Interactions between deep brain stimulation and levodopa in Parkinson's disease.

OBJECTIVE: To quantify the effects of deep brain stimulation (DBS) of globus pallidus interna (GPi) and subthalamic nucleus (STN) on motor fluctuations and dyskinesia in PD and to determine how the response to levodopa was modified by DBS. BACKGROUND: Patients report that DBS reduces levodopa-induced motor fluctuations and dyskinesia throughout the day, but this has not been objectively measured. Further, the means by which DBS alters the response to levodopa to improve motor fluctuations is unknown. METHODS: Twelve subjects, six with bilateral GPi electrodes and six with bilateral STN electrodes, were studied 12 to 33 months after surgery. To quantify motor fluctuations and dyskinesia, subjects were monitored hourly throughout 2 waking days with their usual oral medications, 1 day with DBS on and 1 day with DBS off, with subjects and nurse raters blinded to DBS status. To examine the effects of DBS on levodopa pharmacodynamics, the effects of a 2-hour levodopa infusion were examined, 1 day with DBS on and 1 day with DBS off, again under double-blind conditions. Time course of variations in parkinsonism was evaluated by tapping speed, arising and walking speed, tremor scores, and dyskinesia scores. RESULTS: DBS raised the mean tapping speed and reduced the coefficient of variation during the waking day. This was achieved by increasing the lowest or trough tapping speed between doses of antiparkinson medications. Mean walking speed was modestly increased and mean tremor scores were reduced. DBS increased the drug-off tapping speed, but neither the peak response nor the duration of response to levodopa was affected by DBS. The study was not powered to detect differences between GPi and STN stimulation and the only difference that approached significance was that GPi reduced peak dyskinesia and STN tended to increase peak dyskinesia. CONCLUSION: DBS objectively reduces motor fluctuations. This is achieved by reduction of drug-off disability and not by alterations in levodopa pharmacodynamics. This finding suggests alleviation of interdose trough disability as an alternative strategy to prolonging the effects of each dose of levodopa as a means to reduce motor fluctuations.

DBS and diathermy interaction induces severe CNS damage.

Pulse-modulated radiofrequency diathermy treatment to the maxilla produced permanent diencephalic and brainstem lesions and a vegetative state in a patient with PD with implanted subthalamic electrodes for deep brain stimulation.

Assessments of axial motor control during deep brain stimulation in parkinsonian patients.

OBJECTIVE: We tested the hypothesis that bilateral deep brain stimulation (DBS) in the globus pallidus internus or the subthalamic nucleus improves various components of postural and oromotor function and that some of the components correlate with changes in the Unified Parkinson's Disease Rating Scale (UPDRS) in patients with Parkinson's disease. METHODS: Six patients with Parkinson's disease were evaluated for four postural and two orofacial UPDRS items, and quantitative tests of posture adjustments and oromotor control were performed while the patients were on and off DBS. Measurements of postural adjustments included reactive force and latency before a voluntary step. The oromotor assessments involved velocity and amplitude changes during voluntary jaw movement. RESULTS: DBS significantly improved the total UPDRS motor score by an average of 44%, which included improvement of 18 to 54% in the postural and orofacial items. DBS also decreased foot lift-off latency significantly, but it produced a variable response to the preparatory postural force in the swing limb. DBS significantly improved jaw-opening velocity by 14 to 50% and jaw opening amplitude by 5 to 41%. Significant correlations for the percentage change from off and on DBS occurred among a few UPDRS items and foot lift-off latency and jaw-opening velocities. CONCLUSION: DBS in either the globus pallidus internus or the subthalamic nucleus induces improvements in bradykinesia of specific components of postural and oromotor control, which also can be measured by the postural and orofacial UPDRS items. In some Parkinson's disease patients, DBS results in improvements in force or amplitude control, although these changes are not reflected in changes in UPDRS postural and orofacial items. A battery of quantitative and clinical tests must be used to evaluate the effects of DBS on axial motor control adequately.

Comparison of pallidal and subthalamic nucleus deep brain stimulation for advanced Parkinson's disease: results of a randomized, blinded pilot study.

