Efficacy of deep brain stimulation of the subthalamic nucleus versus globus pallidus internus on sensory complaints.

Pain control after deep brain stimulation (DBS) in Parkinson's disease (PD) remains unclear. Following six months, subthalamic (STN)-DBS reduced sensory complaints related to parkinsonism and bodily discomfort, increasing central beta-endorphin level. Pallidal GPi-DBS decreased bodily discomfort and beta-endorphin levels. Unexplained pain by other conditions and bodily discomfort were negatively correlated with beta-endorphin levels. Thus, DBS regulates central opioids, and prioritizing STN is important for PD patients with significant sensory complications.

Average annual cost of Parkinson's disease in a Brazilian multiethnic population.

INTRODUCTION: With the current demographic transition, it is estimated that by 2050 Brazil will have a population of 90 million people aged 60 years or more, and in parallel Parkinson's disease (PD) will bring a considerable economic burden to our society. Brazil is considered multiracial due to its colonization, generating important social and regional inequalities. Knowing the costs of the PD may aid to improve local public policies. However, in Brazil, no estimates of these values have been made so far. OBJECTIVES: To evaluate direct, indirect, and out-of-pocket costs in Brazilian people with PD (PwP). METHODS: Categorical and numerical data were collected through a customized and standardized cost-related-questionnaire from 1055 PwP nationwide, from 10 tertiary movement disorders centers across all Brazilian regions. RESULTS: The estimated average annual cost of PwP was US$ 4020.48. Direct and indirect costs accounted for 63% and 36% of the total, respectively, and out-of-pocket costs were 49%. There were no evidence of differences in the total cost of PD across the regions of the country; however, differences were reported between the stages of the Hoehn and Yahr scale (H&Y). CONCLUSION: This data suggests a considerable burden of PD for Brazilian society in general, not only for the public health system, but mainly for those with PD.

Clinical assessment of upper limb impairments and functional capacity in Parkinson's disease: a systematic review / Avaliação clínica de comprometimentos de membros superiores e capacidade funcional na doença de Parkinson: uma revisão sistemática

Abstract Background Parkinson's disease (PD) may progressively reduce the upper limb's functionality. Currently, there is no standardized upper limb functional capacity assessment in PD in the rehabilitation field. Objective To identify specific outcome measurements to assess upper limbs in PD and access functional capacity. Methods We systematically reviewed and analyzed the literature in English published from August/2012 to August/2022 according to PRISMA. The following keywords were used in our search: "upper limbs" OR "upper extremity" and "Parkinson's disease." Two researchers searched independently, including studies accordingly to our inclusion and exclusion criteria. Registered at PROSPERO CRD42021254486. Results We found 797 studies, and 50 were included in this review (n = 2.239 participants in H&Y stage 1-4). The most common upper limbs outcome measures found in the studies were: (i) UPDRS-III and MDS-UPDRS to assess the severity and progression of PD motor symptoms (tremor, bradykinesia, and rigidity) (ii) Nine Hole Peg Test and Purdue Pegboard Test to assess manual dexterity; (iii) Spiral test and Funnel test to provoke and assess freezing of upper limbs; (iv) Technology assessment such as wearables sensors, apps, and other device were also found. Conclusion We found evidence to support upper limb impairments assessments in PD. However, there is still a large shortage of specific tests to assess the functional capacity of the upper limbs. The upper limbs' functional capacity is insufficiently investigated during the clinical and rehabilitation examination due to a lack of specific outcome measures to assess functionality.

