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Disability and Rehabilitation Aug 2023Cerebellar impairment (CI) manifests from different etiologies resulting in a heterogenic clinical presentation affecting walking and mobility. Case-reports were... (Review)
Review
Assessment and tailored physical rehabilitation approaches in persons with cerebellar impairments targeting mobility and walking according to the International Classification of Functioning: a systematic review of case-reports and case-series.
PURPOSE
Cerebellar impairment (CI) manifests from different etiologies resulting in a heterogenic clinical presentation affecting walking and mobility. Case-reports were reviewed to provide an analytical clinical picture of persons with CI (PwCI) to differentiate cerebellar and non-cerebellar impairments and to identify interventions and assessments used to quantify impact on walking and mobility according to the International Classification of Functioning, Disability and Health (ICF).
MATERIALS AND METHODS
Literature was searched in PubMed, Web Of Science and Scopus. Case-reports conducting physical rehabilitation and reporting at least one outcome measure of ataxia, gait pattern, walking or mobility were included.
RESULTS
28 articles with a total of 38 different patients were included. Etiologies were clustered to: spinocerebellar degenerations, traumatic brain injuries, cerebellar tumors, stroke and miscellaneous. The interventions applied were activity-based, including gait and balance training. Participation based activities such as tai chi, climbing and dance-based therapy had positive outcomes on mobility. Outcomes on body function such as ataxia and gait pattern were only reported in 22% of the patients.
CONCLUSIONS
A comprehensive test battery to encompass the key features of a PwCI on different levels of the ICF is needed to manage heterogeneity. Measures on body function level should be included in interventions.
PubMed: 37639546
DOI: 10.1080/09638288.2023.2248886 -
Frontiers in Neurology 2023Increasing neuroimaging studies have revealed gray matter (GM) and white matter (WM) anomalies of several brain regions by voxel-based morphometry (VBM) studies on...
PURPOSE
Increasing neuroimaging studies have revealed gray matter (GM) and white matter (WM) anomalies of several brain regions by voxel-based morphometry (VBM) studies on patients with spinocerebellar ataxia type 3 (SCA3); however, the findings of previous studies on SCA3 patients by VBM studies remain inconsistent. The study aimed to identify consistent findings of gray matter (GM) and white matter (WM) changes in SCA3 patients by voxel-wise meta-analysis of whole-brain VBM studies.
METHODS
VBM studies comparing GM or WM changes in SCA3 patients and healthy controls (HCs) were retrieved from PubMed, Embase, Web of Science, and Medline databases from January 1990 to February 2023. Manual searches were also conducted, and authors of studies were contacted for additional data. The coordinates with significant differences in GM and WM between SCA3 patients and HCs were extracted from each cluster. A meta-analysis was performed using anisotropic effect size-based signed differential mapping (AES-SDM) software.
RESULTS
A total of seven studies comprising 160 SCA3 patients and 165 HCs were included in the GM volume meta-analysis. Three studies comprising 57 SCA3 patients and 63 HCs were included for WM volume meta-analysis. Compared with HC subjects, the reduced GM volume in SCA3 patients was found in the bilateral cerebellar hemispheres, cerebellar vermis, pons, right lingual gyrus, and right fusiform gyrus. The decreased WM volume was mainly concentrated in the bilateral cerebellar hemispheres, right corticospinal tract, middle cerebellar peduncles, cerebellar vermis, and left lingual gyrus. No increased density or volume of any brain structures was found. In the jackknife sensitivity analysis, the results remained largely robust.
CONCLUSION
Our meta-analysis clearly found the shrinkage of GM and WM volume in patients with SCA3. These lesions are involved in ataxia symptoms, abnormal eye movements, visual impairment, cognitive impairment, and affective disorders. The findings can explain the clinical manifestations and provide a morphological basis for SCA3.
