Progressive Spinal Cord Degeneration in Friedreich's Ataxia: Results from ENIGMA-Ataxia.

BACKGROUND: Spinal cord damage is a hallmark of Friedreich's ataxia (FRDA), but its progression and clinical correlates remain unclear. OBJECTIVE: The objective of this study was to perform a characterization of cervical spinal cord structural damage in a large multisite FRDA cohort. METHODS: We performed a cross-sectional analysis of cervical spinal cord (C1-C4) cross-sectional area (CSA) and eccentricity using magnetic resonance imaging data from eight sites within the ENIGMA-Ataxia initiative, including 256 individuals with FRDA and 223 age- and sex-matched control subjects. Correlations and subgroup analyses within the FRDA cohort were undertaken based on disease duration, ataxia severity, and onset age. RESULTS: Individuals with FRDA, relative to control subjects, had significantly reduced CSA at all examined levels, with large effect sizes (d > 2.1) and significant correlations with disease severity (r < -0.4). Similarly, we found significantly increased eccentricity (d > 1.2), but without significant clinical correlations. Subgroup analyses showed that CSA and eccentricity are abnormal at all disease stages. However, although CSA appears to decrease progressively, eccentricity remains stable over time. CONCLUSIONS: Previous research has shown that increased eccentricity reflects dorsal column (DC) damage, while decreased CSA reflects either DC or corticospinal tract (CST) damage, or both. Hence our data support the hypothesis that damage to the DC and damage to CST follow distinct courses in FRDA: developmental abnormalities likely define the DC, while CST alterations may be both developmental and degenerative. These results provide new insights about FRDA pathogenesis and indicate that CSA of the cervical spinal cord should be investigated further as a potential biomarker of disease progression. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Automated ICF Coding of Rehabilitation Notes for Low-Resource Languages via Continual Training of Language Models.

The coding of medical documents and in particular of rehabilitation notes using the International Classification of Functioning, Disability and Health (ICF) is a difficult task showing low agreement among experts. Such difficulty is mainly caused by the specific terminology that needs to be used for the task. In this paper, we address the task developing a model based on a large language model, BERT. By leveraging continual training of such a model using ICF textual descriptions, we are able to effectively encode rehabilitation notes expressed in Italian, an under-resourced language.

Effectiveness of rehabilitation intervention in persons with Friedreich ataxia.

Introduction: The relevance of rehabilitation in progressive neurological disorders, such as Friedreich's Ataxia (FRDA), has yet to be convincingly proven. FRDA is characterized by ataxia, loss of gait, scoliosis, cardiomyopathy, dysarthria and dysphagia, with reduced life expectancy. The disease onset is usually in adolescence, leading to progressive disability. Omaveloxolone has been recently approved as the first pharmacological treatment for FRDA in adults and adolescents aged 16 years and older. Regarding non-pharmacological therapies, neurorehabilitation is a valuable aid in addressing the symptoms and in maintaining the residual functioning. We performed a prospective observational cohort study to evaluate the efficacy of inpatient rehabilitation (IR) for people with FRDA. Methods: A total of 42 individuals (29 adults and 13 children) with FRDA were recruited. There were 27 ambulant and 15 non-ambulant participants. The patients underwent IR of 3 and 4 weeks in children and adults, respectively. The IR treatment was designed to be applied within a multidisciplinary setting, so FRDA patients underwent, in addition to physiotherapy, also occupational therapy, practical manual activities and psychological support aiming to enhance transferable skills useful in the activities of daily living. The primary outcome was the Scale for the Assessment and Rating of Ataxia (SARA). Other measures were: Friedreich Ataxia Rating Scale (FARS) and Nine Hole Peg Test (NHPT). Furthermore, we used the 6 Minute Walk Test (6MWT), the Timed Up and Go (TUG) and the Berg Balance Scale (BBS) only on ambulant subjects. Outcomes were evaluated at baseline and at the end of the treatment. Results: We report that the IR significantly improves motor performance and ataxia symptoms in patients with FRDA. Our study shows significant functional improvement in all the outcome measures used, except for NHPT bilaterally. FARS and SARA scores post-IR are significatively reduced when compared (p < 0.001). Discussion: We demonstrate that IR programs in FRDA can provide a meaningful clinical improvement in terms of outcome measures. These findings could be useful when approaching progressive neurological disorders.

Respiratory Function in Friedreich's Ataxia.

