Ataxia Rating Research Articles

Safety and Efficacy of Acetyl-DL-Leucine in Certain Types of Cerebellar Ataxia

Cerebellar ataxia is a neurodegenerative disease impairing motor function characterized by ataxia of stance, gait, speech, and fine motor disturbances. To investigate the efficacy, safety, and tolerability of the modified essential amino acid acetyl-DL-leucine in treating patients who have cerebellar ataxia. The Acetyl-DL-leucine on Cerebellar Ataxia (ALCAT) trial was an investigator-initiated, multicenter, double-blind, randomized, placebo-controlled, clinical crossover trial. The study was conducted at 7 university hospitals in Germany and Austria between January 25, 2016, and February 17, 2017. Patients were aged at least 18 years and diagnosed with cerebellar ataxia of hereditary (suspected or genetically confirmed) or nonhereditary or unknown type presenting with a total score of at least 3 points on the Scale for the Assessment and Rating of Ataxia (SARA). Statistical analysis was performed from April 2018 to June 2018 and January 2020 to March 2020. Patients were randomly assigned (1:1) to receive acetyl-DL-leucine orally (5 g per day after 2 weeks up-titration) followed by a matched placebo, each for 6 weeks, separated by a 4-week washout, or vice versa. The randomization was done via a web-based, permuted block-wise randomization list (block size, 2) that was stratified by disease subtype (hereditary vs nonhereditary or unknown) and site. Primary efficacy outcome was the absolute change of SARA total score from (period-dependent) baseline to week 6. Among 108 patients who were randomly assigned to sequence groups (54 patients each), 55 (50.9%) were female; the mean (SD) age was 54.8 (14.4) years; and the mean (SD) SARA total score was 13.33 (5.57) points. The full analysis set included 105 patients (80 patients with hereditary, 25 with nonhereditary or unknown cerebellar ataxia). There was no evidence of a difference in the mean absolute change from baseline to week 6 in SARA total scores between both treatments (mean treatment difference: 0.23 points [95% CI, -0.40 to 0.85 points]). In this large multicenter, double-blind, randomized, placebo-controlled clinical crossover trial, acetyl-DL-leucine in the investigated dosage and treatment duration was not superior to placebo for the symptomatic treatment of certain types of ataxia. The drug was well tolerated; and ALCAT yielded valuable information about the duration of treatment periods and the role of placebo response in cerebellar ataxia. These findings suggest that further symptom-oriented trials are needed for evaluating the long-term effects of acetyl-DL-leucine for well-defined subgroups of cerebellar ataxia. EudraCT 2015-000460-34.

Longitudinal Assessment Using Optical Coherence Tomography in Patients with Friedreich’s Ataxia

Ocular abnormalities occur frequently in Friedreich’s ataxia (FRDA), although visual symptoms are not always reported. We evaluated a cohort of patients with FRDA to characterise the clinical phenotype and optic nerve findings as detected with optical coherence tomography (OCT). A total of 48 patients from 42 unrelated families were recruited. Mean age at onset was 13.8 years (range 4–40), mean disease duration 19.5 years (range 5–43), mean disease severity as quantified with the Scale for the Assessment and Rating of Ataxia 22/40 (range 4.5–38). All patients displayed variable ataxia and two-thirds had ocular abnormalities. Statistically significant thinning of average retinal nerve fibre layer (RNFL) and thinning in all but the temporal quadrant compared to controls was demonstrated on OCT. Significant RNFL and macular thinning was documented over time in 20 individuals. Disease severity and visual acuity were correlated with RNFL and macular thickness, but no association was found with disease duration. Our results highlight that FDRA is associated with subclinical optic neuropathy. This is the largest longitudinal study of OCT findings in FRDA to date, demonstrating progressive RNFL thickness decline, suggesting that RNFL thickness as measured by OCT has the potential to become a quantifiable biomarker for the evaluation of disease progression in FRDA.

Ataxia due to injury of the cortico-ponto-cerebellar tract in patients with mild traumatic brain injury.