OBJECTIVE: Deep brain stimulation (DBS) of the globus pallidus internus (GPi) and subthalamic nucleus (STN) has been reported to be effective in alleviating the symptoms of advanced Parkinson's disease (PD). Although recent studies suggest that STN stimulation may be superior to GPi stimulation, a randomized, blinded comparison has not been reported. The present study was designed to provide a preliminary comparison of the safety and efficacy of DBS at either site. METHODS: Ten patients with idiopathic PD, L-dopa-induced dyskinesia, and response fluctuations were randomized to implantation of bilateral GPi or STN stimulators. Neurological condition was assessed preoperatively with patients on and off L-dopa and on DBS at 10 days and 3, 6, and 12 months after implantation. Patients and evaluating clinicians were blinded to stimulation site throughout the study period. Complete follow-up data were analyzed for four GPi patients and five STN patients. RESULTS: When off-L-dopa, both GPi and STN groups demonstrated a similar response, with approximately 40% improvement in Unified PD Rating Scale motor scores after 12 months of DBS. Rigidity, tremor, and bradykinesia improved in both groups. In combination with L-dopa, Unified PD Rating Scale motor scores were more improved by GPi stimulation than by STN stimulation. On-L-dopa axial symptoms were clinically improved in the GPi but not the STN group. L-Dopa-induced dyskinesia was reduced by DBS at either site, although medication requirement was reduced only in the STN group. There were no serious intraoperative complications among patients in either group. CONCLUSION: Pallidal and STN stimulation appears to be safe and efficacious for the management of advanced PD. A larger study is needed to investigate further the differences in symptom response and the interaction of L-dopa with stimulation at either site.

Ropinirole for the treatment of early Parkinson disease: a 12-month experience. Ropinirole Study Group.

OBJECTIVE: To evaluate ropinirole hydrochloride as dopaminergic monotherapy in patients with early Parkinson disease. DESIGN: A 6-month extension of a double-blind, placebo-controlled study. SETTING: Ambulatory care at 22 different sites in the United States. PATIENTS: Patients who successfully completed the initial 6-month study could enter the 6-month extension study (ropinirole, n = 70; placebo, n = 77). INTERVENTION: Use of ropinirole or placebo therapy. MAIN OUTCOME MEASURES: The efficacy variables were the number of patients who successfully completed the 12-month study and did not require supplemental levodopa, the number of patients requiring supplemental levodopa, and the proportion of patients having an insufficient therapeutic response. RESULTS: Significantly fewer ropinirole-treated patients met criteria for insufficient therapeutic response (23 [19.8%] of 116) or required the initiation of levodopa therapy (22 [19%] of 116) compared with placebo-treated patients (60 [48%] of 125 patients for insufficient therapeutic response; 57 [45.6%] of 125 patients for additional levodopa). Significantly more ropinirole-treated patients (51 [44.0%] of 116) successfully completed the 12-month study and did not require supplemental levodopa compared with placebo-treated patients (28 [22.4%] of 125). The incidence of adverse experiences and patient withdrawals was low. CONCLUSION: Ropinirole was effective and well tolerated as monotherapy for 12 months in patients with early Parkinson disease.

Ropinirole for the treatment of early Parkinson's disease. The Ropinirole Study Group.

A prospective, randomized, placebo-controlled, double-blind, parallel-group, 6-month study assessed the efficacy and safety of ropinirole, a nonergoline D2-dopamine agonist, in patients with early Parkinson's disease (n = 241; Hoehn & Yahr stages I to III) with limited or no prior dopaminergic therapy. Patients (mean age, 62.8 years), stratified by concomitant use of selegiline, were randomized to ropinirole (n = 116) or placebo (n = 125). The starting dose of ropinirole was 0.25 mg tid with titration to at least 1.5 mg tid (maximum dose, 8 mg tid). Primary efficacy endpoint was the percentage improvement in Unified Parkinson's Disease Rating Scale (UPDRS) motor score. Ropinirole-treated patients had a significantly greater percentage improvement in UPDRS motor score than patients who received placebo (+24% vs -3%; p < 0.001). Ropinirole was well tolerated and patient withdrawals were infrequent. Most adverse experiences were related to peripheral dopaminergic activity. Ropinirole monotherapy is an effective and well-tolerated therapeutic option for treatment of early Parkinson's disease.

