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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 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.

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

In 2018, patisiran was the first-ever RNA interference (RNAi)-based drug approved by the US Food and Drug Administration. Now pharmacology textbooks may include a new drug class that results in the effect first described by Fire and Mello 2 decades ago: post-transcriptional gene silencing by a small-interfering RNA (siRNA). Patients with hereditary transthyretin-mediated amyloidosis (hATTR amyloidosis) present with mutations in the transthyretin (TTR) gene that lead to the formation of amyloid deposits in peripheral nerves and heart. The disease may also affect the eye and central nervous system. The formulation of patisiran comprises the RNAi drug encapsulated into a nanoparticle especially developed to deliver the anti-TTR siRNA into the main TTR producer: the liver. Hepatic cells contain apolipoprotein E receptors that recognize ApoE proteins opsonized in the lipid carrier and internalize the drug by endocytosis. Lipid vesicles are disrupted in the cell cytoplasm, and siRNAs are free to trigger the RNAi-based TTR gene silencing. The silencing process involves the binding of siRNA guide strand to 3′-untranslated region sequence of both mutant and wild-type TTR messenger RNA, which culminates in the TTR mRNA cleavage by the RNA-induced silencing complex (RISC) as the first biochemical drug effect. Patisiran 0.3 mg/kg is administered intravenously every 3 weeks. Patients require premedication with anti-inflammatory drugs and antagonists of histamine H1 and H2 receptors to prevent infusion-related reactions and may require vitamin A supplementation. Following patisiran treatment, TTR knockdown remained stable for at least 2 years. Adverse effects were mild to moderate with unchanged hematological, renal, or hepatic parameters. No drug-related severe adverse effects occurred in a 24-month follow-up phase II open-label extension study. At the recommended dosage of patisiran, Cmax and AUC values (mean ± standard deviation) were 7.15 ± 2.14 μg/mL and 184 ± 159 μg·h/mL, respectively. The drug showed stability in circulation with > 95% encapsulated in lipid particles. Metabolization occurred by ribonuclease enzymes, with less than 1% excreted unchanged in the urine. Patisiran ameliorated neuropathy impairment according to the modified Neuropathy Impairment Score + 7 analysis of the phase III study. The Norfolk Quality of Life-Diabetic Neuropathy score and gait speed improved in 51% of the patisiran-treated group in 18 months. Additionally, the modified body mass index showed positive outcomes. Altogether, the data across phase I–III clinical trials points to patisiran as an effective and safe drug for the treatment of hATTR amyloidosis. It is hoped that real-world data from a larger number of patients treated with patisiran will confirm the effectiveness of this first-approved siRNA-based drug.

Sensory neuronopathies (SN) result from dorsal root ganglia damage and manifest with a combination of sensory deficits and proprioceptive ataxia. Characterization of the natural history and development of therapeutic trials are hampered by the lack of clinical scales that capture the whole spectrum of SN-related manifestations. We propose and validate a rating instrument for SN. Three experienced neuromuscular specialists developed items to rate SN. The resultant instrument was later validated by the assessment of the intra-class correlation coefficient, for inter-rater validity in 48 SN patients, and later in a smaller subset of 16 patients to assess its intra-rater validity. Standardized Crombach's alpha and Oblimin rotation analysis were performed to verify internal consistency and items' relationship, respectively. Evaluation of Sensory Ataxia Rating Scale (SEARS)'s external validity was performed by comparison to: scale for the assessment and rating of ataxia (SARA), Beck balance scale (BBS), and INCAT sensory sum score (ISS). A 10-item scale with an intra-class correlation coefficient >0.95 for intra- and inter-rating measurements with a good internal consistency (standardized Cronbach's alpha of 0.83) were observed. There was a normal distribution of the scores without a floor or ceiling effect. A moderate to good correlation between SEARS and SARA, BBS, and ISS was observed. SEARS is a reliable, easy-to-perform and consistent instrument to rate SN. Larger cohorts and multicenter studies are needed to validate its usefulness towards possible treatment trials.

