Alexandra Rizos

EuroInf: A multicenter comparative observational study of apomorphine and levodopa infusion in Parkinson's disease

Subcutaneous apomorphine infusion (Apo) and intrajejunal levodopa infusion (IJLI) are two treatment options for patients with advanced Parkinsons disease (PD) and refractory motor complications, with varying cost of treatment. There are no multicenter studies comparing the effects of the two strategies. This open‐label, prospective, observational, 6‐month, multicenter study compared 43 patients on Apo (48.8% males, age 62.3 ± 10.6 years; disease duration: 14 ± 4.4 years; median H & Y stage 3; interquartile range [IQR]: 3‐4) and 44 on IJLI (56.8% males, age 62.7 ± 9.1 years; disease duration: 16.1 ± 6.7 years; median H & Y stage 4; IQR, 3‐4). Cohens effect sizes (≥0.8 considered as large) were “large” with both therapies with respect to total motor, nonmotor, and quality‐of‐life scores. The Non‐Motor Symptoms Scale (NMSS) with Apo showed moderate improvement, whereas sleep/fatigue, gastrointestinal, urinary, and sexual dimensions of the NMSS showed significantly higher improvement with IJLI. Seventy‐five percent on IJLI improved in their quality‐of‐life and nonmotor symptoms (NMS), whereas in the Apo group, a similar proportion improved in quality of life, but 40% in NMS. Adverse effects included peritonitis with IJLI and skin nodules on Apo. Based on this open‐label, nonrandomized, comparative study, we report that, in advanced Parkinsons patients, both IJLI and Apo infusion therapy appear to provide a robust improvement in motor symptoms, motor complications, quality‐of‐life, and some NMS. Controlled, randomized studies are required.

Motor and nonmotor complications in Parkinson’s disease: an argument for continuous drug delivery?

The complications of long-term levodopa therapy for Parkinson’s disease (PD) include motor fluctuations, dyskinesias, and also nonmotor fluctuations—at least equally common, but less well appreciated—in autonomic, cognitive/psychiatric, and sensory symptoms. In seeking the pathophysiologic mechanisms, the leading hypothesis is that in the parkinsonian brain, intermittent, nonphysiological stimulation of striatal dopamine receptors destabilizes an already unstable system. Accordingly, a major goal of PD treatment in recent years has been the attainment of continuous dopaminergic stimulation (CDS)—or, less theoretically (and more clinically verifiable), continuous drug delivery (CDD). Improvements in the steadiness of the plasma profiles of various dopaminergic therapies may be a signal of progress. However, improvements in plasma profile do not necessarily translate into CDS, or even into CDD to the brain. Still, it is reassuring that clinical studies of approaches to CDD have generally been positive. Head-to-head comparative trials have often failed to uncover evidence favoring such approaches over an intermittent therapy. Nevertheless, the findings among recipients of subcutaneous apomorphine infusion or intrajejunal levodopa/carbidopa intestinal gel suggest that nonmotor PD symptoms or complications may improve in tandem with motor improvement. In vivo receptor binding studies may help to determine the degree of CDS that a dopaminergic therapy can confer. This may be a necessary first step toward establishing whether CDS is, in fact, an important determinant of clinical efficacy. Certainly, the complexities of optimal PD management, and the rationale for an underlying strategy such as CDS or CDD, have not yet been thoroughly elucidated.

King's Parkinson's disease pain scale, the first scale for pain in PD: An international validation.

