Analysis of static plantar pressure data with capsule networks: Diagnosing ataxia in MS patients with a deep learning-based approach.

In this study, it was aimed to detect ataxia in patients with Multiple Sclerosis (MS) by utilizing static plantar pressure data and capsule networks (CapsNet), one of the deep learning (DL) architectures. CapsNet is also equipped with a robust dynamic routing mechanism that determines the output of the next capsule. MS is a chronic nervous system disease that shows its effect in the central nervous system and manifests itself with attacks. One of the most common and challenging symptoms of MS is known as ataxia. Ataxia causes loss of control of limb muscle tone or gait disorders, leading to loss of balance and coordination. The diagnosis of ataxia in MS is applied employing the standard Expanded Disability Status Scale (EDSS) score. However, due to reasons such as physician misconception, diagnosis differences among physicians, and incorrect patient information, more unbiased solutions are required for the diagnosis. The results included Sensitivity at 96.34 % ± 1.71, Specificity at 98.11 % ± 2.04, Precision at 98.08 % ± 2.16, and Accuracy at 97.13 % ± 0.33. The main motivation of the study is to show that these deep learning methods can successfully detect ataxia in MS patients using static plantar pressure data. The high-performance measurements of sensitivity, specificity, precision and accuracy emphasize that the proposed system can be an effective tool in clinical practice. In addition, it was concluded that the proposed autonomous system would be a support mechanism to assist the physician in the detection of ataxia in patients with MS.

Pearls & Oy-sters: CACNA1A-Related Paroxysmal Tonic Upgaze With Ataxia Responsive to Acetazolamide.

A 9-month-old male infant was evaluated for sudden onset of paroxysmal episodes of forced, conjugate upward eye deviation. Extensive in-hospital evaluation including electrophysiology and neuroimaging studies were reassuring against seizures or a structural abnormality. Given the clinical presentation of sudden onset intermittent upward eye deviations, downbeating saccades, associated ataxia, and typical development, a clinical diagnosis of paroxysmal tonic upgaze (PTU) with ataxia was made. Targeted genetic testing of CACNA1A was performed, which revealed a variant of undetermined significance, which was later classified as a de novo pathogenic variant after protein modeling and parental testing performed. Off-label use of oral acetazolamide was prescribed, which led to dose-responsive decrease in the frequency and intensity of eye movement episodes. After 6 months of episode freedom at 2 years of age, acetazolamide was discontinued without return of episodes. Neurodevelopmental assessments revealed continued typical development. This case is presented to describe the diagnostic formulation, etiologic evaluation, and symptomatic treatment of CACNA1A-related PTU with ataxia.

Clinical and genetic analyses of a Swedish patient series diagnosed with ataxia.

Hereditary ataxia is a heterogeneous group of complex neurological disorders. Next-generation sequencing methods have become a great help in clinical diagnostics, but it may remain challenging to determine if a genetic variant is the cause of the patient's disease. We compiled a consecutive single-center series of 87 patients from 76 families with progressive ataxia of known or unknown etiology. We investigated them clinically and genetically using whole exome or whole genome sequencing. Test methods were selected depending on family history, clinical phenotype, and availability. Genetic results were interpreted based on the American College of Medical Genetics criteria. For high-suspicion variants of uncertain significance, renewed bioinformatical and clinical evaluation was performed to assess the level of pathogenicity. Thirty (39.5%) of the 76 families had received a genetic diagnosis at the end of our study. We present the predominant etiologies of hereditary ataxia in a Swedish patient series. In two families, we established a clinical diagnosis, although the genetic variant was classified as "of uncertain significance" only, and in an additional three families, results are pending. We found a pathogenic variant in one family, but we suspect that it does not explain the complete clinical picture. We conclude that correctly interpreting genetic variants in complex neurogenetic diseases requires genetics and clinical expertise. The neurologist's careful phenotyping remains essential to confirm or reject a diagnosis, also by reassessing clinical findings after a candidate genetic variant is suggested. Collaboration between neurology and clinical genetics and combining clinical and research approaches optimizes diagnostic yield.

Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions.