Jaw movement dysfunction related to Parkinson's disease and partially modified by levodopa.

OBJECTIVES: To test the hypotheses that Parkinson's disease can differentially produce deficits in voluntary and rhythmic jaw movements, which involve different neuronal circuits, and that levodopa treatment improves specific components of the motor deficit. METHODS: Patients with idiopathic Parkinson's disease and control subjects were tested on a series of jaw motor tasks that included simple voluntary movement, isometric clenching, and natural and paced rhythmic movements. Jaw movements were measured by changes in electromagnetic fields and EMG activity. Patients with Parkinson's disease with fluctuations in motor responses to levodopa were tested while off and on. RESULTS: During the off state, patients with Parkinson's disease were significantly worse than the control subjects on most tasks. The deficits included a decrease in amplitude and velocity during jaw opening and closing, aberrant patterns and low amplitude of EMG activity during clenching, and low vertical amplitude and prolonged durations of occlusion during rhythmic movements. No decrements were found in the amplitude of voluntary lateral jaw movements or the frequency of rhythmic movements. During the on state, improvements occurred in the patterns and level of EMG activity during clenching and in the vertical amplitude and duration of occlusion during rhythmic movements, although a significant decrement occurred in the lateral excursion of the jaw. CONCLUSIONS: Parkinson's disease affects the central programming of functionally related muscles involved in voluntary and rhythmic jaw movements and levodopa replacement influences only certain aspects of jaw movement, most likely those requiring sensory feedback.

Patterns of asymmetry do not change over the course of idiopathic parkinsonism: implications for pathogenesis.

We investigated the asymmetry of focal deficits of bradykinesia in a cross-sectional study of 198 patients with idiopathic parkinsonism. We have analyzed the difference in Unified Parkinson's Disease Rating Scale (UPDRS) scores between the more and less affected sides in these patients, whose duration of symptoms ranged from 1 to 15 years. There was no significant change in the asymmetry or focality over this period; the deficit for each side progressed faster initially and then approached the normal age-related linear rate of decline. Previous studies indicate that there is an inverse linear relation between the UPDRS bradykinesia score and the nigral dopaminergic cell count. We infer that the rate of death of nigral dopaminergic neurons is predetermined from the time of onset of pathogenesis. The simplest explanation is that a causal event kills some cells and damages others so that they undergo premature death. This sequence of changes could be implemented through environmental (toxic or viral) damage to the genome. Several diverse sources of evidence support this concept.

Controlled release levodopa/carbidopa 25/100 (Sinemet CR 25/100): pharmacokinetics and clinical efficacy in untreated parkinsonian patients.

The pharmacokinetics of the clinically determined optimal dose of controlled release levodopa/carbidopa 25/100 (Sinemet CR 25/100) after 12 weeks of therapy was studied in nine parkinsonian patients without prior exposure to levodopa. The pharmacokinetics of single oral doses of controlled release levodopa/carbidopa 25/100 and 50/200 were also compared. As predicted from the plasma half-life (1.7 +/- 0.3 h) and confirmed by morning trough levels, levodopa did not accumulate when controlled released levodopa/carbidopa 25/100 was administered twice daily. The absorption and bioavailability of CR 25/100 are minimally greater than CR 50/200. Controlled released levodopa/carbidopa 25/100 levodopa plasma levels peak slightly faster than controlled release levodopa/carbidopa 50/200.

Effect of peripheral catechol-O-methyltransferase inhibition on the pharmacokinetics and pharmacodynamics of levodopa in parkinsonian patients.