The following study protocol describes the rationale and methods of a cohort with a nested case-control study, which aims to identify risk factors and predictors of cognitive dysfunction in Parkinson's disease (PD). It is a study that will follow PD every 18 months with a comprehensive neuropsychological, clinical (motor and non-motor symptoms) and imaging (Magnetic Resonance Imaging) data collection. The criteria for diagnosing mild cognitive impairment (MCI) and dementia will respect the parameters previously published by the International Working Group on Mild Cognitive Impairment, and compared with those recommended by the Fifth edition of the Diagnostic and Statistical Manual of Mental Disorders of the American Psychiatric Association (DSM-5) and the International Parkinson's and Movement Disorders Society (MDS) criteria. We will also evaluate the neural substrate and underpinnings of PD non-motor symptoms, using advanced neuroimaging techniques, such as diffusion tensor imaging (DTI) and gray matter and white matter volumetric measurements.

Sensory neuronopathies (SN) are characterized by asymmetric non-length dependent sensory deficits and sensory ataxia. Autonomic dysfunction in SN was not yet evaluated regarding its frequency, characteristics and relationship to sensory deficits. To address these issues, we performed a comprehensive clinical and neurophysiological evaluation of a large cohort of patients with non-paraneoplastic SN (np-SN).We enrolled 50 consecutive patients with npSN and 32 age/sex-matched healthy controls. They were clinically evaluated (SCOPA-Aut scale) and underwent neurophysiological autonomic assessment (quantitative sudomotor axon reflex test, heart rate variability and sympathetic skin response).Mean age of patients was 50.9 ± 10.3 years and there were 18 men. npSN patients had higher SCOPA-Aut scores than controls (26.63 ± 12.72 vs. 12.66 ± 9.11, p .001). QSART was abnormal in 92% of the patients - sweat volumes in all examined sites were smaller among patients (p .001). Cardiovascular autonomic neuropathy was more frequent in these patients as well (p .001).Altogether our results suggest that autonomic dysfunction in distinct domains is frequent in npSN patients. These findings suggest that the clinical picture of npSN is related to a double neuronopathy: sensory and autonomic.

SPG11 mutations are the most relevant cause of autosomal recessive Hereditary Spastic Paraplegia(HSP). Patients present with marked weight gain, which contrasts from caquexia generally observed in other neurodegenerative disorders. We have chosen to evaluate the hypothalamus as it is an important CNS metabolic control center. We used MRI, and manually segmented the hypothalamus in patients(n=20) and healthy controls(n=20). Also, we collected BMI data and compared SPG11 patients(n=20) against patients with Friedreich Ataxia (n=20), another neurodegenerative disease model. We found significantly higher BMI in the SPG11 group(p=0.034). Also, the SPG11 group had hypothalamic atrophy when compared to controls(p=0.030).This reinforces our hypothesis that loss of Spatacsin function might be related to abnormal metabolic control in SPG11.