Introduction:The cortico-ponto-cerebellar tract (CPCT) is involved in coordination of movement; injury of the CPCT can therefore be accompanied by ataxia. In this study, using diffusion tensor tractography (DTT), we investigated injury of the CPCT in patients with mild traumatic brain injury (TBI).Methods:We recruited 45 consecutive patients with ataxia following mild TBI and 20 normal control subjects. The score of assessment and rating of ataxia (SARA) was used to evaluate of ataxia. The patients were classified into 2 groups based on the SARA; patient group A had with post-traumatic ataxia and patient group B had without post-traumatic ataxia. The fractional anisotropy (FA) value and fiber number (FN) of the CPCT was measured.Results:Significant differences were observed in the FA and FN values of the CPCT between patient group A and the control group and between patient groups A and B (P < .05). In addition, a significant difference was observed in the FA value only of the CPCT between patient group B and the control group (P < .05). However, no significant difference was observed in the FN value of the CPCT between patient group B and the control group (P > .05).Conclusion:By using DTT, injury of the CPCT was demonstrated in patients who showed ataxia following mild TBI. These results suggest that DTT would be useful for evaluation of the CPCT in patients with ataxia after mTBI because mTBI usually does not show any abnormalities on conventional brain MRI.

Clinical features and outcome of patients with autoimmune cerebellar ataxia evaluated with the Scale for the Assessment and Rating of Ataxia.

This study was undertaken to assess the long-term outcome of patients with paraneoplastic and non paraneoplastic autoimmune cerebellar ataxia (ACA) using the Scale for the Assessment and Rating of Ataxia (SARA). Patients with subacute cerebellar ataxia admitted to our institution between September 2012 and April 2020 were prospectively recruited. Serum and/or cerebrospinal fluid was tested for neural autoantibodies by indirect immunofluorescence on mouse brain, cell-based assays, and radioimmunoassay. SARA and modified Rankin Scale (mRS) score were employed to assess patients' outcome. Fifty-five patients were recruited, of whom 23 (42%) met the criteria for cerebellar ataxia of autoimmune etiology. Neural autoantibodies were detected in 22 of 23 patients (Yo-immunoglobulin G [IgG], n = 6; glutamic acid decarboxylase 65-IgG, n = 3; metabotropic glutamate receptor 1-IgG, n = 2; voltage-gated calcium channel P/Q type-IgG, n = 2; Hu-IgG, n = 1; glial fibrillary acidic protein-IgG, n = 1; IgG-binding unclassified antigens, n = 7). Thirteen patients were diagnosed with paraneoplastic cerebellar syndrome (PCS) and 10 with idiopathic ACA. All patients received immunotherapy. Median SARA score was higher in the PCS group at all time points (p=0.0002), while it decreased significantly within the ACA group (p=0.049) after immunotherapy. Patients with good outcome (mRS≤2) had less neurological disability (SARA<15) at disease nadir (p=0.039) and presented less frequently with paraneoplastic neurological syndrome (p=0.0028). The univariate linear regression model revealed a good correlation between mRS and SARA score both at disease onset (p<0.0001) and at last follow-up (p<0.0001). SARA score < 11 identified patients with good outcome. Patients with idiopathic ACA significantly improved after immunotherapy. SARA score accurately reflects patients' clinical status and may be a suitable outcome measure for patients with ACA.

Applicability of quantitative oculomotor and SARA assessment in children.

