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Background: Levodopa-carbidopa intestinal gel (LCIG) therapy has been shown to be a safe and effective treatment for advanced Parkinson's disease (PD). Limited data are available regarding long-term benefits and complications in Canada. Objective of the study was to review long-term experience and clinical outcomes in PD patients with LCIG therapy over 11 years in a multidisciplinary University clinic setting., Methods: Chart review was done on PD patients with LCIG from 2011 to 2022. Data collected: dosing, UPDRS-III motor scores, OFF times, hours with dyskinesias, MoCA, complications, discontinuation reasons, and nursing time requirements., Results: Thirty-three patients received LCIG therapy with a mean follow-up of 3.25±2.09 years. UPDRS-III scores showed reduction of 15% from baseline (mean 35.9) up to 4 years (mean 30.4). Daily OFF time improved from baseline (mean 7.1 ± 3.13 hours) up to 5 years (mean 3.3 ± 2.31 hours; -53.5%; p < 0.048), and dyskinesias remained stable. Nursing time averaged 22 hours per patient per year after PEG-J insertion and titration. Most common complications were PEG-J tube dislodgement and stoma site infection (0-3zero to three events/patient/year). Serious side effects were seen in four (12%) patients resulting in hospitalization and/or death. Nine patients (27.2%) discontinued the treatment due to lack of improved efficacy over oral therapy or development of dementia and 10 (30%) died of causes unrelated to LCIG infusion., Conclusion: Patients on LCIG showed improved motor function over 5-year follow-up. Serious complications were uncommon. Dedicated nursing time is required by LCIG-trained nurses in a multidisciplinary setting for optimum management.

Motor complications in Parkinson's disease (PD) are associated with long-term oral levodopa treatment and linked to pulsatile dopaminergic stimulation. L-dopa-carbidopa intestinal gel (LCIG) is delivered continuously by percutaneous endoscopic gastrojejunostomy tube (PEG-J), which reduces L-dopa-plasma-level fluctuations and can translate to reduced motor complications. We present final results of the largest international, prospective, 54-week, open-label LCIG study. PD patients with severe motor fluctuations (>3 h/day "off" time) despite optimized therapy received LCIG monotherapy. Additional PD medications were allowed >28 days post-LCIG initiation. Safety was the primary endpoint measured through adverse events (AEs), device complications, and number of completers. Secondary endpoints included diary-assessed off time, "on" time with/without troublesome dyskinesia, UPDRS, and health-related quality-of-life (HRQoL) outcomes. Of 354 enrolled patients, 324 (91.5%) received PEG-J and 272 (76.8%) completed the study. Most AEs were mild/moderate and transient; complication of device insertion (34.9%) was the most common. Twenty-seven (7.6%) patients withdrew because of AEs. Serious AEs occurred in 105 (32.4%), most commonly complication of device insertion (6.5%). Mean daily off time decreased by 4.4 h/65.6% (P < 0.001). On time without troublesome dyskinesia increased by 4.8 h/62.9% (P < 0.001); on time with troublesome dyskinesia decreased by 0.4 h/22.5% (P = 0.023). Improvements persisted from week 4 through study completion. UPDRS and HRQoL outcomes were also improved throughout. In the advanced PD population, LCIG's safety profile consisted primarily of AEs associated with the device/procedure, l-dopa/carbidopa, and advanced PD. LCIG was generally well tolerated and demonstrated clinically significant improvements in motor function, daily activities, and HRQoL sustained over 54 weeks., (© 2014 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.)

Parkinson's disease (PD) results from the depletion of dopamine and other neurotransmitters within the basal ganglia, and is typically characterized by motor impairment (e.g., bradykinesia) and difficulty initiating voluntary movements. Difficulty initiating a movement may result from a deficit in accessing or executing a stored representation of the movement, or having to create a new representation each time a movement is required. To date, it is unclear which may be responsible for movement initiation impairments observed in PD. In this study, we used functional magnetic resonance imaging and a task in which participants passively viewed familiar and unfamiliar graspable objects, with no confounding motor task component. Our results show that the brains of PD patients implicitly analyze familiar graspable objects as if the brain has little or no motor experience with the objects. This was observed as a lack of differential activity within brain regions associated with stored movement representations for familiar objects relative to unfamiliar objects, as well as significantly greater activity for familiar objects when off levodopa relative to on medication. Symptom severity modulated this activity difference within the basal ganglia. Levodopa appears to normalize brain activity, but its effect may be one of attenuation of brain hyperactivity within the basal ganglia network, which is responsible for controlling motor behavior and the integration of visuomotor information. Overall, this study demonstrates that difficulty initiating voluntary movements experienced by PD patients may be the result of degradation in stored representations responsible for the movement., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Although it is now generally recognized that the clinical spectrum of Parkinson disease (PD) is broader than its defining motor aspects, its various non-motor symptoms are often not routinely assessed in the clinical setting. As most of these symptoms are amenable to treatment, improved recognition would lead to more comprehensive management of the disease, and ultimately improve the quality of life for PD patients. In an attempt to increase the general awareness of physicians caring for these patients, this article focuses on the clinical manifestations and treatment of the gastrointestinal symptoms most commonly experienced by PD patients, as well as on the gastrointestinal side effects of antiparkinsonian treatments.

