Deep Brain Stimulation in Patients With Mutations in Parkinson's Disease-Related Genes: A Systematic Review.
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ABSTRACT: Background
Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD), and careful selection of candidates is a key component of successful therapy. Although it is recognized that factors such as age, disease duration, and levodopa responsiveness can influence outcomes, it is unclear whether genetic background should also serve as a parameter.Objectives
The aim of this systematic review is to explore studies that have evaluated DBS in patients with mutations in PD-related genes.Methods
We performed a selective literature search for articles regarding the effects of DBS in autosomal dominant or recessive forms of PD or in PD patients with genetic risk factors. Data regarding changes in motor and nonmotor scores and the presence of adverse events after the stimulation were collected.Results
A total of 25 studies were included in the systematic review, comprising 135 patients. In the shorter term, most patients showed marked or satisfactory response to subthalamic DBS, although leucine rich repeat kinase 2 carriers of R114G mutations had higher rates of unsatisfactory outcome. Longer term follow-up data were scarce but suggested that motor benefit is sustained. Patients with the glucosidase beta acid (GBA) mutation showed higher rates of cognitive decline after surgery. Motor outcome was scarce for pallidal DBS. Few adverse events were reported.Conclusions
Subthalamic DBS results in positive outcomes in the short term in patients with Parkin, GBA, and leucine-rich repeat kinase 2 (non-R144G) mutations, although the small sample size limits the interpretation of our findings. Longer and larger cohorts of follow-up, with broader nonmotor symptom evaluations will be necessary to better customize DBS therapy in this population.
SUBMITTER: de Oliveira LM
PROVIDER: S-EPMC6592794 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD) patients with motor fluctuations and dyskinesias. The key DBS efficacy studies were performed in PD patients with unknown genotypes; however, given the estimated monogenic mutation prevalence of approximately 5-10%, most commonly LRRK2, PRKN, PINK1 and SNCA, and risk-increasing genetic factors such as GBA, proper characterization is becoming increasingly relevant. We performed a systematic review of 46 studies that reported DBS effects in 221 genetic PD patients. The results suggest that monogenic PD patients have variable DBS benefit depending on the mutated gene. Outcome appears excellent in patients with the most common LRRK2 mutation, p.G2019S, and good in patients with PRKN mutations but poor in patients with the more rare LRRK2 p.R1441G mutation. The overall benefit of DBS in SNCA, GBA and LRRK2 p.T2031S mutations may be compromised due to rapid progression of cognitive and neuropsychiatric symptoms. In the presence of other mutations, the motor changes in DBS-treated monogenic PD patients appear comparable to those of the general PD population.
| S-EPMC7109183 | biostudies-literature
Project description:IntroductionParkinson's disease (PD) patients have a significantly higher risk of developing dementia in later disease stages, leading to severe impairments in quality of life and self-functioning. Questions remain on how deep brain stimulation (DBS) affects cognition, and whether we can individualize therapy and reduce the risk for adverse cognitive effects. Our aim in this systematic review is to assess the current knowledge in the field and determine if the findings could influence clinical practice.MethodsWe have conducted a systematic review according to PRISMA guidelines through MEDLINE and Embase databases, with studies being selected for inclusion via a set inclusion and exclusion criteria.ResultsSixty-seven studies were included in this systematic review according to the selected criteria. This includes 6 meta-analyses, 18 randomized controlled trials, 17 controlled clinical trials, and 26 observational studies with no control arms. The total number of PD patients encompassed in the studies cited in this review is 3677, not including the meta-analyses.ConclusionCognitive function in PD patients can deteriorate, in most cases mildly, but still impactful to the quality of life. The strongest evidence is present for deterioration in verbal fluency, while inconclusive evidence is still present for executive function, memory, attention and processing speed. Global cognition does not appear to be significantly impacted by DBS, especially if cognitive screening is performed prior to the procedure, as lower baseline cognitive function is connected to poor outcomes. Further randomized controlled studies are required to increase the level of evidence, especially in the case of globus pallidus internus DBS, pedunculopontine nucleus DBS, and the ventral intermediate nucleus of thalamus DBS, and more long-term studies are required for all respective targets.
