Clozapine is beneficial for psychosis in Parkinson's disease.
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Aged↗
Biomedical subjects
J L Juncos
Publications and source records attributed to J L Juncos.
Electrophysiologic analysis of early Parkinson's disease.
We have been interested in the application of quantitative measures of motor performance as a possible means of early detection of Parkinson's disease. To assess motor function, we have measured movement time (the physiologic correlate of bradykinesia) and reaction time (simple and directional choice) with an upper limb motor task, and tremor with accelerometry and electromyographic recordings. In this report we describe preliminary data from a Parkinson's disease patient group with symptoms of fewer than 2 years' average duration (compared with an age- and gender-matched normal control group) which indicate that precise, quantitative tests of motor function can detect the slight deviations from normal that are present in early Parkinson's disease. It appears that tests of bradykinesia are most sensitive, and detection of rest tremor is most specific. These tests may be applicable in screening individuals who are suspected of having or are "at risk for" Parkinson's disease and other related disorders.
Adult↗
Electrophysiologic analysis of early Parkinson's disease.
We have been interested in the application of quantitative measures of motor performance as a possible means of early detection of Parkinson's disease. To assess motor function, we have measured movement time (the physiologic correlate of bradykinesia) and reaction time (simple and directional choice) with an upper limb motor task, and tremor with accelerometry and electromyographic recordings. In this report we describe preliminary data from a Parkinson's disease patient group with symptoms of fewer than 2 years' average duration (compared with an age- and gender-matched normal control group) which indicate that precise, quantitative tests of motor function can detect the slight deviations from normal that are present in early Parkinson's disease. It appears that tests of bradykinesia are most sensitive, and detection of rest tremor is most specific. These tests may be applicable in screening individuals who are suspected of having or are "at risk for" Parkinson's disease and other related disorders.
Adult↗
Movement amplitude choice reaction time performance in Parkinson's disease may be independent of dopaminergic status.
The effect of circulating levels of plasma levodopa on reaction time performance was studied in patients with Parkinson's disease and untreated normal controls when instructed to move either a shorter or longer distance. On half the movements, subjects were pre-cued on the direction and amplitude of an impending movement. On the remaining movements, only the direction was pre-specified, and the amplitude was determined only when the cue to move was presented. Reaction time performance of patients was evaluated at three infusion levels of levodopa so that the patients were optimally, moderately, or minimally medicated. Parkinsonian patients were always slower to react and move than normal subjects. Clinical state correlated with movement time, but not with reaction time. These results contrast with those in which reaction time was related to plasma levodopa levels when movement direction and initiation were processed concomitantly, but the movement amplitude was pre-cued. It is possible that specification of the amount of muscle activity is partially independent of dopaminergic transmission.
Adult↗
Anxiety disorders in patients with Parkinson's disease.
To study the prevalence and importance of anxiety disorders in patients with idiopathic Parkinson's disease, the authors systematically evaluated 24 parkinsonian patients for the presence of DSM-III-R axis I syndromes. Nine subjects (38%) had a clinically significant current anxiety disorder. Severity of anxiety was not correlated with severity of parkinsonian symptoms, cumulative duration of L-dopa exposure, or current dose of L-dopa. These findings suggest that anxiety disorders should be considered in the medical evaluation and treatment of parkinsonian patients and that further attention should be paid to the role of the dopaminergic system in anxiety and phobic disorders.
Adult↗
Motor response complications with chronic levodopa therapy.
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Dose-Response Relationship, Drug↗
Continuous and intermittent levodopa differentially affect rotation induced by D-1 and D-2 dopamine agonists.
The effects of continuous and intermittent levodopa treatment on rotational behavior induced by dopamine agonists were examined in rats with a unilateral 6-hydroxydopamine lesion of the nigrostriatal dopamine pathway. Chronic administration of levodopa by continuous infusion (90-100 mg/kg per day i.p. by osmotic pump for 19 days with a 3 day washout) enhanced the rotational response to the D-2 dopamine receptor agonist quinpirole, but had no effect on rotation induced by the D-1 agonist SKF 38393 or that due to the non-selective dopamine agonist apomorphine. The rotational responses to the selective dopamine agonists differed dramatically in rats treated with levodopa by intermittent injection (45-50 mg/kg i.p., b.i.d. for 19 days with a 3 day washout): they showed a markedly increased response to quinpirole, a greatly diminished response to SKF 38393, and a modestly enhanced response to apomorphine. Continuous and intermittent treatment resulted in equivalent daily plasma levodopa levels. These findings suggest that the intermittence of central dopamine receptor stimulation may be an important factor in determining the subsequent responses of the dopamine system. The dissociation between the effects of both continuous and intermittent levodopa on D-1 and D-2 agonist-induced rotation indicates that D-1 and D-2 dopamine receptor-mediated mechanisms respond differently to chronic levodopa treatment.