In clinical practice, eye movements can provide an early diagnostic marker for early onset ataxia (EOA). However, quantitative oculomotor assessment is not included in the most frequently used and age-validated ataxia rating scale in children, the Scale for the Assessment and Rating of Ataxia (SARA). We aimed to investigate the applicability of semi-quantitative eye movement assessment by the International Cooperative Ataxia Rating Scale (ICARSOCM) and Ocular Motion Score (OMS7-10) complementary to SARA measurements in children. In 52 typically developing children (aged 4-16 years; n=4 per year of age), three independent assessors scored saccadic eye movements and ocular pursuit according to the ICARSOCM and matching parameters from the OMS7-10. For ICARSOCM, we determined 1) construct validity for coordinated eye movements by correlation with OMS7-10, ICARSEYE-HAND-COORDINATION and SARA subscale scores, 2) agreement percentage and inter-rater agreement (Fleiss Kappa) and 3) age-dependency. Spearman's rank correlations of ICARSOCM with OMS7-10 and ICARS- and SARA subscales were moderate to fair (all p<.001). Inter-rater agreement of ICARS-OCM was 80.8%; (Fleiss Kappa: 0.411). ICARSOCM scores revealed a similar exponentially decreasing association with age as the other SARA (sub)scores, reaching a plateau at 10 years of age. ICARSOCM has a valid construct for the measurement of coordinated eye movement performance and is reliably assessable in children. ICARSOCM reveals a similar age-dependent relationship as the other ataxia subscales, reflecting the physiological maturation of the cerebellum. In children, these data may implicate that ICARSOCM can reliably contribute to coordination assessment, complementary to the SARA subscales.

A Case Report of a Patient with Diplopia and Ataxia Diagnosed as Claude’s Syndrome Treated with Korean Medicine

Objective: The aim of this study was to report the effect of Korean medicine treatment on Claude's syndrome with ataxia and diplopia.Methods: We applied electroacupuncture, scalp acupuncture, and physical therapy to the patient. Diplopia was assessed with the distance between two images of one object, and ataxia was assessed with the Korean Version of the Scale for the Assessment and Rating of Ataxia (K-SARA).Results: After 21 days of treatment, diplopia, abnormal extraocular movement, and ataxia were improved on the basis of the K-SARA score.Conclusion: This case demonstrates the effectiveness of Korean medicine treatment in improving the symptoms of Claude's syndrome.

Association of the Level of Neurofilament Light With Disease Severity in Patients With Spinocerebellar Ataxia Type 2.

Background and ObjectivesFew biochemical markers have been identified in spinocerebellar ataxia type 2 (SCA2). This study aimed to determine the levels of neurofilament light (NfL) in patients with SCA2 and to identify whether they are associated with disease severity.MethodsParticipants were recruited from 1 medical center in China, and individuals with SCA2 were genetically diagnosed. NfL levels were assessed with the single molecule array method. Disease severity was evaluated with the Scale for the Assessment and Rating of Ataxia (SARA), the International Cooperative Ataxia Rating Scale (ICARS), and the Inventory of Non-Ataxia Symptoms (INAS). Cerebellum and brainstem volumes were calculated from neuroimaging measurements. We used the Pearson correlation and partial correlation for correlation analyses.ResultsForty-nine patients with manifest SCA2, 10 preclinical individuals with SCA2, and 92 controls were enrolled. A high consistency was identified between serum and CSF NfL (r = 0.868, p < 0.0001). In individuals with SCA2, levels of serum NfL were associated with disease severity (SARA: r = 0.425, p = 0.003; ICARS: r = 0.383, p = 0.009; INAS:, r = 0.390, p = 0.007; cerebellum volume: r = −0.393, p = 0.024) after adjustment for age. NfL levels were higher close to the expected age at onset in preclinical individuals with SCA2 (R2 = 0.43, p = 0.04).DiscussionLevels of serum NfL were correlated with disease intensity in individuals with SCA2 and were higher close to the estimated age at onset in preclinical SCA2. Therefore, NfL is a potential serum biomarker of disease severity in SCA2.Classification of EvidenceThis study provides Class II evidence that elevated NfL levels are associated with disease severity in individuals with SCA2.

Assessment of gait and balance impairment in people with spinocerebellar ataxia using wearable sensors.

