Albert C. Lo

Robot-Assisted Therapy for Long-Term Upper-Limb Impairment after Stroke

BACKGROUND Effective rehabilitative therapies are needed for patients with long-term deficits after stroke. METHODS In this multicenter, randomized, controlled trial involving 127 patients with moderate-to-severe upper-limb impairment 6 months or more after a stroke, we randomly assigned 49 patients to receive intensive robot-assisted therapy, 50 to receive intensive comparison therapy, and 28 to receive usual care. Therapy consisted of 36 1-hour sessions over a period of 12 weeks. The primary outcome was a change in motor function, as measured on the Fugl-Meyer Assessment of Sensorimotor Recovery after Stroke, at 12 weeks. Secondary outcomes were scores on the Wolf Motor Function Test and the Stroke Impact Scale. Secondary analyses assessed the treatment effect at 36 weeks. RESULTS At 12 weeks, the mean Fugl-Meyer score for patients receiving robot-assisted therapy was better than that for patients receiving usual care (difference, 2.17 points; 95% confidence interval [CI], -0.23 to 4.58) and worse than that for patients receiving intensive comparison therapy (difference, -0.14 points; 95% CI, -2.94 to 2.65), but the differences were not significant. The results on the Stroke Impact Scale were significantly better for patients receiving robot-assisted therapy than for those receiving usual care (difference, 7.64 points; 95% CI, 2.03 to 13.24). No other treatment comparisons were significant at 12 weeks. Secondary analyses showed that at 36 weeks, robot-assisted therapy significantly improved the Fugl-Meyer score (difference, 2.88 points; 95% CI, 0.57 to 5.18) and the time on the Wolf Motor Function Test (difference, -8.10 seconds; 95% CI, -13.61 to -2.60) as compared with usual care but not with intensive therapy. No serious adverse events were reported. CONCLUSIONS In patients with long-term upper-limb deficits after stroke, robot-assisted therapy did not significantly improve motor function at 12 weeks, as compared with usual care or intensive therapy. In secondary analyses, robot-assisted therapy improved outcomes over 36 weeks as compared with usual care but not with intensive therapy. (ClinicalTrials.gov number, NCT00372411.)

Improving Gait in Multiple Sclerosis Using Robot-Assisted, Body Weight Supported Treadmill Training:

Background. The majority of patients with multiple sclerosis (MS) develop progressive gait impairment, which can start early in the disease and worsen over a lifetime. A promising outpatient intervention to help improve gait function with potential for addressing this treatment gap is task-repetitive gait training. Methods. Body weight supported treadmill training (BWSTT) with or without robotic assistance (Lokomat) was tested using a randomized crossover design in 13 patients with relapsing-remitting, secondary progressive or primary progressive MS. Patients received 6 training sessions over 3 weeks of each intervention. Outcomes included changes in the timed 25-foot walk (T25FW), the 6-minute walk treadmill test (6MW) distance, the Kurtzke Expanded Disability Status Scale (EDSS), as well as double-limb support time and step length ratio. Results. There were no major differences in outcomes between treatment groups. The study population significantly improved on gait outcomes and the EDSS following BWSTT, including a 31% improvement in the T25FW, a 38.5% improvement in the 6MW, and a 1-point gain for the EDSS. Differences in pre/post changes were noted depending on gender, disease subtype, affected limb, and baseline EDSS. Conclusions. Although no differences in gait outcomes or the EDSS were found between treatment groups, this small pilot study of task-repetitive gait training resulted in significant within-subject improvements. BWSTT appears to be an activity-dependent intervention with potential to reduce gait impairment in MS.

A paradigm shift for rehabilitation robotics

Therapeutic robots enhance clinician productivity in facilitating patient recovery. In this article, we presented an overview of the remarkable growth in the activities in the area of therapeutic robotics and of experiences with our devices. We briefly review the published clinical literature in this emerging field and our initial clinical results in stroke. However, we also report our initial efforts that go beyond stroke, broadening the potential population that might benefit from this class of technology by discussing case studies of applications to other neurological diseases. We will also highlight the underexploited potential of this technology as an evaluation tool.

