Levodopa-carbidopa intestinal gel infusion (LCIG) is an established therapy for advanced Parkinson disease (PD), resulting in a significant improvement of quality of life. With increased LCIG adoption worldwide, potential complications due to abnormal vitamin absorption or metabolism have been reported in these patients. Neurologists are unfamiliar with vitamins physiology and pathophysiological mechanisms in case of their deficiency. Unfortunately, clinical and laboratory guidelines related to vitamin monitoring and supplementation in the context of treatment with LCIG are not available. We herein summarize the current knowledge on three vitamins that are reduced with LCIG therapy reporting on their physiology, laboratory testing, and clinical impact of their deficiency/excess. In addition, we proposed an opinion-based recommendation for clinicians treating LCIG patients. Patients and caregivers should be informed about the risk of vitamin deficiency. Vitamin B12, homocysteine, and methylmalonic acid (MMA) should be tested before starting LCIG, six months after and once/year thereafter. Vitamin B6 and folate testing is not universally available but it should be considered if homocysteine is elevated but MMA and/or total vitamin B12 are normal. Prophylaxis of vitamin deficiency should be started as soon as LCIG is implemented, possibly even before. Dietary recommendations are enough in most patients although a subgroup of patients is at higher risk and should receive Vitamin B12 regularly and cycles of B6. Finally, once diagnosed a vitamin deficiency should be readily treated and accompanied by clinical and laboratory monitoring. Resistant cases should receive non-oral routes of administration and possibly discontinue LCIG, even temporarily.

Objective: This study aimed to systematically review the effects of currently prescribed antiparkinson medication on cognition in patients with mild-to-moderate Parkinson’s disease (PD) who were either cognitively intact or mildly impaired. Methods: English- and French-language studies published between 1969 and 2017 were accessed via MedLine, PsychNET, EMBASE and EBSCO databases. Methodological quality (MQ) was evaluated with the quality assessment instrument of the Cochrane Collaboration Depression, Anxiety and Neurosis Review (scores from 0% to 44% indicate very low quality; scores from 45% to 64% indicate low quality; scores from 65% to 84% indicate medium quality; and scores from 85% to 100% indicate high quality). Hedges’ g and Student’s t-test were performed on all cognitive outcome measures reported. Results: In total, 14 studies assessed the cognitive effects of levodopa (L-D), pramipexole (PRX), selegiline (SEL) and rasagiline (RAS) in mild-to-moderate non-demented PD patients. The MQ was overall low, with an average score of 49.1%. Results for L-D showed deleterious effects on a test of cognitive inhibition, as well as benefits on tests of attention/processing speed/working memory, executive functions and episodic memory. Pramipexole was associated with a worsening of episodic memory and impulse control. Results on SEL indicated a deterioration of global cognition over time and of concept formation. Rasagiline had some benefits on working memory and verbal fluency. Conclusion: Antiparkinson medications can have deleterious (L-D; PRX; SEL) and beneficial (L-D; RAS) effects on cognition. However, randomized double-blind placebo-controlled trials with larger sample sizes are required to better elucidate this issue.

Background: Several factors determine the choice of medications in patients with Parkinson’s disease (PD). We aimed to analyze the pattern of prescription of drugs in patients with PD before attending a tertiary-care center. Methods: The study included chart review of 800 PD patients attending the Department of Neurology of the National Institute of Mental Health and Neurosciences in Bangalore, India. Results: The mean age at onset was 51.1±11.8 years. The mean duration of illness was 41.7±43.6 months. At first visit, 79.4% (group 1, n=635) of patients were on medications, 10% (group 2, n=80) were on medications but later discontinued, and 10.6% (group 3, n=85) were drug-naïve. Overall, levodopa was prescribed in 94.8%, trihexyphenidyl in 40.4%, dopamine agonists in 23.2%, and amantadine in 17.2% either as monotherapy or in combination. In group 1, 37.8% were on monotherapy, with levodopa being the most commonly used agent (33.1%), followed by trihexyphenidyl (2.2%), dopamine agonists (1.6%), and amantadine (0.6%). Among those on polytherapy, levodopa plus trihexyphenidyl was the preferred combination (23.9%). In group 2, levodopa monotherapy was also most common (72.5%), followed by trihexyphenidyl monotherapy (7.5%). Conclusions: Levodopa and trihexyphenidyl were the most commonly prescribed drugs in our patients. A higher use of trihexyphenidyl could be due to its easy availability, low cost, and better tolerability in our patients, who were relatively young at the time of onset of their disease. The choice of antiparkinsonian medications at the primary and secondary care levels in India may be inappropriate, and newer guidelines tailored to the Indian context are warranted.