2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-ben↗
Continuous and intermittent levodopa differentially affect basal ganglia function.
The effects of continuous and intermittent levodopa treatment on behavioral and biochemical indexes of basal ganglia function were compared in rats with unilateral 6-hydroxydopamine lesions of the nigrostriatal dopamine pathway. Animals treated for 30 days with intermittent levodopa exhibited behavioral sensitization manifested by an enhanced rotational response to apomorphine; the rotational response of rats treated with an equivalent dose of levodopa by continuous infusion did not differ from that of saline-treated controls. Dopamine receptor up-regulation in the denervated striatum relative to the intact striatum was statistically significant for D1 but not D2 receptors: This asymmetry in dopamine receptor levels was diminished following intermittent levodopa treatment. Glutamic acid decarboxylase activity, modestly elevated in all groups in the denervated striatum relative to the intact striatum, increased substantially over control values bilaterally as a result of intermittent, but not continuous, levodopa treatment. These findings suggest a relation between the schedule of chronic levodopa administration and the development of behavioral sensitization, possibly as a consequence of alterations in neuronal systems located downstream from striatal dopamine receptors. The behavioral sensitization induced by chronic, intermittent dopaminomimetic treatment may serve as a model for motor fluctuations in Parkinson's disease.
Animals↗
Pathogenesis of dyskinesias in Parkinson's disease.
Abnormal involuntary movements complicate the management of a majority of patients with advanced Parkinson's disease. The ability of levodopa to induce dyskinesias and alleviate parkinsonism has generally been considered a continuous dose-dependent pharmacological spectrum. In this study, the acute dose-response profile of intravenously administered levodopa for both inducing dyskinesia and alleviating parkinsonism, and its duration of action on these motor manifestations were evaluated in 52 parkinsonian patients. The minimum dose of levodopa required to produce mild dyskinetic movements was significantly lower in patients with fluctuations in motor response compared with those who had a stable response to standard oral therapy; the minimum dose for antiparkinsonian benefit, however, failed to show significant differences. The rate of disappearance of dyskinetic movements was faster than the rate of reappearance of parkinsonian signs following withdrawal of a steady-state infusion of levodopa. The dissociation of the pharmacodynamic profile of the two major motor effects of levodopa suggests their mediation through two different central pharmacological mechanisms, perhaps involving the two classes of dopamine receptors or other transmitter systems, and could have important implications for the design of future antiparkinsonian agents.
Adult↗
Rationale for continuous dopaminomimetic therapy of Parkinson's disease.
Levodopa combined with carbidopa (Sinemet) remains the most effective approach to the symptomatic relief of Parkinson's disease. Over time, however, an increasing number of parkinsonian patients evidence motor response complications, notably abnormal involuntary movements and motor fluctuations. Clinical pharmacologic studies suggest that these phenomena may arise as a consequence of factors reflecting both natural disease progression and levodopa toxicity. Simple wearing-off responses appear primarily related to advancing degenerative changes afflicting the dopamine system. The appearance of peak-dose dyskinesias and complex, random motor fluctuations of the on-off type, on the other hand, may signal secondary postjunctional changes arising as a consequence of chronic intermittent excitation of postsynaptic dopamine receptors that are normally tonically stimulated. Therapeutically, prompt correction of wearing-off fluctuations can ordinarily be achieved by measures that deliver dopaminomimetics continuously to the central nervous system. In contrast, fluctuations of the on-off type initially persist despite stable circulating levodopa levels. With continuous levodopa treatment, however, the threshold for dyskinesias begins to rise and the dose-response relation shifts to the right; clinically, the severity of both dyskinesias and on-off fluctuations tends to diminish. It is thus tempting to speculate that the early and continuing treatment of Parkinson's disease with compounds providing a relatively constant level of central dopamine stimulation will preclude wearing-off phenomena and mitigate on-off fluctuations and severe dyskinesias.
Antiparkinson Agents↗
Motor fluctuations in Parkinson's disease: central pathophysiological mechanisms, Part I.