| S-EPMC9135964 | biostudies-literature
Project description:OBJECTIVE:To review and synthesise qualitative research studies that have explored patients' experience of deep brain stimulation (DBS) in advanced Parkinson's disease (PD). DESIGN:Systematic review and meta-synthesis of 7 original papers, using metaethnography. SETTING:Studies conducted in Denmark, France and Sweden. PARTICIPANTS:116 patients who had undergone DBS and 9 spouses of patients. RESULTS:Prior to surgery, the experience of advancing PD is one of considerable loss and a feeling of loss of control. There are significant hopes for what DBS can bring. Following surgery, a sense of euphoria is described by many, although this does not persist and there is a need for significant transitions following this. We suggest that normality as a concept is core to the experience of DBS and that a sense of control may be a key condition for normality. Experience of DBS for patients and spouses, and of the transitions that they must undertake, is influenced by their hopes of what surgery will enable them to achieve, or regain (ie, a new normality). CONCLUSIONS:There is a need for further qualitative research to understand the nature of these transitions to inform how best patients and their spouses can be supported by healthcare professionals before, during and after DBS. In assessing the outcomes of DBS and other treatments in advanced PD, we should consider how to capture holistic concepts such as normality and control. Studies that examine the outcomes of DBS require longer term follow-up.
| S-EPMC4932278 | biostudies-other
Project description:BackgroundThe up-to-date literature systematically reviewing the predictive value of preoperative levodopa responsiveness after deep brain stimulation (DBS) surgery in motor outcomes in Parkinson's disease (PD) is lacking.ObjectiveTo address this issue in patients with PD undergoing bilateral subthalamic nucleus (STN) or globus pallidus interna (GPi) DBS.MethodsWe used the existing PRISMA consensus statement. A comprehensive review of literature from 1993 to May 2021 retrieved from PubMed was conducted.ResultsThe STN-DBS responsiveness was significantly correlated with the preoperative levodopa responsiveness for the total score of UPDRS-III at both 6- and 12-month follow-ups (P < 0.001). Such correlations were significant after controlling for age at time of surgery and disease duration. The significance of correlation disappeared for longer follow-up times. For the sub-scores of UPDRS-III, a significant correlation between the preoperative levodopa responsiveness and STN DBS responsiveness was observed for rigidity, bradykinesia, and axial symptoms, but not for tremor (P = 0.002, 0.010, 0.007, and 0.542, respectively). The preoperative levodopa responsiveness was significantly correlated with GPi DBS responsiveness for the UPDRS-III total score at a median follow-up of 12 months (P = 0.030).ConclusionThe current study confirmed the value of preoperative levodopa responsiveness for prediction of the short-term motor outcome after DBS (for both STN and GPi). The predictive value of levodopa responsiveness in short-term outcomes for respective cardinal motor disabilities and the loss of its predictive value after STN DBS for long-term motor outcomes were highlighted by this study.
| S-EPMC8810442 | biostudies-literature
Project description:Deep brain stimulation (DBS) is considered a safe and well tolerated surgical procedure to alleviate Parkinson's disease (PD) and other movement disorders symptoms along with some psychiatric conditions. Over the last few decades DBS has been shown to provide remarkable therapeutic effect on carefully selected patients. Although its precise mechanism of action is still unknown, DBS improves motor functions and therefore quality of life. To date, two main targets have emerged in PD patients: the globus pallidus pars interna and the subthalamic nucleus. Two other targets, the ventralis intermedius and zona incerta have also been selectively used, especially in tremor-dominant PD patients. The main indications for PD DBS have traditionally been motor fluctuations, debilitating medication induced dyskinesias, unpredictable "off time" state, and medication refractory tremor. Medication refractory tremor and intolerable dyskinesia are potential palliative indications. Besides aforementioned targets, the brainstem pedunculopontine nucleus (PPN) is under investigation for the treatment of ON-state freezing of gait and postural instability. In this article, we will review the most recent literature on DBS therapy for PD, including cutting-edge advances and data supporting the role of DBS in advanced neural-network modulation.
