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PubMed2005

Parkinson's disease. Diagnosis and the initiation of therapy.

Parkinson's disease (PD) is the most common cause of parkinsonism. Parkinsonism is characterized by resting tremor, bradykinesia, rigidity and gait impairment. There is no specific diagnostic test for PD and it is important for clinicians to understand the clinical signs which help to distinguish PD from parkinsonism. It is equally important to be aware of the clinical signs which can be an indication that the diagnosis is not PD. These so-called Parkinson-plus syndromes include progressive supranuclear palsy (PSP), multiple systems atrophy (MSA), corticobasal degeneration (CBD), vascular parkinsonism (VP) and parkinsonism with dementia (Lewy body dementia, LBD). The differential diagnosis of parkinsonism will be discussed. Initiating pharmacologic therapy for PD must take into consideration the degree of dysfunction the patient is experiencing, the question of neuroprotection, the degree of motor response required, and the potential complications of long-term treatment. Neuropro-tective trials of coenzyme Q10 (CoQ), vitamin C, vitamin E, monoamine oxidase B inhibitors (MAO-I) and dopamine agonists do not support the use of any of these drugs for a neuroprotective effect. There is recent supportive evidence that levodopa may have a neuroprotective effect. Either dopamine agonists or levodopa may be initiated. Dopamine agonists are associated with fewer motor fluctuations and dyskinesias, while levodopa is associated with better motor performance. Initiation of therapy should be tailored to individual patients with the emphasis on symptom control, with the hope that new approaches to treatment of PD (including neuroprotection) will be forthcoming.

Antioxidants↗
PubMed1975

Physiopathology of experimental Parkinsonism in the monkey.

Postural or Parkinson-like tremor, which results from the impairment of mechanisms which are predominantly lateralized in the brain, is most likely related to the combined impairment of the dopaminergic nigrostriatal pathway and the corresponding rubro-olivo-cerebello-rubral loop (without excluding the possiblity that other nervous mechanisms interconnected with these structures may represent an alternative disturbance). The integrity of the internal division of the pallidum and the ventrolateral area of the thalamus and their efferent fibers as well as the motor cortex and certain of its cortico-subcortico-spinal pathways (Figures 1 and 2) is apparently an essential feature for the elaboration of the rhythmic bursts associated with the appearance of postural tremor. The integrity of the spinal sensory roots and the rubro-tegmentospinal tract is not a prerequisite for the expression of postural tremor, a condition which seems essential for the production of rigidity. The latter facts suggest that the disturbances which subserve these two types of motor impairment, often concomitantly present in Parkinsonism, partially involve the impairment of different mechanisms although the loss of the DA fibers originating in the substantia nigra and ending in the neostriatum (Figure 1) appears to represent a disturbance common to both types of disorders. Bradykinesia which may be associated with an impairment of catecholamine metabolism (and more especially the neostriatal DA mechanisms) on both sides of the brain may also result from bilateral lesions of the pallidum or of its outflow corresponding, in the main, to the pallidothalamic fibers ending in the ventrolateral thalamus. The latter types of lesion most likely exclude the influence of the monoaminergic, cholinergic and gabaminergic activities normally originating in the striopallidal system and influencing the activity transmitted to other CNS mechanisms. Severe akinesia, however, apparently depends on more profound and generalized disturbances of brain monoamine metabolism with or without the involvement of other ill-defined mechanisms. At any rate the impairment of the brain DA mechanisms (and especially those of the neostriatum) seems to represent a major feature in the production of the Parkinsonian type of akinesia. Further work is needed to establish the relative importance of the loss of catecholaminergic mechanisms other than those of the neostriatum in the production of akinesia.

Animals↗
PubMed1995

Hypokinesia in Parkinson's disease: influence of age, disease severity, and disease duration.

The aim of this cross-sectional study was to compare the role of aging in measures reflecting diurnal activity and immobility in 60 parkinsonian patients with predominant features of hypokinesia and rigidity and 100 healthy subjects aged 50 to 98 years. In the patients, we also studied the relation between disease duration and subjective and objective measures of disease severity. Motor activity was recorded during 5 successive days at home with a wrist-worn activity monitor. For each subject, two mean measures reflecting the diurnal activity level and the relative proportion of activity and immobility were calculated. Diurnal measures of activity revealed in both groups a prominent absolute reduction of activity and an increase of the time spent without movement ("immobility") with advancing age. Parkinsonian patients showed significantly lower values for both motor-activity measures than did the healthy subjects. The rate of the age-related decline of both diurnal activity measures in both groups, however, is comparable. Disease duration showed no relation with subjective and objective measures reflecting disease severity. This study shows that if care is taken to control for disease severity, the rate of the age-related decline of measures reflecting diurnal activity and immobility is similar in both groups. The lack of relation between disease duration and subjective and objective measures of disease severity suggests that the rate of progression of Parkinson's disease can be reliably studied only by means of longitudinal studies.