To explore the use of wearable sensors for objective measurement of motor impairment in spinocerebellar ataxia (SCA) patients during clinical assessments of gait and balance. In total, 14 patients with genetically confirmed SCA (mean age 61.6 ± 8.6years) and 4 healthy controls (mean age 49.0 ± 16.4years) were recruited through the Massachusetts General Hospital (MGH) Ataxia Center. Participants donned seven inertial sensors while performing two independent trials of gait and balance assessments from the Scale for the Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS2). Univariate analysis was used to identify sensor-derived metrics from wearable sensors that discriminate motor function between the SCA and control groups. Multivariate linear regression models were used to estimate the subjective in-person SARA/BARS2 ratings. Spearman correlation coefficients were used to evaluate the performance of the model. Stride length variability, stride duration, cadence, stance phase, pelvis sway, and turn duration were different between SCA and controls (p < 0.05). Similarly, sway and sway velocity of the ankle, hip, and center of mass differentiated SCA and controls (p < 0.05). Using these features, linear regression models showed moderate-to-strong correlation with clinical scores from the in-person rater during SARA assessments of gait (r = 0.73, p = 0.003) and stance (r = 0.90, p < 0.001) and the BARS2 gait assessment (r = 0.74, p = 0.003). This study demonstrates that sensor-derived metrics can potentially be used to estimate the level of motor impairment in patient with SCA quickly and objectively. Thus, digital biomarkers from wearable sensors have the potential to be an integral tool for SCA clinical trials and care.

Quantitative clinical and radiological recovery in post-operative patients with superficial siderosis by an iron chelator.

Superficial siderosis is a rare neurodegenerative disease caused by hemosiderin deposition on the brain surface. Although the efficacy of the iron chelator-deferiprone-in superficial siderosis has recently been documented, a comparative study of patients who underwent surgical ablation of their bleeding source and subsequently received treatment with or without deferiprone has not yet been conducted. Fifteen postoperative patients with superficial siderosis were recruited, and seven patients were administered deferiprone (combination therapy group). Quantitative changes in the hypointense signals on T2*-weighted magnetic resonance images were acquired; additionally, cerebellar ataxia was assessed (International Cooperative Ataxia Rating Scale score and Scale for the Assessment and Rating of Ataxia). Audiometry was performed and the results were compared with those of patients who did not receive deferiprone (surgical treatment group; controls). Significant improvements in signal contrast ratios were noted in the lateral orbitofrontal gyrus, superior temporal lobe, insular lobe, brainstem, lingual gyrus, and cerebellar lobe in the combination therapy group. The scores of patients in the combination therapy group on the cerebellar ataxia scales significantly improved. The degree of signal improvement in the cerebellar lobe correlated with the improvement of cerebellar ataxia scores. Early deferiprone administration after disease onset and long-term administration were correlated with greater signal improvements on magnetic resonance imaging. No adverse effects were observed in the clinical or laboratory parameters. Deferiprone administration significantly improved radiological and clinical outcomes in patients with postoperative superficial siderosis. Earlier and longer courses of deferiprone could result in better patient prognosis.

A CASE STUDY ON AYURVEDIC MANAGEMENT OF SPINOCEREBELLAR ATAXIA

Spinocerebellar Ataxias (SCAs) is a neurodegenerative heterogeneous group of disorders that often-characterized progressive derangement in coordination and Balance. Presently there is no definitive cure for this genetic disease. Only a few Ayurveda case studies were reported in SCA. In the present study, a case of SCA was admitted in the IPD was treated through four phases - Deepana Pachana, Dosa Shodhana, Dosa Samana and Rasayana. The du- ration of therapy was around two months. Treatments were aimed at understanding and avoiding the predisposing factors, reversing the pathology (Samprapti Vighatana) and improving the quality of Dhatus (Rasayana), thereby improving the symptoms and arresting the progress of the disease. Scale for Assessment and Rating of Ataxia (SARA) score on 23/12/2020 and 19/02/2021 showed progressive improvement while discharging. Keywords: Vata Vyadhi, Avarana, Dhatukshaya, Spinocerebellar ataxia, Neurodegeneration

Microvascular Breakdown Due to Retinal Neurodegeneration in Ataxias.

