Sandra Szymanski
Ruhr University Bochum
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Featured researches published by Sandra Szymanski.
Neurology | 2006
Tanja Schmitz-Hübsch; S. Tezenas du Montcel; László Balikó; José Berciano; S Boesch; Chantal Depondt; Paola Giunti; Christoph Globas; Jon Infante; Jun-Suk Kang; Berry Kremer; C. Mariotti; Bela Melegh; Massimo Pandolfo; Maryla Rakowicz; Pascale Ribai; Rafal Rola; Ludger Schöls; Sandra Szymanski; B.P.C. van de Warrenburg; Alexandra Durr; Thomas Klockgether
Objective: To develop a reliable and valid clinical scale measuring the severity of ataxia. Methods: The authors devised the Scale for the Assessment and Rating of Ataxia (SARA) and tested it in two trials of 167 and 119 patients with spinocerebellar ataxia. Results: The mean time to administer SARA in patients was 14.2 ± 7.5 minutes (range 5 to 40). Interrater reliability was high, with an intraclass coefficient (ICC) of 0.98. Test-retest reliability was high with an ICC of 0.90. Internal consistency was high as indicated by Cronbachs α of 0.94. Factorial analysis revealed that the rating results were determined by a single factor. SARA ratings showed a linear relation to global assessments using a visual analogue scale, suggesting linearity of the scale (p < 0.0001, r2 = 0.98). SARA score increased with the disease stage (p < 0.001) and was closely correlated with the Barthel Index (r = −0.80, p < 0.001) and part IV (functional assessment) of the Unified Huntingtons Disease Rating Scale (UHDRS-IV) (r = −0.89, p < 0.0001), whereas it had only a weak correlation with disease duration (r = 0.34, p < 0.0002) Conclusions: The Scale for the Assessment and Rating of Ataxia is a reliable and valid measure of ataxia, making it an appropriate primary outcome measure for clinical trials.
Neurology | 2008
Tanja Schmitz-Hübsch; Mathieu Coudert; Peter Bauer; Paola Giunti; Christoph Globas; László Balikó; Alessandro Filla; C. Mariotti; Maryla Rakowicz; Perrine Charles; Pascale Ribai; Sandra Szymanski; Jon Infante; B.P.C. van de Warrenburg; Alexandra Durr; Dagmar Timmann; S Boesch; Roberto Fancellu; Rafal Rola; Chantal Depondt; Ludger Schöls; E Zdienicka; J-S Kang; S Döhlinger; Berry Kremer; D A Stephenson; Bela Melegh; Massimo Pandolfo; S. Di Donato; S. Tezenas du Montcel
Objective: To identify factors that determine disease severity and clinical phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526 patients with SCA1, SCA2, SCA3. or SCA6. Methods: To measure the severity of ataxia we used the Scale for the Assessment and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of nonataxia symptoms in each patient. Results: An analysis of covariance with SARA score as dependent variable and repeat lengths of the expanded and normal allele, age at onset, and disease duration as independent variables led to multivariate models that explained 60.4% of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the expanded allele, age at onset, and disease duration. The only factors determining the SARA score in SCA6 were age at onset and disease duration. The INAS count was 5.0 ± 2.3 in SCA1, 4.6 ± 2.2 in SCA2, 5.2 ± 2.5 in SCA3, and 2.0 ± 1.7 in SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest predictors of the INAS count. In SCA6, only age at onset and disease duration had an effect on the INAS count. Conclusions: Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors.
Movement Disorders | 2006
Tanja Schmitz-Hübsch; Sophie Tezenas du Montcel; László Balikó; S Boesch; Sara Bonato; Roberto Fancellu; Paola Giunti; Christoph Globas; Jun Suk J.S. Kang; Berry Kremer; Caterina Mariotti; Béla Melegh; Maryla Rakowicz; Rafal Rola; Sylvie S. Romano; Lodger L. Schöls; Sandra Szymanski; Bart P. van de Warrenburg; Zdzienicka E; Alexandra Durr; Thomas Klockgether
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.
