Ataxia Rating Research Articles

P-MD008. Differential effects of thyrotropin releasing hormone on motor performance and motor adaptation in patients with spinocerebellar degeneration

Introduction . The cerebellum is known to play an important role in motor adaptation, including prism adaptation. Thyrotropin releasing hormone (TRH) has been used as a treatment for cerebellar ataxia in Japan. However, effects of TRH on cerebellar adaptation function have not been studied. Herein, we studied effects of TRH treatment on the prism adaptation task. Methods . Eighteen patients with spinocerebellar degeneration (SCD), including MSA-C, SCA3, SCA6, SCA31, participated in this study. The participants received intravenous injection of 2 mg/day protirelin tartrate once a day for 14 days. In the prism adaptation task, the participants reached to the target on the screen wearing wedge prisms. We compared the Scale for Assessment and Rating of Ataxia (SARA), baseline errors and the after effect (AE) of the prism adaptation task between before and after TRH therapy. We also performed correlation analysis between improvement of baseline errors or AE in the adaptation task, and 1) improvement of the total SARA score, 2) improvement of upper limb ataxia score, and 3) improvement of axial ataxia score. Results . TRH therapy significantly improved SARA (p = 0.005). Multiple regression analysis revealed that improvement of SARA score was mainly due to improvement of “Stance” category score. TRH decreased baseline errors of the prism adaptation task (p = 0.021), while unaffected AEs (p = 0.25). Correlation analysis revealed no significant correlation between any factors. Conclusion . TRH differentially affected cerebellar ataxic symptoms including baseline reaching performance in the prism adaptation task, whereas TRH did not affect the learning process of prism adaptation. Different cerebellar functional aspects may underlie the learning process of motor adaptation and simple motor performance (classical ataxia).

Ataxia and mobility in children following surgical resection of posterior fossa tumour: A longitudinal cohort study

PurposeTo report the course of ataxia in children up to 2 years post-operatively, following surgical resection of a posterior fossa tumour (PFT).MethodsThirty-five children, (median age 9 years, range 4–15) having resection of PFT, were assessed using the Scale for the Assessment and Rating of Ataxia (SARA), Brief Ataxia Rating Scale (BARS) and the mobility domain of the Paediatric Evaluation of Disability Index (PEDI-m) at initial post-operative period (baseline), 3 months, 1 year and 2 years post-operatively.ResultsBaseline median scores of the SARA and BARS were 8.5 (range 0–35.5), and 7 (0–25) respectively. Ataxia improved at 3 months (median SARA and BARS reduction 3.5 and 4, respectively). Additional gradual improvements in SARA were recorded at 1 (median reduction 2) and 2 years post-operatively (median reduction 0.5). Median baseline PEDI-m was 54.75 (range 15.2–100) with improvement at 3 months (median increase 36.95) and small improvement at 1 year (median increase 2.5) and 2 years (median increase 5.8). Children with medulloblastoma and midline tumours (median baseline SARA 10 and 11, respectively) demonstrated more severe ataxia than children with low-grade gliomas and unilateral tumours (median baseline SARA 7.5 and 6.5, respectively).ConclusionThe largest improvement in ataxia scores and functional mobility scores is demonstrated within the first 3 months post-operatively, but ongoing gradual improvement is observed at 2 years. Children with medulloblastoma and midline tumour demonstrated higher ataxia scores long term.

Serum neurofilament light chain as a severity marker for spinocerebellar ataxia

Since the serum neurofilament light (NfL) chain is known as a promising biomarker in neurodegenerative diseases, we aimed to evaluate serum NfL as a biomarker indicating neuronal damage in autosomal-dominant (AD) spinocerebellar ataxia (SCA). We reviewed patients diagnosed with AD SCA in the outpatient clinic of Seoul National University Hospital’s (SNUH) Department of Neurology between May and August of 2019. We reviewed the demographic data, clinical characteristics, Scale for the Assessment and Rating of Ataxia (SARA) score, and brain magnetic resonance imaging (MRI) scans. The serum NfL was measured by electrochemiluminescence (ECL) immunoassay. Forty-nine patients with AD SCA were reviewed and their serum NfL level was determined. The median serum NfL level (109.5 pg/mL) was higher than control (41.1 pg/mL) (p-value < 0.001). Among the AD SCA patients, there was a positive correlation between the serum NfL level and the trinucleotide repeat number (r = 0.47, p-value = 0.001), disease duration (r = 0.35, p-value = 0.019), disease duration/age × trinucleotide repeat number (r = 0.330, p-value = 0.021), and SARA score (n = 33; r = 0.37, p-value = 0.033). This study shows that serum NfL is elevated in AD SCA patients and correlates with clinical severity.

