Cerebellar ataxia with sensory ganglionopathy; does autoimmunity have a role to play?

Background and purpose: Cerebellar ataxia with sensory ganglionopathy (SG) is a disabling combination of neurological dysfunction usually seen as part of some hereditary ataxias. However, patients may present with this combination without a genetic cause. Methods: We reviewed records of all patients that have been referred to the Sheffield Ataxia Centre who had neurophysiological and imaging data suggestive of SG and cerebellar ataxia respectively. We excluded patients with Friedreich's ataxia, a common cause of this combination. All patients were screened for genetic causes and underwent extensive investigations. Results: We identified 40 patients (45% males, mean age at symptom onset 53.7 ± 14.7 years) with combined cerebellar ataxia and SG. The majority of patients (40%) were initially diagnosed with cerebellar dysfunction and 30% were initially diagnosed with SG. For 30% the two diagnoses were made at the same time. The mean latency between the two diagnoses was 6.5 ± 8.9 years (range 0-44). The commonest initial manifestation was unsteadiness (77.5%) followed by patchy sensory loss (17.5%) and peripheral neuropathic pain (5%).Nineteen patients (47.5%) had gluten sensitivity, of whom 3 patients (7.5%) had biopsy proven coeliac disease. Other abnormal immunological tests were present in another 15 patients. Six patients had malignancy, which was diagnosed within 5 years of the neurological symptoms. Only 3 patients (7.5%) were classified as having a truly idiopathic combination of cerebellar ataxia with SG. Conclusion: Our case series highlights that amongst patients with the unusual combination of cerebellar ataxia and SG, immune pathogenesis plays a significant role

Quantitative oculomotor assessment in hereditary ataxia: discriminatory power, correlation with severity measures, and recommended parameters for specific genotypes

Characterizing bedside oculomotor deficits is a critical factor in defining the clinical presentation of hereditary ataxias. Quantitative assessments are increasingly available and have significant advantages, including comparability over time, reduced examiner dependency, and sensitivity to subtle changes. To delineate the potential of quantitative oculomotor assessments as digital-motor outcome measures for clinical trials in ataxia, we searched MEDLINE for articles reporting on quantitative eye movement recordings in genetically confirmed or suspected hereditary ataxias, asking which paradigms are most promising for capturing disease progression and treatment response. Eighty-nine manuscripts identified reported on 1541 patients, including spinocerebellar ataxias (SCA2, n = 421), SCA3 (n = 268), SCA6 (n = 117), other SCAs (n = 97), Friedreich ataxia (FRDA, n = 178), Niemann-Pick disease type C (NPC, n = 57), and ataxia-telangiectasia (n = 85) as largest cohorts. Whereas most studies reported discriminatory power of oculomotor assessments in diagnostics, few explored their value for monitoring genotype-specific disease progression (n = 2; SCA2) or treatment response (n = 8; SCA2, FRDA, NPC, ataxia-telangiectasia, episodic-ataxia 4). Oculomotor parameters correlated with disease severity measures including clinical scores (n = 18 studies (SARA: n = 9)), chronological measures (e.g., age, disease duration, time-to-symptom onset; n = 17), genetic stratification (n = 9), and imaging measures of atrophy (n = 5). Recurrent correlations across many ataxias (SCA2/3/17, FRDA, NPC) suggest saccadic eye movements as potentially generic quantitative oculomotor outcome. Recommendation of other paradigms was limited by the scarcity of cross-validating correlations, except saccadic intrusions (FRDA), pursuit eye movements (SCA17), and quantitative head-impulse testing (SCA3/6). This work aids in understanding the current knowledge of quantitative oculomotor parameters in hereditary ataxias, and identifies gaps for validation as potential trial outcome measures in specific ataxia genotypes

Quantitative oculomotor assessment in hereditary ataxia: systematic review and consensus by the ataxia global initiative working group on digital-motor biomarkers

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias

Bioinformatics-Based Identification of Expanded Repeats: A Non-reference Intronic Pentamer Expansion in RFC1 Causes CANVAS

