Search

Aim: Our aim was to describe the rearrangements of the brain activity related to genetic mutations in the SPAST gene. Methods: Ten SPG4 patients and ten controls underwent a 5 min resting state magnetoencephalography recording and neurological examination. A beamformer algorithm reconstructed the activity of 90 brain areas. The phase lag index was used to estimate synchrony between brain areas. The minimum spanning tree was used to estimate topological metrics such as the leaf fraction (a measure of network integration) and the degree divergence (a measure of the resilience of the network against pathological events). The betweenness centrality (a measure to estimate the centrality of the brain areas) was used to estimate the centrality of each brain area. Results: Our results showed topological rearrangements in the beta band. Specifically, the degree divergence was lower in patients as compared to controls and this parameter related to clinical disability. No differences appeared in leaf fraction nor in betweenness centrality. Conclusion: Mutations in the SPAST gene are related to a reorganization of the brain topology.

Monoallelic variants in the KIF1A gene are associated with a large set of clinical phenotypes including neurodevelopmental and neurodegenerative disorders, underpinned by a broad spectrum of central and peripheral nervous system involvement. In a multicenter study conducted in patients presenting spastic gait or complex neurodevelopmental disorders, we analyzed the clinical, genetic and neuroradiological features of 28 index cases harboring heterozygous variants in KIF1A. We conducted a literature systematic review with the aim to comparing our findings with previously reported KIF1A-related phenotypes. Among 28 patients, we identified nine novel monoallelic variants, and one a copy number variation encompassing KIF1A. Mutations arose de novo in most patients and were prevalently located in the motor domain. Most patients presented features of a continuum ataxia-spasticity spectrum with only five cases showing a prevalently pure spastic phenotype and six presenting congenital ataxias. Seventeen mutations occurred in the motor domain of the Kinesin-1A protein, but location of mutation did not correlate with neurological and imaging presentations. When tested in 15 patients, muscle biopsy showed oxidative metabolism alterations (6 cases), impaired respiratory chain complexes II + III activity (3/6) and low CoQ10 levels (6/9). Ubiquinol supplementation (1gr/die) was used in 6 patients with subjective benefit. This study broadened our clinical, genetic, and neuroimaging knowledge of KIF1A-related disorders. Although highly heterogeneous, it seems that manifestations of ataxia-spasticity spectrum disorders seem to occur in most patients. Some patients also present secondary impairment of oxidative metabolism; in this subset, ubiquinol supplementation therapy might be appropriate.

Purpose of ReviewWe summarized peer-reviewed literature on aggressive episodes perpetrated by adult patients admitted to general hospital units, especially psychiatry or emergency services. We examined the main factors associated with aggressive behaviors in the hospital setting, with a special focus on the European experience.Recent FindingsA number of variables, including individual, historical, and contextual variables, are significant risk factors for aggression among hospitalized people. Drug abuse can be considered a trans-dimensional variable which deserves particular attention.SummaryAlthough mental health disorders represent a significant component in the risk of aggression, there are many factors including drug abuse, past history of physically aggressive behavior, childhood abuse, social and cultural patterns, relational factors, and contextual variables that can increase the risk of overt aggressive behavior in the general hospital. This review highlights the need to undertake initiatives aimed to enhance understanding, prevention, and management of violence in general hospital settings across Europe.

AIM To examine the incidence of with first-episode psychosis (FEP) in the Integrated Department of Mental Health and Pathological Addictions in Ferrara, Italy, and to examine the association between the Duration of Untreated Psychosis (DUP) and the clinical course. METHODS Participants recruited in 2013-2019 were assessed with the Health of the Nation Outcome Scale (HoNOS) every 6 months for 24 months. Hierarchical growth models analysed changes of global severity (HoNOS total scores) and symptom dimensions. Regression modelled factors associated with remission (HoNOS

Spinocerebellar ataxia type 2 (SCA2) is among the most common forms of autosomal dominant ataxias, accounting for 15% of the total families. Occurrence is higher in specific populations such as the Cuban and Southern Italian. The disease is caused by a CAG expansion in ATXN2 gene, leading to abnormal accumulation of the mutant protein, ataxin‐2, in intracellular inclusions. The clinical picture is mainly dominated by cerebellar ataxia, although a number of other neurological signs have been described, ranging from parkinsonism to motor neuron involvement, making the diagnosis frequently challenging for neurologists, particularly when information about the family history is not available. Although the functions of ataxin‐2 have not been completely elucidated, the protein is involved in mRNA processing and control of translation. Recently, it has also been shown that the size of the CAG repeat in normal alleles represents a risk factor for ALS, suggesting that ataxin‐2 plays a fundamental role in maintenance of neuronal homeostasis.