BACKGROUND: SCA27B caused by FGF14 intronic heterozygous GAA expansions with at least 250 repeats accounts for 10-60% of cases with unresolved cerebellar ataxia. We aimed to assess the size and frequency of FGF14 expanded alleles in individuals with cerebellar ataxia as compared with controls and to characterize genetic and clinical variability. METHODS: We sized this repeat in 1876 individuals from France sampled for research purposes in this cross-sectional study: 845 index cases with cerebellar ataxia and 324 affected relatives, 475 controls, as well as 119 cases with spastic paraplegia, and 113 with familial essential tremor. FINDINGS: A higher frequency of expanded allele carriers in index cases with ataxia was significant only above 300 GAA repeats (10.1%, n = 85) compared with controls (1.1%, n = 5) (p < 0.0001) whereas GAA250-299 alleles were detected in 1.7% of both groups. Eight of 14 index cases with GAA250-299 repeats had other causal pathogenic variants (4/14) and/or discordance of co-segregation (5/14), arguing against GAA causality. We compared the clinical signs in 127 GAA≥300 carriers to cases with non-expanded GAA ataxia resulting in defining a key phenotype triad: onset after 45 years, downbeat nystagmus, episodic ataxic features including diplopia; and a frequent absence of dysarthria. All maternally transmitted alleles above 100 GAA were unstable with a median expansion of +18 repeats per generation (r2 = 0.44; p < 0.0001). In comparison, paternally transmitted alleles above 100 GAA mostly decreased in size (-15 GAA (r2 = 0.63; p < 0.0001)), resulting in the transmission bias observed in SCA27B pedigrees. INTERPRETATION: SCA27B diagnosis must consider both the phenotype and GAA expansion size. In carriers of GAA250-299 repeats, the absence of documented familial transmission and a presentation deviating from the key SCA27B phenotype, should prompt the search for an alternative cause. Affected fathers have a reduced risk of having affected children, which has potential implications for genetic counseling. FUNDING: This work was supported by the Fondation pour la Recherche Médicale, grant number 13338 to JLM, the Association Connaître les Syndrome Cérébelleux - France (to GS) and by the European Union's Horizon 2020 research and innovation program under grant agreement No 779257 ("SOLVE-RD" to GS). DP holds a Fellowship award from the Canadian Institutes of Health Research (CIHR). SK received a grant (01GM1905C) from the Federal Ministry of Education and Research, Germany, through the TreatHSP network. This work was supported by the Australian Government National Health and Medical Research Council grants (GNT2001513 and MRFF2007677) to MB and PJL.

Machine Learning-Based Scoring System to Predict the Risk and Severity of Ataxic Speech Using Different Speech Tasks.

The assessment of speech in Cerebellar Ataxia (CA) is time-consuming and requires clinical interpretation. In this study, we introduce a fully automated objective algorithm that uses significant acoustic features from time, spectral, cepstral, and non-linear dynamics present in microphone data obtained from different repeated Consonant-Vowel (C-V) syllable paradigms. The algorithm builds machine-learning models to support a 3-tier diagnostic categorisation for distinguishing Ataxic Speech from healthy speech, rating the severity of Ataxic Speech, and nomogram-based supporting scoring charts for Ataxic Speech diagnosis and severity prediction. The selection of features was accomplished using a combination of mass univariate analysis and elastic net regularization for the binary outcome, while for the ordinal outcome, Spearman's rank-order correlation criterion was employed. The algorithm was developed and evaluated using recordings from 126 participants: 65 individuals with CA and 61 controls (i.e., individuals without ataxia or neurotypical). For Ataxic Speech diagnosis, the reduced feature set yielded an area under the curve (AUC) of 0.97 (95% CI 0.90-1), the sensitivity of 97.43%, specificity of 85.29%, and balanced accuracy of 91.2% in the test dataset. The mean AUC for severity estimation was 0.74 for the test set. The high C-indexes of the prediction nomograms for identifying the presence of Ataxic Speech (0.96) and estimating its severity (0.81) in the test set indicates the efficacy of this algorithm. Decision curve analysis demonstrated the value of incorporating acoustic features from two repeated C-V syllable paradigms. The strong classification ability of the specified speech features supports the framework's usefulness for identifying and monitoring Ataxic Speech.

An atypical case of hypomagnesemia-induced cerebellar syndrome with literature review.

Cerebellar ataxia in adults is always a diagnostic challenge. One of the important causes of late-onset cerebellar ataxia is hypomagnesemia. Hypomagnesemia can have varied manifestations and is attributable to numerous causes. Identification of hypomagnesemia-induced cerebellar syndrome (HiCS) is important as it is reversible but often missed. HiCS has distinct clinical findings and characteristic magnetic resonance imaging (MRI) findings. HiCS presents with distinct clinical, biochemical, and neuroimaging findings, but it cannot be ruled out even in the absence of neuroimaging findings. This condition has to be treated promptly and meticulously to avoid precipitating any serious complications, and a strong suspicion is required for the diagnosis. The underlying cause should be evaluated and managed, as HiCS is a serious but potentially reversible disease with a good prognosis. We present a case of HiCS presenting with a characteristic history of recurrent ataxia, tremor, and vertigo that improved with treatment. Our patient was atypical, as there were no significant MRI findings attributable to hypomagnesemia. Only seven case reports are available throughout the world that show such disparity.