Magnetic resonance imaging and spectroscopy in late-onset GM2-gangliosidosis

ObjectiveOur study aimed to quantify structural changes in relation to metabolic abnormalities in the cerebellum, thalamus, and parietal cortex of patients with late-onset GM2-gangliosidosis (LOGG), which encompasses late-onset Tay-Sachs disease (LOTS) and Sandhoff disease (LOSD). MethodsWe enrolled 10 patients with LOGG (7 LOTS, 3 LOSD) who underwent a neurological assessment battery and 7 age-matched controls. Structural MRI and MRS were performed on a 3 T scanner. Structural volumes were obtained from FreeSurfer and normalized by total intracranial volume. Quantified metabolites included N-acetylaspartate (NAA), choline (Cho), myo-inositol (mI), creatine (Cr), and combined glutamate-glutamine (Glx). Metabolic concentrations were corrected for partial volume effects. ResultsStructural analyses revealed significant cerebellar atrophy in the LOGG cohort, which was primarily driven by LOTS patients. NAA was lower and mI higher in LOGG, but this was also significantly driven by the LOTS patients. Clinical ataxia deficits (via the Scale for the Assessment and Rating of Ataxia) were associated with neuronal injury (via NAA), neuroinflammation (via mI), and volumetric atrophy in the cerebellum. InterpretationThe decrease of NAA in the cerebellum suggests that, in addition to cerebellar atrophy, there is ongoing impaired neuronal function and/or loss, while an increase in mI indicates possible neuroinflammation in LOGG (more so within the LOTS subvariant). Quantifying cerebellar atrophy in relation to neurometabolic differences in LOGG may lead to improvements in assessing disease severity, progression, and pharmacological efficacy. Lastly, additional neuroimaging studies in LOGG are required to contrast LOTS and LOSD more accurately.

Spinocerebellar Ataxia Type 1: One-Year Longitudinal Study to Identify Clinical and MRI Measures of Disease Progression in Patients and Presymptomatic Carriers.

Spinocerebellar ataxias type 1 (SCA1) is an autosomal dominant disease usually manifesting in adulthood. We performed a prospective 1-year longitudinal study in 14 presymptomatic mutation carriers (preSCA1), 11 ataxic patients, and 21 healthy controls. SCA1 patients had a median disease duration of 6years (range 2-16) and SARA score of 7 points (range 3.5-20). PreSCA1 had an estimated time before disease onset of 9.7years (range 4-30), and no signs of ataxia. At baseline, SCA1 patients significantly differed from controls in SARA score (Scale for Assessment and Rating of Ataxia), cognitive tests, and structural MRI measures. Significant volume loss was found in cerebellum, brainstem, basal ganglia, and cortical thinning in frontal, temporal, and occipital regions. PreSCA1 did not differ from controls. At 1-year follow-up, SCA1 patients showed significant increase in SARA score, and decreased volume of cerebellum (- 0.6%), pons (- 5.5%), superior cerebellar peduncles (- 10.7%), and midbrain (- 3.0%). Signs of disease progression were also observed in preSCA1 subjects, with increased SARA score and reduced total cerebellar volume. Our exploratory study suggests that clinical scores and MRI measures provide valuable data to monitor and quantify the earliest changes associated with the preclinical and the symptomatic phases of SCA1 disease.

Case Report of Ataxia, Gait Disturbance, Tremor, and Dizziness with Cerebellar Atrophy Treated by Korean Traditional Medicine, Including Kuibiondam-tang-gami

This study reported on the effect of traditional Korean medicine on ataxia, gait disturbance, tremor, and dizziness with cerebellar atrophy. The patient was treated with traditional Korean medicines, such as acupuncture, moxibustion, and herbal medicine (Kuibiondam-tang-gami). The effectiveness of the treatment was evaluated with the scale for the assessment and rating of ataxia (SARA). After treatment, the symptoms had improved. The SARA score decreased by 18 points after Korean medicine treatment. According to this study, traditional Korean medicine can be effective to treat ataxia, gait disturbance, tremor, and dizziness in patients with cerebellar atrophy. Keywords: Kuibiondam-tang-gami, cerebellar atrophy, ataxia, gait disturbance, dizziness

