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Background Spinocerebellar ataxia type 2 (SCA2) affects several neurological structures, giving rise to multiple symptoms. However, only the natural history of ataxia is well known, as measured during the study duration. We aimed to describe the progression rate of ataxia, by the Scale for the Assessment and Rating of Ataxia (SARA), as well as the progression rate of the overall neurological picture, by the Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), and not only during the study duration but also in a disease duration model. Comparisons between these models might allow us to explore whether progression is linear during the disease duration in SCA2; and to look for potential modifiers. Results Eighty–eight evaluations were prospectively done on 49 symptomatic subjects; on average (SD), study duration and disease duration models covered 13 (2.16) months and 14 (6.66) years of individuals’ life, respectively. SARA progressed 1.75 (CI 95%: 0.92–2.57) versus 0.79 (95% CI 0.45 to 1.14) points/year in the study duration and disease duration models. NESSCA progressed 1.45 (CI 95%: 0.74–2.16) versus 0.41 (95% CI 0.24 to 0.59) points/year in the same models. In order to explain these discrepancies, the progression rates of the study duration model were plotted against disease duration. Then an acceleration was detected after 10 years of disease duration: SARA scores progressed 0.35 before and 2.45 points/year after this deadline (p = 0.013). Age at onset, mutation severity, and presence of amyotrophy, parkinsonism, dystonic manifestations and cognitive decline at baseline did not influence the rate of disease progression. Conclusions NESSCA and SARA progression rates were not constant during disease duration in SCA2: early phases of disease were associated with slower progressions. Modelling of future clinical trials on SCA2 should take this phenomenon into account, since disease duration might impact on inclusion criteria, sample size, and study duration. Our database is available online and accessible to future studies aimed to compare the present data with other cohorts. Electronic supplementary material The online version of this article (10.1186/s13023-017-0725-y) contains supplementary material, which is available to authorized users.

The aim of the present study is to describe the serum concentrations of a broad spectrum of cytokines in symptomatic and asymptomatic carriers of Machado Joseph disease (SCA3/MJD) CAG expansions. Molecularly confirmed carriers and controls were studied. Age at onset, disease duration, and clinical scales Scale for the Assessment and Rating of Ataxia (SARA), Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), SCA Functional Index (SCAFI), and Composite Cerebellar Functional Score (CCFS) were obtained from the symptomatic carriers. Serum was obtained from all individuals and a cytokine panel "consisted of" eotaxin, granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-α, IFN-γ, interleukin (IL)-1β, IL-1RA, IL-2, IL-2R, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-15, IL-17, interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, monokine induced by gamma interferon (MIG), macrophage inflammatory protein (MIP)-a, MIP-b, regulated on activation, normal T cell expressed and secreted (RANTES) and tumor necrosis factor (TNF)-α was analyzed. In a subgroup of symptomatic carriers, the cytokine panel was repeated after 360 days. Cytokine distribution among groups was studied by discriminant analysis; changes in serum levels after 360 days were studied by generalized estimation equation. Sixty-six symptomatic carriers, 13 asymptomatic carriers, and 43 controls were studied. No differences in cytokine patterns were found between controls and carriers of the CAG expansions or between controls and symptomatic carriers only. In contrast, eotaxin concentrations were significantly higher in asymptomatic than in symptomatic carriers or in controls (p = 0.001, ANCOVA). Eotaxin did not correlate with age, disease duration, CAG expansion, NESSCA score, and SARA score. Among symptomatic carriers, eotaxin dropped after 360 days (p = 0.039, GEE). SCA3/MJD patients presented a benign pattern of serum cytokines. In contrast, levels of eotaxin, a peptide secreted by astrocytes, were elevated in the asymptomatic carriers, suggesting that a specific response of these cells can be related to symptom progression, in SCA3/MJD.

