Pleuropulmonary Toxicity of Another Anti-Parkinson’s Drug: Cabergoline

Many drugs may cause toxic injury to the lungs and the pleura. Cabergoline is an ergoline derivative which has been used in Spain for seven years to control symptoms of Parkinson’s disease. We report a patient with dyspnea, bilateral pleural effusion and distal swelling. After a series of complementary tests (blood analysis, chest CT, echocardiogram, pleural tap, pleural biopsy), etiological screening ruled out infection, malignancy or inflammation. Given the patient’s history of three years’ treatment with cabergoline, the drug was considered a possible cause and was progressively withdrawn. The patient’s clinical condition improved and radiological images were disease-free. Using Karch and Lasagna’s classical criteria, we defined a relationship of “probable causality” between the drug and the adverse effects reported

Noves formes farmacèutiques i vies d'administració de levodopa per al tractament de la malaltia de Parkinson : nou anys d'experiència en infusió intraduodenal de gel de levodopa/carbidopa /

Malgrat que la malaltia de Parkinson (MP) fou descrita fa 200 anys, només fa 50 anys de l'aplicació clínica exitosa de la levodopa pel seu tractament simptomàtic. La seva biodisponibilitat i les fluctuacions dels nivells plasmàtics però, es relacionen en part amb les complicacions motores i no motores de la MP, i motiva la investigació d'altres formes i vies d'administració, com la intestinal. Es revisen les observacions clíniques, sèries de casos, estudis comparatius, retrospectius, prospectius, controlats, aleatoritzats i un assaig clínic doble cec que demostren que l'administració de gel intestinal de levodopa/carbidopa (GILC) redueix les fluctuacions motores. L'objectiu de l'estudi és descriure una llarga experiència de 9 anys en el maneig del tractament amb GILC per a la MP que respon a levodopa amb fluctuacions motores intenses malgrat el tractament convencional optimitzat. Amb un estudi prospectiu, obert, observacional, de 116 mesos de durada, de la pràctica clínica habitual, examinant aspectes clínics motors i no motors a l'inici, al mes, als tres, sis, dotze mesos, i anualment de tractament. També es recullen els efectes adversos (EA) i les mesures adoptades per resoldre'ls i les causes de retirada del tractament. Es realitzen quatre subestudis prospectius: 1- de cognició i conducta, en subgrup de 5 pacients amb una bateria de tests neuropsicològics a l'inici i als tres-sis mesos. 2: de qualitat del son en 5 pacients amb bateria de tests subjectius i polisomnografia a l'inici i als tres-sis mesos i 3: de l'estat de salut, qualitat de vida i la càrrega del cuidador en 9 pacients a l'inici a la setmana,3, 6 i 12 mesos amb qüestionaris de qualitat de vida la càrrega de cuidador. S'inclogueren 37 pacients (22 homes/15 dones), amb una mitjana de 6,03 + 1,42 hores diàries en Off , que van seguir el tractament amb GILC una mitjana de 40,86 + 31,26 mesos (rang 1 a 116mesos). Amb el tractament tots experimenten milloria de les fluctuacions motores, reduint de 4,87 + 1,08 hores Off el dia als 3 mesos, de 4,91 + 1,12 al cap d'1 any, de 4,90 + 1,20 al cap de cinc anys i de 6,25 + 0,35 als 9 anys en dos pacients. Les discinèsies es redueixen en duració però els canvis en la gravetat no són estadísticament significatius. A mitjà termini milloren els estadis motors i activitats de vida diària, varien poc la resta d'aspectes motors, millora l'activitat mental, conducta i ànim, no s'agreugen els trastorns neuropsiquiàtrics i milloren els trastorns de control d'impulsos. Presenten un alt nombre de EA que generalment són ben controlats. En els subestudis no hi ha deterior neuropsicològic amb el tractament i milloren funcions atencionals, de fluència semàntica i de control motor voluntari. La qualitat del son, que és dolenta basalment, no s'agreuja, tampoc es modifica. Malgrat l'alt nombre de complicacions la qualitat de vida millora significativament el 26% en test emprat, sense agreujament, ans reduint la càrrega del seu cuidador. Amb aquest estudi, el més llarg prospectiu, concloem que el tractament amb GILC és ben tolerat i segur, millora eficaç i sostingudament les fluctuacions motores en la pràctica clínica habitual, millora o no agreuja altres trastorns motors, cognitius i de la son, i millora la qualitat de vida i la càrrega del cuidador.Even Parkinson's disease (PD) was first described 200 years ago, it's been only 50 years of successful clinical use of levodopa for its symptomatic treatment. Levodopa bioavailability and fluctuations in plasma levels however, are related in part to motor and non-motor complications of PD and encourages research of other forms and routes of administration, such as the intestinal delivery. Clinical observations, case series, comparative, retrospective, prospective, controlled, randomized and double-blind clinical trials that demonstrate that administration of levodopa / carbidopa intestinal gel (LCIG) reduces the motor fluctuations are reviewed. However LCIG is a complex and expensive treatment, long-term management and the effects on cognition and behaviour, sleep and the impact in patient's quality of life and caregiver burden are not well stablished. The aim of the study is to describe a long experience of nine years in the management of treatment with LCIG for PD responding to levodopa with severe motor fluctuations despite optimal conventional therapy. In a prospective, open, observational study of 116 months of clinical practice, PD motor an non-motor clinical aspects were collected, UPDRS scale and patient diaries were used to evaluate the motor condition, previously, at the beginning LCIG treatment, at three and six months, and annually until nine years of follow up. Adverse events (AE) were collected as well as the corresponding action taken to solve them, the causes of treatment withdrawal were also collected. Four prospective sub-studies were performed: 1 of cognition and behavior: in a subgroup of 5 patients evaluated with a specific battery of neuropsychological tests at baseline and at three-six months. 2 of quality of sleep: in a subgroup of 5 patients evaluated with Epworth scale, fatigue scale, Pittsburg quality of sleep questionnaire, Beck depression scale, and Hamilton anxiety scale, and overnight polysomnography study at baseline and at three-six months and 3 of health status, quality of life and caregiver burden: in 9 patients evaluated with quality of life questionnaire in PD (PDQ-39), health status questionnaires (EQ-5D and EQ-VAS), global clinical impression scale (CGI) and caregiver burden questionnaire (Zarit Burden index) at the start of LCIG, first week, 3, 6 and 12 months of treatment. Thirty seven patients were included (22M/15F) with a mean of 6.03 + 1.42 hours a day in Off state, they followed ILCG treatment an average of 40.86 + 31.26 months (range 1 to 116). All patients experienced improvement in motor fluctuations, reducing 4.87 + 1.08 hours a day in Off state at 3 months, 4.91 + 1.12 after 1 year, 4.90 + 1 20 after five years and 6.25 + 0.35 to 9 years of treatment in two patients. Dyskinesias were reduced in duration but changes in severity of disability were not statistically significant. H&Y stages and S&E activities of daily living scale improved at mid term, with little variation of other motor aspects. Mental activity, behavior and mood improved, most of neuropsychiatric disorders were not exacerbated and impulse control disorders improved. Patients under LCIG had a high number of AE which were usually well controlled. In sub-studies no neuropsychological impairment was found with treatment and attentional functions, semantic fluency and voluntary motor control improved. The quality of sleep, which was bad at baseline, did not worse, either modified. Despite the high number of complications, quality of life significantly improved 26% of PDQ39 without worsening, but reducing the caregiver burden. Our experience with this study, the largest prospective, confirms that treatment with ILCG is well tolerated and safe, effective and sustained for improving motor fluctuations of PD in routine clinical practice, improves or not worsens other motor aspects, cognitive and sleep, and improves quality of life and caregiver burden, where the correct management requires the organization of a multidisciplinary team