Sixty-six patients with possible or probable MSA (multiple system atrophy) cerebellar type, personally observed between 2006 and 2018 were retrospectively reviewed. The time point of data collection was January 1, 2019. Forty-nine patients lost independent walking after a median time of 5 years (95% C. I. 4–6). Thirty-two patients were confined to wheelchair after a median time of 7 years (95% C. I. 7–8). Twenty-seven patients were deceased after a median time of 9 years (95% C. I. 8–10). A later onset predicted an earlier loss of independent walking (HR 1.07; 95% C.I. 1.03–1.11; p = 0.001). Higher UMSARS score predicted shorter time to loss of independent walking (HR 1.04; 95% C.I. 1.02–1.06; p = 0.001) and to wheelchair (HR 1.03; 95% C.I. 1.01–1.06; p = 0.021). No predictor of time to death was found.

INTRODUCTION Use of peripheral nerve ultrasound alongside standard electrodiagnostic tests may help to gain insight into the pathophysiology of peripheral nerve involvement in type 2 spinocerebellar ataxia (SCA2). METHODS Twenty-seven patients with SCA2 underwent ultrasound cross-sectional area (CSA) measurement of median, ulnar, sural and tibial nerves, and motor (median, ulnar, tibial) and sensory (median, ulnar, radial, sural) nerve conduction studies. RESULTS Twenty patients had pathologically small-nerve CSAs, suggestive of sensory neuronopathy. In these patients, electrophysiology showed non-length-dependent sensory neuropathy (14 of 20), "possible sensory neuropathy" (1 of 20), or normal findings (5 of 20). Four different patients had length-dependent sensory neuropathy on electrophysiology, and 1 had enlarged nerve CSAs. Regression analysis showed an inverse relationship between ataxia scores and upper limb nerve CSA (P

Introduction: There are several reported cases of patients developing motor and cognitive neurological impairment under treatment with valproic acid (VPA). We describe a woman who developed a subacute encephalopathy after VPA intake, harboring a mitochondrial DNA variant, previously described as causing VPA sensitivity in one pediatric patient. Material and Methods: A 65-year old woman developed a progressive, severe neurological deterioration after a 3 month treatment with valproate sodium, 800 mg daily. Magnetic resonance spectroscopy (MRS), muscle histochemical analysis and assay of mitochondrial enzymatic activities, and mitochondrial DNA sequencing were performed. Results: Neurological examination showed drowsiness, vertical gaze palsy, inability to either stand or walk, diffuse weakness, increased tendon reflexes. Blood lactate was increased, EEG showed diffuse theta and delta activity, MRI subcortical atrophy and leukoencephalopathy, MRS marked reduction of the NAA spectrum, with a small signal compatible with presence of lactate. Muscle biopsy evidenced presence of ragged red fibers (20%) and reduced COX reactivity. Assay of the muscle enzymatic activities showed multiple deficiencies of the electron transport chain and reduced ATP production. The mt.8393C>T variant in the MT-ATP8 gene was found in homoplasmy. The patient considerably improved after valproate withdrawal. Conclusion: The variant we found has been reported both as a polymorphism and, in a single patient, as related to the valproate-induced encephalopathy. The present case is the first bearing this mutation in homoplasmy. In case of neurological symptoms after starting VPA therapy, once hyperammonemia and liver failure have been ruled out, mtDNA abnormalities should be considered.

