Christopher T. Bever

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.)

Induction of a non-encephalitogenic type 2 T helper-cell autoimmune response in multiple sclerosis after administration of an altered peptide ligand in a placebo- controlled, randomized phase II trial

In this ‘double-blind’, randomized, placebo-controlled phase II trial, we compared an altered peptide ligand of myelin basic protein with placebo, evaluating their safety and influence on magnetic resonance imaging in relapsing–remitting multiple sclerosis. A safety board suspended the trial because of hypersensitivity reactions in 9% of the patients. There were no increases in either clinical relapses or in new enhancing lesions in any patient, even those with hypersensitivity reactions. Secondary analysis of those patients completing the study showed that the volume and number of enhancing lesions were reduced at a dose of 5 mg. There was also a regulatory type 2 T helper-cell response to altered peptide ligand that cross-reacted with the native peptide.

Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years

In a randomized, placebo-controlled, double-blind study, glatiramer acetate (Copaxone®) reduced the relapse rate and slowed accumulation of disability for patients with relapsing-remitting multiple sclerosis. Of the original 251 patients randomized to receive glatiramer acetate or placebo, 208 chose to continue in an open-label study with all patients receiving active drug. The majority of the original double-blind cohort continues to receive glatiramer acetate by daily subcutaneous injection and are evaluated at 6-month intervals and during suspected relapse. The data reported here are from approximately 6 years of organized evaluation, including the double-blind phase of up to 35 months and the open-label phase of over 36 months. Daily subcutaneous injections of 20 mg glatiramer acetate were well tolerated. The mean annual relapse rate of the patients who received glatiramer acetate since randomization and continued into the open-label study was 0.42 (95% confidence interval (CI), CI=0.34-0.51). The rate per year has continued to drop and for the sixth year is 0.23. Of the group who have received glatiramer acetate without interruption for 5 or more years, 69.3% were neurologically unchanged or have improved from baseline by at least one step on the Expanded Disability Status Scale (EDSS). Patients who left the open-label phase were surveyed by questionnaire. The majority responded, providing information about their current status and reasons for dropping out. This study demonstrates the sustained efficacy of glatiramer acetate in reducing the relapse rate and in slowing the accumulation of disability in patients with relapsing forms of multiple sclerosis.

Robot-Aided Neurorehabilitation: A Novel Robot for Ankle Rehabilitation

In this paper, we present the design and characterization of a novel ankle robot developed at the Massachusetts institute of technology (MIT). This robotic module is being tested with stroke patients at Baltimore Veterans administration medical center. The purpose of the on-going study is to train stroke survivors to overcome common foot drop and balance problems in order to improve their ambulatory performance. Its design follows the same guidelines of our upper extremity designs, i.e., it is a low friction, backdriveable device with intrinsically low mechanical impedance. Here, we report on the design and mechanical characteristics of the robot. We also present data to demonstrate the potential of this device as an efficient clinical measurement tool to estimate intrinsic ankle properties. Given the importance of the ankle during locomotion, an accurate estimate of ankle stiffness would be a valuable asset for locomotor rehabilitation. Our initial ankle stiffness estimates compare favorably with previously published work, indicating that our method may serve as an accurate clinical measurement tool.

Hematopoietic progenitors express neural genes

Bone marrow, or cells selected from bone marrow, were reported recently to give rise to cells with a neural phenotype after in vitro treatment with neural-inducing factors or after delivery into the brain. However, we showed previously that untreated bone marrow cells express products of the neural myelin basic protein gene, and we demonstrate here that a subset of ex vivo bone marrow cells expresses the neurogenic transcription factor Pax-6 as well as neuronal genes encoding neurofilament H, NeuN (neuronal nuclear protein), HuC/HuD (Hu-antigen C/Hu-antigen D), and GAD65 (glutamic acid decarboxylase 65), as well as the oligodendroglial gene encoding CNPase (2′,3′ cyclic nucleotide 3′-phosphohydrolase). In contrast, astroglial glial fibrillary acidic protein (GFAP) was not detected. These cells also were CD34+, a marker of hematopoietic stem cells. Cultures of these highly proliferative CD34+ cells, derived from adult mouse bone marrow, uniformly displayed a phenotype comparable with that of hematopoietic progenitor cells (CD45+, CD34+, Sca-1+, AA4.1+, cKit+, GATA-2+, and LMO-2+). The neuronal and oligodendroglial genes expressed in ex vivo bone marrow also were expressed in all cultured CD34+ cells, and GFAP was not observed. After CD34+ cell transplantation into adult brain, neuronal or oligodendroglial markers segregated into distinct nonoverlapping cell populations, whereas astroglial GFAP appeared, in the absence of other neural markers, in a separate set of implanted cells. Thus, neuronal and oligodendroglial gene products are present in a subset of bone marrow cells, and the expression of these genes can be regulated in brain. The fact that these CD34+ cells also express transcription factors (Rex-1 and Oct-4) that are found in early development elicits the hypothesis that they may be pluripotent embryonic-like stem cells.

The effects of 4‐aminopyridine in multiple sclerosis patients Results of a randomized, placebo‐controlled, double‐blind, concentration‐controlled, crossover trial

Because 4-aminopyridine (AP) improves residual deficits in some multiple sclerosis (MS) patients but has a narrow toxic-to-therapeutic margin, we compared the safety and efficacy of two target peak serum concentration ranges (low: 30 to 59 ng/ml and high: 60 to 100 ng/ml). We enrolled eight MS patients with temperature-sensitive visual and motor deficits in a randomized, placebo-controlled, double-blind, crossover trial of short-term oral AP treatment. We randomized patients to a sequence of three treatments on three separate days: placebo, low serum concentration, and high serum concentration. We determined dosing to achieve the desired steady-state peak serum concentration ranges from a test dose and population pharmacokinetic parameters using bayesian estimation. Contrast sensitivity, standard neurologic examination, ratings of videotaped neurologic examinations, and quantitative strength assessment all improved with treatment, but flicker fusion frequency, visual evoked response latencies, and Expanded Disability Status Scale scores did not. All patients experienced side effects during the high-serum-concentration arm. A grand mal seizure occurred at a serum AP level of 104 ng/ml, and an acute confusional episode occurred at 114 ng/ml. AP treatment produced improvements in residual deficits in MS patients, but the occurrence of significant toxicity suggests that AP serum levels should be monitored and peak levels above 100 ng/ml should be avoided. Concentration-control methodology may be useful in testing putative treatments for other neurologic diseases.

