Entacapone improves the pharmacokinetic and therapeutic response of controlled release levodopa/carbidopa in Parkinson's patients.

The aim of this trial was to evaluate the effects of the COMT inhibitor entacapone on both the pharmacokinetic profile and clinical efficacy of controlled release levodopa in Parkinson's disease (PD) patients. Twelve PD patients experiencing "end-of-dose" type motor fluctuations were evaluated in this single-blind, randomized cross-over study. A single dose of either entacapone (200 mg) or placebo was co-administered with controlled release levodopa. Blood samples were taken every 30 minutes for 3 hours, and in 6 patients, sampling was continued for a further 3 hours. The clinical response to treatment was evaluated using the Unified Parkinson's Disease Rating Scale motor score. Addition of entacapone to levodopa treatment prolonged the "on" phase of the PD patients by 37% (p<0.05). This increased duration of 'on' time was concomitant with a significant increase in levodopa bioavailability (AUC). These data confirm the ability of entacapone to enhance the clinical efficacy of controlled release levodopa formulations, and provide further evidence that entacapone is of value in extending the benefits of levodopa in PD patients experiencing motor fluctuations.

The feasibility of statistical parametric mapping for the analysis of positron emission tomography studies using 11C-2-beta-carbomethoxy-3-beta-(4-fluorophenyl)-tropane in patients with movement disorders.

Movement disorders, including Parkinson's disease and parkinsonian syndromes, e.g. progressive supranuclear palsy, multiple system atrophy, and Lewy body dementia, may be difficult to differentiate among each other at an early stage, since they may share similar clinical features and response to dopaminergic drugs. As new tracers for imaging the dopamine transporters become available, the use of positron emission tomography (PET) for the differential diagnosis of movement disorders is gaining clinical relevance. Visual interpretation is generally used for PET image analysis. However, the use of some form of less subjective analysis is desirable in order to detect subtle changes that may be difficult to identify by visual interpretation and to achieve an operator independent analysis. To this end this study was aimed at assessing the feasibility of using statistical parametric mapping (SPM) for the clinical evaluation of single PET scans performed with 2-beta-carbomethoxy-3-beta-(4-fluorophenyl)-tropane ( C-beta-CIT-FE). Eleven healthy volunteers and five patients with movement disorders (Parkinson's disease, essential tremor, PSP and Lewy body dementia) were included in this study. Each subject underwent a PET study after i.v. injection of C-beta-CIT-FE. The PET images of C-beta-CIT-FE distribution acquired between 60 and 90 min were spatially fitted into the Talairach and Tournoux space. A template of normal C-beta-CIT-FE distribution was derived from studies in the 11 normal control subjects. Different patterns of reduction of the uptake of the tracer were detected in the basal ganglia of the five patients, in relation to each pathological condition. The patterns of distribution were all consistent with the severity and type of disease. The results of this study demonstrate the feasibility of differentiating among different states of dopaminergic impairment, due to Parkinson's disease and parkinsonian syndromes, by using PET scans with C-beta-CIT-FE and by using the SPM procedure for analysis of the data.

Effect of bilateral subthalamic electrical stimulation in Parkinson's disease.

BACKGROUND: Bilateral high frequency subthalamic stimulation has been reported to be effective in the treatment of Parkinson's disease and levodopa-induced dyskinesias. To analyze the results of this surgical procedure we critically reviewed 17 parkinsonian patients with advanced disease complicated by motor fluctuations and dyskinesias. METHODS: Between January 1998 and June 1999 these 17 consecutive patients (age 48-68 years; illness duration 8-27 years) underwent bilateral stereotactically guided implantation of electrodes into the subthalamic nucleus in the Department of Neurosurgery of the Istituto Nazionale Neurologico "C. Besta." Parameters used for continuous high-frequency stimulation were: frequency 160 Hz, pulse width 90 microsec, mean amplitude 2.05 +/- 0.45 V. Parts II and III of the UPDRS were used to assess motor performance before and after operation by the neurologic team. The follow-up ranged between 6 and 18 months. RESULTS: At latest examination, mean UPDRS II and III scores had improved by 30% (on stimulation, off therapy) with mean 50% reduction in daily off time. Peak dyskinesias and early morning dystonias also improved in relation to therapy reduction. Side effects were persistent postoperative supranuclear oculomotor palsy and postural instability in one case, worsened off-medication hypophonia in three, and temporary nocturnal confusion episodes in three. Postoperative MRI revealed a clinically silent intracerebral haematoma in one case. One electrode required repositioning. CONCLUSIONS: Continuous high frequency STN stimulation is an effective treatment for advanced PD. A functionally useful and safe electrode placement can be performed without microrecording.

Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease. A randomized multicenter study.

Objectives: levodopa improves the quality of life in parkinsonian patients, however long term response is compromised by the emergence of motor fluctuations and dyskinesias. The aim of this study was to compare the occurrence of motor fluctuations and dyskinesias in previously untreated patients assigned to receive levodopa, a dopamine agonist or deprenyl.Thirty-five neurological departments in Italian hospitals participated in this randomized open trial. Patients with Parkinson's disease, who required the initiation of an effective antiparkinsonian treatment, were randomly assigned to receive levodopa, dopamine agonists or deprenyl. The end-points were motor dyskinesias and motor fluctuations occurring in a median follow-up period of about 3years.After a median follow-up of 34months, motor fluctuations and dyskinesias were less frequent in patients assigned to a dopamine agonist or deprenyl than in patients assigned to levodopa (relative risk [RR] 0.5, 95% confidence interval [95% CI] 0.3-0.8, and RR=0.6, 95% CI 0.3-0.9, respectively), but dopamine agonists were less effective and less well tolerated than levodopa. The lower frequency of motor fluctuations in patients assigned to deprenyl was no longer statistically significant when prognostic predictors were considered in a multivariable analysis. Long-term mortality did not differ in the three arms of the study. Dopamine agonists and deprenyl can be considered as an alternative to levodopa for starting treatment in Parkinson's disease patients. However, on clinical grounds, only small advantages are expected over the traditional therapy initiation with levodopa.

Sporadic choreas: analysis of a general hospital series.

The incidence of sporadic chorea among general hospital admissions is unknown, and the relation of clinical manifestations and etiological factors to neuroimaging findings has been little investigated in this condition. We reviewed the 7,829 cases admitted to the neurology departments of two general hospitals over 3.25 years and identified 23 (8 male and 15 female) cases of apparently sporadic chorea. Analysis of the records of these patients permitted etiological classification as follows: drug-induced chorea (5 patients), vascular chorea (6 patients), chorea-vasculitis (1 patient), Sydenham's chorea (1 patient), AIDS-related chorea (5 patients) and in 4 patients neither etiological factors nor neuroradiological alterations were found. Finally in 1 patient, the genetic test for Huntington's disease was positive. Thirteen patients had pathological neuroimaging findings; however, in only 3 were basal ganglia lesions considered to be the cause of the chorea. We conclude that sporadic chorea is not rare among neurological department admissions (we found 2.94 cases per 1,000 admissions) and only in a minority of cases is the symptomatology attributable to gross basal ganglia lesions; HIV infection is an emerging cause of chorea.

Cognitive dysfunction and impaired organization of complex motility in degenerative parkinsonian syndromes.