Activities of Daily Living↗
PubMed1999

Correlations between in vitro affinity of antipsychotics to various central neurotransmitter receptors and clinical incidence of their adverse drug reactions.

OBJECTIVE: This study was performed to determine whether in vitro affinities of currently available antipsychotics toward dopamine or other neuronal receptor systems are associated with their in vivo incidence of central and peripheral adverse drug reactions (ADRs). METHODS: For 17 antipsychotic drugs available in Japan, the clinical incidences of 7 different types of drug-induced ADRs (i.e., akathisia, dyskinesia, tremor, rigidity, drowsiness, hypotension and dry mouth) were obtained from both post-marketing ADR databases and the investigational clinical trials of eight pharmaceutical companies. Affinity constants (K(i)) of the respective drugs toward dopamine D(1) and D(2) receptors, alpha(1)-adrenoceptors, histamine H(1) receptors, serotonin 5-HT(2) receptors and muscarinic cholinoceptors, determined using rat brain synaptosomes, were obtained from the literature. Relationships between in vitro receptor-binding properties and in vivo incidences of the respective types of antipsychotic-related ADRs were analyzed using Spearman's rank correlation. RESULTS: Significant (P < 0.05) correlations were observed between the K(i) values for dopamine D(2) receptor and the clinical incidences of akathisia and dyskinesia (r(s) = -0.68 and -0. 66, respectively). Significant (P < 0.05) correlations were also observed between the K(i) values for alpha(1)-adrenoceptor and histamine H(1) receptor and the incidence of drowsiness (r(s)=-0.65 and -0.55, respectively), and between the K(i) values for three receptor systems (i.e., dopamine D(1) receptor, alpha(1)-adrenoceptor and histamine H(1) receptor) and the incidence of dry mouth (r(s) = -0.50, -0.81 and -0.62, respectively). CONCLUSION: Preclinical receptor-binding data of antipsychotic drugs toward central dopamine and other ancillary neurotransmitter systems may be useful for predicting not only in vivo antipsychotic potency but also clinical incidence of akathisia and dyskinesia for this class of agents. Newly developed antipsychotic drugs with more potent and selective antagonistic activity against the dopamine D(2) receptor may not necessarily be associated with a lower incidence of extrapyramidal ADRs.

Adverse Drug Reaction Reporting Systems↗
PubMed1998

Gamma knife radiosurgery as a lesioning technique in movement disorder surgery.

OBJECT: To increase knowledge of the safety and efficacy of the use of gamma knife radiosurgery in patients with movement disorders, the authors describe their own experience in this field and include blinded independent assessments of their results. METHODS: Fifty-five patients underwent radiosurgical placement of lesions either in the thalamus (27 patients) or globus pallidus (28 patients) for treatment of movement disorders. Patients were evaluated pre- and postoperatively by a team of observers skilled in the assessment of gait and movement disorders who were blinded to the procedure performed. The observers were not associated with the surgical team and concomitantly and blindly also assessed a group of 11 control patients with Parkinson's disease who did not undergo any surgical procedures. All stereotactic lesions were made with the Leksell gamma unit using the 4-mm secondary collimator helmet and a single isocenter with maximum doses from 120 to 160 Gy. Clinical follow-up evaluation indicated that 88% of patients who underwent thalamotomy became tremor free or nearly tremor free. Statistically significant improvements in performance were noted in the independent assessments of Unified Parkinson's Disease Rating Scale (UPDRS) scores in the patients undergoing thalamotomy. Of patients undergoing pallidotomy who had exhibited levodopainduced dyskinesias, 85.7% had total or near-total relief of that symptom. Clinical assessment indicated improvements in bradykinesia and rigidity in 64.3% of patients who underwent pallidotomy. Independent blinded assessments did not reveal statistically significant improvements in Hoehn and Yahr scores or UPDRS scores. On the other hand, 64.7% of patients showed improvements in subscores of the UPDRS, including activities of daily living (58%), total contralateral score (58%), and contralateral motor scores (47%). Total ipsilateral score and ipsilateral motor scores were both improved in 59% of patients. One (1.8%) of 55 patients experienced a homonymous hemianopsia 9 months after pallidotomy due to an unexpectedly large lesion. No other complications of any kind were seen. Neuropsychological test scores that were obtained for the combined pallidotomy and thalamotomy treatment groups preoperatively and at 6 months postoperatively demonstrated an absence of cognitive morbidity. Follow-up neuroimaging confirmed correct lesion location in all patients, with a mean maximum deviation from the planned target of 1 mm in the vertical axis. Measurements of lesions at regular intervals on postoperative magnetic resonance images demonstrated considerable variability in lesion volumes. The safety and efficacy of functional lesions made with the gamma knife appear to be similar to those made with the assistance of electrophysiological guidance with open functional stereotactic procedures. CONCLUSIONS: Functional lesions may be made safely and accurately using gamma knife radiosurgical techniques. The efficacy is equivalent to that reported for open techniques that use radiofrequency lesioning methods with electrophysiological guidance. Complications are very infrequent with the radiosurgical method. The use of functional radiosurgical lesioning to treat movement disorders is particularly attractive in older patients and in those with major systemic diseases or coagulopathies; its use in the general movement disorder population seems reasonable as well.