Aplicação simultânea de estimulação transcraniana por corrente contínua cerebelar anódica para reabilitação do equilíbrio na ataxia cerebelar: relato de caso

INTRODUÇÃO: As ataxias cerebelares são um extenso grupo de doenças, que causam diversos distúrbios na marcha e no equilíbrio que comprometem seriamente a qualidade de vida, sem opções de tratamento eficazes. A cinesioterapia é a base de programas multifacetados que incorporam mais de um enfoque, como o treinamento de coordenação e equilíbrio. Recentemente, a estimulação transcraniana por corrente contínua (tDCS) sobre o cerebelo surgiu como uma intervenção para melhorar os distúrbios do equilíbrio. OBJETIVO: Descrever a aplicação simultânea de tDCS anódica cerebelar e cinesioterapia, em sessões múltiplas diárias para reabilitação da ataxia cerebelar. MATERIAIS E MÉTODOS: Este relato de caso incluiu um paciente do sexo masculino, de 34 anos, com história de ataxia espinocerebelar há 10 anos. Seus principais objetivos eram melhorar a marcha e o equilíbrio. Ele apresentava ataxia axial e apendicular, dificuldades na marcha e no equilíbrio. O protocolo de estimulação do cerebelo consistiu na aplicação de tDCS por 20 minutos, 2mA, diariamente, durante duas semanas, com ânodo posicionado sobre o ínion e cátodo sobre o músculo deltóide direito. A cinesioterapia simultânea incluiu exercícios funcionais progressivos com objetivo principal de treinamento de equilíbrio. RESULTADOS: A melhora clínica foi particularmente evidenciada por uma redução de 4 pontos na Escala para Avaliação e Graduação da Ataxia após 10 sessões, enquanto a literatura recomenda a eficácia de uma nova terapia que retardaria a progressão da ataxia em 1 ponto por ano. CONCLUSÃO: Nossos resultados sugerem que a associação entre tDCS e cinesioterapia foi eficaz neste paciente; as sessões de tDCS foram seguras e bem toleradas e podem ter desempenhado um papel na melhora nos testes funcionais. Novos estudos controlados envolvendo um número maior de pacientes são necessários para analisar os benefícios destas técnicas combinadas para maximizar a reabilitação motora nesta população.

Motor and cognitive outcomes of cerebello-spinal stimulation in neurodegenerative ataxia.

Cerebellar ataxias represent a heterogeneous group of disabling disorders characterized by motor and cognitive disturbances, for which no effective treatment is currently available. In this randomized, double-blind, sham-controlled trial, followed by an open-label phase, we investigated whether treatment with cerebello-spinal transcranial direct current stimulation (tDCS) could improve both motor and cognitive symptoms in patients with neurodegenerative ataxia at short and long-term. Sixty-one patients were randomized in two groups for the first controlled phase. At baseline (T0), Group 1 received placebo stimulation (sham tDCS) while Group 2 received anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5 days/week for 2 weeks (T1), with a 12-week (T2) follow-up (randomized, double-blind, sham controlled phase). At the 12-week follow-up (T2), all patients (Group 1 and Group 2) received a second treatment of anodal cerebellar tDCS and cathodal spinal tDCS (real tDCS) for 5 days/week for 2 weeks, with a 14-week (T3), 24-week (T4), 36-week (T5) and 52-week follow-up (T6) (open-label phase). At each time point, a clinical, neuropsychological and neurophysiological evaluation was performed. Cerebellar-motor cortex connectivity was evaluated using transcranial magnetic stimulation. We observed a significant improvement in all motor scores (scale for the assessment and rating of ataxia, international cooperative ataxia rating scale), in cognition (evaluated with the cerebellar cognitive affective syndrome scale), in quality-of-life scores, in motor cortex excitability and in cerebellar inhibition after real tDCS compared to sham stimulation and compared to baseline (T0), both at short and long-term. We observed an addon-effect after two repeated treatments with real tDCS compared to a single treatment with real tDCS. The improvement at motor and cognitive scores correlated with the restoration of cerebellar inhibition evaluated with transcranial magnetic stimulation. Cerebello-spinal tDCS represents a promising therapeutic approach for both motor and cognitive symptoms in patients with neurodegenerative ataxia, a still orphan disorder of any pharmacological intervention.