Objective: To determine the outcomes of patients with Parkinson disease (PD) with pathological gambling (PG) from one Canadian Movement Disorders Clinic., Methods: Assessments were performed in-person during routine clinic visits of all patients currently followed by one neurologist (OS). Pathological gambling was defined according to DSM-IV-TR criteria. Chart review was performed to obtain details on medication use, dosages, and patient demographics. Follow-up of patients with PG collected information on gambling behavior, PG management interventions, medications, treatment, and psychosocial outcomes., Results: 146 patients were surveyed with an overall prevalence of PG of 4.1% (6/146). The rate of pathological gambling for those patients on dopamine agonist therapy (DA) was 8.1% (6/74). Only patients who were recreational gamblers prior to starting DA developed PG. All PG patients discontinued, decreased, or switched to another DA, and experienced a partial or full remission of PG. 3 (50%) patients described financial losses of $100,000 or more, and 75% (3/4) patients described significant marital stresses. At follow-up (August 2008), 4 of the 6 patients with PG continued to gamble in a controlled fashion despite medication changes. No significant difference in levodopa equivalent daily dose (LEDD) pre- and post-PG were observed; however, the relative amount of DA was decreased (p= 0.0593), while levodopa was relatively increased (p= 0.5277). Despite control of PG, patients still experience financial and marital strains., Conclusions: DA (in combination with levodopa) was associated with a significantly higher prevalence of PG in PD, particularly in patients who were recreational gamblers previously. Despite control of PG, patients continued to experience significant financial and marital stresses that should be regularly enquired upon in follow-up care and managed appropriately.

Objective: Peripheral neuropathy (PN) is thought to be coincidental in patients with idiopathic Parkinson disease (IPD). We sought to examine the prevalence of PN in a population of IPD patients and a potential relationship to levodopa use and fasting methylmalonic acid (MMA) levels., Methods: In a prospective cohort study, IPD patients randomly selected from a comprehensive database were compared to control subjects regarding the presence and severity of PN using clinical and electrophysiological measures. IPD severity was determined using the Unified Parkinson's Disease Rating Scale (UPDRS). We determined the relation of levodopa use with serum levels of cobalamin, MMA, and homocysteine (Hcy). We also explored the association between presence and severity of PN and age, duration of IPD, cumulative levodopa dosing, cobalamin, MMA, and Hcy levels., Results: Fifty-eight randomly selected IPD patients were compared to 58 age- and sex-matched controls. PN was present in 55% of IPD patients and 9% of controls. Patients with IPD had greater prevalence of PN and fasting MMA/Hcy levels than controls. IPD patients with PN were older and exhibited higher UPDRS scores, fasting MMA/Hcy levels, and cumulative levodopa exposure. PN severity in IPD subjects positively correlated with both levodopa exposure and MMA levels., Interpretation: IPD patients have a higher prevalence of PN than controls. Although causality is not established, levodopa exposure is associated with MMA elevation and sensorimotor neuropathy in IPD patients. Cobalamin replacement concurrent with levodopa therapy should be considered to protect against development of PN in IPD patients.

