Tanja Schmitz-Hübsch

Reliability and Validity of the international cooperative ataxia rating scale: A study in 156 spinocerebellar ataxia patients

To evaluate the efficacy of treatments in spinocerebellar ataxias (SCAs), appropriate clinical scales are required. This study evaluated metric properties of the International Cooperative Ataxia Rating Scale (ICARS) in 156 SCA patients and 8 controls. ICARS was found to be a reliable scale satisfying accepted criteria for interrater reliability, test–retest reliability, and internal consistency. Although validity testing was limited, we found evidence of validity of ICARS when ataxia disease stages and Barthel index were used as external criteria. On the other hand, our study revealed two major problems associated with the use of ICARS. First, the redundant and overlapping nature of several items gave rise to a considerable number of contradictory ratings. Second, a factorial analysis showed that the rating results were determined by four different factors that did not coincide with the ICARS subscales, thus questioning the justification of ICARS subscore analysis in clinical trials.

Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: A longitudinal cohort study

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).

Connectivity Predicts deep brain stimulation outcome in Parkinson disease

The benefit of deep brain stimulation (DBS) for Parkinson disease (PD) may depend on connectivity between the stimulation site and other brain regions, but which regions and whether connectivity can predict outcome in patients remain unknown. Here, we identify the structural and functional connectivity profile of effective DBS to the subthalamic nucleus (STN) and test its ability to predict outcome in an independent cohort.

Accuracy and Reliability of the Kinect Version 2 for Clinical Measurement of Motor Function

Background The introduction of low cost optical 3D motion tracking sensors provides new options for effective quantification of motor dysfunction. Objective The present study aimed to evaluate the Kinect V2 sensor against a gold standard motion capture system with respect to accuracy of tracked landmark movements and accuracy and repeatability of derived clinical parameters. Methods Nineteen healthy subjects were concurrently recorded with a Kinect V2 sensor and an optical motion tracking system (Vicon). Six different movement tasks were recorded with 3D full-body kinematics from both systems. Tasks included walking in different conditions, balance and adaptive postural control. After temporal and spatial alignment, agreement of movements signals was described by Pearson’s correlation coefficient and signal to noise ratios per dimension. From these movement signals, 45 clinical parameters were calculated, including ranges of motions, torso sway, movement velocities and cadence. Accuracy of parameters was described as absolute agreement, consistency agreement and limits of agreement. Intra-session reliability of 3 to 5 measurement repetitions was described as repeatability coefficient and standard error of measurement for each system. Results Accuracy of Kinect V2 landmark movements was moderate to excellent and depended on movement dimension, landmark location and performed task. Signal to noise ratio provided information about Kinect V2 landmark stability and indicated larger noise behaviour in feet and ankles. Most of the derived clinical parameters showed good to excellent absolute agreement (30 parameters showed ICC(3,1) > 0.7) and consistency (38 parameters showed r > 0.7) between both systems. Conclusion Given that this system is low-cost, portable and does not require any sensors to be attached to the body, it could provide numerous advantages when compared to established marker- or wearable sensor based system. The Kinect V2 has the potential to be used as a reliable and valid clinical measurement tool.