PubMed: 37576018
DOI: 10.3389/fneur.2023.1197822 -
Cells Mar 2023Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall... (Review)
Review
INTRODUCTION
Hereditary cerebellar ataxias (HCAs) are a heterogenous group of neurodegenerative disorders associated with severe disability. Treatment options are limited and overall restricted to symptomatic approaches, leading to poor prognoses. In recent years, there has been extensive research on gene suppression therapies (GSTs) as a new hope for disease-modifying strategies. In this article, we aim to perform a review of studies investigating the efficacy and safety profile of GSTs in HCAs.
METHODS
A structured PubMed search on GSTs in HCAs from January 1993 up to October 2020 was performed. Inclusion and exclusion criteria were defined, and the selection process was conducted accordingly. The screening process was independently carried out by two authors and was initially based on title and abstract, followed by full-text reading. The risk-of-bias assessment was performed with SYRCLE's tool. A data extraction sheet was created to collect relevant information from each selected article.
RESULTS
The initial search yielded 262 papers, of which 239 were excluded. An additional article was obtained following reference scrutiny, resulting in a total of 24 articles for final analysis. Most studies were not clear on the tools used to assess bias. In SCA1, SCA2, MJD/SCA3 and SCA7, RNA interference (iRNA) and antisense oligonucleotide (ASO) therapies proved to be well tolerated and effective in suppressing mutant proteins, improving neuropathological features and the motor phenotype. In SCA6, the phenotype was improved, but no investigation of adverse effects was performed. In FRDA, only the suppression efficacy of the electroporation of the clustered regularly interspaced short palindromic repeats associated with Cas9 enzyme system (CRISPR-Cas9) system was tested and confirmed.
CONCLUSION
The literature reviewed suggests that GSTs are well tolerated and effective in suppressing the targeted proteins, improving neuropathological features and the motor phenotype . Nonetheless, there is no guarantee that these results are free of bias. Moreover, further investigation is still needed to clarify the GST effect on HCAs such as FRDA, SCA6 and SCA2.
Topics: Animals; Cerebellar Ataxia; Trinucleotide Repeats; Spinocerebellar Degenerations; Proteins
PubMed: 37048110
DOI: 10.3390/cells12071037 -
Frontiers in Neurology 2023To determine the effectiveness of transcranial magnetic stimulation in improving cerebellar ataxia.
OBJECTIVE
To determine the effectiveness of transcranial magnetic stimulation in improving cerebellar ataxia.
DATA SOURCES
PubMed, EMBASE, the Cochrane Library, Springer, Science Direct, the China National Knowledge Infrastructure (CNKI) and the China Science and Technology Journal Database (VIP) were searched until 2022.
REVIEW METHODS
Trials with transcranial magnetic stimulation on the effects on cerebellar ataxia were included, and the effect size was evaluated using the standardized mean difference (SMD) or mean difference (MD) and a 95% confidence interval (CI).
RESULTS
Eight studies comprising 272 participants, published between 2014 and 2022, were included. The results revealed that the effect of TMS on patients with cerebellar ataxia as assessed by the International Cooperative Ataxia Rating Scale (ICRAS), the Scale for the Assessment and Rating of Ataxia (SARA), the Berg Balance Scale (BBS), and the Timed Up and Go (TUG) test was statistically significant ( < 0.01) with low heterogeneity among the studies (I = 4, 27, 0, and 0% respectively).
CONCLUSION
The effects of transcranial magnetic stimulation in improving cerebellar ataxia in the affected patients are significant. TMS targeting the cerebellar structures can induce changes in the excitability of the cerebellar-thalamus-cortical pathways; thus, it is necessary to carry out large-scale research with good design and high quality in the future.