Resumo Antecedentes A doença de Parkinson (DP) reduz progressivamente a funcionalidade do membro superior. Não existe uma avaliação padronizada da capacidade funcional do membro superior na DP na área da reabilitação. Objetivo Identificar medidas de resultados específicos para avaliar membros superiores na DP e avaliar capacidade funcional. Métodos Revisamos e analisamos sistematicamente a literatura publicada de agosto/2012 a agosto/2022 de acordo com PRISMA. Usamos as seguintes palavras-chave "membros superiores" OU "extremidade superior" e "doença de Parkinson." Dois pesquisadores fizeram a busca de forma independente, incluindo estudos de acordo com os critérios de inclusão e exclusão. Registro PROSPERO CRD42021254486. Resultados Encontramos 797 estudos, 50 foram incluídos no estudo(n = 2.239 participantes no estágio 1-4 de H&Y). As medidas de resultados de membros superiores mais comuns encontradas foram: (i) UPDRS-III e MDS-UPDRS, para avaliar a gravidade e a progressão dos sintomas motores da DP (tremor, bradicinesia, e rigidez); (ii) Nine Hole Peg Test e Purdue Pegboard Test para avaliar a destreza manual; (iii) Teste da Espiral e Teste do Funil para provocar e avaliar o congelamento de membros superiores; (iv) Avaliação de tecnologia, como sensores vestíveis, aplicativos e outros dispositivos também foram encontrados. Conclusão Encontramos evidências para dar suporte para as avaliações de deficiências de membros superiores na DP. No entanto, ainda há grande escassez de testes específicos para avaliar a capacidade funcional dos membros superiores. A capacidade funcional dos membros superior é insuficientemente investigada durante o exame clínico e de reabilitação devido à falta de medidas de resultados específicos para avaliar a funcionalidade.

Clinical assessment of upper limb impairments and functional capacity in Parkinson's disease: a systematic review.

BACKGROUND: Parkinson's disease (PD) may progressively reduce the upper limb's functionality. Currently, there is no standardized upper limb functional capacity assessment in PD in the rehabilitation field. OBJECTIVE: To identify specific outcome measurements to assess upper limbs in PD and access functional capacity. METHODS: We systematically reviewed and analyzed the literature in English published from August/2012 to August/2022 according to PRISMA. The following keywords were used in our search: "upper limbs" OR "upper extremity" and "Parkinson's disease." Two researchers searched independently, including studies accordingly to our inclusion and exclusion criteria. Registered at PROSPERO CRD42021254486. RESULTS: We found 797 studies, and 50 were included in this review (n = 2.239 participants in H&Y stage 1-4). The most common upper limbs outcome measures found in the studies were: (i) UPDRS-III and MDS-UPDRS to assess the severity and progression of PD motor symptoms (tremor, bradykinesia, and rigidity) (ii) Nine Hole Peg Test and Purdue Pegboard Test to assess manual dexterity; (iii) Spiral test and Funnel test to provoke and assess freezing of upper limbs; (iv) Technology assessment such as wearables sensors, apps, and other device were also found. CONCLUSION: We found evidence to support upper limb impairments assessments in PD. However, there is still a large shortage of specific tests to assess the functional capacity of the upper limbs. The upper limbs' functional capacity is insufficiently investigated during the clinical and rehabilitation examination due to a lack of specific outcome measures to assess functionality.

ANTECEDENTES: A doença de Parkinson (DP) reduz progressivamente a funcionalidade do membro superior. Não existe uma avaliação padronizada da capacidade funcional do membro superior na DP na área da reabilitação. OBJETIVO: Identificar medidas de resultados específicos para avaliar membros superiores na DP e avaliar capacidade funcional. MéTODOS: Revisamos e analisamos sistematicamente a literatura publicada de agosto/2012 a agosto/2022 de acordo com PRISMA. Usamos as seguintes palavras-chave "membros superiores" OU "extremidade superior" e "doença de Parkinson." Dois pesquisadores fizeram a busca de forma independente, incluindo estudos de acordo com os critérios de inclusão e exclusão. Registro PROSPERO CRD42021254486. RESULTADOS: Encontramos 797 estudos, 50 foram incluídos no estudo(n = 2.239 participantes no estágio 1­4 de H&Y). As medidas de resultados de membros superiores mais comuns encontradas foram: (i) UPDRS-III e MDS-UPDRS, para avaliar a gravidade e a progressão dos sintomas motores da DP (tremor, bradicinesia, e rigidez); (ii) Nine Hole Peg Test e Purdue Pegboard Test para avaliar a destreza manual; (iii) Teste da Espiral e Teste do Funil para provocar e avaliar o congelamento de membros superiores; (iv) Avaliação de tecnologia, como sensores vestíveis, aplicativos e outros dispositivos também foram encontrados. CONCLUSãO: Encontramos evidências para dar suporte para as avaliações de deficiências de membros superiores na DP. No entanto, ainda há grande escassez de testes específicos para avaliar a capacidade funcional dos membros superiores. A capacidade funcional dos membros superior é insuficientemente investigada durante o exame clínico e de reabilitação devido à falta de medidas de resultados específicos para avaliar a funcionalidade.