Orientador: Marcondes Cavalcante França Júnior Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas Resumo: As paraparesias espásticas hereditárias (PEH) constituem um grupo heterogêneo de doenças que compartilham o aspecto clínico predominante de espasticidade e fraqueza dos membros inferiores. Dentre as formas complexas da doença o subtipo ligado ao gene SPG11 aparece como o mais prevalente, sendo pouco conhecidos os aspectos clínicos e morfológicos da doença. O presente trabalho teve como objetivos determinar a frequência relativa de PEH-SPG11 dentre os pacientes com formas complexas de PEH por meio do sequenciamento completo do exoma. Subsequentemente, os pacientes com diagnóstico molecular de PEH-SPG11 foram estudados e comparados a controles por meio de escalas clínicas padronizadas (escala de avaliação de paraplegia espástica, Inventário Neuropsiquiátrico, exame cognitivo de Addenbrooke versão revisada e Montreal Cognitive Assessment), análises multimodais de Ressonância Magnética (Freesurfer, T1 MultiAtlas, DTi MultiAtlas, Spineseg), eletroneuromiografia e estudo funcional da via nigroestriatal (Single photon emission computed tomography utilizando o radiotraçador 99mTc-TRODAT-1) visando identificar correlatos estruturais e bioquímicos das variadas manifestações clínicas da doença. Dezenove famílias com PEH foram investigadas e o diagnóstico molecular foi possível em 13 (68,4%), sendo que 6 destas (31,6%) apresentavam variantes patogênicas bialélicas no gene SPG11. A idade média e duração dos sintomas dos 25 pacientes com PEH-SPG11 foram de 29 e 13,2 anos respectivamente. Foi diagnosticada síndrome demencial em 84% dos pacientes, com um padrão frontotemporal de disfunção. A taxa anual de progressão da doença foi de 3,65 pontos na escala de avaliação de paraplegia espástica (variação de 0 a 52), sendo 64% dos probandos cadeirantes. Pudemos revelar um padrão difuso de dano microestrutural da substância branca assim como redução volumétrica dos núcleos profundos de substância cinzenta e da ME. Achados estes que contrastaram com um padrão mais restrito de atrofia cortical, acometendo regiões dos córtices motores, límbicos e parietais. A atrofia dos córtices motores, núcleos da base e medula espinhal se correlacionou com o grau de incapacidade motora. No que tange o comprometimento cognitivo, atrofia do córtex associativo, tálamo direito e dano microestrutural ao corpo caloso foram envolvidos. Neuronopatia motora foi identificada em 96% dos casos por meio da eletroneuromiografia. Correlações com variáveis temporais indicaram um acometimento progressivo da substância cinzenta e medula espinhal contrastando com um quadro aparentemente estático de disfunção da substância branca encefálica. Indicando que a haploinsuficiência do gene SPG11 caracteriza-se por vulnerabilidade neuronal seletiva, onde um distúrbio do desenvolvimento das vias de substância branca associa-se posteriormente a uma degeneração da substância cinzenta. O estudo funcional da via nigroestriatal revelou uma redução universal e simétrica da densidade de transportador de dopamina nos pacientes (N=22) em relação aos controles pareados para idade (N=19). Tal redução correlacionou-se com a duração da doença bem como com a gravidade do acometimento motor e cognitivo. Um ensaio clínico simples cego avaliou o efeito terapêutico da Levodopa em 13 indivíduos, não tendo ocorrido melhora sintomática significativa. Pudemos concluir que a degeneração nigroestriatal pré-sináptica é um fenômeno universal na SPG11, afetando inclusive os pacientes sem parkinsonismo. A ausência de resposta ao tratamento pode estar relacionada ao dano pós-sináptico adicional ou a questões metodológicas do ensaio clínico Abstract: Hereditary spastic paraplegias (HSP) are a group of neurodegenerative monogenic disorders that share key clinical aspects: spasticity and weakness of the lower limbs. SPG11 is the commonest genetic subtype among the complex cases of HSP, clinical and anatomical aspects of the disease are not fully understood. The first objective of the present study was to determine the relative frequency of HSP-SPG11 among patients with complex HSP through whole exome sequencing (WES). Subsequently, probands with confirmed HSP-SPG11 were subjected to neurological evaluation, quantification of the disease through the Spastic Paraplegia Rating Scale, characterization of cognitive deficits through Addenbrooke Cognitive Examination-Revised and Montreal Cognitive Assessment as well as evaluation of behavioral disturbances with the Neuropsychiatric Inventory. Multimodal Magnetic Ressonance Imaging (Freesurfer, T1 MultiAtlas, DTi MultiAtlas, Spineseg), electromyopgraphy and Dopamine Transporter Imaging were performed to investigate the anatomical and biochemical basis of the disease and how they correlate with clinical manifestations. Nineteen families were submitted to WES and the diagnostic yield was 68,4% (13 families), 31,6% (6 families) were affected by HSP-SPG11. Mean age and disease duration among the 25 probands with HSP-SPG11 were 29 and 13.2 years respectively. Sixty-four percent of the probands were wheelchair bound and 84% were demented with predominant frontotemporal dysfunction. The disease¿s annual rate of progression was of 3.65 points in the Spastic Paraplegia Rating Scale (range 0-52), 64% were wheelchair-bound. We could reveal a diffuse pattern of white matter (WM) integrity loss as well as deep grey matter (GM) nuclei. These findings were in contrast to a more restricted pattern of cortical thinning affecting motor, limbic and parietal regions. Motor cortices, basal ganglia and spinal cord atrophy were associated with motor handicap. Poor cognitive performance correlated with WM integrity loss at the fornices and corpus callosum as well as associative cortices and thalamic damage. In regard to neurophysiological studies, we were able to unfold a motor neuronopathy affecting 96% of the probands. Several correlations with time-related measures pointed towards a progressive degeneration of multiple GM structures and spinal cord, but not of the WM. In brief, it seems that GM and WM are distinctly affected in the disease, not only in terms of extension but also in relation to temporal course. SPG11 is characterized by selective neuronal vulnerability, where a neurodevelopmental disorder of WM is latter associated with neurodegeneration of the GM. In regard to the Nigrostriatal paths we identified a universal and symmetrical reduction of dopamine transporter among patients (N=22) in comparison with controls (N=19). Nigral degeneration correlated with disease duration, motor and cognitive handicap. Thirteen patient underwent a single-blind trial with Levodopa, no statistically significant symptomatic improvement was demonstrated. At last, we were able to conclude disruption of pre-synaptic dopaminergic pathways is a widespread phenomenon in patients with SPG11 mutations even in the absence of parkinsonism. Unresponsiveness to treatment could be related to post-synaptic damage or lack of statistical power of the trial Doutorado Fisiopatologia Médica Doutora em Ciências CNPQ 141244/2015-1