Dyskinesia is an extrapyramidal movement disorder characterized by involuntary, repetitive, irregular motions that affect the mouth and face and/or the limbs and trunk. Tardive dyskinesia (TD) is a well-known complication of long-term treatment with antipsychotic drugs. Dyskinesia is also induced with levodopa, a treatment for Parkinson's disease, and it occurs spontaneously as a symptom of Huntington's disease. Research on the pathogenesis of TD has focused on a dysfunction of either the dopaminergic or serotonergic system. However, recent evidence has suggested that we should focus on the possible damage of GABAergic medium spiny neurons (MSNs). MSNs are the first station in the cortico-striato-thalamo-cortical circuit that regulates the amplitude and velocity of movements. Two pathways can be distinguished in this circuit: a direct pathway, which increases movements (hyperkinesia), and an indirect pathway, which decreases movements (hypokinesia). Both pathways are activated by glutamatergic corticostriatal neurons. Here, we discuss some evidence that supports the hypothesis that indirect pathway MSNs are damaged in dyskinesia.

We report on the treatment of a patient suffering from dementia with Lewy bodies who initially presented with severe neurological and psychopathological symptoms. After treating the patient with levodopa and clozapine, these symptoms remitted.

ABSTRACT

The MONOCOMB study was a double-blind, randomized, controlled trial initiated to examine the impact of selegiline monotherapy on time to the start of levodopa therapy and, subsequently, to compare the progression of PD in patients treated with individualized levodopa plus selegiline or placebo.

Previously untreated patients with idiopathic PD (N = 157) were randomized to receive selegiline 10 mg/day or placebo until levodopa was required; experimental medication was then withdrawn for 8 weeks. Patients were then randomized to levodopa (50 mg/day, titrated in 50 mg/day increments to 150 mg/day) plus either selegiline or placebo. Treatment was continued until patients required additional antiparkinsonian therapy or up to 7 years after initial randomization. The primary efficacy outcome for the monotherapy phase of the study was time to introduction of levodopa. Primary efficacy endpoints for the combined therapy phase were: time to development of fluctuations in disability; and time to the addition of supplementary antiparkinsonian treatment.

Selegiline significantly delayed the time when levodopa therapy became necessary during the monotherapy phase, although mean total UPDRS scores at time of initiation of levodopa were similar in both groups. Selegiline was also associated with improvements in PD' symptom status and disability as reflected in a broad range of well-established indices. After the 8 week wash out period the disability of the clinical condition of the patients in the selegiline group was still significantly better in the selegiline group than in the placebo group. During the combination phase of the study, the use of selegiline as an adjunct to levodopa enabled a given degree of therapeutic effect to be achieved with a demonstrably lower total consumption of levodopa. Patients treated with selegiline plus levodopa also exhibited a distinct (p = 0.005) slowing in the anticipated increase in the UPDRS scores over time, as for example in a mean UPDRS total score after 5 years 10 points lower than in patients on levodopa and placebo. The emergence of motor (wearing-off) fluctuations was delayed by selegiline, and the proportion of patients experiencing these events was lower than with placebo (20% versus 34%; p = 0.053).

Mild gastrointestinal events were significantly more common with selegiline monotherapy than with placebo (12 versus. 3; p = 0.028). The overall rates of AEs during the combination therapy phase were 69% in the selegiline group and 54% in the placebo group (p = 0.053). Significantly more patients in the selegiline group reported nausea. Of the five deaths that occurred during the combination therapy phase of the study (selegiline N = 4, placebo N = 1) none was expressly attributed to study medication.

The results of MONOCOMB, among the largest and longest-duration placebo-controlled studies to report experience with selegiline monotherapy in early-phase PD, confirm that selegiline is effective in retarding the progression of early PD, that it has levodopa-sparing qualities in more advanced disease, and that it is reasonably well-tolerated in long-term use.

To investigate the effects of dopamine on the dynamics of semantic activation, 39 healthy volunteers were randomly assigned to ingest either a placebo (n = 24) or a levodopa (n = 16) capsule. Participants then performed a lexical decision task that implemented a masked priming paradigm. Direct and indirect semantic priming was measured across stimulus onset asynchronies (SOAs) of 250, 500 and 1200 ms. The results revealed significant direct and indirect semantic priming effects for the placebo group at SOAs of 250 ms and 500 ms, but no significant direct or indirect priming effects at the 1200 ms SOA. In contrast, the levodopa group showed significant direct and indirect semantic priming effects at the 250 ms SOA, while no significant direct or indirect priming effects were evident at the SOAs of 500 ms or 1200 ms. These results suggest that dopamine has a role in modulating both automatic and attentional aspects of semantic activation according to a specific time course. The implications of these results for current theories of dopaminergic modulation of semantic activation are discussed. (JINS, 2004, 10, 15–25.)