Degenerative 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.

Multifeature quantitative motor assessment of upper limb ataxia including drawing and reaching.

Voluntary upper limb movements are an ecologically important yet insufficiently explored digital-motor outcome domain for trials in degenerative ataxia. We extended and validated the trial-ready quantitative motor assessment battery "Q-Motor" for upper limb movements with clinician-reported, patient-focused, and performance outcomes of ataxia. Exploratory single-center cross-sectional assessment in 94 subjects (46 cross-genotype ataxia patients; 48 matched controls), comprising five tasks measured by force transducer and/or position field: Finger Tapping, diadochokinesia, grip-lift, and-as novel implementations-Spiral Drawing, and Target Reaching. Digital-motor measures were selected if they discriminated from controls (AUC >0.7) and correlated-with at least one strong correlation (rho ≥0.6)-to the Scale for the Assessment and Rating of Ataxia (SARA), activities of daily living (FARS-ADL), and the Nine-Hole Peg Test (9HPT). Six movement features with 69 measures met selection criteria, including speed and variability in all tasks, stability in grip-lift, and efficiency in Target Reaching. The novel drawing/reaching tasks best captured impairment in dexterity (|rho9HPT| ≤0.81) and FARS-ADL upper limb items (|rhoADLul| ≤0.64), particularly by kinematic analysis of smoothness (SPARC). Target hit rate, a composite of speed and endpoint precision, almost perfectly discriminated ataxia and controls (AUC: 0.97). Selected measures in all tasks discriminated between mild, moderate, and severe impairment (SARA upper limb composite: 0-2/>2-4/>4-6) and correlated with severity in the trial-relevant mild ataxia stage (SARA ≤10, n = 20). Q-Motor assessment captures multiple features of impaired upper limb movements in degenerative ataxia. Validation with key clinical outcome domains provides the basis for evaluation in longitudinal studies and clinical trial settings.

Transcranial Sonography Characteristics of Cerebellar Neurodegenerative Ataxias.

Cerebellar neurodegenerative ataxias are a group of disorders affecting the cerebellum and its pathways with different neurological structures. Transcranial sonography (TCS) has been used for the evaluation of brain parenchymal structures in various diseases because of its fast and safe utilization, especially in neuropsychiatric and neurodegenerative diseases. The aim of our study was to investigate TCS characteristics of patients with neurodegenerative cerebellar ataxias. In our study, we included 74 patients with cerebellar degenerative ataxia; 36.5% had autosomal dominant onset, while 33.8% had sporadic onset. Standardized ultrasonographic planes were used for the identification of brain structures of interest. The SARA, INAS, neuropsychological and psychiatric scales were used for the further clinical evaluation of our study participants. The brainstem raphe was discontinued in 33.8% of the patients. The substantia nigra (SN) hyperechogenicity was identified in 79.7%. The third and fourth ventricle enlargement had 79.7% and 45.9% of patients, respectively. A positive and statistically significant correlation was found between SN hyperechogenicity with dystonia (p < 0.01), rigidity and dyskinesia (p < 0.05). The higher SARA total score is statistically significantly correlated with the larger diameter of the III (r = 0.373; p = 0.001) and IV ventricles (r = 0.324; p = 0.005). In such patients, the echogenicity of substantia nigra has been linked to extrapyramidal signs, and raphe discontinuity to depression. Furthermore, ataxia and its clinical subtypes have positively correlated with the IV ventricle diameter, indicating brain atrophy and brain mass reduction.

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.

The Use of the Voice Trainer App for Vocal Control in People with a Degenerative Ataxia: A Pilot Intervention Study.

Dysarthria is disabling in persons with degenerative ataxia. There is limited evidence for speech therapy interventions. In this pilot study, we used the Voice trainer app, which was originally developed for patients with Parkinson's disease, as a feedback tool for vocal control. We hypothesized that patients with ataxic dysarthria would benefit from the Voice trainer app to better control their loudness and pitch, resulting in a lower speaking rate and better intelligibility. This intervention study consisted of five therapy sessions of 30min within 3weeks using the principles of the Pitch Limiting Voice Treatment. Patients received real-time visual feedback on loudness and pitch during the exercises. Besides, they were encouraged to practice at home or to use the Voice trainer in daily life. We used observer-rated and patient-rated outcome measures. The primary outcome measure was intelligibility, as measured by the Dutch sentence intelligibility test. Twenty-one out of 25 included patients with degenerative ataxia completed the therapy. We found no statistically significant improvements in intelligibility (p = .56). However, after the intervention, patients were speaking slower (p = .03) and the pause durations were longer (p < .001). The patients were satisfied about using the app. At the group level, we found no evidence for an effect of the Voice trainer app on intelligibility in degenerative ataxia. Because of the heterogeneity of ataxic dysarthria, a more tailor-made rather than generic intervention seems warranted.

