Degenerative Cerebellar Ataxia Research Articles

Longitudinal Analysis of Natural History Progression of Rare and Ultra-Rare Cerebellar Ataxias Using Item Response Theory.

Degenerative cerebellar ataxias comprise a heterogeneous group of rare and ultra-rare genetic diseases. While disease-modifying treatments are now on the horizon for many ataxias, robust trial designs and analysis methods are lacking. To better inform trial designs, we applied item response theory (IRT) modeling to evaluate the natural history progression of several ataxias, assessed with the widely used scale for assessment and rating of ataxia (SARA). A longitudinal IRT model was built utilizing real-world data from the large autosomal recessive cerebellar ataxia (ARCA) registry. Disease progression was evaluated for the overall cohort as well as for the 10 most common ARCA genotypes. Sample sizes were calculated for simulated trials with autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS) and polymerase gamma (POLG) ataxia, as showcased, across multiple design and analysis scenarios. Longitudinal IRT models were able to describe the changes in the latent variable underlying SARA as a function of time since ataxia onset for both the overall ARCA cohort and the common genotypes. The typical progression rates varied across genotypes between relatively high in POLG (~ 0.98 SARA points/year at SARA = 20) and very low in COQ8A ataxia (~ 0.003 SARA points/year at SARA = 20). Smaller trial sizes were required in case of faster progression, longer trials (~ 75-90% less with 5 years vs. 2 years), and larger drug effects (~ 70-80% less with 100% vs. 50% inhibition). Simulating under the developed IRT model, the longitudinal IRT model had the highest power, with a well-controlled type I error, compared to total score models or end-of-treatment analyses. The established longitudinal IRT framework allows efficient utilization of natural history data and ultimately facilitates the design and analysis of treatment trials in rare and ultra-rare genetic ataxias.

Neuropsychiatric Manifestations of Degenerative Cerebellar Ataxia.

Degenerative cerebellar ataxias (DCA) present a group of complex neurological disorders primarily affecting the cerebellum and its pathways. Classic manifestations include motor symptoms of cerebellar ataxia. However, emerging evidence suggests that the cerebellum also plays a crucial role in various cognitive and emotional processes. The objective was to assess the psychiatric profile of a heterogeneous group of patients with degenerative cerebellar ataxia. Our sample comprised 107 participants diagnosed with cerebellar degenerative ataxia. All patients were clinically evaluated using SARA, INAS, and different neuropsychiatric scales (ACE-R, HAMA, HAMD, AS, and GAF). The majority of patients had autosomal dominant ataxia (38.3%) followed by sporadic ataxia (32.7%) with an average age at the moment of diagnosis of 35.3 ± 16.23 years, while the mean duration of disease at the study beginning was 12.1 ± 9.9 years. Psychiatric disorders were present in 40 patients (37.4%), with dysthymia (14.2%), major depressive disorder (9.4%), and MDD with melancholic features (7.6%). The presence of MDD with melancholic features was statistically significantly correlated with a lower ACE-R total score (r = -0.223; p = 0.022), while dysthymia was statistically significantly associated with a shorter duration of the disease (r = -0.226; p = 0.020) and older age (r = 0.197; p = 0.043). Statistically significant differences were observed between MSA-C patients and those with sporadic ataxia (HDRS p < 0.001, HARS p < 0.001, Apathy Scale p = 0.003, and GAF p = 0.004). Based on our findings, we can conclude that the degree of motor deficit has a significant impact on the development of psychiatric disorders, including depression, anxiety, and apathy. However, it is not the only factor, and the impact also depends on the type of DCA.

