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The A-wave is a late response related either to demyelination or early axonal regeneration. It may be helpful in the evaluation of some peripheral neuropathies. In leprosy, previous studies suggested that A-waves could be a neurophysiological marker of pain in patients during reactions. Herein we have attempted to further assess the profile and clinical correlates of A-waves by exploring a large leprosy cohort.Between 2015 and 2018, 63 patients with leprosy (47 men and 16 women) had A-waves in nerve conduction studies and were included in this study. We included patients regardless of whether they were experiencing leprosy reactions or not. We then compared clinical features in nerves with and without A-waves.The mean age of study participants was 46.5 ± 12.3 years and most had borderline leprosy. From this cohort, we assessed separately 83 motor nerves that demonstrated A-waves (group AThese results show that A-waves are associated with neuropathic pain in leprosy patients, regardless of the nerves affected and the immune status (in reaction or not).

BACKGROUND Spinal cord (SC) damage is a hallmark in Friedreich's ataxia (FRDA). Neuroimaging has been able to capture some SC macroscopic changes, but no study has evaluated microstructural SC white matter (WM) damage in vivo. OBJECTIVES We designed a cross-sectional study to evaluate microstructural integrity in SC WM tracts of FRDA patients using diffusion tensor imaging (DTI) with an automated analysis pipeline. METHODS Thirty patients and 30 matched healthy controls underwent 3 Tesla (T) magnetic resonance imaging (MRI). We obtained cervical SC T2 and diffusion-weighted imaging (DWI) acquisitions. Images were processed using the Spinal Cord Toolbox v.4.3.0. For levels C2-C5, we measured cross-sectional area (CSA) and WM DTI parameters (axial diffusivity [AD], fractional anisotropy [FA], radial diffusivity [RD], and mean diffusivity [MD]). Age, duration, and FARS scores were also obtained. RESULTS Mean age and disease duration of patients were 31 ± 10 and 11 ± 9 years, respectively. There was CSA reduction in FRDA amongst all levels. Between-group differences in FA, MD, and RD in total white matter (TWM), dorsal columns (DC), fasciculus gracilis (FG), fasciculus cuneatus (FC), and corticospinal tracts (CST) were present in all levels. FA and RD from TWM, DC, FC, and CST correlated with FARS scores, and in CST they also correlated with disease duration. CONCLUSION DTI uncovered abnormalities in SC WM tracts, which correlated with clinical features in FRDA. CSA and CST FA in C2 correlated best with disease severity, whereas DC FA showed the largest effect size to differentiate patients and healthy controls. SC WM microstructure is a potential neuroimaging biomarker to be explored in the disease. © 2021 International Parkinson and Movement Disorder Society.

Objective Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontemporal dementia (FTD), inclusion body myopathy (hIBM) or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium-dependent phospholipid-binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11). Methods We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls. Results Clinico-radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb-girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP-43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions). Interpretation These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS. This article is protected by copyright. All rights reserved.

BACKGROUND Hereditary spastic paraplegia presents spasticity as the main clinical manifestation, reducing gait quality and producing incapacity. Management with botulinum toxin type A (BoNT-A) is not well elucidated. The objective of the current study was to evaluate the efficacy and safety of BoNT-A in patients with hereditary spastic paraplegias. METHODS This was a double-blind, randomized, placebo-controlled crossover trial. Each participant was randomly assigned to receive 1 injection session of either BoNT-A (100 IU/2 mL of Prosigne in each adductor magnus and each triceps surae) or saline 0.9% (2 mL). The primary outcome measure was change from baseline in maximal gait velocity, and secondary outcome measures included changes in gait at self-selected velocity, spasticity, muscle strength, Spastic Paraplegia Rating Scale, pain, fatigue, and subjective perception of improvement. We also looked at adverse events reported by the patients. RESULTS We enrolled 55 patients, 36 of whom were men and 41 with the pure phenotype. Mean age was 43 ± 13.4 years (range, 19-72 years), mean age of onset waws 27 ± 13.1 years (range