Sleep Disorders in Parkinsonian and Nonparkinsonian LRRK2 Mutation Carriers

Objective: In idiopathic Parkinson disease (IPD) sleep disorders are common and may antedate the onset of parkinsonism. Based on the clinical similarities between IPD and Parkinson disease associated with LRRK2 gene mutations (LRRK2-PD), we aimed to characterize sleep in parkinsonian and nonmanifesting LRRK2 mutation carriers (NMC). Methods: A comprehensive interview conducted by sleep specialists, validated sleep scales and questionnaires, and video-polysomnography followed by multiple sleep latency test (MSLT) assessed sleep in 18 LRRK2-PD (17 carrying G2019S and one R1441G mutations), 17 NMC (11 G2019S, three R1441G, three R1441C), 14 non-manifesting non-carriers (NMNC) and 19 unrelated IPD. Results: Sleep complaints were frequent in LRRK2-PD patients; 78% reported poor sleep quality, 33% sleep onset insomnia, 56% sleep fragmentation and 39% early awakening. Sleep onset insomnia correlated with depressive symptoms and poor sleep quality. In LRRK2-PD, excessive daytime sleepiness (EDS) was a complaint in 33% patients and short sleep latencies on the MSLT, which are indicative of objective EDS, were found in 71%. Sleep attacks occurred in three LRRK2-PD patients and a narcoleptic phenotype was not observed. REM sleep behavior disorder (RBD) was diagnosed in three LRRK2-PD. EDS and RBD were always reported to start after the onset of parkinsonism in LRRK2-PD. In NMC, EDS was rarely reported and RBD was absent. When compared to IPD, sleep onset insomnia was more significantly frequent, EDS was similar, and RBD was less significantly frequent and less severe in LRRK2-PD. In NMC, RBD was not detected and sleep complaints were much less frequent than in LRRK2-PD. No differences were observed in sleep between NMC and NMNC. Conclusions: Sleep complaints are frequent in LRRK2-PDand show a pattern that when compared to IPD is characterized by more frequent sleep onset insomnia, similar EDS and less prominent RBD. Unlike in IPD, RBD and EDS seem to be not markers of the prodromal stage of LRRK2-PD

