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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- Guidelines for Parkinson's disease treatment consensus from the Movement Disorders Scientific Department of the Brazilian Academy of Neurology- motor symptoms(2022) SABA, Roberta Arb; MAIA, Debora Palma; CARDOSO, Francisco Eduardo Costa; BORGES, Vanderci; ANDRADE, Luiz Augusto F.; FERRAZ, Henrique Ballalai; BARBOSA, Egberto Reis; RIEDER, Carlos Roberto de Mello; SILVA, Delson Jose da; CHIEN, Hsin Fen; CAPATO, Tamine; ROSSO, Ana Lucia; LIMA, Carlos Frederico Souza; BEZERRA, Jose Marcelo Ferreia; NICARETTA, Denise; BARSOTTINI, Orlando Graziani Povoas; GODEIRO-JUNIOR, Clecio; BARCELOS, Lorena Broseghini; CURY, Rubens Gisbert; SPITZ, Mariana; SILVA, Sonia Maria Cesar Azevedo; COLLETTA, Marcus Vinicius DellaThe treatment of Parkinson's disease (PD) is challenging, especially since it is considered highly individualized. The Brazilian Academy of Neurology has recognized the need to disseminate knowledge about the management of PD treatment, adapting the best evidence to the Brazilian reality. Thus, the main published treatment guidelines were reviewed based on the recommendations of group from the Movement Disorders Scientific Department of the Brazilian Academy of Neurology.
- Should the Globus Pallidus Targeting Be Refined in Dystonia?(2022) LAPA, Jorge Dornellys da Silva; GODINHO, Fabio Luiz Franceschi; TEIXEIRA, Manoel Jacobsen; LISTIK, Clarice; IGLESIO, Ricardo Ferrareto; DUARTE, Kleber Paiva; CURY, Rubens GisbertBackground and Study Aims Deep brain stimulation (DBS) of the globus pallidus internus (GPi) is a highly effective therapy for primary generalized and focal dystonias, but therapeutic success is compromised by a nonresponder rate of up to 20%. Variability in electrode placement and in tissue stimulated inside the GPi may explain in part different outcomes among patients. Refinement of the target within the pallidal area could be helpful for surgery planning and clinical outcomes. The objective of this study was to discuss current and potential methodological (somatotopy, neuroimaging, and neurophysiology) aspects that might assist neurosurgical targeting of the GPi, aiming to treat generalized or focal dystonia. Methods We selected published studies by searching electronic databases and scanning the reference lists for articles that examined the anatomical and electrophysiologic aspects of the GPi in patients with idiopathic/inherited dystonia who underwent functional neurosurgical procedures. Results The sensorimotor sector of the GPi was the best target to treat dystonic symptoms, and was localized at its lateral posteroventral portion. The effective volume of tissue activated (VTA) to treat dystonia had a mean volume of 153mm (3) in the posterior GPi area. Initial tractography studies evaluated the close relation between the electrode localization and pallidothalamic tract to control dystonic symptoms. Regarding the somatotopy, the more ventral, lateral, and posterior areas of the GPi are associated with orofacial and cervical representation. In contrast, the more dorsal, medial, and anterior areas are associated with the lower limbs; between those areas, there is the representation of the upper limb. Excessive pallidal synchronization has a peak at the theta band of 3 to 8Hz, which might be responsible for generating dystonic symptoms. Conclusions Somatotopy assessment of posteroventral GPi contributes to target-specific GPi sectors related to segmental body symptoms. Tractography delineates GPi output pathways that might guide electrode implants, and electrophysiology might assist in pointing out areas of excessive theta synchronization. Finally, the identification of oscillatory electrophysiologic features that correlate with symptoms might enable closed-loop approaches in the future.
- 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.
- 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.
- Controversies and Clinical Applications of Non-Invasive Transspinal Magnetic Stimulation: A Critical Review and Exploratory Trial in Hereditary Spastic Paraplegia(2022) CARRA, Rafael Bernhart; SILVA, Guilherme Diogo; PARAGUAY, Isabela Bruzzi Bezerra; LIMA, Fabricio Diniz de; MENEZES, Janaina Reis; PINEDA, Aruane Mello; NUNES, Glaucia Aline; SIMOES, Juliana da Silva; JR, Marcondes Cavalcante Franca; CURY, Rubens GisbertMagnetic stimulation is a safe, non-invasive diagnostic tool and promising treatment strategy for neurological and psychiatric disorders. Although most studies address transcranial magnetic stimulation, transspinal magnetic stimulation (TsMS) has received recent attention since trials involving invasive spinal cord stimulation showed encouraging results for pain, spasticity, and Parkinson's disease. While the effects of TsMS on spinal roots is well understood, its mechanism of action on the spinal cord is still controversial. Despite unclear mechanisms of action, clinical benefits of TsMS have been reported, including improvements in scales of spasticity, hyperreflexia, and bladder and bowel symptoms, and even supraspinal gait disorders such as freezing and camptocormia. In the present study, a critical review on the application of TsMS in neurology was conducted, along with an exploratory trial involving TsMS in three patients with hereditary spastic paraplegia. The goal was to understand the mechanism of action of TsMS through H-reflex measurement at the unstimulated lumbosacral level. Although limited by studies with a small sample size and a low to moderate effect size, TsMS is safe and tolerable and presents consistent clinical and neurophysiological benefits that support its use in clinical practice.