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

Friedreich’s ataxia (FDRA) is the most common inherited ataxia worldwide, caused by homozygous GAA expansions in the FXN gene. Patients usually have early onset ataxia, areflexia, Babinski sign, scoliosis and pes cavus, but at least 25 % of cases have atypical phenotypes. Disease begins after the age of 25 in occasional patients (late-onset Friedreich ataxia (LOFA)). Little is known about the frequency and clinical profile of LOFA patients. One hundred six patients with molecular confirmation of FDRA and followed in three Brazilian outpatient centers were enrolled. General demographics, GAA expansion size, age at onset, cardiac, endocrine, and skeletal manifestations were evaluated and compared between LOFA and classic FDRA (cFDRA) groups. We used Mann–Whitney and Fisher tests to compare means and proportions between groups; p values

The authors present an historical review about the main contributions of Professor Derek Denny-Brown to neurology. Some of his achievements include the first description of sensory neuronopathies, and some of the essential textbooks on the function and anatomy of the basal ganglia. In 2016, on the 35th anniversary of his death, modern neurologists are still strongly influenced by his legacy.

Background Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an important form of inherited ataxia with a varied clinical spectrum. Detailed studies of phenotype and genotype are necessary to improve diagnosis and elucidate this disorder pathogenesis. OBJECTIVE AND METHODS: To investigate the clinical phenotype, retinal architecture, neuroimaging features and genetic profile of Brazilian patients with ARSACS, we performed neurological and ophthalmological evaluation in thirteen Brazilian patients with molecularly confirmed ARSACS, and examined their mutation profiles. Optical coherence tomography protocol (OCT) consisted in peripapillary retinal nerve fiber layer (RNFL) measurement and qualitative analysis of perifoveal scans. Neuroimaging protocol accessed the frequency of atrophy in cerebellum, corpus callosum and parietal lobe, brainstem signal abnormalities, and posterior fossa arachnoid cysts. We reviewed the literature to delineate the ARSACS phenotype in the largest series worldwide. RESULTS: All patients had ataxia and spasticity, and 11/13 had peripheral neuropathy. Macular microcysts were present in two patients. Peripapillary striations, dentate appearance of inner retina and papillomacular fold were found in eleven cases. All individuals exhibited thickening of RNFL in OCT. The most frequent radiological signs were cerebellar atrophy (13/13), biparietal atrophy (12/13), and linear pontine hypointensities (13/13). Genetic analysis revealed 14 different SACS variants, of which two are novel. CONCLUSION: Macular microcysts, inner retina dentate appearance and papillomacular fold are novel retinal imaging signs of ARSACS. Ophthalmological and neuroimaging changes are common findings in Brazilian patients. The core clinical features of ARSACS are ataxia, spasticity and peripheral neuropathy with onset predominantly in the first decade of life.

