Roy A. E. Bakay
Andrew D. Firlik, Howard Yonas, Anthony M. Kaufmann, Lawrence R. Wechsler, Charles A. Jungreis, Melanie B. Fukui and Robert L. Williams
Object. The purpose of this study was to determine whether cerebral blood flow (CBF) measurements in acute stroke could be correlated with the subsequent development of cerebral edema and life-threatening brain herniation.
Methods. Twenty patients with aggressively managed acute middle cerebral artery (MCA) territory strokes who underwent xenon-enhanced computerized tomography (Xe-CT) CBF scanning within 6 hours of onset of symptoms were retrospectively reviewed. The relationship among CBF and follow-up CT evidence of edema and clinical evidence of brain herniation during the 36 to 96 hours following stroke onset was analyzed.
Initial CT scans displayed abnormal findings in 11 patients (55%), whereas the Xe-CT CBF scans showed abnormal findings in all patients (100%). The mean CBF in the symptomatic MCA territory was 10.4 ml/100 g/minute in patients who developed severe edema compared with 19 ml/100 g/minute in patients who developed mild edema (p < 0.05). The mean CBF in the symptomatic MCA territory was 8.6 ml/100 g/minute in patients who developed clinical brain herniation compared with 18 ml/100 g/minute in those who did not (p < 0.01). The mean CBF in the symptomatic MCA territory that was 15 ml/100 g/minute or lower was significantly associated with the development of severe edema and herniation (p < 0.05).
Conclusions. Within 6 hours of acute MCA territory stroke, Xe-CT CBF measurements can be used to predict the subsequent development of severe edema and progression to clinical life-threatening brain herniation. Early knowledge of the anatomical and clinical sequelae of stroke in the acute phase may aid in the triage of such patients and alert physicians to the potential need for more aggressive medical or neurosurgical intervention.
Gary K. Steinberg, Douglas Kondziolka, Lawrence R. Wechsler, L. Dade Lunsford, Anthony S. Kim, Jeremiah N. Johnson, Damien Bates, Gene Poggio, Casey Case, Michael McGrogan, Ernest W. Yankee and Neil E. Schwartz
The aim of this study was to evaluate the safety and clinical outcomes associated with stereotactic surgical implantation of modified bone marrow–derived mesenchymal stem cells (SB623) in patients with stable chronic ischemic stroke.
This was a 2-year, open-label, single-arm, phase 1/2a study; the selected patients had chronic motor deficits between 6 and 60 months after nonhemorrhagic stroke. SB623 cells were administered to the target sites surrounding the subcortical stroke region using MRI stereotactic image guidance.
A total of 18 patients were treated with SB623 cells. All experienced at least 1 treatment-emergent adverse event (TEAE). No patients withdrew due to adverse events, and there were no dose-limiting toxicities or deaths. The most frequent TEAE was headache related to the surgical procedure (88.9%). Seven patients experienced 9 serious adverse events, which resolved without sequelae. In 16 patients who completed 24 months of treatment, statistically significant improvements from baseline (mean) at 24 months were reported for the European Stroke Scale (ESS) score, 5.7 (95% CI 1.4–10.1, p < 0.05); National Institutes of Health Stroke Scale (NIHSS) score, −2.1 (95% CI −3.3 to −1.0, p < 0.01), Fugl-Meyer (F-M) total score, 19.4 (95% CI 9.9–29.0, p < 0.01); and F-M motor scale score, 10.4 (95% CI 4.0–16.7, p < 0.01). Measures of efficacy reached plateau by 12 months with no decline thereafter. There were no statistically significant changes in the modified Rankin Scale score. The size of transient lesions detected by T2-weighted FLAIR imaging in the ipsilateral cortex at weeks 1–2 postimplantation significantly correlated with improvement in ESS (0.619, p < 0.05) and NIHSS (−0.735, p < 0.01) scores at 24 months.
In this completed 2-year phase 1/2a study, implantation of SB623 cells in patients with stable chronic stroke was safe and was accompanied by improvements in clinical outcomes.
Clinical trial registration no.: NCT01287936 (clinicaltrials.gov)
Douglas Kondziolka, Gary K. Steinberg, Lawrence Wechsler, Carolyn C. Meltzer, Elaine Elder, James Gebel, Sharon DeCesare, Tudor Jovin, Ross Zafonte, Jonathan Lebowitz, John C. Flickinger, David Tong, Michael P. Marks, Catriona Jamieson, Desiree Luu, Teresa Bell-Stephens and Jeffrey Teraoka
No definitive treatment exists to restore lost brain function following a stroke. Transplantation of cultured neuronal cells has been shown to be safe and effective in animal models of stroke and safe in a Phase 1 human trial. In the present study the authors tested the usefulness of human neuron transplantation followed by participation in a 2-month stroke rehabilitation program compared with rehabilitation alone in patients with substantial fixed motor deficits associated with a basal ganglia stroke.