A Novel c.3636-4 A>G Mutation in the CCDC88C Plays a Causative Role in Familial Spinocerebellar Ataxia.

INTRODUCTION: Spinocerebellar ataxia (SCA) is an autosomal dominant genetic disease characterized by cerebellar neurological deficits. Specifically, its primary clinical manifestation is ataxia accompanied by peripheral nerve damage. A total of 48 causative genes of SCA have been identified. This study aimed to identify causative genes of autosomal dominant SCA in a four-generation Chinese kindred comprising eight affected individuals. METHODS: Genomic DNA samples were extracted from the pedigree members, and genomic whole-exome sequencing was performed, followed by bidirectional Sanger sequencing, and minigene assays to identify mutation sites. RESULTS: A novel pathogenic heterozygous mutation in the splice region of the coiled-coil domain containing the 88C (CCDC88C) gene (NM_001080414:c.3636-4 A>G) was identified in four affected members. The minigene assay results indicated that this mutation leads to the insertion of CAG bases (c.3636-1_3636-3 insCAG). CONCLUSION: CCDC88C gene mutation leads to SCA40 (OMIM:616053), which is a rare subtype of SCA without symptoms during childhood. Our findings further demonstrated the role of the CCDC88C gene in SCA and indicated that the c.3636-4 A>G (NM_001080414) variant of CCDC88C is causative for a later-onset phenotype of SCA40. Our findings enrich the mutation spectrum of CCDC88C gene and provide a theoretical basis for the genetic counseling of SCA40.

Frontal ataxia: historical aspects and clinical definition.

Frontal ataxia, originally described by Bruns, is characterized by the presence of signs of frontal lobe dysfunction, such as perseveration, paratonia, frontal release signs, cognitive changes, and urinary difficulty, associated with imbalance, slow gait, broad-based, the presence of postural instability and falls, retropulsion, and bradykinesia in the lower limbs. The goal of the present study is to recall the historical aspects of this condition, to draw attention to the importance of this clinical finding for the differential diagnosis of ataxias and to review the main semiological differences between primary ataxias (frontal, cerebellar, and sensory ataxia).

A ataxia frontal, originalmente descrita por Bruns, caracteriza-se pela presença de sinais de disfunção do lobo frontal, como perseveração, paratonia, sinais de liberação frontal, alterações cognitivas e dificuldade urinária, associados a desequilíbrio, marcha lenta, base ampla, presença de instabilidade postural e quedas, retropulsão e bradicinesia em membros inferiores. O objetivo do presente trabalho é recordar os aspectos históricos desta condição, ressaltar a importância deste achado clínico para o diagnóstico diferencial das ataxias e revisar as principais diferenças semiológicas entre as ataxias primárias (ataxia frontal, cerebelar e sensitiva).

Instrumented Gait Classification Using Meaningful Features in Patients with Impaired Coordination.

Early onset ataxia (EOA) and developmental coordination disorder (DCD) both affect cerebellar functioning in children, making the clinical distinction challenging. We here aim to derive meaningful features from quantitative SARA-gait data (i.e., the gait test of the scale for the assessment and rating of ataxia (SARA)) to classify EOA and DCD patients and typically developing (CTRL) children with better explainability than previous classification approaches. We collected data from 18 EOA, 14 DCD and 29 CTRL children, while executing both SARA gait tests. Inertial measurement units were used to acquire movement data, and a gait model was employed to derive meaningful features. We used a random forest classifier on 36 extracted features, leave-one-out-cross-validation and a synthetic oversampling technique to distinguish between the three groups. Classification accuracy, probabilities of classification and feature relevance were obtained. The mean classification accuracy was 62.9% for EOA, 85.5% for DCD and 94.5% for CTRL participants. Overall, the random forest algorithm correctly classified 82.0% of the participants, which was slightly better than clinical assessment (73.0%). The classification resulted in a mean precision of 0.78, mean recall of 0.70 and mean F1 score of 0.74. The most relevant features were related to the range of the hip flexion-extension angle for gait, and to movement variability for tandem gait. Our results suggest that classification, employing features representing different aspects of movement during gait and tandem gait, may provide an insightful tool for the differential diagnoses of EOA, DCD and typically developing children.

