Tanja Schmitz-Hübsch

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. © 2011 Movement Disorder Society

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. © 2010 Movement Disorder Society

Objective: To determine the longitudinal metric properties of recently developed clinical assessment tools in spinocerebellar ataxia (SCA). Methods: A subset of 171 patients from the EUROSCA natural history study cohort (43 SCA1, 61 SCA2, 37 SCA3, and 30 SCA6) were examined after 1 year of follow-up. Score changes and effect size indices were calculated for clinical scales (Scale for the Assessment and Rating of Ataxia [SARA], Inventory of Non-Ataxia Symptoms [INAS]), functional tests (SCA Functional Index [SCAFI] and components), and a patient-based scale for subjective health status (EQ-5D visual analogue scale [EQVAS]). Responsiveness was determined in relation to the patient9s global impression (PGI) of change and reproducibility described as retest reliability for the stable groups and smallest detectable change. Results: Within the 1-year follow-up period, SARA, INAS, and SCAFI but not EQVAS indicated worsening in the whole group and in the groups with subjective (PGI) worsening. SCAFI and its 9-hole pegboard (9HPT) component also deteriorated in the stable groups. Standardized response means were highest for 9HPT (−0.67), SARA (0.50), and SCAFI (−0.48) with accordingly lower sample size estimates of 143, 250, or 275 per group for a 2-arm interventional trial that aims to reduce disease progression by 50%. SARA and EQVAS performed best to distinguish groups classified as worse by PGI. All scales except EQVAS reached the criterion for retest reliability. Conclusion: While both the Scale for the Assessment and Rating of Ataxia and the SCA Functional Index (SCAFI) (and its 9-hole pegboard component) had favorable measurement precision, the clinical relevance of SCAFI and 9-hole pegboard score changes warrants further exploration. The EQ-5D visual analogue scale proved insufficient for longitudinal assessment, but validly reflected patients9 impression of change.

Onset of genetically determined neurodegenerative diseases is difficult to specify due to the insidious and slowly progressive nature of these disorders. 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 (i) the definition of disease onset, (ii) people defining onset and (iii) duration of symptoms. Gait difficulty was the initial symptom in about two thirds of SCA patients. Symptoms preceding gait ataxia were in the order of frequency cramps, dysarthria, sleep disturbance, double vision, impaired hand writing, episodic vertigo, neuropathic symptoms, restless legs syndrome, urinary urgency, reduced visual acuity and frequent throat clearing. Episodic vertigo occurred especially frequent as the initial symptom in SCA6 patients. Data about onset of disease varied for 1 year or more in 44% of cases between SCA patients and their relatives and for more than 5 years in 8.5% of cases. Influence of repeat length on age of onset was maximum when onset was defined as beginning of permanent gait disturbance after discussion between patients and relatives and when cases who had symptoms for more than 10 years were excluded. Even under these conditions the number of CAG repeats determined only 64% of onset variability in SCA1, 67% in SCA2, 46% in SCA3 and 41% in SCA6. This study demonstrates substantial influence of non-repeat factors on disease onset in all SCA subtypes but especially in SCA3 and SCA6. Identification of these factors will be interesting since they may provide potential therapeutic targets for disease modifying compounds. In this respect recognition of early symptoms that develop before onset of gait ataxia is mandatory to determine the shift from presymptomatic to affected status in SCA as early as possible.

Einleitung: Die parkinson-typische Dysarthrophonie ist unter anderem durch eine Störung der Prosodie mit Veränderungen von Sprechtempo und -rhythmus sowie der Intonationsvariation gekennzeichnet, deren Pathomechanismen bislang erst unzureichend geklärt sind. Auch bei Patienten mit zerebellären Erkrankungen gehört eine Sprechstörung zum charakteristischen klinischen Bild, wobei es hinsichtlich Ausmaß und Art der Veränderungen manche Gemeinsamkeiten, aber auch erhebliche Unterschiede zu Patienten mit IPS gibt. Ziel: Untersuchung verschiedener objektivierbarer Parameter der gestörten Prosodie bei Patienten mit SCA und IPS mittels akustischer Analyse und Vergleich mit gesunden Kontrollpersonen. Methode: N=32 Patienten mit SCA (20Männer, 12 Frauen), n=42 Patienten mit IPS (20Männer, 22 Frauen) und 40 altersgematchte gesunde Kontrollpersonen (20Männer, 20 Frauen) wurden anhand eines standardisierten Sprechprogramms, bestehend aus freiem Monolog und Leseaufgabe, mittels akustischer Analyse untersucht. Als Maß für die Tonhöhenvariation wurde die Grundfrequenzvariation (F0SD und F0range) ermittelt; Sprechtempo (Gesamtsprechzeit/TSR und Nettosprechzeit/NSR) und Pausenanteile (PR%) wurden anhand der Messung von Silben- und Pausenlängen definiert. Ergebnisse: TSR und NSR waren bei Patienten mit SCA geringer als bei den Patienten mit IPS, die wiederum diskret höhere Werte aufwiesen als die Kontrollpersonen. PR% war entsprechend bei den SCA-Patienten höher als in den beiden anderen Untersuchungsgruppen. Hinsichtlich der Intonationsvariation fand sich bei den SCA-Patienten eine signifikant höhere F0SD und F0range als bei Patienten mit IPS; nur die F0range war auch signifikant höher als bei Kontrollpersonen. Bei einer Analyse der genetisch determinierten SCA-Subgruppen (SCA-1, -2, -3 und -6) zeigten sich TSR und NSR bei den SCA-1-Patienten am niedrigsten und bei den Patienten mit SCA-3 am höchsten; Patienten mit SCA-3 und -6 wiesen eine niedrigere F0SD und F0range auf als Patienten mit SCA-1 und -2. Schlussfolgerungen: Die Ergebnisse lassen die Vermutung zu, dass eine zerebelläre Störung (SCA) zu einer Reduktion des Sprechtempos bei weitgehend unbeeinträchtigter Intonationsvariation führt, die wiederum bei nigrostriatalen Störungen (IPS) reduziert ist. Veränderungen der prosodischen Parameter zeigen eine unterschiedliche Ausprägung bei verschiedenen genetisch determinierten SCA-Formen, wobei eine Bestätigung dieser Befunde an größeren Fallzahlen zu fordern ist.