Catechol-O-methyltransferase (COMT) metabolizes a portion of administered levodopa and thus makes it unavailable for conversion to dopamine in the brain. In an open-label trail, we examined the effects of entacapone, a peripheral inhibitor of COMT, administered acutely or for 8 weeks, on the pharmacokinetics and pharmacodynamics of levodopa in 15 parkinsonian subjects with a fluctuating response to levodopa. Acutely and chronically administered entacapone similarly decreased the plasma elimination of orally and intravenously administered levodopa. Absorption of levodopa was minimally affected. During chronic entacapone treatment, daily levodopa dosages were reduced by 27% yet mean plasma levodopa concentrations were increased by 23%. Plasma 3-O-methyldopa concentrations were decreased by 60%. Entacapone increased the duration of action of single doses of levodopa by a mean of 56%. The percent of the day "on" after 8 weeks of entacapone treatment was 77%; it dropped to 44% upon withdrawal of entacapone. We conclude that inhibition of COMT by entacapone increases the plasma half-life of levodopa and augments the antiparkinsonian effects of single and repeated doses of levodopa.

Tendon jerks in Parkinson's disease.

Tendon reflexes were examined in 119 patients with idiopathic parkinsonism (IP) and 40 spouse controls to estimate the type and frequency of any alterations in the reflexes. Forty one of 119 patients and 2 of 40 controls had reflex ratings of 3+ at two or more sites (p < 0.001). There was no correlation of reflex score with the severity of disease or with the cardinal signs of IP. In 21 patients with asymmetric tendon jerks the side with the more active reflexes correlated with the side with greater parkinsonian signs. We conclude that an increase in tendon jerks is a feature of IP. The pathophysiology of this change in reflexes should be investigated further to establish if it is a heretofore overlooked manifestation of basal ganglia dysfunction or a link with other neurodegenerative diseases.

The transport of L-6-fluorodopa and its metabolites from blood to cerebrospinal fluid and brain.

The transport of L-6-fluorodopa and its major metabolites from the blood to the brain, cerebrospinal fluid (CSF), and muscle was studied in carbidopa-pretreated cynomolgus monkeys. A bolus intravenous injection of 18F-L-6-fluorodopa was followed by serial positron emission tomography scans and sampling of cisternal CSF and arterial blood. The relative concentrations of L-6-fluorodopa and its metabolites were determined in blood plasma and CSF by high-performance liquid chromatography. Raising the blood concentration of phenylalanine by intraperitoneal injection markedly reduced the accumulation of tracer in the brain. This indicates that L-6-fluorodopa and 3-O-methylfluorodopa, like native L-dopa and its O-methylated derivative, are transported at the brain capillary by the large neutral amino acid carrier-mediated system, which is subject to saturation and competition by other large neutral amino acids (such as phenylalanine) at physiological plasma concentrations. In contrast, administration of phenylalanine had no effect on the accumulation of tracer either in muscle, or as L-6-fluorodopa and 3-O-methylfluorodopa, in CSF. This suggests that the transport of L-dopa and its derivatives at the blood-CSF barrier differs from the transport at the blood-brain barrier and also that measurement of CSF L-dopa is not a good index of the transport and pharmacokinetics of L-dopa in the brain. However, the effect of phenylalanine administration in reducing the concentration of fluorohomovanillic acid in the CSF suggests that the concentration of homovanillic acid in the CSF is an accurate reflection of dopamine turnover in the brain.

Does tolerance develop to levodopa? Comparison of 2- and 21-H levodopa infusions.

To determine if acute tolerance to levodopa develops, we compared the response to 2- and 21-h levodopa infusions with the rate adjusted during the long infusion to yield the same plasma concentration as at the end of the 2-h infusion. The duration of response after discontinuing the long infusions was briefer than after discontinuing the short infusion, suggesting the development of tolerance. Furthermore, dyskinesia severity was greater during long infusions. We conclude that continuous dopaminergic stimulation with levodopa may not offer optimal control of parkinsonism in patients with response fluctuations.

L-dopa pharmacokinetics in plasma and cisternal and lumbar cerebrospinal fluid of monkeys.