Neurodegenerative ataxias are devastating disorders of the cerebellum and spinal cord, accompanied by death of retinal ganglion cells, leading to relentlessly progressive decline of motor coordination and permanent disability. Retinal microvascular affection has not yet been determined. The aim of this study is to assess whether retinal microvascular alterations occur and, if so, whether they are concurrent with or follow cell death in the retina in neurodegenerative diseases. This study involves the cross-sectional observational study of 43 patients with ataxia and 43 controls enrolled from August 1, 2018, to September 30, 2020. The extent of ataxia was determined by the Scale for the Assessment and Rating of Ataxia. Changes in retinal vasculature were examined by optical coherence tomography angiography (OCT-A) and retinal cell and fiber density by OCT in ataxias concurrently. When comparing the ataxia cohort with healthy subjects, ataxia patients exhibited reduced vessel density in the radial peripapillary capillary (RPC) network (P=0.005), capillary density inside the optic nerve head (cdONH) (P < 0.001), nasal superficial vascular plexus (P=0.03) as well as reduced ganglion cell layer (GCL) volume (P=0.04), and temporal peripapillary retinal nerve fiber layer thickness (P=0.04). Mixed effect analysis modeling laterality confirmed these findings. These findings demonstrate a distinct pattern of concurrent changes in vessel density of the retinal superficial vascular complex, encompassing the superficial vascular plexus, RPC network and cdONH, and retinal GCL volume, providing new insights into the ongoing degeneration in ataxias. Our findings may have relevance for design of novel therapeutic approaches for ataxias and possibly other neurodegenerative diseases.

Reducing Ataxic Side Effects from Ventral Intermediate Nucleus of the Thalamus Deep Brain Stimulation Implantation in Essential Tremor: Potential Advantages of Directional Stimulation

Objective: The aim of the study was to retrospectively evaluate the effect of directional deep brain stimulation (DBS) on ataxia in an essential tremor patient population. Materials and Methods: A retrospective chart review of documented Scale for Assessment and Rating of Ataxia (SARA) scores were analyzed using a case-control design. All subjects we evaluated were treated at a single, tertiary care academic center. We reviewed 14 patients who underwent bilateral ventral intermediate nucleus of the thalamus (VIM) implantation with microelectrode recording, with electrodeposition and segmented contact orientation confirmed via postoperative computed tomography. The main outcome was to determine change in ataxia scores between directional versus monopolar circumferential stimulation. Results: Fourteen patients (9 males, median age at implantation 69 [range 63–82]) underwent surgery between October 2017 and July 2020 at the UNC Movement Disorders Center. SARA scores between directional stimulation and monopolar circumferential stimulation demonstrated a significant reduction in total scores with best possible segmented stimulation (n = 13, p < 0.0001, 95% confidence interval [CI] −3.496 to −6.789). This difference remained statistically significant even after removing the SARA tremor subscore (n = 13, p < 0.0001, 95% CI −3.155 to −6.274). In line with prior reports, SARA score changes from the preoperative state were generally worsened when applying monopolar circumferential stimulation bilaterally (n = 13, p = 0.655; 95% CI −2.836 to 4.359), but improved with directional stimulation (n = 13, p = 0.010; 95% CI −1.216 to −7.547). Conclusion: This retrospective analysis appears to show evidence for improved outcomes through directional stimulation in bilateral VIM DBS implantation with reduction of ataxic side effects that have traditionally plagued postoperative results, all while providing optimized tremor reduction via stimulation.

Nicotinamide Riboside Improves Ataxia Scores and Immunoglobulin Levels in Ataxia Telangiectasia.

BackgroundTreatment of animal models with ataxia telangiectasia (A‐T) with nicotinamide riboside (NR) improved their neurological outcome and survival.ObjectiveThe aim of this study is to investigate the effects of NR in patients with A‐T.MethodsIn this open‐label, proof‐of‐concept study, 24 patients with A‐T were treated with NR during four consecutive months. The effects of NR on ataxia, dysarthria, quality of life, and laboratory parameters were analyzed.ResultsDuring treatment, ataxia scores improved; mean total Scale for the Assessment and Rating of Ataxia and International Cooperative Ataxia Rating Scale scores decreased to 2.4 and 10.1 points, respectively. After NR withdrawal, ataxia scores worsened. In immunodeficient patients, the mean serum IgG concentration increased substantially until the end of the study period with 0.52 g/L. Untargeted metabolomics analysis revealed increased plasma levels of NR metabolites and purine nucleosides during treatment. Adverse effects did not occur.ConclusionsTreatment with NR is tolerated well and associated with improvement in ataxia and serum immunoglobulin concentrations in patients with A‐T. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Gait training with a wearable curara\xae robot for cerebellar ataxia: a single-arm study