- Deep brain stimulation in Parkinson's disease: state of the art and future perspectives(2022) FRANCA, Carina; CARRA, Rafael Bernhart; DINIZ, Juliete Melo; MUNHOZ, Renato Puppi; CURY, Rubens GisbertFor more than 30 years, Deep Brain Stimulation (DBS) has been a therapeutic option for Parkinson's disease (PD) treatment. However, this therapy is still underutilized mainly due to misinformation regarding risks and clinical outcomes. DBS can ameliorate several motor and non-motor symptoms, improving patients' quality of life. Furthermore, most of the improvement after DBS is long-lasting and present even in advanced PD. Adequate patient selection, precise electric leads placement, and correct DBS programming are paramount for good surgical outcomes. Nonetheless, DBS still has many limitations: axial symptoms and signs, such as speech, balance and gait, do not improve to the same extent as appendicular symptoms and can even be worsened as a direct or indirect consequence of surgery and stimulation. In addition, there are still unanswered questions regarding patient's selection, surgical planning and programming techniques, such as the role of surgicogenomics, more precise imaging-based lead placement, new brain targets, advanced programming strategies and hardware features. The net effect of these innovations should not only be to refine the beneficial effect we currently observe on selected symptoms and signs but also to improve treatment resistant facets of PD, such as axial and non-motor features. In this review, we discuss the current state of the art regarding DBS selection, implant, and programming, and explore new advances in the DBS field.
- 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.
- Teaching Video NeuroImage: Peculiar Hobby Horse Gait in Huntington Disease-like 2(2022) GUIMARAES, Thiago G.; PARMERA, Jacy Bezerra; BARBOSA, Egberto Reis; HADDAD, Monica S.; CURY, Rubens Gisbert
- Safety and Outcomes of Dentate Nucleus Deep Brain Stimulation for Cerebellar Ataxia(2022) CURY, Rubens Gisbert; FRANCA, Carina; DUARTE, Kleber Paiva; PARAGUAY, Isabela; DINIZ, Juliete Melo; CUNHA, Paulina; GALHARDONI, Ricardo; SILVA, Valquiria; IGLESIO, Ricardo; BISSOLI, Andre Bortolon; LEPSKI, Guilherme; BARBOSA, Egberto Reis; TEIXEIRA, Manoel Jacobsen; ANDRADE, Daniel Ciampi deCerebellar symptoms remain orphan of treatment options despite being prevalent and incapacitating. Investigate whether dentate nucleus deep brain stimulation (DN DBS) is safe and leads to improvements in cerebellar symptoms when compared to sham stimulation. This randomized double-blind crossover pilot trial enrolled five patients with spinocerebellar ataxia type 3 or post-lesion ataxia. Active or sham phases were randomly performed three months apart. The primary outcome was ataxia improvement as measured by the Scale for the Assessment and Rating of Ataxia (SARA) after the active compared to the sham period. Secondary outcome measures included safety and tolerability, the Fahn-Tolosa-Marin Tremor Rating Scale (FTMRS), quality of life measurements, and patients' global impression of change. The effects on ataxia were numerically better in four out of five patients after active versus sham stimulation. The composite SARA score did not change after comparing active to sham stimulation (8.6 +/- 3.6 versus 10.1 +/- 4.1; p = 0.223). The FTMRS showed significant improvement after active stimulation versus sham (18.0 +/- 17.2 versus 22.2 +/- 19.5; p = 0.039) as did patients' global impression of change (p = 0.038). The quality of life was not modified by stimulation (p = 0.337). DN DBS was well tolerated without serious adverse events. One patient had the electrode repositioned. DN DBS is a safe and well tolerated procedure that is effective in alleviating cerebellar tremor. In this small cohort of ataxic patients, DN DBS did not achieve statistical significance for ataxia improvement.
- 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.