Effects of Non-Invasive Brain Stimulation for Degenerative Cerebellar Ataxia: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis aimed to assess the effectiveness of non-invasive brain stimulation (NIBS), including repetitive transcranial magnetic stimulation (rTMS) and transcranial electrical stimulation (tES), as a neurological intervention for degenerative cerebellar ataxia (DCA) based on preregistration (PROSPERO: CRD42023379192). We aimed to explore clinical outcomes and examine the parameters associated with NIBS efficacy in DCA patients. The PubMed, Cochrane Library, CHINAL, and PEDro databases were searched for relevant randomized controlled trials (RCTs). Data extraction, quality assessment, and heterogeneity analyses were conducted; the Grading, Recommendations, Assessment, Development, and Evaluation was used to assess the quality of evidence and a meta-analysis was performed. Seventeen RCTs that included 661 patients on the scale for assessment and rating of ataxia (SARA) and 606 patients on the International Cooperative Ataxia Rating Scale (ICARS) were included. These RCTs showed a serious risk of bias (RoB) and low certainty of evidence for both outcomes. NIBS significantly reduced SARA (MD = -2.49, [95% confidence interval: -3.34, -1.64]) and ICARS (-5.27 [-7.06, -3.47]); the subgroup analysis showed significant effects: rTMS and tES reduced both outcomes. However, there were no significant differences in the effects of rTMS and tES. Additional subgroup analysis indicated the impact of rTMS frequency and the total number of tES sessions on ataxia. Non-invasive brain stimulation may reduce ataxia in DCA patients, but the estimated effect size may change in future studies because the RoB was serious and the certainty of evidence was low, and the heterogeneity was high. To establish evidence for selecting NIBS methods and parameters, continued high-quality RCTs are required.

Quantification of Solid Embryonic Cerebellar Graft Volume in a Degenerative Ataxia Model.

Substitution of lost neurons by neurotransplantation would be a possible management of advanced degenerative cerebellar ataxias in which insufficient cerebellar reserve remains. In this study, we examined the volume and structure of solid embryonic cerebellar grafts in adult Lurcher mice, a model of olivocerebellar degeneration, and their healthy littermates. Grafts taken from enhanced green fluorescent protein (EGFP)-positive embryos were injected into the cerebellum of host mice. Two or six months later, the brains were examined histologically. The grafts were identified according to the EGFP fluorescence in frozen sections and their volumes were estimated using the Cavalieri principle. For gross histological evaluation, graft-containing slices were processed using Nissl and hematoxylin-eosin staining. Adjustment of the volume estimation approach suggested that it is reasonable to use all sections without sampling, but that calculation of values for up to 20% of lost section using linear interpolation does not constitute substantial error. Mean graft volume was smaller in Lurchers than in healthy mice when examined 6months after the transplantation. We observed almost no signs of graft destruction. In some cases, compact grafts disorganized the structure of the host's cerebellar cortex. In Lurchers, the grafts had a limited contact with the host's cerebellum. Also, graft size was of greater variability in Lurchers than in healthy mice. The results are in compliance with our previous findings that Lurcher phenotype-associated factors have a negative effect on graft development. These factors can hypothetically include cerebellar morphology, local tissue milieu, or systemic factors such as immune system abnormalities.

Impaired cognitive flexibility and disrupted cognitive cerebellum in degenerative cerebellar ataxias.

There is a clinically unmet need for a neuropsychological tool that reflects the pathophysiology of cognitive dysfunction in cerebellar degeneration. We investigated cognitive flexibility in degenerative cerebellar ataxia patients and aim to identify the pathophysiological correlates of cognitive dysfunction in relation to cerebellar cognitive circuits. We prospectively enrolled degenerative cerebellar ataxia patients with age-matched healthy controls who underwent 3 T 3D and resting-state functional MRI. All 56 participants were evaluated with the Scale for Assessment and Rating of Ataxia and neuropsychological tests including the Wisconsin Card Sorting Test, Trail Making Test, Montreal Cognitive Assessment and Mini-Mental State Examination. From MRI scans, we analysed the correlation of whole-brain volume and cortico-cerebellar functional connectivity with the Wisconsin Card Sorting Test performances. A total of 52 participants (29 ataxia patients and 23 healthy controls) were enrolled in this study. The Wisconsin Card Sorting Test scores (total error percentage, perseverative error percentage, non-perseverative error percentage and categories completed), Trail Making Test A and Montreal Cognitive Assessment were significantly impaired in ataxia patients (P < 0.05) compared to age-matched healthy controls. The Wisconsin Card Sorting Test error scores showed a significant correlation with the ataxia score (P < 0.05) controlling for age and sex. In volumetric analysis, the cerebellar right crus I, II, VIIb and VIII atrophy correlated with non-perseverative error percentage in the ataxia group. In functional connectivity analysis, the connectivity between crus I, II and VIIb of the cerebellum and bilateral superior parietal and superior temporal gyrus was significantly altered in ataxia patients. The functional connectivity between left crus II and VIIb of the cerebellum and dorsolateral prefrontal and superior frontal/parietal cortices showed a positive correlation with perseverative error percentage. The connectivity between left crus VIIb and pontine nucleus/middle cerebellar peduncle showed a significant negative correlation with non-perseverative error percentage in the ataxia group. The impaired cognitive flexibility represented by the Wisconsin Card Sorting Test was significantly impaired in degenerative cerebellar ataxia patients and correlated with disease severity. The Wisconsin Card Sorting Test performance reflects hypoactivity of the cognitive cerebellum and disrupted cortico-cerebellar connectivity in non-demented patients with degenerative cerebellar ataxia.