Retinal Architecture in Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS): Insights into Disease Pathogenesis and Biomarkers.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) causes unique retinal abnormalities, which have not been systematically investigated. To deeply phenotype the retina in ARSACS in order to better understand its pathogenesis and identify potential biomarkers. We evaluated 29 patients with ARSACS, 66 with spinocerebellar ataxia (SCA), 38 with autosomal recessive cerebellar ataxia (ATX), 22 with hereditary spastic paraplegia (SPG), 21 cases of papilledema, and 20 healthy controls (total n=196 subjects). Participants underwent visual acuity assessment, intraocular pressure measurement, fundoscopy, and macular and peripapillary optical coherence tomography (OCT). Macular layers thicknesses in ARSACS were compared with those of age-matched healthy controls. Ophthalmologists analyzed the scans for abnormal signs in the different patient groups. Linear regression analysis was conducted to look for associations between retinal changes and age, age at onset, disease duration, and Scale for the Assessment and Rating of Ataxia (SARA) scores in ARSACS. Only patients with ARSACS exhibited peripapillary retinal striations (82%) on fundoscopy, and their OCT scans revealed foveal hypoplasia (100%), sawtooth appearance (89%), papillomacular fold (86%), and macular microcysts (18%). Average peripapillary retinal nerve fiber layer (pRNFL) was thicker in ARSACS than in SCA, ATX, SPG, and controls; a cut-off of 121 μm was 100% accurate in diagnosing ARSACS. All macular layers were thicker in ARSACS when compared to healthy controls. RNFL thickness in the inferior sector of the macula positively correlated with SARA scores. Retinal abnormalities are highly specific for ARSACS, and suggest retinal hyperplasia due to abnormal retinal development. OCT may provide potential biomarkers for future clinical trials. © 2021 International Parkinson and Movement Disorder Society.

Instrumented Objective Clinical Examination of Cerebellar Ataxia: the Upper and Lower Limb—a Review

Cerebellar dysfunction results in impairments in co-ordination or 'ataxia'. Bedside examination of cerebellar function has changed little since the early nineteenth century with the exception being the oculomotor examination which has become instrumented. Otherwise, competence and confidence in performing the clinical assessment relies heavily on the skill and experience of the clinician. Potentially, instrumented objective measurement will more accurately assess the severity of ataxia and the changes brought about by advancing therapies in pharmaceutical trials and in rehabilitation intervention. This study describes instrumented versions of several bedside tests of cerebellar function, including rhythmic tapping of the hand (RTH), finger-nose test (FNT), dysdiadochokinesia (DDK), ramp tracking (RMT), ballistic tracking (BT), rhythmic tapping of the foot (RTF) and the heel shin (HST) examination which were validated against scores from Ataxia Rating Scales (ARS) such as the Scale of Assessment and Rating of Ataxia (SARA). While all of the instrumented tests accurately distinguished between ataxic subjects and controls, there was a difference in performance, with the best four performing upper limb tests being RTH, FNT, DDK and BT. A combination of BT plus RTH provided the best correlation with the SARA and outperformed a combination of all the bedside tests (Spearman 0.8; p < 0.001 compared to 0.68; p < 0.001 for the combined set) in identifying the presence and severity of ataxia. This indicates that there is redundancy in the information provided by the bedside tests and that adding other tests to BT plus RTH does not add accuracy to the assessment of ataxia. This analysis highlighted the need for metrics that could be generalised to each of the assessments of ataxia, so, in turn, domains of stability, timing, accuracy and rhythmicity (STAR domains) were developed and compared to the SARA. The STAR criteria could potentially influence the future of instrumented assessment in CA and pave the way for further research into the objective measurement of the cerebellar examination.

Determining the Validity of Conducting Rating Scales in Friedreich Ataxia through Video.

