Transcutaneous tibial nerve home stimulation for overactive bladder in women with Parkinson's disease: A randomized clinical trial.

AIMS: This study aims to investigate the efficacy of transcutaneous tibial nerve home stimulation for overactive bladder (OAB) in women with Parkinson's disease (PD). METHODS: The current study is a prospective, randomized, double-blind, sham-controlled trial. Home intervention was carried out and assessments were conducted at a tertiary hospital in South Brazil. Women with PD and OAB symptoms were included in the study. Patients were randomly divided into two groups: (1) stimulation and (2) sham. Both groups underwent intervention at home for 12 weeks. Patients were evaluated at baseline and at 12 weeks (end of intervention), 30- and 90-day follow-up. The primary outcome was the mean reduction in the number of urgency incontinence episodes, and secondary outcomes included daytime and nighttime urinary frequency, urinary urgency episodes, use of pad (reported in a 24-h bladder diary), OAB-V8 and King's Health Questionnaire scores, and maintenance of symptom relief after discontinuation of the intervention. RESULTS: In total, 30 consecutive patients completed the study (15/group). The stimulation group showed a reduction in nighttime urinary frequency (0.9 ± 0.6), urinary urgency (1.0 ± 1.2), urgency incontinence episodes (0.5 ± 0.6), use of pads (1.3 ± 1.2), and OAB-V8 (1.3 ± 1.2) and King's Health Questionnaire scores. In a 30-day and 90-day follow-up, 8 (53.3%) and 5 (33.3%) stimulation patients, respectively, reported full maintenance of symptom relief after discontinuation of the intervention. Stimulation patients presented a statistically significant improvement of symptoms as compared with sham patients (p = .001). CONCLUSIONS: Transcutaneous tibial nerve home stimulation can be used in clinical practice as an effective nonpharmacological resource for the reduction of OAB symptoms in women with PD, and the resulting relief seems to persist in the follow-up (30 and 90 days).

Plantar stimulation alters brain connectivity in idiopathic Parkinson's disease.

OBJECTIVE: Individuals with Parkinson's disease (PD) and freezing of gait (FOG) present peripheral and central sensitivity disturbances that impair motor performance. This study aimed to investigate long-term effects of plantar sensory stimulation on brain activity, brain connectivity, and gait velocity of individuals with PD and FOG. METHODS: Twenty-five participants were enrolled in this clinical trial (NCT02594540). Plantar sensory stimulation was delivered using the Automated Mechanical Peripheral Stimulation therapy (AMPS). Volunteers were randomly assigned to real or placebo AMPS groups and received eight sessions of treatment. The primary outcome was brain activity (task-based fMRI-active ankle dorsi-plantar flexion). Secondary outcomes were brain connectivity (resting state-RS fMRI) and gait velocity. fMRI was investigated on the left, right, and mid-sensory motor regions, left and right basal ganglia. RESULTS: No changes in brain activity were observed when task-based fMRI was analyzed. After real AMPS, RS functional connectivity between basal ganglia and sensory-related brain areas increased (insular and somatosensory cortices). Gait velocity also increased after real AMPS. A positive correlation was found between gait velocity and the increased connectivity between sensory, motor and supplementary motor cortices. CONCLUSION: Plantar sensory stimulation through AMPS was not able to modify brain activity. AMPS increased the RS brain connectivity mainly in areas related to sensory processing and sensorimotor integration. Plantar stimulation could be a way to improve plantar sensitivity and consequently ameliorate gait performance. However, the mechanisms behind the way AMPS influences brain pathways are still not completely known.

Cortisol levels, motor, cognitive and behavioral symptoms in Parkinson's disease: a systematic review.