Background Spinocerebellar ataxia type 2 (SCA2) is due to a CAG expansion (CAGexp) at ATXN2. SCA2 presents great clinical variability, alongside characteristic ataxia with saccadic slowness. Aims To study parkinsonism, dementia, dystonia, and amyotrophy as subphenotypes of SCA2, and to explore the effect of CAG repeats at different loci and of mitochondrial polymorphism A10398G as modifiers of phenotype. Methods Symptomatic subjects were classified by presence/absence of neurological signs mentioned above; SARA and NESSCA scores were obtained. CAG repeats at ATXN1, ATXN2, ATXN3, CACNA1A, ATXN7 and RAI1, and polymorphism A10398G at mtDNA were established. Group characteristics were compared, with a p Results Forty-eight SCA2 individuals were included. Age at onset, CAGexp, and disease duration explained 53% and 43% of SARA and NESSCA variations, respectively. CAGexp of subjects with and without parkinsonism were different (medians of 42 and 39 repeats) as well as of subjects with and without dystonia (44 and 40 repeats). Amyotrophy was not significantly related to any variable under study. Concerning polymorphism A10398G, 83% of subjects with and 34% of those without cognitive decline carried 10398G at (p = 0.003). Discussion Treating the four phenotypic subgroups as outcomes was a valid strategy to identify modifiers of disease. Among correlations found, some confirmed previous reports, such as that between dystonia and CAGexp. Of note was the association between cognitive decline and the variant G at mitochondrial polymorphism A10398G, a variant formerly related to earlier ages at onset in SCA2.

Background Because lithium exerts neuroprotective effects in preclinical models of polyglutamine disorders, our objective was to assess the safety and efficacy of lithium carbonate (0.5-0.8 milliequivalents per liter) in patients with Machado-Joseph disease (spinocerebellar ataxia type 3 [MJD/SCA3]). Methods For this phase 2, single-center, double-blind, parallel, placebo-controlled trial (ClinicalTrials.gov identifier NCT01096082), 62 patients who had MJD/SCA3 with a disease duration ≤10 years and an independent gait were randomly assigned (1:1) to receive either lithium or placebo. Results After 24 weeks, 169 adverse events were reported, including 50.3% in the lithium group (P = 1.00; primary safety outcome). Sixty patients (31 in the placebo group and 29 in the lithium group) were analyzed for efficacy (intention-to-treat analysis). Mean progression between groups did not differ according to scores on the Neurological Examination Score for the Assessment of Spinocerebellar Ataxia (NESSCA) after 48 weeks (−0.35; 95% confidence interval, −1.7 to 1.0; primary efficacy outcome). The lithium group exhibited minor progression on the PATA speech-rate (P = 0.002), the nondominant Click Test (P = 0.023), the Spinocerebellar Ataxia Functional Index (P = 0.003), and the Composite Cerebellar Functional Score (P = 0.029). Conclusions Lithium was safe and well tolerated, but it had no effect on progression when measured using the NESSCA in patients with MJD/SCA3. This slowdown in secondary outcomes deserves further clarification. © 2014 International Parkinson and Movement Disorder Society

The requirement for dopaminergic drugs in Parkinson's disease (PD) is highly variable. Visual hallucinations are a frequent and serious complication of chronic levodopa therapy. Polymorphisms in the DAT1 gene might affect the reuptake of dopamine in the synaptic cleft, but the influence of this variability on adverse effects or levodopa equivalent dose on PD patients is still poorly investigated. Therefore, the aim of the present study was to investigate DAT1 gene polymorphisms on levodopa equivalent dose and visual hallucination occurrence in PD patients. Altogether, 196 PD patients in treatment with at least 200 mg levodopa equivalent dose for at least 1 yr were included. These patients were genotyped for the −839 C > T and 3′ VNTR DAT1 polymorphisms by PCR-based methodologies. Visual hallucinations occurred in 25.5% of the sample. After controlling for confounders, the dopamine transporter (DAT) −839 C allele was associated with visual hallucinations (prevalence ratio 2.5, 95% confidence intervals 1.13–5.5, p = 0.02). Levodopa equivalent dose was lower in carriers of the nine repeat allele of the DAT 3′UTR VNTR (741.2 ± 355.0 vs. 843.4 ± 445.7), explaining 21% of dose variability (p = 0.01). Our results support an effect of DAT1 polymorphisms in adverse effects of anti-Parkinsonian drugs and in levodopa equivalent dose usage.