Targeting Fibroblast Activation Protein in Tumor Stroma with Chimeric Antigen Receptor T Cells Can Inhibit Tumor Growth and Augment Host Immunity without Severe Toxicity

Wang, Lo, and colleagues report the efficacy and safety of chimeric antigen receptor T cells specific for mouse fibroblast activation protein in inhibiting the growth of subcutaneously transplanted tumors when used alone and in combination with an antitumor vaccine. The majority of chimeric antigen receptor (CAR) T-cell research has focused on attacking cancer cells. Here, we show that targeting the tumor-promoting, nontransformed stromal cells using CAR T cells may offer several advantages. We developed a retroviral CAR construct specific for the mouse fibroblast activation protein (FAP), comprising a single-chain Fv FAP [monoclonal antibody (mAb) 73.3] with the CD8α hinge and transmembrane regions, and the human CD3ζ and 4-1BB activation domains. The transduced muFAP-CAR mouse T cells secreted IFN-γ and killed FAP-expressing 3T3 target cells specifically. Adoptively transferred 73.3-FAP-CAR mouse T cells selectively reduced FAPhi stromal cells and inhibited the growth of multiple types of subcutaneously transplanted tumors in wild-type, but not FAP-null immune-competent syngeneic mice. The antitumor effects could be augmented by multiple injections of the CAR T cells, by using CAR T cells with a deficiency in diacylglycerol kinase, or by combination with a vaccine. A major mechanism of action of the muFAP-CAR T cells was the augmentation of the endogenous CD8+ T-cell antitumor responses. Off-tumor toxicity in our models was minimal following muFAP-CAR T-cell therapy. In summary, inhibiting tumor growth by targeting tumor stroma with adoptively transferred CAR T cells directed to FAP can be safe and effective, suggesting that further clinical development of anti-human FAP-CAR is warranted. Cancer Immunol Res; 2(2); 154–66. ©2013 AACR.

Continuous Positive Airway Pressure: evaluation of a Novel Therapy for Patients with Acute Ischemic Stroke

BACKGROUND New approaches are needed to treat patients with stroke. Among acute ischemic stroke patients, our primary objectives were to describe the prevalence of sleep apnea and demonstrate the feasibility of providing auto-titrating continuous positive airway pressure (auto-CPAP). A secondary objective was to examine the effect of auto-CPAP on stroke severity. METHODS Stroke patients randomized to the intervention group received 2 nights of auto-CPAP, but only those with evidence of sleep apnea received auto-CPAP for the remainder of the 30-day period. Intervention patients received polysomnography 30 days post-stroke. Control patients received polysomnography at baseline and after 30 days. Acceptable auto-CPAP adherence was defined as ≥ 4 h/night for ≥ 75% nights. Change in stroke severity was assessed comparing the NIH Stroke Scale (NIHSS) at baseline versus at 30 days. RESULTS The 2 groups (intervention N = 31, control N = 24) had similar baseline stroke severity (both median NIHSS, 3.0). Among patients with complete polysomnography data, the majority had sleep apnea: baseline, 13/15 (86.7%) control patients; 30 days, 24/35 (68.6%) control and intervention patients. Intervention patients had greater improvements in NIHSS (-3.0) than control patients (-1.0); P = 0.03. Among patients with sleep apnea, greater improvement was observed with increasing auto-CPAP use: -1.0 for control patients not using auto-CPAP; -2.5 for intervention patients with some auto-CPAP use; and -3.0 for intervention patients with acceptable auto-CPAP adherence. CONCLUSIONS The majority of acute stroke patients had sleep apnea. Auto-CPAP was well tolerated, appears to improve neurological recovery from stroke, and may represent a new therapeutic approach for selected patients with acute cerebral infarction.

Treatment of progressive multiple sclerosis: what works, what does not, and what is needed

Disease-modifying drugs have mostly failed as treatments for progressive multiple sclerosis. Management of the disease therefore solely aims to minimise symptoms and, if possible, improve function. The degree to which this approach is based on empirical data derived from studies of progressive disease or whether treatment decisions are based on what is known about relapsing-remitting disease remains unclear. Symptoms rated as important by patients with multiple sclerosis include balance and mobility impairments, weakness, reduced cardiovascular fitness, ataxia, fatigue, bladder dysfunction, spasticity, pain, cognitive deficits, depression, and pseudobulbar affect; a comprehensive literature search shows a notable paucity of studies devoted solely to these symptoms in progressive multiple sclerosis, which translates to few proven therapeutic options in the clinic. A new strategy that can be used in future rehabilitation trials is therefore needed, with the adoption of approaches that look beyond single interventions to concurrent, potentially synergistic, treatments that maximise what remains of neural plasticity in patients with progressive multiple sclerosis.