Genomic technologies such as next-generation sequencing (NGS) are revolutionizing molecular diagnostics and clinical medicine. However, these approaches have proven inefficient at identifying pathogenic repeat expansions. Here, we apply a collection of bioinformatics tools that can be utilized to identify either known or novel expanded repeat sequences in NGS data. We performed genetic studies of a cohort of 35 individuals from 22 families with a clinical diagnosis of cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS). Analysis of whole-genome sequence (WGS) data with five independent algorithms identified a recessively inherited intronic repeat expansion [(AAGGG)exp] in the gene encoding Replication Factor C1 (RFC1). This motif, not reported in the reference sequence, localized to an Alu element and replaced the reference (AAAAG)11 short tandem repeat. Genetic analyses confirmed the pathogenic expansion in 18 of 22 CANVAS-affected families and identified a core ancestral haplotype, estimated to have arisen in Europe more than twenty-five thousand years ago. WGS of the four RFC1-negative CANVAS-affected families identified plausible variants in three, with genomic re-diagnosis of SCA3, spastic ataxia of the Charlevoix-Saguenay type, and SCA45. This study identified the genetic basis of CANVAS and demonstrated that these improved bioinformatics tools increase the diagnostic utility of WGS to determine the genetic basis of a heterogeneous group of clinically overlapping neurogenetic disorders

Lithium side effects and toxicity: prevalence and management strategies

Despite its virtually universal acceptance as the gold standard in treating bipolar disorder, prescription rates for lithium have been decreasing recently. Although this observation is multifactorial, one obvious potential contributor is the side effect and toxicity burden associated with lithium. Additionally, side effect concerns assuredly play some role in lithium nonadherence. This paper summarizes the knowledge base on side effects and toxicity and suggests optimal management of these problems. Thirst and excessive urination, nausea and diarrhea and tremor are rather common side effects that are typically no more than annoying even though they are rather prevalent. A simple set of management strategies that involve the timing of the lithium dose, minimizing lithium levels within the therapeutic range and, in some situations, the prescription of side effect antidotes will minimize the side effect burden for patients. In contrast, weight gain and cognitive impairment from lithium tend to be more distressing to patients, more difficult to manage and more likely to be associated with lithium nonadherence. Lithium has adverse effects on the kidneys, thyroid gland and parathyroid glands, necessitating monitoring of these organ functions through periodic blood tests. In most cases, lithium-associated renal effects are relatively mild. A small but measurable percentage of lithium-treated patients will show progressive renal impairment. Infrequently, lithium will need to be discontinued because of the progressive renal insufficiency. Lithium-induced hypothyroidism is relatively common but easily diagnosed and treated. Hyperparathyroidism from lithium is a relatively more recently recognized phenomenon

Sustainable development and forestation rate in selected voivodships in Poland

This paper is an attempt to find interdependencies between selected variables of sustainable development and forestation rate. The scope of paper included 16 Polish Voivodships in the period 2004-2016. The descriptive method supplemented by tools of descriptive statistics has been used (Pearson Correlation Coefficient). Research results indicated above all high interdependency between forestation rate and EU funds for EU programmes and projects in Podlaskie, Śląskie and Warmińsko-Mazurskie Voivodships. Moreover, Voivodeships received support for afforestation in accordance with the arable land available for afforestation (land of lass V and VI). Voivodeships in which land of classes V and VI constituted about 20% of their area (Dolnośląskie, Lubuskie, Śląskie, Warmińsko-Mazurskie, and Zachodniopomorskie) received significant financial resources from the European Union for afforestation

Afforestation funded by RPD in the period 2007-2013: the example of Podlaskie and Wielkopolskie voivodships