Summary Background Spinocerebellar ataxias are dominantly inherited progressive ataxia disorders that can lead to premature death. We aimed to study the overall survival of patients with the most common spinocerebellar ataxias (SCA1, SCA2, SCA3, and SCA6) and to identify the strongest contributing predictors that affect survival. Methods In this longitudinal cohort study (EUROSCA), we enrolled men and women, aged 18 years or older, from 17 ataxia referral centres in ten European countries; participants had positive genetic test results for SCA1, SCA2, SCA3, or SCA6 and progressive, otherwise unexplained, ataxias. Survival was defined as the time from enrolment to death for any reason. We used the Cox regression model adjusted for age at baseline to analyse survival. We used prognostic factors with a p value less than 0·05 from a multivariate model to build nomograms and assessed their performance based on discrimination and calibration. The EUROSCA study is registered with ClinicalTrials.gov, number NCT02440763. Findings Between July 1, 2005, and Aug 31, 2006, 525 patients with SCA1 (n=117), SCA2 (n=162), SCA3 (n=139), or SCA6 (n=107) were enrolled and followed up. The 10-year survival rate was 57% (95% CI 47–69) for SCA1, 74% (67–81) for SCA2, 73% (65–82) for SCA3, and 87% (80–94) for SCA6. Factors associated with shorter survival were: dysphagia (hazard ratio 4·52, 95% CI 1·83–11·15) and a higher value for the Scale for the Assessment and Rating of Ataxia (SARA) score (1·26, 1·19–1·33) for patients with SCA1; older age at inclusion (1·04, 1·01–1·08), longer CAG repeat length (1·16, 1·03–1·31), and higher SARA score (1·15, 1·10–1·20) for patients with SCA2; older age at inclusion (1·44, 1·20–1·74), dystonia (2·65, 1·21–5·53), higher SARA score (1·26, 1·17–1·35), and negative interaction between CAG and age at inclusion (0·994, 0·991–0·997) for patients with SCA3; and higher SARA score (1·17, 1·08–1·27) for patients with SCA6. The nomogram-predicted probability of 10-year survival showed good discrimination ( c index 0·905 [SD 0·027] for SCA1, 0·822 [0·032] for SCA2, 0·891 [0·021] for SCA3, and 0·825 [0·054] for SCA6). Interpretation Our study provides quantitative data on the survival of patients with the most common spinocerebellar ataxias, based on a long follow-up period. These results have implications for the design of future interventional studies of spinocerebellar ataxias; for example, the prognostic survival nomogram could be useful for selection and stratification of patients. Our findings need validation in an external population before they can be used to counsel patients and their families. Funding European Union 6th Framework programme, German Ministry of Education and Research, Polish Ministry of Scientific Research and Information Technology, European Union 7th Framework programme, and Fondation pour la Recherche Medicale.

One hundred-eighteen spinocerebellar ataxia type 2 patients from 35 distinct families personally observed between 1973 and 2016 were retrospectively reviewed. The time point of data collection was 1 January 2017. Thirty-one patients were confined to wheelchair. The median time to wheelchair was 21 years (95% CI, 17.5-24.6). Thirty-seven patients were deceased. The median time to death was 25 years (95% CI, 22.9-27.1). CAG repeat number and ataxia score at first visit influenced the time to wheelchair and death.

Animal-assisted therapy (AAT) includes a set of nonpharmacological interventions aimed at improving human health through the use of trained or untrained animals. In recent decades, AAT has been trialed for different neurological and psychiatric disorders. In patients with dementia, interaction with animals seems to have a positive influence on aggressiveness and anxiety and to ameliorate quality of life and relationship skills. In psychiatric patients, AAT seems to increase motivation and self-esteem, improve prosocial conduct, and decrease behavioral problems. The aim of this study is to review the literature on AAT for elderly people with dementia and psychiatric disorders. Other fields of possible application for AAT are suggested.

Hereditary spastic paraplegia (HSP) refers to a group of genetically heterogeneous neurodegenerative motor neuron disorders characterized by progressive age-dependent loss of corticospinal motor tract function, lower limb spasticity, and weakness. Recent clinical use of next generation sequencing (NGS) methodologies suggests that they facilitate the diagnostic approach to HSP, but the power of NGS as a first-tier diagnostic procedure is unclear. The larger-than-expected genetic heterogeneity—there are over 80 potential disease-associated genes—and frequent overlap with other clinical conditions affecting the motor system make a molecular diagnosis in HSP cumbersome and time consuming. In a single-center, cross-sectional study, spanning 4 years, 239 subjects with a clinical diagnosis of HSP underwent molecular screening of a large set of genes, using two different customized NGS panels. The latest version of our targeted sequencing panel (SpastiSure3.0) comprises 118 genes known to be associated with HSP. Using an in-house validated bioinformatics pipeline and several in silico tools to predict mutation pathogenicity, we obtained a positive diagnostic yield of 29% (70/239), whereas variants of unknown significance (VUS) were found in 86 patients (36%), and 83 cases remained unsolved. This study is among the largest screenings of consecutive HSP index cases enrolled in real-life clinical-diagnostic settings. Its results corroborate NGS as a modern, first-step procedure for molecular diagnosis of HSP. It also disclosed a significant number of new mutations in ultra-rare genes, expanding the clinical spectrum, and genetic landscape of HSP, at least in Italy.