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.

The Impact of Demographic and Clinical Factors on the Quality of Life in Patients with Neurodegenerative Cerebellar Ataxias.

In neurodegenerative cerebellar ataxias, not only ataxia but also extra-cerebellar signs have a significant impact on patients' health related to quality of life (HRQoL). The aim of this study was to evaluate the various aspects of HRQoL and predictors of QoL in patients with neurodegenerative cerebellar ataxias. We included a total of 107 patients with cerebellar degenerative ataxia. Patients filled out the validated Serbian version of the SF-36 used for the assessment of HRQoL. All patients were clinically evaluated using SARA, INAS, and neuropsychological tests to assess their global cognitive status and different psychiatric scales. The most frequent types of neurodegenerative cerebellar ataxias were autosomal dominant ataxias (38.3%) and sporadic ataxias (32.7%). Mean age at diagnosis was 35.3 ± 16.23 years, and disease duration was on average 12.1 ± 9.91 years. Mean total SF-36 score was 50.63 ± 20.50. Hierarchical regression analysis showed that in the case of the PHC score, the most significant predictors are the patient's actual age, severity of ataxia, and ACE total score. For MHC, the Hamilton depression score was the most important predictor. Our study has shown that HRQoL measured by SF-36 in patients with neurodegenerative cerebellar disorders is strongly influenced by impaired mobility and depression.

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.

Cognitive Complaints and Their Impact on Daily Life in Patients with Degenerative Cerebellar Disorders

Cognitive and affective sequelae of cerebellar disease are receiving increased attention, but their actual rate of occurrence remains unclear. Complaints may have a significant impact on patients, affecting social behavior and psychological well-being. This study aims to explore the extent of subjective cognitive and affective symptoms in patients with degenerative ataxias in the Netherlands. An explorative study was set up in a heterogeneous group of degenerative ataxia patients. Self-reported cognition was evaluated in terms of executive functioning and affect (Dysexecutive Questionnaire/DEX), and memory/attention (Cognitive Failures Questionnaire/CFQ). The Daily Living Questionnaire (DLQ) was administered to quantify the impact on daily life. Furthermore, informants completed questionnaires to obtain insight into patients’ self-awareness and social cognition (Observable Social Cognition Rating Scale/OSCARS). This study shows that subjective complaints in the domains of (1) executive functioning and/or (2) memory and attention were reported by 29% of all patients (n = 24/84). In addition, more difficulties in daily life in terms of language/comprehension and community/participation were reported, and this was more common for patients with cognitive complaints than those without. Discrepancies between patients and informants about executive functioning were present in both directions. Deficits in social cognition were not identified at the group level, but more social-cognitive problems were observed in patients with more executive problems rated by informants. Taken together, our findings indicate that cognitive complaints are common in patients with degenerative cerebellar disorders and have an impact on daily life functioning. These results may help to increase awareness of cognitive symptoms and their impact in patients with cerebellar ataxia, their significant others, and professional caregivers.

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...

Quantitative Oculomotor Assessment in Hereditary Ataxia: Systematic Review and Consensus by the Ataxia Global Initiative Working Group on Digital-motor Biomarkers