The presence and potential etiologies of peripheral neuropathy (PN) in patients with Parkinson's Disease (PD) is unknown. We examined for presence of PN in patients with PD. From a PD patient population of 500 patients screened for features of symptomatic PN, patients were further selected for clinical, electrophysiological, and laboratory studies related to PN. This PD patient population with idiopathic PN (PD-IPN) was compared to a group of PD patients without PN (PD-only), and a large group of patients without PD with idiopathic PN (IPN) for abnormalities in Cbl, fasting homocysteine (Hcy), and fasting methylmalonic acid (MMA) levels. PD-IPN and IPN patients identified with abnormalities in Cbl, Hcy, or MMA levels were treated with intramuscular Cbl for 1 to 2 years. Of 49 PD patients with symptomatic PN, 34 patients (69%) had PD-IPN, and 32/34 (94%) had abnormal Hcy or MMA levels as compared to 26/258 (10%) of IPN patients. Cumulative lifetime L-dopa dosage and fasting MMA levels were associated with PN severity. Cbl therapy led to improvements in Hcy and MMA levels in all groups, and PN in PD-IPN patients stabilized during therapy. PN in PD patients may be associated with iatrogenic Cbl metabolic abnormalities. Alternatively PN may be a peripheral nervous system manifestation of PD., ((c) 2008 Movement Disorder Society.)

Parkinson's disease (PD) patients can perform many daily activities, but movement deficits are evident. Those deficits may be increased when the required movement is constrained in accuracy. Variable improvements in performance with PD medication have been demonstrated, and sensitivity to task constraint has been evident in some studies. The authors quantified both specific movement deficits and improvements for PD patients in a reaching task. PD patients (N=8) both on and off medication showed a need for greater ongoing control in movements with higher task-accuracy constraints. Increased task-accuracy constraints further compromised movement timing and structure among PD patients who were off medication, suggesting that unmedicated PD patients may typically compensate by using more conscious control of movement, resulting in increased slowing and segmentation of components when higher task accuracy is required.

Objective: To determine effects of dopaminergic medication and pallidal deep brain stimulation (DBS) on skilled reach in Parkinson's disease (PD)., Background: PD is a neurodegenerative disorder affecting motor control. While speed and execution of movements are improved by L-dopa, not all motor symptoms are alleviated. Little is known about the effects of DBS or medication on reaching., Design Method: Eight PD patients with unilateral pallidal DBS reached with the contra-lateral hand for a piece of food, placing it in the mouth, and returning to starting position. Testing was performed on no treatment, medication only, DBS only, and combined treatment. Reaches were digitally recorded and analyzed on a 21 point scale adapted from Eshkol-Wachman Notation. Analysis was blinded, with patients compared to age-matched controls., Results: Patients were tested 6-13 months after surgery. All showed significant improvement clinically and in UPDRS (III) scores. The following data were obtained on the reaching scale: normal controls 16.5-21.0 (mean 18.3), no treatment 3.0-12.5 (mean 7.4), medication only 7.0-14.0 (mean 10.3), DBS only 4.5-16.0 (mean 9.2), combined treatment 4.0-15.0 (mean 9.5). The difference between controls and all treatment groups was statistically significant (P<0.005). All aspects of reach were compromised. No significant differences were found among the four conditions., Conclusions: This study is consistent with accumulating evidence that some aspects of motor performance in PD patients, such as reaching, are resistant to L-dopa. Also, pallidal DBS does not improve those parameters that are resistant to L-dopa, either alone or in combination with medication.

Parkinson's disease, a common neurodegenerative disorder, results in significant morbidity 10 to 15 years after disease onset and increased mortality. Levodopa is the mainstay of therapy and provides benefit for the duration of the illness. However, within 5 years, up to 50% of individuals develop fluctuations, including dyskinesias, wearing off, and "on/off" effects. Optimal management of Parkinson's disease patients requires careful titration of medications, with use of polypharmacy, including levodopa, dopamine agonists, catechol-O-methyltransferase inhibitors, amantadine, and anticholinergics in order to maintain good motor function and quality of life. With advancing disease, problems such as dysphagia, dysarthria, and gait and balance abnormalities occur, which are not responsive to dopaminergic medication. Due to extradopaminergic neuronal system degeneration, autonomic dysfunction can also be prominent. Recognition and management of these problems is helpful in improving quality of life in late-stage disease. In very late stages, dementia may complicate treatment, requiring discontinuation of combination therapy and use of low-dose levodopa with atypical neuroleptics.