To study the long-term evolution of patient-reported outcome measures (PROMs) in the most common spinocerebellar ataxias (SCAs), we analyzed 8 years follow-up data of the EUROSCA Natural History Study, a cohort study of 526 patients with SCA1, SCA2, SCA3 and SCA6. To assess the functional capacity in daily living, we used the functional assessment (part IV) of the Unified Huntington’s Disease Rating Scale (UHDRS-IV), for health-related quality of life the visual analogue scale of the EuroQol Five Dimensions Questionnaire (EQ-5D VAS), and for depressive symptoms the Patient Health Questionnaire (PHQ-9). Severity of ataxia was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and neurological symptoms other than ataxia with the Inventory of Non-Ataxia Signs (INAS). UHDRS-IV [SCA1: − 1.35 (0.12); SCA2: − 1.15 (0.11); SCA3: − 1.16 (0.11); SCA6: − 0.99 (0.12)] and EQ-5D [SCA1: − 2.88 (0.72); SCA2: − 1.97 (0.49); SCA3: − 2.06 (0.55); SCA6: − 1.03 (0.57)] decreased linearly, whereas PHQ-9 increased [SCA1: 0.15 (0.04); SCA2: 0.09 (0.03); SCA3: 0.06 (0.04); SCA6: 0.07 (0.04)] during the observational period. Standard response means (SRMs) of UHDRS-IV (0.473–0.707) and EQ-5D VAS (0.053–0.184) were lower than that of SARA (0.404–0.979). In SCA1, higher SARA scores [− 0.0288 (0.01), p = 0.0251], longer repeat expansions [− 0.0622 (0.02), p = 0.0002] and the presence of cognitive impairment at baseline [− 0.5381 (0.25), p = 0.0365] were associated with faster UHDRS-IV decline. In SCA3, higher INAS counts were associated with a faster UHDRS-IV decline [− 0.05 (0.02), p = 0.0212]. In SCA1, PHQ-9 progression was faster in patients with cognitive impairment [0.14 (0.07); p = 0.0396]. In the common SCAs, PROMs give complementary information to the information provided by neurological scales. This underlines the importance of PROMs as additional outcome measures in future interventional trials.

International audience; Importance: Molecular diagnosis is difficult to achieve in disease groups with a highly heterogeneous genetic background, such as cerebellar ataxia (CA). In many patients, candidate gene sequencing or focused resequencing arrays do not allow investigators to reach a genetic conclusion. Objectives: To assess the efficacy of exome-targeted capture sequencing to detect mutations in genes broadly linked to CA in a large cohort of undiagnosed patients and to investigate their prevalence. Design, Setting, and Participants: Three hundred nineteen index patients with CA and without a history of dominant transmission were included in the this cohort study by the Spastic Paraplegia and Ataxia Network. Centralized storage was in the DNA and cell bank of the Brain and Spine Institute, Salpetriere Hospital, Paris, France. Patients were classified into 6 clinical groups, with the largest being those with spastic ataxia (ie, CA with pyramidal signs [n = 100]). Sequencing was performed from January 1, 2014, through December 31, 2016. Detected variants were classified as very probably or definitely causative, possibly causative, or of unknown significance based on genetic evidence and genotype-phenotype considerations. Main Outcomes and Measures: Identification of variants in genes broadly linked to CA, classified in pathogenicity groups. Results: The 319 included patients had equal sex distribution (160 female [50.2%] and 159 male patients [49.8%]; mean [SD] age at onset, 27.9 [18.6] years). The age at onset was younger than 25 years for 131 of 298 patients (44.0%) with complete clinical information. Consanguinity was present in 101 of 298 (33.9%). Very probable or definite diagnoses were achieved for 72 patients (22.6%), with an additional 19 (6.0%) harboring possibly pathogenic variants. The most frequently mutated genes were SPG7 (n = 14), SACS (n = 8), SETX (n = 7), SYNE1 (n = 6), and CACNA1A (n = 6). The highest diagnostic rate was obtained for patients with an autosomal recessive CA with oculomotor apraxia-like phenotype (6 of 17 [35.3%]) or spastic ataxia (35 of 100 [35.0%]) and patients with onset before 25 years of age (41 of 131 [31.3%]). Peculiar phenotypes were reported for patients carrying KCND3 or ERCC5 variants. Conclusions and Relevance: Exome capture followed by targeted analysis allows the molecular diagnosis in patients with highly heterogeneous mendelian disorders, such as CA, without prior assumption of the inheritance mode or causative gene. Being commonly available without specific design need, this procedure allows testing of a broader range of genes, consequently describing less classic phenotype-genotype correlations, and post hoc reanalysis of data as new genes are implicated in the disease.

