Expanding the phenotypic spectrum of CLCN2-related leucoencephalopathy and ataxia.

Mutations in CLCN2 are a rare cause of autosomal recessive leucoencephalopathy with ataxia and specific imaging abnormalities. Very few cases have been reported to date. Here, we describe the clinical and imaging phenotype of 12 additional CLCN2 patients and expand the known phenotypic spectrum of this disorder. Informed consent was obtained for all patients. Patients underwent either whole-exome sequencing or focused/panel-based sequencing to identify variants. Twelve patients with biallelic CLCN2 variants are described. This includes three novel likely pathogenic missense variants. All patients demonstrated typical MRI changes, including hyperintensity on T2-weighted images in the posterior limbs of the internal capsules, midbrain cerebral peduncles, middle cerebellar peduncles and cerebral white matter. Clinical features included a variable combination of ataxia, headache, spasticity, seizures and other symptoms with a broad range of age of onset. This report is now the largest case series of patients with CLCN2-related leucoencephalopathy and reinforces the finding that, although the imaging appearance is uniform, the phenotypic expression of this disorder is highly heterogeneous. Our findings expand the phenotypic spectrum of CLCN2-related leucoencephalopathy by adding prominent seizures, severe spastic paraplegia and developmental delay.

Guidelines for Parkinson's disease treatment: consensus from the Movement Disorders Scientific Department of the Brazilian Academy of Neurology - motor symptoms.

The 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.

Guidelines for Parkinson's disease treatment: consensus from the Movement Disorders Scientific Department of the Brazilian Academy of Neurology - motor symptoms / Diretrizes para o tratamento da doença de Parkinson: consenso do Departamento Científico de Transtornos do Movimento da Academia Brasileira de Neurologia - sintomas motores

ABSTRACT The 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.

Resumo O tratamento da doença de Parkinson (DP) constitui um desafio, especialmente por ser considerado muito individualizado. A Academia Brasileira de Neurologia (ABN) identificou a necessidade de disseminar o conhecimento sobre o manejo do tratamento da DP, adaptando as melhores evidências à realidade brasileira. Assim, foi realizada uma revisão sobre as principais orientações de tratamento publicadas, baseada nas recomendações elaboradas por um grupo de especialistas em transtornos do movimento do departamento científico da ABN.

Toll-like receptor 10 controls TLR2-induced cytokine production in monocytes from patients with Parkinson's disease.

Peripheral inflammation, particularly mediated by monocytes, can cause neuroinflammation in Parkinson's disease (PD). We investigated the mechanism of TLR2-induced cytokine impairment in peripheral monocytes from PD patients and the association between the presence of CD14+ TLR10+ monocytes and PD severity. Peripheral blood mononuclear cells from PD patients and healthy individuals were evaluated for TLR expression on monocyte subsets (CD14 and CD16 expression) using flow cytometry. Moreover, cytokines were evaluated using flow cytometry after stimulation with Pam3 Cys (TLR2/TLR1 agonist) in the absence or presence of neutralizing antibodies to TLR10. The severity of PD was assessed using the unified PD rating scale (UPDRS) and motor activity, anxiety (BAI), depression (BDI), and fatigue (PD Fatigue Scale-16) scales. The frequency of CD14+ TLR10+ monocytes and expression intensity of TLR2 and TLR10 were higher in patients with PD than healthy individuals. The frequency of intermediate monocytes (CD14++ CD16+ ) was not significantly increased in patients with PD, but was the main monocyte subset expressing TLR10. The TLR2/TLR1-impaired cytokine production (IL-6, TNFα, IL-8, and IL-10) in PD patients was reversed by neutralizing TLR10. The high frequency of total CD14+ TLR10+ monocytes was associated with a reduction in the severity of PD according to the evaluation of motor and nonmotor symptoms. Peripheral monocytes from patients with PD showed phenotypic and functional alterations. The expression of TLR10 on monocytes can protect against PD by controlling TLR2-induced cytokine production. Furthermore, data suggested that a low frequency of CD14+ TLR10+ monocytes indicates the severity of PD. The results identified new opportunities for the development of novel PD neuroprotective therapies.