The Friedreich Ataxia Rating Scale (FARS) and the Scale for the Assessment and Rating of Ataxia (SARA) are commonly used neurological rating scales in Friedreich ataxia (FRDA). The modified Friedreich Ataxia Rating Scale (mFARS) has been accepted as an appropriate outcome measure for clinical trials in FRDA. The COVID-19 pandemic has resulted in limited face-to-face interactions with individuals involved in natural history studies and clinical trials. The aim of this study was to determine the validity of conducting the mFARS and SARA through video. Individuals who had the mFARS administered face-to-face in the previous 6 months were invited to participate. Participants were sent instructions and asked to have a carer present to assist. The mFARS and SARA were then administered by video. Differences between face-to-face and video scores and the reliability between scores obtained face-to-face and by video were examined. The mFARS and SARA were conducted by video with 19 individuals. Excellent test-retest reliability was seen in the mFARS lower limb coordination (ICC=0.96, 95% CI 0.90-0.98) and upright stability sections (ICC=0.97, 95% CI 0.93-0.99), total mFARS (ICC=0.97, 95% CI 0.92-0.99) and SARA scores (ICC=0.98, 95% CI 0.95-0.99). Excellent test-retest reliability was demonstrated in the majority of the mFARS sections, and in the total mFARS and SARA scores, suggesting that video is a valid method of conducting these scales. This method enables inclusion of participants who are unable to travel to study sites. A larger cohort will be required to further validate the use of video mFARS and SARA for future studies.

Anxiety and depression in spinocerebellar ataxia patients during the COVID-19 pandemic in China: A cross-sectional study

Coronavirus disease 2019 (COVID-19) is currently a global concern, and the psychological impact cannot be overlooked. Our purpose was to evaluate the anxiety and depression in spinocerebellar ataxia (SCA) patients during the pandemic and to analyse the influencing factors. We conducted an online questionnaire survey among 307 SCA patients from China and selected 319 healthy people matched by sex and age as the control group. The questionnaire included general information, the self-rating anxiety scale (SAS), and the self-rating depression scale (SDS). The relevant factors included COVID-19 risk factors, age, sex, body mass index (BMI), educational background, disease course, score on the scale for the assessment and rating of ataxia (SARA), Mini-mental State Examination (MMSE) and International Cooperative Ataxia Rating Scale (ICARS). The proportion of SCA patients with anxiety was 34.9%, and the proportion with depression was 56.7%. The SAS and SDS scores of the SCA patients were significantly higher than those of the control group (SAS: 45.8 ± 10.1 vs. 40.6 ± 8.9, P < 0.01; SDS: 55.1 ± 12.2 vs. 43.6 ± 11.9, P < 0.01). In SCA3, the risk of exposure to COVID-19, educational level, disease course and the severity of ataxia may be factors affecting patients’ mental health. More attention should be paid to the mental health of SCA patients during the COVID-19 pandemic.

Neurophysiological and ophthalmological findings of SPG7-related spastic ataxia: a phenotype study in an Irish cohort.

Mutations in SPG7 are increasingly identified as a common cause of spastic ataxia. We describe a cohort of Irish patients with recessive SPG7-associated phenotype. Comprehensive phenotyping was performed with documentation of clinical, neurophysiological, optical coherence tomography (OCT) and genetic data from individuals with SPG7 attending two academic neurology units in Dublin, including the National Ataxia Clinic. Thirty-two symptomatic individuals from 25 families were identified. Mean age at onset was39.1years (range 12-61), mean disease duration 17.8years (range 5-45), mean disease severity as quantified with the scale for the assessment and rating of ataxia 9/40 (range 3-29). All individuals displayed variable ataxia and spasticity within a spastic-ataxic phenotype, and additional ocular abnormalities. Two had spasmodic dysphonia and three had colour vision deficiency. Brain imaging consistently revealed cerebellar atrophy (n = 29); neurophysiology demonstrated a length-dependent large-fibre axonal neuropathy in 2/27 studied. The commonest variant was c.1529C > T (p.Ala510Val), present in 21 families. Five novel variants were identified. No significant thinning of average retinal nerve fibre layer (RNFL) was demonstrated on OCT (p = 0.61), but temporal quadrant reduction was evident compared to controls (p < 0.05), with significant average and temporal RNFL decline over time. Disease duration, severity and visual acuity were not correlated with RNFL thickness. Our results highlight that recessive SPG7 mutations may account for spastic ataxia with peripheral neuropathy in only a small proportion of patients. RNFL abnormalities with predominant temporal RNFL reduction are common and OCT should be considered part of the routine assessment in spastic ataxia.

