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.
Summary 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<0·0001). Factors that were associated with faster progression of the SARA score were short duration of follow-up (p=0·0179), older age at inclusion (0.04 SE 0·02 per additional year; p=0·0476), and longer repeat expansions (0·06 SE 0·02 per additional repeat unit; p=0·0128) in SCA1, short duration of follow-up (p<0·0001), lower age at onset (–0·02 SE 0·01 per additional year; p=0·0014), and lower baseline SARA score (–0·02 SE 0·01 per additional SARA point; p=0·0083) in SCA2, and lower baseline SARA score (–0·03 SE 0·01 per additional SARA point; p=0·0195) in SCA6. In SCA3, we did not identify factors that affected progression of the SARA score. Interpretation Our study provides quantitative data on the progression of the most common spinocerebellar ataxias based on a follow-up period that exceeds those of previous studies. Our data could prove useful for sample size calculation and patient stratification in interventional trials. Funding EU FP6 (EUROSCA), German Ministry of Education and Research (BMBF; GeneMove), Polish Ministry of Science, EU FP7 (NEUROMICS).
Abstract Purpose To determine the prognostic factors of long-term visual outcome in Birdshot Retinochoroidopathy (BRC). Methods Design: Retrospective case series. Study population Successive HLA-A29+ ...BRC patients whose latest visit was between May and August 2013 at a single tertiary centre (Pitié-Salpétrière Hospital, Paris). Observation procedure Endpoint visual status (remission or deterioration) was determined for each patient based on clinical and ancillary data from the latest visit including optical coherence tomography (OCT), automated visual field (AVF) and angiograms. Main outcome measure Epidemiological, clinical, OCT, AVF, angiographic and electrophysiological data at baseline were correlated to final visual status. Results 55 patients were included. Mean observation period was 8 years (range: 0.6-23). Mean disease duration was 9.8 years (range: 1.2-32.7). Female-to-male sex ratio was 1.6. Factors of good visual prognosis (Remission vs Deterioration) included at baseline: late age of disease onset (49.5 vs 45 years, p=0.05), presence of vitreous inflammatory reactions>2+ (35.9% vs 6.2%, p=0.04), vascular leakage on fluorescein angiograms (FA) (44.4% vs 12.5%, p=0.03) absence of macular pigment epithelium atrophy on FA (88,9% vs 62,5%, p=0.05) and presence of macular oedema on OCT (33.3% vs 6.2%, p=0.04). Preserved electro-oculography light peak and Arden ratio (p=0.06), and presence of choroidal spots on ICG angiograms (80% vs 53.3%, p=0.08) seemed associated with the best prognoses. Conclusion This study suggests a series of prognostic factors of long-term visual outcome in BRC. Keeping in mind the insidious evolution of the disease, knowledge of such prognostic factors should help tailor the treatment and monitoring of Birdshot patients.
•The clinical heterogeneity of hereditary spastic paraplegia is unpredictable.•Perception of spasticity is modified by intrinsic and extrinsic factors.•Participants report that stressful situations ...exacerbate spasticity.•Physiotherapy most effectively reduces lower limb spasticity.•Physiotherapy and physical activity should be performed at least 3 times a week.
Background: Phenotypic variability is a consistent finding in neurogenetics and therefore applicable to hereditary spastic paraparesis. Identifying reasons for this variability is a challenge. We hypothesized that, in addition to genetic modifiers, extrinsic factors influence variability.
Objectives: Our aim was to describe the clinical variability in hereditary spastic paraparesis from the person's perspective. Our goals were to identify individual and environmental factors that influence muscle tone disorders and derive interventions which could improve spasticity.
Methods: This study was based on self-assessments with questions on nominal and ordinal scales completed by participants with hereditary spastic paraparesis. A questionnaire was completed either in-person in the clinic or electronically via lay organization websites.
Results: Among the 325 responders, most had SPG4/SPAST (n = 182, 56%) with a mean age at onset of 31.7 (SD 16.7) years and a mean disease duration of 23 (SD 13.6) years at the time of participation. The 2 factors identified as improving spasticity for > 50% of the responders were physiotherapy (193/325, 59%), and superficial warming (172/308, 55%). Half of the responders (n = 164, 50%) performed physical activity at least once a month and up to once a week. Participants who reported physiotherapy as effective were significantly more satisfied with ≥ 3 sessions per week. Psychologically stressful situations (246/319, 77%) and cold temperatures (202/319, 63%) exacerbated spasticity for most participants.
Conclusion: Participants perceived that physiotherapy reduced spasticity and that the impact of physiotherapy on spasticity was much greater than other medical interventions. Therefore, people should be encouraged to practice physical activity at least 3 times per week. This study reported participants’ opinions: in hereditary spastic paraparesis only functional treatments exist, therefore the participant's expertise is of particular importance.
Purpose Macular edema is the leading cause of vision loss in bilateral chronic non-infectious posterior uveitis, and is used to being treated using corticosteroids, immunosuppressive agents and ...biotherapies. The aim of this trial was to assess and compare the efficacy and safety of corticosteroids and IFN-α in adults with such conditions. Study design Randomized controlled trial Subjects Adult patients with bilateral posterior autoimmune non-infectious and non-tumoral uveitis complicated by macular edema in at least one eye, were recruited. Intervention Patients received either subcutaneous IFN-α2a, systemic corticosteroids or no treatment for 4 months. The efficacy and safety were assessed for up to 4 months. Main outcome The main endpoint was the change of the central foveal thickness (CFT) obtained by optical coherence tomography. Results Forty-eight patients were included. In intention-to-treat analysis, the median CFT change showed no significant difference. However, the per-protocol analysis showed a significant difference between groups for both eyes (OD and OS), and for the worse and better eyes. Statistically significant difference was found between the control and corticosteroid groups for the OD (p=0.0285), and between the control and IFN-α groups for the OD (p=0.0424) and worse eye (p=0.0354). Serious adverse events occurred in two patients in IFN group, in one patient in corticosteroid group, in two patients in the control group and were completely resolved after switch. Conclusions IFN-α and systemic corticosteroids, compared to no treatment, were associated with significant anatomic and visual improvement shown in the per-protocol study.