In a recent phase 2 clinical trial in spinocerebellar ataxia type 3/Machado Joseph disease (SCA3/MJD), a neurogenetic disorder without specific therapy, benefits of lithium carbonate were found only on secondary efficacy outcomes, all related to ataxic features. In order to help designing future studies, we further analyzed the trial data searching for treatment response modifiers and metric properties of spinocerebellar ataxia (SCA) scales.Efficacy analysis was performed with the Neurological Examination Score for the Assessment of Spinocerebellar Ataxia (NESSCA) and the Scale for the Assessment and Rating of Ataxia (SARA) subscores and with the subgroup of patients with independent gait according to the 8-meter walking-time (8MW). Interactions of clinical/molecular findings with treatment response, minimally important differences (MIDs), and sample size estimations for NESSCA, SARA, Spinocerebellar Ataxia Functional Index (SCAFI) and Composite Cerebellar Functional Score (CCFS) were evaluated.62 SCA3/MJD patients had been randomly assigned (1:1) for the double-blind, placebo-controlled trial. While cerebellar NESSCA (range: 0-7 points) differed between groups 0.64 points (95% CI 0.23 to 1.05, p0.001) over the whole 48weeks of study, favoring lithium, no effect was found on non-ataxia subscores. Among patients able to perform the 8MW on baseline, NESSCA (p=0.010) and SCAFI (p=0.015) differed between groups favoring lithium. Finally, estimated sample sizes for the scales were provided.Lithium efficacy on cerebellar NESSCA, and on SCAFI and CCFS in the primary analysis, together with the lack of effect on non-ataxia features suggests that lithium should be tested in phase 3 trials in SCA3/MJD and that ataxia scales should be preferred to multisystem neurological instruments as the primary outcome. The inclusion of early stage patients is advisable in future clinical trials in SCA3/MJD.clinicaltrials.gov identifier: NCT01096082.

Objectives: It was the aim of this study to determine the depression scores of Machado-Joseph disease (MJD) patients, their spouses, and individuals at 50% risk for MJD, and second, to verify the existence of a correlation between depressive symptoms and the degree of motor incapacitation. Subjects and Methods: Two hundred and forty-six individuals aged ≧18 years were studied: 79 MJD patients (group 1), 43 spouses of MJD patients (group 2), 80 individuals at risk for MJD (group 3), and a control group (group 4) composed of 44 patients with multiple sclerosis (MS). The following two tools were applied: the Beck Depression Inventory and the Barthel index of physical incapacitation, both in an adapted Brazilian Portuguese version. Results: Moderate to severe depressive scores were found in 33.5% of patients in the MJD families, in 16.3% of the spouses, and in 6.3% of the individuals at risk. This linear reduction between MJD family members was statistically significant (p < 0.0001, ANOVA). Depressive scores were also associated with age and the female sex. A direct correlation between Beck Depression Inventory scores and motor incapacitation was found in MJD patients (r = 0.507, Pearson correlation, p < 0.0001). Although the depressive symptoms in the control group with MS were higher than those found in MJD patients (59% of MS patients showed moderate to severe scores), depression did not correlate with physical incapacitation, age, or education attainment in the MS group. Conclusions: Depressive symptoms are rather common in MJD patients and in their spouses (caregivers). In this condition, depression seemed to be more reactive than primarily related to the disease process itself.