Music Therapy Reduces Radiotherapy-Induced Fatigue in Patients With Breast or Gynecological Cancer: A Randomized Trial.

PURPOSE: To investigate the influence of music therapy on the reduction of fatigue in women with breast or gynecological malignant neoplasia during radiotherapy, since it is one of the most frequent side effects of this type of treatment, and may interfere with self-esteem, social activities, and quality of life. EXPERIMENTAL DESIGN: Randomized controlled trial (control group [CG] and music therapy group [MTG]) to assess fatigue, quality of life, and symptoms of depression in women undergoing radiotherapy using the Functional Assessment of Cancer Therapy: Fatigue (FACT-F) version 4, Functional Assessment of Cancer Therapy-General (FACT-G) version 4, and Beck Depression Inventory in 3 separate times, namely, during the first week of radiotherapy, on the week of the intermediary phase, and during the last week of radiotherapy. Individual 30- to 40-minute sessions of music therapy with the presence of a trained music therapist were offered to participants. RESULTS: In this study, 164 women were randomized and 116 (63 CG and 53 MTG) were included in the analyses, with mean age of 52.90 years (CG) and 51.85 years (MTG). Participants in the MTG had an average of 10 music therapy sessions, totaling 509 sessions throughout the study. FACT-F results were significant regarding Trial Outcome Index ( P = .011), FACT-G ( P = .005), and FACT-F ( P = .001) for the MTG compared with the CG. CONCLUSIONS: Individual music therapy sessions may be effective to reduce fatigue related to cancer and symptoms of depression, as well as to improve quality of life for women with breast or gynecological cancer undergoing radiotherapy. Further well-designed research studies are needed to adequately determine the effects of music therapy on fatigue.

Cognitive evaluation of patients with glaucoma and its comparison with individuals with Alzheimer's disease.

PURPOSE: To evaluate the cognitive performance of patients with glaucoma and compare it to individuals with Alzheimer's disease (AD). METHODS: This is a prospective, cross-sectional and case-control study. All subjects were assessed using the Mini-Mental State Examination (MMSE) and its subtests verbal fluency, word list memory, delayed recall of the word list, word list recognition test, Boston naming and constructive praxis from Consortium to Establish a Registry for Alzheimer's Disease (CERAD). The results were compared among the groups. RESULTS: A total of 50 healthy elderly with a mean age of 71.2 ± 5.2 years; 41 patients with glaucoma (72.2 ± 4.4 years); and 21 patients with AD (79.0 ± 7.6 years) were included. There was a reduction in all cognitive assessment tests evaluated, both for patients with glaucoma, and for those with AD compared with controls (p < 0.001 for all). Comparing the patients with glaucoma and AD, it was noted that the last had lower cognitive function (p < 0.001), except for the CERAD tests Boston (p = 0.1) and praxis (p = 0.6). Glaucoma patients, however, presented results of cognitive tests similar to those described for patients with mild AD, including lower values for MMSE (21.9 ± 3.7), Boston (10.6 ± 2.6) and praxis (5.9 ± 2.3). CONCLUSION: Glaucoma patients had reduction in cognition when compared to normal individuals. They were similar to the values reported in the literature for patients with mild AD, mostly, and also in some subjects with the presence of advanced AD.