Parkinson's disease (PD) is a progressive and multifactorial neurodegenerative disease. It has been suggested that a dysregulation of the hypothalamic-pituitary-adrenal axis (HPA) occurs in PD. Furthermore, this dysregulation may be involved in triggering, exacerbation or progression of disease. The objective of this study was to systematically review the literature regarding cortisol levels and their relation with motor, cognitive and behavioral symptoms in patients with PD. A systematic search was performed in PubMed and Embase databases, according to PRISMA norms. Twenty-one studies were included, which evaluated baseline levels of cortisol and motor, cognitive, behavioral symptoms, drugs administration or deep brain stimulation to PD treatment. Sample size ranged from 7 to 249 individuals. In 14 studies that assessed cortisol levels in PD patients, seven showed elevation of cortisol levels. In relation to symptomatology, high levels of cortisol were associated with worst functional scores evaluated by UPDRS, depression and behavior in risk preference. Medication interactions showed an influence on the regulation of cortisol release, mainly, conventional drugs used in the PD's treatment, such as levodopa. The results found in this review point to a possible relationship between cortisol levels and symptoms in PD, indicating that an HPA axis dysfunction related to cortisol level occurs in PD.

DNAJC6 Mutations Associated With Early-Onset Parkinson's Disease.

OBJECTIVE: DNAJC6 mutations were recently described in two families with autosomal recessive juvenile parkinsonism (onset age < 11), prominent atypical signs, poor or absent response to levodopa, and rapid progression (wheelchair-bound within ∼10 years from onset). Here, for the first time, we report DNAJC6 mutations in early-onset Parkinson's disease (PD). METHODS: The DNAJC6 open reading frame was analyzed in 274 patients with early-onset sporadic or familial PD. Selected variants were followed up by cosegregation, homozygosity mapping, linkage analysis, whole-exome sequencing, and protein studies. RESULTS: We identified two families with different novel homozygous DNAJC6 mutations segregating with PD. In each family, the DNAJC6 mutation was flanked by long runs of homozygosity within highest linkage peaks. Exome sequencing did not detect additional pathogenic variants within the linkage regions. In both families, patients showed severely decreased steady-state levels of the auxilin protein in fibroblasts. We also identified a sporadic patient carrying two rare noncoding DNAJC6 variants possibly effecting RNA splicing. All these cases fulfilled the criteria for a clinical diagnosis of early-onset PD, had symptoms onset in the third-to-fifth decade, and slow disease progression. Response to dopaminergic therapies was prominent, but, in some patients, limited by psychiatric side effects. The phenotype overlaps that of other monogenic forms of early-onset PD. INTERPRETATION: Our findings delineate a novel form of hereditary early-onset PD. Screening of DNAJC6 is warranted in all patients with early-onset PD compatible with autosomal recessive inheritance. Our data provide further evidence for the involvement of synaptic vesicles endocytosis and trafficking in PD pathogenesis.

Successful electroconvulsive therapy in a drug-refractory depressed patient with idiopathic intracranial hypertension.

The condition of a 42-year-old woman with drug-refractory major depression, severe headache, and progressive visual impairment was diagnosed as idiopathic intracranial hypertension (IICH). Idiopathic intracranial hypertension is a relative contraindication to electroconvulsive therapy (ECT), chiefly due to the theoretical risk of brain herniation. Although the diagnosis of IICH was unequivocal, the patient's headache was interpreted as being unassociated with IICH. Nine ECT sessions were performed, and both depression and headache improved dramatically. People with IICH are at an increased risk of depression and report more physical complains, including headache. Cases of IICH may be considered for ECT if depression is drug-refractory. In this case, cerebrospinal fluid open pressure should be closely monitored.

Genetics of Parkinson's disease in Brazil: a systematic review of monogenic forms.

BACKGROUND: Increasing numbers of mutations causing monogenic forms of Parkinson's disease (PD) have been described, mostly among patients in Europe and North America. Since genetic architecture varies between different populations, studying the specific genetic profile of Brazilian patients is essential for improving genetic counseling and for selecting patients for clinical trials. OBJECTIVE: We conducted a systematic review to identify genetic studies on Brazilian patients and to set a background for future studies on monogenic forms of PD in Brazil. METHODS: We searched MEDLINE, EMBASE and Web of Science from inception to December 2019 using terms for "Parkinson's disease", "genetics" and "Brazil". Two independent reviewers extracted the data. For the genes LRRK2 and PRKN, the estimated prevalence was calculated for each study, and a meta-analysis was performed. RESULTS: A total of 32 studies were included, comprising 94 Brazilian patients with PD with a causative mutation, identified from among 2,872 screened patients (3.2%). PRKN mutations were causative of PD in 48 patients out of 576 (8.3%). LRRK2 mutations were identified in 40 out of 1,556 patients (2.5%), and p.G2019S was the most common mutation (2.2%). CONCLUSIONS: PRKN is the most common autosomal recessive cause of PD, and LRRK2 is the most common autosomal dominant form. We observed that there was a lack of robust epidemiological studies on PD genetics in Brazil and, especially, that the diversity of Brazil's population had not been considered.