Background and purpose Neurological manifestations have been identified in the context of autoimmune hepatitis (AIH). Previous case reports highlighted the association between AIH and sensory neuronopathy (SN). Despite that, little is known about the frequency of AIH-related SN and its clinical/neurophysiological profile. Moreover, it is not clear whether SN is an AIH-specific manifestation or related to chronic liver damage. Methods Seventy consecutive AIH patients were enrolled and their characteristics were compared with 52 consecutive patients with chronic active hepatitis B. All subjects underwent clinical and neurophysiological evaluation. Further comparisons were performed between AIH SN and AIH non-SN patients. Results Mean ages and male:female proportions in the AIH and chronic active hepatitis B groups were 42.2 ± 16.3/51.7 ± 13.6 years and 14:56/29:23, respectively. The frequencies of carpal tunnel syndrome, radiculopathy and polyneuropathy were similar between groups. In contrast, SN was identified only in AIH patients (5/70 vs. 0/52, P = 0.04); the overall prevalence of AIH-related SN was 7% with an average profile of a woman in her 40s with asymmetric onset of sensory deficits that chronically evolved to disabling proprioceptive ataxia associated with marked dysautonomia. Neurological disability and hepatocellular damage did not follow in parallel. Anti-fibroblast growth factor receptor type 3 antibodies were found in 3/5 (60%) of the patients with AIH-related SN. Clinical or demographic predictors of SN in the context of AIH could not be identified. Conclusion Sensory neuronopathy, but not other peripheral nervous system diseases, is a specific AIH neurological manifestation. It is often disabling and, in contrast to hepatocellular injury, does not respond to immunosuppression.

Autosomal recessive cerebellar ataxias (ARCAs) comprisecomplex genetic ataxia disorders with variable central andperipheral nervous system involvement and systemic changes.They can overlap with other conditions such as hereditary spas-tic paraplegia, inborn errors of metabolism, and genetic enceph-alopathies.1While usually starting in childhood or youngadulthood, late adult-onset may occur. The advanced applica-tion of next-generation sequencing has allowed the moleculardefinition of many previously undetermined ARCAs in the lastdecade, including many new ARCA genes.

Background Molecular imaging has proven to be a powerful tool to elucidate degenerated paths in a wide variety of neurological diseases and has not been systematically studied in hereditary spastic paraplegias. Objectives To investigate dopaminergic degeneration in a cohort of 22 patients with hereditary spastic paraplegia attributed to SPG11 mutations and evaluate treatment response to l-dopa. Methods Patients and controls underwent single-photon emission computed tomography imaging utilizing 99m Tc-TRODAT-1 tracer. A single-blind trial with 600 mg of l-dopa was performed comparing UPDRS scores. Results Reduced dopamine transporter density was universal among patients. Nigral degeneration was symmetrical and correlated with disease duration and motor and cognitive handicap. No statistically significant benefit could be demonstrated with l-dopa intake during the trial. Conclusion Disruption of presynaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations, even in the absence of parkinsonism. Unresponsiveness to treatment could be related to postsynaptic damage that needs to be further investigated.

Objective Machado-Joseph disease (SCA3/MJD) is the most frequent spinocerebellar ataxia worldwide and characterized by brainstem, basal ganglia, and cerebellar damage. However, little is known about the natural history of the disease. This motivated us to determine the extension and progression of central nervous system involvement in SCA3/MJD using multimodal magnetic resonance imaging (MRI)-based analyses in a large cohort of patients (n = 79) and presymptomatic subjects (n = 12). Methods All subjects underwent MRI in a 3T device to assess gray and white matter. To evaluate the cerebral and cerebellar cortices, we used measures from FreeSurfer and SUIT. T1-multiatlas assessed deep gray matter. Diffusion tensor imaging multiatlas was used to investigate cerebral white matter (WM) and SpineSeg to assess the cervical spinal cord. Results There was widespread WM and cerebellar damage, in contrast to the restricted motor cortex involvement when all patients are compared to age- and sex-matched controls. Presymtomatic patients showed WM microstructural abnormalities mainly in the cerebellar and cerebral peduncles and volumetric reduction of midbrain, spinal cord, and substantia nigra. To assess the disease progression, we divided patients into four subgroups defined by time from ataxia onset. There was a clear pattern of evolving structural compromise, starting in infratentorial structures and progressing up to the cerebral cortex. Conclusion Structural damage in SCA3/MJD begins in the spinal cord, cerebellar peduncles, as well as substantia nigra and progresses to cerebral areas in the long term. These structural differences reveal some insights into the pathogenesis of SCA3/MJD and suggest a staging scheme to map the progression of the disease. Ann Neurol 2018;84:401-408.