PubMed: 36779066
DOI: 10.3389/fneur.2023.1049813 -
Neural Regeneration Research Jun 2023Trehalose, a unique nonreducing crystalline disaccharide, is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding... (Review)
Review
Trehalose, a unique nonreducing crystalline disaccharide, is a potential disease-modifying treatment for neurodegenerative diseases associated with protein misfolding and aggregation due to aging, intrinsic mutations, or autophagy dysregulation. This systematic review summarizes the effects of trehalose on its underlying mechanisms in animal models of selected neurodegenerative disorders (tau pathology, synucleinopathy, polyglutamine tract, and motor neuron diseases). All animal studies on neurodegenerative diseases treated with trehalose published in Medline (accessed via EBSCOhost) and Scopus were considered. Of the 2259 studies screened, 29 met the eligibility criteria. According to the SYstematic Review Center for Laboratory Animal Experiment (SYRCLE) risk of bias tool, we reported 22 out of 29 studies with a high risk of bias. The present findings support the purported role of trehalose in autophagic flux and protein refolding. This review identified several other lesser-known pathways, including modifying amyloid precursor protein processing, inhibition of reactive gliosis, the integrity of the blood-brain barrier, activation of growth factors, upregulation of the downstream antioxidant signaling pathway, and protection against mitochondrial defects. The absence of adverse events and improvements in the outcome parameters were observed in some studies, which supports the transition to human clinical trials. It is possible to conclude that trehalose exerts its neuroprotective effects through both direct and indirect pathways. However, heterogeneous methodologies and outcome measures across the studies rendered it impossible to derive a definitive conclusion. Translational studies on trehalose would need to clarify three important questions: 1) bioavailability with oral administration, 2) optimal time window to confer neuroprotective benefits, and 3) optimal dosage to confer neuroprotection.
PubMed: 36453391
DOI: 10.4103/1673-5374.360164 -
Movement Disorders : Official Journal... Mar 2023Spinocerebellar ataxia type 17 or ATX-TBP is a CAG/CAA repeat expansion disorder characterized by marked clinical heterogeneity. Reports of affected carriers with... (Review)
Review
Spinocerebellar ataxia type 17 or ATX-TBP is a CAG/CAA repeat expansion disorder characterized by marked clinical heterogeneity. Reports of affected carriers with subthreshold repeat expansions and of patients with Parkinson's disease (PD) with expanded repeats have cast doubt on the established cutoff values of the expansions and the phenotypic spectrum of this disorder. The objective of this systematic review was to explore the genotype-phenotype relationships for repeat expansions in TBP to delineate the ATX-TBP phenotype and reevaluate the pathological range of repeat expansions. The International Parkinson and Movement Disorder Society Genetic Mutation Database (MDSGene) standardized data extraction protocol was followed. Clinically affected carriers of reported ATX-TBP expansions were included. Publications that contained repeat sizes in screened cohorts of patients with PD and/or healthy individuals were included for a separate evaluation of cutoff values. Phenotypic and genotypic data for 346 ATX-TBP patients were curated. Overall, 97.7% of the patients had ≥41 repeats, while 99.6% of patients with PD and 99.9% of healthy individuals had ≤42 repeats, with a gray zone of reduced penetrance between 41 and 45 repeats. Pure parkinsonism was more common in ATX-TBP patients with 41 to 45 repeats than in the group with ≥46 repeats, which conversely more often presented with a complex phenotype with mixed movement disorders. An updated genotype-phenotype assessment for ATX-TBP is provided, and new repeat expansion cutoff values of reduced penetrance (41-45 expanded repeats) and full penetrance (46-66 expanded repeats) are proposed. These adjusted cutoff values will have diagnostic and counseling implications and may guide future clinical trial protocol. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Topics: Humans; Genetic Association Studies; Parkinson Disease; Spinocerebellar Ataxias; TATA-Box Binding Protein; Trinucleotide Repeat Expansion
PubMed: 36374860
DOI: 10.1002/mds.29278 -
Movement Disorders Clinical Practice Nov 2022Cerebellar ataxias comprise a large group of heterogeneous disorders with both motor and non-motor symptoms (NMS). (Review)
Review
BACKGROUND
Cerebellar ataxias comprise a large group of heterogeneous disorders with both motor and non-motor symptoms (NMS).
OBJECTIVE
We wanted to ascertain the reported prevalence of NMS in different subtypes of hereditary cerebellar ataxias.