Pain in Parkinson disease: mechanistic substrates, main classification systems, and how to make sense out of them.

ABSTRACT: Parkinson 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.

The Therapeutic Potential of Non-Invasive and Invasive Cerebellar Stimulation Techniques in Hereditary Ataxias.

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.

Recent Advances in the Treatment of Genetic Forms of Parkinson's Disease: Hype or Hope?

Parkinson'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 α-synuclein. Although the α-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.

Non-motor effects of deep brain stimulation in Parkinson's disease motor subtypes.

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.

Does TRODAT-1 SPECT Uptake Correlate with Cerebrospinal Fluid α-Synuclein Levels in Mid-Stage Parkinson's Disease?

BACKGROUND: Parkinson's disease (PD) is characterized by a progressive loss of nigrostriatal dopaminergic neurons with impaired motor and non-motor symptoms. It has been suggested that motor asymmetry could be caused due to an imbalance in dopamine levels, as visualized by dopamine transporter single emission computed tomography test (DAT-SPECT), which might be related to indirect measures of neurodegeneration, evaluated by the Montreal Cognitive Assessment (MOCA) and α-synuclein levels in the cerebrospinal fluid (CSF). Therefore, this study aimed to understand the correlation between disease laterality, DAT-SPECT, cognition, and α-synuclein levels in PD. METHODS: A total of 28 patients in the moderate-advanced stage of PD were subjected to neurological evaluation, TRODAT-1-SPECT/CT imaging, MOCA, and quantification of the levels of α-synuclein. RESULTS: We found that α-synuclein in the CSF was correlated with global cognition (positive correlation, r2 = 0.3, p = 0.05) and DAT-SPECT concentration in the putamen (positive correlation, r2 = 0.4, p = 0.005), and striatum (positive correlation, r2 = 0.2, p = 0.03), thus working as a neurodegenerative biomarker. No other correlations were found between DAT-SPECT, CSF α-synuclein, and cognition, thus suggesting that they may be lost with disease progression. CONCLUSIONS: Our data highlight the importance of understanding the dysfunction of the dopaminergic system in the basal ganglia and its complex interactions in modulating cognition.

Use of Objective Outcomes Measures to Verify the Effects of ICF-Based Gait Treatment in Huntington's Disease Patient on Globus Pallidus Deep Brain Stimulation: A Case Report.

In advanced stages of in Huntington's disease (HD) gait impairments and severe chorea are usually medication-refractory. The long-term effects on gait in HD of physiotherapy ICF-based management post- globus pallidus deep brain stimulation (GPi DBS) are not well-established. Physiotherapy has been recognized as an essential element in HD treatment. Here, we present a case report of a 56-year-old woman with HD on the advanced stage and severe chorea medication-refractory after GPi-DBS. We performed multidisciplinary motor assessments ICF-based to identify the disability at clinical and home-setting, including environmental and personal factors before and after GPi-DBS surgery and at 11-time points follow-up. The surgery was very successful and directly post GPi-DBS, there were a significant improvement in chorea and a substantial decrease in medication dose. A framework ICF- based physiotherapy protocol with external cues was developed to improve gait was delivered post-surgery and was continued three times/week during 18-months. Physiotherapy sessions consisted of a personalized protocol of exercises with functional movements, balance, and gait training with external cues. Improvements in gait were observed in 3-months post-intervention and were more expressive in 6-months follow-up. Our patient improved substantially HD motor symptoms and her quality of life after GPi-DBS intervention and a physiotherapy program ICF-based. The objective outcomes measures used to assess gait have served as endpoints to assessing the patient's motor profile during the pre-operative period. Assessments were helpful to verify the efficacy of the multidisciplinary intervention in long-term. Conclusion: Periodically assessing function and disability using outcome improvements may support clinicians' decisions about DBS, medication adjustments and guide physiotherapists to personalize the ICF-based intervention.