Introduction Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities, and slowly progressive ataxia. However, some individuals manifest the disease after the age of 25 years and are classified as late-onset FRDA (LOFA). Therefore, we propose a transversal multimodal MRI-based study to investigate which anatomical substrates are involved in classical (cFRDA) and LOFA. Methods We enrolled 36 patients (13 with LOFA) and 29 healthy controls. All subjects underwent magnetic resonance imaging in a 3 T device; three-dimensional high-resolution T1-weighted images and diffusion tensor images were used to assess gray and white matter, respectively. We used T1 multiatlas approach to assess deep gray matter and cortical thickness measures to evaluate cerebral cortex and DTI multiatlas approach to assess white matter. All analyses were corrected for multiple comparisons. Results Group comparison showed that both groups presented gray matter atrophy mostly in the motor cortex. Regarding white matter, we found abnormalities in the cerebellar peduncles, pyramidal tracts, midbrain, pons, and medulla oblongata for both groups, but the microstructural abnormalities in the cFRDA group were more widespread. In addition, we found that the corticospinal tract presented more severe microstructural damage in the LOFA group. Finally, the midbrain volume of the cFRDA, but not of the LOFA group, correlated with disease duration (R = −0.552, P = 0.012) and severity (R = −0.783, P

Different types of mutations in the DMD gene underlie Duchenne muscular dystrophies (DMD) and Becker muscular dystrophies (BMD). Large deletions and duplications are the most frequent causative genetic alterations worldwide, but little is known about DMD/BMD genetic profile in Brazil. Hence, we recruited patients with DMD and BMD from 8 neuromuscular reference centers along the country, and performed a comprehensive molecular investigation that included Multiplex Ligation-dependent Probe Amplification and Next generation sequencing (NGS) analyses. We evaluated 199 patients from 177 unrelated families: 166 with DMD, 32 with BMD and 1 1.5 years old asymptomatic patient with persistent hiperCKemia. Overall, large deletions (58.2%) followed by nonsense mutations (12.4%) and large duplications (11.3%) were the most frequent variants in Brazilian families. Large deletions were less frequent in BMD than in DMD (44.8% vs 60.8%). We identified 19 new DMD variants. Nonsense mutations were significantly more frequent in patients from northeastern region than from southern/southeastern regions of Brazil (27.7% vs 8.5%, P

Background and purpose Non-motor manifestations are frequently overlooked in degenerative disorders and little is known about their frequency and clinical relevance in SPG4 hereditary spastic paraplegia (SPG4-HSP). Methods Thirty patients with SPG4-HSP and 30 healthy controls answered the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, Brief Pain Inventory and Beck Depression Inventory. Student's t test was used to compare groups and linear regression was used to assess correlations. Results Patients had higher fatigue scores than controls (31.0 ± 16.5 vs. 14.5 ± 16.0, P = 0.002) as well as pain (3.4 ± 2.7 vs. 1.0 ± 1.6, P = 0.001) and depression (12.7 ± 8.9 vs. 4.4 ± 3.8, P

Introduction Spinal cord and peripheral nerves are classically known to be damaged in Friedreich's ataxia, but the extent of cerebral involvement in the disease and its progression over time are not yet characterized. The aim of this study was to evaluate longitudinally cerebral damage in Friedreich's ataxia Methods We enrolled 31 patients and 40 controls, which were evaluated at baseline and after 1 and 2 years. To assess gray matter, we employed voxel-based morphometry and cortical thickness measurements. White matter was evaluated using diffusion tensor imaging. Statistical analyses were both cross-sectional and longitudinal (corrected for multiple comparisons). Results Group comparison between patients and controls revealed widespread macrostructural differences at baseline: gray matter atrophy in the dentate nuclei, brainstem, and precentral gyri; and white matter atrophy in the cerebellum and superior cerebellar peduncles, brainstem, and periventricular areas. We did not identify any longitudinal volumetric change over time. There were extensive microstructural alterations, including superior cerebellar peduncles, corpus callosum, and pyramidal tracts. Longitudinal analyses identified progressive microstructural abnormalities at the corpus callosum, pyramidal tracts, and superior cerebellar peduncles after 1 year of follow-up. Conclusion Patients with Friedreich's ataxia present more widespread gray and white matter damage than previously reported, including not only infratentorial areas, but also supratentorial structures. Furthermore, patients with Friedreich's ataxia have progressive microstructural abnormalities amenable to detection in a short-term follow-up. © 2015 International Parkinson and Movement Disorder Society