Local Dynamic Stability of Trunk During Gait is Responsive to Rehabilitation in Subjects with Primary Degenerative Cerebellar Ataxia

This study aimed to assess the responsiveness to the rehabilitation of three trunk acceleration-derived gait indexes, namely the harmonic ratio (HR), the short-term longest Lyapunov’s exponent (sLLE), and the step-to-step coefficient of variation (CV), in a sample of subjects with primary degenerative cerebellar ataxia (swCA), and investigate the correlations between their improvements (∆), clinical characteristics, and spatio-temporal and kinematic gait features. The trunk acceleration patterns in the antero-posterior (AP), medio-lateral (ML), and vertical (V) directions during gait of 21 swCA were recorded using a magneto-inertial measurement unit placed at the lower back before (T0) and after (T1) a period of inpatient rehabilitation. For comparison, a sample of 21 age- and gait speed-matched healthy subjects (HSmatched) was also included. At T1, sLLE in the AP (sLLEAP) and ML (sLLEML) directions significantly improved with moderate to large effect sizes, as well as SARA scores, stride length, and pelvic rotation. sLLEML and pelvic rotation also approached the HSmatched values at T1, suggesting a normalization of the parameter. HRs and CV did not significantly modify after rehabilitation. ∆sLLEML correlated with ∆ of the gait subscore of the SARA scale (SARAGAIT) and ∆stride length and ∆sLLEAP correlated with ∆pelvic rotation and ∆SARAGAIT. The minimal clinically important differences for sLLEML and sLLEAP were ≥ 36.16% and ≥ 28.19%, respectively, as the minimal score reflects a clinical improvement in SARA scores. When using inertial measurement units, sLLEAP and sLLEML can be considered responsive outcome measures for assessing the effectiveness of rehabilitation on trunk stability during walking in swCA.

Effectiveness of Vestibular Rehabilitation for Patients with Degenerative Cerebellar Ataxia: A Retrospective Cohort Study.

Many patients with cerebellar ataxia have dizziness caused by oculomotor or peripheral vestibular deficits; however, there is little evidence supporting the use of vestibular rehabilitation for this population. The purpose of this study was to determine whether patients with degenerative cerebellar diseases improve following rehabilitation including vestibular exercises. A secondary aim was to identify variables associated with the outcomes. A retrospective chart review identified 42 ambulatory patients (23 men and 19 women; mean age = 54.5 ± 14.4 years) with cerebellar degeneration. Fourteen patients had ataxia only, twenty had ataxia and oculomotor abnormalities, and eight had ataxia with oculomotor and peripheral vestibular deficits. Patients received customized physical therapy including balance and gait training, as well as gaze stabilization and habituation exercises for vestibular hypofunction and motion-provoked dizziness. Primary outcome measures (Activities-specific Balance Confidence Scale, Tinetti Performance Oriented Mobility Assessment, Dynamic Gait index, and Sensory Organization Test) were evaluated at baseline and discharge. Patients improved (p < 0.05) on all outcome measures. Patients with vestibular deficits were seen for more visits compared to those with gait ataxia only (7.1 vs. 4.8 visits). This study provides evidence that patients with degenerative cerebellar disease improve in balance confidence, fall risk and sensory integration with therapy that includes vestibular rehabilitation.