Background and purpose Friedreich's ataxia (FRDA) is the most common autosomal-recessive ataxia worldwide. It is characterized by early onset, sensory abnormalities and slowly progressive ataxia. All magnetic resonance imaging (MRI)-based studies have focused on the evaluation of adult patients. Therefore, we designed a cross-sectional multimodal MRI-based study to investigate the anatomical substrates involved in the early stages of FRDA. Methods We enrolled 37 patients (12 children) and 38 controls. All subjects underwent MRI in a 3T device to assess gray and white matter. We used measures from FreeSurfer and CERES to evaluate the cerebral and cerebellar cortices. The T1 multiatlas assessed deep gray matter. The diffusion tensor imaging multiatlas was used to investigate microstructural abnormalities in brain white matter and SpineSeg was used to assess the cervical spinal cord. All analyses were corrected for multiple comparisons. Results Comparison with age-matched controls showed that pediatric patients have spinal cord, inferior cerebellar peduncle and red nucleus damage. In contrast, adult patients showed more widespread white matter damage than pediatric patients. With regard to gray matter, we found cortical thinning at the left central sulcus and volumetric reduction in the thalami and hippocampi only in adult patients. Finally, values of fractional anisotropy in adult patients and radial diffusivity in pediatric patients from the inferior cerebellar peduncle correlated with disease duration and ataxia severity, respectively. Conclusions Structural damage in FRDA begins in the spinal cord and inferior cerebellar peduncle as well as the red nucleus, and progresses to cerebral areas in adulthood. These results shed some light on the early stages of FRDA and highlight potential neuroimaging markers for therapeutic trials.

Spinocerebellar ataxia type 1 is an autosomal dominant disorder caused by a CAG repeat expansion in ATXN1, characterized by progressive cerebellar and extracerebellar symptoms. MRI-based studies in SCA1 focused in the cerebellum and connections, but there are few data about supratentorial/spinal damage and its clinical relevance. We have thus designed this multimodal MRI study to uncover the structural signature of SCA1. To accomplish that, a group of 33 patients and 33 age-and gender-matched healthy controls underwent MRI on a 3T scanner. All patients underwent a comprehensive neurological and neuropsychological evaluation. We correlated the structural findings with the clinical features of the disease. In addition, we evaluated the disease progression looking at differences in SCA1 subgroups defined by disease duration. Ataxia and pyramidal signs were the main symptoms. Neuropsychological evaluation disclosed cognitive impairment in 53% with predominant frontotemporal dysfunction. Gray matter analysis unfolded cortical thinning of primary and associative motor areas with more restricted impairment of deep structures. Deep gray matter atrophy was associated with motor handicap and poor cognition skills. White matter integrity loss was diffuse in the brainstem but restricted in supratentorial structures. Cerebellar cortical thinning was found in multiple areas and correlated not only with motor disability but also with verbal fluency. Spinal cord atrophy correlated with motor handicap. Comparison of MRI findings in disease duration-defined subgroups identified a peculiar pattern of progressive degeneration.

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.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.Patients and controls underwent single-photon emission computed tomography imaging utilizingReduced 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.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.