Progression characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS): a 4-year cohort study

The European Friedreich's Ataxia Consortium for Translational Studies (EFACTS) investigates the natural history of Friedreich's ataxia. We aimed to assess progression characteristics and to identify patient groups with differential progression rates based on longitudinal 4-year data to inform upcoming clinical trials in Friedreich's ataxia. EFACTS is a prospective, observational cohort study based on an ongoing and open-ended registry. Patients with genetically confirmed Friedreich's ataxia were seen annually at 11 clinical centres in seven European countries (Austria, Belgium, France, Germany, Italy, Spain, and the UK). Data from baseline to 4-year follow-up were included in the current analysis. Our primary endpoints were the Scale for the Assessment and Rating of Ataxia (SARA) and the activities of daily living (ADL). Linear mixed-effect models were used to analyse annual disease progression for the entire cohort and subgroups defined by age of onset and ambulatory abilities. Power calculations were done for potential trial designs. This study is registered with ClinicalTrials.gov, NCT02069509. Between Sept 15, 2010, and Nov 20, 2018, of 914 individuals assessed for eligibility, 602 patients were included. Of these, 552 (92%) patients contributed data with at least one follow-up visit. Annual progression rate for SARA was 0·82 points (SE 0·05) in the overall cohort, and higher in patients who were ambulatory (1·12 [0·07]) than non-ambulatory (0·50 [0·07]). ADL worsened by 0·93 (SE 0·05) points per year in the entire cohort, with similar progression rates in patients who were ambulatory (0·94 [0·07]) and non-ambulatory (0·91 [0·08]). Although both SARA and ADL showed slightly greater worsening in patients with typical onset (symptom onset at ≤24 years) than those with late onset (symptom onset ≥25 years), differences in progression slopes were not significant. For a 2-year parallel-group trial, 230 (115 per group) patients would be required to detect a 50% reduction in SARA progression at 80% power: 118 (59 per group) if only individuals who are ambulatory are included. With ADL as the primary outcome, 190 (95 per group) patients with Friedreich's ataxia would be needed, and fewer patients would be required if only individuals with early-onset are included. Our findings for stage-dependent progression rates have important implications for clinicians and researchers, as they provide reliable outcome measures to monitor disease progression, and enable tailored sample size calculation to guide upcoming clinical trial designs in Friedreich's ataxia. European Commission, Voyager Therapeutics, and EuroAtaxia.

The cerebellar cognitive affective syndrome scale reveals early neuropsychological deficits in SCA3 patients

BackgroundThe cerebellar cognitive affective syndrome scale (CCAS-S) was recently developed to detect specific neuropsychological deficits in patients with cerebellar diseases in an expedited manner.ObjectivesTo evaluate the discriminative ability of the CCAS-S in an etiologically homogeneous cohort of spinocerebellar ataxia type 3 (SCA3) patients and to examine relationships between cognitive deficits and motor symptom severity.MethodsThe CCAS-S was administered to twenty mildly to moderately affected SCA3 patients and eighteen healthy controls matched for age, sex, and educational level. Disease severity was measured by the Scale for the Assessment and Rating of Ataxia (SARA), Inventory of Non-Ataxia Signs (INAS), 8 m walk test, nine-hole peg test (9HPT), and Patient Health Questionnaire-9 (PHQ-9).ResultsSCA3 patients had a lower total CCAS-S score (p < 0.001) and higher number of failed tests (p = 0.006) than healthy controls. Patients displayed impairments in semantic fluency, phonemic fluency, category switching, cube drawing, and affect regulation. Total CCAS-S score showed high discriminative ability (area under the curve [AUC]: 0.96) and was associated with disease duration, SARA score, walking speed, and dominant hand 9HPT performance. No correlations were observed with INAS count, repeat length, and PHQ-9 score. Discriminative capacity of the number of failed tests was moderate (AUC: 0.76).ConclusionEssentially all SCA3 patients exhibited some form of cognitive impairment. The CCAS-S differentiates SCA3 patients from healthy controls, detects neuropsychological deficits early in the disease course, and correlates with relevant ataxia severity measures.