Background NSE and S100B are considered as neuronal and glial peripheral markers of central nervous system pathologies, respectively. We evaluated the potential use of S100B and NSE serum concentrations as peripheral markers of symptomatic patients with Machado Joseph disease (MJD). Methods We measured S100B and NSE peripheral concentrations of 22 MJD patients and compared with healthy subjects concentrations. The correlations of both markers with CAG repeat size, age of onset, disease duration, and the scores of the Extended Disability Status Scale of Kurtzke, Unified Parkinson's Disease Rating Scale, and the Montgomery-Asberg depression rating scale were also assessed. Results S100B serum concentrations between control and MJD subjects were not statistically different, whereas NSE serum concentrations were higher in MJD patients than in control subjects (p=0.00001). S100B presented a moderate correlation with disease duration and depression score, whereas NSE presented a moderate correlation with depression score and a good negative correlation with EDSS score. Conclusions Symptomatic MJD patients present increased concentrations of NSE and normal concentrations of S100B in blood.

Context – Machado-Joseph Disease (MJD/SCA3) is an autosomal dominant spinocerebellar degeneration that evolves to disability and death. Experimental data have shown that serotonin is an important cerebellar neurotransmitter and that impairment of the serotoninergic cerebellar system can induce cerebellar ataxia. Objectives – To evaluate the efficacy of fluoxetine, a serotonin reuptake inhibitor, in treating neurologic dysfunction in patients with MJD. Patients and methods – Thirteen MJD patients were treated with fluoxetine (20 mg/day) and were followed-up for 6 weeks. Outcome measures included functional capacity, standardized neurologic and cognitive ratings. The Montgomery-Asberg depression rating scale was used to control depressive symptoms. Results – There was no significant improvement in motor abilities after 6 weeks of treatment. Conclusions – These results suggest that fluoxetine has no benefit in motor function of patients with MJD/SCA3.

Because lithium exerts neuroprotective effects in preclinical models of polyglutamine disorders, our objective was to assess the safety and efficacy of lithium carbonate (0.5-0.8 milliequivalents per liter) in patients with Machado-Joseph disease (spinocerebellar ataxia type 3 [MJD/SCA3]).For this phase 2, single-center, double-blind, parallel, placebo-controlled trial (ClinicalTrials.gov identifier NCT01096082), 62 patients who had MJD/SCA3 with a disease duration ≤10 years and an independent gait were randomly assigned (1:1) to receive either lithium or placebo.After 24 weeks, 169 adverse events were reported, including 50.3% in the lithium group (P = 1.00; primary safety outcome). Sixty patients (31 in the placebo group and 29 in the lithium group) were analyzed for efficacy (intention-to-treat analysis). Mean progression between groups did not differ according to scores on the Neurological Examination Score for the Assessment of Spinocerebellar Ataxia (NESSCA) after 48 weeks (-0.35; 95% confidence interval, -1.7 to 1.0; primary efficacy outcome). The lithium group exhibited minor progression on the PATA speech-rate (P = 0.002), the nondominant Click Test (P = 0.023), the Spinocerebellar Ataxia Functional Index (P = 0.003), and the Composite Cerebellar Functional Score (P = 0.029).Lithium was safe and well tolerated, but it had no effect on progression when measured using the NESSCA in patients with MJD/SCA3. This slowdown in secondary outcomes deserves further clarification.

Levodopa is the most effective symptomatic therapy for Parkinson's disease, but its chronic use could lead to chronic adverse outcomes, such as motor fluctuations, dyskinesia and visual hallucinations. HOMER1 is a protein with pivotal function in glutamate transmission, which has been related to the pathogenesis of these complications. This study investigates whether polymorphisms in the HOMER1 gene promoter region are associated with the occurrence of the chronic complications of levodopa therapy. A total of 205 patients with idiopathic Parkinson's disease were investigated. Patients were genotyped for rs4704559, rs10942891 and rs4704560 by allelic discrimination with Taqman assays. The rs4704559 G allele was associated with a lower prevalence of dyskinesia (prevalence ratio (PR)=0.615, 95% confidence interval (CI) 0.426-0.887, P=0.009) and visual hallucinations (PR=0.515, 95% CI 0.295-0.899, P=0.020). Our data suggest that HOMER1 rs4704559 G allele has a protective role for the development of levodopa adverse effects.

