Motor Fluctuations In Patients Research Articles

Optimization of oral entacapone administration in patients undergoing levodopa–carbidopa intestinal gel treatment

BackgroundLevodopa–carbidopa intestinal gel (LCIG) treatment markedly reduces motor fluctuations in patients with Parkinson's disease; however, some patients undergoing LCIG treatment may demonstrate clinical deterioration in the afternoon. Entacapone, a catechol-O-methyltransferase inhibitor, may be a promising adjunctive option for LCIG-treated patients; however, the optimal timing of oral entacapone administration to ameliorate clinical symptoms in the afternoon remains unexplored. This study aimed to investigate the optimal timing of oral entacapone administration in patients with Parkinson's disease undergoing LCIG treatment. MethodsPharmacokinetic analysis and symptom assessment were performed on three days: a day without entacapone administration, day with oral entacapone administration at 13:00, and day with oral entacapone administration at 15:00. ResultsEight LCIG-treated patients were enrolled, of whom seven completed this study. The relative plasma concentrations of levodopa with entacapone administration at 13:00 were gradually increased, especially at 18:00 and were significantly higher than those without entacapone administration (127.10 ± 25.06% vs. 97.51 ± 22.20%). The relative plasma concentrations of 3-O-methyldopa were gradually increased without entacapone administration, whereas those with entacapone administration at 13:00 were lower than those without entacapone administration, especially at 17:00 (97.47 ± 3.70% vs. 110.71 ± 9.84%). Administering oral entacapone at 15:00 increased and decreased the relative plasma concentrations of levodopa and 3-O-methyldopa, respectively, but without significant difference. The “Off” time was shorter with entacapone administration at 13:00 (0.43 ± 0.79 h) and at 15:00 (0.57 ± 0.79 h) than that without entacapone administration (1.14 ± 1.46 h). ConclusionsThe concomitant use of oral entacapone in the early afternoon may be effective in improving afternoon symptoms in patients undergoing LCIG treatment.

Foslevodopa-Foscarbidopa (Vyalev)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses Foslevodopa-foscarbidopa (Vyalev), 240 mg/mL foslevodopa and 12 mg/mL foscarbidopa solution, subcutaneous infusion.
 Indication: For the treatment of motor fluctuations in patients with advanced levodopa-responsive Parkinson’s disease who do not have satisfactory control of severe, debilitating motor fluctuations and hyper- /dyskinesia despite optimized treatment with available combinations of Parkinson’s medicinal products.

Bradykinesia and rigidity modulated by functional connectivity between the primary motor cortex and globus pallidus in Parkinson's disease.

The mechanisms underlying motor fluctuations in patients with Parkinson's disease (PD) are currently unclear. Regional brain stimulation reported the changing of motor symptoms, but the correlation with functional connectivity (FC) in the brain network is not fully understood. Hence, our study aimed to explore the relationship between motor symptom severity and FC using resting-state functional magnetic resonance imaging (rsfMRI) in the "on" and "off" states of PD. In 26 patients with sporadic PD, FC was assessed using rsfMRI, and clinical severity was analyzed using the motor part of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS Part III) in the on and off states. Correlations between FC values and MDS-UPDRS Part III scores were assessed using Pearson's correlation coefficient. The correlation between FC and motor symptoms differed in the on and off states. FC between the ipsilateral precentral gyrus (PreCG) and globus pallidus (GP) correlated with the total MDS-UPDRS Part III scores and those for bradykinesia/rigidity in the off state. Lateralization analysis indicated that FC between the PreCG and GP correlated with the contralateral total MDS-UPDRS Part III scores and those for bradykinesia/rigidity in the off state. Aberrant FC in cortico-striatal circuits correlated with the severity of motor symptoms in PD. Cortico-striatal hyperconnectivity, particularly in motor pathways involving PreCG and GP, is related to motor impairments in PD. These findings may facilitate our understanding of the mechanisms underlying motor symptoms in PD and aid in developing treatment strategies such as brain stimulation for motor impairment.