Neurology | 2008
Tanja Schmitz-Hübsch; Paola Giunti; D A Stephenson; Christoph Globas; L. Baliko; Francesco Saccà; C. Mariotti; Maria Rakowicz; Sandra Szymanski; Jon Infante; B.P.C. van de Warrenburg; Dagmar Timmann; Roberto Fancellu; Rafal Rola; Chantal Depondt; Ludger Schöls; Zdzienicka E; J-S Kang; S Döhlinger; Berry Kremer; Béla Melegh; Alessandro Filla; Thomas Klockgether
Objective: To evaluate the usefulness of functional measures in patients with spinocerebellar ataxia (SCA). Methods: We assessed three functional measures—8 m walking time (8MW), 9-hole peg test (9HPT), and PATA repetition rate—in 412 patients with autosomal dominant SCA (genotypes 1, 2, 3, and 6) in a multicenter trial. Results: While PATA rate was normally distributed (mean/median 21.7/20.5 per 10 s), the performance times for 8MW (mean/median 10.8/7.5 s) or 9HPT (mean/median 47.2/35.0 s in dominant, 52.2/37.9 s in nondominant hand) were markedly skewed. Possible learning effects were small and likely clinically irrelevant. A composite functional index (SCAFI) was formed after appropriate transformation of subtest results. The Z-scores of each subtest correlated well with the Scale for the Assessment and Rating of Ataxia (SARA), the Unified Huntingtons disease Rating Scale functional assessment, and disease duration. Correlations for SCAFI with each of these parameters were stronger (Pearson r = −0.441 to −0.869) than for each subtest alone. Furthermore, SCAFI showed a linear decline over the whole range of disease severity, while 9HPT and 8MW had floor effects with respect to SARA. Analysis of possible confounders showed no effect of genotype or study site and only minor effects of age for 8MW. Conclusion: The proposed functional measures and their composite SCAFI have favorable properties to assess patients with spinocerebellar ataxia.
Brain | 2014
Sophie Tezenas du Montcel; Alexandra Durr; Peter Bauer; Karla P. Figueroa; Yaeko Ichikawa; Alessandro Brussino; Sylvie Forlani; Maria Rakowicz; Ludger Schöls; Caterina Mariotti; Bart P. van de Warrenburg; Laura Orsi; Paola Giunti; Alessandro Filla; Sandra Szymanski; Thomas Klockgether; José Berciano; Massimo Pandolfo; Sylvia Boesch; Béla Melegh; Dagmar Timmann; Paola Mandich; Agnès Camuzat; Jun Goto; Tetsuo Ashizawa; Cécile Cazeneuve; Shoji Tsuji; Stefan M. Pulst; Olaf Riess; Alexis Brice
Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50-70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1-3, 6-7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.
Movement Disorders | 2008
Christoph Globas; Sophie Tezenas du Montcel; Laslo Baliko; Syliva Boesch; Chantal Depondt; Stefano DiDonato; Alexandra Durr; Alessandro Filla; Thomas Klockgether; Caterina Mariotti; Béla Melegh; Maryla Rakowicz; Pascale Ribai; Rafal Rola; Tanja Schmitz-Hübsch; Sandra Szymanski; Dagmar Timmann; Bart P. van de Warrenburg; Peter Bauer; Ludger Schöls
Onset of genetically determined neurodegenerative diseases is difficult to specify because of their insidious and slowly progressive nature. This is especially true for spinocerebellar ataxia (SCA) because of varying affection of many parts of the nervous system and huge variability of symptoms. We investigated early symptoms in 287 patients with SCA1, SCA2, SCA3, or SCA6 and calculated the influence of CAG repeat length on age of onset depending on (1) the definition of disease onset, (2) people defining onset, and (3) duration of symptoms. Gait difficulty was the initial symptom in two‐thirds of patients. Double vision, dysarthria, impaired hand writing, and episodic vertigo preceded ataxia in 4% of patients, respectively. Frequency of other early symptoms did not differ from controls and was regarded unspecific. Data about disease onset varied between patients and relatives for 1 year or more in 44% of cases. Influence of repeat length on age of onset was maximum when onset was defined as beginning of permanent gait disturbance and cases with symptoms for more than 10 years were excluded. Under these conditions, CAG repeat length determined 64% of onset variability in SCA1, 67% in SCA2, 46% in SCA3, and 41% in SCA6 demonstrating substantial influence of nonrepeat factors on disease onset in all SCA subtypes. Identification of these factors is of interest as potential targets for disease modifying compounds. In this respect, recognition of early symptoms that develop before onset of ataxia is mandatory to determine the shift from presymptomatic to affected status in SCA.