BACKGROUND: A frontostriatal pattern of cognitive decline, consisting of a frontal lobe-like syndrome without genuine cortical defects such as amnesia, apraxia, aphasia, or agnosia, is well established in basal ganglial diseases. Recent pathological investigations, however, have again noted cortical damage in progressive supranuclear palsy (PSP), suggesting that cortical defects could be present. OBJECTIVES: To delineate the pattern of cognitive impairment and to detect higher-order motor impairments (including ideomotor apraxia) in parkinsonian syndromes. PATIENTS AND METHODS: We assessed ideomotor apraxia, and simple and sequential tapping in patients with Parkinson disease, multiple system atrophy, and PSP with similar disease severity, age range, and education. We also administered a comprehensive battery of neuropsychological tests to examine general intelligence, memory, executive functions, attention, and visuospatial orientation. The results were compared between groups and with a matched normal control group. RESULTS: Sequential tapping and the imitation of sequences of gestures were impaired in all patient groups, with patients with PSP performing worse than the other groups. Based on ideomotor apraxia scores and a qualitative analysis of errors, 3 patients with PSP and 2 with multiple system atrophy were considered apraxic. General intelligence and executive functions were compromised in all patient groups. The impairment of patients with PSP was more pervasive than that of the other groups, and included compromise of visuospatial functions, attention, and memory. Discriminant analysis of all cognitive and motor tests showed that the tapping and ideomotor apraxia tests best identified the patients vs control subjects. CONCLUSIONS: The presence of cortical as well as subcortical damage in patients with PSP and those with multiple system atrophy is indicated by the presence of pervasive cognitive and motor disturbances in the former, substantial motor disorganization in the latter, and the finding of ideomotor apraxia in some patients with these diseases. Furthermore, the discovery that tests of motor and gesture best identified all patients vs control subjects is consistent with the existence of a common motor disorganization in these parkinsonian syndromes, in agreement with the known damage to the corticostriatal pathways in these conditions.

Learning manual pursuit tracking skills in patients with Parkinson's disease.

Evidence from a number of sources identifies the putamen and its ultimate cortical projection sites as forming a possible substrate for motor learning. The present paper describes two experiments which explored motor learning of a pursuit tracking task under first (position) and second (velocity) order control dynamics, in patients with Parkinson's disease on and off (experiment 2 only) their normal dopaminergic medication. In neither experiment did the medicated patients show evidence of significant impairment in learning the tasks. In the velocity tracking task, however, the patients off medication showed significantly less improvement in performance with practice. The discussion considers a number of possible interpretations of this finding. Contemporary cognitive theories of motor learning consider behavioural change with practice to be the combined action of an automatic procedural system, together with input from a conscious declarative system. Development of declarative knowledge about the task may have changed the nature of the process involved, from a visually guided task to a more predictive one based upon an internal representation. Evidence from various sources suggests that patients with Parkinson's disease have particular problems with this mode of control, thus making the task more difficult. It is suggested that motor control deficits have not been adequately considered in previous studies on motor learning, and that the evidence from clinical studies for a role of the putamen/supplementay motor area in motor learning remains equivocal.

Variations in axial, proximal, and distal motor response to L-dopa in multisystem atrophy and Parkinson's disease.

The purpose of this study was to quantitatively compare the motor response to L-dopa in Parkinson's disease (PD) and striatonigral-type multisystem atrophy (MSA) patients. Ten consecutive MSA patients were compared with nine PD patients selected to have similar overall motor compromise, age, and mental state. The performance of simple repetitive axial movements plus bilateral proximal and distal limb movements; overall motor response assessed by the Unified Parkinson Disease Rating Scale (UPDRS); as well as scores from the UPDRS items evaluating speech/facial expression, postural stability, and posture/gait were assessed 90 min and 12 h (baseline) after L-dopa administration. The total UPDRS score, all subcategory scores, and all body movements improved significantly in the PD group. Proximal and distal limb akinesias and speech/facial expression improved in some MSA patients. Lack of response of axial akinesia to L-dopa in MSA correlates with a presumed greater loss of postsynaptic dopaminergic receptors in the dorsolateral putamen, while improvement in distal and proximal limb muscle akinesias in MSA patients may be related to relative preservation of the ventral putamen.

Increased plasma bilirubin in Parkinson patients on L-dopa: evidence against the free radical hypothesis?

Oxidative damage by free radicals may contribute to the etiology of Parkinson's disease (PD), and increased oxidative stress in the nigral cells of PD patients may occur following L-dopa treatment, prompting suggestions that L-dopa therapy should be delayed as long as possible. Bilirubin is a potent antioxidant in vitro, even when bound to albumin, suggesting a physiological role as an antioxidant. Calculations indicate that bilirubin can pass the blood-brain barrier in sufficient quantity to exert a significant antioxidant effect in the brain. We have found a highly significant (about 20%) increase in plasma bilirubin in 162 PD patients on chronic L-dopa treatment compared to 93 untreated parkinsonians and 224 non-parkinsonian controls. We propose that L-dopa-induced increase in nigral oxidative stress in PD may be effectively counteracted by increased bilirubin levels. The mechanism by which plasma bilirubin is increased in patients receiving L-dopa is at present unknown.