BACKGROUND: Friedreich's ataxia is an inherited, rare, progressive disorder of children and young adults. It is characterized by ataxia, loss of gait, scoliosis, cardiomyopathy, dysarthria and dysphagia, with reduced life expectancy. Alterations of respiratory dynamics and parameters are frequently observed. However, in the literature there are few, dated studies with small cohorts. Our study aims to make an objective analysis of the respiratory condition of both early and late stage FRDA patients, looking for correlations with the motor, skeletal, speech and genetic aspects of this condition. MATERIALS AND METHODS: This retrospective observational study is based on the collection of clinical and instrumental respiratory data of 44 subjects between 13 and 51 years attending a tertiary rehabilitation centre in northern Italy. The analysis was carried out using Pearson's correlation test, ANOVA test and post hoc tests. RESULTS: Data show the presence of a recurrent pattern of respiratory dysfunction of a restrictive type, with reduction in forced vital capacity and of flow and pressure parameters. The severity of the respiratory condition correlates with the disease severity (measured with disease-specific scales), with pneumophonic alterations and with the severity of the thoracic scoliotic curve. CONCLUSIONS: Respiratory function is impaired at various degrees in FRDA. The complex condition of inco-ordination and hyposthenia in FRDA affects daytime and night-time respiratory efficiency. We believe that the respiratory deficit and the inefficiency of cough are indeed a clinical problem deserving consideration, especially in the context of the concomitant postural difficulty and the possible presence of dysphagia. Therefore, the rehabilitation project for the subject with FRDA should also consider the respiratory function.

Efficacy of a Combined Treatment of Botulinum Toxin and Intensive Physiotherapy in Hereditary Spastic Paraplegia.

INTRODUCTION: The Hereditary Spastic Paraplegia (HSP) is a heterogeneous group of neurodegenerative disorders characterized by progressive spasticity and lower limbs (LL) weakness. There is no treatment to cure or halt the disease, except for symptomatic therapy. The use of botulinum toxin type A (BoNT-A) is one of the primary treatment for focal spasticity. Physiotherapy (PT) can help in maintaining residual functioning. We performed a retrospective study to evaluate the effect of the combined BoNT-A and intensive PT in patients with HSP. METHODS: Eighteen adult patients (50% females) with clinical diagnosis of HSP were recruited. Eleven patients had a genetic diagnosis of SPG4, 5, 7, 8, 11, 72. Patients were all autonomously deambulant or needed support. BoNT-A was injected in 36 LL in different spastic muscles under electromyographic guidance and followed by intensive PT sessions. Outcome measures included disease severity, motor functional measures, perceived pain self-report and quality of life. Assessments occurred at baseline, 1 and 3 months after BoNT-A injection. RESULTS: Most inoculated muscles were hamstrings, rectus femoris and gastrocnemius. We observed an improvement in muscle tone, in the gait velocity and distance length. Spastic Paraplegia Rating Scale was significantly reduced after treatment, in addition to improving pain and quality of life. These results were riconfirmed in 3 months time. CONCLUSION: Our study indicates that combined treatment of BoNT-A and PT can lead to improvement of spasticity and quality of life in patients with HSP.

Brain Magnetic Spectroscopy Imaging and Hereditary Spastic Paraplegia: A Focused Systematic Review on Current Landmarks and Future Perspectives.

Magnetic resonance spectroscopy (MRS) is a non-invasive neuroimaging technique used to investigate in vivo brain metabolites. MRS could provide a sensitive tool for the study of hereditary spastic paraplegia (HSP) by helping to unveil the underlying biochemical mechanisms and monitoring response to treatment. This focused systematic review aimed to summarize the brain metabolite findings in studies performed in genetically determined HSP. The second aim was to provide a critical analysis and recommendations for well-designed protocols for future studies. Fourteen MRS studies have been analyzed with overall 61 HSP patients, falling within a wide range of age at onset, disease duration, and age at the MRS scan, including children and adults. The genetic diagnosis included several subtypes (SPG2/3/4/5/10/11/28/31/54). SPG11 and SPG54 have been more frequently investigated. The MRS methodology included different MR field strength, not easily comparable spectra areas varying from whole brain to various cortical areas, brain stem and cerebellum sampling. No consistency in disease severity and other outcome measures was observed. The main MRS findings corresponded to the white matter metabolite abnormalities in the corticospinal tracts. In summary, this focused review provides insights on the current knowledge of brain metabolites in HSP and, in particular, in SPG11 and SPG54. Despite the inhomogeneity of the studies to date reported, brain metabolites as assessed by MRS could represent potentially useful diagnostic markers and prognostic indicators of disease progression in HSP. Specific recommendations regarding the MRS technical protocol, CNS area sampling, study design, and applicability of findings are given.

Optical Coherence Tomography in a Cohort of Genetically Defined Hereditary Spastic Paraplegia: A Brief Research Report.