The efficacy and safety of two dosages of tolcapone were compared in a 12-week crossover trial involving 118 nonfluctuating patients with PD on a stable dose of levodopa (L-Dopa). At trial onset, all patients received open-label tolcapone 100 mg three times daily for 4 weeks. At week 4, 116 eligible patients entered an 8-week double-blind treatment period and were randomized to receive tolcapone three times daily at either 100 mg (group 1; n = 58) or 200 mg (group 2; n = 58) until week 8, followed by the alternative tolcapone dosage until week 12. Ratings included Unified Parkinson's Disease Rating Scale (UPDRS), Schwab & England, and patient diaries, assessed at baseline and at 4, 8, and 12 weeks. At week 4, the investigator's global assessment (IGA) of efficacy showed improvement in 76% of patients. The mean total daily L-Dopa dose and mean UPDRS scores for subscales II and III decreased significantly (p < 0.001). During the double-blind treatment period, IGA showed improvements at either or both dosages in 61% of patients; further changes in other efficacy variables were minimal and were similar with both tolcapone dosages. The most frequent adverse events were dopaminergic (nausea and dyskinesia); the most frequent nondopaminergic adverse event was diarrhea. The incidence of adverse events during double-blind treatment was slightly higher with tolcapone 200 mg three times daily (33%) than with tolcapone 100 mg three times daily (24%). The authors conclude that tolcapone dosages of 100 mg three times daily and 200 mg three times daily are well tolerated and equally effective in improving function in L-Dopa-treated nonfluctuating patients with PD.

Patients with Parkinson's Disease (PD) have a variable response to tolcapone, a catechol-O-methyltransferase (COMT) inhibitor. In addition, a subset of patients develop severe diarrhea as a side effect. Two codominant alleles for the COMT gene exist, coding for low and high activity, resulting in low-, medium-, and high-activity genotypes. This study investigates the relationship between this variation in genotype and clinical effects in patients with PD taking tolcapone. To investigate the relationship between COMT polymorphism and clinical response, 24 patients who completed tolcapone clinical trials provided blood samples for COMT genotype analysis. Change in levodopa dose and United Parkinson Disease Rating Scale (UPDRS) Part III (motor subscale) were analyzed at baseline, at 1-2 weeks, and 6 months after initiation of tolcapone. Genotype analysis was performed on seven patients who had diarrhea as a side effect. There was no significant correlation between genotype and improvement in UPDRS score (p = 0.29) according to a linear models approach that adjusted for the subject's severity of PD, tolcapone dose (either 100 or 200 mg three times daily) and initial differences in baseline scores. No significant difference was seen in change in daily levodopa intake and genotype. There was also no relation between diarrhea and COMT genotype. These results indicate that, in the treatment of Parkinson's disease, COMT genotype is not a major contributor to the clinical response to tolcapone.

The management of Parkinson's disease has undergone recent changes with the advent of new therapies, both pharmacotherapy and surgery. Available interventions are discussed. Levodopa remains the mainstay of therapy. New drugs include the dopamine agonists and COMT inhibitors. New dopamine agonists which may have a levodopa "sparing effect;" it has been suggested that some of the drugs should be considered as first line treatments for newly diagnosed Parkinson's disease patients. We review roles of these drugs. The concept of neuroprotection in neurodegenerative disorders such as Parkinson's disease became popular in the mid 1980s and it is hoped that eventually therapy will be directed at slowing progression of the disease. A great deal more work needs to be done before a suitable agent is identified as being neuroprotective. Potential neuroprotective agents are reviewed. Surgical therapies for Parkinson's disease consisting of various forms of lesion surgery as well as stimulation procedures are reviewed. Complications of drug therapy include motor problems such as motor response fluctuations, as well as psychiatric complications including levodopa-induced psychosis. Atypical neuroleptic agents and ECT for psychiatric syndromes associated with Parkinson's disease are discussed. Algorithms for the management of early disease as well as the management of psychosis in Parkinson's disease are included. Treatment options for advanced disease are tabulated.

The manufacturer of deprenyl (selegeline; Eldepryl) (Somerset Pharmaceuticals, Tampa, FL) recently advised physicians to avoid prescribing the drug in combination with an antidepressant because of potentially serious CNS toxicity that may represent the serotonin syndrome. Manifestations of the serotonin syndrome vary but may include changes in mental status and motor and autonomic function. To better estimate the frequency of the serotonin syndrome in patients with Parkinson's disease (PD) treated with deprenyl and an antidepressant, we surveyed all investigators in the Parkinson Study Group. Based on estimates provided by the 47 investigators (75%) who responded, 4,568 patients were treated with the combination of deprenyl and an antidepressant medication. Eleven patients (0.24%) were reported to have experienced symptoms possibly consistent with the serotonin syndrome. Only two patients (0.04%) experienced symptoms considered to be serious. No deaths were reported. We also reviewed all published case reports and adverse experiences reported to the U.S. Food and Drug Administration and the manufacturer of Eldepryl. Available information indicates that serious adverse experiences resulting from the combined use of deprenyl and an antidepressant medication in patients with PD are quite rare and that the frequency of the true "serotonin syndrome" is even rarer.