The duration of the antiparkinsonian action of levodopa was studied in 48 patients with various response patterns to the oral administration of the dopamine precursor. Deterioration in motor scores after abrupt cessation of a steady-state intravenous levodopa infusion occurred at two successive rates: an initial rapid phase followed by a terminal slower phase. Efficacy half-time decreased and initial efficacy decay slope increased with progression of levodopa response groups from never treated to stable responders, and then to fluctuating responders of the wearing-off type and finally of the on-off type. Efficacy half-time exceeded plasma levodopa half-life in the 2 nonfluctuating groups, approximated it in those patients with wearing-off responses, and was significantly shorter in patients with fluctuations of the on-off type. The half-times for the decline in antiparkinsonian efficacy and dyskinesia severity differed significantly, suggesting different pharmacological mechanisms. Motor fluctuation severity correlated best with initial efficacy decay slope, and both were best predicted by parkinsonian symptom severity. The dyskinesia decay rate correlated most closely with levodopa dose. These results support the view that progressive dopamine neuron degeneration reduces the brain's ability to buffer shifts in levodopa availability attending its periodic oral administration; the clinical result is wearing-off phenomenon. The on-off phenomenon as well as dyskinesia apparently reflects additional secondary changes related to levodopa therapy and occurring postsynaptically.
Adult↗
Motor fluctuations in Parkinson's disease: central pathophysiological mechanisms, Part II.
The contribution of central pharmacodynamic mechanisms to the pathogenesis of motor fluctuations in advanced Parkinson's disease was studied in 29 patients by evaluating their acute response to intravenously injected levodopa. While the threshold dose for an antiparkinsonian effect did not change, that for induction of dyskinesia showed a progressive reduction in 4 groups: (1) levodopa-naive patients, (2) those with a stable response to oral administration, and (3) those with wearing-off or (4) on-off fluctuations. Concomitantly, the therapeutic window for levodopa narrowed and the levodopa dose-antiparkinsonian response slope increased. The antiparkinsonian threshold dose correlated best with duration of symptoms; the dyskinesia threshold dose, therapeutic window, and dose-response slope related most closely with the duration of levodopa treatment. The differing dose-response profiles for the antiparkinsonian and dyskinetic effects suggest involvement of separate pharmacological mechanisms. The present results, taken together with previous observations that the wearing-off phenomenon responds promptly to plasma levodopa stabilization while on-off fluctuations tend to diminish over several days, suggest that postsynaptic modifications, presumably at the receptor level, serve as the major determinant for the increasing difficulty with optimal dose adjustment and the motor fluctuations, especially of the on-off type, which complicate levodopa therapy of patients with advanced Parkinson's disease.
Adult↗
Pathogenetic studies of motor fluctuations in Parkinson's disease.
Pharmacokinetic and pharmacodynamic mechanisms for levodopa have been studied in relation to the pathogenesis of the motor fluctuations which complicate advanced Parkinson's disease. Since levodopa clearance from the general circulation was found to be similar in patients with wearing-off or on-off phenomena and those with a stable response to levodopa, peripheral pharmacokinetic factors are unlikely to be involved. Efficacy half-time for levodopa, on the other hand, was significantly reduced in patients with mainly wearing-off fluctuations in comparison to those manifesting a stable response to oral levodopa; individuals with predominantly on-off phenomenon had an even more extreme reduction in the duration of the antiparkinsonian action of levodopa. Conversion from oral to intravenous levodopa treatment immediately stabilized plasma levodopa levels in both the wearing-off and on-off groups; motor variability also decreased, especially in those with wearing-off phenomenon. During 11 days of continuous intravenous levodopa therapy, additional reductions in motor fluctuations occurred in both groups, but at a significantly faster rate in patients with wearing-off than in those with on-off responses. These results suggest that wearing-off phenomenon may arise as a consequence of the degeneration of dopamine terminals due to natural disease progression with a resultant inability to buffer variations in levodopa availability; on-off phenomenon, may reflect additional postsynaptic dopamine receptor dysregulation, possibly in response to the resultant, nonphysiologic fluctuations in synaptic dopamine.
Biomechanical Phenomena↗
Dopaminergic effects on simple and choice reaction time performance in Parkinson's disease.