Current Pharmacological Treatment for Parkinson's Disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder and its global incidence is on the rise. A well-established dopamine replacement therapy for PD is based on dopamine deficiency, primarily due to dopaminergic neuronal loss in the substantia nigra. Current dopaminergic pharmacotherapy for PD consists of levodopa and other dopaminergic drugs, such as a dopamine agonist (DA) and monoamine oxidase B (MAOB) inhibitor, and patients with PD are administered these mainly according to age, disability of parkinsonism, and tolerance of the drugs. In the advanced stage, patients with PD usually experience motor complications, mainly the wearing-off phenomenon and dyskinesias, resulting in disabled activities of daily life. Many pharmacological options are available against motor fluctuations in patients with advanced PD, including long-acting DAs, MAOB inhibitors, and catechol-O-methyltransferase inhibitors, as adjunct alternatives for dopamine-replacement therapy. Non-dopaminergic pharmacological approaches, including zonisamide and istradefylline, which have been mainly developed in Japan, are also available. Amantadine and anticholinergic drugs may be useful in specific situations. Device-aided therapies, such as deep brain stimulation and levodopa-carbidopa intestinal gel infusion therapy, can be performed at the advanced stage. In this article, we provide an overview of recent pharmacological treatments for PD.

Off-time Treatment Options for Parkinson's Disease.

Motor fluctuations (MF) are deemed by patients with Parkinson's disease (PD) as the most troublesome disease feature resulting from the increasing impairment in responsiveness to dopaminergic drug treatments. MF are characterized by the loss of a stable response to levodopa over the nychthemeron with the reappearance of motor (and non-motor) parkinsonian clinical signs at various moments during the day and night. They normally appear after a few years of levodopa treatment and with a variable, though overall increasing severity, over the disease course. The armamentarium of first-line treatment options has widened in the last decade with new once-a-daily compounds, including a catechol O-methyltransferase inhibitor - Opicapone-, two MAO-B inhibitors plus channel blocker - Zonisamide and Safinamide and one amantadine extended-release formulation - ADS5012. In addition to apomorphine injection or oral levodopa dispersible tablets, which have been available for a long time, new on-demand therapies such as apomorphine sublingual or levodopa inhaled formulations have recently shown efficacy as rescue therapies for Off-time treatment. When the management of MF becomes difficult in spite of oral/on-demand options, more complex therapies should be considered, including surgical, i.e. deep brain stimulation, or device-aided therapies with pump systems delivering continuous subcutaneous or intestinal levodopa or subcutaneous apomorphine formulation. Older and less commonly used ablative techniques (radiofrequency pallidotomy) may also be effective while there is still scarce data regarding Off-time reduction using a new lesional approach, i.e. magnetic resonance-guided focused ultrasound. The choice between the different advanced therapies options is a shared decision that should consider physician opinion on contraindication/main target symptom, patients' preference, caregiver's availability together with public health systems and socio-economic environment. The choice of the right/first add-on treatment is still a matter of debate as well as the proper time for an advanced therapy to be considered. In this narrative review, we discuss all the above cited aspects of MF in patients with PD, including their phenomenology, management, by means of pharmacological and advanced therapies, on-going clinical trials and future research and treatment perspectives.

Efficacy and safety of apomorphine pump infusion in Filipino patients insufficiently controlled on oral anti-Parkinson medications: an open-label, pilot study