BackgroundAtaxic gait is one of the most common and disabling symptoms in people with degenerative cerebellar ataxia. Intensive and well-coordinated inpatient rehabilitation improves ataxic gait. In addition to therapist-assisted gait training, robot-assisted gait training has been used for several neurological disorders; however, only a small number of trials have been conducted for degenerative cerebellar ataxia. We aimed to validate the rehabilitative effects of a wearable “curara®” robot developed in a single-arm study of people with degenerative cerebellar ataxia.MethodsTwenty participants with spinocerebellar ataxia or multiple system atrophy with predominant cerebellar ataxia were enrolled. The clinical trial duration was 15 days. We used a curara® type 4 wearable robot for gait training. We measured the following items at days 0, 7, and 14: Scale for the Assessment and Rating of Ataxia, 10-m walking time (10 mWT), 6-min walking distance (6 mWD), and timed up and go test. Gait parameters (i.e., stride duration and length, standard deviation of stride duration and length, cadence, ratio of the stance and swing phases, minimum and maximum knee joint angles, and minimum and maximum hip joint angles) were obtained using a RehaGait®. On days 1–6 and 8–13, the participants were instructed to conduct gait training for 30 ± 5 min with curara®. We calculated the improvement rate as the difference of values between days 14 and 0 divided by the value on day 0. Differences in the gait parameters were analyzed using a generalized linear mixed model with Bonferroni’s correction.ResultsData from 18 participants were analyzed. The mean improvement rate of the 10 mWT and 6 mWD was 19.0% and 29.0%, respectively. All gait parameters, except the standard deviation of stride duration and length, improved on day 14.ConclusionsTwo-week RAGT with curara® has rehabilitative effects on gait function comparable to those of therapist-assisted training. Although the long-term effects after a month of RAGT with curara® are unclear, curara® is an effective tool for gait training of people with degenerative ataxia.Trial registration jRCT, jRCTs032180164. Registered: 27 February 2019; retrospectively registered. https://jrct.niph.go.jp/en-latest-detail/jRCTs032180164.

Safety and Outcomes of Dentate Nucleus Deep Brain Stimulation for Cerebellar Ataxia.

Cerebellar symptoms remain orphan of treatment options despite being prevalent and incapacitating. Investigate whether dentate nucleus deep brain stimulation (DN DBS) is safe and leads to improvements in cerebellar symptoms when compared to sham stimulation. This randomized double-blind crossover pilot trial enrolled five patients with spinocerebellar ataxia type 3 or post-lesion ataxia. Active or sham phases were randomly performed three months apart. The primary outcome was ataxia improvement as measured by the Scale for the Assessment and Rating of Ataxia (SARA) after the active compared to the sham period. Secondary outcome measures included safety and tolerability, the Fahn-Tolosa-Marin Tremor Rating Scale (FTMRS), quality of life measurements, and patients' global impression of change. The effects on ataxia were numerically better in four out of five patients after active versus sham stimulation. The composite SARA score did not change after comparing active to sham stimulation (8.6 ± 3.6 versus 10.1 ± 4.1; p = 0.223). The FTMRS showed significant improvement after active stimulation versus sham (18.0 ± 17.2 versus 22.2 ± 19.5; p = 0.039) as did patients' global impression of change (p = 0.038). The quality of life was not modified by stimulation (p = 0.337). DN DBS was well tolerated without serious adverse events. One patient had the electrode repositioned. DN DBS is a safe and well tolerated procedure that is effective in alleviating cerebellar tremor. In this small cohort of ataxic patients, DN DBS did not achieve statistical significance for ataxia improvement.

Is the dynamic gait index a useful outcome to measure balance and ambulation in patients with cerebellar ataxia?