Oculomotor deficits are common in hereditary ataxia, but disproportionally neglected in clinical ataxia scales and as outcome measures for interventional trials. Quantitative assessment of oculomotor function has become increasingly available and thus applicable in multicenter trials and offers the opportunity to capture severity and progression of oculomotor impairment in a sensitive and reliable manner. In this consensus paper of the Ataxia Global Initiative Working Group On Digital Oculomotor Biomarkers, based on a systematic literature review, we propose harmonized methodology and measurement parameters for the quantitative assessment of oculomotor function in natural-history studies and clinical trials in hereditary ataxia. MEDLINE was searched for articles reporting on oculomotor/vestibular properties in ataxia patients and a study-tailored quality-assessment was performed. One-hundred-and-seventeen articles reporting on subjects with genetically confirmed (n=1134) or suspected hereditary ataxia (n=198), and degenerative ataxias with sporadic presentation (n=480) were included and subject to data extraction. Based on robust discrimination from controls, correlation with disease-severity, sensitivity to change, and feasibility in international multicenter settings as prerequisite for clinical trials, we prioritize a core-set of five eye-movement types: (i) pursuit eye movements, (ii) saccadic eye movements, (iii) fixation, (iv) eccentric gaze holding, and (v) rotational vestibulo-ocular reflex. We provide detailed guidelines for their acquisition, and recommendations on the quantitative parameters to extract. Limitations include low study quality, heterogeneity in patient populations, and lack of longitudinal studies. Standardization of quantitative oculomotor assessments will facilitate their implementation, interpretation, and validation in clinical trials, and ultimately advance our understanding of the evolution of oculomotor network dysfunction in hereditary ataxias.

A Comparison Between Somatosensory Evoked Potentials and Spine MRI in the Diagnosis of Non-compressive Myelopathy: Which Is More Accurate?

Non-compressive myelopathy is a neurological disorder due to pathological processes affecting the spinal cord in the absence of clinical and radiological evidence of spinal cord compression. Two commonly used diagnostic tools for non-compressive myelopathy are somatosensory evoked potentials (SSEPs) and magnetic resonance imaging (MRI). SSEPs are a neurophysiological tool used to assess the functional integrity of the spinal cord. MRI, on the other hand, is the mainstay imaging modality used for identifying compressive lesions and other structural abnormalities in the spinal cord.The aim of this study was to test the diagnostic accuracy of SSEPs versus spine MRI in the diagnosis and assessment of the severity of non-compressive myelopathy using the Modified Japanese Orthopaedic Association (mJOA) clinical severity score. Our study included 63 subjects. Whole spine MRI and SSEPs (median and tibial SSEP bilaterally) were done for all subjects; their results were compared according to their relation to the mJOAscore and classified into mild, moderate, and severe. The control group was examined to establish normative data for SSEPresults and compared with cases. Blood investigations such as complete blood count, thyroid function test, A1C, HIVtests, venereal disease research laboratory test, erythrocyte sedimentation rate, C-reactive protein, and antinuclear antibodytests were done. Blood tests for vitamin B12 levels were done for patients who were suspected of sub-acute combined degeneration of the spinal cord; cerebrospinal fluid (CSF) analysis was done for patients suspected of multiple sclerosis (MS), acute transverse myelitis (ATM), or other inflammatory/infectious diseases. CSF was analyzed for cell count, cytology, protein, and oligoclonal bands (if indicated). No mild categories were registered in this study; 30%of patients were moderateand 70%were severe. Causes for non-compressive myelopathy in this study werehereditary degenerative ataxias in 12 (38.71%), ATM in 8 (25.81%), and MS in 5 (16.13%); other causes included vitamin B12 deficiency in 2 (6.45%), ischemia in 2 (6.45%), and an unknown cause in 2 (6.45%). SSEPs showed abnormal results in all patients (31; 100%) whereas MRI showed abnormality in only seven patients (22.6%). SSEPsensitivity for detecting severe cases was around 63.6% while that for MRI was 27.3%. The study concluded that SSEPs were more reliable for the detection of non-compressive myelopathies rather than MRI and correlated better with clinical severity. Performing SSEPs is recommended for all patients with non-compressive myelopathy, especially those with negative imaging.

The Therapeutic Potential of Non-Invasive and Invasive Cerebellar Stimulation Techniques in Hereditary Ataxias.