Digital Motor Biomarkers of Cerebellar Ataxia Using an RGB-Depth Camera-Based Motion Analysis System.

This study aimed to identify quantitative biomarkers of motor function for cerebellar ataxia by evaluating gait and postural control using an RGB-depth camera-based motion analysis system. In 28 patients with degenerative cerebellar ataxia and 33 age- and sex-matched healthy controls, motor tasks (short-distance walk, closed feet stance, and stepping in place) were selected from a previously reported protocol, and scanned using Kinect V2 and customized software. The Clinical Assessment Scale for the Assessment and Rating of Ataxia (SARA) was also evaluated. Compared with the normal control group, the cerebellar ataxia group had slower gait speed and shorter step lengths, increased step width, and mediolateral trunk sway in the walk test (all P < 0.001). Lateral sway increased in the stance test in the ataxia group (P < 0.001). When stepping in place, the ataxia group showed higher arrhythmicity of stepping and increased stance time (P < 0.001). In the correlation analyses, the ataxia group showed a positive correlation between the total SARA score and arrhythmicity of stepping in place (r = 0.587, P = 0.001). SARA total score (r = 0.561, P = 0.002) and gait subscore (ρ = 0.556, P = 0.002) correlated with mediolateral truncal sway during walking. These results suggest that the RGB-depth camera-based motion analyses on mediolateral truncal sway during walking and arrhythmicity of stepping in place are useful digital motor biomarkers for the assessment of cerebellar ataxia, and could be utilized in future clinical trials.

Excessive excitability of inhibitory cortical circuit and disturbance of ballistic targeting movement in degenerative cerebellar ataxia

This study aimed to investigate abnormalities in inhibitory cortical excitability and motor control during ballistic-targeting movements in individuals with degenerative cerebellar ataxia (DCA). Sixteen participants took part in the study (DCA group [n = 8] and healthy group [n = 8]). The resting motor-threshold and cortical silent period (cSP) were measured in the right-hand muscle using transcranial magnetic stimulation over the left primary motor cortex. Moreover, the performance of the ballistic-targeting task with right wrist movements was measured. The Scale for the Assessment and Rating of Ataxia was used to evaluate the severity of ataxia. The results indicated that the cSP was significantly longer in participants with DCA compared to that in healthy controls. However, there was no correlation between cSP and severity of ataxia. Furthermore, cSP was linked to the ballistic-targeting task performance in healthy participants but not in participants with DCA. These findings suggest that there is excessive activity in the gamma-aminobutyric acid-mediated cortical inhibitory circuit in individuals with DCA. However, this increase in inhibitory activity not only fails to contribute to the control of ballistic-targeting movement but also shows no correlation with the severity of ataxia. These imply that increased excitability in inhibitory cortical circuits in the DCA may not contribute the motor control as much as it does in healthy older adults under limitations associated with a small sample size. The study's results contribute to our understanding of motor control abnormalities in people with DCA and provide potential evidence for further research in this area.

Effects of non-invasive brain stimulation for degenerative cerebellar ataxia: a protocol for a systematic review and meta-analysis

IntroductionTo date, the medical and rehabilitation needs of people with degenerative cerebellar ataxia (DCA) are not fully met because no curative treatment has yet been established. Movement disorders such as...

A Proof of Concept Combined Using Mixed Reality for Personalized Neurorehabilitation of Cerebellar Ataxic Patients.

Guidelines for degenerative cerebellar ataxia neurorehabilitation suggest intensive coordinative training based on physiotherapeutic exercises. Scientific studies demonstrate virtual exergaming therapeutic value. However, patient-based personalization, post processing analyses and specific audio-visual feedbacks are not provided. This paper presents a wearable motion tracking system with recording and playback features. This system has been specifically designed for ataxic patients, for upper limbs coordination studies with the aim to retrain movement in a neurorehabilitation setting. Suggestions from neurologists and ataxia patients were considered to overcome the shortcomings of virtual systems and implement exergaming. The system consists of the mixed-reality headset Hololens2 and a proprietary exergaming implemented in Unity. Hololens2 can track and save upper limb parameters, head position and gaze direction in runtime. Data collected from a healthy subject are reported to demonstrate features and outputs of the system. Although further improvements and validations are needed, the system meets the needs of a dynamic patient-based exergaming for patients with cerebellar ataxia. Compared with existing solutions, the mixed-reality system is designed to provide an effective and safe therapeutic exergaming that supports both primary and secondary goals of an exergaming: what a patient should do and how patient actions should be performed.