Clinical and structural brain correlates of hypomimia in early-stage Parkinson's disease

Altres ajuts: acord transformatiu CRUE-CSICBackground and purpose: Reduced facial expression of emotions is a very frequent symptom of Parkinson's disease (PD) and has been considered part of the motor features of the disease. However, the neural correlates of hypomimia and the relationship between hypomimia and other non-motor symptoms of PD are poorly understood. Methods: The clinical and structural brain correlates of hypomimia were studied. For this purpose, cross-sectional data from the COPPADIS study database were used. Age, disease duration, levodopa equivalent daily dose, Unified Parkinson's Disease Rating Scale part III (UPDRS-III), severity of apathy and depression and global cognitive status were collected. At the imaging level, analyses based on gray matter volume and cortical thickness were used. Results: After controlling for multiple confounding variables such as age or disease duration, the severity of hypomimia was shown to be indissociable from the UPDRS-III speech and bradykinesia items and was significantly related to the severity of apathy (β = 0.595; p < 0.0001). At the level of neural correlates, hypomimia was related to motor regions brodmann area 8 (BA 8) and to multiple fronto-temporo-parietal regions involved in the decoding, recognition and production of facial expression of emotions. Conclusion: Reduced facial expressivity in PD is related to the severity of symptoms of apathy and is mediated by the dysfunction of brain systems involved in motor control and in the recognition, integration and expression of emotions. Therefore, hypomimia in PD may be conceptualized not exclusively as a motor symptom but as a consequence of a multidimensional deficit leading to a symptom where motor and non-motor aspects converge

Identifying comorbidities and lifestyle factors contributing to the cognitive profile of early Parkinson's disease

Background: Identifying modifiable risk factors for cognitive impairment in the early stages of Parkinson's disease (PD) and estimating their impact on cognitive status may help prevent dementia (PDD) and the design of cognitive trials. Methods: Using a standard approach for the assessment of global cognition in PD and controlling for the effects of age, education and disease duration, we explored the associations between cognitive status, comorbidities, metabolic variables and lifestyle variables in 533 PD participants from the COPPADIS study. Results: Among the overall sample, 21% of participants were classified as PD-MCI (n = 114) and 4% as PDD (n = 26). The prevalence of hypertension, diabetes and dyslipidemia was significantly higher in cognitively impaired patients while no between-group differences were found for smoking, alcohol intake or use of supplementary vitamins. Better cognitive scores were significantly associated with regular physical exercise (p < 0.05) and cognitive stimulation (< 0.01). Cognitive performance was negatively associated with interleukin 2 (Il2) (p < 0.05), Il6 (p < 0.05), iron (p < 0.05), and homocysteine (p < 0.005) levels, and positively associated with vitamin B12 levels (p < 0.005). Conclusions: We extend previous findings regarding the positive and negative influence of various comorbidities and lifestyle factors on cognitive status in early PD patients, and reinforce the need to identify and treat potentially modifiable variables with the intention of exploring the possible improvement of the global cognitive status of patients with PD

Staging Parkinson's Disease Combining Motor and Nonmotor Symptoms Correlates with Disability and Quality of Life.