Clinical profiles associated with LRRK2 and GBA mutations in Brazilians with Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by remarkable phenotypic variability. Accumulated evidence points that the manifestation of PD clinical signs might be differentially modified by genetic factors, as mutations in LRRK2 and GBA genes. In this sense, the clarification of the genotype-phenotype correlations in PD has important implications in predicting prognosis and can contribute to the development of specific therapeutic approaches. METHODS: Here, we conducted the first comparative analysis of motor and non-motor features in 17 LRRK2 and 22 GBA mutation carriers and 93 non-carriers unrelated PD patients from Brazil, a highly admixed population. RESULTS: Significant differences were found between the three groups. LRRK2 PD patients presented more occurrence of familiar history. Resting tremor was observed in a lower frequency in GBA mutation carries. In contrast, gait freezing and dysautonomia was present in lower frequencies in LRRK2 carriers. Besides that, LRRK2 and GBA mutation carriers showed a higher incidence of depressive symptoms and a younger age at onset, when compared to non-carriers. CONCLUSION: Our results suggest that specific mutations in GBA and LRRK2 influence the clinical signs of the disease, with significant implications for handling of specific patient groups.

Autosomal dominant Parkinson's disease: Incidence of mutations in LRRK2, SNCA, VPS35 and GBA genes in Brazil.

INTRODUCTION: Amongst Parkinson's disease (PD) genetic factors, mutations in LRRK2, SNCA, VPS35 and GBA genes are recognized causes of PD. Nonetheless, few genetic screenings have been conducted in families with a history of PD consistent with autosomal dominant inheritance (ADPD), and their relevance to the etiology of PD has been poorly explored in Latin American populations, such as the Brazilian one, with a high degree of admixture. METHODS: In order to assess the contribution of specific mutations in LRRK2, SNCA, VPS35 and GBA genes to ADPD in Brazil, we conducted the first molecular evaluation in a cohort of 141 index cases from families with ADPD. Genomic DNA was isolated from peripheral blood or saliva, and the molecular analysis was performed by TaqMan allelic discrimination assays or bidirectional sequencing. RESULTS: Heterozygous mutations in LRRK2 and GBA genes were identified in 10 (7.0%) probands, and all presented typical signs of classical PD. No mutations were found in SNCA or VPS35 genes. CONCLUSION: Our findings in a representative series of index cases from families with ADPD emphasize the important contribution of LRRK2 G2019S and GBA (L444P and N370S) mutations to parkinsonism in Brazilian families. The absence of mutations in VPS35 and SNCA genes reveals that they are uncommon causes of PD in Brazil, corroborating previous studies that also failed to detect these genetic variants in PD patients from other populations. Recent discoveries of novel causative genes of autosomal dominant forms of PD expand the investigative possibilities and should be targeted on future studies.

Decreased Toll-Like Receptor 2 and Toll-Like Receptor 7/8-Induced Cytokines in Parkinson's Disease Patients.

OBJECTIVES: Toll-like receptors (TLRs) are expressed in several immune cells including blood monocytes and resident macrophages, such as microglia in the central nervous system. TLRs recognize pathogen- or damage-associated molecular patterns, leading to the release of inflammatory and toxic molecules, which can contribute to neuroinflammation associated with Parkinson's disease (PD). The aim of this study was to compare the potential of peripheral blood cells from PD patients or healthy subjects to produce cytokines after exposure to TLR agonists, and to investigate TLR2 and TLR4 expression on monocyte subsets. METHODS: Twenty-one patients and 21 healthy controls were recruited. Patients were evaluated according to the Unified Parkinson's Disease Rating Scale, and Hoehn and Yahr stage. Cytokines were measured in supernatants of whole blood cultures after incubation with TLR2, TLR4, or TLR7/8 agonists, by cytometric bead array. Expression of CD14, CD16, TLR2, and TLR4 was analyzed by cytometry. RESULTS: Patient blood cells produced lower levels of cytokines in response to TLR2 and also after TLR7/8/R848 activation than controls. Percentages of CD14+CD16+ or CD14+CD16- monocytes and TLR2 and TLR4 expression were similar between patients and controls. CONCLUSIONS: Blood leukocyte TLR2 and TLR7/8 responses are impaired in PD. This was neither associated with imbalance in monocyte subsets nor with TLR2/TLR4 expression on these cells. The association between a decreased TLR response in periphery and damage of brain in PD must be further investigated.

