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.
- Advances in DBS Technology and Novel Applications: Focus on Movement Disorders(2022) POTEL, Sina R.; MARCEGLIA, Sara; MEONI, Sara; KALIA, Suneil K.; CURY, Rubens G.; MORO, ElenaPurpose of Review Deep brain stimulation (DBS) is an established treatment in several movement disorders, including Parkinson's disease, dystonia, tremor, and Tourette syndrome. In this review, we will review and discuss the most recent findings including but not limited to clinical evidence. Recent Findings New DBS technologies include novel hardware design (electrodes, cables, implanted pulse generators) enabling new stimulation patterns and adaptive DBS which delivers potential stimulation tailored to moment-to-moment changes in the patient's condition. Better understanding of movement disorders pathophysiology and functional anatomy has been pivotal for studying the effects of DBS on the mesencephalic locomotor region, the nucleus basalis of Meynert, the substantia nigra, and the spinal cord. Eventually, neurosurgical practice has improved with more accurate target visualization or combined targeting. A rising research domain emphasizes bridging neuromodulation and neuroprotection. Recent advances in DBS therapy bring more possibilities to effectively treat people with movement disorders. Future research would focus on improving adaptive DBS, leading more clinical trials on novel targets, and exploring neuromodulation effects on neuroprotection.
- 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).
- Recent Advances in the Treatment of Genetic Forms of Parkinson's Disease: Hype or Hope?(2023) CAVALLIERI, Francesco; CURY, Rubens G.; GUIMARAES, Thiago; FIORAVANTI, Valentina; GRISANTI, Sara; ROSSI, Jessica; MONFRINI, Edoardo; ZEDDE, Marialuisa; FONZO, Alessio Di; VALZANIA, Franco; MORO, ElenaParkinson's disease (PD) is a multifarious neurodegenerative disease. Its pathology is characterized by a prominent early death of dopaminergic neurons in the pars compacta of the substantia nigra and the presence of Lewy bodies with aggregated alpha-synuclein. Although the alpha-synuclein pathological aggregation and propagation, induced by several factors, is considered one of the most relevant hypotheses, PD pathogenesis is still a matter of debate. Indeed, environmental factors and genetic predisposition play an important role in PD. Mutations associated with a high risk for PD, usually called monogenic PD, underlie 5% to 10% of all PD cases. However, this percentage tends to increase over time because of the continuous identification of new genes associated with PD. The identification of genetic variants that can cause or increase the risk of PD has also given researchers the possibility to explore new personalized therapies. In this narrative review, we discuss the recent advances in the treatment of genetic forms of PD, focusing on different pathophysiologic aspects and ongoing clinical trials.
- 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.
- Editorial: Advances in Invasive and Non-invasive Brain Stimulation in Parkinson's Disease: From Basic Science to New Technologies(2022) ROCHA, Maria Sheila Guimaraes; AQUINO, Camila Catherine; PICILLO, Marina; CURY, Rubens Gisbert; GODINHO, Fabio