Sensory neuronopathies (SN) are a group of disorders characterized by primary damage to the dorsal root ganglia neurons. Clinical features include multifocal areas of hypoaesthesia, pain, dysautonomia, and sensory ataxia, which is the major source of disability. Diagnosis relies upon clinical assessment and nerve conductions studies, but sometimes it is difficult to distinguish SN from similar conditions, such as axonal polyneuropathies and some myelopathies. In this scenario, underdiagnosis is certainly an important issue for SN patients and additional diagnostic tools are needed. MRI is able to evaluate the dorsal columns of the spinal cord and has proven useful in the workup of SN patients. Although T2 weighted hyperintensity restricted to the posterior fasciculi without contrast enhancement is the typical finding, additional abnormalities have been recently reported. The aim of this review is to gather available information on neuroimaging findings of SN, discuss their clinical correlates and the potential impact of novel MRI-based techniques.

Spinocerebellar ataxia type 3 or Machado-Joseph disease is the most common spinocerebellar ataxia worldwide, and the high frequency of nonmotor manifestations in Machado-Joseph disease demonstrates how variable is the clinical expression of this single genetic entity. Anatomical, physiological, clinical, and functional neuroimaging data reinforce the idea of a degenerative process involving extracerebellar regions of the nervous system in Machado-Joseph disease. Brain imaging and neuropathologic studies have revealed atrophy of the pons, basal ganglia, midbrain, medulla oblongata, multiple cranial nerve nuclei, and thalamus and of the frontal, parietal, temporal, occipital, and limbic lobes. This review provides relevant information about nonmotor manifestations and extracerebellar symptoms in Machado-Joseph disease. The main nonmotor manifestations of Machado-Joseph disease described in previous data and discussed in this article are: sleep disorders, cognitive and affective disturbances, psychiatric symptoms, olfactory dysfunction, peripheral neuropathy, pain, cramps, fatigue, nutritional problems, and dysautonomia. In addition, we conducted a brief discussion of noncerebellar motor manifestations, highlighting movement disorders. © 2013 Movement Disorder Society.

Although white matter damage may play a major role in the pathogenesis of spinocerebellar ataxia 3 (SCA3), available data rely exclusively upon macrostructural analyses. In this setting we designed a study to investigate white matter integrity. We evaluated 38 genetically-confirmed SCA3 patients (mean age, 52.76 ± 12.70 years; 21 males) with clinical scales and brain magnetic resonance imaging (MRI) and 38 healthy subjects as a control group (mean age, 48.86 ± 12.07 years, 20 male). All individuals underwent the same protocol for high-resolution T1 and T2 images and diffusion tensor imaging acquisition (32 directions) in a 3-T scanner. We used Tract-Based Spatial Statistics (FSL 4.1.4) to analyze diffusion data and SPM8/DARTEL for voxel-based morphometry of infratentorial structures. T2-relaxometry of cerebellum was performed with in-house-developed software Aftervoxel and Interactive Volume Segmentation (IVS). Patients' mean age at onset was 40.02 ± 11.48 years and mean duration of disease was 9.3 ± 2.7 years. Mean International Cooperative Ataxia Rating Scale (ICARS) and Scale for Assessment and Rating of Ataxia (SARA) scores were 32.08 ± 4.01 and 14.65 ± 7.33, respectively. Voxel-based morphometry demonstrated a volumetric reduction of gray and white matter in cerebellum and brainstem (P

BACKGROUND/PURPOSE Previous imaging studies in the Machado-Joseph disease (MJD/SCA3) have mostly concentrated on the cerebellum and brainstem. Our goal was to perform a whole brain longitudinal evaluation. METHODS We included 45 patients and 51 controls, who underwent two brain magnetic resonance imaging and magnetic resonance spectroscopy (mean interval of 12.5 ± 1.5 months). We used voxel-based morphometry (VBM) and the MarsBar analysis toolbox to extract grey matter density (GMD) values from regions of interest. We used a linear regression model and a general linear model to correlate GMD with clinical markers, and paired t-test for the longitudinal evaluation. RESULTS We observed decreased GMD (P < .01) at frontal, parietal, temporal and occipital lobes, subcortical grey matter, cerebellum, and brainstem. White matter atrophy was restricted to the cerebellum. Age, CAG, and disease duration predicted GMD in different areas, but age and CAG were the most important predictors. The longitudinal analysis failed to demonstrate changes. Changes in regions other than the cerebellum appeared to contribute significantly to the final International Cooperative Ataxia Rating Scale score. CONCLUSION We confirmed cortical involvement in MJD/SCA3. The most important factors in predicting GMD were age and CAG. The lack of progression of atrophy may indicate floor effect and/or short duration of follow-up.