Prediction of the age at onset in spinocerebellar ataxia type 1, 2, 3 and 6

Background The most common spinocerebellar ataxias (SCA)—SCA1, SCA2, SCA3, and SCA6—are caused by (CAG)n repeat expansion. While the number of repeats of the coding (CAG)n expansions is correlated with the age at onset, there are no appropriate models that include both affected and preclinical carriers allowing for the prediction of age at onset. Methods We combined data from two major European cohorts of SCA1, SCA2, SCA3, and SCA6 mutation carriers: 1187 affected individuals from the EUROSCA registry and 123 preclinical individuals from the RISCA cohort. For each SCA genotype, a regression model was fitted using a log-normal distribution for age at onset with the repeat length of the alleles as covariates. From these models, we calculated expected age at onset from birth and conditionally that this age is greater than the current age. Results For SCA2 and SCA3 genotypes, the expanded allele was a significant predictor of age at onset (−0.105±0.005 and −0.056±0.003) while for SCA1 and SCA6 genotypes both the size of the expanded and normal alleles were significant (expanded: −0.049±0.002 and −0.090±0.009, respectively; normal: +0.013±0.005 and −0.029±0.010, respectively). According to the model, we indicated the median values (90% critical region) and the expectancy (SD) of the predicted age at onset for each SCA genotype according to the CAG repeat size and current age. Conclusions These estimations can be valuable in clinical and research. However, results need to be confirmed in other independent cohorts and in future longitudinal studies. ClinicalTrials.gov, number NCT01037777 and NCT00136630 for the French patients.

Validity of visual perceptive computing for static posturography in patients with multiple sclerosis

Background: Multiple sclerosis (MS) patients frequently have postural control impairment but quantitative posturography is difficult to perform in clinical care. Recent technology facilitates new posturography approaches. Objective: To evaluate construct validity of visual perceptive computing (VPC) for static posturography to study postural control in MS patients. Methods: A total of 90 MS patients and 59 healthy controls (HCs) performed three stance tests: open, closed and tandem stance. Static posturography was performed using a VPC system with Microsoft Kinect. Clinical assessments included Expanded Disability Status Scale (EDSS), Timed-25-Foot-Walk, Short-Maximum-Speed-Walk and 12-item MS Walking Scale (MSWS-12) questionnaire. Reliability was assessed with intra-class correlation coefficients at retest. Results: As a group, MS patients performed worse than HCs in all tests. The closed stance test showed best applicability and reliability. With closed eyes, in 36.7% of patients, the three-dimensional mean angular sway velocity (MSV-3D) was above HCs’ 95th percentile. Higher MSV-3D was associated with decreased walking speed (p < 0.001); worse clinical scores, mainly attributable to the cerebellar functional system score (p < 0.001); and reflected in self-reported walking disability (MSWS-12, p < 0.001). Conclusion: Postural control can be reliably assessed by VPC-based static posturography in patients with MS. Abnormal postural control seems to predominantly reflect involvement of cerebellar circuits with impact on gait and walking disability.

Accuracy and repeatability of two methods of gait analysis – GaitRite™ und Mobility Lab™ – in subjects with cerebellar ataxia

Instrumental gait analysis is increasingly recognized as a useful tool for the evaluation of movement disorders. The various assessment devices available to date have mostly been evaluated in healthy populations only. We aimed to explore whether reliability and validity seen in healthy subjects can also be assumed in subjects with cerebellar ataxic gait. Gait was recorded simultaneously with two devices - a sensor-embedded walkway and an inertial sensor based system - to explore test accuracy in two groups of subjects: one with mild to moderate cerebellar ataxia due to a subtype of autosomal-dominantly inherited neurodegenerative disorder (SCA14), the other were healthy subjects matched for age and height (CTR). Test precision was assessed by retest within session for each device. In conclusion, accuracy and repeatability of gait measurements were not compromised by ataxic gait disorder. The accuracy of spatial measures was speed-dependent and a direct comparison of stride length from both devices will be most reliably made at comfortable speed. Measures of stride variability had low agreement between methods in CTR and at retest in both groups. However, the marked increase of stride variability in ataxia outweighs the observed amount of imprecision.