Background Apomorphine hydrochloride is used in the management of advanced Parkinson disease (PD), either as a rescue medication for off periods during levodopa therapy or as a maintenance pump medication. This is the first study to describe the effects of apomorphine in Filipino patients with PD. Objective To evaluate the safety and efficacy of apomorphine ampules (APO-go®) pump infusion in the treatment of motor fluctuations in patients inadequately controlled on oral anti-Parkinson medications. Methods Patients diagnosed with PD who developed motor fluctuations with levodopa were evaluated at baseline and at the end of the study using the Modified Hoehn and Yahr (H&Y) Scale, the Unified Parkinson’s Disease Rating Scale (UPDRS) and the Abnormal Involuntary Movement Scale (AIMS). After initial assessment, patients were administered 20 ampules of apomorphine hydrochloride 10 mg/mL by infusion pump over 20 days. Intention-to-treat (ITT) analysis included all patients who completed at least one posttreatment assessment. Motor disability based on modified H&Y scores, motor function and complications of therapy pre- and posttreatment were compared using Wilcoxon Signed Rank test. Chi-squared test was used to compare outcomes by age and sex. Frequencies of adverse reactions were recorded to evaluate the tolerability of the medication. Results Ten patients (mean age 63 ± 9.7 years), 3 male and 7 female, were enrolled in the study. Patients were given apomorphine for at most 16 days. The doses used were 2.5 mg/0.50 mL (n = 2), 3 mg/0.60 mL (n = 6), 4 mg/0.80 mL (n = 1) and 7 mg/1.40 mL (n = 1). After obtaining the threshold dose, two patients discontinued treatment. Eight of nine patients showed significant improvement in H&Y scores after treatment (p < 0.017). There was marked improvement after 10 days of treatment in at least five of 10 patients in terms of motor function using UPDRS, which included tremor (p < 0.034), rigidity (p < 0.002), facial expression (p < 0.014), finger taps (p < 0.008), foot taps (p < 0.014) and gait (p < 0.006). Significant changes from pre- to posttreatment scores in the frequency of dyskinesias (p < 0.010) and dystonia (p < 0.025) were observed. Nine focus areas of AIMS showed significant improvements in the muscles of facial expression (p < 0.020), upper (p < 0.016) and lower extremities (p < 0.010), incapacitation by abnormal movement (p < 0.010) and patients’ awareness of abnormal movements (p < 0.039). Six patients experienced adverse events, none of which were related to the study drug. Conclusion Apomorphine hydrochloride pump infusion therapy is potentially effective and safe in the treatment of motor fluctuations in Filipino patients with PD. This pilot study springboards safe engagements of Filipino PD patients in multicenter, large-scale trials.

The relationship between the distinct ratios of benserazide and carbidopa to levodopa and motor complications in Parkinson's disease: A retrospective cohort study

BackgroundIn Japan, only two medications of immediate-release levodopa with distinct ratios of decarboxylase inhibitor (DCI), namely levodopa/benserazide 100/25 mg and levodopa/carbidopa 100/10 mg, are available for the treatment of Parkinson's disease (PD). The relationship between the difference in the DCI to levodopa ratio and the development of motor complications in long-term administration of levodopa is unknown. PurposeWe assessed the duration from initiation of levodopa/DCI to the emergence of motor fluctuations in patients with PD treated with levodopa/benserazide and levodopa/carbidopa. MethodsWe retrospectively assessed the disease course, especially the period from the onset of motor symptoms or initiation of levodopa/DCI to the emergence of motor fluctuations, in patients with PD who were initially treated with either levodopa/benserazide (300/75 mg/day) or levodopa/carbidopa (300/30 mg/day). ResultsOf the 186 candidates, 52 patients were enrolled. The mean duration to the emergence of motor fluctuations in the levodopa/carbidopa group was significantly longer than that in the levodopa/benserazide group (5.0 ± 1.4 vs 3.1 ± 1.2 years, p < 0.01). The mean duration from onset of motor symptoms to the emergence of motor fluctuations in the levodopa/carbidopa group was also significantly longer than that in the levodopa/benserazide group (6.6 ± 1.6 vs 4.7 ± 1.3 years, p < 0.01). ConclusionOur study suggests that levodopa/carbidopa therapy with a DCI to levodopa ratio of 1:10 may delay the occurrence of motor fluctuations when compared to levodopa/benserazide therapy with that of 1:4. The difference in the blending ratio of levodopa/DCI may influence the disease progression in PD.

Inhaled Levodopa (CVT-301) for the Treatment of Parkinson Disease: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

To investigate the efficacy and safety of CVT-301 in treating motor fluctuation in patients with Parkinson disease (PD). This study demonstrated that the CVT-301 group had a higher proportion of patients achieving an ON state than the placebo group (odds ratio [OR] = 2.68; 95% confidence interval [CI]: 1.86-3.86; p < 0.00001). Moreover, CVT-301 had also shown to improve motor function by Unified Parkinson Disease Rating Scale part III score (standardized mean difference = 3.83; 95% CI: 2.44-5.23; p < 0.00001) and promote an overall improvement of PD by Patient Global Impression of Change self-rating (OR = 2.95; 95% CI: 1.78-4.9; p < 0.00001). The most common adverse events encountered were respiratory symptoms (OR = 12.18; 95% CI: 5.01-29.62; p < 0.00001) and nausea (OR = 3.95; 95% CI: 1.01-15.41; p = 0.05). CVT-301 had the potential to be an alternative or even a preferred treatment for motor fluctuation in patients with PD.

