Introduction
Discrete patterns of progression have been suggested for patients with Parkinson disease and presenting tremor dominant (TD) or postural instability gait disorders (PIGD). However, ...longitudinal prospective assessments need to take into consideration the variability in clinical manifestations and the evidence that only 40% of initially classified PIGD remain in this subtype at subsequent visits.
Methods
We analyzed clinical progression of PIGD compared to TD using longitudinal clinical data from the PPMI. Given the reported instability of such clinical classification, we only included patients who were reported as PIGD/TD at each visit during the 4-year observation. We used linear mixed-effects models to test differences in progression in these subgroups in 51 dependent variables.
Results
There were 254 patients with yearly assessment. The number of PIGD was 36/254 vs 144/254 TD. PIGD had more severe motor disease at baseline but progressed faster than TD only in three non-motor items of the MDS-UPDRS: cognitive impairment, hallucinations, and psychosis plus features of DDS. Our analysis also showed in PIGD faster increase in the average time with dyskinesia.
Conclusions
PIGD are characterized by more severe disease manifestations at diagnosis and greater cognitive progression, more frequent hallucinations, psychosis as well as features of DDS than TD patients. We interpret these findings as expression of greater cortical and subcortical involvement in PIGD already at onset. Since PIGD/TD classification is very unstable at onset, our analysis based on stricter definition criteria provides important insight for clinical trial stratification and definition of related outcome measures.
Summary Background Retroperitoneal and pleuropulmonary fibrosis are well known but rare complications of the treatment of Parkinson's disease with ergolinic dopamine agonists; however, until now, ...these complications have not substantially affected the routine clinical use of these drugs. The occurrence of restrictive valvular heart disease during treatment with pergolide and cabergoline caused concern about the safety of dopamine agonists in Parkinson's disease. Specifically, there is uncertainty whether fibrotic cardiac valvulopathy is due to exposure to these two ergolinic dopamine agonists or whether the abnormality is reversible. Changes in the heart valves can incur additional disability and worsen the clinical disorders of Parkinson's disease. Recent developments Population studies of patients with Parkinson's disease compared with non-parkinsonian controls have reported that pergolide and cabergoline have a similar risk of inducing fibrotic changes in cardiac valve leaflets. The fibrotic changes cause thickening, retraction, and stiffening of valves, which result in incomplete leaflet coaptation and clinically significant regurgitation, and have necessitated surgical valve replacement in some patients. Pergolide and cabergoline have high affinity for the 5-HT2B serotonin receptors, which are expressed in heart valves and might mediate mitogenesis and, in turn, the proliferation of fibroblasts. When analysed together, current population studies of similar designs and doses report 102 patients on cabergoline, 245 patients on pergolide, 181 patients on non-ergot agonists (pramipexole and ropinirole), and 177 non-parkinsonian controls. The frequency of moderate-to-severe regurgitation in at least one heart valve was higher in patients receiving cabergoline or pergolide than in patients taking non-ergot agonists or controls, and the incidence of new-onset valvulopathy was high in patients taking the ergot-derived drugs. Where next? Because of the routine prescription of pergolide and cabergoline, the switching of patients to different treatment regimens might be difficult. Moreover, whether the fibrotic changes are reversible is unknown. Finally, these adverse events do not occur in all patients, and no susceptibility factors are known. Prospective studies will assess the full effect of these abnormalities and help establish whether and when mitral valve tenting area abnormalities become clinically relevant during chronic treatment. The exact pathway leading to valvulopathy is unknown, although agonism of 5-HT2B receptors in the heart is implicated as a mediator in the process. Other ergolinic dopamine agonists, such as lisuride, and non-ergot dopamine agonists are devoid of 5-HT2B agonistic activity; therefore, their use might not induce fibrotic changes in heart valves. However, further prospective studies are needed. Such studies should also clarify the clinical relevance of mild-to-moderate echocardiographic changes and their natural history. Because of the clinical consequences of the adverse reactions, we suggest that affinity for 5-HT2B receptors is routinely tested in future drugs, in the laboratory or in animals, before they are given to patients.
Abstract Introduction Intermittent oral delivery of levodopa is a major contributing factor for motor complications in Parkinson's disease (PD). Continuous infusion of levodopa-carbidopa intestinal ...gel (LCIG) into the jejunum using a portable pump via percutaneous endoscopic gastrostomy (PEG) improves motor complications and quality of life (QoL). Objectives To record long-term effectiveness of advanced PD patients undergoing LCIG infusion in routine care, by Unified Parkinson's Disease Rating Scale (UPDRS), Non-Motor Symptoms Scale (NMSS), PDQ-8 and EQ-5D questionnaires. Methods Overall, 375 patients from 75 movement disorder centers in 18 countries were enrolled in this prospective non-interventional study. The 12-month interim outcomes of the first 172 included patients are presented here. Results There were reductions of mean daily “Off” time from baseline (BL) (7.1 ± 3.5 h) and “On” time with dyskinesias (5.2 ± 4.5 h) at month 12 (M12) of −4.7 ± 3.4 and −1.7 ± 5.0 h respectively (p < 0.0001; p = 0.0228). UPDRS II and III “On” scores decreased from BL to M12 (p = 0.0107 and p = 0.0128). Total NMSS and PDQ-8 scores improved at M12 (p = 0.0014 and p = 0.0100). Mean LCIG dose administered through PEG at first visit (day after implantation) was 1304 ± 618 mg/day and remained stable through M12. Continuous LCIG infusion tolerability and adverse drug reactions were consistent with the known safety profile of previous studies. Conclusions This observational, routine-care study supports long-term safety and efficacy of LCIG infusion in advanced PD including motor, non-motor and QoL improvements.
