The progression rate of spinocerebellar ataxia type 2 changes with stage of disease.

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.

Peripheral Oxidative Stress Biomarkers in Spinocerebellar Ataxia Type 3/Machado-Joseph Disease.

OBJECTIVES: Spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD) is a polyglutamine disorder with no current disease-modifying treatment. Conformational changes in mutant ataxin-3 trigger different pathogenic cascades, including reactive oxygen species (ROS) generation; however, the clinical relevance of oxidative stress elements as peripheral biomarkers of SCA3/MJD remains unknown. We aimed to evaluate ROS production and antioxidant defense capacity in symptomatic and presymptomatic SCA3/MJD individuals and correlate these markers with clinical and molecular data with the goal of assessing their properties as disease biomarkers. METHODS: Molecularly confirmed SCA3/MJD carriers and controls were included in an exploratory case-control study. Serum ROS, measured by 2',7'-dichlorofluorescein diacetate (DCFH-DA) as well as superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) antioxidant enzyme activities, levels were assessed. RESULTS: Fifty-eight early/moderate stage symptomatic SCA3/MJD, 12 presymptomatic SCA3/MJD, and 47 control individuals were assessed. The DCFH-DA levels in the symptomatic group were 152.82 nmol/mg of protein [95% confidence interval (CI), 82.57-223.08, p < 0.001] higher than in the control and 243.80 nmol/mg of protein (95% CI, 130.64-356.96, p < 0.001) higher than in the presymptomatic group. The SOD activity in the symptomatic group was 3 U/mg of protein (95% CI, 0.015-6.00, p = 0.048) lower than in the presymptomatic group. The GSH-Px activity in the symptomatic group was 13.96 U/mg of protein (95% CI, 5.90-22.03, p < 0.001) lower than in the control group and 20.52 U/mg of protein (95% CI, 6.79-34.24, p < 0.001) lower than in the presymptomatic group and was inversely correlated with the neurological examination score for spinocerebellar ataxias (R = -0.309, p = 0.049). CONCLUSION: Early/moderate stage SCA3/MJD patients presented a decreased antioxidant capacity and increased ROS generation. GSH-Px activity was the most promising oxidative stress disease biomarker in SCA3/MJD. Further longitudinal studies are necessary to identify both the roles of redox parameters in SCA3/MJD pathophysiology and as surrogate outcomes for clinical trials.

Neurological phenotypes in spinocerebellar ataxia type 2: Role of mitochondrial polymorphism A10398G and other risk factors.

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 < 0.05. 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.

Cytokines in Machado Joseph Disease/Spinocerebellar Ataxia 3.

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)-1ß, 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.

Planning future clinical trials in Machado Joseph disease: Lessons from a phase 2 trial.

BACKGROUND: 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. METHODS: 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. RESULTS: 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, p<0.001) 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. CONCLUSION: 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. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01096082.

A randomized, phase 2 clinical trial of lithium carbonate in Machado-Joseph disease.

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.

Progression rate of neurological deficits in a 10-year cohort of SCA3 patients.

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).

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.

Cerebral trypanosomiasis and AIDS.

UNLABELLED: 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, suggesting 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 immunocompromised 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 immunocompromised patients from endemic regions.

Cerebral trypanosomiasis and AIDS

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

Investigaçäo dos quadros demenciais / Research of dementiais

As demências, definidas como a deterioraçäo global das funçöes cognitivas, säo um problema freqüente na prática médica. Apesar de serem as demências primárias, principalmente a doença de Alzheimer, as mais freqüentes, em até 15% dos casos encontra-se causas potencialmente reversíveis e em até 30% dos casos, causas em que pode haver benefício terapêutico. Salienta-se também a importância do diagnóstico diferencial com as pseudodemências. O objetivo do presente artigo é fornecer um roteiro para investigaçäo dos quadro potencialmente reversíveis e o adequado manejo de tais distúrbios

O efeito do chá de chuchu (Sechium edule) sobre a pressäo arterial e outros parâmetros em voluntários jovens normotensos / The effect of Sechium edule leaves infusion on blood pressure and other parameters in normotensive young voluteers

A partir de plantas extraem-se muitos fármacos, em processo demorado e oneroso. Uma proposiçäo alternativa é o emprego da planta "in natura", tal como é usada na medicina popular, desde que seja devidamente comprovada sua eficácia. Com esse objetivo, investigou-se o efeito agudo do chá de chuchu (Sechium edule) sobre a pressäo arterial, a freqüência cardíaca, o volume urinário e as taxas urinárias de sódio e potássio de 21 voluntários jovens normotensos, em ensaio clínico cruzado, contra-placebo, randomizado e duplo-cego. Os voluntários receberam chá intervençäo, chá placebo ou nada (período só com medidas) em seqüência aleatória. Durante as três horas seguintes foram determinados aqueles parâmetros. Os resultados somente mostraram aumento significativo do volume urinário quando da ingestäo dos chás, näo se evidenciado, nas presentes condiçöes experimentais, o propalado efeito hipotensor do chuchu