MR-guided focused ultrasound pallidotomy for Parkinson's disease: safety and feasibility.

Stereotactic radiofrequency pallidotomy has demonstrated improvement in motor fluctuations in patients with Parkinson's disease (PD), particularly levodopa (L-dopa)-induced dyskinesias. The authors aimed to determine whether or not unilateral pallidotomy with MR-guided focused ultrasound (MRgFUS) could safely improve Unified Dyskinesia Rating Scale (UDysRS; the primary outcome measure) scores over baseline scores in patients with PD. Twenty patients with PD and L-dopa responsiveness, asymmetrical motor signs, and motor fluctuations, including dyskinesias, participated in a 1-year multicenter open-label trial of unilateral MRgFUS ablation of the globus pallidus internus. The sonication procedure was successfully completed in all 20 enrolled patients. MRgFUS-related adverse neurological events were generally mild and transient, including visual field deficit (n = 1), dysarthria (n = 4, 2 mild and 2 moderate), cognitive disturbance (n = 1), fine motor deficit (n = 2), and facial weakness (n = 1). Although 3 adverse events (AEs) were rated as severe (transient sonication-related pain in 2, nausea/vomiting in 1), no AE fulfilled US FDA criteria for a Serious Adverse Effect. Total UDysRS, the primary outcome measure, improved 59% after treatment (baseline mean score 36.1, 95% CI 4.88; at 3 months 14.2, 95% CI 5.72, p < 0.0001), which was sustained throughout the study (at 12 months 20.5, 95% CI 7.39, 43% improvement, p < 0.0001). The severity of motor signs on the treated side (Movement Disorder Society version of the United Parkinson's Disease Rating Scale [MDS-UPDRS] part III) in the "off" medication state also significantly improved (baseline mean score 20.0, 95% CI 2.4; at 3 months 10.6, 95% CI 1.86, 44.5% improvement, p < 0.0001; at 12 months 10.4, 95% CI 2.11, 45.2% improvement, p > 0.0001). The vast majority of patients showed a clinically meaningful level of improvement on the impairment component of the UDysRS or the motor component of the UPDRS, while 1 patient showed clinically meaningful worsening on the UPDRS at month 3. This study supports the feasibility and preliminary efficacy of MRgFUS pallidotomy in the treatment of patients with PD and motor fluctuations, including dyskinesias. These preliminary data support continued investigation, and a placebo-controlled, blinded trial is in progress. Clinical trial registration no.: NCT02263885 (clinicaltrials.gov).

Ambulatory surface electromyography with accelerometry for evaluating daily motor fluctuations in Parkinson’s disease

ObjectiveTo evaluate motor fluctuations in patients with advanced Parkinson’s disease (PD) using a small-sized wearable device for surface electromyography (EMG) with accelerometry (ACC) for 24 hours. MethodsSeven PD patients with medication were measured once, and nine patients with directional deep brain stimulation (dDBS) twice: before and after the dDBS reprogramming. EMG and ACC parameters were compared with clinical rating scores and patients’ home diaries. ResultsThe combination of EMG and ACC parameters (first principal component PC1) correlated significantly with patient’s condition as quantified by the motor score of Unified Parkinson’s Disease Rating Scale and it changed significantly with dDBS reprogramming in line with decreased PD symptoms. Monitoring data detected in comparison with the home diaries: 91 % concordance with tremor, 76 % with rigidity, and 74 % with dyskinesia. In the DBS group, the wake-up time with abnormal neuromuscular function was reduced with reprogramming in all except one patient based on measurements. ConclusionsA wearable device measuring simultaneously both muscle activity and motion can provide continuous and dynamic information about patient’s condition and motor fluctuations at home. SignificanceThe present method may help to modify pharmacologic management and DBS treatment in advanced PD.