Quality improvement in neurology: AAN Parkinson disease quality measures: Report of the Quality Measurement and Reporting Subcommittee of the American Academy of Neurology

Background: Measuring the quality of health care is a fundamental step toward improving health care and is increasingly used in pay-for-performance initiatives and maintenance of certification requirements. Measure development to date has focused on primary care and common conditions such as diabetes; thus, the number of measures that apply to neurologic care is limited. The American Academy of Neurology (AAN) identified the need for neurologists to develop measures of neurologic care and to establish a process to accomplish this. Objective: To adapt and test the feasibility of a process for independent development by the AAN of measures for neurologic conditions for national measurement programs. Methods: A process that has been used nationally for measure development was adapted for use by the AAN. Topics for measure development are chosen based upon national priorities, available evidence base from a systematic literature search, gaps in care, and the potential impact for quality improvement. A panel composed of subject matter and measure development methodology experts oversees the development of the measures. Recommendation statements and their corresponding level of evidence are reviewed and considered for development into draft candidate measures. The candidate measures are refined by the expert panel during a 30-day public comment period and by review by the American Medical Association for Current Procedural Terminology (CPT) II codes. All final AAN measures are approved by the AAN Board of Directors. Results: Parkinson disease (PD) was chosen for measure development. A review of the medical literature identified 258 relevant recommendation statements. A 28-member panel approved 10 quality measures for PD that included full specifications and CPT II codes. Conclusion: The AAN has adapted a measure development process that is suitable for national measurement programs and has demonstrated its capability to independently develop quality measures.

A prospective open-label study of glatiramer acetate: Over a decade of continuous use in multiple sclerosis patients

A decade of continuous glatiramer acetate (GA) use by relapsing remitting multiple sclerosis (RRMS) patients was evaluated in this ongoing, prospective study, and the neurological status of ‘Withdrawn’ patients was assessed at a 10-year long-term follow-up (LTFU) visit. Modified intention-to-treat (mITT, n=232) patients received ≥ 1 GA dose since 1991; ‘Ongoing’ patients (n=108) continued in November 2003. Of 124 patients, 50 Withdrawn patients returned for LTFU. Patients were evaluated every six months (EDSS). Mean GA exposure was 6.99, 10.1 and 4.26 years for mITT, Ongoing, and Withdrawn/LTFU patients, respectively. While on GA, mITT relapse rates declined from 1.18/year prestudy to ∼1 relapse/5 years; median time to ≥ 1 EDSS point increase was 8.8 years; mean EDSS change was 0.739±1.66 points; 58% had stable/improved EDSS scores; and 24, 11 and 3% reached EDSS 4, 6 and 8, respectively. For Ongoing patients, EDSS increased 0.509±1.65; 62% were stable/improved; and 24, 8 and 1% reached EDSS 4, 6 and 8, respectively. For Withdrawn patients at 10-year LTFU, EDSS increased 2.249±1.86; 28% were stable/improved; and 68, 50 and 10% reached EDSS 4, 6 and 8, respectively. While on GA nearly all patients (mean disease duration 15 years) remained ambulatory. At LTFU, Withdrawn patients had greater disability than Ongoing patients.

Hereditary Adult-Onset Leukodystrophy Simulating Chronic Progressive Multiple Sclerosis

We studied a large kindred with a chronic progressive neurologic disorder affecting at least 10 men and 11 women in four generations in a pattern compatible with autosomal dominant inheritance. In 20 of the affected subjects, evaluated before the availability of computerized tomography and without regard to family history, the diagnosis was multiple sclerosis. Symptoms of the neurologic disorder begin in the fourth and fifth decades and include cerebellar, pyramidal, and autonomic abnormalities. The autonomic symptoms, which involve bowel and bladder regulation and orthostatic hypotension, may be the earliest changes but are frequently disregarded. Survival for 20 years after onset is common. The CT scan is striking and shows a symmetrical decrease in white-matter density, beginning in the frontal lobes but extending to all of the centrum ovale and the cerebellar white matter. Limited pathological observation reveals gross white-matter degeneration with microscopic vacuolation, preservation of U fibers and cortical structures, and no inflammatory changes or reactive gliosis. Because of its hereditary basis, the disorder should be susceptible to genetic definition and ultimately to treatment or prevention.

The brief repeatable battery of neuropsychological tests for multiple sclerosis: a preliminary serial study

The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) for MS consisting of the selective reminding, 10136 spatial recall, symbol digit modalities, paced auditory serial addition (PASAT) and word list generation tests is a sensitive measure of early cognitive impairment in MS patients. We administered it to 19 chronic stable MS patients every 60 days for 120 days to examine variability. The mean coefficient of variation for the tests ranged from 18% to 22%. A significant practice effect was seen in the PASAT results (P<0.05) using the Wilcoxon signed rank test These results suggest that cognitive fluctuations analogous to motor fluctuations may occur in MS patients and that the BRB-N may be useful in clinical trials of agents expected to alter cognitive function in MS patients if test-retest variability and practice effects are taken into account Further study is warranted.