Activities of Daily Living↗
PubMed1989

[Sufentanil: the effect on cardiocirculatory parameters and intubation conditions on administration of pancuronium or vecuronium].

A lack of uniform methodology used in the assessment of moderate doses of sufentanil in combination with non-depolarizing neuromuscular blocking drugs formed the basis of the current study which compared under randomized conditions the effects of sufentanil-pancuronium versus sufentanil-vecuronium on hemodynamics, intubating conditions and chest wall rigidity during induction of anesthesia. MATERIAL and METHODS. One hundred and twenty ASA physical status I and II patients aged between 20 and 40 years of age who were undergoing elective urological surgery were included in the study. Premedication consisted of 0.15 mg kg-1 diazepam, given orally 60 min prior to induction of anesthesia. Patients were randomly divided into eight groups of 15 each to receive 0.5 microgram kg-1 sufentanil or placebo in combination with pancuronium (groups I-IV) or vecuronium (groups V-VIII) Within each group, patients were randomly allocated to receive the relaxant either as a single bolus dose of 0.095 mg kg-1 pancuronium or 0.1 mg kg-1 vecuronium, or in divided doses (the priming principle), the smaller priming dose (0.015 mg kg-1 pancuronium or 0.015 mg kg-1 vecuronium) being administered 2 min before induction of anesthesia with 5 mg kg-1 thiopentone, followed by the second intubating dose of 0.080 mg kg-1 pancuronium or 0.085 mg kg-1 vecuronium. To maintain blind study conditions in the groups, the patients given the relaxants in one dose were given an equivalent volume of saline 2 min prior before 5 mg kg-1 thiopentone. Intubating was attempted 60 s after administration of the main dose of the relaxant, and conditions were assessed on a four-point scale: excellent, satisfactory, fair, or poor. Neuromuscular transmission was monitored with the Datex Relaxograph, a neuromuscular transmission analyzer, that utilizes the integration of the EMG response. Producing train-of-four (TOF) stimuli, with a pulse width of 100 microseconds and a frequency of 2 Hz every 20 s the following parameters were recorded by the Datex Relaxograph: The percentage of first twitch amplitude compared with the reference (T1), and the train-of-four (TOF) ratio, i.e., the ratio of last twitch height to first height. Measurements were taken after premedication in the operating room, the value which served as a baseline (t0), 1 min after sufentanil or placebo (t1), 1 min after priming or placebo (t2), 1 min after thiopentone (t3), and 1 min after intubation (t4).(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1996

Objective measurement of activation of rigidity: diagnostic, pathogenetic and therapeutic implications in parkinsonism.