Predictors of Response for "Off" Time Improvement With Levodopa-Carbidopa Intestinal Gel Treatment: An Analysis of the GLORIA Registry.

Background: Levodopa-carbidopa intestinal gel (LCIG) is a long-term therapy for motor fluctuations in patients with advanced Parkinson's disease (PD). The aim of this analysis was to identify the baseline characteristics that predict “Off” time reduction in advanced PD patients treated with LCIG under routine clinical care in the GLORIA registry.Methods: Patients were followed under routine care for 24 months (M) with delivery of LCIG via percutaneous gastrojejunostomy. Analysis of covariance (ANCOVA) and logistic regression were performed to identify baseline characteristics that predict “Off” time reduction.Results: Compared to baseline, 86% (n/N = 131/152; mean ± SD baseline “Off” time: 3.4 ± 2.2 h) of M24 completers had ≥ 1 h reduction in “Off” time and 64% (n/N = 97/152; mean ± SD baseline “Off” time: 7.6 ± 2.9 h) had ≥ 3 h “Off” time reduction at M24. Most baseline characteristics were similar across responder subgroups; however, patients with ≥ 3 h “Off” time improvement had more “Off” time and less time with dyskinesia at baseline compared to patients with <3 h “Off” time reduction. Despite having less improvement in absolute “Off” h at M24, patients with <3 h “Off” time reduction experienced a 33% median reduction in “Off” time and a 44% median reduction in dyskinesia duration at M24, which was similar to the dyskinesia improvement observed among patients with ≥ 3 h “Off” time improvement (50% median reduction). Baseline “Off” time was both the best predictor of and the only significant factor associated with “Off” time improvement (P <0.0001).Conclusions: LCIG treatment led to clinically meaningful improvements in “Off” time in 86% of advanced PD patients and those with greater “Off” time are likely to experience the largest absolute reduction in hours “Off.”

A systematic review on the clinical experience with melevodopa/carbidopa fixed combination in patients with Parkinson disease

We have performed a systematic literature review to evaluate the current evidence of the pharmacokinetic (PK), efficacy and safety profile of oral melevodopa/carbidopa fixed combination in the management of motor fluctuations in patients with Parkinson disease (PD). Search has been started from common libraries and was then restricted to articles of studies in humans with melevodopa/carbidopa as fixed combination. Abstracts of international congresses have been also explored. The search has led to the identification of one PK study and five efficacy/safety studies that included more 743 PD patients overall, 488 of which treated with melevodopa/carbidopa effervescent tablets (Sirio®, Chiesi Farmaceutici S.p.A., Parma, Italy). Melevodopa/carbidopa has a more rapid absorption, less apparent drug accumulation, less inter-patient variability and more effective LD delivery after the early morning and early afternoon dose compared to standard LD. Although they differed in used dose regimens, duration of treatment and endpoints, the results of the efficacy/safety studies suggest that treatment with melevodopa/carbidopa may determine improvements in motor fluctuations compared to treatment with standard LD/CD formulations, with no increased risk of adverse effects or LD-induced dyskinesias. Data from literature have shown that melevodopa/carbidopa in a highly soluble formulation as effervescent oral tablets is effective in improving control of motor complications in PD patients compared to conventional levodopa. Further research is needed to confirm this evidence in large controlled trials and to explore if melevodopa/carbidopa may have a potential role in the earlier phases of the disease or in special PD populations.

A systematic review and meta-analysis of safety and efficacy of safinamide for motor fluctuations in patients with Parkinson's disease.

