Thais Lampert Monte

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.

DRD2 haplotype is associated with dyskinesia induced by levodopa therapy in Parkinson’s disease patients

AIM Dyskinesia and motor fluctuation are frequent and serious complications of chronic levodopa therapy in patients with Parkinsons 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 Parkinsons 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.

A Randomized, Phase 2 Clinical Trial of Lithium Carbonate in Machado-Joseph Disease

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]).

Depressive Symptoms in Machado-Joseph Disease (SCA3) Patients and Their Relatives

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.

Use of fluoxetine for treatment of Machado‐Joseph disease: an open‐label study

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.

Cerebral trypanosomiasis and AIDS

UNLABELLED A 36 year-old black female, complaining of headache of one months 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.

Psychometric properties of the Parkinson's Disease Sleep Scale – Brazilian version

Parkinsons Disease Sleep Scale (PDSS) is a specific scale for the assessment of sleep disturbances in subjects with Parkinsons 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 Parkinsons 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 (Cronbachs 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 in 114 Brazilian families: clinical and molecular findings.

To the Editor: Dominant spinocerebellar ataxias (SCAs) are a group of neurodegenerative diseases that affect the cerebellum, brain stem, and spinocerebellar tracts. SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17 and dentatorubral pallidoluysian atrophy (DRPLA) are caused by CAG trinucleotide repeat expansions (1). SCA8 has a CTG expansion in the causative gene. SCA10 has been found to represent a large expansion of a pentanucleotide (ATTCT) repeat (2). The frequency of each SCA varies between regions and ethnic groups. Machado–Joseph disease (MJD/SCA3) is the most common SCA among populations with Portuguese and Azorean background and populations in Japan and Germany (3–10). SCA2 is common in Cuba, India, Korea, and Italy (11– 14). SCA10 has been only described in the New World (15–19). Our aim was to determine the frequency of the SCA1, SCA2, SCA3, SCA6, SCA7, SCA10, SCA17 and DRPLA among SCA families who have the same geographic origin, namely southern Brazil (Rio Grande do Sul). Clinical, epidemiological, and molecular features are also described herein. Cases were recruited based on the following inclusion criteria: (1) ataxia, often associated with other neurological signs; and (2) inheritance as an autosomal dominant trait. Neurological examination followed a standard examination already published (19). Presence and gradation of several neurological findings were evaluated as numeric ordinal variables. Peripheral blood was collected, and genomic DNA was isolated from peripheral blood leukocytes, using the salting-out technique, as previously described (20). Molecular analyses of the repeat loci were performed by molecular tests specific to each ataxia by PCR amplification. Southern blot was performed to SCA10 locus. Patients were stratified according to their molecular diagnosis. Clinical variables were then compared between these groups. Comparisons were performed using analysis of variance (ANOVA), when the variable was parametric, or the Kruskal–Wallis test (KW test), when the variable was nonparametric. A Bonferroni procedure was done, in order to correct for multiple testing. This study was approved by the ethics committee of the institution where it was conducted; informed consent forms were filled out by all patients. A total of 114 families with autosomal dominant trait were investigated during an 8-year period (up to 2004). Diagnosis, ethnicity, and main clinical features are presented in Tables 1 and 2. SCA3 was the most prevalent, comprising 84.2% of all SCAs. The other SCAs were far less common and represented from one to five pedigrees each. The number of clinically examined patients with the diverse molecular diagnoses was variable. Due to this, some statistical comparisons could not be done: SCA1 and SCA10 patients were excluded from comparisons. Neurological findings that showed statistical differences among groups were (1) nystagmus, less frequent in cases with SCA2 and SCA7 than in the general sample; (2) limb ataxia, more severe in SCA6 patients; and (3) pyramidal findings and optic atrophy, more common in SCA7 patients than in other groups (p , 0.0025, 0.0025, 0.041 and 0.0411, respectively; KW test). Most of the present families were of mixed ancestry but Portuguese surnames prevailed. In our region, the main Portuguese ancestry was Azorean in origin, dating from circa 1750 (7). The Amerindians are another important ancestry. The composition of mitochondrial Amerindian markers in urban Brazilian populations is high and varies between 22% and 54% (26). This finding shows the importance of this Brazilian ancestry. So far, SCA10 has only been described in American families (15–18, 27). The finding of two SCA10 kindreds is in line with the hypothesis that this mutation is somehow restricted to patients with an Amerindian ancestry. Although some of the present families have already been described (7, 18, 19, 28), they had never been compared. We made these comparisons

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.

Adenosine deaminase 2 deficiency presenting as spastic paraplegia and systemic vasculitis

Deficiency of adenosine deaminase-2 (DADA2), a monogenic autoinflammatory disorder manifesting with a spectrum of systemic inflammation and vasculitis/vasculopathyrelated symptoms, was recently described [1, 2]. DADA2 is caused by bi-allelic loss-of-function mutations in CECR1 gene. Several patients were identified in populations with founder effects such as Georgian Jewish, Turkish and Pakistani [1, 2]. Here, we report the first molecularly confirmed case of DADA2 in Brazil. A now 25-year-old female, born to non-consanguineous parents fromRio Grande do Sul, Brazil, was referred in 2005 to Hospital de Clinicas de Porto Alegre with a history of progressive weakness and spasticity of the lower limbs. At the age of 6 she presented with acute/subacute spasticity, weakness and vascular manifestations in lower extremities (Fig. 1b). Over the next years, motor function progressively worsened and at age of 12 she developed dysarthria, dysphagia and nasal speech. Neurological examination showed spastic tetraparesis, mild upper-limb ataxia and dysfunction of cranial nerves VII, IX and X. BrainMRI showed nomajor abnormalities. She was investigated for infectious causes of spastic paraplegia, multiple sclerosis and inborn errors of metabolism with no diagnostic conclusion. The patient presented prominent vascular manifestations including Raynaud phenomena and livedo reticularis, and during one of her flare-ups in the year 2006, she had righthand forth finger necrosis that required amputation (Fig. 1c). At this moment, C-reactive protein was 20.4 mg/ L and erythrocyte sedimentation rate was 28 mm/h. Autoantibodies were normal, with the exception of the presence of lupus anticoagulant. She received a presumed diagnosis of antiphospholipid syndrome and started oral anticoagulation. In spite of treatment, patient’s vascular phenomena continued to worsen. After 22 months of anticoagulation, she presented a major intestinal bleeding, leading to warfarin withdrawal. During the follow-up, antiphospholipid antibodies were repeated several times, all with negative results. In 2013, it was noticed that two of her sisters presented with early-onset livedo reticularis (Fig. 1a, d) suggesting an autosomal recessive condition and the family was referred for genetic consultation. Soon after DADA2 description in 2014, we reviewed this family complex phenotype, and DADA2 diagnosis was suspected. CECR1 sequencing revealed compound heterozygous mutations, p.Gly47Arg/p.Tyr453Cys [1–3], in the studied subjects (index case and one sister). Both mutations were previously described as pathogenic [1–3], confirming DADA2 diagnosis. Brain MRI was repeated showing a few FLAIR hyperintensities in the deep frontal white matter, while spine MRI showed no major abnormalities (Fig. 2). Treatment with a TNF-inhibitor, etanercept, was indicated. DADA2 results from loss-of-function mutations in CECR1, which encodes adenosine deaminase 2, an enzyme that plays a role in differentiation of endothelial and & Jonas Alex Morales Saute jsaute@hcpa.edu.br