Introduction: In-vivo objective documentation of pathological changes in neurodegenerative disease is a major aim to possibly improve our ability to monitor disease progression and response to treatment. Temporal thinning of the retinal nerve fiber layer (RNFL) thickness shown by spectral domain optical coherence tomography (SD-OCT) has been reported in association with the complex forms in hereditary spastic paraplegia (HSP). We performed an assessment of the RNFL thickness in a group of HSP patients, including a longitudinal follow-up in a subgroup. Our aim was to measure and compare the changes and correlate them to clinical progression. Materials and Methods: Twenty-three HSP patients were recruited and studied with the SD-OCT including papillary and macular scan by Spectralis. The clinical severity was assessed using the Spastic Paraplegia Rating Scale. Results: Thinning of the superior, nasal and inferior quadrants bilaterally were observed compared to the normative data in both pure and complicated forms, that were clearly pathological only in a proportion of cases. Thinning correlated with age and disease duration, but not with clinical severity. The longitudinal study (n = 9) showed no significant change compared to the baseline data for the period of observation (mean 10.7 months). Conclusions: RFNL is frequently thinned in HSP with no specific recognizable pattern of quadrants involved and SPG types. The small sample size and the short follow-up time showed no clear progression. Although SD-OCT appraisal of RFNL deserves to be explored in neurodegenerative conditions, it might not be suitable for use as a biomarker in HSP as it appears not to be specific to this condition and can be a feature of aging.

Functional and Structural Brain Damage in Friedreich's Ataxia.

Friedreich's ataxia (FRDA) is a rare hereditary neurodegenerative disorder caused by a GAA repeat expansion in the FXN gene. There is still no cure or quantitative biomarkers reliaby correlating with the progression rate and disease severity. Investigation of functional and structural alterations characterizing white (WM) and gray matter (GM) in FRDA are needed prerequisite to monitor progression and response to treatment. Here we report the results of a multimodal cross-sectional MRI study of FRDA including Voxel-Based Morphometry (VBM), diffusion-tensor imaging (DTI), functional MRI (fMRI), and a correlation analysis with clinical severity scores. Twenty-one early-onset FRDA patients and 18 age-matched healthy controls (HCs) were imaged at 3T. All patients underwent a complete cognitive and clinical assessment with ataxia scales. VBM analysis showed GM volume reduction in FRDA compared to HCs bilaterally in lobules V, VI, VIII (L>R), as well as in the crus of cerebellum, posterior lobe of the vermis, in the flocculi and in the left tonsil. Voxel-wise DTI analysis showed a diffuse fractional anisotropy reduction and mean, radial, axial (AD) diffusivity increase in both infratentorial and supratentorial WM. ROI-based analysis confirmed the results showing differences of the same DTI metrics in cortico-spinal-tracts, forceps major, corpus callosum, posterior thalamic radiations, cerebellar penduncles. Additionally, we observed increased AD in superior (SCP) and middle cerebellar peduncles. The WM findings correlated with age at onset (AAO), short-allelle GAA, and disease severity. The intragroup analysis of fMRI data from right-handed 14 FRDA and 15 HCs showed similar findings in both groups, including activation in M1, insula and superior cerebellar hemisphere (lobules V-VIII). Significant differences emerged only during the non-dominant hand movement, with HCs showing a stronger activation in the left superior cerebellar hemisphere compared to FRDA. Significant correlations were found between AAO and the fMRI activation in cerebellar anterior and posterior lobes, insula and temporal lobe. Our multimodal neuroimaging protocol suggests that MRI is a useful tool to document the extension of the neurological impairment in FRDA.

Clinical and Paraclinical Indicators of Motor System Impairment in Hereditary Spastic Paraplegia: A Pilot Study.

BACKGROUND: Hereditary spastic paraplegias (HSP) are a composite and genetically heterogeneous group of conditions mainly expressed by the impairment of the central motor system ("pure" forms). The involvement of other components of the central nervous system or of other systems is described in the "complicate" forms. The definition of an investigation protocol capable, by assembling clinical and paraclinical indicators to fully represent the extent of the motor system impairment, would help both the clinical handling of these conditions and contribute to our understanding of their pathogenesis. METHODS: We applied a clinical and paraclinical protocol which included tools exploring motor and non motor functioning, neurophysiology and MRI to a composite cohort of 70 molecularly defined HSP patients aged 3 to 65, to define for each indicator its significance in detailing the presence and the severity of the pathology. RESULTS: Clinically increased deep tendon reflexes and lower limb (LL) weakness are constant findings in all patients. The "complicated" forms are characterized by peripheral motor impairment, cognitive and cerebellar involvement. The Spastic Paraplegia Rating Scale efficiently reflects the severity of functional problems and correlates with disease duration. Neurophysiology consistently documents the impairment of the central motor pathway to the LLs. Nevertheless, the upper extremities and sensory system involvement is a frequent finding. MRI diffusion tensor imaging (DTI) highlighted a significant alteration of FA and MD. Combining the sampling of the various portion of the cortico-spinal tract (CST) DTI consistently discriminated patients from controls. CONCLUSION: We propose a graded clinical and paraclinical protocol for HSP phenotype definition, indicating for each tool the discriminative and descriptive capacity. Our protocol applied to 9 different forms of HSP showed that the functional impairment often extends beyond the CST. The novel DTI approach may add significant elements in disease recognition, staging and mapping.