Cabergoline in Parkinson's disease complicated by motor fluctuations.

Cabergoline is a long-acting D2 dopamine (DA) agonist. We conducted an open study to investigate the effectiveness and tolerability of cabergoline, administered once a day orally, in 50 consecutive patients with Parkinson's disease complicated by motor fluctuations and dyskinesias. In 15 patients cabergoline replaced another direct DA agonist. Evaluation after 6 months of treatment (also including patients who dropped out during this period), showed an improvement in off or on hours, or both, in excess of 50% in 27 patients, comprising 20 of the 35 patients (57%) previously untreated with DA agonists and seven of the 15 patients (47%) already on DA agonists when the study began. Of the 22 patients who received the treatment for 1 year, the improvement was maintained up to final evaluation in the patients not on DA agonists at admission (n = 16), whereas a slight deterioration in clinical condition was observed in the patients already on DA agonists at admission (n = 6). Only six patients showed a detectable increase in dyskinesias. The most common side effects were gastric upset (n = 12), orthostatic hypotension (n = 3), and ankle edema (n = 3), all mild; also observed were two cases of pleural effusion/pulmonary fibrosis. Twenty patients (40%) failed to complete the treatment; of these, five (10% of total) dropped out because of adverse effects. It is concluded that once-daily administrations of cabergoline are useful for treating patients with Parkinson's disease with motor fluctuations and may advantageously substitute other DA agonists. The side effects of the drug are generally mild, although two cases involving pleuropulmonary complications did emerge.

Psychiatric symptoms do not correlate with cognitive decline, motor symptoms, or CAG repeat length in Huntington's disease.

OBJECTIVES: To investigate the hypothesis that psychiatric disturbances in Huntington's disease are related to degree of cognitive or motor compromise and to determine correlations between CAG repeat length within the gene for Huntington's disease and disease severity. DESIGN: Consecutive series of patients with Huntington's disease. SETTING: Neurological specialty hospital. PATIENTS: Seventeen men and 12 women from 24 families. MAIN OUTCOME MEASURES: The Hamilton Psychiatric and Anxiety Rating Scales and Brief Psychiatric Rating Scale were used to assess psychiatric disturbances; Folstein's Quantified Neurological Examination to evaluate motor status; and the Mini-Mental State Examination, Raven Progressive Matrices), Phonemic Verbal Fluency Test, Short Tale Test, Visual Search Test, and Benton's Visual Orientation Line Test to evaluate cognitive function. The length of the CAG repeat sequence in the Huntington's gene was determined by quantitative polymerase chain reaction. RESULTS: Cognitive test scores correlated significantly with each other; of these, results of the Visual Search and Short Tale tests correlated significantly with the Folstein's Quantified Neurological Examination score (P = .05 and P = .03, respectively). Results of the Folstein's Quantified Neurological Examination also correlated with the illness duration and the length of the CAG repeat. Although psychiatric scores correlated significantly among themselves (P < .01), neither cognitive compromise, motor deterioration, nor CAG length were related to the extent of psychiatric compromise. Patients who were depressed when they were examined tended to have a history of psychiatric disorders. CONCLUSIONS: The lack of correlation between disease severity and psychiatric disturbances indicates that psychiatric disorders progress nonlinearly, possibly because of differential degeneration of the striatal-cortical circuits; the possibility that psychiatric disorders are prevalent in certain families with a member who has Huntington's disease is being further investigated. The lack of correlation between CAG length and cognitive and psychiatric variables needs further investigation.

Survival in multiple system atrophy: a study of prognostic factors in 59 cases.