The pharmacokinetics of levodopa (L-dopa) in plasma and in cisternal and lumbar cerebrospinal fluid (CSF) were studied in Rhesus monkeys that were given 2- to 3-hour intravenous infusions of L-dopa. Steady-state L-dopa concentrations in cisternal CSF correlated well with plasma levels, and yielded a CSF:plasma ratio of 0.17. The disappearance of L-dopa from plasma and cisternal CSF compartments fits an open, two-compartment pharmacokinetic model. Although slower, the distribution and elimination half-lives for L-dopa from cisternal CSF (8.9 and 49.2 minutes, respectively) were of a similar magnitude to those from plasma (4.9 and 33.2 minutes, respectively). If cisternal CSF reflects brain extracellular fluid, then plasma pharmacokinetics of L-dopa are a reasonable approximation of those in the brain. In contrast to cisternal CSF, the disappearance of L-dopa from lumbar CSF fits an open, one-compartment model with an elimination half-life of 100 minutes. This indicates that the lumbar CSF compartment is unsuitable for investigation of the pharmacokinetics of L-dopa in the brain.

Cerebellum plus locus coeruleus in tissue culture. II: Development and metabolism of catecholamines.

In contrast to locus coeruleus neurons in vivo, dopamine was the predominant catecholamine synthesized, stored, and released by neonatal mouse locus coeruleus cultures which included target cerebellar tissue, and norepinephrine was present in these cultures only at very low levels. Developmentally, norepinephrine increased slightly in the explants during the first 4 days in vitro and declined thereafter to barely detectable levels, whereas dopamine began to rise after 4 days and reached maximal levels by 7 days. Dopamine beta-hydroxylase was present in these cultures throughout maturation. These results suggest that the high ratio of dopamine to norepinephrine in locus coeruleus cultures cannot be attributed to the absence of appropriate target tissue or to a lack of the enzyme, dopamine beta-hydroxylase.

Buspirone in Parkinson's disease.

Buspirone, an anxiolytic unrelated to benzodiazepines that may act at the presynaptic dopamine receptor, was given to 11 patients with Parkinson's disease in an open label study. Seven patients completed the initial 10 week study achieving doses of 50-70 mg/day without any significant change in their clinical status. Six patients continued for an additional 3-11 weeks with increases in dose to 65-100 mg/day. Two of the three most severely affected patients had mild worsening of parkinsonian symptoms. Buspirone is ineffective in the treatment of Parkinson's disease, but at anxiolytic doses (less than 40 mg/day) does not adversely affect parkinsonian disability.

Lisuride treatment of focal dystonias.

Nine patients with various focal dystonias participated in a 12-week, double-blind, crossover comparison of the dopamine agonist, lisuride, and placebo. Lisuride produced mild objective and subjective improvement in six subjects, but the improvement was not sustained with continued therapy. Because the patients generally identified the active drug by side effects, biasing the study toward finding an effect, and because the benefits were mild and transient, we conclude that lisuride is of limited use in the treatment of focal dystonias.

The "on-off" phenomenon in Parkinson's disease. Relation to levodopa absorption and transport.

To determine whether the oscillating clinical response to levodopa in Parkinson's disease (the "on-off" phenomenon) reflects fluctuations in absorption and transport of the drug, we investigated this phenomenon in nine patients with an oscillating motor state. We studied the response to continuous infusion of levodopa and the effects of meals on the plasma levodopa concentrations and on the clinical response during oral and intravenous administration of the drug. Meals reduced peak plasma levodopa concentrations by 29 per cent and delayed absorption by 34 minutes. Bypassing absorption by constant infusion of the drug produced a stable clinical state lasting for 12 hours in all of six patients and for up to 36 hours in some. High-protein meals or oral phenylalanine, leucine, or isoleucine (100 mg per kilogram of body weight) reversed the therapeutic effect of infused levodopa without reducing plasma levodopa concentrations. Glycine and lysine at identical doses had no effect. We conclude that interference with absorption of levodopa by food and by competition between large neutral amino acids and levodopa for transport from plasma to the brain may be partly responsible for the fluctuating clinical response in patients with Parkinson's disease.

Cranial dystonia: double-blind crossover study of anticholinergics.

In patients with cranial dystonia, we compared the effects of central anticholinergic, peripheral anticholinergic, and placebo treatments in a double-blind crossover study. One of the nine patients who completed the study improved markedly with central anticholinergic therapy. The three treatments were indistinguishable in the other eight patients except for the higher incidence of central and peripheral anticholinergic side effects with trihexyphenidyl.