Ataxia can adversely affect balance and gait and increase the incidence of falls, which puts individuals at greater risk for injury. Thus, interventions focused on balance and gait are integral in rehabilitation training. In order to determine if rehabilitation interventions are effective, we need an outcome measure to detect change. To our knowledge, no activity level outcome measures have been established for balance and gait in cerebellar ataxia. The aim of the current study is to determine the reliability and validity of the Dynamic Gait Index (DGI) for ataxia. Twenty adult participants (23-84 years) with ataxia were evaluated to assess construct validity, inter-rater reliability, and same day test-retest reliability of the DGI. Participants completed ataxia-specific impairment level outcome measures, as well as the DGI. In addition to the in-person rater, three additional physical therapists scored video recordings of DGI test and retests. Construct validity was assessed via Spearman's rank order correlation coefficient (Spearman's rho) between the impairment measures (Scale for Assessment and Rating of Ataxia (SARA), International Cooperative of Ataxia Rating Scale (ICARS) and the DGI. Reliability was assessed by Spearman's rho and Intraclass Correlation Coefficient ICC (2,1). In terms of construct validity, we found significant correlations between the activity level DGI and impairment level outcome measures (-0.81 for SARA; -0.88 with ICARS). The interrater reliability of the DGI applied to participants with ataxia was high (Spearman rho: range 0.71-0.98; ICC (2,1) 0.98) as was test-retest reliability (Spearman rho: 0.95; ICC (2,1) 0.98). We showed that the DGI is a reliable and valid outcome measure to be used in the clinic for individuals with cerebellar ataxia. The DGI had excellent inter-rater and test-retest reliability for raters with varying years of clinical experience. Therefore, the DGI can be a useful clinical outcome measure for assessing balance and ambulation for individuals with cerebellar ataxia.

Instrumented classification of patients with early onset ataxia or developmental coordination disorder and healthy control children combining information from three upper limb SARA tests.

Early Onset Ataxia (EOA) and Developmental Coordination Disorder (DCD) share several phenotypical characteristics, which can be clinically hard to distinguish. To combine quantified movement information from three tests obtained from inertial measurements units (IMUs), to improve the classification of EOA and DCD patients and healthy controls compared to using a single test. Using IMUs attached to the upper limbs, we collected data from EOA, DCD and healthy control children while they performed the three upper limb tests (finger to nose, finger chasing and fast alternating movements) from the Scale for the Assessment and Rating of Ataxia (SARA) test. The most relevant features for classification were extracted. A random forest classifier with 300 trees was used for classification. The area under the receiver operating curve (ROC-AUC) and precision-recall plots were used for classification performance assessment. The most relevant discerning features concerned smoothness and velocity of movements. Classification accuracy on group level was 85.6% for EOA, 63.5% for DCD and 91.2% for healthy control children. In comparison, using only the finger to nose test for classification 73.7% of EOA and 53.4% of DCD patients and 87.2% of healthy controls were accurately classified. For the ROC/precision recall plots the AUC was 0.96/0.89 for EOA, 0.92/0.81 for DCD and 0.97/0.94 for healthy control children. Using quantified movement information from all three SARA-kinetic upper limb tests improved the classification of all diagnostic groups, and in particular of the DCD group compared to using only the finger to nose test.

Exploring the clinical meaningfulness of the Scale for the Assessment and Rating of Ataxia: A comparison of patient and physician perspectives at the item level

BackgroundThe Scale for the Assessment and Rating of Ataxia (SARA) is commonly used as the primary outcome measure in therapeutic trials. Driven by spontaneous comments from ataxia patients participating in a trial, we aimed to examine the clinical meaningfulness of the SARA from their perspective. MethodsTwenty mildly to moderately affected individuals with spinocerebellar ataxia type 3 (SARA score 11.3 ± 4.1) completed a custom-designed survey. SARA item scores were compared with self-reported complaints in everyday life. Discrepancies between SARA ratings and patients’ daily life experiences were reported as “overestimation” (i.e., a SARA item score more than 0, but no corresponding complaints) or “underestimation” (i.e., a SARA item score of 0, yet accompanying complaints). ResultsPatient-physician discrepancies were present in essentially all SARA items except for gait. The mean number of overestimated SARA points per patient was 3.1 ± 2.1. Underestimation occurred less frequently, but was relatively common in stance and fast alternating hand movements. Three quarters of patients marked gait as the most valuable SARA item, while the remaining 25% selected stance. ConclusionOn average, a quarter of total SARA score does not reflect meaningful impairments from a patient's perspective. Our data suggest that it is doubtful whether potential improvements at some of the items will be perceived as comparably important by mildly to moderately affected ataxia patients. These observations question the utility of delta SARA score as the most appropriate primary endpoint in clinical trials and call for the addition of outcome measures, such as the Patient Global Impression of Change scale and validated ataxia-specific patient-reported outcome measures.