Objective: To evaluate the usefulness of functional measures in patients with spinocerebellar ataxia (SCA).

Hintergrund: Die Rolle des Melatonin beim idiopathischen Parkinson-Syndrom (IPS) wird kontrovers diskutiert. Melatonin unterliegt einer zirkadianen Rhythmik und steuert den Tag-Nacht-Rhythmus des Menschen. Seine Ausschüttung wird in Abhängigkeit vom Lichteinfall auf die Retina reguliert. Dunkelheit führt zur Stimulation und helles Licht (>2500 Lux) zur Unterdrückung der Melatoninsekretion. Bei Patienten mit IPS wurden Phasen- und Amplitudenverschiebung der Melatoninsekretion beschrieben. Melatonin werden einerseits antioxidative Eigenschaften zugesprochen, anderseits konnten auch antidopaminerge Effekte des Hormons im Striatum nachgewiesen werden. Im Tiermodell wurde durch Reduktion der Melatonin-Bioverfügbarkeit ein Schutz vor experimentell induziertem Parkinsonsyndrom erzielt. Vor dem Hintergrund dieser Befunde soll die Studie klären, ob die bislang hauptsächlich zur Behandlung von Depressionen eingesetzte Therapie mit Vollspektrumlicht einen Einfluss auf motorische Symptome, Schlafstörungen, Tagesmüdigkeit und Depression beim IPS hat. Methoden: In eine prospektive, plazebokontrollierte, doppelblinde Fall-Kontroll-Studie wurden zwei nach Geschlecht, Alter, Krankheitsdauer, Depression und Hoehn & Yahr Stadium gematchte Gruppen von jeweils 20 Patienten mit IPS eingeschlossen. Alle Patienten erhielten über mindestens 14 Tage an jedem Morgen eine dreißigminütige Lichttherapie, wobei die Beleuchtungsstärke in der Verumgruppe 10.000 Lux und in der Plazebogruppe 400 Lux betrug. Vor und nach Lichtbehandlung wurden Erkrankungsgrad (UPDRS Skala I-IV, Hoehn & Yahr Skala, Finger-Tapping-Test, Stand-Walk-Sit-Test), Schlafqualität und Tagesmüdigkeit (Schlafprotokoll, Epworth Sleepiness Scale, Modified Pittsburgh Sleep Quality Index), Depression (Beck'sches Depressions Inventar) und Lebensqualität (EQ-5D) gemessen. Ergebnisse: Die Zwischenauswertung zeigte eine signifikante Verbesserung (p<0,05; paired t-test) in der Verumgruppe für die UPDRS-Subskalen I (Kognition, Verhalten, Stimmung) und II (Aktivitäten des täglichen Lebens), Tagesmüdigkeit und Depression. Des Weiteren wurde in der UPDRS-Subskala III (Motorik) eine Verbesserung des Unterpunktes Tremors dokumentiert. In der Placebogruppe war eine signifikante Besserung von Tagesmüdigkeit und Depression zu sehen. Detaillierte Analyse, Darstellung und Diskussion aller Untersuchungsergebnisse werden nach Abschluss der Studie dargestellt.

Validated instruments for standardized graded assessment of symptom severity are essential prerequisites for clinical trials. To date, such instruments are lacking for cerebellar ataxia. Although ataxia rating scales have been published, they have not been sufficiently validated. We therefore developed a new scale named Scale for the Assessment and Rating of Ataxia (SARA) that allows a graded assessment of ataxia symptoms on an impairment level. Items were chosen for their specificity for cerebellar involvement and the possibility for standardized performance and rating. To determine essential biometric properties two multicentric validation trials involving 11 centers from 8 European countries were performed in 167 and 119 spinocerebellar ataxia (SCA) patients, respectively. SARA is composed of 8 items including gait, stance, sitting, speech, finger chase, finger-nose test, fast alternating hand movements and heel-shin slide with a sum score range of 0–40 (0=no ataxia, 40=severe ataxia). The scale is supplemented by an Inventory of Non-Ataxia Symptoms (INAS) aiming at a standardized full clinical description of symptoms in SCA patients. The first validation trial allowed to determine objectivity and practicability, as well as reliability (internal consistency, inter-rater reliability, intra-rater reliability) and validity (concurrent validity, comparison with convergent criterion). Results showed sufficient practicability with a mean performance time of 17min. Factorial analysis showed that all items except one were determined by a single factor. Internal consistency was good with Cronbach's alpha 0,90. Inter-rater reliability was very good for the sum score (0.97) but only limited (0.7) for finger-nose test. Mean sum score increased with higher ataxia disability stages. However, data were insufficient to show linearity of the scale due to bias towards less severely affected patients. Unexpectedly, side differences were reported in 33.5% of items measuring limb ataxia. According to these results, a modified scale underwent a second validation trial. The study was performed within the European integrated project on spinocerebellar ataxias (EUROSCA), funded by the European commission. Contributing clinical centers were: Bochum (D), Bonn (D), Brussels (B), Frankfurt a.M. (D), Innsbruck (A), London (UK), Milano (I), Nijmegen (NL), Paris (F), Pecs (H), Santander (E),Tübingen (D), Warsaw (PL).