreased reactive astrocytosis and increased vascular density, which were reflected by a significant reduction in glial fibrillary acidic protein–expressing-cell area nearest to the ischemic region and an increase in platelet endothelial cell adhesion molecule-1 expression within 1.050 mm adjacent to the lesion border, respectively. Finally, Western blot examinations showed no difference in glial-derived neurotrophic factor and vascular endothelial growth factor expression between the vehicle- and memantine-treated mice; however, there was a significant increase in brain-derived neurotrophic factor and phospho-tyrosine kinase receptor expression near the infarct in memantinetreated mice, suggesting a possible function in peri-infarct recovery and plasticity. We commend López-Valdés et al on their work. The potential for memantine to improve functional outcome in neurological diseases associated with ischemic complications is intriguing. Many diseases seen by neurosurgeons have ischemia as part of their pathophysiology, including, but not limited to, subarachnoid hemorrhage, intracerebral hemorrhage, and embolic stroke from carotid stenosis. Additionally, ischemic injury is a potential complication related to neurosurgical interventions. For this reason, it is our hope that this study will stimulate the conduction of high-quality clinical trials to examine the role of memantine for these difficult clinical problems. Youssef J. Hamade, MD Samer G. Zammar, MD Najib E. El Tecle, MD, MS Northwestern University Chicago, Illinois Tarek Y. El Ahmadieh, MD University of Texas Southwestern Dallas, Texas Allan D. Nanney III, MD Bernard R. Bendok, MD, MS Northwestern University Chicago, Illinois
REFERENCES 1. Go AS, Mozaffarian D, Roger VL, et al. Executive summary: heart disease and stroke statistics—2014 update: a report from the American Heart Association. Circulation. 2014;129(3):399-410. 2. Jauch EC, Saver JL, Adams HP Jr, et al. Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2013;44(3):870-947. 3. Rossini PM, Dal Forno G. Neuronal post-stroke plasticity in the adult. Restor Neurol Neurosci. 2004;22 (3-5):193-206. 4. López-Valdés HE, Clarkson AN, Ao Y, et al. Memantine enhances recovery from stroke. Stroke. 2014;45 (7):2093-2100.
NEUROSURGERY
Long-term Outcomes of a Randomized Clinical Trial of Stenting vs Aggressive Medical Therapy for Intracranial Arterial Stenosis
S
troke is a leading cause of morbidity and mortality and the most significant source of disability in the United States. Patients with recent transient ischemic attacks or stroke and significant intracranial stenosis are at particularly high risk of recurrent stroke. Recent trials have demonstrated that although outcomes for stroke patients are improving with aggressive medical therapy,1-3 the overall long-term prognosis is poor. In the initial Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial, patients with a recent transient ischemic attack or stroke attributed to stenosis of 70% to 99% of the diameter of a major intracranial artery were randomized to aggressive medical management alone or aggressive medical management plus percutaneous transluminal angioplasty and stenting (PTAS) with the Wingspan stent system (Stryker Neurovascular, Fremont, California; formerly Boston Scientific Neurovascular).3 Aggressive medical management includes antiplatelet therapy, intensive management of vascular risk factors, and lifestyle modification program. The primary end point was stroke or death within 30 days after enrollment or after a revascularization procedure for the qualifying lesion during the follow-up period or stroke in the territory of the qualifying artery beyond 30 days. Enrollment was stopped after 451 patients underwent randomization because the 30-day rate of stroke or death was 5.8% in the medical cohort compared with 14.7% in the PTAS cohort. Only preliminary results were available for follow-up in these patients, which did not appear to demonstrate a difference in recurrent events. Recently, the final results of the SAMMPRIS trial were announced.4 During a median followup of 32.4 months, the primary end point was significantly higher in those receiving PTAS (23%) compared with those receiving aggressive medical therapy alone (15%). The cumulative probability of the primary end points was smaller in the medical group than in the PTAS group (P ¼ .03; Figure). Beyond 30 days, 10% of patients in the medical group and 10% of the 191 patients in the stenting group had a primary end point. Additionally, the occurrence of any
stroke was higher in the PTAS group (26%) compared with the medical cohort (19%), and major hemorrhage was seen in 13% of those in the PTAS group vs 4% in the medical management cohort. Thus, the early benefit of aggressive medical over PTAS was sustained for high-risk patients with intracranial arterial stenosis. Stroke rates in the medical therapy cohort were lower than expected, as demonstrated in recent trials.1-3 Compared with the Warfarin-Aspirin Symptomatic Intracranial Disease Trial (WASID), which had similar enrollment criteria,5 the stroke rates were much lower in the SAMMPRIS medical cohort. This may be partially explained by the fact that patients in WASID were treated with risk factor management and either warfarin or aspirin, but patients in SAMMPRIS were treated with aggressive risk factor management along with aspirin and clopidogrel for 90 days followed by aspirin alone. The number of patients attaining blood pressure and low-density lipoprotein control was much higher in the SAMMPRIS trial. This must be taken into account in plans for future stroke trials. Concerns have been raised that the aggressive medical therapy achieved in SAMMPRIS does not reflect current practice and may partially explain the significantly higher number of patients lost to follow-up in the medical therapy cohort. The question remains as to what the optimal therapy is in patients with repeated strokes despite best medical therapy in the setting of significant intracranial stenosis. It is unclear in the current trial how many patients in the interventional cohort had significant in-stent stenosis or thrombosis. A number of prior studies have raised concerns over the significant rates of in-stent stenosis and thrombosis associated with the Wingspan stent, which may be .30%.6 This is significantly higher than the rates for alternative intracranial stents used for other pathologies.7 Currently, the Wingspan stent is the only stent approved by the US Food and Drug Administration (under a humanitarian device exemption) for use in patients with atherosclerotic intracranial arterial stenosis. Limitations of the Wingspan stent include the necessity of angioplasty with a separate balloon before stent deployment followed by a microwire exchange for stent placement. Balloon-mounted stents commonly used in coronary angioplasty may have lower rates of in-stent stenosis and thrombosis and can be quickly deployed with a rapid exchange system without the use of a microwire exchange. Select series of patients with intracranial arterial stenosis experiencing repeated strokes after initiation of best medical therapy suggest that this may be a beneficial alternative.8 This may also be a favorable therapeutic option in patients who cannot achieve the
VOLUME 75 | NUMBER 4 | OCTOBER 2014 | N19
Copyright © Congress of Neurological Surgeons. Unauthorized reproduction of this article is prohibited.