Discordance Between Patient-Reported Outcomes and Physician-Rated Motor Symptom Severity in Early-to-Middle-Stage Spinocerebellar Ataxia Type 3

Assessment of patient-reported outcome measures (PROMs) in spinocerebellar ataxias (SCAs) could provide valuable insights into self-perceived health status. Although they are considered additional endpoints in future clinical trials, determinants and interactions of different PROMs in early disease stages remain largely unknown. The aims of the present study were to evaluate health-related quality of life, depressive symptoms, fatigue, and physical activity in mildly to moderately affected SCA3 patients and to examine interrelations between these PROMs and objective disease severity indices. Twenty SCA3 patients and twenty healthy controls of comparable age and sex completed the EQ-5D-5L, Patient Health Questionnaire-9, Profile of Mood States, and International Physical Activity Questionnaire. Disease severity was quantified by the Scale for the Assessment and Rating of Ataxia (SARA) and Inventory of Non-Ataxia Signs (INAS). Mildly to moderately affected SCA3 patients reported lower quality of life (p = 0.049), more depressive symptoms (p = 0.028), and higher levels of fatigue (p = 0.001) than healthy controls. The amount of physical activity did not differ between both groups. Linear regression analyses revealed that quality of life was primarily determined by fatigue and not by ataxia severity, while physical activity was independently associated with SARA score and INAS count but not fatigue. Depressive symptoms were related to disease duration and fatigue but not to markers of motor disease progression. Taken together, decreased quality of life, increased levels of fatigue, and a higher number of depressive symptoms do not merely reflect motor impairment in early-to-middle-stage SCA3 patients. The observed discordance between patient-reported and clinician-based outcomes indicates that these measures genuinely evaluate distinct aspects of disease and emphasizes their complementariness in therapeutic trials. By contrast, the volume of self-reported physical activity is not associated with fatigue, reflects both ataxia severity and extracerebellar involvement, and could therefore represent a useful marker of motor impairment in a home setting.

\u201cHot cross bun\u201d is a potential imaging marker for the severity of cerebellar ataxia in MSA-C

To evaluate the correlation between “hot cross bun” sign (HCBs) and disease severity in multiple system atrophy (MSA). We recruited patients with probable and possible MSA with parkinsonism (MSA-P) or the cerebellar ataxia (MSA-C) subtypes. Clinical and imaging characteristics were collected and comparison was performed between MSA-C and MSA-P cases. Spearman test was used to evaluate the correlation between HCBs and other variables. Curve estimate and general linear regression was performed to evaluate the relationship between HCBs and the Scale for Assessment and Rating of Ataxia (SARA). Unified Multiple System Atrophy Rating Scale (UMSARS) IV was used to assess the severity of disease. Multinomial ordered logistic regression was used to confirm the increased likelihood of disability for the disease. Eighty-one MSA with HCBs comprising of 50 MSA-C and 31 MSA-P were recruited. We demonstrated that the severity of HCBs showed a positive linear correlation with SARA scores in MSA-C. Multinomial ordered logistic regression test revealed that the increase in the HCBs grade may be associated with an increased likelihood of disability for the disease severity in MSA, especially in those with cerebellar ataxia subtype. We demonstrated that HCBs is a potential imaging marker for the severity of cerebellar ataxia. The increase in the HCBs grade may be associated with an increased likelihood of disability in MSA-C, but not MSA-P cases, suggesting that it may be a useful imaging indicator for disease progression in Chinese patients with MSA-C.

Validation of the 5-domain Niemann-Pick type C Clinical Severity Scale

BackgroundNiemann-Pick disease type C (NPC) is an ultra-rare, progressive, genetic disease leading to impaired lysosomal function and neurodegeneration causing serious morbidity and shortened life expectancy.The Niemann-Pick type C Clinical Severity Scale (NPCCSS) is a 17 domain, disease-specific, clinician-reported outcome measure of disease severity and progression. An abbreviated 5-domain NPCCSS scale has been developed (measuring Ambulation, Swallow, Cognition, Speech, and Fine Motor Skills) and the scale reliability has been established. Additional psychometric properties and meaningful change of the scale need, however, to be assessed.MethodsMixed method studies were conducted to ascertain which NPCCSS domains were most important, as well as to explore meaningful change: 1) surveys in caregivers/patients (n = 49) and 2) interviews with clinicians (n = 5) as well as caregivers/patients (n = 28). Clinical trial data (n = 43) assessed construct validity and meaningful change through an anchor-based approach.ResultsDomains identified as most important by clinicians, caregivers, and patients (independent of current age, age of onset, and disease severity) were Ambulation, Swallow, Cognition, Speech, and Fine Motor Skills, indicating content validity of the 5-domain NPCCSS.Criterion validity was shown with the 5-domain NPCCSS being highly correlated with the 17-item NPCCSS total score (excluding hearing domains), r2 = 0.97. Convergent validity was demonstrated against the 9 Hole Peg Test, r2 = 0.65 (n = 31 patients), and the Scale for Assessment and Rating of Ataxia (SARA), r2 = 0.86 (n = 49 patients). Any change was seen as meaningful by patients/caregivers across domains. Meaningful change using trial data and interviews with NPC experts (n = 5) and patients/caregivers (n = 28) suggested that a 1-category change on a domain is equivalent to 1-point change or greater in the 5-domain NPCCSS total score.ConclusionsQualitative and quantitative data support content and construct validity of the 5-domain NPCCSS score as a valid endpoint in NPC trials. A 1-category change on any domain is equivalent to 1-point change or greater in the 5 domain NPCCSS total score, representing a clinically meaningful transition and reflecting loss of complex function and increased disability.Trial registration NCT02612129. Registered 23 November 2015, https://clinicaltrials.gov/ct2/show/NCT02612129