Tumor-promoting desmoplasia is disrupted by depleting FAP-expressing stromal cells

Malignant cells drive the generation of a desmoplastic and immunosuppressive tumor microenvironment. Cancer-associated stromal cells (CASC) are a heterogeneous population that provides both negative and positive signals for tumor cell growth and metastasis. Fibroblast activation protein (FAP) is a marker of a major subset of CASCs in virtually all carcinomas. Clinically, FAP expression serves as an independent negative prognostic factor for multiple types of human malignancies. Prior studies established that depletion of FAP(+) cells inhibits tumor growth by augmenting antitumor immunity. However, the potential for immune-independent effects on tumor growth have not been defined. Herein, we demonstrate that FAP(+) CASCs are required for maintenance of the provisional tumor stroma because depletion of these cells, by adoptive transfer of FAP-targeted chimeric antigen receptor (CAR) T cells, reduced extracellular matrix proteins and glycosaminoglycans. Adoptive transfer of FAP-CAR T cells also decreased tumor vascular density and restrained growth of desmoplastic human lung cancer xenografts and syngeneic murine pancreatic cancers in an immune-independent fashion. Adoptive transfer of FAP-CAR T cells also restrained autochthonous pancreatic cancer growth. These data distinguish the function of FAP(+) CASCs from other CASC subsets and provide support for further development of FAP(+) stromal cell-targeted therapies for the treatment of solid tumors.

Sodium channel blockade with phenytoin protects spinal cord axons, enhances axonal conduction, and improves functional motor recovery after contusion SCI

Accumulation of intracellular sodium through voltage-gated sodium channels (VGSCs) is an important event in the cascade leading to anatomic degeneration of spinal cord axons and poor functional outcome following traumatic spinal cord injury (SCI). In this study, we hypothesized that phenytoin, a sodium channel blocker, would result in protection of axons with concomitant improvement of functional recovery after SCI. Adult male Sprague-Dawley rats underwent T9 contusion SCI after being fed normal chow or chow containing phenytoin; serum levels of phenytoin were within therapeutic range at the time of injury. At various timepoints after injury, quantitative assessment of lesion volumes, axonal degeneration, axonal conduction, and functional locomotor recovery were performed. When compared to controls, phenytoin-treated animals demonstrated reductions in the degree of destruction of gray and white matter surrounding the lesion epicenter, sparing of axons within the dorsal corticospinal tract (dCST) and dorsal column (DC) system rostral to the lesion site, and within the dorsolateral funiculus (DLF) caudal to the lesion site, and enhanced axonal conduction across the lesion site. Improved performance in measures of skilled locomotor function was observed in phenytoin-treated animals. Based on these results, we conclude that phenytoin provides neuroprotection and improves functional outcome after experimental SCI, and that it merits further examination as a potential treatment strategy in human SCI.

Neuroprotection of axons with phenytoin in experimental allergic encephalomyelitis.

Voltage-gated sodium channels contribute to the development of axonal degeneration in white matter, and sodium channel blocking drugs are known to have a protective effect on acutely injured white matter axons in vitro. To determine whether phenytoin has a protective effect on axons in a neuroinflammatory model in vivo, we studied the effect of phenytoin on axonal degeneration in the optic nerve in MOG-induced experimental allergic encephalomyelitis (EAE). We report that, whereas ∼50% of optic nerve axons are lost at 27–28 days in untreated EAE, only ∼12% of the axons are lost if mice with MOG-induced EAE are treated with phenytoin. These results demonstrate that it is possible to achieve substantial protection of white matter axons in EAE, a model neuroinflammatory/demyelination disease, with a sodium channel blocking agent.

Regulation of spinal motoneuron survival by GDNF during development and following injury.

Abstract.During normal development of many vertebrate species, substantial numbers of neurons in the central and peripheral nervous system undergo naturally occurring (or programmed) cell death. For example, approximately 50% of spinal motoneurons degenerate and die at a time when these cells are establishing synaptic connections with their target muscles in the chick, mouse, rat, and human. It is generally thought that the survival of developing motoneurons depends on access to trophic molecules. Motoneurons that survive the period of programmed cell death may also die following injury in the developing or adult animal. Increasing evidence suggests that glial-cell-line-derived neurotrophic factor (GDNF) plays a physiological and/or pharmacological role in the survival of various neuronal cell types, including motoneurons. In this paper, we review the survival and growth-promoting effects of GDNF on spinal motoneurons during the period of programmed cell death and following injury.