Trientine tetrahydrochloride versus penicillamine for maintenance therapy in Wilson disease (CHELATE): a randomised, open-label, non-inferiority, phase 3 trial.

BACKGROUND: 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 µg/L), 24 h urinary copper excretion (100-900 µg/24 h), and alanine aminotransferase (ALT; <2 × 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 µg/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 µg/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 µg/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 µg/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 µg/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 µg/L (99% CI -9·5 to 44·7) with penicillamine and -6·3 µg/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. FUNDING: Orphalan.

Advances in DBS Technology and Novel Applications: Focus on Movement Disorders.

PURPOSE 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.

The Parkinson disease pain classification system: results from an international mechanism-based classification approach.

ABSTRACT: Pain 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.

Beneficial nonmotor effects of subthalamic and pallidal neurostimulation in Parkinson's disease.

BACKGROUND: 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.

Effects of cerebellar transcranial magnetic stimulation on ataxias: A randomized trial.

INTRODUCTION: Cerebellar ataxia remains a neurological symptom orphan of treatment interventions, despite being prevalent and incapacitating. We aimed to study, in a double-blind design, whether cerebellar modulation could improve ataxia. METHODS: We included patients with diagnosis of spinocerebellar ataxia type 3, multiple systems atrophy cerebellar type, or post-lesion ataxia. Patients received five sessions each of sham and active cerebellar 1 Hz deep repetitive transcranial magnetic stimulation in randomized order. Our primary outcome was the decrease in the Scale for the Assessment and Rating of Ataxia when comparing phases (active x sham). Secondary outcomes measures included the International Cooperative Ataxia Rating Scale, and other motor, cognitive, and quality of life scales. This study was registered at clinicaltrials.gov (protocol NCT03213106). RESULTS: Twenty-four patients aged 29-74 years were included in our trial. After active stimulation, the Scale for the Assessment and Rating of Ataxia score was significantly lower than the score after sham stimulation [median (interquartile range) of 10.2 (6.2, 16.2) versus 12.8 (9.6, 17.8); p = 0.002]. The International Cooperative Ataxia Rating Scale score also improved after active stimulation versus sham [median (interquartile range) of 29.0 (21.0, 43.5) versus 32.8 (22.0, 47.0); p = 0.005]. Other secondary outcomes were not significantly modified by stimulation. No patient presented severe side effects, and nine presented mild and self-limited symptoms. CONCLUSIONS: Our protocol was safe and well-tolerated. These findings suggest that cerebellar modulation may improve ataxic symptom and provide reassurance about safety for clinical practice.

Deep brain stimulation in Tourette's syndrome: evidence to date.

Tourette's syndrome (TS) is a neurodevelopmental disorder that comprises vocal and motor tics associated with a high frequency of psychiatric comorbidities, which has an important impact on quality of life. The onset is mainly in childhood and the symptoms can either fade away or require pharmacological therapies associated with cognitive-behavior therapies. In rare cases, patients experience severe and disabling symptoms refractory to conventional treatments. In these cases, deep brain stimulation (DBS) can be considered as an interesting and effective option for symptomatic control. DBS has been studied in numerous trials as a therapy for movement disorders, and currently positive data supports that DBS is partially effective in reducing the motor and non-motor symptoms of TS. The average response, mostly from case series and prospective cohorts and only a few controlled studies, is around 40% improvement on tic severity scales. The ventromedial thalamus has been the preferred target, but more recently the globus pallidus internus has also gained some notoriety. The mechanism by which DBS is effective on tics and other symptoms in TS is not yet understood. As refractory TS is not common, even reference centers have difficulties in performing large controlled trials. However, studies that reproduce the current results in larger and multicenter randomized controlled trials to improve our knowledge so as to support the best target and stimulation settings are still lacking. This article will discuss the selection of the candidates, DBS targets and mechanisms on TS, and clinical evidence to date reviewing current literature about the use of DBS in the treatment of TS.