SPG11 mutations are the major cause of autosomal recessive Hereditary Spastic Paraplegia. The disease has a wide phenotypic variability indicating many regions of the nervous system besides the corticospinal tract are affected. Despite this, anatomical and phenotypic characterization is restricted. In the present study, we investigate the anatomical abnormalities related to SPG11 mutations and how they relate to clinical and cognitive measures. Moreover, we aim to depict how the disease course influences the regions affected, unraveling different susceptibility of specific neuronal populations. We performed clinical and paraclinical studies encompassing neuropsychological, neuroimaging, and neurophysiological tools in a cohort of twenty-five patients and age matched controls. We assessed cortical thickness (FreeSurfer software), deep grey matter volumes (T1-MultiAtlas tool), white matter microstructural damage (DTI-MultiAtlas) and spinal cord morphometry (Spineseg software) on a 3 T MRI scan. Mean age and disease duration were 29 and 13.2 years respectively. Sixty-four percent of the patients were wheelchair bound while 84% were demented. We were able to unfold a diffuse pattern of white matter integrity loss as well as basal ganglia and spinal cord atrophy. Such findings contrasted with a restricted pattern of cortical thinning (motor, limbic and parietal cortices). Electromyography revealed motor neuronopathy affecting 96% of the probands. Correlations with disease duration pointed towards a progressive degeneration of multiple grey matter structures and spinal cord, but not of the white matter. SPG11-related hereditary spastic paraplegia is characterized by selective neuronal vulnerability, in which a precocious and widespread white matter involvement is later followed by a restricted but clearly progressive grey matter degeneration., Highlights • SPG11 leads to widespread White matter (WM) and deep grey matter (GM) damage. • Cortical thinning is restricted to motor, limbic and parietal regions. • Motor Cortex thinning as well as Spinal Cord and basal ganglia atrophy correlate with motor handicap and disease duration. • WM and thalamic damage correlate with cognitive impairment. • Progressive damage of GM contrasts with an apparently static WM involvement.

The authors have constructed a brief timeline of major clinical research related to hereditary spastic paraplegia (HSP). This timeline summarizes the evolution of HSP research, from the first clinical descriptions by Adolf von Strümpell in 1880 to the present day, with the transformation of these diseases into a rapidly-growing and heterogeneous group of neurogenetic diseases. RESUMO Os autores constroem uma breve linha do tempo com as principais pesquisas clinicas relacionadas as paraplegias espásticas hereditárias. Desde a descrição clínica inicial em 1880, feita por Adolf von Strümpell, até os dias atuais com a transformação dessas doenças em um grupo de doenças neurogenéticas com grande variabilidade na apresentação fenotípica e genotípica.

Motor and non-motor manifestations are common and disabling features of hereditary spastic paraplegia (HSP). Botulinum toxin type A (Btx-A) is considered effective for spasticity and may improve gait in these patients. Little is known about the effects of Btx-A on non-motor symptoms in HSP patients. Objective To assess the efficacy of Btx-A on motor and non-motor manifestations in HSP patients. Methods Thirty-three adult patients with a clinical and molecular diagnosis of HSP were evaluated before and after Btx-A injections. Results Mean age was 41.7 ± 13.6 years and there were 18 women. Most patients had a pure phenotype and SPG4 was the most frequent genotype. The Btx-A injections resulted in a decrease in spasticity at the adductor muscles, and no other motor measure was significantly modified. In contrast, fatigue scores were significantly reduced after Btx-A injections. Conclusion Btx-A injections resulted in no significant functional motor improvement for HSP, but fatigue improved after treatment. RESUMO Manifestações motoras e não motoras são comuns e incapacitantes nas paraparesias espásticas hereditárias (PEH). Toxina botulínica do tipo A (TB-A) é considerada eficaz no tratamento da espasticidade e pode melhorar a marcha nesses pacientes. Pouco se sabe sobre os efeitos da TB-A sobre sintomas não-motores. Objetivo avaliar a eficácia da TB-A sobre manifestações motoras e não-motoras nas PEH. Método trinta e três pacientes adultos com PEH foram avaliados antes e depois das aplicações de TB-A. Resultados A média de idade foi 41,7 ± 13,6 anos e havia 18 mulheres. A maioria dos pacientes portava a forma pura e o genótipo mais comum foi SPG4. Houve diminuição da espasticidade dos músculos adutores da coxa sem melhora da marcha. A pontuação da fadiga reduziu após as injeções. Conclusão As aplicações de TB-A não melhoraram a marcha nos pacientes mas a redução da fadiga foi significativa após o tratamento.