Background: Spinocerebellar ataxias are rare dominantly inherited neurodegenerative diseases that lead to severe disability and premature death. Objective: To quantify the impact of disease progression measured by the Scale for the Assessment and Rating of Ataxia on survival, and to identify different profiles of disease progression and survival. Methods: Four hundred sixty-two spinocerebellar ataxia patients from the EUROSCA prospective cohort study, suffering from spinocerebellar ataxia type 1, spinocerebellar ataxia type 2, spinocerebellar ataxia type 3, and spinocerebellar ataxia type 6, and who had at least two measurements of Scale for the Assessment and Rating of Ataxia score, were analyzed. Outcomes were change over time in Scale for the Assessment and Rating of Ataxia score and time to death. Joint model was used to analyze disease progression and survival. Results: Disease progression was the strongest predictor for death in all genotypes: An increase of 1 standard deviation in total Scale for the Assessment and Rating of Ataxia score increased the risk of death by 1.28 times (95% confidence interval: 1.18–1.38) for patients with spinocerebellar ataxia type 1; 1.19 times (1.12–1.26) for spinocerebellar ataxia type 2; 1.30 times (1.19–1.42) for spinocerebellar ataxia type 3; and 1.26 times (1.11–1.43) for spinocerebellar ataxia type 6. Three subgroups of disease progression and survival were identified for patients with spinocerebellar ataxia type 1: “severe” (n = 13; 12%), “intermediate” (n = 31; 29%), and “moderate” (n = 62; 58%). Patients in the severe group were more severely affected at baseline with higher Scale for the Assessment and Rating of Ataxia scores and frequency of nonataxia signs compared to those in the other groups. Conclusion: Rapid ataxia progression is associated with poor survival of the most common spinocerebellar ataxia. Theses current results have implications for the design of future interventional studies of spinocerebellar ataxia. © 2019 International Parkinson and Movement Disorder Society., SCOPUS: ar.j, info:eu-repo/semantics/published

Item does not contain fulltext BACKGROUND: Spinocerebellar ataxias are dominantly inherited neurodegenerative diseases. As potential treatments for these diseases are being developed, precise knowledge of their natural history is needed. We aimed to study the long-term disease progression of the most common spinocerebellar ataxias: SCA1, SCA2, SCA3, and SCA6. Furthermore, we aimed to establish the order and occurrence of non-ataxia symptoms, and identify predictors of disease progression. METHODS: In this longitudinal cohort study (EUROSCA), we enrolled men and women with positive genetic testing for SCA1, SCA2, SCA3, or SCA6 and with progressive, otherwise unexplained ataxia who were aged 18 years or older from 17 ataxia referral centres in ten European countries. Patients were seen every year for 3 years, and at irregular intervals thereafter. The primary outcome was the scale for the assessment and rating of ataxia (SARA), and the inventory of non-ataxia signs (INAS). We used linear mixed models to analyse progression. To account for dropouts, we applied a pattern-mixture model. This study is registered with ClinicalTrials.gov, number NCT02440763. FINDINGS: Between July 1, 2005, and Aug 31, 2006, 526 patients with SCA1, SCA2, SCA3, or SCA6 were enrolled. We analysed data for 462 patients with at least one follow-up visit. Median observation time was 49 months (IQR 35-72). SARA progression data were best fitted with a linear model in all genotypes. Annual SARA score increase was 2.11 (SE 0.12) in patients with SCA1, 1.49 (0.07) in patients with SCA2, 1.56 (0.08) in patients with SCA3, and 0.80 (0.09) in patients with SCA6. The increase of the number of non-ataxia signs reached a plateau in SCA1, SCA2, and SCA3. In patients with SCA6, the number of non-ataxia symptoms increased linearly, but more slowly than in patients with SCA1, SCA2, and SCA3 (p

Rasmussen's encephalitis (RE) is an immune-mediated disease, typically affecting a single cerebral hemisphere. Intractable epilepsy, hemiplegia and cognitive decline represent the clinical features; movement disorders have rarely been described. We report a case of adult-onset RE which developed hemiparkinsonism after an extraordinarily long prodromal period; to date, this is the first description of parkinsonism in RE. The association between cortical symptoms and extrapyramidal features evokes a clinical suspect of corticobasal syndrome (CBS); our patient satisfies the diagnostic criteria for possible CBS. Clinical and neuro-radiological reasons might further explain why RE accompanied by extrapyramidal signs may present as a CBS.

