RUBENS GISBERT CURY
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/62 - Laboratório de Fisiopatologia Cirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/62 - Laboratório de Fisiopatologia Cirúrgica, Hospital das Clínicas, Faculdade de Medicina
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- Non-motor effects of deep brain stimulation in Parkinson?s disease motor subtypes(2023) JOST, Stefanie T.; KONITSIOTI, Agni; LOEHRER, Philipp A.; ASHKAN, Keyoumars; RIZOS, Alexandra; SAUERBIER, Anna; GHILARDI, Maria Gabriela dos Santos; ROSENKRANZ, Franz; STROBEL, Lena; GRONOSTAY, Alexandra; BARBE, Michael T.; EVANS, Julian; VISSER-VANDEWALLE, Veerle; NIMSKY, Christopher; FINK, Gereon R.; SILVERDALE, Monty; CURY, Rubens G.; FONOFF, Erich T.; ANTONINI, Angelo; CHAUDHURI, K. Ray; TIMMERMANN, Lars; MARTINEZ-MARTIN, Pablo; DAFSARI, Haidar S.Introduction: Deep brain stimulation (DBS) is a well-established treatment for patients with Parkinson's disease (PD) improving quality of life, motor, and non-motor symptoms. However, non-motor effects in PD subtypes are understudied. We hypothesized that patients with 'postural instability and gait difficulty' (PIGD) experience more beneficial non-motor effects than 'tremor-dominant' patients undergoing DBS for PD.Methods: In this prospective, observational, international multicentre study with a 6-month follow-up, we assessed the Non-Motor Symptom Scale (NMSS) as primary and the following secondary outcomes: Unified PD Rating Scale-motor examination (UPDRS-III), Scales for Outcomes in PD (SCOPA)-activities of daily living (ADL) and-motor complications, PDQuestionnaire-8 (PDQ-8), and levodopa-equivalent daily dose (LEDD). We analysed within-group longitudinal changes with Wilcoxon signed-rank test and Benjamini-Hochberg correction for multiple comparisons. Additionally, we explored outcome between-group differences of motor subtypes with Mann-Whitney U-tests.Results: In 82 PIGD and 33 tremor-dominant patients included in this study, baseline NMSS total scores were worse in PIGD patients, both groups experienced postoperative improvements of the NMSS sleep/fatigue domain, and between-group differences in postoperative outcomes were favourable in the PIGD group for the NMSS total and miscellaneous domain scores.Conclusions: This study provides evidence of a favourable outcome of total non-motor burden in PIGD compared to tremor-dominant patients undergoing DBS for PD. These differences of clinical efficacy on non-motor aspects should be considered when advising and monitoring patients with PD undergoing DBS.
- The Parkinson disease pain classification system: results from an international mechanism-based classification approach(2021) MYLIUS, Veit; LLORET, Santiago Perez; CURY, Rubens G.; TEIXEIRA, Manoel J.; BARBOSA, Victor R.; BARBOSA, Egberto R.; I, Larissa Moreira; LISTIK, Clarice; FERNANDES, Ana M.; VEIGA, Diogo de Lacerda; BARBOUR, Julio; HOLLENSTEIN, Nathalie; OECHSNER, Matthias; WALCH, Julia; BRUGGER, Florian; HAGELE-LINK, Stefan; BEER, Serafin; RIZOS, Alexandra; CHAUDHURI, Kallol Ray; BOUHASSIRA, Didier; LEFAUCHEUR, Jean-Pascal; TIMMERMANN, Lars; GONZENBACH, Roman; KAGI, Georg; MOELLER, Jens Carsten; ANDRADE, Daniel Ciampi dePain is a common nonmotor symptom in patients with Parkinson disease (PD) but the correct diagnosis of the respective cause remains difficult because suitable tools are lacking, so far. We developed a framework to differentiate PD- from non-PD-related pain and classify PD-related pain into 3 groups based on validated mechanistic pain descriptors (nociceptive, neuropathic, or nociplastic), which encompass all the previously described PD pain types. Severity of PD-related pain syndromes was scored by ratings of intensity, frequency, and interference with daily living activities. The PD-Pain Classification System (PD-PCS) was compared with classic pain measures (ie, brief pain inventory and McGill pain questionnaire [MPQ], PDQ-8 quality of life score, MDS-UPDRS scores, and nonmotor symptoms). 159 nondemented PD patients (disease duration 10.2 +/- 7.6 years) and 37 healthy controls were recruited in 4 centers. PD-related pain was present in 122 patients (77%), with 24 (15%) suffering one or more syndromes at the same time. PD-related nociceptive, neuropathic, or nociplastic pain was diagnosed in 87 (55%), 25 (16%), or 35 (22%), respectively. Pain unrelated to PD was present in 35 (22%) patients. Overall, PD-PCS severity score significantly correlated with pain's Brief Pain Inventory and MPQ ratings, presence of dyskinesia and motor fluctuations, PDQ-8 scores, depression, and anxiety measures. Moderate intrarater and interrater reliability was observed. The PD-PCS is a valid and reliable tool for differentiating PD-related pain from PD-unrelated pain. It detects and scores mechanistic pain subtypes in a pragmatic and treatment-oriented approach, unifying previous classifications of PD-pain.