Neurological Erdheim-Chester Disease Manifesting with Subacute or Progressive Cerebellar Ataxia: Novel Case Series and Review of the Literature.

Neurological involvement is relatively common in Erdheim-Chester disease (ECD), a rare clonal disorder of histiocytic myeloid precursors characterized by multisystem involvement. In ECD patients, neurological symptoms can occur either at onset or during the disease course and may lead to various degrees of neurological disability or affect patients' life expectancy. The clinical neurological presentation of ECD often consists of cerebellar symptoms, showing either a subacute or progressive course. In this latter case, patients manifest with a slowly progressive cerebellar ataxia, variably associated with other non-specific neurological signs, infratentorial leukoencephalopathy, and cerebellar atrophy, possibly mimicking either adult-onset degenerative or immune-mediated ataxia. In such cases, diagnosis of ECD may be particularly challenging, yet some peculiar features are helpful to address it. Here, we retrospectively describe four novel ECD patients, all manifesting cerebellar symptoms at onset. In two cases, slow disease progression and associated brain MRI features simulated a degenerative cerebellar ataxia. Three patients received a definite diagnosis of histiocytosis, whereas one case lacked histology confirmation, although clinical diagnostic features were strongly suggestive. Our findings regarding existing literature data focused on neurological ECD will be also discussed to highlight those diagnostic clues helpful to address diagnosis.

P 6 Visuomotor adaptation is impaired in Essential Tremor

Introduction: Evidence has accumulated to support the theory that the cerebellum is crucially involved in the primary pathophysiology of Essential Tremor (ET). The cerebellum is critical for integration of sensorimotor information to create an internal model of movement using prediction errors. Neurological disorders causing cerebellar injury, such as degenerative cerebellar ataxia or cerebellar stroke, disrupt visuomotor integration and impede error-based learning. We hypothesized that cerebellar dysfunction in ET is also associated with impairment of visuomotor integration and error-based learning. Materials & Methods: To test this hypothesis, mildly to moderately affected ET patients (N=34; mean TETRAS score: 32.15 ± 13.78) and age-matched healthy controls performed a visuomotor adaptation task (Fig. 1A). The task was displayed on a PC monitor and movements were captured using a digital tablet. The experiment was divided into 3 phases (Fig. 1C): a baseline phase (BL), including simple center-to-target movements; an adaptation phase (ADP), in which a 30° visuomotor perturbation was introduced and a de-adaptation phase (DA), in which this perturbation was removed. The angle between the hand path and the center-target path, termed angular error, was calculated to assess visuomotor adaptation (Fig. 1B). Adaptation indices (AI; AI1 = ADP1 – BL2; AI2 = ADP8 – BL2; AI3 = DA1 – ADB8) were evaluated to assess the differences in angular error in each phase of the task (Fig. 2B). Covariates recorded were: clinical characteristics of ET patients, such as disease duration, alcohol responsivity, current medication, clinical measures of tremor and ataxia (as indexed by the TETRAS and SARA score), and basic motor performance as assessed by reaction and movement times. Results: AIs were significantly lower in ET patients compared to controls (Fig. 2A). No differences were found between ET patients and controls at BL or at DA, suggesting that the effects were specific to the adaptation phase. No differences in basic motor performance between groups were evident (all p>0.2), indicating that adaptation deficits in ET were not caused by impaired motor functions. In addition, there was no association between clinical parameters of ET and visuomotor adaptation abilities, suggesting that the reduced ability to adapt the motor response to the visual perturbation was unlikely to result from the tremulous movement. Conclusion: We found that visuomotor adaptation was impaired in ET, specifically in the adaptation phase. These results provide further evidence for linking ET to cerebellar dysfunction. Because the impairment was unrelated to clinical measures of tremor or ataxia and to basic motor performance, cerebellar dysfunction underlying visuomotor impairment in ET may be differentiated from the pathophysiological origin of other cerebellar diseases.