Lancet Neurology | 2015
Heike Jacobi; Sophie Tezenas du Montcel; Peter Bauer; Paola Giunti; Arron Cook; Robyn Labrum; Michael H Parkinson; Alexandra Durr; Alexis Brice; Perrine Charles; Cecilia Marelli; Caterina Mariotti; Lorenzo Nanetti; Marta Panzeri; Maria Rakowicz; Anna Sulek; Anna Sobanska; Tanja Schmitz-Hübsch; Ludger Schöls; Holger Hengel; László Balikó; Béla Melegh; Alessandro Filla; Antonella Antenora; Jon Infante; José Berciano; Bart P. van de Warrenburg; Dagmar Timmann; Sandra Szymanski; Sylvia Boesch
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).
The Cerebellum | 2012
Heike Jacobi; Till Karsten Hauser; Paola Giunti; Christoph Globas; Peter Bauer; Tanja Schmitz-Hübsch; László Balikó; Alessandro Filla; Caterina Mariotti; Maria Rakowicz; Perine Charles; Pascale Ribai; Sandra Szymanski; Jon Infante; Bart P. van de Warrenburg; Alexandra Durr; Dagmar Timmann; Sylvia Boesch; Roberto Fancellu; Rafal Rola; Chantal Depondt; Ludger Schöls; Zdzienicka E; Jun Suk Kang; Susanne Ratzka; Berry Kremer; Dennis A. Stephenson; Bela Melegh; Massimo Pandolfo; Sophie Tezenas du Montcel
To assess the clinical spectrum of ataxia and cerebellar oculomotor deficits in the most common spinocerebellar ataxias (SCAs), we analysed the baseline data of the EUROSCA natural history study, a multicentric cohort study of 526 patients with either spinocerebellar ataxia type 1, 2, 3 or 6. To quantify ataxia symptoms, we used the Scale for the Assessment and Rating of Ataxia (SARA). The presence of cerebellar oculomotor signs was assessed using the Inventory of Non-Ataxia Symptoms (INAS). In a subgroup of patients, in which magnetic resonance images (MRIs) were available, we correlated MRI morphometric measures with clinical signs on an exploratory basis. The SARA subscores posture and gait (items 1–3), speech (item 4) and the limb kinetic subscore (items 5–8) did not differ between the genotypes. The scores of SARA item 3 (sitting), 5 (finger chase) and 6 (nose–finger test) differed between the subtypes whereas the scores of the remaining items were not different. In SCA1, ataxia symptoms were correlated with brainstem atrophy and in SCA3 with both brainstem and cerebellar atrophy. Cerebellar oculomotor deficits were most frequent in SCA6 followed by SCA3, whereas these abnormalities were less frequent in SCA1 and SCA2. Our data suggest that vestibulocerebellar, spinocerebellar and pontocerebellar circuits in SCA1, SCA2, SCA3 and SCA6 are functionally impaired to almost the same degree, but at different anatomical levels. The seemingly low prevalence of cerebellar oculomotor deficits in SCA1 and SCA2 is most probably related to the defective saccadic system in these disorders.