- Gaps and roadmap of novel neuromodulation targets for treatment of gait in Parkinson's disease(2022) CURY, Rubens Gisbert; PAVESE, Nicola; KRAUSS, Joachim K.; MORO, ElenaGait issues in Parkinson's disease (PD) are common and can be highly disabling. Although levodopa and deep brain stimulation (DBS) of the subthalamic nucleus and the globus pallidus internus have been established therapies for addressing the motor symptoms of PD, their effects on gait are less predictable and not well sustained with disease progression. Given the high prevalence of gait impairment in PD and the limitations in currently approved therapies, there has been considerable interest in alternative neuromodulation targets and techniques. These have included DBS of pedunculopontine nucleus and substantia nigra pars reticulata, spinal cord stimulation, non-invasive modulation of cortical regions and, more recently, vagus nerve stimulation. However, successes and failures have also emerged with these approaches. Current gaps and controversies are related to patient selection, optimal electrode placement within the target, placebo effects and the optimal programming parameters. Additionally, recent advances in pathophysiology of oscillation dynamics have driven new models of closed-loop DBS systems that may or may not be applicable to gait issues. Our aim is to describe approaches, especially neuromodulation procedures, and emerging challenges to address PD gait issues beyond subthalamic nucleus and the globus pallidus internus stimulation.
- Pain in Parkinson's Disease: Current Concepts and a New Diagnostic Algorithm(2015) MYLIUS, Veit; ANDRADE, Daniel Ciampi de; CURY, Rubens Gisbert; TEEPKER, Michael; EHRT, Uwe; EGGERT, Karla Maria; BEER, Serafin; KESSELRING, Juerg; STAMELOU, Maria; OERTEL, Wolfgang H.; MOELLER, Jens Carsten; LEFAUCHEUR, Jean-PascalBackground: Pain is a significant burden for patients with Parkinson's disease (PD) with a high impact on quality of life. The present article aims at summarizing epidemiological, pathophysiological, clinical, and neurophysiological data regarding pain in PD. Methods: In this domain, a procedure of systematic assessment is still lacking for the syndromic diagnosis and should take into account pain characteristics, effects of dopaminergic treatment, motor fluctuations, and non-PD-associated pain. Findings: We propose an original questionnaire addressing an algorithm suitable for daily clinical practice. The questionnaire is based on a three-step approach addressing first the relationship between pain and PD (including temporal relationship with the course of the disease, association with motor fluctuations, and impact of antiparkinsonian treatment), before classifying pain into one of three main syndromes (i.e., musculoskeletal pain, psychomotor restlessness pain, and neuropathic pain). Conclusions: The proposed questionnaire allows the characteristics of each pain type to be determined according to its relationship with the disease and its treatment. The validation of the clinical use of this questionnaire will be the goal of a forthcoming work.
- Application of machine learning and complex network measures to an EEG dataset from ayahuasca experiments(2022) ALVES, Caroline L.; CURY, Rubens Gisbert; ROSTER, Kirstin; PINEDA, Aruane M.; RODRIGUES, Francisco A.; THIELEMANN, Christiane; CIBA, ManuelAyahuasca is a blend of Amazonian plants that has been used for traditional medicine by the inhabitants of this region for hundreds of years. Furthermore, this plant has been demonstrated to be a viable therapy for a variety of neurological and mental diseases. EEG experiments have found specific brain regions that changed significantly due to ayahuasca. Here, we used an EEG dataset to investigate the ability to automatically detect changes in brain activity using machine learning and complex networks. Machine learning was applied at three different levels of data abstraction: (A) the raw EEG time series, (B) the correlation of the EEG time series, and (C) the complex network measures calculated from (B). Further, at the abstraction level of (C), we developed new measures of complex networks relating to community detection. As a result, the machine learning method was able to automatically detect changes in brain activity, with case (B) showing the highest accuracy (92%), followed by (A) (88%) and (C) (83%), indicating that connectivity changes between brain regions are more important for the detection of ayahuasca. The most activated areas were the frontal and temporal lobe, which is consistent with the literature. F3 and PO4 were the most important brain connections, a significant new discovery for psychedelic literature. This connection may point to a cognitive process akin to face recognition in individuals during ayahuasca-mediated visual hallucinations. Furthermore, closeness centrality and assortativity were the most important complex network measures. These two measures are also associated with diseases such as Alzheimer's disease, indicating a possible therapeutic mechanism. Moreover, the new measures were crucial to the predictive model and suggested larger brain communities associated with the use of ayahuasca. This suggests that the dissemination of information in functional brain networks is slower when this drug is present. Overall, our methodology was able to automatically detect changes in brain activity during ayahuasca consumption and interpret how these psychedelics alter brain networks, as well as provide insights into their mechanisms of action.