The objective of this study is to identify differences between the afforestation subsidies from European Union (EU) obtained by beneficiaries from Podlaskie and Wielkopolskie Voivodships (918 and 618 beneficiaries respectively) as part of RDP 2007-2013. The survey results showed faster increase of forest rate growth in Podlaskie Voivodship, which is classified as a less economically developed region. When compared to Wielkopolskie Voivodship, Podlaskie Voivodship received higher subsidies; nevertheless, the average sum obtained (in thousand EURO) per beneficiary was lower in Podlaskie than in Wielkopolskie

Are major depression and bipolar disorder neuropsychologically distinct? A meta-analysis of comparative studies

Background: Neuropsychological deficits are present in both major depression and bipolar disorder. So far, however, reports directly comparing these mood disorders with regard to cognitive outcomes have been scant and yielded inconsistent results. This work aims to combine the findings of comparative studies of cognition in major depression and bipolar disorder in order to explore whether these neuropsychiatric conditions present with distinct cognitive features. Methods: The main online databases were extensively searched to retrieve reports assessing neurocognitive functioning in two groups of mood disorder patients, one with major depressive disorder and another with bipolar disorder, both in the same phase of illness. Between-group effect sizes for cognitive variables were obtained from selected studies and pooled by means of meta-analytic procedures. Results: During euthymia, a significant overall effect size (Hedges’g = 0.64, P < 0.001) favoring major depressive disorder was found for verbal memory as assessed with list learning tests, whereas no significant between-group differences were found for the remaining variables analyzed. During depressive episodes, similar cognitive outcomes were observed between groups. Conclusion: At present, it is not possible to postulate specific neuropsychological profiles for major depression and bipolar disorder in light of available evidence. It remains to be ascertained whether the differences found for verbal memory constitute an expression of distinct underlying mechanisms or whether they are best explained by sample characteristics or differential exposure to variables with a negative impact on cognition.Fil: Samame, Cecilia. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; Argentina. Universidad de Buenos Aires. Facultad de Psicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Szmulewicz, A. G.. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Emergencias Psiquiáicas "Torcuato de Alvear"; ArgentinaFil: Valerio, Marina Paula. Gobierno de la Ciudad de Buenos Aires. Hospital de Emergencias Psiquiáicas "Torcuato de Alvear"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Martino, Diego Javier. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Strejilevich, S. A.. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; Argentin

Characterization of Mood Instability through Bipolar Disorders: A cluster-analytic approach using weekly prospective life-chart methodology

BackgroundThe aim of this study was to characterize mood instability (MI) in Bipolar Disorder (BD) and to investigate potential differences between subtype I and II.MethodsLife-charts from weekly mood ratings of 90 patients were used to compute: weeks spent with symptoms, number of episodes, and MI. Regression analyses were conducted to assess the relationship between BD subtype and MI adjusting by all potential confounding factors. Hierarchical cluster analysis was performed to determine the appropriate number of clusters that described the data and to assign subjects to a specific cluster based on their MI. We then compared clusters on clinical and psychosocial outcomes.ResultsMedian follow-up was 5 years (IQR: 3.6?7.9). Patients spent 15.2%, 5%, and 3% of follow-up with depressive, manic, and mixed symptoms, respectively. BD type II presented higher MI (β = 1.83, 95% CI: 0.66?3.00) and subsydromal symptoms than BD type I patients. No differences in functioning or recurrences were found between subtypes. Differences in MI between the two clusters mimicked those between type I and II but enhanced (β = 3.86, 95%CI -4.72, -2.66). High MI (n = 43) patients presented poorer functioning and higher recurrences compared to Low MI patients (n = 43).ConclusionBD type II presented higher MI and subsyndromal symptoms than BD type I patients. However, these differences did not translate into clinically relevant outcomes. A classification based on MI may provide useful clinical insights.Fil: Szmulewicz, A.G.. Harvard University. Harvard School of Public Health; Estados UnidosFil: Martino, Diego Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Neurociencia Cognitiva. Fundación Favaloro. Instituto de Neurociencia Cognitiva; ArgentinaFil: Strejilevich, S. A.. Universidad Favaloro. Facultad de Medicina. Instituto de Neurociencias; Argentin