The effect of robot-assisted therapy and rehabilitative training on motor recovery following stroke.

BACKGROUND: We used MIT-Manus, a robot designed to provide interactive, goal-directed motor activity for clinical neurologic applications. OBJECTIVE: To test whether this robotic manipulation of the impaired limb influenced motor recovery in patients with hemiplegia. METHODS: Sequential patients with a history of a single stroke and hemiplegia (N = 20) hospitalized on the same acute care rehabilitation floor were enrolled in a standard rehabilitation program supplemented by either robot-aided therapy or sham robot-aided therapy. These 2 groups were comparable in age, initial physical impairment, and time between onset of the stroke and enrollment in the trial. Patients, clinical team members, and the clinical evaluator were blinded to the treatment group assignments. Standardized assessment tools measured outcomes. RESULTS: Impairment and disability declined in both groups between hospital admission and discharge. The robot-treated group showed a greater degree of improvement in all 3 measures of motor recovery, and the change in motor status measured in the proximal upper limb musculature was significant (P = .002). No adverse events resulted from robot-assisted therapy. CONCLUSIONS: These results suggest that robotic manipulation of the impaired limb may favorably add to recovery following stroke and that robotics may provide new strategies for neurologic rehabilitation.

Baclofen toxicity in a patient with subclinical renal insufficiency.

Baclofen, a centrally acting gamma-aminobutyric acid agonist is a commonly used pharmacotherapy for spasticity of spinal origin. It is primarily excreted by glomerular filtration with a clearance proportional to creatinine clearance. We describe a 39-year-old quadriplegic women who, over a 16-week period, developed clinical signs of baclofen toxicity confirmed by progressively rising serum baclofen levels while on a conventional stable dosing regimen. During this period blood urea nitrogen and creatinine concentrations were normal and stable (9mg/dL and 0.8mg/dL, respectively). However, creatinine clearance values were consistently low (55 to 60m/min), suggesting renal insufficiency as the underlying cause. After a decrease in baclofen dosage, evidence of baclofen toxicity resolved. Clinicians should be alert to signs of evolving baclofen toxicity even in patients on an apparently stable regimen. Baclofen dosage adjustments based on systemic baclofen level may play a role in optimizing the clinical management of spasticity.

Glutethimide treatment of disabling action tremor in patients with multiple sclerosis and traumatic brain injury.

Glutethimide has been used to control essential tremor. Its efficacy in the treatment of disabling cerebellar and rubral tremor was assessed in an open study of six patients with multiple sclerosis and two patients with traumatic brain injury. Functional and quantitative tremor severity was assessed before treatment and 7 to 14 days after a stable dose was achieved. Six of eight patients exhibited visible functional benefit from treatment with glutethimide; abstract testing results correlated well with functional status in most cases. Four patients chose to continue to receive medication. Controlled trials of glutethimide to compare its efficacy with that of other medications used in the treatment of action tremor are indicated.

"Early" initiation of levodopa treatment does not promote the development of motor response fluctuations, dyskinesias, or dementia in Parkinson's disease.

We reviewed the histories of patients seen in a large Parkinson's disease clinic from 1983 to 1989 to determine if there is a relationship between the timing of initiation of levodopa therapy and the development of motor response fluctuations, dyskinesias, and dementia. There were no factors predisposing to the development of response fluctuations or dementia. Younger age at disease onset predisposed to the development of dyskinesia. Dyskinesias occurred in a greater proportion of patients in whom the initiation of levodopa therapy was delayed by more than 2 years from disease diagnosis than among those in whom treatment was started earlier. We thus failed to identify any adverse consequences of early levodopa treatment in our patient population.

Activation of rehabilitation.

Following the demonstration that catecholamine levels in the cerebral hemispheres were considerably reduced with stroke, efforts were made to change this situation in experimental animals. It was found that the use of amphetamine (CAS 300-62-9) greatly enhanced the recovery time of animals following experimental stroke, and that agents which block the release or function of catecholamines in the central nervous system seem to delay recovery. These observations have been used to determine whether or not the same conditions exist for humans with stroke. To date in one study there is evidence that use of amphetamine early after a stroke may enhance the rehabilitation process. The rehabilitation process can be impaired by a number of situations, the most common of which is depression. It has been shown that treatment of depression for patients with stroke in rehabilitation may improve the outcome as well as the speed of outcome. Prognosis for patients with stroke who enter rehabilitation programs is related to the degree of central nervous system damage. Those patients with only motor dysfunction tend to do much better in programs than those who have in addition sensory or visual disturbances. Usually maximum improvement of function following stroke and rehabilitation care occurs in the first three months. Carefully planned rehabilitation programs for patients following stroke with realistic goals can greatly improve the patients' function and enable them to remain as independent as possible.

Potentiation of rehabilitation: Medication effects on the recovery of function after brain injury and stroke.

In neurologic rehabilitation nothing is currently in clinical use that is effective in restoring lost neurologic function. This paper presents an overview of the various medicines that have been studied for their potential to facilitate recovery after brain injury. Early studies of acetylcholine and anticholinesterase drugs were reported favorably, but subsequent experience with them has not substantiated the initial enthusiasm. In the last two decades, data from work on rodents and cats suggest that certain drugs may facilitate or impede neurologic recovery after brain injury. Human studies on the effects of d-amphetamine and related compounds are sparse, and, although provocative, several problems make the results controversial. Data from studies in the laboratory suggest that clinicians may be impeding clinical outcome in stroke patients with some frequently used poststroke medications. A table lists (with references) the drugs that may impede recovery or reinstate deficits and drugs that may accelerate recovery.