- Beneficial nonmotor effects of subthalamic and pallidal neurostimulation in Parkinson's disease(2020) DAFSARI, Haidar S.; GHILARDI, Maria Gabriela dos Santos; VISSER-VANDEWALLE, Veerle; RIZOS, Alexandra; ASHKAN, Keyoumars; SILVERDALE, Monty; EVANS, Julian; MARTINEZ, Raquel C. R.; CURY, Rubens G.; JOST, Stefanie T.; BARBE, Michael T.; FINK, Gereon R.; ANTONINI, Angelo; RAY-CHAUDHURI, K.; MARTINEZ-MARTIN, Pablo; FONOFF, Erich Talamoni; TIMMERMANN, LarsBackground: Subthalamic (STN) and pallidal (GPi) deep brain stimulation (DBS) improve quality of life, motor, and nonmotor symptoms (NMS) in advanced Parkinson's disease (PD). However, few studies have compared their nonmotor effects. Objective: To compare nonmotor effects of STN-DBS and GPi-DBS. Methods: In this prospective, observational, multicenter study including 60 PD patients undergoing bilateral STN-DBS (n = 40) or GPi-DBS (n = 20), we examined PDQuestionnaire (PDQ), NMSScale (NMSS), Unified PD Rating Scale-activities of daily living, -motor impairment, -complications (UPDRS-II, -III, -IV), Hoehn&Yahr, Schwab&England Scale, and levodopa-equivalent daily dose (LEDD) preoperatively and at 6-month follow-up. Intra-group changes at follow-up were analyzed with Wilcoxon signed-rank or paired t-test, if parametric tests were applicable, and corrected for multiple comparisons. Inter-group differences were explored with Mann-Whitney-U/unpaired t-tests. Analyses were performed before and after propensity score matching which balanced out demographic and preoperative clinical characteristics. Strength of clinical changes was assessed with effect size. Results: In both groups, PDQ UPDRS-II, -IV, Schwab&England Scale, and NMSS improved significantly at follow-up. STN-DBS was significantly better for LEDD reduction, GPi-DBS for UPDRS-IV. While NMSS total score outcomes were similar, explorative NMSS domain analyses revealed distinct profiles: Both targets improved sleep/fatigue and mood/cognition, but only STN-DBS the miscellaneous (pain/olfaction) and attention/memory and only GPi-DBS cardiovascular and sexual function domains. Conclusions: To our knowledge, this is the first study to report distinct patterns of beneficial nonmotor effects of STN-DBS and GPi-DBS in PD. This study highlights the importance of NMS assessments to tailor DBS target choices to patients' individual motor and nonmotor profiles. (C) 2020 The Author(s).
- Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial(2022) SCHILSKY, Michael L.; CZLONKOWSKA, Anna; ZUIN, Massimo; CASSIMAN, David; TWARDOWSCHY, Carlos; POUJOIS, Aurelia; GONDIM, Francisco De Assis A.; DENK, Gerald; CURY, Rubens G.; OTT, Peter; MOORE, Joanna; ALA, Aftab; D'INCA, Renata; COUCHONNAL-BEDOYA, Eduardo; D'HOLLANDER, Koenraad; DUBOIS, Nicolas; KAMLIN, C. Omar F.; WEISS, Karl HeinzBackground Wilson disease is an inherited disorder of copper transport. Whereas penicillamine is used therapeutically to re-establish copper balance, trientine is indicated for patients with penicillamine intolerance. We aimed to compare penicillamine with trientine tetrahydrochloride (TETA4) for maintenance therapy in patients with Wilson disease. Methods We conducted a randomised, open-label, non-inferiority, phase 3 trial at 15 health-care centres across nine countries (patients were recruited from 13 of these health-care centres across Brazil, Europe, and the USA). We enrolled patients aged 18-75 years with stable Wilson disease who were treated for at least 1 year with penicillamine. Patients entered a 12-week period to determine stability through clinical assessment by site investigators and predefined thresholds for serum non-caeruloplasmin-bound copper (NCC; by an exchangeable copper assay; 25-150 mu g/L), 24 h urinary copper excretion (100-900 mu g/24 h), and alanine aminotransferase (ALT; <2 x upper limit of normal). Stable patients were randomly assigned (1:1) to continue receiving the maintenance twice daily dose of oral penicillamine or switched mg-for-mg to oral TETA4 centrally with a web-based system using minimisation. The primary endpoint, assessed 24 weeks after randomisation, was NCC by speciation assay. The non-inferiority margin of mean difference in NCC by speciation assay was -50 mu g/L, as estimated by a general linear model for repeated visits, adjusted for baseline values. Further data on safety and efficacy were collected during a 24-week extension period. Data were analysed using an intention-to-treat approach. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT03539952 (active, not recruiting). Findings Between June 4, 2018, and March 10, 2020, 77 patients were screened. 53 patients were randomly assigned (27 to the penicillamine group and 26 to the TETA4 group). After 24 weeks, the mean difference in serum NCC by speciation assay between the penicillamine group and TETA4 group was -9.1 mu g/L (95% CI -24.2 to 6.1), with the lower limit of the 95% CI within the defined non-inferiority margin. At 24 weeks, urinary copper excretion was lower with TETA4 than with penicillamine (mean difference 237.5 mu g/24 h (99% CI 115.6 to 359.4). At 48 weeks, TETA4 remained non-inferior to penicillamine in terms of NCC by speciation assay (mean difference NCC -15.5 mu g/L [95% CI -34.5 to 3.6]). Urinary copper excretion at 48 weeks remained in the expected range for well treated patients in both study groups, and the mean difference (124.8 mu g/24 h [99% CI -37.6 to 287.1]) was not significantly different. At 24 weeks and 48 weeks, masked clinical adjudication of stability assessed by three independent clinicians confirmed clinical stability (100%) of all participants, in agreement with the stability seen with the NCC by speciation assay. There were no notable changes in either the Clinical Global Impression of Change or Unified Wilson Disease Rating Scale (neurological assessment) from baseline (pre-randomisation) at weeks 24 and 48. The mean change in serum total copper from baseline to 24 weeks was 17.6 mu g/L (99% CI -9.5 to 44.7) with penicillamine and -6.3 mu g/L (-34.7 to 22.1) with TETA4, and the mean change in serum total caeruloplasmin from baseline to 24 weeks was 1.8 mg/L (-19.2 to 22.8) with penicillamine and -2.2 mg/L (-6.1 to 1.7) with TETA4. All liver enzymes were similar at 24 weeks and 48 weeks, with the exception of elevated ALT concentration at 48 weeks for patients in the TETA4 group. Penicillamine was associated with three post-randomisation serious adverse events (leukopenia, cholangiocarcinoma, and hepatocellular cancer); none were reported for TETA4. The most common treatment-emergent adverse events were headache for penicillamine (five [19%] of 27 patients vs two [8%] of 26) and abdominal pain for TETA4 (one [4%] vs four [15%]); all treatment-emergent adverse events resolved and were mild to moderate. One patient developed a rash with TETA4 that resolved on discontinuation of therapy. Interpretation The efficacy of TETA4 as oral maintenance therapy was non-inferior to penicillamine and well tolerated in adults with Wilson disease.
- The Therapeutic Potential of Non-Invasive and Invasive Cerebellar Stimulation Techniques in Hereditary Ataxias(2023) BENUSSI, Alberto; BATSIKADZE, Giorgi; FRANCA, Carina; CURY, Rubens G.; MAAS, Roderick P. P. W. M.The degenerative ataxias comprise a heterogeneous group of inherited and acquired disorders that are characterized by a progressive cerebellar syndrome, frequently in combination with one or more extracerebellar signs. Specific disease-modifying interventions are currently not available for many of these rare conditions, which underscores the necessity of finding effective symptomatic therapies. During the past five to ten years, an increasing number of randomized controlled trials have been conducted examining the potential of different non-invasive brain stimulation techniques to induce symptomatic improvement. In addition, a few smaller studies have explored deep brain stimulation (DBS) of the dentate nucleus as an invasive means to directly modulate cerebellar output, thereby aiming to alleviate ataxia severity. In this paper, we comprehensively review the clinical and neurophysiological effects of transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and dentate nucleus DBS in patients with hereditary ataxias, as well as the presumed underlying mechanisms at the cellular and network level and perspectives for future research.