SPG5 is a rare subtype of Hereditary Spastic Paraplegia caused by mutations in the oxysterol-7 alpha-hydroxylase gene CYP7B1. Schols et al. study properties of lipid biomarkers in SPG5 and evaluate a treatment strategy targeting oxysterol accumulation in a randomized controlled trial (STOP-SPG5).Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7 alpha-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683-1113] to 641 (IQR 507-694) (-31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.

Background and objective The prevalence and clinical consequences of diaphragmatic dysfunction (DD) during acute exacerbations of COPD (AECOPD) remain unknown. The aim of this study was (i) to evaluate the prevalence of DD as assessed by ultrasonography (US) and (ii) to report the impact of DD on non-invasive mechanical ventilation (NIV) failure, length of hospital stay and mortality in severe AECOPD admitted to respiratory intensive care unit (RICU). Methods Forty-one consecutive AECOPD patients with respiratory acidosis admitted over a 12-month period to the RICU of the University Hospital of Modena were studied. Diaphragmatic ultrasound (DU) was performed on admission before starting NIV. A change in diaphragmatic thickness (ΔTdi) less than 20% during spontaneous breathing was considered to confirm the presence of dysfunction (DD+). NIV failure and other clinical outcomes (duration of mechanical ventilation MV, tracheostomy, length of hospital stay and mortality) were recorded. Results A total of 10 out of 41 patients (24.3%) presented DD+, which was significantly associated with steroid use (P = 0.002, R-squared = 0.19). DD+ correlated with NIV failure (P

Background Spinocerebellar ataxias (SCAs) are dominantly inherited, progressive ataxia disorders. Disease progression could be preceded by weight loss. Objectives We aimed to study the course of weight loss in patients who had the most common SCAs (SCA1, SCA2 SCA3, and SCA6). Additional objectives were to identify subgroups of weight evolution, to determine the factors influencing these evolutions, and to assess the impact of these evolutions on disease progression. Methods In total, 384 patients from the EUROSCA prospective cohort study were analyzed who had SCA1, SCA2, SCA3, or SCA6 and at least 3 measurements of weight. Age was used as a time scale. Clinical outcomes were body mass index (BMI) and the Scale for the Assessment and Rating Ataxia (SARA), with scores ranging from 0 to 40. We used a linear mixed model to analyze the course of BMI and a latent class mixed model to identify subgroup BMI evolution. Results Overall, BMI declined over time (−0.11 ± 0.03 kg/m2 per decade; P = 0.0009). Three subgroups of BMI evolution were identified: “decreasing BMI” (n = 88; 23%), “increasing BMI” (n = 70; 18%) and “stable BMI” (n = 226; 59%). Patients in the decreasing BMI group were more severely affected at baseline with higher SARA scores and a higher frequency of non-ataxia signs (especially motor symptoms) compared with those in the other groups. Weight loss was associated with faster disease progression (5.7 ± 0.7 SARA points per decade; P = 0.036). Conclusions The current data have substantial implications for the design of future interventional studies in SCA, as they provide a basis for patient stratification and emphasize the usefulness of BMI as a biomarker for monitoring disease progression.