Pain is a key unmet need and a major aspect of non‐motor symptoms of Parkinsons disease (PD). No specific validated scales exist to identify and grade the various types of pain in PD. We report an international, cross‐sectional, open, multicenter, one‐point‐in‐time evaluation with retest study of the first PD‐specific pain scale, the Kings PD Pain Scale. Its seven domains include 14 items, each item scored by severity (0‐3) multiplied by frequency (0‐4), resulting in a subscore of 0 to 12, with a total possible score range from 0 to 168. One hundred seventy‐eight PD patients with otherwise unexplained pain (age [mean ± SD], 64.38 ± 11.38 y [range, 29‐85]; 62.92% male; duration of disease, 5.40 ± 4.93 y) and 83 nonspousal non‐PD controls, matched by age (64.25 ± 11.10 y) and sex (61.45% males) were studied. No missing data were noted, and floor effect was observed in all domains. The difference between mean and median Kings PD Pain Scale total score was less than 10% of the maximum observed value. Skewness was marginally high (1.48 for patients). Factor analysis showed four factors in the Kings PD Pain Scale, explaining 57% of the variance (Kaiser‐Mayer‐Olkin, 0.73; sphericity test). Cronbachs alpha was 0.78, item‐total correlation mean value 0.40, and item homogeneity 0.22. Correlation coefficients of the Kings PD Pain Scale domains and total score with other pain measures were high. Correlation with the Scale for Outcomes in PD‐Motor, Non‐Motor Symptoms Scale total score, and quality of life measures was high. The Kings PD Pain Scale seems to be a reliable and valid scale for grade rating of various types of pain in PD.

Intrajejunal levodopa versus conventional therapy in Parkinson disease: motor and nonmotor effects

AbstractSeventeen patients with advanced Parkinson disease (PD) were treated with intrajejunal L-dopa infusion (IJL) and compared with a matched group of 9 patients (termed comparator [C]) not given IJL because of funding restriction by primary care trusts (PCTs) in the UK, although considered to be clinically eligible for IJL. Assessments were baseline and follow-up (6 months) with Hoehn and Yahr staging, unified PD rating scale (UPDRS-III and UPDRS-IV), Parkinson disease questionnaire (PDQ-8, quality of life [QoL]) and nonmotor symptom scale (NMSS).Baseline characteristics were comparable between the groups. The IJL-treated group showed highly significant improvements in UPDRS-III (P = 0.005), UPDRS-IV (P = 0.0004), total NMSS score (P = 0.004), and QoL (P = 0.01), whereas the C group showed no change in these parameters. A large effect size of IJL was seen in treated patients for UPDRS-III (1.13), UPDRS-IV (1.52), NMSS score (0.82), and QoL (1.12), whereas continuing conventional treatment registered no effect in C.This study confirms the robust effect of IJL on motor and, in particular, nonmotor symptoms and QoL in advanced PD as described in open-label studies but additionally points to the need for such treatment in those denied this therapy because of centrally dictated funding policies leading to inequalities in health care.

The burden of non-motor symptoms in Parkinson's disease using a self-completed non-motor questionnaire: a simple grading system.

BACKGROUND Non-motor symptoms (NMS) of Parkinsons disease (PD) affect virtually every patient, yet they are under-recognized and under-treated. The NMS Questionnaire (NMSQuest) is a validated 30-item self-assessment instrument useful for NMS screening in clinic. OBJECTIVE Development of a straight forward grading classification of the burden of non-motor symptoms in PD based on the number of NMS as assessed by the NMS Questionnaire. METHODS In an observational, cross-sectional, international study of 383 consecutive patients distribution of the declared NMS as per NMSQuest was analyzed according to previously published levels based on the Non-Motor Symptoms Scale and also the median and interquartile range (IR, percentiles 25 and 75) of the total NMSQuest scores. After post hoc checking, these values were proposed as cut-off points for estimating NMS burden based only on the accumulation of symptoms. RESULTS Burden and number of NMS correlate closely (r ≥ 0.80). On the basis of this finding, five levels (0 = No NMS to 4 = Very severe) of NMSQuest grading were proposed after identification of their cut-offs by ordinal logistic regression and median and interquartile range distribution. These values coincided almost completely with those obtained by median and interquartile range in an independent sample. Concordance between this classification and HY staging was weak (weighted kappa = 0.30), but was substantial (weighted kappa = 0.68) with the Non-Motor Symptoms Scale grading. CONCLUSION Completion of NMSQuest and subsequent grading of the burden could allow the health care professional to approach the severity of NMS burden using the self completed NMSQuest in a primary care setting.