- Development and Validation of the Dystonia-Pain Classification System: A Multicenter Study(2023) LISTIK, Clarice; LISTIK, Eduardo; ROLIM, Flavia de Paiva Santos; PORTELA, Denise Maria Meneses Cury; LLORET, Santiago Perez; ARAUJO, Natalia Rebeca de Alves; CARVALHO, Pedro Rubens Araujo; SANTOS, Graziele Costa; LIMONGI, Joao Carlos Papaterra; CARDOSO, Francisco; MYLIUS, Veit; BRUGGER, Florian; FERNANDES, Ana Mercia; BARBOSA, Egberto Reis; TEIXEIRA, Manoel Jacobsen; FERRAZ, Henrique Ballalai; CAMARGOS, Sarah Teixeira; CURY, Rubens Gisbert; ANDRADE, Daniel de Ciampi deBackgroundDystonia is associated with disabling nonmotor symptoms like chronic pain (CP), which is prevalent in dystonia and significantly impacts the quality of life (QoL). There is no validated tool for assessing CP in dystonia, which substantially hampers pain management. ObjectiveThe aim was to develop a CP classification and scoring system for dystonia. MethodsA multidisciplinary group was established to develop the Dystonia-Pain Classification System (Dystonia-PCS). The classification of CP as related or unrelated to dystonia was followed by the assessment of pain severity score, encompassing pain intensity, frequency, and impact on daily living. Then, consecutive patients with inherited/idiopathic dystonia of different spatial distribution were recruited in a cross-sectional multicenter validation study. Dystonia-PCS was compared to validated pain, mood, QoL, and dystonia scales (Brief Pain Inventory, Douleur Neuropathique-4 questionnaire, European QoL-5 Dimensions-3 Level Version, and Burke-Fahn-Marsden Dystonia Rating Scale). ResultsCP was present in 81 of 123 recruited patients, being directly related to dystonia in 82.7%, aggravated by dystonia in 8.8%, and nonrelated to dystonia in 7.5%. Dystonia-PCS had excellent intra-rater (Intraclass Correlation Coefficient - ICC: 0.941) and inter-rater (ICC: 0.867) reliability. In addition, pain severity score correlated with European QoL-5 Dimensions-3 Level Version's pain subscore (r = 0.635, P < 0.001) and the Brief Pain Inventory's severity and interference scores (r = 0.553, P < 0.001 and r = 0.609, P < 0.001, respectively). ConclusionsDystonia-PCS is a reliable tool to categorize and quantify CP impact in dystonia and will help improve clinical trial design and management of CP in patients affected by this disorder. (c) 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
- Pain in Parkinson disease: mechanistic substrates, main classification systems, and how to make sense out of them(2023) ANDRADE, Daniel Ciampi de; MYLIUS, Veit; PEREZ-LLORET, Santiago; CURY, Rubens G.; BANNISTER, Kirsty; MOISSET, Xavier; KUBOTA, Gabriel Taricani; FINNERUP, Nanna B.; BOUHASSIRA, Didier; CHAUDHURI, Kallol Ray; GRAVEN-NIELSEN, Thomas; TREEDE, Rolf-DetlefParkinson disease (PD) affects up to 2% of the general population older than 65 years and is a major cause of functional loss. Chronic pain is a common nonmotor symptom that affects up to 80% of patients with (Pw) PD both in prodromal phases and during the subsequent stages of the disease, negatively affecting patient's quality of life and function. Pain in PwPD is rather heterogeneous and may occur because of different mechanisms. Targeting motor symptoms by dopamine replacement or with neuromodulatory approaches may only partially control PD-related pain. Pain in general has been classified in PwPD according to the motor signs, pain dimensions, or pain subtypes. Recently, a new classification framework focusing on chronic pain was introduced to group different types of PD pains according to mechanistic descriptors: nociceptive, neuropathic, or neither nociceptive nor neuropathic. This is also in line with the International Classification of Disease-11, which acknowledges the possibility of chronic secondary musculoskeletal or nociceptive pain due to disease of the CNS. In this narrative review and opinion article, a group of basic and clinical scientists revise the mechanism of pain in PD and the challenges faced when classifying it as a stepping stone to discuss an integrative view of the current classification approaches and how clinical practice can be influenced by them. Knowledge gaps to be tackled by coming classification and therapeutic efforts are presented, as well as a potential framework to address them in a patient-oriented manner.