Subthalamic deep brain stimulation modulates conscious perception of sensory function in Parkinson's disease.

Subthalamic deep brain stimulation (STN-DBS) is used to treat refractory motor complications in Parkinson disease (PD), but its effects on nonmotor symptoms remain uncertain. Up to 80% of patients with PD may have pain relief after STN-DBS, but it is unknown whether its analgesic properties are related to potential effects on sensory thresholds or secondary to motor improvement. We have previously reported significant and long-lasting pain relief after DBS, which did not correlate with motor symptomatic control. Here we present secondary data exploring the effects of DBS on sensory thresholds in a controlled way and have explored the relationship between these changes and clinical pain and motor improvement after surgery. Thirty-seven patients were prospectively evaluated before STN-DBS and 12 months after the procedure compared with healthy controls. Compared with baseline, patients with PD showed lower thermal and mechanical detection and higher cold pain thresholds after surgery. There were no changes in heat and mechanical pain thresholds. Compared with baseline values in healthy controls, patients with PD had higher thermal and mechanical detection thresholds, which decreased after surgery toward normalization. These sensory changes had no correlation with motor or clinical pain improvement after surgery. These data confirm the existence of sensory abnormalities in PD and suggest that STN-DBS mainly influenced the detection thresholds rather than painful sensations. However, these changes may depend on the specific effects of DBS on somatosensory loops with no correlation to motor or clinical pain improvement.

Caudal Zona Incerta/VOP Radiofrequency Lesioning Guided by Combined Stereotactic MRI and Microelectrode Recording for Posttraumatic Midbrain Resting-Kinetic Tremor.

OBJECTIVE: Reporting the outcome of two patients who underwent unilateral ablative stereotactic surgery to treat pharmacologic resistant posttraumatic tremor (PTT). METHODS: We present two patients (31 and 47 years old) with refractory PTT severely affecting their quality of life. Under stereotactic guidance, refined by T2-weighted magnetic resonance imaging and double-channel multiunit microelectrode recording (MER), three sequential radiofrequency lesions were performed in the caudal zona incerta (cZi) up to the base of thalamus (VOP). Effects of cZi/VOP lesion were prospectively rated with a tremor rating scale. RESULTS: Both patients demonstrated intraoperative tremor suppression with sustained results up to 18 months follow-up, with improvement of 92% and 84%, respectively, on the tremor rating scale. Tremor improvement was associated with enhancement functionality and quality of life for the patients. The patients returned to their work after the procedure. No adverse effects were observed up to the last follow-up. CONCLUSION: Radiofrequency lesion of the cZi/VOP target was effective for posttraumatic tremor in both cases. The use of T2-weighted images and MER was found helpful in increasing the precision and safety of the procedure, because it leads the RF probe by relying on neighbor structures based on thalamus and subthalamic nucleus.

Hypertrophic olivary degeneration and holmes' tremor secondary to bleeding of cavernous malformation in the midbrain.

BACKGROUND: Hypertrophic olivary degeneration (HOD) is a rare phenomenon, probably related to transsynaptic degeneration of the inferior olivary nucleus. It usually occurs as a response to primary injury of dento-rubro-olivary pathways. CASE REPORT: A young man developed Holmes' tremor 7 months after a cavernous malformation bleed in the midbrain. Typical findings of HOD were observed in the magnetic resonance images: bilateral and asymmetric hypertrophy of the olivary nucleus with slight hypersignal in T2-weighted images. Because of the striking disability related to drug-resistant tremor, the patient underwent stereotactic thalamotomy (nucleus ventralis intermedius of the thalamus/zona incerta) with pronounced functional improvement over time. DISCUSSION: Disruption of circuits in the Guillain-Mollaret triangle classically results in palatal myoclonus, however midbrain (Holmes') tremor can also occur, as we now describe.