Aim: Dyskinesia and motor fluctuation are frequent and serious complications of chronic levodopa therapy in patients with Parkinson’s disease. Since genetic factors could play a role in determining the occurrence of these problems, the aim of the present study was to investigate whether possible functional polymorphisms among DRD2 and ANKK1 genes are associated with the risk of developing dyskinesia and motor fluctuations in Parkinson’s disease patients. Patients & methods: One hundred and ninety nine patients in treatment with levodopa were genotyped for the -141CIns/Del, rs2283265, rs1076560, C957T, TaqIA and rs2734849 polymorphisms at the DRD2/ANKK1 gene region. Results: Carriers of the TTCTA haplotype showed an increased risk for the presence of dyskinesia (p = 0.007; 1.538 [95% CI: 1.126–2.101]). Conclusion: Our data suggest an influence of the DRD2/ANKK1 gene region on levodopa-induced dyskinesia. Original submitted 8 May 2012; Revision submitted 29 August 2012

Spinocerebellar ataxia 3 is an untreatable CAG repeat expansion disorder whose natural history is not completely understood. Our aims were to describe the progression of neurological manifestations in a long-term cohort of spinocerebellar ataxia 3, and to verify if CAG expanded repeat, gender, and age at onset were associated with the rate of progression. Patients entered the study between 1998 and 2005 and were seen until 2007. On each visit, the validated NESSCA scale, an inventory of 18 neurological manifestations, was applied. Scores observed in each year of disease duration produced a Growth Curve, which was analyzed through the random coefficients model. Scores obtained in some individual items were described through multi-state Markov models. One hundred fifty-six patients (78 families) were recruited; 28 were lost, and 23 died. Mean (sd) ages at onset and at baseline were 32.8 (10.6) and 40.7 (12.8) years; median (range) expanded CAGn was 74 (67-85). Three hundred fifteen NESSCA evaluations were performed, comprising disease durations from zero to 34 years. The 105 patients who completed the study were seen over 5 (sd = 2.4) years at intervals of 2.5 (sd = 1.5) years. The trajectory of NESSCA obtained for the overall group increased by 1.26 points per year. This slope increased by 0.15 points per each additional CAG in the expanded repeat (p 0.0002) and decreased by 0.03 points per each additional year of age at onset (p = 0.005). NESSCA worsened steadily, producing linear trajectories, which were faster among patients with longer expanded repeats (74) and with lower ages at onset (34 years).

Parkinson's Disease Sleep Scale (PDSS) is a specific scale for the assessment of sleep disturbances in subjects with Parkinson's Disease (PD). This cross-sectional study set out to validate the PDSS in a Brazilian Portuguese Version (PDSS-BR). Ninety-five patients with PD participated in the study; their PD symptoms were evaluated by Unified Parkinson's Disease Rating Scale (UPDRS sections I-IV) and Hoehn and Yahr scale. Patients completed Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Beck Depression Inventory (BDI) and PDSS-BR. PDSS-BR internal consistency was satisfactory (Cronbach's alpha: 0.82; all PDSS-BR items were significantly and positively associated with total score). Test-retest reliability for total PDSS-BR score was 0.94. PDSS-BR score was highly correlated with sleep PSQI scale (r(s) = -0.63; p < 0.0001) and moderately with ESS (r(s) = -0.32; p < 0.001) and UPDRS sections I (r(s) = -0.38; p < 0.0001) and II (r(s) = -0.36; p < 0.0001) and BDI (r(s) = -0.55; p < 0.0001). Depressive symptoms, as determined by the BDI, were associated with significantly worse quality of nocturnal sleep, as measured by the PDSS-BR. The psychometric attributes of the PDSS-BR were satisfactory and consistent with those of previous studies. In summary, PDSS-BR can be useful for clinical and research purposes in Brazil.