Movement Disorders | 2011
Tanja Schmitz-Hübsch; Mathieu Coudert; Sophie Tezenas du Montcel; Paola Giunti; Robyn Labrum; Alexandra Durr; Pascale Ribai; Perrine Charles; Christoph Linnemann; Ludger Schöls; Maryla Rakowicz; Rafal Rola; Elszbieta Zdzienicka; Roberto Fancellu; Caterina Mariotti; L. Baliko; Bela Melegh; Alessandro Filla; Elena Salvatore; Bart P. van de Warrenburg; Sandra Szymanski; Jon Infante; Dagmar Timmann; S Boesch; Chantal Depondt; Jun Suk Kang; Jörg B. Schulz; Thomas Klopstock; Nicole Lossnitzer; Bernd Löwe
This is a description of the prevalence and profile of depressive symptoms in dominant spinocerebellar ataxia (SCA). Depressive symptoms were assessed in a convenience sample of 526 genetically confirmed and clinically affected patients (117 SCA1, 163 SCA2, 139 SCA3, and 107 SCA6) using the Patient Health Questionnaire (PHQ). In addition, depressive status according to the examiner and the use of antidepressants was recorded. Depression self‐assessment was compared with an interview‐based psychiatric assessment in a subset of 26 patients. Depression prevalence estimates were 17.1% according to the PHQ algorithm and 15.4% when assessed clinically. The sensitivity of clinical impression compared with PHQ classification was low (0.35), whereas diagnostic accuracy of PHQ compared with psychiatric interview in the subset was high. Antidepressants were used by 17.7% of patients and in >10% of patients without current clinically relevant depressive symptoms. Depression profile in SCA did not differ from a sample of patients with major depressive disorder except for the movement‐related item. Neither depression prevalence nor use of antidepressants differed between genetic subtypes, with only sleep disturbance more common in SCA3. In a multivariate analysis, ataxia severity and female sex independently predicted depressive status in SCA. The PHQ algorithmic classification is appropriate for use in SCA but should stimulate further psychiatric evaluation if depression is indicated. Despite a higher risk for depression with more severe disease, the relation of depressive symptoms to SCA neurodegeneration remains to be shown.
Movement Disorders | 2010
Tanja Schmitz-Hübsch; Mathieu Coudert; Paola Giunti; Christoph Globas; László Balikó; Roberto Fancellu; Caterina Mariotti; Alessandro Filla; Maryla Rakowicz; Perrine Charles; Pascale Ribai; Sandra Szymanski; Jon Infante; Bart P. van de Warrenburg; Alexandra Durr; Dagmar Timmann; S Boesch; Rafal Rola; Chantal Depondt; Ludger Schöls; Elszbieta Zdzienicka; Jun Suk Kang; Susanne Ratzka; Berry Kremer; Jörg B. Schulz; Thomas Klopstock; Bela Melegh; Sophie Tezenas du Montcel; Thomas Klockgether
Patient‐based measures of subjective health status are increasingly used as outcome measures in interventional trials. We aimed to determine the variability and predictors of subjective health ratings in a possible target group for future interventions: the spinocerebellar ataxias (SCAs). A consecutive sample of 526 patients with otherwise unexplained progressive ataxia and genetic diagnoses of SCA1 (117), SCA2 (163), SCA3 (139), and SCA6 (107) were enrolled at 18 European referral centers. Subjective health status was assessed with a generic measure of health related quality of life, the EQ‐5D (Euroqol) questionnaire. In addition, we performed a neurological examination and a screening questionnaire for affective disorders (patient health questionnaire). Patient‐reported health status was compromised in patients of all genotypes (EQ‐5D visual analogue scale (EQ‐VAS) mean 61.45 ± 20.8). Specifically, problems were reported in the dimensions of mobility (86.9% of patients), usual activities (68%), pain/discomfort (49.4%), depression/anxiety (46.4%), and self care (38.2%). Multivariate analysis revealed three independent predictors of subjective health status: ataxia severity, extent of noncerebellar involvement, and the presence of depressive syndrome. This model explained 30.5% of EQ‐VAS variance in the whole sample and might be extrapolated to other SCA genotypes.