Treatment of Alzheimers disease in Brazil: II. Behavioral and psychological symptoms of dementia / Tratamento da doença de Alzheimer no Brasil: II. Dos sintomas comportamentais e psicológicos da demência

This article reports the recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology for the treatment of Alzheimers disease (AD) in Brazil, with special focus on behavioral and psychological symptoms of dementia (BPSD). It constitutes a revision and broadening of the 2005 guidelines based on a consensus involving researchers (physicians and non-physicians) in the . The authors carried out a search of articles published since 2005 on the MEDLINE, LILACS and Cochrane Library databases. The search criteria were pharmacological and non-pharmacological treatment of the behavioral and psychological symptoms of AD. Studies retrieved were categorized into four classes, and evidence into four levels, based on the 2008 recommendations of the American Academy of Neurology. The recommendations on therapy are pertinent to the dementia phase of AD. Recommendations are proposed for the treatment of BPSD encompassing both pharmacological (including acetyl-cholinesterase inhibitors, memantine, neuroleptics, anti-depressives, benzodiazepines, anti-convulsants plus other drugs and substances) and non-pharmacological (including education-based interventions, physiotherapy, occupational therapy, music therapy, therapy using light, massage and art therapy) approaches. Recommendations for the treatment of cognitive disorders of AD symptoms are included in a separate article of this edition.

Esse texto apresenta as recomendações da Academia Brasileira de Neurologia, por intermédio do seu Departamento Científico de Neurologia Cognitiva e do Envelhecimento, para o tratamento da doença de Alzheimer (DA) no Brasil, enfocando os sintomas comportamentais e psicológicos da demência (SCPD). Trata-se de uma revisão ampliada das diretrizes publicadas em 2005, resultada de um consenso envolvendo pesquisadores da área, médicos e não médicos. Os autores realizaram uma busca de artigos publicados a partir de 2005 nas bases MEDLINE, LILACS e Cochrane Library. A busca foi direcionada para tratamento farmacológico e não farmacológico dos sintomas comportamentais e psicológicos da DA. Os estudos foram categorizados em quatro classes e as evidências em quatro níveis, com base nas recomendações da Academia Americana de Neurologia publicadas em 2008. As recomendações terapêuticas referem-se à fase demencial da DA. Apresentam-se recomendações para o tratamento dos SCPD, tanto farmacológico (incluindo inibidores da acetilcolinesterase, memantina, neurolépticos, antidepressivos, benzodiazepínicos, anticonvulsivantes e outros fármacos e substâncias), como não farmacológico (incluindo intervenções educacionais, fisioterapia, terapia ocupacional, musicoterapia, terapia com luz, massagem e arterapia). As recomendações para o tratamento dos transtornos cognitivos da DA são apresentadas em outro artigo desse fascículo.

Treatment of Alzheimers disease in Brazil: I. Cognitive disorders / Tratamento da doença de Alzheimer no Brasil: I. dos transtornos cognitivos

This article reports the recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology for the treatment of Alzheimers disease (AD) in Brazil, with special focus on cognitive disorders. It constitutes a revision and broadening of the 2005 guidelines based on a consensus involving researchers (physicians and non-physicians) in the . The authors carried out a search of articles published since 2005 on the MEDLINE, LILACS and Cochrane Library databases. The search criteria were pharmacological and non-pharmacological treatment of cognitive disorders in AD. Studies retrieved were categorized into four classes, and evidence into four levels, based on the 2008 recommendations of the American Academy of Neurology. The recommendations on therapy are pertinent to the dementia phase of AD. Recommendations are proposed for the treatment of cognitive disorders encompassing both pharmacological (including acetyl-cholinesterase inhibitors, memantine and other drugs and substances) and non-pharmacological (including cognitive rehabilitation, physical activity, occupational therapy, and music therapy) approaches. Recommendations for the treatment of behavioral and psychological symptoms of dementia due to Alzheimers disease are included in a separate article of this edition.