Summary Background Spinocerebellar ataxias (SCAs) are autosomal, dominantly inherited, fully penetrant neurodegenerative diseases. Our aim was to study the preclinical stage of the most common SCAs: SCA1, SCA2, SCA3, and SCA6. Methods Between Sept 13, 2008, and Dec 1, 2011, offspring or siblings of patients with SCA1, SCA2, SCA3, or SCA6 were enrolled into a prospective, longitudinal observational study at 14 European centres. To be eligible for inclusion in our study, individuals had to have no ataxia and be aged 18–50 years if directly related to individuals with SCA1, SCA2, or SCA3, or 35–70 years if directly related to individuals with SCA6. We did anonymous genetic testing to identify mutation carriers. We assessed participants with clinical scales, questionnaires, and performance-based coordination tests. In eight of the 14 centres, participants underwent MRI. We analysed relations between outcome variables and time from onset (defined as the difference between present age and estimated age at ataxia onset). This study is registered with ClinicalTrials.gov, number NCT01037777. Findings 276 participants met inclusion criteria and agreed to participate, of whom 12 (4%) were excluded from final analysis because DNA samples were missing or genotyping failed. Estimated time from onset was −9 years (IQR −13 to −6) in 50 carriers of the SCA1 mutation, −12 years (–15 to −9) in 31 SCA2 mutation carriers, −8 years (–11 to −6) in 26 SCA3 mutation carriers, and −18 years (–22 to −16) in 16 SCA6 mutation carriers. Compared with non-carriers of each mutation, SCA1 mutation carriers had higher median scores on the scale for the assessment and rating of ataxia (SARA; 0·5 [IQR 0–1·0] vs 0 [0–0]; p=0·0052), as did SCA2 mutation carriers (0·5 [0–2·0] vs 0 [0–0·5]; p=0·0037). SCA2 mutation carriers had lower SCA functional index scores than did non-carriers (–0·43 [–0·91 to −0·07] vs 0·09 [–0·30 to 0·56]; p=0·0007). SCA2 mutation carriers had worse composite cerebellar functional scores than did their non-carrier counterparts (0·915 [0·861–0·959] vs 0·849 [0·764–0·886]; p=0·0039). All other differences between carriers and non-carriers were non-significant. In SCA1 and SCA2 mutation carriers, SARA scores were increased in participants who were closer to the estimated age at onset (SCA1: r =0·36, p=0·0112; SCA2: r =0·50, p=0·0038). 83 individuals (30%) underwent MRI. Voxel-based morphometry showed grey-matter loss in the brainstem and cerebellum in SCA1 and SCA2 mutation carriers, and normalised brainstem volume was lower in SCA2 mutation carriers (median 0·015, range 0·012–0·016) than in non-carriers (0·019, 0·017–0·021; p=0·0107). Interpretation Preclinical SCA1 and SCA2 mutation carriers seem to have mild coordination deficits and abnormalities in the brain that are more common in carriers who are closer to the estimated onset of ataxia. Individuals in this early disease stage could be targeted in future preventive trials. Funding ERA-Net E-Rare and Polish Ministry of Science and Higher Education.

Background The evolution of the techniques used in the intensive care setting over the past decades has led on one side to better survival rates in patients with acute conditions and severely impaired vital functions. On the other side, it has resulted in a growing number of patients who survive an acute event, but who then become dependent on one or more life support techniques. Such patients are called chronically critically ill patients. Materials & Methods No absolute definition of the disease is currently available, although most patients are characterized by the need for prolonged mechanical ventilation. Mortality rates are still high even after dismissal from intensive care unit (ICU) and transfer to specialized rehabilitation care settings. Results In recent years, some studies have tried to clarify the pathophysiological characteristics underlying chronic critical illness (CCI), a disease that is also characterized by severe endocrine and inflammatory impairments, partly accounting for the almost constant set of symptoms. Discussion Currently, no specific treatment is available. However, a strategic early therapeutic approach on ICU admission might try to prevent the progress of the acute disease towards chronic critical illness.

Chorea is a movement disorder which may be associated with immunologic diseases, in particular in the presence of antiphospholipid antibodies (aPL). Choreic movements have been linked to the isolated presence of plasmatic aPL, or to primary, or secondary antiphospholipid syndrome. The highest incidence of aPL-related chorea is detected in children and females. The presentation of chorea is usually subacute and the course monophasic. Choreic movements can be focal, unilateral, or generalized. High plasmatic titers of aPL in a choreic patient can suggest the diagnosis of aPL-related chorea; neuroimaging investigation does not provide much additional diagnostic information. The most relevant target of aPL is β2-glycoprotein I, probably responsible for the thrombotic manifestations of antiphospholipid syndrome. Etiology of the movement disorder is not well understood but a neurotoxic effect of aPL has been hypothesized, leading to impaired basal ganglia cell function and development of neuroinflammation. Patients affected by aPL-related chorea have an increased risk of thrombosis and should receive antiplatelet or anticoagulant treatment.

Mutations in the SPG3A gene represent a significant cause of autosomal dominant hereditary spastic paraplegia with early onset and pure phenotype. We describe an Italian family manifesting a complex phenotype, characterized by cerebellar involvement in the proband and amyotrophic lateral sclerosis-like syndrome in her father, in association with a new mutation in SPG3A. Our findings further widen the notion of clinical heterogeneity in SPG3A mutations.