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions. Paraplegias espásticas hereditárias (PEH) constituem um grupo de desordens geneticamente determinadas caracterizadas por espasticidade e paraparesia de progressão insidiosa. Paraplegia espástica aparentemente esporádica de início no adulto constitui problema frequente na prática neurológica. Evidências recentes sugerem que uma proporção significativa destes casos é geneticamente determinada. O grupo das PEH é dividido clinicamente em formas puras e complicadas de acordo com a concomitância de outras manifestações clinicas e neurológicas. Até o momento 60 tipos genéticos foram identificados. Todos os modos de herança monogênica já foram descritos: autossômica dominante, autossômica recessiva, ligada ao X e mitocondrial. Avanços recentes indicam que alterações do transporte axonal estão implicadas na degeneração dos longos axônios motores no sistema nervoso central na PEH. Nesta revisão abordamos recentes avanços na área com ênfase nos aspectos clínicos chave que ajudam o neurologista geral no diagnóstico e manejo correto deste grupo de doenças.

Systemic manifestations are frequent in autoimmune rheumatic diseases and include peripheral nervous system damage. Neuron cell body, axons and myelin sheath may all be affected in this context. This involvement results in severe and sometimes disabling symptoms. Sensory, motor and autonomic features may be present in different patterns that emerge as peculiar clinical pictures. Prompt recognition of these neuropathies is pivotal to guide treatment and reduce the risks of long term disability. In this review, we aim to describe the main immune-mediated neuropathies associated to rheumatic diseases: sensory neuronopathies, multiple mononeuropathies and chronic inflammatory demyelinating polyradiculoneuropathy, with an emphasis on clinical features and therapeutic options.

Hereditary spastic paraplegias (HSP) are characterized by progressive lower limb weakness and spasticity. There are no validated instruments to quantify disease severity in Portuguese. Objective To translate and validate the Spastic Paraplegia Rating Scale (SPRS) into Brazilian-Portuguese. Method Two experienced and English-fluent neurologists translated SPRS into Portuguese, creating SPRS-BR. We then assessed inter and intra-rater reliability of this version using coefficients of correlation and variability in a cohort of 30 patients. Results Mean age of patients and disease duration were 47.7 ± 10.5 and 17.0 ± 10.6 years, respectively. Twenty-one had pure HSP and SPG4 was the most frequent genotype. Mean Rankin and SPRS-BR scores were 2.2 ± 0.9 and 19.9 ± 9.9, respectively. Mean intra and inter-rater correlation coefficients of SPRS-BR scores were 0.951 and 0.934, whereas coefficients of variation were 11.5% (inter-rater) and 9.9% (intra-rater). Cronbach’s alpha for the whole SPRS-BR scale was 0.873. Conclusion SPRS-BR is a useful, reliable and valid clinical instrument.

Fatigue has been described in several neurodegenerative diseases, reducing quality of life. A systematic evaluation of this clinical feature is lacking in SCA3/MJD. The aim of this study was to evaluate the frequency and the factors associated with fatigue in SCA3/MJD. Patients with SCA3/MJD and matched healthy controls answered the Modified Fatigue Impact Scale (MFIS), Beck Inventory Depression (BDI) and Epworth Sleepiness Scale (ESS). Scale for the assessment and rating of ataxia (SARA) was used to determine ataxia severity. We used Mann-Whitney and Fisher exact tests to compare mean scores and proportions between groups. Linear regression analyses were employed to investigate factors associated with fatigue in SCA3/MJD. Seventy-four patients were included with a mean age and disease duration of 47.2 ± 12.8 and 9.5 ± 6.37 years, respectively. There were 38 men and 36 women. Mean (CAG)n was 72.2 ± 3.8. Mean MFIS score was higher in patients with SCA3/MJD (41.4 ± 16.2 vs 18.4 ± 12.9, p