Detection and discovery of repeat expansions in ataxia enabled by next-generation sequencing: present and future.

Hereditary cerebellar ataxias are a heterogenous group of progressive neurological disorders that are disproportionately caused by repeat expansions (REs) of short tandem repeats (STRs). Genetic diagnosis for RE disorders such as ataxias are difficult as the current gold standard for diagnosis is repeat-primed PCR assays or Southern blots, neither of which are scalable nor readily available for all STR loci. In the last five years, significant advances have been made in our ability to detect STRs and REs in short-read sequencing data, especially whole-genome sequencing. Given the increasing reliance of genomics in diagnosis of rare diseases, the use of established RE detection pipelines for RE disorders is now a highly feasible and practical first-step alternative to molecular testing methods. In addition, many new pathogenic REs have been discovered in recent years by utilising WGS data. Collectively, genomes are an important resource/platform for further advancements in both the discovery and diagnosis of REs that cause ataxia and will lead to much needed improvement in diagnostic rates for patients with hereditary ataxia.

Immune-mediated ataxias: Guide to clinicians.

Immune-mediated cerebellar ataxias were initially described as a clinical entity in the 1980s, and since then, an expanding body of evidence has contributed to our understanding of this topic. These ataxias encompass various etiologies, including postinfectious cerebellar ataxia, gluten ataxia, paraneoplastic cerebellar degeneration, opsoclonus-myoclonus-ataxia syndrome and primary autoimmune cerebellar ataxia. The increased permeability of the brain-blood barrier could potentially explain the vulnerability of the cerebellum to autoimmune processes. In this manuscript, our objective is to provide a comprehensive review of the most prevalent diseases within this group, emphasizing clinical indicators, pathogenesis, and current treatment approaches.

Parkinsonism in complex neurogenetic disorders: lessons from hereditary dementias, adult-onset ataxias and spastic paraplegias.

Parkinsonism is a syndrome characterized by bradykinesia in combination with either rest tremor, rigidity, or both. These features are the cardinal manifestations of Parkinson's disease, the most common cause of parkinsonism, and atypical parkinsonian disorders. However, parkinsonism can be a manifestation of complex neurological and neurodegenerative genetically determined disorders, which have a vast and heterogeneous motor and non-motor phenotypic features. Hereditary dementias, adult-onset ataxias and spastic paraplegias represent only few of this vast group of neurogenetic diseases. This review will provide an overview of parkinsonism's clinical features within adult-onset neurogenetic diseases which a neurologist could face with. Understanding parkinsonism and its characteristics in the context of the aforementioned neurological conditions may provide insights into pathophysiological mechanisms and have important clinical implications, including diagnostic and therapeutic aspects.

A patient with neuropathy and ataxia: what do I have to consider?

PURPOSE OF REVIEW: An increasing number of peripheral neuro(no)pathies are identified as involving other components of the neurological system, particularly those that further impair balance. Here we aim to outline an evidence-based approach to the diagnosis of patients who present with a somatosensory disorder which also involves at least one other area of neurological impairment such as the vestibular, auditory, or cerebellar systems. RECENT FINDINGS: Detailed objective investigation of patients who present with sensory impairment, particularly where the degree of imbalance is greater than would be expected, aids the accurate diagnosis of genetic, autoimmune, metabolic, and toxic neurological disease. SUMMARY: Diagnosis and management of complex somatosensory disorders benefit from investigation which extends beyond the presenting sensory impairment.

Amiodarone-Induced Nystagmus and Ataxia: Case Report and Systematic Review of Case Reports.

Amiodarone is an antiarrhythmic drug with a significant adverse effect profile, including neurotoxicity. While ataxia, neuropathy, and tremors are more commonly seen forms of amiodarone neurotoxicity, very few cases of nystagmus are reported. We report the case of an 86-year-old man who presented with abrupt-onset ataxia, dizziness, and inability to ambulate, 10 days after initiating amiodarone for atrial fibrillation. His examination revealed gaze-evoked nystagmus along with features of cerebellar dysfunction. After excluding other etiologies, amiodarone was stopped. His nystagmus resolved, and his ataxia improved within 48 h of stopping amiodarone. Due to the rarity of this drug-induced adverse effect, we performed a systematic review of available case reports in the literature (PubMed and Scopus) using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and presented our findings. Nystagmus is a rarely reported adverse effect of amiodarone, which can occur within days to months of starting the medication. Treatment includes stopping the drug and monitoring for resolution of nystagmus.