Abraham Lieberman

Clinical evaluation of pramipexole in advanced Parkinson's disease: Results of a double-blind, placebo-controlled, parallel-group study

We compared the efficacy, safety, an tolerability of pramipexole, an aminobenzathiazol-derived dopamine agonist with novel properties, with those of placebo in advanced PD patients with motor fluctuations under levodopa treatment. Pramipexole improved motor function of patients during on andoff periods, decreased the time spent in off periods, reduced the severity of off periods, decreased disability and PD severity during on and off periods, as assessed by the Unified Parkinson Disease Rating Scale, and permitted a reduction in levodopa dosage. Adverse effects related to the central nervous system were similar to those reported with other dopamine agonists, and the gastrointestinal and cardiovascular tolerability of the compound was satisfactory.

Safety of Intrastriatal Neurotransplantation for Huntington's Disease Patients

Fetal neural transplantation has been shown to be a feasible, safe, and according to a number of recent reports, effective treatment for Parkinsons disease (PD). Fetal striatal transplantation may be as feasible, safe, and effective a treatment for Huntingtons disease (HD), a disorder for which there is currently no effective treatment. This report describes our experience with fetal striatal transplantation to adult striatum in three HD patients. Three moderately advanced, nondemented HD patients received transplantation of fetal striatal tissue. The striatal precursor was selectively obtained from the lateral ganglionic eminence. Each patient received bilateral grafts from five to eight donors, placed into the caudate nucleus (one graft on each side) and the putamen (four grafts on each side). All three patients had HD as documented by family history, DNA heterozygosity (17-20 and 48-51 repeats), magnetic resonance imaging (MRI) revealing striatal atrophy, and 2-deoxyglucose positron emission tomography revealing striatal hypometabolism. All patients had been evaluated using the Unified Huntingtons Disease Rating Scale and appropriate neuropsychological tests for at least 3 months prior to transplantation. One year following transplantation, MRI of all three patients revealed that the grafts survived and grew within the striatum without displacing the surrounding tissue. No patients demonstrated adverse effects of the surgery or the associated cyclosporin immunosuppression, nor did any patient exhibit deterioration following the procedure. The limited experience provided by these three patients indicates that fetal tissue transplantation can be performed in HD patients without unexpected complications.

Deprenyl in the treatment of symptom fluctuations in advanced Parkinson's disease.

Deprenyl, a selective inhibitor of monoamine oxidase, type B, which is free of the tyramine effect, may ameliorate symptom fluctuations in advanced Parkinsons disease (PD). We randomized 96 patients with marked symptom fluctuations at three centers to receive either deprenyl 5 mg b.i.d. or placebo in parallel fashion in addition to a previously optimized levodopa/carbidopa (Sinemet) regimen. Disability was recorded hourly at home by patients 3 days weekly during the 2-week baseline and the 6-week treatment period. Disability during the on state was assessed each week by examination. Mean hourly self-assessment of gait improved in 28 of 50 patients (56%) receiving deprenyl (mean degree of improvement 0.25 points on a 0-2 scale) and in 14 of 46 (30.4%) taking placebo (mean 0.15). Mean hourly overall symptom control improved in 29 (58%) taking deprenyl (mean 0.34) and in 12 (26.1%) taking placebo (mean 0.15) (p less than 0.01 for each parameter). No significant improvement occurred in the objective quality of the on state with deprenyl. Mean daily Sinemet dosage decreases were 17% in the deprenyl group and 7% in the placebo group. Adverse effects included nausea, light-headedness, dyskinesias, and hallucinations, all of which abated after the Sinemet dose was reduced. We conclude that deprenyl is of moderate benefit in a majority of patients with symptom fluctuations complicating PD and is generally well tolerated.

Sensory feedback therapy as a modality of treatment in central nervous system disorders of voluntary movement

Sensory feedback therapy may significantly improve the function of neurologic patients with disorders of voluntary movement, including torticollis, dystonia, and hemiparetic-spastic disorders of varied etiology. Thirty-six consecutively selected patients were studied, most of whom had received conventional therapy for up to 25 years with limited or no improvement. The patients learned volitional control of the functionally defective muscle group by means of audiovisual displays of integrated myoelectric activity from the monitored muscles. As volitional control of motor activity was achieved, the exteroceptive feedback was gradually withdrawn. Thirty-two of the patients responded with varying degrees of improvement ranging from functional recovery to symptomatic relief within 8 to 12 weeks. Apparently, a significant number of patients with disrupted internal feedback loops can incorporate the learned movement pattern by using those components of neuromuscular system that are still functionally available.

Studies on the antiparkinsonian efficacy of lergotrile

The antiparkinsonian activity of lergotrile mesylate, a presumed dopaminergic receptor stimulating agent, was investigated in monkeys with surgically induced tremor and in parkinsonian patients. The administration of lergotrile resulted in a dose-dependent reduction in the intensity of tremor in the monkeys. In 13 patients with Parkinsons disease treated with lergotrile (up to 12 mg a day), overall improvement was observed in five. Tremor was the main clinical feature to benefit, and the improvement reached statistical significance. In a subgroup of four patients treated with a higher dose of lergotrile (up to 20 mg a day), further improvement in rigidity and bradykinesia was noted, but again, only improvement in tremor was statistically significant. Adverse effects included orthostatic hypotension, behavioral alterations, and nausea and vomiting. These were severe enough to result in drug withdrawal in three patients.