Identification of Gait Unbalance and Fallers Among Subjects with Cerebellar Ataxia by a Set of Trunk Acceleration-Derived Indices of Gait.

This study aimed to assess the ability of 25 gait indices to characterize gait instability and recurrent fallers among persons with primary degenerative cerebellar ataxia (pwCA), regardless of gait speed, and investigate their correlation with clinical and kinematic variables. Trunk acceleration patterns were acquired during the gait of 34 pwCA, and 34 age- and speed-matched healthy subjects (HSmatched) using an inertial measurement unit. We calculated harmonic ratios (HR), percent recurrence, percent determinism, step length coefficient of variation, short-time largest Lyapunov exponent (sLLE), normalized jerk score, log-dimensionless jerk (LDLJ-A), root mean square (RMS), and root mean square ratio of accelerations (RMSR) in each spatial direction for each participant. Unpaired t-tests or Mann-Whitney tests were performed to identify significant differences between the pwCA and HSmatched groups. Receiver operating characteristics were plotted to assess the ability to characterize gait alterations in pwCA and fallers. Optimal cutoff points were identified, and post-test probabilities were calculated. The HRs showed to characterize gait instability and pwCA fallers with high probabilities. They were correlated with disease severity and stance, swing, and double support duration, regardless of gait speed. sLLEs, RMSs, RMSRs, and LDLJ-A were slightly able to characterize the gait of pwCA but failed to characterize fallers.

Quantitative susceptibility mapping reveals alterations of dentate nuclei in common types of degenerative cerebellar ataxias.

The cerebellar nuclei are a brain region with high iron content. Surprisingly, little is known about iron content in the cerebellar nuclei and its possible contribution to pathology in cerebellar ataxias, with the only exception of Friedreich’s ataxia. In the present exploratory cross-sectional study, quantitative susceptibility mapping was used to investigate volume, iron concentration and total iron content of the dentate nuclei in common types of hereditary and non-hereditary degenerative ataxias. Seventy-nine patients with spinocerebellar ataxias of types 1, 2, 3 and 6; 15 patients with Friedreich’s ataxia; 18 patients with multiple system atrophy, cerebellar type and 111 healthy controls were also included. All underwent 3 T MRI and clinical assessments. For each specific ataxia subtype, voxel-based and volumes-of-interest-based group analyses were performed in comparison with a corresponding age- and sex-matched control group, both for volume, magnetic susceptiblity (indicating iron concentration) and susceptibility mass (indicating total iron content) of the dentate nuclei. Spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type patients showed higher susceptibilities in large parts of the dentate nucleus but unaltered susceptibility masses compared with controls. Friedreich’s ataxia patients and, only on a trend level, spinocerebellar ataxia of type 2 patients showed higher susceptibilities in more circumscribed parts of the dentate. In contrast, spinocerebellar ataxia of type 6 patients revealed lower susceptibilities and susceptibility masses compared with controls throughout the dentate nucleus. Spinocerebellar ataxia of type 3 patients showed no significant changes in susceptibility and susceptibility mass. Lower volume of the dentate nuclei was found to varying degrees in all ataxia types. It was most pronounced in spinocerebellar ataxia of type 6 patients and least prominent in spinocerebellar ataxia of type 3 patients. The findings show that alterations in susceptibility revealed by quantitative susceptibility mapping are common in the dentate nuclei in different types of cerebellar ataxias. The most striking changes in susceptibility were found in spinocerebellar ataxia of type 1, multiple system atrophy, cerebellar type and spinocerebellar ataxia of type 6. Because iron content is known to be high in glial cells but not in neurons of the cerebellar nuclei, the higher susceptibility in spinocerebellar ataxia of type 1 and multiple system atrophy, cerebellar type may be explained by a reduction of neurons (increase in iron concentration) and/or an increase in iron-rich glial cells, e.g. microgliosis. Hypomyelination also leads to higher susceptibility and could also contribute. The lower susceptibility in SCA6 suggests a loss of iron-rich glial cells. Quantitative susceptibility maps warrant future studies of iron content and iron-rich cells in ataxias to gain a more comprehensive understanding of the pathogenesis of these diseases.