To the Editor: Mycobacterium marseillense was recently described as a new species belonging to the Mycobacterium avium complex (MAC) (1). We describe a case of pulmonary disease caused by M. marseillense in an immunocompetent patient. All strains isolated from the patient were preliminarily identified as M. intracellulare; however, a retrospective molecular analysis corrected the identification to M. marseillense. In December 2005, a 65-year-old man was admitted to the University Hospital, Modena, Italy, with a 2-week history of fever, cough, and hemoptysis. Physical examination detected diffuse rales, and chest radiographs showed a diffuse nodular opacity and bronchial thickening, confirmed by high-resolution computed tomography (CT) of the chest (Figure, panel A). The patient had experienced several previous episodes of hemoptysis and persistent productive cough since 1998, and tubular bronchiectasis had been detected on previous high-resolution CT images. The patient had a history of thalassemia minor, was HIV negative, and was formerly a mild smoker (10 cigarettes/day for 4 years during his youth). He had no chronic disorders and no history of immunosuppressive-drug or alcohol use. Figure High-resolution computed tomographic chest images of a man with prolonged pulmonary disease caused by Mycobacterium marseillense, Italy. A) October 6, 2005. Bilateral bronchiectasis, mainly in the middle lobe and lingula, associated with multiple nodules ... Bacterial and fungal cultures and a smear for acid-fast bacilli performed on a bronchoalveolar lavage (BAL) sample were all negative. A nontuberculous mycobacterium strain was isolated by culture and preliminarily identified as M. intracellulare by using the GenoType Mycobacterium CM/AS Kit (Hain Lifesciences, Nehren, Germany). At that time, a drug susceptibility test for isoniazid, rifampin, streptomycin, and ethambutol was improperly performed (i.e., was not applicable for MAC) by using the agar proportion method; sensitivity information for macrolides was unavailable. The strain was resistant to ethambutol and susceptible to the other drugs. The physician prescribed rifampin, isoniazid, and amikacin. After remission of fever and hemoptysis and improvement of chronic cough, the patient was discharged from the hospital. In March 2006, he was readmitted to the hospital for worsening of his condition and onset of side effects associated with rifampin and isoniazid use. The treatment was discontinued and replaced by levofloxacin, terizidone, and azithromycin, which resulted in remission of symptoms. This therapy was continued after hospital discharge. In 2007, the patient was twice admitted for follow-up and microbiological testing to determine bacteriologic status. All 3 separate sputum samples were negative for mycobacteria, other bacteria, and fungi. However, BAL sample culture results were positive for the same mycobacterium despite continued therapy with levofloxacin, terizidone, and azithromycin. During 2008, as an investigation of the possibility of persistent excretion of organisms, additional samples were collected 5 times. The sputum cultures were intermittently positive, while the BAL sample cultures were persistently positive. In May 2009, after the patient had been persistently stable and had negative culture results for 14 months, the antimicrobial drug therapy was stopped. In December 2010, the patient’s only symptom was persistent productive cough; however, the sputum culture was again positive, and high-resolution CT revealed a worsening condition of his lungs (Figure, panel B). A new antimycobacterial drug regimen of ethambutol, rifampin, and azithromycin was started, in accordance with the international guidelines of the American Thoracic Society and the Infectious Diseases Society of America (2). After the patient had received 6 months of therapy, the sputum culture result was again negative. The acid-fast bacilli smear and culture results remained negative until November 2012. The latest treatment resulted in recovery from symptoms and a more stable condition. However, cough and sputum production, although attenuated, persisted despite treatment and negative microbiological test results. High-resolution CT images (Figure, panel C) indicated overall progression of pulmonary involvement from the time of first admission. In February 2011, on the basis of the known cross-reactivity of the M. intracellulare probe with most MAC species when the GenoType Mycobacterium CM/AS assay is used (3), we determined the sequences of a portion of the rpoB gene and internal transcribed spacer–1 region in 2 strains isolated from sputum in March 2006 and June 2010. All sequences overlapped with M. marseillense type strain sequences in GenBank, showing an identity of 100% in internal transcribed spacer–1 with {"type":"entrez-nucleotide","attrs":{"text":"EU266631","term_id":"167515227","term_text":"EU266631"}}EU266631 and 99.8% (1 mismatch) in rpoB with {"type":"entrez-nucleotide","attrs":{"text":"EF584434","term_id":"157851003","term_text":"EF584434"}}EF584434. We therefore show the association of M. marseillense infection with pulmonary disease in an immunocompetent patient, helping define the clinical features and natural history of pulmonary disease caused by M. marseillense. We cannot assert whether the clinical course is associated with the intrinsic characteristics of M. marseillense infection or with the therapeutic regimen, possibly influenced by numerous adverse effects that may have compromised its effectiveness. More careful management in accordance with the American Thoracic Society and the Infectious Diseases Society of America guidelines for management of nontuberculous mycobacterial diseases could have achieved a more effective course of treatment. More case reports of pulmonary disease caused by M. marseillense are needed to support our observations and to provide more insight into its clinical picture.