Use of non-invasive stimulation in movement disorders: a critical review.

BACKGROUND: Noninvasive stimulation has been widely used in the past 30 years to study and treat a large number of neurological diseases, including movement disorders. OBJECTIVE: In this critical review, we illustrate the rationale for use of these techniques in movement disorders and summarize the best medical evidence based on the main clinical trials performed to date. METHODS: A nationally representative group of experts performed a comprehensive review of the literature in order to analyze the key clinical decision-making factors driving transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS) in movement disorders. Classes of evidence and recommendations were described for each disease. RESULTS: Despite unavoidable heterogeneities and low effect size, TMS is likely to be effective for treating motor symptoms and depression in Parkinson's disease (PD). The efficacy in other movement disorders is unclear. TMS is possibly effective for focal hand dystonia, essential tremor and cerebellar ataxia. Additionally, it is likely to be ineffective in reducing tics in Tourette syndrome. Lastly, tDCS is likely to be effective in improving gait in PD. CONCLUSIONS: There is encouraging evidence for the use of noninvasive stimulation on a subset of symptoms in selected movement disorders, although the means to optimize protocols for improving positive outcomes in routine clinical practice remain undetermined. Similarly, the best stimulation paradigms and responder profile need to be investigated in large clinical trials with established therapeutic and assessment paradigms that could also allow genuine long-term benefits to be determined.

WHOQOL-OLD assessment of quality of life in elderly patients with Parkinson's disease: influence of sleep and depressive symptoms.

OBJECTIVE: Parkinson's disease is a neurodegenerative disease with a number of motor and non-motor features that can affect quality of life. In this study, we aimed to assess quality of life, as well as to evaluate the potential determinants of quality of life, such as sleep quality, motor and depressive symptoms, in elderly patients with Parkinson's disease. METHOD: This was a cross-sectional study in which we applied the World Health Organization Quality of Life Assessment for Older Adults in 57 Parkinson's disease patients over 60 years of age. RESULTS: Total World Health Organization Quality of Life Assessment for Older Adults score was found to be associated with Parkinson's disease severity (rs = -0.43; p < 0.001). World Health Organization Quality of Life Assessment for Older Adults scores for sensory abilities (facet 1) and social participation (facet 4) were higher among the patients with mild Parkinson's disease than among those in the more advanced stages (rs = -0.43; p < 0.001). Facet 1 scores were found to be associated with Pittsburgh Sleep Quality Index and Parkinson's Disease Sleep Scale score (rp = -0.46 and rp = 0.41; p < 0.001, respectively). The Geriatric Depression Scale score showed an association with the total score on the World Health Organization Quality of Life Assessment for Older Adults (rp = -0.70; p < 0.001) CONCLUSION: Quality of life in Parkinson's disease patients can be assessed by the World Health Organization Quality of Life Assessment for Older Adults. Greater Parkinson's disease severity can worsen patient quality of life, as can the presence of depressive symptoms.

Dysphonia and Dysarthria in People With Parkinson's Disease After Subthalamic Nucleus Deep Brain Stimulation: Effect of Frequency Modulation.