1. Quantification of the effect on rigidity of its 'activation', by isometric grip, of standardized pressure, of the contralateral hand, was explored. Torque required to move the forearm through a fixed angle of 40 degrees, at a controlled rate of 0.5 Hz, in a horizontal plane about a pivotal axis aligned to the elbow joint, was recorded before (12 'baseline' recordings), during (10), and after (> or = 8) activation. Work required per unit displacement was calculated. 2. Specificity: Pilot serial daytime measurements gave an overall mean ratio, work required on activation over baseline, of 2.94 (95% CI 2.53, 3.42) in two elderly untreated parkinsonians, and 3.19 (2.75, 3.71) in two elderly subjects with isolated, clinically activation phenomenon, compared with 1.90 (1.64, 2.21) in two elderly without (P < 0.001), whilst two young adults did not activate, 0.98 (0.85, 1.14). In elderly subjects, work required under activation decreased during the day in health (-10 (-5, -14)% h-1, P = 0.0002), showed no significant change in those with clinical activation (4 (-1, 9)% h-1), and increased in parkinsonians (6 (0, 12)% h-1, P = 0.05): there appeared to be a transitionary state. 3. Validation of methodology: Quantifying the same work ratio on a single occasion in 20 aged parkinsonians (P), their spouses (Ps), 20 index controls (C) without parkinsonism, matched to (P), and their spouses (Cs) gave corroborative evidence of a pre-clinical state, defined by other measurements, in the spouses of sufferers. Values for C, Cs and Ps, 1.89 (1.42, 2.52), 2.38 (1.79, 3.17) and 2.93 (2.20, 3.90) respectively, were in consecutive positions, from health to (P, 2.96 (2.22, 3.95)) disease (P = 0.001 for Ps c.f. C; P = 0.1 for Ps c.f. Cs). Data on change over the day may enhance discrimination. 4. Sensitivity to medicines was illustrated, in two parkinsonians, by randomised, placebo balanced and controlled challenges: 1 and 2 tablets, Sinemet CR (Du Pont Pharmaceuticals, each levodopa 200 mg/carbidopa 50 mg) and 1 tablet, Sinemet-Plus (levodopa 100 mg/carbidopa 25 mg), then two 2 mg tablets, benzhexol. The dopaminergic effect (P < 0.001) was selective for activation (treatment.test-condition interaction, P = 0.004), and showed the expected time profiles. The effect of benzhexol (P = 0.008) lacked such selectivity. Its onset (> 4, < or = 6 h) was delayed, compatible with a gastrointestinal anti-muscarinic action and the subjects' ages. 5. Reliability (Fleiss's criterion) was shown to be good in 30 untreated parkinsonians.

Adult↗
PubMed1991

Tremor at onset. Predictor of cognitive and motor outcome in Parkinson's disease?

We examined 46 male patients with idiopathic Parkinson's disease to see whether tremor at onset was as useful a predictor of benign clinical outcome as tremor predominance after several years. When we compared patients with tremor at onset (n = 27) with those whose disease began with brady-kinesia/rigidity (n = 9), or gait disorder (n = 10), we found no significant differences after a mean of 7 years in motor, cognitive, or affective status. Sixteen of the tremor-onset patients continued to have tremor predominance with minimal gait disorder after about 7 years. These tremor-predominant patients had significantly better motor outcome and somewhat better cognitive outcome than either tremor-onset patients who subsequently developed gait disorder (n = 11) or patients without tremor at onset (n = 19). Tremor predominance after several years appears to be a better predictor of a benign clinical course of Parkinson's disease than tremor at onset.

Cognition↗
PubMed1991

Cumulative risks of developing extrapyramidal signs, psychosis, or myoclonus in the course of Alzheimer's disease.

Cumulative risks of developing extrapyramidal signs, psychosis, and myoclonus in the course of Alzheimer's disease (AD) were estimated in 72 patients with probable AD by the Kaplan-Meier survival method. The cumulative risk functions were found to increase at different rates for different signs as AD progressed. Comparisons of the cumulative risk functions revealed that in the early stages of AD, extrapyramidal signs and psychosis were more likely to develop than myoclonus. As AD progressed, the risk of developing myoclonus became as great as that of developing the other two signs. This study suggests that extrapyramidal signs, psychosis, and myoclonus represent developmental features that mark the progression of AD, rather than indicators of disease subtypes. The estimated cumulative risk functions set a reasonable expectation for the timing and likelihood of the emergence of the clinical signs. This, in turn, might aid in disease prognosis because the biological bases of these signs have been established and they have been shown to be predictive of other markers of disease course.

Aged↗
PubMed1991

Interrater reliability of extrapyramidal signs in a group assessed for dementia.

Extrapyramidal signs were rated by three neurologists in 20 patients who had either been diagnosed as having probable Alzheimer's disease or who were being evaluated for dementia. In general, good interrater reliability was found for the presence or absence of extrapyramidal signs, although agreement over the presence of some signs was reduced when distinctions between normality and slight departures from normality were required.

Aged↗