Gauging Gait Disorders with a Method Inspired by Motor Control Theories: A Pilot Study in Friedreich's Ataxia.

To date, it has been challenging for clinicians and researchers alike to use the multiple outcome measures available to create a meaningful clinical picture and perform effective longitudinal follow-up. It has been found that instrumented gait analysis can provide information associated with a patient’s performance and help to remedy the shortcomings of the currently available outcome measures. The goal of this methodological article is to set the background and justify a new outcome measure inspired by the motor control theories to analyze gait using spatiotemporal parameters. The method is applied in a population of individuals living with Friedreich’s ataxia (FRDA), a neurodegenerative disease. The sample population consisted of 19 subjects, 11 to 65 years of age with FRDA, who either ambulated independently, with a cane, or with a rollator. Three scores based on the distance from healthy normative data were used: Organization Score, Variability Score, and an overall measurement, the Global Ambulation Score. The scores were then compared to the Scale for Assessment and Rating of Ataxia (SARA) Gait Score (SARA-GS), a clinical scale currently being used for gait analysis in FRDA. Organization Scores demonstrated a longitudinal deterioration in the gait characteristics from independent ambulators to those who ambulated with a rollator. Variability Scores mostly reflected dynamic instability, which became greater as the requirement of an ambulation aid or the switch from a cane to a rollator was imminent. The global value given by the Global Ambulation Score, which takes into consideration both the Organization Score, the Variability Score, and the level of assistive device, demonstrated a logarithmic relationship with the SARA-GS. Overall, these results highlight that both components introduced should be analyzed concurrently and suggest that the Global Ambulation Score may be a valuable outcome measure for longitudinal disease progression.

Inverse associations between cerebellar inhibition and motor impairment in spinocerebellar ataxia type 3

BackgroundCerebellar ataxia generally results from a lesion disrupting the corticopontocerebellar or cerebellothalamocortical tract. The cerebellar inhibition (CBI) paradigm represents a dual-coil transcranial magnetic stimulation protocol that interrogates the integrity of the latter pathway. Whether CBI has clinical relevance in ataxia patients remains largely unknown because associations with pertinent disease severity measures in etiologically homogeneous cohorts have not been previously examined. ObjectiveTo investigate if CBI correlates with clinical and functional indices of disease severity in individuals with spinocerebellar ataxia type 3 (SCA3). MethodsCBI was assessed in fourteen SCA3 patients by paired-pulse cerebellar-motor cortex (M1) stimulation using interstimulus intervals of 3, 5, and 10 ms. Correlation coefficients were determined between CBI and ataxia severity, manual dexterity, and walking speed. ResultsSuppression of M1 excitability occurred 5 ms following a contralateral cerebellar conditioning stimulus in SCA3 patients, but, on average, CBI was significantly reduced as compared to a healthy control group from the literature (p < 0.001). A significant association was found between decreased CBI levels and higher Scale for the Assessment and Rating of Ataxia (SARA) scores (r = −0.62, p = 0.019). CBI was negatively correlated with axial, appendicular, and speech subscores, as well as with nine-hole peg test performance (r = −0.69, p = 0.006). No association was observed between CBI and walking speed. As expected, there were no significant clinical-neurophysiological correlations at 3 and 10 ms interstimulus intervals. ConclusionOur results provide the first neurophysiological evidence for an inverse association between cerebellothalamocortical tract integrity, as reflected by reduced levels of CBI, and ataxia severity in SCA3 patients. Longitudinal studies are required to evaluate if CBI could serve as a marker of disease progression.