PURPOSE: Subthalamic nucleus deep brain stimulation (STN-DBS) parameters, for example the frequency of stimulation, seem to affect speech and voice aspects. However, this influence is not well understood. This study aimed to investigate the impact of low- and high-frequency STN-DBS on voice and speech for people with Parkinson's disease. METHODS: Nineteen individuals with Parkinson's disease who received bilateral STN-DBS were assessed for motor performance (Unified Parkinson's Disease Rating Scale-III), perceptual evaluation of voice (grade, roughness, breathiness, asthenia, strain, and instability [GRBASI]), dysarthria assessment, and computerized acoustic analysis of voice upon receiving low-frequency (60 Hz) and high-frequency (130 Hz) STN-DBS. RESULTS: In the GRBASI protocol, asthenia, and instability were significantly better at 130 Hz of stimulation. In the dysarthria evaluation, the phonation aspect, articulation, and grade of dysarthria showed deterioration at the same high-frequency condition. There was no significant difference for any vocal acoustic measures. CONCLUSION: The high-frequency of STN-DBS may affect speech and voice differently, leading to an amelioration of the vocal production, but with adverse effects in the speech control.

Nordic Walking and Free Walking Improve the Quality of Life, Cognitive Function, and Depressive Symptoms in Individuals with Parkinson's Disease: A Randomized Clinical Trial.

Nordic walking's (NW) degree of effectiveness regarding health-related parameters in people with Parkinson's Disease (PD) is a subject of debate. While NW seems to improve functionality, a clear non-motor benefit has not been demonstrated. The aim of this randomized controlled trial was to compare the effects of 9-week NW and free walking (FW) training programs on quality of life, cognitive function, and depressive symptoms in individuals with PD. Thirty-three people with PD, (Hoehn and Yahr 1-4) were randomized into two groups: NW (n = 16) and FW (n = 17). We analyzed quality of life, cognitive function, depressive symptoms, and motor symptoms. Significant improvements were found in the overall, physical, psychological, social participation, and intimacy domains of quality of life, as well as in cognitive function and depressive symptoms for both groups. Only the NW group showed improvement in the autonomy domain. Individuals with PD had a similar enhancement of non-motor symptoms after walking training, with or without poles. However, the NW group showed a more significant improvement in the autonomy domain, strengthening the applied and clinical potential of NW in people with PD. Future studies are needed to determine the efficacy of walking training without poles in subjects with PD.

Diagnostic prediction model for levodopa-induced dyskinesia in Parkinson's disease.

BACKGROUND: There are currently no methods to predict the development of levodopa-induced dyskinesia (LID), a frequent complication of Parkinson's disease (PD) treatment. Clinical predictors and single nucleotide polymorphisms (SNP) have been associated to LID in PD. OBJECTIVE: To investigate the association of clinical and genetic variables with LID and to develop a diagnostic prediction model for LID in PD. METHODS: We studied 430 PD patients using levodopa. The presence of LID was defined as an MDS-UPDRS Part IV score ≥1 on item 4.1. We tested the association between specific clinical variables and seven SNPs and the development of LID, using logistic regression models. RESULTS: Regarding clinical variables, age of PD onset, disease duration, initial motor symptom and use of dopaminergic agonists were associated to LID. Only CC genotype of ADORA2A rs2298383 SNP was associated to LID after adjustment. We developed two diagnostic prediction models with reasonable accuracy, but we suggest that the clinical prediction model be used. This prediction model has an area under the curve of 0.817 (95% confidence interval [95%CI] 0.77‒0.85) and no significant lack of fit (Hosmer-Lemeshow goodness-of-fit test p=0.61). CONCLUSION: Predicted probability of LID can be estimated with reasonable accuracy using a diagnostic clinical prediction model which combines age of PD onset, disease duration, initial motor symptom and use of dopaminergic agonists.

Eosinophilic meningitis outbreak related to religious practice.

Three patients with eosinophilic meningitis (EoM) were investigated in two hospitals in Porto Alegre, Southern Brazil. These patients had a common exposure after the ingestion of raw mollusks in a religious ritual. Two of them had an uncommon presentation with intense lower distal extremities pain and small fiber neuropathy as defined by an electroneuromyography (ENMG) study. All three patients were positive for Angiostrongylus cantonensis serology and recovered after antihelminthic and anti-inflammatory treatment. Increased awareness of A. cantonensis infection is important to avoid new infections and to improved recognition and handling of cerebral angiostrongyliasis.

Interleukin-6 serum levels in patients with Parkinson's disease.