Esse texto apresenta as recomendações da Academia Brasileira de Neurologia, por intermédio do seu Departamento Científico de Neurologia Cognitiva e do Envelhecimento, para o tratamento da doença de Alzheimer (DA) no Brasil, enfocando os transtornos cognitivos. Trata-se de uma revisão ampliada das diretrizes publicadas em 2005, resultada de um consenso envolvendo pesquisadores da área, médicos e não médicos. Os autores realizaram uma busca de artigos publicados a partir de 2005 nas bases MEDLINE, LILACS e Cochrane Library. A busca foi direcionada para tratamento farmacológico e não farmacológico dos transtornos cognitivos da DA. Os estudos foram categorizados em quatro classes e as evidências em quatro níveis, com base nas recomendações da Academia Americana de Neurologia publicadas em 2008. As recomendações terapêuticas referem-se à fase demencial da DA. Apresentam-se recomendações para o tratamento dos transtornos cognitivos, tanto farmacológico (incluindo inibidores da acetilcolinesterase, memantina e outros fármacos e substâncias), como não farmacológico (incluindo reabilitação cognitiva, atividade física, terapia ocupacional e musicoterapia). As recomendações para o tratamento dos sintomas comportamentais e psicológicos da demência da DA são apresentadas em outro artigo desse fascículo.

Treatment of Alzheimer's disease in Brazil: I. Cognitive disorders.

This article reports the recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology for the treatment of Alzheimer's disease (AD) in Brazil, with special focus on cognitive disorders. It constitutes a revision and broadening of the 2005 guidelines based on a consensus involving researchers (physicians and non-physicians) in the field. The authors carried out a search of articles published since 2005 on the MEDLINE, LILACS and Cochrane Library databases. The search criteria were pharmacological and non-pharmacological treatment of cognitive disorders in AD. Studies retrieved were categorized into four classes, and evidence into four levels, based on the 2008 recommendations of the American Academy of Neurology. The recommendations on therapy are pertinent to the dementia phase of AD. Recommendations are proposed for the treatment of cognitive disorders encompassing both pharmacological (including acetyl-cholinesterase inhibitors, memantine and other drugs and substances) and non-pharmacological (including cognitive rehabilitation, physical activity, occupational therapy, and music therapy) approaches. Recommendations for the treatment of behavioral and psychological symptoms of dementia due to Alzheimer's disease are included in a separate article of this edition.

Esse texto apresenta as recomendações da Academia Brasileira de Neurologia, por intermédio do seu Departamento Científico de Neurologia Cognitiva e do Envelhecimento, para o tratamento da doença de Alzheimer (DA) no Brasil, enfocando os transtornos cognitivos. Trata-se de uma revisão ampliada das diretrizes publicadas em 2005, resultada de um consenso envolvendo pesquisadores da área, médicos e não médicos. Os autores realizaram uma busca de artigos publicados a partir de 2005 nas bases MEDLINE, LILACS e Cochrane Library. A busca foi direcionada para tratamento farmacológico e não farmacológico dos transtornos cognitivos da DA. Os estudos foram categorizados em quatro classes e as evidências em quatro níveis, com base nas recomendações da Academia Americana de Neurologia publicadas em 2008. As recomendações terapêuticas referem-se à fase demencial da DA. Apresentam-se recomendações para o tratamento dos transtornos cognitivos, tanto farmacológico (incluindo inibidores da acetilcolinesterase, memantina e outros fármacos e substâncias), como não farmacológico (incluindo reabilitação cognitiva, atividade física, terapia ocupacional e musicoterapia). As recomendações para o tratamento dos sintomas comportamentais e psicológicos da demência da DA são apresentadas em outro artigo desse fascículo.

Treatment of Alzheimer's disease in Brazil: II. Behavioral and psychological symptoms of dementia.