The present study examined whether premovement central neural processing in Parkinson's disease was related to functional motor disability and plasma L-dopa concentration. Reaction time (RT) performance in simple and choice RT tasks was assessed while plasma L-dopa levels were controlled by continuous IV L-dopa infusion in five parkinsonian patients. Five age-matched controls performed the same RT tasks for comparison. Simple RT for the patients was longer than the normal control RT at all infusion levels (p less than or equal to 0.005). However, choice RT was normal when the patients were "on," but became prolonged as plasma L-dopa levels decreased (p less than or equal to 0.01). The results show that there are abnormalities of premovement central neural processing in Parkinson's disease, and that simple and choice RTs are differentially affected by L-dopa replacement. This suggests that different neural mechanisms may be involved in the processing of these tasks.
Adult↗
Dietary influences on the antiparkinsonian response to levodopa.
The ability of dietary factors to modify the response to levodopa was evaluated in six patients with idiopathic Parkinson's disease who manifested fluctuations in motor performance. The single oral administration of a high-protein formula substantially elevated plasma large neutral amino acid levels, and prematurely terminated the antiparkinsonian response to levodopa/carbidopa. In contrast, during oral or intravenous administration of levodopa, the ingestion of diets meeting the recommended daily allowance (RDA) for protein had no significant effect on plasma levodopa or large neutral amino acid levels or variance, nor on parkinsonian scores or variance. The results suggest that while protein intake in excess of the RDA can diminish the antiparkinsonian response to orally administered levodopa/carbidopa in patients with advanced disease, diets adhering to RDA protein guidelines have no clinically appreciable effect.
Amino Acids↗
Controlled release levodopa-carbidopa (CR-5) in the management of parkinsonian motor fluctuations.
Parkinsonian patients receiving long-term levodopa-carbidopa (Sinemet) therapy often develop fluctuations in motor performance. Although maintenance of stable levels of plasma levodopa by means of its continuous intravenous infusion diminishes these fluctuations, practical limitations attending this therapeutic approach have prompted continuing attempts to develop oral controlled release levodopa-carbidopa formulations. In a double-blind, crossover clinical trial, one such preparation, CR-5 (Merck, Sharp & Dohme), produced significantly less plasma levodopa variations and substantially improved motor performance over Sinemet in 15 patients with mild to moderate fluctuations, all but one of whom chose to continue on CR-5 therapy after the study. Eight patients with severe motor fluctuations could not adjust to this preparation during the open phase and consequently withdrew from the study. Subjectively, most patients noted the convenience of less frequent dosing, improved sleep, and the amelioration of early morning akinesia and dystonia.
Adult↗
Motor fluctuations in Parkinson's disease: pathogenetic and therapeutic studies.
The response to continuous intravenous infusion of levodopa was evaluated in 23 patients with Parkinson's disease complicated by motor fluctuations. Conversion from oral to intravenous levodopa treatment resulted in an immediate and sustained stabilization of plasma levodopa levels in both the wearing-off and on-off groups. Motor variability also diminished within the first 24 hours of infusion, although to a much greater extent in patients with the wearing-off phenomenon. Over the next 5 to 11 days of intravenous treatment, further reductions in motor fluctuations occurred in both groups, at a substantially faster rate in the wearing-off group than in the on-off group. The degree of immediate stabilization of parkinsonian motor response correlated best with disease duration, whereas the rate of subsequent improvement correlated most closely with levodopa dose. The results support the view that the wearing-off phenomenon may reflect the degeneration of dopamine terminals as a consequence of natural disease progression with a resultant inability to buffer variations in levodopa availability; the on-off phenomenon may reflect additional postsynaptic changes, possibly occurring in response to the nonphysiological fluctuations in synaptic dopamine, which gradually remit during continuous levodopa administration.
Administration, Oral↗
Idiopathic cranial polyneuropathy. A fifteen-year experience.
Fourteen cases of idiopathic multiple cranial neuropathy seen over fifteen years are reviewed and contrasted with 6 cases of the Tolosa-Hunt syndrome, the closest and better known clinical entity. The syndrome consists of subacute onset of facial pain preceding the onset of cranial nerve palsies. There were 5 men and 9 women aged 21 to 83 years. Eight of the 9 patients treated with corticosteroids showed improvement, with pain usually receding within 48 hours. The cerebrospinal fluid was abnormal in 7 of 12 cases, with either a mild pleocytosis or raised protein content. The cranial nerves most frequently involved were the third and sixth. Motor nerves were affected more than sensory. Corticosteroid therapy appeared to hasten recovery of function. Clinical features are shared by both syndromes, the resulting spectrum of illness probably reflecting diverse aetiologies. Historical perspectives, differential diagnosis and aetiological considerations are discussed so that a coherent prospective clinical approach to the problem can be developed.
Adrenal Cortex Hormones↗