Background: Safinamide, a recently developed drug with several mechanisms of action has been investigated as an add-on therapy for Parkinson's disease patients suffering from motor complications due to the usage of anti-Parkinson's medications such as levodopa and dopaminergic drugs. The aim of the study is to investigate the efficacy and safety of Safinamide as add-on therapy for Parkinson's disease patients. Methods: A computerized literature search was conducted of PubMed, EMBASE, ClinicalTrial.gov and Cochrane Library until August 2019. We selected relevant randomized controlled trials comparing safinamide groups to placebo groups. Relevant outcomes were pooled as mean difference (MD) and risk ratio (RR) using Review Manager 5.3. Results: We found that the overall MD of changes in "off-time" and "on time without troublesome dyskinesia" favored the safinamide group over the placebo group (MD -0.72 h, 95% CI -0.89 to -0.56 and MD 0.71 h, 95% CI 0.52 to 0.90, respectively). Additionally, the overall MD of change in Unified Parkinson's Disease Rating Scale part three (UPDRS III) favored the safinamide group (MD -1.83, 95% CI -2.43 to -1.23). In case of adverse events, the pooled meta-analysis did not favor the safinamide group over the placebo group. Conclusions: In this study, we provide class I evidence about the potential role of safinamide as an add-on therapy for Parkinson's disease patients suffering from motor fluctuations. However, a few included studies did not mention the data of important outcomes. Also, we report high risk of bias in individual studies. Future randomized controlled trials with different doses are recommended to provide more evidence for the efficacy and safety of safinamide as a treatment for motor complications of anti-Parkinson's medications.

Levodopa/Carbidopa Enteral Suspension: A Review in Advanced Parkinson's Disease.

An enteral suspension (ES)/intestinal gel formulation of levodopa/carbidopa (hereafter referred to as levodopa/carbidopa ES) [Duodopa® (EU); Duopa™ (USA)] has been developed to overcome the fluctuating plasma levodopa concentrations associated with oral levodopa/carbidopa formulations. In various countries, including those of the EU (under the Mutual Recognition Procedure), it is approved for the treatment of advanced levodopa-responsive Parkinson's disease (PD) with severe motor fluctuations and hyperkinesia or dyskinesia when available combinations of Parkinson medicinal products have not given satisfactory results. In several other countries, including the USA, it is approved for the treatment of motor fluctuations in patients with advanced PD. In adults with advanced PD, levodopa/carbidopa ES improved motor fluctuations, activities of daily living and health-related quality of life (HR-QOL) during short-term (12-week) treatment, with the beneficial effects on motor fluctuations largely sustained over the longer term (up to 7years). Levodopa/carbidopa ES was generally well tolerated in this patient population, with adverse events (AEs) associated with aging, advanced PD-related comorbidities, the procedure/device or dopaminergic therapy. Its safety profile was comparable to that of oral levodopa/carbidopa with respect to non-procedure/device-associated AEs; most procedure/device-associated AEs were consistent in nature and incidence with medically recognised complications of the procedure in non-PD patients. Current evidence indicates that levodopa/carbidopa ES is an effective and generally well tolerated option for the treatment of motor fluctuations in patients with levodopa-responsive advanced PD who are not being effectively managed with non-invasive therapies.

Different Generations of Type-B Monoamine Oxidase Inhibitors in Parkinson's Disease: From Bench to Bedside.

Three inhibitors of type-B monoamine oxidase (MAOB), selegiline, rasagiline, and safinamide, are used for the treatment of Parkinson’s disease (PD). All three drugs improve motor signs of PD, and are effective in reducing motor fluc-tuations in patients undergoing long-term L-DOPA treatment. The effect of MAOB inhibitors on non-motor symptoms is not uniform and may not be class-related. Selegiline and rasagiline are irreversible inhibitors forming a covalent bond within the active site of MAOB. In contrast, safinamide is a reversible MAOB inhibitor, and also inhibits voltage-sensitive sodium channels and glutamate release. Safinamide is the prototype of a new generation of multi-active MAOB inhibitors, which in-cludes the antiepileptic drug, zonisamide. Inhibition of MAOB-mediated dopamine metabolism largely accounts for the an-tiparkinsonian effect of the three drugs. Dopamine metabolism by MAOB generates reactive oxygen species, which contrib-ute to nigro-striatal degeneration. Among all antiparkinsonian agents, MAOB inhibitors are those with the greatest neuropro-tective potential because of inhibition of dopamine metabolism, induction of neurotrophic factors, and, in the case of safina-mide, inhibition of glutamate release. The recent development of new experimental animal models that more closely mimic the progressive neurodegeneration associated with PD will allow to test the hypothesis that MAOB inhibitors may slow the progression of PD.