Spinocerebellar ataxias (SCAs) are characterized by a heterogeneous set of clinical manifestations. Our aims were to assess the neurological features of SCA3, and to describe and test the feasibility, reliability, and validity of a comprehensive Neurological Examination Score for Spinocerebellar Ataxia (NESSCA). The NESSCA was administered to molecularly diagnosed SCA3 patients at an outpatient neurogenetics clinic. The scale, based on the standardized neurological examination, consisted of 18 items that yielded a total score ranging from 0 to 40. The score's interrater reliability and internal consistency were investigated, and a principal components analysis and a correlation with external measures were performed. Ninety-nine individuals were evaluated. Interrater reliability ranged from 0.8 to 1 across individual items (P < 0.001); internal consistency, indicated by Cronbach's alpha, was 0.77. NESSCA scores were significantly correlated with measures of disease severity: disease stage (rho = 0.76, P < 0.001), duration (rho = 0.56, P < 0.001), and length of CAG repeat (rho = 0.30, P < 0.05). NESSCA was a reliable measure for the assessment of distinct neurological deficits in SCA3 patients. Global scores correlated with all external variables tested, showing NESSCA to be a comprehensive measure of disease severity that is both clinically useful and scientifically valid.

A 36 year-old black female, complaining of headache of one month's duration presented with nausea, vomiting, somnolence, short memory problems, loss of weight, and no fever history. Smoker, intravenous drugs abuser, promiscuous lifestyle. Physical examination: left homonimous hemianopsia, left hemiparesis, no papilledema, diffuse hyperreflexia, slowness of movements. Brain CT scan: tumor-like lesion in the splenium of the corpus calosum, measuring 3.5 x 1.4 cm, with heterogeneous enhancing pattern, sugesting a primary CNS tumor. Due to the possibility of CNS infection, a lumbar puncture disclosed an opening pressure of 380 mmH(2)0; 11 white cells (lymphocytes); glucose 18 mg/dl (serum glucose 73 mg/dl); proteins 139 mg/dl; presence of Trypanosoma parasites. Serum Elisa-HIV tests turned out to be positive. Treatment with benznidazole dramatically improved clinical and radiographic picture, but the patient died 6 weeks later because of respiratory failure. T. cruzi infection of the CNS is a rare disease, but we have an increasing number of cases in HIV immunecompromised patients. Diagnosis by direct observation of CSF is uncommon, and most of the cases are diagnosed by pathological examination. It is a highly lethal disease, even when properly diagnosed and treated. This article intends to include cerebral trypanosomiasis in the differential diagnosis of intracranial space-occupying lesions, especially in immunecompromised patients from endemic regions. Uma mulher negra de 36 anos, procurou a emergência do hospital com quadro de cefaléia holocraniana há 1 mês. Evoluiu com náuseas e vômitos, sonolência e diminuição da memória, associadas a emagrecimento, sem história de febre. Tabagista, usuária de drogas endovenosas, história de promiscuidade sexual. Exame físico: hemianopsia homômima esquerda, hemiparesia esquerda, sem papiledema, hiperreflexia profunda difusa e lentificação dos movimentos. A TC de crânio mostou lesão expansiva no esplênio do corpo caloso com 3,5 x 1,4 cm, com impregnação heterogênea pelo contraste, sugestiva de tumor primário do SNC. Por causa da possibilidade de neuroinfecção, foi realizada uma punção lombar que revelou pressão de abertura de 380 mmH2O; 11 leucócitos (mononucleares), glicose 18 mg/dl (glicemia 73mg/dl), proteínas 139 mg/dl, presença de parasitas com características de Trypanossoma. Testes para HIV foram reagentes. Iniciado tratamento com benzonidazol, a paciente apresentou melhora neurológica e tomográfica. Faleceu 6 semanas após, por insuficiência respiratória. A infecção por T. cruzi no SNC é entidade rara, observando-se número crescente de casos em pacientes imunocomprometidos por infecção pelo HIV. O diagnóstico por exame direto no líquor é incomum, em sua maioria sendo os casos diagnosticados por exame anátomo-patológico (biópsia ou necrópsia). É doença de alta letalidade, mesmo com diagnóstico e tratamento adequados. É necesário incluir a tripanossomíase cerebral no diagnóstico diferencial das patologias expansivas intracranianas, principalmente em pacientes imunodeprimidos e provenientes de áreas endêmicas.