Gait Variability in Spinocerebellar Ataxia Assessed Using Wearable Inertial Sensors.

Quantitative assessment of severity of ataxia-specific gait impairments from wearable technology could provide sensitive performance outcome measures with high face validity to power clinical trials. The aim of this study was to identify a set of gait measures from body-worn inertial sensors that best discriminate between people with prodromal or manifest spinocerebellar ataxia (SCA) and age-matched, healthy control subjects (HC) and determine how these measures relate to disease severity. One hundred and sixty-three people with SCA (subtypes 1, 2, 3, and 6), 42 people with prodromal SCA, and 96 HC wore 6 inertial sensors while performing a natural pace, 2-minute walk. Areas under the receiver operating characteristic curves (AUC) were compared for 25 gait measures, including standard deviations as variability, to discriminate between ataxic and normal gait. Pearson's correlation coefficient assessed the relationships between the gait measures and severity of ataxia. Increased gait variability was the most discriminative gait feature of SCA; toe-out angle variability (AUC=0.936; sensitivity=0.871; specificity=0.896) and double-support time variability (AUC=0.932; sensitivity=0.834; specificity=0.865) were the most sensitive and specific measures. These variability measures were also significantly correlated with the scale for the assessment and rating of ataxia (SARA) and disease duration. The same gait measures discriminated gait of people with prodromal SCA from the gait of HC (AUC=0.610, and 0.670, respectively). Wearable inertial sensors provide sensitive and specific measures of excessive gait variability in both manifest and prodromal SCAs that are reliable and related to the severity of the disease, suggesting they may be useful as clinical trial performance outcome measures. © 2021 International Parkinson and Movement Disorder Society.

Pattern of cerebellar grey matter loss associated with ataxia severity in spinocerebellar ataxias type 3: a multi-voxel pattern analysis.

Spinocerebellar ataxias type 3 (SCA3) patients are clinically characterized by progressive cerebellar ataxia combined with degeneration of the cerebellum. Previous neuroimaging studies have indicated ataxia severity associated with cerebellar atrophy using univariate methods. However, whether cerebellar atrophy patterns can be used to quantitatively predict ataxia severity in SCA3 patients at the individual level remains largely unexplored. In this study, a group of 66 SCA3 patients and 58 healthy controls were included. Disease duration and ataxia assessment, including theScale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS), were collected for SCA3 patients. The high-resolution T1-weighted MRI was obtained, and cerebellar grey matter (GM) was extracted using a spatially unbiased infratentorial template toolbox for all participants. We investigated the association between the pattern of cerebellar grey matter (GM) loss and ataxia assessment in SCA3 by using a multivariate machine learning technique. We found that the application of RVR allowed quantitative prediction of both SARA scores (leave-one-subject-out cross-validation: correlation = 0.56, p-value = 0.001; mean squared error (MSE) = 20.51, p-value = 0.001; ten-fold cross-validation: correlation = 0.52, p-value = 0.001; MSE = 21.00, p-value = 0.001) and ICARS score (leave-one-subject-out cross-validation: correlation = 0.59, p-value = 0.001; MSE = 139.69, p-value = 0.001; ten-fold cross-validation: correlation = 0.57, p-value = 0.001; MSE = 145.371, p-value = 0.001) with statistically significant accuracy. These results provide proof-of-concept that ataxia severity in SCA3 patients can be predicted by the alteration pattern of cerebellar GM using multi-voxel pattern analysis.