Introduction: In a degenerative disorder such as Parkinson's disease (PD), it is important to establish clinical stages that allow to know the course of the disease. Our aim was to analyze whether a scale combining Hoehn and Yahr's motor stage (H&Y) and the nonmotor symptoms burden (NMSB) (assessed by the nonmotor symptoms scale (NMSS)) provides information about the disability and the patient's quality of life (QoL) with regard to a defined clinical stage. Materials and methods: Cross-sectional study in which 603 PD patients from the COPPADIS cohort were classified according to H&Y (1, stage I; 2, stage II; 3, stage III; 4, stage IV/V) and NMSB (A: NMSS = 0-20; B: NMSS = 21-40; C: NMSS = 41-70; D: NMSS ≥ 71) in 16 stages (HY.NMSB, from 1A to 4D). QoL was assessed with the PDQ-39SI, PQ-10, and EUROHIS-QOL8 and disability with the Schwab&England ADL (Activities of Daily Living) scale. Results: A worse QoL and greater disability were observed at a higher stage of H&Y and NMSB (p < 0.0001). Combining both (HY.NMSB), patients in stages 1C and 1D and 2C and 2D had significantly worse QoL and/or less autonomy for ADL than those in stages 2A and 2B and 3A and 3B, respectively (p < 0.005; e.g., PDQ-39SI in 1D [n = 15] vs 2A [n = 101]: 28.6 ± 17.1 vs 7.9 ± 5.8; p < 0.0001). Conclusion: The HY.NMSB scale is simple and reflects the degree of patient involvement more accurately than the HΨ Patients with a lower H&Y stage may be more affected if they have a greater NMS burden

Diplopia Is Frequent and Associated with Motor and Non-Motor Severity in Parkinson’s Disease: Results from the COPPADIS Cohort at 2-Year Follow-Up

Malaltia de Parkinson; Fenotip; TremolorEnfermedad de Parkinson; Fenotipo; TemblorParkinson’s disease; Phenotype; TremorBackground and objective: Diplopia is relatively common in Parkinson’s disease (PD) but is still understudied. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it. Patients and Methods: PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort were included in this longitudinal prospective study. The patients and controls were classified as “with diplopia” or “without diplopia” according to item 15 of the Non-Motor Symptoms Scale (NMSS) at V0, V1 (1-year ± 15 days), and V2 for the patients and at V0 and V2 for the controls. Results: The frequency of diplopia in the PD patients was 13.6% (94/691) at V0 (1.9% in controls [4/206]; p < 0.0001), 14.2% (86/604) at V1, and 17.1% (86/502) at V2 (0.8% in controls [1/124]; p < 0.0001), with a period prevalence of 24.9% (120/481). Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269–4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012–1.024; p = 0.015), and a greater increase from V0 to V2 on the Unified Parkinson’s Disease Rating Scale–III (OR = 1.039; 95%CI, 1.023–1.083; p < 0.0001) and Neuropsychiatric Inventory (OR = 1.028; 95%CI, 1.001–1.057; p = 0.049) scores were independent factors associated with diplopia (R2 = 0.25; Hosmer and Lemeshow test, p = 0.716). Conclusions: Diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity.Solano Vila B. has received honoraria for educational presentations and advice service by UCB, Zambon, Teva, Abbvie, Bia

Diplopia is frequent and associated with motor and non-motor severity in parkinson's disease : Results from the COPPADIS cohort at 2-year follow-up

Background and objective: Diplopia is relatively common in Parkinson's disease (PD) but is still understudied. Our aim was to analyze the frequency of diplopia in PD patients from a multicenter Spanish cohort, to compare the frequency with a control group, and to identify factors associated with it. Patients and Methods: PD patients who were recruited from January 2016 to November 2017 (baseline visit; V0) and evaluated again at a 2-year ± 30 days follow-up (V2) from 35 centers of Spain from the COPPADIS cohort were included in this longitudinal prospective study. The patients and controls were classified as "with diplopia" or "without diplopia" according to item 15 of the Non-Motor Symptoms Scale (NMSS) at V0, V1 (1-year ± 15 days), and V2 for the patients and at V0 and V2 for the controls. Results: The frequency of diplopia in the PD patients was 13.6% (94/691) at V0 (1.9% in controls [4/206]; p < 0.0001), 14.2% (86/604) at V1, and 17.1% (86/502) at V2 (0.8% in controls [1/124]; p < 0.0001), with a period prevalence of 24.9% (120/481). Visual hallucinations at any visit from V0 to V2 (OR = 2.264; 95%CI, 1.269-4.039; p = 0.006), a higher score on the NMSS at V0 (OR = 1.009; 95%CI, 1.012-1.024; p = 0.015), and a greater increase from V0 to V2 on the Unified Parkinson's Disease Rating Scale-III (OR = 1.039; 95%CI, 1.023-1.083; p < 0.0001) and Neuropsychiatric Inventory (OR = 1.028; 95%CI, 1.001-1.057; p = 0.049) scores were independent factors associated with diplopia (R = 0.25; Hosmer and Lemeshow test, p = 0.716). Conclusions: Diplopia represents a frequent symptom in PD patients and is associated with motor and non-motor severity