Impulse control disorders in Parkinson's disease: decreased striatal dopamine transporter levels

Objective Impulse control disorders are commonly associated with dopaminergic therapy in Parkinsons disease (PD). PD patients with impulse control disorders demonstrate enhanced dopamine release to conditioned cues and a gambling task on [11C]raclopride positron emission tomography (PET) imaging and enhanced ventral striatal activity to reward on functional MRI. We compared PD patients with impulse control disorders and age-matched and gender-matched controls without impulse control disorders using [123I]FP-CIT (2β-carbomethoxy-3β-(4-iodophenyl)tropane) single photon emission computed tomography (SPECT), to assess striatal dopamine transporter (DAT) density. Methods The [123I]FP-CIT binding data in the striatum were compared between 15 PD patients with and 15 without impulse control disorders using independent t tests. Results Those with impulse control disorders showed significantly lower DAT binding in the right striatum with a trend in the left (right: F(1,24)=5.93, p=0.02; left: F(1,24)=3.75, p=0.07) compared to controls. Conclusions Our findings suggest that greater dopaminergic striatal activity in PD patients with impulse control disorders may be partly related to decreased uptake and clearance of dopamine from the synaptic cleft. Whether these findings are related to state or trait effects is not known. These findings dovetail with reports of lower DAT levels secondary to the effects of methamphetamine and alcohol. Although any regulation of DAT by antiparkinsonian medication appears to be modest, PD patients with impulse control disorders may be differentially sensitive to regulatory mechanisms of DAT expression by dopaminergic medications.

Non-motor symptoms burden in treated and untreated early Parkinson's disease patients: argument for non-motor subtypes.

Non‐motor symptoms (NMSs) occurring at an early stage of Parkinsons disease (PD) may impair quality of life more than motor symptoms. This study aimed to evaluate the severity of overall NMS profile and burden of NMSs in early PD patients, treated (time since confirmed diagnosis of 5 years or less) or drug naive (DN).

A European multicentre survey of impulse control behaviours in Parkinson's disease patients treated with short‐ and long‐acting dopamine agonists

Impulse control disorders (ICDs) in Parkinsons disease (PD) are associated primarily with dopamine agonist (DA) use. Comparative surveys of clinical occurrence of impulse control behaviours on longer acting/transdermal DA therapy across age ranges are lacking. The aim of this study was to assess the occurrence of ICDs in PD patients across several European centres treated with short‐ or long‐acting [ropinirole (ROP); pramipexole (PPX)] and transdermal [rotigotine skin patch (RTG)] DAs, based on clinical survey as part of routine clinical care.

Characterizing motor and non-motor aspects of early-morning off periods in Parkinson's disease: An international multicenter study

INTRODUCTION The characteristic off periods that develop over time in subjects with Parkinsons disease (PD) on chronic levodopa therapy are usually considered to be motor complications but more recently the important contribution of non-motor off and non-motor fluctuations has also been acknowledged. Early-morning off (EMO) periods in PD patients are known to be a cause of significant disability, in addition to having a negative impact on quality of life. Yet EMOs are poorly defined, particularly in relation to non-motor symptoms (NMS). METHODS This European, multicentre, observational study was undertaken to characterize the range and patterns of NMS that occur during EMO periods in a consecutive series of PD patients. RESULTS The results demonstrate that EMO periods are common and occur in 59.7% of subjects across all disease stages in line with other reports. However, importantly, in 88.0% of those, EMOs were found to be associated with NMS. The predominant NMS associated with EMO were urinary urgency, anxiety, dribbling of saliva, pain, low mood, limb paresthesia and dizziness. The patterns of dopaminergic treatment being taken by patients in this study suggested that a prolonged-release or continuous drug delivery strategy can alleviate some NMS associated with EMO. CONCLUSIONS In light of these findings it is suggested that greater awareness, recognition and appropriate treatment of EMO and NMS could improve the overall 24-h management of PD. An EMO-specific scale/questionnaire which captures both motor and NMS associated with EMO over the off time period is warranted.

Night‐time sleep in Parkinson's disease – the potential use of Parkinson's KinetiGraph: a prospective comparative study

Night‐time sleep disturbances are important non‐motor symptoms and key determinants of health‐related quality of life (HRQoL) in patients with Parkinsons disease (PD). The Parkinsons KinetiGraph (PKG) can be used as an objective measure of different motor states and periods of immobility may reflect episodes of sleep. Our aim was to evaluate whether PKG can be used as an objective marker of disturbed night‐time sleep in PD.