Human neuronal cells (LBS-Neurons; Layton BioScience, Inc.) were delivered frozen and then thawed and formulated on the morning of surgery. The entry criteria in this randomized, observer-blinded trial of 18 patients included age between 18 and 75 years, completed stroke duration of 1 to 6 years, presence of a fixed motor deficit that was stable for at least 2 months, and no contraindications to stereotactic surgery. Patients were randomized at two centers to receive either 5 or 10 million implanted cells in 25 sites (seven patients per group) followed by participation in a stroke rehabilitation program, or to serve as a nonsurgical control group (rehabilitation only; four patients). The surgical techniques used were the same at both centers. All patients underwent extensive pre- and postoperative motor testing and imaging. Patients received cyclosporine A for 1 week before and 6 months after surgery. The primary efficacy measure was a change in the European Stroke Scale (ESS) motor score at 6 months. Secondary outcomes included Fugl-Meyer, Action Research Arm Test, and Stroke Impact Scale scores, as well as the results of other motor tests. Nine strokes were ischemic in origin and nine were hemorrhagic.
All 14 patients who underwent surgery (ages 40–70 years) underwent uncomplicated surgeries. Serial evaluations (maximum duration 24 months) demonstrated no cell-related adverse serological or imaging-defined effects. One patient suffered a single seizure, another had a syncopal event, and in another there was burr-hole drainage of an asymptomatic chronic subdural hematoma. Four of seven patients who received 5 million cells (mean improvement 6.9 points) and two of seven who received 10 million cells had improved ESS scores at 6 months; however, there was no significant change in the ESS motor score in patients who received cell implants (p = 0.756) compared with control or baseline values (p = 0.06). Compared with baseline, wrist movement and hand movement scores recorded on the Fugl-Meyer Stroke Assessment instrument were not improved (p = 0.06). The Action Research Arm Test gross hand-movement scores improved compared with control (p = 0.017) and baseline (p = 0.001) values. On the Stroke Impact Scale, the 6-month daily activities score changed compared with baseline (p = 0.045) but not control (p = 0.056) scores, and the Everyday Memory test score improved in comparison with baseline (p = 0.004) values.
Human neuronal cells can be produced in culture and implanted stereotactically into the brains of patients with motor deficits due to stroke. Although a measurable improvement was noted in some patients and this translated into improved activities of daily living in some patients as well, this study did not find evidence of a significant benefit in motor function as determined by the primary outcome measure. This experimental trial indicates the safety and feasibility of neuron transplantation for patients with motor stroke.
Philip M. Meyers, H. Christian Schumacher, Michael J. Alexander, Colin P. Derdeyn, Anthony J. Furlan, Randall T. Higashida, Christopher J. Moran, Robert W. Tarr, Donald V. Heck, Joshua A. Hirsch, Mary E. Jensen, Italo Linfante, Cameron G. McDougall, Gary M. Nesbit, Peter A. Rasmussen, Thomas A. Tomsick, Lawrence R. Wechsler, John A. Wilson and Osama O. Zaidat
Stroke is the third leading cause of death in the USA, Canada, Europe, and Japan. According to the American Heart Association and the American Stroke Association, there are now 750,000 new strokes that occur each year, resulting in 200,000 deaths, or 1 of every 16 deaths, per year in the USA alone. Endovascular therapy for patients with acute ischemic stroke is an area of intense investigation. The American Stroke Association has given a qualified endorsement of intraarterial thrombolysis in selected patients. Intraarterial thrombolysis has been studied in two randomized trials and numerous case series. Although two devices have been granted FDA approval with an indication for mechanical stroke thrombectomy, none of these thrombectomy devices has demonstrated efficacy for the improvement of patient outcomes. The purpose of the present document is to define what constitutes adequate training to perform neuroendovascular procedures in patients with acute ischemic stroke and what performance standards should be adopted to assess outcomes. These guidelines have been written and approved by multiple neuroscience societies which historically have been directly involved in the medical, surgical and endovascular care of patients with acute stroke. The participating member organizations of the Neurovascular Coalition involved in the writing and endorsement of this document are the Society of NeuroInterventional Surgery, the American Academy of Neurology, the American Association of Neurological Surgeons/Congress of Neurological Surgeons Cerebrovascular Section, and the Society of Vascular & Interventional Neurology.