Subjective and objective assessment of physical activity in multiple sclerosis and their relation to health-related quality of life

BackgroundPhysical activity (PA) is frequently restricted in people with multiple sclerosis (PwMS) and aiming to enhance PA is considered beneficial in this population. We here aimed to explore two standard methods (subjective plus objective) to assess PA reduction in PwMS and to describe the relation of PA to health-related quality of life (hrQoL).MethodsPA was objectively measured over a 7-day period in 26 PwMS (EDSS 1.5–6.0) and 30 matched healthy controls (HC) using SenseWear mini® armband (SWAmini) and reported as step count, mean total and activity related energy expenditure (EE) as well as time spent in PA of different intensities. Measures of EE were also derived from self-assessment with IPAQ (International Physical Activity Questionnaire) long version, which additionally yielded information on the context of PA and a classification into subjects’ PA levels. To explore the convergence between both types of assessment, IPAQ categories (low, moderate, high) were related to selected PA parameters from objective assessment using ANOVA. Group differences and associated effect sizes for all PA parameters as well as their relation to clinical and hrQoL measures were determined.ResultsBoth, SWAmini and IPAQ assessment, captured differences in PA between PwMS and HC. IPAQ categories fit well with common cut-offs for step count (p = 0.002) and mean METs (p = 0.004) to determine PA levels with objective devices. Correlations between specifically matched pairs of IPAQ and SWAmini parameters ranged between r .288 and r .507. Concerning hrQoL, the lower limb mobility subscore was related to four PA measures, while a relation with patients’ report of general contentment was only seen for one.ConclusionsBoth methods of assessment seem applicable in PwMS and able to describe reductions in daily PA at group level. Whether they can be used to track individual effects of interventions to enhance PA levels needs further exploration. The relation of PA measures with hrQoL seen with lower limb mobility suggests lower limb function not only as a major target for intervention to increase PA but also as a possible surrogate for PA changes.

Survival in patients with spinocerebellar ataxia types 1, 2, 3, and 6 (EUROSCA): a longitudinal cohort study

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 Médicale.

Maximum walking speed in multiple sclerosis assessed with visual perceptive computing

Background Gait is often impaired in people with multiple sclerosis (PwMS), but detailed assessment of gait impairment in research and care remains challenging. In a previous pilot study we reported the feasibility of visual perceptive computing (VPC) for gait assessment in PwMS using the Short Maximum Speed Walk (SMSW), which assesses gait on recording distances confined to less than 4 meters. Objective To investigate the equivalence of SMSW to rater-based timed 25ft. walk (T25FW) in a large cohort of PwMS, and to investigate the association of SMSW-derived gait parameters with clinical disability, as well as subjective and objective gait impairment, in order to validate the SMSW as a quick and objective measure of clinical relevance possibly superior to T25FW. Methods 95 PwMS and 60 healthy controls (HC) performed the SMSW using a VPC system with Microsoft Kinect. All participants received two immediate retests to establish test-retest-reliability. Both PwMS and HC performed the T25FW. PwMS were rated according to the Expanded Disability Status Scale (EDSS) and answered the 12-item Multiple Sclerosis Walking Scale (MSWS-12) as a measure of self-perceived walking impairment. Results PwMS showed reduced average speed (p<0.001) and higher mediolateral deviation (p = 0.002) during SMSW than HC. Average speed was the most reliable SMSW parameter in PwMS and HC (intra-class correlation coefficient (ICC) in PwMS = 0.985, and in HC = 0.977). Average speed declined with age in PwMS and HC (r in PwMS = -0.648, and in HC = -0.452, both p<0.001). Correlation of SMSW average speed and T25FW speed was high in both groups (r in PwMS = 0.783, and in HC = 0.747, both p<0.001) and mean difference (0.0013 m/s) between methods was below smallest detectable change. Average speed correlated well with both clinical disability based on EDSS (r = -0.586, p<0.001) and self-perceived walking impairment based on MSWS-12 (r = -0.546, p<0.001). Conclusion VPC-assessed walking parameters during SMSW can reliably detect gait disturbance in PwMS over very short distance. Specifically, maximum gait speed can be obtained with high accuracy in this simple test set-up. Cross-sectional associations with disability and self-perceived walking impairment support clinical relevance. Given its objectivity in a simple test set-up, SMSW is superior to T25FW.