Several lines of evidence suggest that neuroimmune mechanisms may be involved in the neurodegenerative process of Parkinson's disease (PD). Interleukin-6 (IL-6) is increased in the nigrostriatal region and in the cerebrospinal fluid of patients with PD. IL-6 serum level was evaluated in PD patients. The effects of levodopa treatment and disease severity on IL-6 were also studied. The IL-6 levels were similar between PD patients (treated and not treated) and controls. However, there was a negative correlation of IL-6 levels and the activities of daily living scale (P < 0.05), indicating that patients with more severe disease have higher levels of this cytokine. No correlation involving levodopa treatment and IL-6 serum level was found. The results suggest that only marginal effects of IL-6 occur on the peripheral immune system, and that the role of IL-6 and others neuroimmune factors needs to be well elucidated on PD.

Clinimetrics of the 9- and 19-Item Wearing-Off Questionnaire: A Systematic Review.

The treatment of Parkinson's disease (PD) with dopaminergic therapy improves functionality and quality of life. However, as the disease progresses, the wearing-off phenomenon develops, which necessitates complex posology adjustment or adjuvant therapy. This phenomenon may not be well recognized, especially if it is mild or involves nonmotor symptoms. Questionnaires were developed to improve the recognition of the wearing-off phenomenon. The questionnaires consist of a list of symptoms that patients must check if they have and if the symptoms improve with medication. A recent review by the Movement Disorder Society suggested the 19-item (WOQ-19) and 9-item (WOQ-9) questionnaires as screening tools for the wearing-off phenomenon. However, there has not been a systematic review to assess the questionnaires' clinimetric properties, such as sensitivity, specificity, test-retest reliability, and responsiveness. We conducted an extensive search for studies using these two tools. We identified 3 studies using WOQ-19 and 5 studies using WOQ-9. Both questionnaires seem to have good sensitivity (0.81-1). WOQ-19 has variable specificity (0.39-0.8), depending on the number of positive items, while WOQ-9 lacks specificity (0.1-0.69). Only one study using WOQ-19 reported test-retest, and only two studies reported responsiveness. Thus, this report describes the first independent systematic review to exam quantitatively the clinimetric properties of these two questionnaires.

Translation, linguistic and cultural adaptation, reliability and validity of the Radboud Oral Motor Inventory for Parkinson's Disease - ROMP questionnaire.

OBJECTIVE: To translate and linguistically and culturally adapt to Brazilian Portuguese, and verify the reliability and validity of the Radboud Oral Motor Inventory for Parkinson's Disease (ROMP). METHODS: The ROMP was translated and retranslated, and the instrument reliability was verified by analyzing the internal consistency and the reproducibility of the intra-examiner retest. The final version was applied to 27 participants with Parkinson's disease. RESULTS: Internal consistency was 0.99 for the total ROMP and 0.96 to 0.99 for the three domains. Intraclass correlation coefficients for reproducibility were 0.99 for the total ROMP and 0.93 to 0.99 for the subscales. The ROMP and its subscales correlated substantially with the Likert-type scale, as well as with the unified Parkinson's disease rating scale II and III items. CONCLUSION: The linguistic and cultural equivalence of the ROMP in Brazilian Portuguese is now available, with excellent reliability and validity.

Automated Mechanical Peripheral Stimulation Improves Gait Parameters in Subjects With Parkinson Disease and Freezing of Gait: A Randomized Clinical Trial.