METHODS
Systematic review of studies of hereditary cerebellar ataxias (involving >5 patients) who were assessed for NMS, published in the English literature in PUBMED and EMBASE databases from 1947 to 2021.
RESULTS
A total of 35 papers, with data from 1311 autosomal dominant spinocerebellar ataxia (SCA), 893 autosomal recessive cerebellar ataxia (ARCA), and 53 X-linked ataxia cases were included with a total of 450 controls. Mean age for SCA cases at diagnosis was 47.6 (SD, 14.9) years, for ARCA cases was 34.6 (SD, 14.7) years and for X-linked ataxia cases was 68.6 (9.1) years. The prevalence of cognitive problems in SCAs was between 23% and 75% (ranging from mild to severe), being least prevalent in SCA6. The prevalence of depression in SCAs was between 13% and 69% and sleep disorders were between 7% and 80%. Pain was reported by 18% to 60% of patients, especially in SCA3, and fatigue by 53% to 70%. The prevalence of reported cognitive dysfunction in ARCA was 12.5% to 100% and depression between 14% and 51%. The prevalence of anxiety in X-linked ataxias (FXTAS) was 17 % and depression 55%.
CONCLUSIONS
The presence of NMS in hereditary cerebellar ataxias is common. The prevalence and spectrum of NMS in SCAs, ARCAs, and X-linked ataxias vary. In routine clinical practice, NMS in cerebellar ataxias are under-recognized and certainly under-reported. Therefore, they are unlikely to be addressed adequately. Improved ascertainment of NMS in cerebellar ataxias in clinical practice will enable holistic treatment of these patients.
PubMed: 36339305
DOI: 10.1002/mdc3.13532 -
Tremor and Other Hyperkinetic Movements... 2022The significance of falls and their repercussions in Parkinson's disease has been extensively researched. However, despite potentially serious effects on health and... (Review)
Review
BACKGROUND
The significance of falls and their repercussions in Parkinson's disease has been extensively researched. However, despite potentially serious effects on health and quality of life and negative impact on the healthcare system, there is not a sufficient understanding of the role of falls in hyperkinetic movement disorders (HKMDs). This review aims to provide an overview of the prevalence of falls, injuries, and preventive measures in the most common HKMDs.
METHODS
Studies up to May 1, 2022 were searched in PubMed using Medical Subjects Headings of relatively prevalent HKMDs associated with the terms "accidental falls", "injuries", "fractures", and "accident prevention".
RESULTS
In our review of 37 studies out of 155, we found evidence that for several HKMDs, such as spinocerebellar ataxia, essential tremor, Huntington's disease, and dystonia, fall risk is increased. Falls were reported in up to 84% of spinocerebellar ataxia patients, 59% of essential tremor patients, and 79% of Huntington's patients, with 65% of the latter falling frequently. Injuries occurred in up to 73% in Huntington and 74% in ataxia patients. Most of the common diseases characterized by HKMDs were investigated for both fall causes and consequences, but prevention studies were limited to spinocerebellar ataxia and Huntington's disease.
DISCUSSION
The limited available data suggest that patients with several HKMDs can be considered to be at increased risk of falling and that the consequences can be serious. As a result, physicians should be advised to include fall exploration in their routine workup and provide advice for safer mobility. In general, more research into fall-related concerns in HKMDs is necessary.
HIGHLIGHTS
In contrast to Parkinson's disease, the prevalence of accidental falls, their repercussions, and preventive strategies are under-investigated in hyperkinetic movement disorders (HKMDs). Several HKMDs such as essential tremor, ataxia, and Huntington's disease have reported fall rates of up to 84% and fall-related injury rates of up to 74%. Therefore, routine examinations of HKMD patients should include a fall exploration and provide advice on safe mobility.