The various clinical features of multiple system atrophy (MSA) make the diagnosis of the disease difficult, especially in its early stages, when signs of differentiated neuroanatomical system involvement have not yet appeared. Mortality studies may be affected by the variability of the diagnostic criteria and selection bias. We used strict clinical and MRI criteria to diagnose MSA in 59 patients. Patients with parkinsonian and cerebellar onset were compared. Median survival time from the onset of the first motor symptom was 7.5 years. Our results indicated a trend (P = 0.09) for the Northwestern University Disability Scale score to correlate with mortality, but we failed to find other characteristics identifying subgroups or predictors for survival.

Progression of motor and cognitive impairment in Parkinson's disease.

We performed a longitudinal study (mean follow-up 86.7 months) to evaluate motor and mental deterioration in patients with Parkinson's disease. Of the original 91 patients, only 61 could be re-examined 7 years later and 11 of these had become demented (PD-Dems). PD-Dems were older with worse motor and, obviously, cognitive performance than non-demented parkinsonian patients (PDs). A global cognitive decay index (DI) was calculated for each patient. Based on this, non-demented PDs were further split into 38 stable parkinsonian patients (S-PDs) with DI-30% to +30%, and 10 deteriorated but non-demented parkinsonian patients (D-PDs) with a DI worse than -30% (as had PD-Dems). D-PDs were older and had greater motor impairment than S-PDs but did not differ from PD-Dems on these measures. D-PDs and PD-Dems deteriorated especially in attention, visuospatial and executive ability tests. Ageing seems to be the main predictive factor for mental deterioration.

Clinical/metabolic correlations in multiple system atrophy. A fludeoxyglucose F 18 positron emission tomographic study.

OBJECTIVE: To evaluate the regional cerebral metabolic involvement; the relationships among regional brain metabolism, clinical features, and quantitative measures of disease severity; and the patterns of brain involvement that can be related to the different types of onset: striatonigral degeneration vs olivopontocerebellar atrophy. DESIGN: Fludeoxyglucose F 18 positron emission tomography (PET) studies performed in patients with multiple system atrophy (MSA) were evaluated for their clinical features at the onset of the disease and at the time of the PET study. CASES: Seventeen patients diagnosed as having probable MSA and 10 age-matched controls. RESULTS: The hypometabolism in the putamen-pallidum complex and in the cerebellum was the best discriminant for disease classification. The efficacy of levodopa treatment was positively correlated with the metabolic activity of the putamen-pallidum complex. The patients with olivopontocerebellar atrophy type (N = 8) had a prevalent hypometabolism in the cerebellum, while the patients with striatonigral degeneration type (N = 9) had a prevalent impairment in the pallidum-putamen complex. We demonstrated a negative correlation between (1) severity of parkinsonism and metabolic values of putamen and caudate; (2) severity of cerebellar signs and metabolism in the cerebellum; and (3) autonomic dysfunction and metabolic activity in the thalamus, frontal, and temporal regions, bilaterally. CONCLUSIONS: These findings support the selective metabolic reduction in the putamen and cerebellum as a marker of MSA. The clinical/metabolic correlations, demonstrating the expected dependence of extrapyramidal and cerebellar signs by dysfunction of basal ganglia and cerebellum, also support a possible involvement of central nervous system structures in autonomic control.

Reliability among neurologists in the severity assessment of blepharospasm and oromandibular dystonia: a multicenter study.

The reliability of a scale of 0 to 4 (where 0 is normal) in rating the severity of blepharospasm (BS) and oromandibular dystonia (OMD) was evaluated by the concordance among six neurologists from different neurological institutions. As expressed by k index, interobserver agreement was moderate either for BS or for OMD according to the Landis classification. Neurologists showed different rating attitude toward BS and OMD. In fact, the category analysis showed that raters were inclined to overestimate BS and to underestimate OMD. The familiarity with dystonia influenced reliability more than the length of professional experience in neurology. In fact, when examiners were subdivided into subgroups (each of three raters) according to the former criteria, the level of interobserver agreement increased significantly. Almost perfect agreement was obtained in intrarater comparisons. These results may be of value with regard to the conduct of multicenter epidemiologic and clinical studies on focal dystonias.