The degenerative ataxias comprise a heterogeneous group of inherited and acquired disorders that are characterized by a progressive cerebellar syndrome, frequently in combination with one or more extracerebellar signs. Specific disease-modifying interventions are currently not available for many of these rare conditions, which underscores the necessity of finding effective symptomatic therapies. During the past five to ten years, an increasing number of randomized controlled trials have been conducted examining the potential of different non-invasive brain stimulation techniques to induce symptomatic improvement. In addition, a few smaller studies have explored deep brain stimulation (DBS) of the dentate nucleus as an invasive means to directly modulate cerebellar output, thereby aiming to alleviate ataxia severity. In this paper, we comprehensively review the clinical and neurophysiological effects of transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), and dentate nucleus DBS in patients with hereditary ataxias, as well as the presumed underlying mechanisms at the cellular and network level and perspectives for future research.

Standards of NGS Data Sharing and Analysis in Ataxias: Recommendations by the NGS Working Group of the Ataxia Global Initiative

The Ataxia Global Initiative (AGI) is a worldwide multi-stakeholder research platform to systematically enhance trial-readiness in degenerative ataxias. The next-generation sequencing (NGS) working group of the AGI aims to improve methods, platforms, and international standards for ataxia NGS analysis and data sharing, ultimately allowing to increase the number of genetically ataxia patients amenable for natural history and treatment trials. Despite extensive implementation of NGS for ataxia patients in clinical and research settings, the diagnostic gap remains sizeable, as approximately 50% of patients with hereditary ataxia remain genetically undiagnosed. One current shortcoming is the fragmentation of patients and NGS datasets on different analysis platforms and databases around the world. The AGI NGS working group in collaboration with the AGI associated research platforms—CAGC, GENESIS, and RD-Connect GPAP—provides clinicians and scientists access to user-friendly and adaptable interfaces to analyze genome-scale patient data. These platforms also foster collaboration within the ataxia community. These efforts and tools have led to the diagnosis of > 500 ataxia patients and the discovery of > 30 novel ataxia genes. Here, the AGI NGS working group presents their consensus recommendations for NGS data sharing initiatives in the ataxia field, focusing on harmonized NGS variant analysis and standardized clinical and metadata collection, combined with collaborative data and analysis tool sharing across platforms.

Real-life ankle submovements and computer mouse use reflect patient-reported function in adult ataxias.

Novel disease-modifying therapies are being evaluated in spinocerebellar ataxias and multiple system atrophy. Clinician-performed disease rating scales are relatively insensitive for measuring disease change over time, resulting in large and long clinical trials. We tested the hypothesis that sensors worn continuously at home during natural behaviour and a web-based computer mouse task performed at home could produce interpretable, meaningful and reliable motor measures for potential use in clinical trials. Thirty-four individuals with degenerative ataxias (spinocerebellar ataxia types 1, 2, 3 and 6 and multiple system atrophy of the cerebellar type) and eight age-matched controls completed the cross-sectional study. Participants wore an ankle and wrist sensor continuously at home for 1 week and completed the Hevelius computer mouse task eight times over 4 weeks. We examined properties of motor primitives called 'submovements' derived from the continuous wearable sensors and properties of computer mouse clicks and trajectories in relationship to patient-reported measures of function (Patient-Reported Outcome Measure of Ataxia) and ataxia rating scales (Scale for the Assessment and Rating of Ataxia and the Brief Ataxia Rating Scale). The test-retest reliability of digital measures and differences between ataxia and control participants were evaluated. Individuals with ataxia had smaller, slower and less powerful ankle submovements during natural behaviour at home. A composite measure based on ankle submovements strongly correlated with ataxia rating scale scores (Pearson's r = 0.82-0.88), strongly correlated with self-reported function (r = 0.81), had high test-retest reliability (intraclass correlation coefficient = 0.95) and distinguished ataxia and control participants, including preataxic individuals (n = 4) from controls. A composite measure based on computer mouse movements and clicks strongly correlated with ataxia rating scale total (r = 0.86-0.88) and arm scores (r = 0.65-0.75), correlated well with self-reported function (r = 0.72-0.73) and had high test-retest reliability (intraclass correlation coefficient = 0.99). These data indicate that interpretable, meaningful and highly reliable motor measures can be obtained from continuous measurement of natural movement, particularly at the ankle location, and from computer mouse movements during a simple point-and-click task performed at home. This study supports the use of these two inexpensive and easy-to-use technologies in longitudinal natural history studies in spinocerebellar ataxias and multiple system atrophy of the cerebellar type and shows promise as potential motor outcome measures in interventional trials.