Characterization of both myocardial extracellular volume expansion and myocyte mypertrophy by CMR detect early signs of myocardial tissue remodeling in Friedreich’s ataxia patients without heart failure. Otavio R Coelho-Filho, Ravi V Shah, Thiago D Venancio, Alberto R Martinez, Tomas G Neilan, Irene Righetti, Cynthia B da Silva, Ingrid Faber, Iscia Lopes-Cendes, Marcondes Franca Jr, Michael Jerosch-Herold

Introduction Electromyography (EMG) is a useful ancillary test in the diagnosis of neuromuscular disorders. EMG patterns may be helpful to identify specific subtypes of inherited muscle disease. There are few studies looking at the EMG profile in congenital myopathies, and centronuclear myopathy (CNM) in particular. The objective of this study is to describe clinical and EMG findings in patients with CNM from a tertiary Brazilian university hospital. Methods We selected all patients with pathological confirmation (muscle biopsy) of CNM and regularly followed at UNICAMP (State University of Campinas), from 2016 to 2017. Individuals with X-linked CNM were not included. For each patient, we reviewed nerve conduction studies (NCS) and EMG findings at rest and during contraction of upper and lower limbs. We looked specifically at the presence of myotonic discharges. The total score of motor function measure scale (MFM32) was employed as a clinical examination marker of disease severity. Results Eleven patients were enrolled in this study. There were six children, seven females, mean age 18.1 years when first examined in our service; a boy with 4-years-old, was the youngest and a 54-year-old lady was the oldest. The mean/median of MFM32 total score was 65.0%.The motor and sensory NCS were normal for all nerves tested. Regarding EMG and the occurrence of abnormal spontaneous activity: the myotonic discharges, when present, predominated in distal muscles: tibialis anterior and abductor pollicis brevis, and all occurred at rest. During activation, all muscles presented short duration and polyphasic motor unit action potentials without proximal or distal preferential involvement. None of the patients had clinical myotonia (either percussion or action), but electrical myotonia was found in 6 out of the 11 patients (54%). Five women and one men had clinical phenotype similar to juvenile or classical Steinert disease (DM1). Two patients had negative genetic test for the disease, and in one of the was found a mutation in the DNM2 gene. We do highlight that two patients were followed up for decades as DM1 until properly diagnosed as CNM at our hospital. Conclusion CNM must be included in the differential diagnosis of a patient with electrical, but not clinical myotonia. Clinical neurophysiologists must be aware of this profile to assist in the recognition of CNM. The frequency of abnormal spontaneous activity at EMG is similar to other studies.

Hereditary spastic paraplegia (HSP) is a diverse group of single-gene disorders that share the predominant clinical feature of progressive lower limb spasticity and weakness. More than 70 different genetic subtypes have been described and all modes of inheritance are possible. Intellectual dysfunction in HSP is frequent in recessive forms but rare in dominant families. It may manifest by either mental retardation and/or cognitive decline. The latter may be subtle, restricted to executive dysfunction or may evolve to severe dementia. The cognitive profile is thought to depend largely on the genetic subtype of HSP, although wide phenotypic variability within the same genetic subtype and also within the same family can be found. RESUMO As paraplegias espásticas hereditárias (PEH) constituem um grupo heterogêneo de doenças monogenicamente determinadas que compartilham o aspecto clínico predominante de espasticidade e fraqueza progressivos. Mais de 70 subtipos genéticos já foram identificados, sendo que todos os modos de herança são possíveis. Disfunção intelectual é frequente nas formas de herança autossômica recessiva, enquanto nos subtipos dominantes sua ocorrência é considerada rara. Tais transtornos podem se manifestar como retardo mental e/ou declínio cognitivo progressivo. O último pode ser leve, restrito a disfunção executiva, ou evoluir para demência incapacitante. Acredita-se que o perfil cognitivo dos pacientes dependa grandemente do subtipo genético, contudo, grande variabilidade fenotípica pode ser verificada dentro de um mesmo subtipo e mesmo dentro da mesma família com paraparesia espástica hereditária.