This article reports the recommendations of the Scientific Department of Cognitive Neurology and Aging of the Brazilian Academy of Neurology for the treatment of Alzheimer's disease (AD) in Brazil, with special focus on behavioral and psychological symptoms of dementia (BPSD). It constitutes a revision and broadening of the 2005 guidelines based on a consensus involving researchers (physicians and non-physicians) in the field. The authors carried out a search of articles published since 2005 on the MEDLINE, LILACS and Cochrane Library databases. The search criteria were pharmacological and non-pharmacological treatment of the behavioral and psychological symptoms of AD. Studies retrieved were categorized into four classes, and evidence into four levels, based on the 2008 recommendations of the American Academy of Neurology. The recommendations on therapy are pertinent to the dementia phase of AD. Recommendations are proposed for the treatment of BPSD encompassing both pharmacological (including acetyl-cholinesterase inhibitors, memantine, neuroleptics, anti-depressives, benzodiazepines, anti-convulsants plus other drugs and substances) and non-pharmacological (including education-based interventions, physiotherapy, occupational therapy, music therapy, therapy using light, massage and art therapy) approaches. Recommendations for the treatment of cognitive disorders of AD symptoms are included in a separate article of this edition.

Esse texto apresenta as recomendações da Academia Brasileira de Neurologia, por intermédio do seu Departamento Científico de Neurologia Cognitiva e do Envelhecimento, para o tratamento da doença de Alzheimer (DA) no Brasil, enfocando os sintomas comportamentais e psicológicos da demência (SCPD). Trata-se de uma revisão ampliada das diretrizes publicadas em 2005, resultada de um consenso envolvendo pesquisadores da área, médicos e não médicos. Os autores realizaram uma busca de artigos publicados a partir de 2005 nas bases MEDLINE, LILACS e Cochrane Library. A busca foi direcionada para tratamento farmacológico e não farmacológico dos sintomas comportamentais e psicológicos da DA. Os estudos foram categorizados em quatro classes e as evidências em quatro níveis, com base nas recomendações da Academia Americana de Neurologia publicadas em 2008. As recomendações terapêuticas referem-se à fase demencial da DA. Apresentam-se recomendações para o tratamento dos SCPD, tanto farmacológico (incluindo inibidores da acetilcolinesterase, memantina, neurolépticos, antidepressivos, benzodiazepínicos, anticonvulsivantes e outros fármacos e substâncias), como não farmacológico (incluindo intervenções educacionais, fisioterapia, terapia ocupacional, musicoterapia, terapia com luz, massagem e arterapia). As recomendações para o tratamento dos transtornos cognitivos da DA são apresentadas em outro artigo desse fascículo.

Unilateral subthalamic nucleus lesioning: a safe and effective treatment for Parkinson's disease.

The present study, the largest in the literature, was performed to assess the effectiveness and safety of unilateral subthalamic nucleus (STN) lesioning for Parkinson's disease (PD). From August 1999 to September 2000, 21 consecutive patients evaluated pre- and postoperatively by a single examiner were operated. Levodopa intake and dyskinesia, Hoehn & Yahr, Schwab & England and UPDRS motor scores were recorded. Stereotactic CT and MRI and the effects of macrostimulation were used to determine STN coordinates. A single radiofrequency lesion was made (60-75 degrees C/60"). Concomitant ipsilateral Vim/VOp lesions were made in 8 patients. Using a new technique, we were able to determine the territory of STN involved by the surgical lesion. The Wilcoxon and Mann-Whitney statistical tests were applied to evaluate the surgical results. All recorded parameters showed stable improvement after a mean follow up of 13.5 months. Recurrence occurred in two patients. Contralateral tremor arrest and decrease of rigidity and bradykinesia should be regarded as STN hallmarks to stimulation. Hyperintense lesions in the early-phase MRI seem to be a poor prognostic factor. Lateral territory lesioning correlates with better results. There was no significant difference between the cohorts with and without a Vim/VOp lesion. Dyskinesias happened in two patients (promptly abolished by a Vim/VOp lesion). Other complications were transient and/or rare. In conclusion, STN lesioning is a safe and very effective procedure to treat PD and probably an underutilized operation for those who can not afford the costs of DBS.