An examination of male-female differences in progression and mortality of Parkinson's disease.

We conducted disability and mortality studies to determine if the male preponderance usually found in Parkinson's disease (PD) was reflected in different courses of the diseases in the 2 sexes. We analyzed longitudinal disability score in 47 men and 23 women with PD followed for 6 years at UCLA. We found no significant differences between the sexes in mean disability scores in any of the 6 years. Mean dopa dosage was significantly higher in men, possibly reflecting their generally larger body mass. Choreoathetosis, dementia, or other side effects did not differ between the 2 groups. We obtained observed to expected mortality ratios in 239 men and 132 women followed for 3,831 person-years from records of 4 medical centers. Using the sex-specific US Life Tables to calculate expected mortality, we found the observed to expected ratio for the men was 1.7457 and for the women 2.4740, a significantly greater excess in female mortality. Analyses of mortality using tables which are not sex-specific will fail to uncover the decreased longevity in women with PD. We conclude that, despite the male preponderance in PD, men and women acquire it at the same age, have the same progression and duration of disease, and die at the same age; whereas, in the general population, women have a longer life expectancy than men. It is not known what factors protect women from incurring PD and what lowers their life expectancy to that of men when they do have the disease.

Results of long-term treatment with controlled-release levodopa/carbidopa (Sinemet CR).

35 Parkinson's disease patients with motor response fluctuations (RF) participated in controlled clinical trials comparing Sinemet CR to Standard Sinemet (STD) at our institutions. 13 of 25 eligible patients continued to two years (the longest possible follow-up from the second study), and 5 of 11 have continued taking CR up to 4 years. At the end of both two and four years, patients were taking significantly fewer medication doses, with a significantly longer interdose interval, and up to two years, experienced fewer "off" periods than when on Standard Sinemet (STD) alone. Most patients required STD at at least one dose each day to hasten to onset of antiparkinson effect. Sinemet CR is a useful adjunct in the long-term management of motor response fluctuations in Parkinson's disease.

A pharmacokinetic and pharmacodynamic comparison of Sinemet CR (50/200) and standard Sinemet (25/100).

Seventeen patients with advanced Parkinson's disease who had fluctuations in motor performance while taking standard Sinemet (STD) 25/100 underwent daylong pharmacokinetic and clinical observation studies while taking both STD and Sinemet CR, a new controlled-release formulation containing 50 mg carbidopa and 200 mg levodopa. During treatment with Sinemet CR, there was an increase in the interdose interval, a reduction in the number of medication doses taken each day, an increase in total "on" time, and a reduction in the number of "off" episodes. Total daily levodopa intake was greater with Sinemet CR, although the bioavailability of levodopa and carbidopa from the two preparations was equivalent. The variability in plasma levodopa levels was significantly less with Sinemet CR. The slower release of drug from Sinemet CR was reflected in a prolongation of the Tmax for levodopa and a prolongation of the interval from Tmax to the succeeding trough levodopa level. Clinically, peak antiparkinsonian effect occurred later and lasted longer with the CR preparation.

Effect of age at onset on progression and mortality in Parkinson's disease.

We examined longitudinal disability scores in 54 patients with Parkinson's disease followed for 6 years at UCLA. We sorted data into 3 groups based on age at onset of symptoms: group A, onset under 50 years; group B, 50 to 59 years; group C, 60 years or older. There were no significant differences between groups initially. All 3 groups improved dramatically when levodopa was given, but group A showed significantly less disability in years 4, 5, and 6 than did group C. The groups did not differ with respect to side effects. To determine if age at onset affected mortality, we sorted records from 4 geographically diverse centers into the same 3 groups. Results on 359 patients followed for 3,314 person-years, covering a period of 17 years after onset of symptoms, showed that group A had the most favorable observed-to-expected mortality ratio, 1.82, compared with 2.17 and 2.20 for groups B and C respectively, but the difference was not statistically significant. Results from the disability analyses indicate that patients with onset of Parkinson's disease under 50 years of age may have a more favorable prognosis than those whose symptoms begin in later years.

A double-blind crossover comparison of Sinemet CR4 and standard Sinemet 25/100 in patients with Parkinson's disease and fluctuating motor performance.

Fourteen Parkinsonian patients with fluctuations in therapeutic response to levodopa completed a double-blind, crossover trial of controlled-release levodopa/carbidopa (Sinemet CR4) vs standard Sinemet 25/100 (STD). Significant increases in mean interdose interval and per cent of the waking day spent "on", as well as reductions in the number of daily medication doses and number of "off" episodes were noted. In the double-blind part of the study, relative to open treatment with STD, ten patients rated themselves as improved while taking CR4, whereas only three considered themselves improved with STD. Difficulties using CR4 included an increased "lag-time" to the onset of antiparkinson effect, a tendency to produce increasingly severe dyskinesia late in the day, and a somewhat lessened predictability of motor response. Nonetheless, since the overall level of motor function through the day was equal to or better than that attained with STD, but with fewer medication administrations, Sinemet CR4 should prove a useful antiparkinsonian agent.