Impulse control disorders/other compulsive behaviours ('ICD behaviours') occur in Parkinson's disease (PD), but prospective studies are scarce, and prevalence and clinical characteristics of patients ...are insufficiently defined.
To assess the presence of ICD behaviours over a 2-year period, and evaluate patients' clinical characteristics.
A prospective, non-interventional, multicentre study (ICARUS (Impulse Control disorders And the association of neuRopsychiatric symptoms, cognition and qUality of life in ParkinSon disease); SP0990) in treated Italian PD outpatients. Study visits: baseline, year 1, year 2. Surrogate primary variable: presence of ICD behaviours and five ICD subtypes assessed by modified Minnesota Impulsive Disorder Interview (mMIDI).
1069/1095 (97.6%) patients comprised the Full Analysis Set. Point prevalence of ICD behaviours (mMIDI; primary analysis) was stable across visits: 28.6% (306/1069) at baseline, 29.3% (292/995) at year 1, 26.5% (245/925) at year 2. The most prevalent subtype was compulsive eating, followed by punding, compulsive sexual behaviour, gambling and buying disorder. Patients who were ICD positive at baseline were more likely to be male, younger, younger at PD onset, have longer disease duration, more severe non-motor symptoms (including mood and sexual function), depressive symptoms, sleep impairment and poorer PD-related quality of life. However, they did not differ from the ICD-negative patients in their severity of PD functional disability, motor performance and cognitive function.
Prevalence of ICD behaviours was relatively stable across the 2-year observational period. ICD-positive patients had more severe depression, poorer sleep quality and reduced quality of life.
Development of motor fluctuations and dyskinesia characterizes the transition from early to advanced Parkinson disease stage. Current therapeutic strategies to manage motor complications aim at ...increasing the number of levodopa administrations and extending its benefit by the association of enzyme blockers and dopamine agonists. However, as disease progresses, mobility becomes progressively dependent on levodopa absorption and its plasma bioavailability, resulting in loss of independence, worse quality of life and increased caregiver burden. If patients continue to experience off-time with functional impact on activities of daily living after best medication adjustments, implementation of infusion with apomorphine or levodopa, and surgical therapies should be considered. Presence of troublesome dyskinesia would also favor the choice of an advanced treatment. Compared with pulsatile oral therapy, both apomorphine and levodopa infusion determine more continuous striatal dopamine receptors stimulation than oral levodopa resulting in significant reduction of off-time and dyskinesia, particularly peak-dose, although not in their complete resolution. This observation proves that abnormal synaptic plasticity and connectivity changes cannot be reversed once they are established. Early implementation of these therapeutic strategies ideally would target patients as soon as motor complications begin rather than at late stage of advanced Parkinson’s disease (PD) before dyskinesia have manifested. Preliminary evidence from early deep brain stimulation in patients with short disease duration and modest motor complications suggests that this approach can positively impact quality of life. It is conceivable that changing our PD treatment algorithm and implementing device-aided therapies at the beginning of the advanced phase before dyskinesia has established, will provide more stable motor conditions and longer functional autonomy.
Background: Lack of a global consensus on the definition of advanced Parkinson's disease (APD) and considerations for timing of device-aided therapies may result in heterogeneity in care.
Objectives: ...To reach consensus among movement disorder specialists regarding key patient characteristics indicating transition to APD and guiding appropriate use of device-aided therapies in the management of PD symptoms.
Methods: A Delphi-panel approach was utilized to synthesize opinions of movement disorder specialists and build consensus.
Results: A panel was comprised of movement disorder specialists from 10 European countries with extensive experience of treating PD patients (mean =24.8 ± 7.2 years). Consensus on indicators of suspected APD and eligibility for device-aided therapies were based on motor symptoms, non-motor symptoms, and functional impairments. Key indicators of APD included: (i) motor-moderate troublesome motor fluctuations, ≥1 h of troublesome dyskinesia/day, ≥2 h "off" symptoms/day, and ≥5-times oral levodopa doses/day; (ii) non-motor-mild dementia, and non-transitory troublesome hallucinations; (iii) functional impairment-repeated falls despite optimal treatment, and difficulty with activities of daily living. Patients with good levodopa response, good cognition, and <70 years of age were deemed as good candidates for all three device-aided therapies. Patients with troublesome dyskinesia were considered good candidates for both levodopa-carbidopa intestinal gel and Deep Brain Stimulation (DBS). PD patients with levodopa-resistant tremor were considered good candidates for DBS.
Conclusion: Identifying patients progressing to APD and suitable for device-aided therapies will enable general neurologists to assess the need for referral to movement disorder specialists and improve the quality of care and patient outcomes.
A cohort of patients with Parkinson's disease treated with either ergot-derived or non–ergot-derived dopamine agonists underwent echocardiographic evaluation. As compared with a group of normal ...control subjects, patients taking pergolide or cabergoline had a higher frequency of clinically important valve regurgitation and more evidence of stiffening and displacement of the mitral leaflet, as measured by the tenting area of the mitral valve.
Patients with Parkinson's disease taking pergolide or cabergoline had a higher frequency of clinically important valve regurgitation and more evidence of stiffening and displacement of the mitral leaflet than controls.
Several studies and case reports strongly support a causal relationship between the occurrence of drug-induced “restrictive” valvular heart disease and treatment with pergolide, an ergot-derived dopamine receptor agonist mainly used to treat Parkinson's disease.
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More specifically, pergolide may induce fibrotic changes in valve leaflets and in the mitral subvalvular apparatus, causing thickening, retraction, and stiffening of valves and resulting in incomplete leaflet coaptation and valve regurgitation.
Valvular heart damage has also been reported with the ergot-derived dopamine agonists bromocriptine and cabergoline.
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This is important, since cabergoline is widely prescribed in many countries for Parkinson's disease and, at low . . .
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