| S-EPMC4529685 | biostudies-literature
Project description:Introduction Subthalamic Deep Brain Stimulation (STN-DBS) is a safe and well-established therapy for the management of motor symptoms refractory to best medical treatment in patients with Parkinson's disease (PD). Early intervention is discussed especially for Early-onset PD (EOPD) patients that present with an age of onset ≤ 45–50 years and see themselves often confronted with high psychosocial demands. Methods We retrospectively assessed the effect of STN-DBS at 12 months follow-up (12-MFU) in 46 EOPD-patients. Effects of stimulation were evaluated by comparison of disease-specific scores for motor and non-motor symptoms including impulsiveness, apathy, mood, quality of life (QoL), cognition before surgery and in the stimulation ON-state without medication. Further, change in levodopa equivalent dosage (LEDD) after surgery, DBS parameter, lead localization, adverse and serious adverse events as well as and possible additional clinical features were assessed. Results PD-associated gene mutations were found in 15% of our EOPD-cohort. At 12-MFU, mean motor scores had improved by 52.4 ± 17.6% in the STIM-ON/MED-OFF state compared to the MED-OFF state at baseline (p = 0.00; n = 42). These improvements were accompanied by a significant 59% LEDD reduction (p < 0.001), a significant 6.6 ± 16.1 points reduction of impulsivity (p = 0.02; n = 35) and a significant 30 ± 50% improvement of QoL (p = 0.01). At 12-MFU, 9 patients still worked full- and 6 part-time. Additionally documented motor and/or neuropsychiatric features decreased from n = 41 at baseline to n = 14 at 12-MFU. Conclusion The present study-results demonstrate that EOPD patients with and without known genetic background benefit from STN-DBS with significant improvement in motor as well as non-motor symptoms. In line with this, patients experienced a meaningful reduction of additional neuropsychiatric features. Physicians as well as patients have an utmost interest in possible predictors for the putative DBS outcome in a cohort with such a highly complex clinical profile. Longitudinal monitoring of DBS-EOPD-patients over long-term intervals with standardized comprehensive clinical assessment, accurate phenotypic characterization and documentation of clinical outcomes might help to gain insights into disease etiology, to contextualize genomic information and to identify predictors of optimal DBS candidates as well as those in danger of deterioration and/or non-response in the future.
| S-EPMC9713840 | biostudies-literature
Project description:BackgroundPrevious studies investigated the risk of suicide in patients with Parkinson's disease (PD) but reported discrepant results. Deep brain stimulation (DBS) is an effective therapy for PD, while its effect on suicide risk has seldom been researched. This meta-analysis aimed to estimate the risk of suicide and/or suicidal ideation in PD patients and in PD patients who underwent DBS.MethodsRelevant articles published in the PubMed or EMBASE or CNKI database from 1990 to December 2019 were sourced, and the combined standardized mortality rate (SMR) or odds ratio (OR) was pooled.ResultA total of 1070 articles were found. After screening, 4 cross-sectional studies, 4 cohort studies, 2 randomized controlled trial studies, and 2 case-control studies were included in this meta-analysis. Pooled data indicated that PD patients may have increased risk of suicide (lnSMR, 0.459; 95% confidence interval (CI), 0.286 to 0.632; p < 0.001). No significant difference was found in the risk of suicide when comparing PD patients who underwent DBS with PD patients who received only drug therapy (OR = 2.844, 95%CI: 0.619 to 13.072, p=0.179). DBS may increase the risk of suicide and/or suicidal ideation in PD patients compared with general population (lnSMR = 3.383, 95%CI: 2.839 to 3.927, p < 0.001).ConclusionPD patients have higher risk of suicide and/or suicidal ideation compared with controls, while PD patients who received DBS tend to have an increased risk of suicide or suicidal ideation. Psychological evaluation is needed in PD patients, and pre- and post-operation evaluations are necessary for PD patients who underwent DBS.
| S-EPMC7537696 | biostudies-literature
Project description:Previous studies have shown less access to deep brain stimulation (DBS) for Parkinson's disease (PD) in women compared to men raising concerns about a potential gender gap resulting from nonclinical factors or gender differences in clinical efficacy for postoperative quality of life (QoL), motor, and nonmotor symptoms (NMS) outcomes. This was a cross-sectional and a longitudinal, prospective, observational, controlled, quasi-experimental, international multicenter study. A total sample size of 505 consisted of 316 consecutively referred patients for DBS indication evaluation at the University Hospital Cologne (01/2015-09/2020) and 189 consecutively treated patients at DBS centers in the University Hospitals Cologne and Marburg, Salford's Royal Hospital Manchester, and King's College Hospital London. In the cross-sectional cohort, we examined gender proportions at referral, indication evaluations, and DBS surgery. In the longitudinal cohort, clinical assessments at preoperative baseline and 6-month follow-up after surgery included the PD Questionnaire-8, NMSScale, Scales for Outcomes in PD-motor scale, and levodopa-equivalent daily dose. Propensity score matching resulted in a pseudo-randomized sub-cohort balancing baseline demographic and clinical characteristics between women with PD and male controls. 316 patients were referred for DBS. 219 indication evaluations were positive (women n = 102, respectively n = 82). Women with PD were disproportionally underrepresented in referrals compared to the general PD population (relative risk [RR], 0.72; 95%CI, 0.56-0.91; P = 0.002), but more likely to be approved for DBS than men (RR, 1.17; 95%CI, 1.03-1.34; P = 0.029). Nonetheless, their total relative risk of undergoing DBS treatment was 0.74 (95%CI, 0.48-1.12) compared to men with PD. At baseline, women had longer disease duration and worse dyskinesia. Exploring QoL domains, women reported worse mobility and bodily discomfort. At follow-up, all main outcomes improved equally in both genders. Our study provides evidence of a gender gap in DBS for PD. Women and men with PD have distinct preoperative nonmotor and motor profiles. We advocate that more focus should be directed toward the implementation of gender equity as both genders benefit from DBS with equal clinical efficacy. This study provides Class II evidence of beneficial effects of DBS in women with PD compared to male controls.