OBJECTIVE: This study aimed to assess spatiotemporal gait parameters and range of motion of lower limbs in subjects with Parkinson disease (PD) and freezing of gait, treated with automated mechanical peripheral stimulation (AMPS) or AMPS SHAM (placebo). DESIGN: This randomized clinical trial included 30 subjects allocated into two groups: AMPS (15 subjects with PD) and AMPS SHAM (15 subjects with PD). Fourteen age-matched healthy subjects were also included as a reference group. Both PD groups received the treatment twice a week during 4 weeks. Automated mechanical peripheral stimulation was applied using a commercial medical device (Gondola) and consisted of mechanical pressure in four areas of feet. For AMPS SHAM group, a subliminal stimulus was delivered. Gait analysis were measured before, after the first, after the fourth, and after the eighth sessions. RESULTS: We did not find significant differences between AMPS and AMPS SHAM groups either for spatiotemporal gait parameters or for range of motion of lower limbs. However, within-group analysis showed that AMPS group significantly improved spatiotemporal gait parameters and hip rotation range of motion throughout the treatment period. The AMPS SHAM group did not show any improvement. CONCLUSIONS: Automated mechanical peripheral stimulation therapy induces improvements in spatiotemporal parameters and hip rotation range of motion of subjects with PD and freezing of gait. TO CLAIM CME CREDITS: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Understand the impact of reduced plantar sensitivity on gait in individuals with Parkinson disease; (2) Identify the improvements on spatiotemporal gait parameters in subjects with Parkinson disease and freezing of gait after automated mechanical peripheral stimulation therapy; and (3) Recommend the use of new strategies of plantar stimulus for gait disorders of subjects with Parkinson disease. LEVEL: Advanced ACCREDITATION: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Plantar stimulation in parkinsonians: From biomarkers to mobility - randomized-controlled trial.

BACKGROUND: The decrease of Brain-Derived Neurotrophic Factor (BDNF) serum levels has been related to the pathophysiology of several neurodegenerative diseases as well as to neural plasticity and rehabilitation. Automated Mechanical Peripheral Stimulation (AMPS) has been investigated as a complementary therapy for Parkinson Disease (PD). OBJECTIVES: (1) to investigate the effects of AMPS on BDNF and Cortisol serum levels of subjects with PD; (2) to evidence the interplay between BDNF and Cortisol serum levels and the functional mobility improvement after AMPS treatment. METHODS: Thirty-three subjects with PD were randomized into two groups: effective stimulation (AMPS, n = 16) or placebo stimulation (AMPS SHAM, n = 17). Fourteen healthy aged-matched subjects were included as a reference group. Each AMPS group received eight sessions of treatment using a commercial medical device (Gondola™). BDNF and Cortisol serum levels, spatiotemporal gait parameters and TUG test were assessed at baseline and after eight sessions of treatment. RESULTS: After the treatment, AMPS group showed significantly higher levels of BDNF and lower levels of Cortisol compared to AMPS SHAM. AMPS group also showed a positive effect on gait pattern as a higher improvement on gait velocity, stride length, and TUG performance was shown. CONCLUSION: Effective AMPS treatment increased BDNF and decreased Cortisol serum levels and produced improvements in functional mobility.

Erratum: Variable frequency of LRRK2 variants in the Latin American research consortium on the genetics of Parkinson's disease (LARGE-PD), a case of ancestry.

[This corrects the article DOI: 10.1038/s41531-017-0020-6.].

Levels of vascular cell adhesion molecule-1 and endothelin-1 in ischemic stroke: a longitudinal prospective study.

OBJECTIVES: To determine levels of vascular cellular adhesion molecule (VCAM)-1 and endothelin (ET)-1 in patients with stroke. DESIGN AND METHODS: Thirty-four patients were prospectively studied. Plasma levels of VCAM-1 and ET-1 were measured by ELISA within 72 h of the event, at 7 and 90 days. RESULTS: Levels of VCAM-1 increased overtime, whereas ET-1 values were initially and persistently elevated. CONCLUSIONS: Increased circulating levels of VCAM-1 and ET-1 are present during stroke.

A double-blind, randomized, crossover study of prosigne versus botox in patients with blepharospasm and hemifacial spasm.

There is a lack of evidence on the clinical efficacy and safety of the recently released Chinese botulinum toxin serotype A (Prosigne) for the treatment of focal dystonias and hemifacial spasm. Determining a more precise role of Prosigne in the treatment of such conditions is of paramount importance, because botulinum toxin type A treatments have a huge economic implication in health services, especially in developing countries. The aim of our study was to compare the efficacy and safety of Prosigne in the treatment of blepharospasm and hemifacial spasm in comparison to Botox. We performed a double-blind, randomized, crossover study enrolling 26 patients. There were no significant differences between Prosigne and Botox regarding subjective global improvement, response onset, efficacy duration, and incidence and severity of adverse events. Our results suggest that Prosigne and Botox are comparable with respect to efficacy and safety for the short-term treatment of blepharospasm and hemifacial spasm.