Temporal dissociation of the prehension pattern in Parkinson's disease

This study assesses the reach to grasp movement of eight Parkinson and eight control subjects. The reach was of either 15, 27.5 or 40 cm. The grasp was either of a small (0.7 cm) or a large diameter (8 cm) dowel. When comparing Parkinson to control subjects, no differences were found in the regulation of movement parameters according to changes in object distance or size. However, for Parkinsons disease patients the onset of the manipulation component was delayed with respect to the onset of the transport component. It is proposed that this reflects a deficit in the simultaneous or sequential implementation of different segments of a complex movement.

Clinical study of fetal mesencephalic intracerebral transplants for the treatment of Parkinson's disease

This study reports our findings from 22 patients (ages ranging from 42 to 73 yr; mean = 55.2) with recalcitrant idiopathic Parkinsons disease (PD) who received implants of fetal ventral mesencephalic tissue using an MRI-guided stereotactic procedure and who have been followed for at least 6 mo postoperatively, employing the guidelines established by the Core Assessment Program for Intracerebral Transplantations. Evaluations were videotaped and were performed both on and off levodopa medications. To date, we have seven patients with 24 mo, three with 18 mo, three with 12 mo, and nine with 6 mo post-surgical assessments. Comparing surgical outcomes to levels prior to fetal transplants we found: 1) mean levodopa levels were reduced 46% at 6 mo, 12% at 12 mo, 20% at 18 mo, and 54% at 24 mo; 2) Unified Parkinsons Disease Rating Scale (UPDRS) scores with patients on levodopa were improved by an average of 38% (6 mo), 50.2% (12 mo), 69.3% (18 mo), and 73.9% (24 mo), while off medication scores showed reductions ranging from 24.7% at 6 mo to 55.1% at 24 mo. Other measures, including Hoehn-Yahr staging, Activities of Daily Living, and dyskinesia rating scales, were also significantly improved following fetal transplants. Timed motor tasks (finger dexterity, supination-pronation, foot tapping, and Stand-Walk-Sit) performance also demonstrated highly significant improvements. Patients self-rating scores indicated that the patients typically perceived substantial improvements in their condition. However, substantial variability in the improvements following surgery still persists and range from nominal improvements in performance to significant changes that can be classified as altering the overall lifestyle of the patients. To date, 4 of the 22 subjects were considered by the physicians to be nonresponders; that is, there were no clinically relevant improvements in these patients conditions.

Managing the neuropsychiatric symptoms of Parkinson's disease

Neuropsychiatric symptoms frequently complicate the treatment of Parkinsons disease (PD). Approximately 27% of PD patients are demented, and approximately 19% are cognitively impaired without being demented. These 46% of patients are prone to development of delirium when they take antiparkinsonian drugs. Approximately 40% of PD patients are depressed. The depression may be endogenous or exogenous, apathetic or agitated. Approximately 40% of PD patients are anxious or have panic attacks. The attacks may or may not be associated with depression. This article reviews the diagnosis of these symptoms and discusses their management.

Long term survival among patients with malignant brain tumors

Eight of 57 patients (14%) with malignant astrocytomas lived at least 2 years. The mean survival time was 143 weeks (range, 104 to 250 weeks). All of the patients were treated with operation, radiation, and chemotherapy. Four of the 8 patients died because of tumor recurrence, 1 died from a second primary tumor, 2 died of cases unrelated to the tumor, and 1 is still alive. Diffuse cortical dysfunction associated with cortical atrophy that could not be related to tumor regrowth and was not explained by focal deficits, psychotic of depressive thought disorders, metabolic or endocrine abnormalities, or hydrocephalus developed in the 3 longest-surviving patients. The diffuse dysfunction was initially apparent only through psychometric testing, but eventually became so disabling as to result in 2 of the 3 patients retiring from work. Although small, but gratifying, gains have been made in the treatment of patients with malignant brain tumors, accompanying these gains have been problems of a magnitude that is only now beginning to be appreciated.

Treatment of advanced Parkinson disease with pergolide.

Pergolide mesylate, a semisynthetic ergoline and a potent, long-acting central dopamine agonist, was tested in 13 patients with advanced Parkinson disease and diurnal oscillations in performance (“wearing-off” or “on-off” phenomena or both) whose response to levodopa had diminished considerably. Among all nine patients who completed the initial clinical trial, pergolide alone (two patients) or combined with levodopa (seven patients) had a marked antiparkinsonian effect. There was a significant reduction (p < 0.05) in rigidity, bradykinesia, gait disorder, and total Parkinson disease disability score. Pergolide had a marked effect in all the patients with “wearing-off” or “on-off” phenomena or both, resulting in a significant increase (p <0.01) in the duration of the time patients were “on.” The number of hours in which patients were “on” increased from 3.8 ± 0.5 (SEM) to 11.4 ± 0.8 (SEM). The mean daily dose of pergolide was 2.4 mg (range, 2 to 5 mg). Ten months later, all nine patients are doing well. Pergolide is an effective drug in patients with advanced Parkinson disease and reduces “on-off” phenomena.