Topics: Humans; Accidental Falls; Essential Tremor; Parkinson Disease; Huntington Disease; Hyperkinesis; Quality of Life; Ataxia; Spinocerebellar Ataxias
PubMed: 36303814
DOI: 10.5334/tohm.709 -
Brain Sciences Aug 2022Ataxia is a constellation of symptoms that involves a lack of coordination, imbalance, and difficulty walking. Hereditary ataxia occurs when a person is born with... (Review)
Review
Ataxia is a constellation of symptoms that involves a lack of coordination, imbalance, and difficulty walking. Hereditary ataxia occurs when a person is born with defective genes, and this degenerative disorder may progress for several years. There is no effective cure for ataxia, so we need to search for new treatments. Recently, interest in riluzole in the treatment of ataxia has emerged. We conducted this systematic review to analyze the safety and efficacy of riluzole for treating hereditary ataxia in recent clinical trials. We conducted a systematic review using PubMed and Google Scholar as databases in search of this relationship. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Meta-analysis of Observational Studies in Epidemiology (MOOSE) protocols to conduct this study. For inclusion criteria, we included full-text clinical trials on humans written in English and found three clinical trials. We excluded case reports, literature reviews, systematic reviews, and meta-analyses for this analysis. We aimed to evaluate the Scale for the Assessment and Rating of Ataxia (SARA) score, the International Cooperative Ataxia Rating Scale (ICARS) score, and the safety of the medication. Two out of the three clinical trials showed statistically significant clinical improvement in the ICARS and SARA scores, while the other trial did not show improvement in the clinical or radiological outcomes. The drug was safe in all clinical trials. Overall, the results of this analysis of riluzole for the treatment of hereditary ataxia are encouraging. Further clinical trials are needed to investigate the efficacy of riluzole on hereditary ataxia.
PubMed: 36009103
DOI: 10.3390/brainsci12081040 -
Frontiers in Neuroscience 2022Spinocerebellar ataxia type 3 (SCA3) is a complex cerebrocerebellar disease primarily characterized by ataxia symptoms alongside motor and cognitive impairments. The...
BACKGROUND
Spinocerebellar ataxia type 3 (SCA3) is a complex cerebrocerebellar disease primarily characterized by ataxia symptoms alongside motor and cognitive impairments. The heterogeneous clinical presentation of SCA3 necessitates correlations between magnetic resonance imaging (MRI) and clinical findings in reflecting progressive disease changes. At present, an attempt to systematically examine the brain-behavior relationship in SCA3, specifically, the correlation between MRI and clinical findings, is lacking.
OBJECTIVE
We investigated the association strength between MRI abnormality and each clinical symptom to understand the brain-behavior relationship in SCA3.
METHODS
We conducted a systematic review on Medline and Scopus to review studies evaluating the brain MRI profile of SCA3 using structural MRI (volumetric, voxel-based morphometry, surface analysis), magnetic resonance spectroscopy, and diffusion tensor imaging, including their correlations with clinical outcomes.
RESULTS
Of 1,767 articles identified, 29 articles met the eligibility criteria. According to the National Institutes of Health quality assessment tool for case-control studies, all articles were of excellent quality. This systematic review found that SCA3 neuropathology contributes to widespread brain degeneration, affecting the cerebellum and brainstem. The disease gradually impedes the cerebral cortex and basal ganglia in the late stages of SCA3. Most findings reported moderate correlations ( = 0.30-0.49) between MRI features in several regions and clinical findings. Regardless of the MRI techniques, most studies focused on the brainstem and cerebellum.
CONCLUSIONS
Clinical findings suggest that rather than individual brain regions, the connectivity between different brain regions in distributed networks (i.e., cerebellar-cerebral network) may be responsible for motor and neurocognitive function in SCA3. This review highlights the importance of evaluating the progressive changes of the cerebellar-cerebral networks in SCA3 patients, specifically the functional connectivity. Given the relative lack of knowledge about functional connectivity on SCA3, future studies should investigate possible functional connectivity abnormalities in SCA3 using fMRI.
PubMed: 35757531
DOI: 10.3389/fnins.2022.859651