Brain susceptibility imaging provides valuable in vivo insights into cerebellar diseases, but biological interpretations remain elusive.

This scientific commentary relates to: 'Quantitative susceptibility mapping reveals alterations of dentate nuclei in common types of degenerative cerebellar ataxias' by Deistung et al. (https://doi.org/10.1093/braincomms/fcab306).

Clinical and Molecular Spectrum of Degenerative Cerebellar Ataxia: A Single Centre Study.

Cerebellar ataxia is a disabling neurological symptom with extreme clinical and etiological heterogeneity. To study the clinical and molecular characteristics in patients with degenerative cerebellar ataxia. In this study, 150 South-Indian patients with degenerative cerebellar ataxia underwent a phenotype guided, sequential tiered testing. Phenotypic features studied included cerebellar symptoms, pyramidal and extrapyramidal features, and ophthalmic and systemic findings. Tier one included conventional tests such as short PCR/fragment analysis for spinocerebellar ataxia (SCA) subtypes 1, 2, 3, 6, 7, 8, 12, 17, and 36 and TP-PCR for Friedreich ataxia (FA). Tier two testing comprised next-generation sequencing (NGS)-based strategies reserved for select undiagnosed cases. The clinical features were highly overlapping and had limited specificity, except in autosomal recessive ataxias and SCA 34. The overall diagnostic yield of our study was 49.3%. SCA 1, 2, and 3 were noted in 13 (12.6%), 12 (11.6%) and 14 (13.5%), respectively, out of the 103 tested, and FA was noted in 17/55 (30.9%) patients. SCA subtypes 6, 7, 8, 12, 17, and 36 were absent in the cohort studied. Targeted Sanger sequencing and NGS revealed some rare diagnoses in 17 among the 18 patients tested. Whole exome sequencing uncovered a novel genotype-phenotype association in a sibling-pair with ataxia, dysmorphism, and retinopathy. SCA 1, 2, 3 and FRDA were the most common causes of ataxia. SCA 6, 7, 8, 12, 17, and 36 were absent in the cohort studied. NGS testing revealed several rare forms of ataxia. Clinical features based testing is cost-effective, achieves good genotype-phenotype correlation, and prioritizes variants for further studies.

Primary Sjögren's syndrome (pSS)-related cerebellar ataxia: a systematic review and meta-analysis.

Primary Sjögren's syndrome (pSS) is a chronic autoimmune disorder characterized by lymphocytic infiltrates of the exocrine glands, particularly the salivary and lacrimal glands, resulting in oral and ocular dryness. pSS has been linked to various neurological manifestations, including cerebellar dysfunction. We aimed to provide a comprehensive analysis of the currently available evidence regarding pSS-related cerebellar ataxia. A systematic literature search in the PubMed database was performed and 19 papers were eligible to be included in this paper. The pooled prevalence of cerebellar ataxia in pSSis estimated to be 1.5% (95% CI 0.3-6.8%). pSS patients with cerebellar involvement have a female-to-male ratio of 6:1. Although most of the patients are adults in their fifth decade of life when diagnosed, cases of children with pSS and cerebellar involvement have been reported. Typical cerebellar ataxia related to pSS manifests with vermian dysfunction, namely gait ataxia and/or cerebellar speech. Cerebellar ataxia due to pSS may also mimic degenerative cerebellar ataxia, especially when the onset is progressive. The diagnostic approach to a patient with cerebellar ataxia of unknown etiology should include evaluation for an underlying pSS. A thorough history and clinical examination, antibody testing, brain MRI imaging and/or MRS of the cerebellum will assist in establishing the diagnosis. Setting up a joint neuro-rheumatology clinic can be valuable given that rheumatic and neurological diseases share comorbidities.

Human allogeneic bone marrow-derived mesenchymal stem cell therapy for cerebellar ataxia: A case report

To date, there is no curable treatment option for non-hereditary degenerative cerebellar ataxia. Here we report the case of a patient with sporadic adult-onset ataxia (SAOA) who underwent allogeneic bone marrow-derived mesenchymal stem cell (MSC) therapy via the intrathecal route.

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.