Peripheral neuropathy (PN) has long been recognized in Machado–Joseph disease (MJD), but its natural history is an unsettled issue. Therefore, we prospectively assessed 40 with MJD for 13 months with nerve conduction (NC) studies and the revised total neuropathy score (TNSr) to study the progression of PN. There was no significant change in the TNSr score over the follow-up period. In contrast, the average sural sensory nerve action potential (SNAP) amplitude decreased significantly over the same interval from a mean of 13.2 μV to 9.8 μV (P < 0.001). There was an inverse correlation between the change in the sural SNAP amplitude and the length of the CAG triplet repeat expansion (r = 0.574, P < 0.001). The reduction in the mean sural SNAP amplitude also correlated with progression of ataxia. This indicates that PN progresses faster in individuals with larger (CAG)n expansions, and nerve conduction studies may be useful to study disease progression in MJD. Muscle Nerve, 2009

Although ataxia is the most distressing manifestation of Machado-Joseph disease (MJD), little is known about its natural history. Therefore, we prospectively followed a cohort of patients with MJD for 13 months to characterize the progression of ataxia and identify its contributory factors. The international cooperative ataxia rating scale (ICARS) was used to estimate severity of ataxia at baseline and at follow-up. Thirty-four patients were enrolled in the study, 22 of whom were men. Mean age at onset of the disease was 34.7 years and length of expanded CAG repeat was 66. Mean ICARS scores at baseline was 37.6 and at follow-up was 42.7 (P < 0.001). Multivariate analysis did not find significant association of progression of disease and age at disease onset, length of expanded (CAG), or duration of disease.

Spinocerebellar ataxia (SCA) types 2 and 3 are autosomal-dominant neurodegenerative disorders caused by mutations in two different genes. We identified mutations for SCA2 and SCA3 segregating simultaneously in a single Brazilian family. The index patient had SCA2, whereas her two second-degree cousins had SCA3. Disease was more rapidly progressive in the SCA2 patient, who presented severe brainstem and pancerebellar atrophy, as opposed to the two SCA3 patients, who had only mild cerebellar vermian atrophy. In such situations, molecular confirmation of all patients may avoid misdiagnosis of SCA subtypes and eventual errors in predictive testing of unaffected family members.

Background and purpose Machado−Joseph disease (MJD/SCA3) is the most frequent spinocerebellar ataxia, characterized by brainstem, basal ganglia and cerebellar damage. Few magnetic resonance imaging based studies have investigated damage in the cerebral cortex. The objective was to determine whether patients with MJD/SCA3 have cerebral cortex atrophy, to identify regions more susceptible to damage and to look for the clinical and neuropsychological correlates of such lesions. Methods Forty-nine patients with MJD/SCA3 (mean age 47.7 ± 13.0 years, 27 men) and 49 matched healthy controls were enrolled. All subjects underwent magnetic resonance imaging scans in a 3 T device, and three-dimensional T1 images were used for volumetric analyses. Measurement of cortical thickness and volume was performed using the FreeSurfer software. Groups were compared using ancova with age, gender and estimated intracranial volume as covariates, and a general linear model was used to assess correlations between atrophy and clinical variables. Results Mean CAG expansion, Scale for Assessment and Rating of Ataxia (SARA) score and age at onset were 72.1 ± 4.2, 14.7 ± 7.3 and 37.5 ± 12.5 years, respectively. The main findings were (i) bilateral paracentral cortex atrophy, as well as the caudal middle frontal gyrus, superior and transverse temporal gyri, and lateral occipital cortex in the left hemisphere and supramarginal gyrus in the right hemisphere; (ii) volumetric reduction of basal ganglia and hippocampi; (iii) a significant correlation between SARA and brainstem and precentral gyrus atrophy. Furthermore, some of the affected cortical regions showed significant correlations with neuropsychological data. Conclusions Patients with MJD/SCA3 have widespread cortical and subcortical atrophy. These structural findings correlate with clinical manifestations of the disease, which support the concept that cognitive/motor impairment and cerebral damage are related in disease.