| S-EPMC9021281 | biostudies-literature
Project description:BackgroundThe use of alternate frequencies, amplitudes, and pulse widths to manage motor symptoms in Parkinson's disease (PD) patients with subthalamic nucleus deep brain stimulation (STN-DBS) is of clinical interest, but currently lacks systematic evidence.Objective/hypothesisSystematically review whether alternate STN-DBS settings influence the therapy's efficacy for managing PD motor symptoms.MethodsSystematic searches identified studies that; involved bilateral STN-DBS PD patients; manipulated???1 STN-DBS parameter (e.g., amplitude); assessed???1 motor symptom (e.g., tremor); and contrasted the experimental and chronic stimulation settings. A Mantel-Haenszel random-effects meta-analysis compared the UPDRS-III sub-scores at low (60-Hz) and high frequencies (???130?Hz). Inter-study heterogeneity was assessed with the Cohen's ?2 and I2 index, while the standard GRADE evidence assessment examined strength of evidence.ResultsOf the 21 included studies, 17 investigated the effect of alternate stimulation frequencies, five examined alternate stimulation amplitudes, and two studied changes in pulse width. Given the available data, meta-analyses were only possible for alternate stimulation frequencies. Analysis of the heterogeneity amongst the included studies indicated significant variability between studies and, on the basis of the GRADE framework, the pooled evidence from the meta-analysis studies was of very low quality due to the significant risks of bias.ConclusionsThe meta-analysis reported a very low quality of evidence for the efficacy of low-frequency STN-DBS for managing PD motor symptoms. Furthermore, it highlighted that lower amplitudes lead to the re-emergence of motor symptoms and further research is needed to understand the potential benefits of alternate STN-DBS parameters for PD patients.
| S-EPMC6335519 | biostudies-literature
Project description:IntroductionThe globus pallidus internus (GPi) region has evolved as a potential target for deep brain stimulation (DBS) in Parkinson's disease (PD). DBS of the GPi (GPi DBS) is an established, safe and effective method for addressing many of the motor symptoms associated with advanced PD. It is important that clinicians fully understand this target when considering GPi DBS for individual patients.MethodsThe literature on GPi DBS in PD has been comprehensively reviewed, including the anatomy, physiology and potential pitfalls that may be encountered during surgical targeting and post-operative management. Here, we review and address the implications of lead location on GPi DBS outcomes. Additionally, we provide a summary of randomized controlled clinical trials conducted on DBS in PD, together with expert commentary on potential applications of the GPi as target. Finally, we highlight future technologies that will likely impact GPi DBS, including closed-loop adaptive approaches (e.g. sensing-stimulating capabilities), advanced methods for image-based targeting and advances in DBS programming, including directional leads and pulse shaping.ResultsThere are important disease characteristics and factors to consider prior to selecting the GPi as the DBS target of PD surgery. Prior to and during implantation of the leads it is critical to consider the neuroanatomy, which can be defined through the combination of image-based targeting and intraoperative microelectrode recording strategies. There is an increasing body of literature on GPi DBS in patients with PD suggesting both short- and long-term benefits. Understanding the GPi target can be useful in choosing between the subthalamic (STN), GPi and ventralis intermedius nucleus as lead locations to address the motor symptoms and complications of PD.ConclusionGPi DBS can be effectively used in select cases of PD. As the ongoing DBS target debate continues (GPi vs. STN as DBS target), clinicians should keep in mind that GPi DBS has been shown to be an effective treatment strategy for a variety of symptoms, including bradykinesia, rigidity and tremor control. GPi DBS also has an important, direct anti-dyskinetic effect. GPi DBS is easier to program in the outpatient setting and will allow for more flexibility in medication adjustments (e.g. levodopa). Emerging technologies, including GPi closed-loop systems, advanced tractography-based targeting and enhanced programming strategies, will likely be future areas of GPi DBS expansion. We conclude that although the GPi as DBS target may not be appropriate for all PD patients, it has specific clinical advantages.
| S-EPMC8140010 | biostudies-literature