Current Practices for Outpatient Initiation of Levodopa-Carbidopa Intestinal Gel for Management of Advanced Parkinson’s Disease in the United States

In 2015, the US Food and Drug Administration approved levodopa-carbidopa intestinal gel (LCIG; also known as carbidopa-levodopa enteral suspension in the US) for the treatment of motor fluctuations in patients with advanced Parkinson’s disease. LCIG provides a continuous infusion of levodopa and carbidopa by means of a portable pump and percutaneous endoscopic gastrojejunostomy tube. The delivery system has a two-fold pharmacokinetic advantage over orally administered carbidopa/levodopa. First, levodopa is delivered in a continuous rather than intermittent, pulsatile fashion. Second, delivery to levodopa’s site of absorption in the jejunum bypasses the stomach, thereby avoiding issues with erratic gastric emptying. In blinded prospective clinical trials and observational studies, LCIG has been shown to significantly decrease “off” time, increase “on” time without troublesome dyskinesia, and reduce dyskinesia. Consistent with procedures in previous studies, LCIG initiation and titration in the pivotal US clinical trial were performed in the inpatient setting and followed a standardized protocol. In clinical practice, however, initiation and titration of LCIG have a great degree of flexibility and, in the US, almost always take place in the outpatient setting. Nonetheless, there remains a significant amount of clinician uncertainty regarding titration in outpatient clinical practice. This review aims to shed light on and provide guidance as to the current methods of titration in the outpatient setting, as informed by the medical literature and the authors’ experiences.FundingAbbVie, Inc.Plain Language SummaryPlain language summary available for this article.

Apomorphine infusion in advanced Parkinson disease.

The TOLEDO study provides new evidence to support the use of subcutaneous apomorphine infusion to control motor fluctuations in patients with advanced Parkinson disease. The findings should encourage neurologists to consider implementing apomorphine infusion or other device-aided therapies earlier in the disease course, before the emergence of troublesome dyskinesias.

Deep brain stimulation therapy of levodopa-responsive motor fluctuations in patients with multiple system atrophy

Deep brain stimulation therapy of levodopa-responsive motor fluctuations in patients with multiple system atrophy

Analysis of Correlation between an Accelerometer-Based Algorithm for Detecting Parkinsonian Gait and UPDRS Subscales.

Our group earlier developed a small monitoring device, which uses accelerometer measurements to accurately detect motor fluctuations in patients with Parkinson's (On and Off state) based on an algorithm that characterizes gait through the frequency content of strides. To further validate the algorithm, we studied the correlation of its outputs with the motor section of the Unified Parkinson's Disease Rating Scale part-III (UPDRS-III). Seventy-five patients suffering from Parkinson's disease were asked to walk both in the Off and the On state while wearing the inertial sensor on the waist. Additionally, all patients were administered the motor section of the UPDRS in both motor phases. Tests were conducted at the patient's home. Convergence between the algorithm and the scale was evaluated by using the Spearman's correlation coefficient. Correlation with the UPDRS-III was moderate (rho -0.56; p < 0.001). Correlation between the algorithm outputs and the gait item in the UPDRS-III was good (rho -0.73; p < 0.001). The factorial analysis of the UPDRS-III has repeatedly shown that several of its items can be clustered under the so-called Factor 1: "axial function, balance, and gait." The correlation between the algorithm outputs and this factor of the UPDRS-III was -0.67 (p < 0.01). The correlation achieved by the algorithm with the UPDRS-III scale suggests that this algorithm might be a useful tool for monitoring patients with Parkinson's disease and motor fluctuations.

Opicapone for the management of end-of-dose motor fluctuations in patients with Parkinson’s disease treated with L-DOPA

ABSTRACTIntroduction: Opicapone is a third generation, highly potent and effective catechol O‑methyltransferase (COMT) inhibitor that optimizes the pharmacokinetics and bioavailability of L-DOPA therapy.Areas covered: In this review, the authors describe the preclinical and clinical development of opicapone. In PD patients with motor fluctuations, once daily opicapone administration was well-tolerated and consistently reduced OFF-time and increased ON-time without increasing the frequency of troublesome dyskinesia, and these benefits were maintained over at least a year of continued open-label therapy.Expert commentary: With its convenient once-daily regimen, adjunct opicapone should be considered as an effective option for use in L-DOPA treated PD patients experiencing motor fluctuations.