RESUMO
Multiple Sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system (CNS) characterized by damage to the myelin sheaths of oligodendrocytes. Currently, there is no specific biomarker to identify the disease; however, a diagnostic criterion has been established based on patient's clinical, laboratory, and imaging characteristics, which assists in identifying this condition. The primary method for diagnosing MS is the McDonald criteria, first described in 2001 and revised in the years 2005, 2012, and 2017. These criteria have been continuously reviewed to enhance specificity and sensitivity in the diagnosis of MS, thereby reducing errors in its differential diagnosis. An important differential diagnosis that shares overlapping features with MS, mainly the progressive forms, are leukodystrophies with demyelination as underlying pathology. Leukodystrophies comprise a rare group of genetically determined disorders that lead to either demyelination or hypomyelination of the central nervous system that can result neuroimaging changes as well as clinical findings similar to those observed in MS. Thus, systematic evaluation encompassing clinical presentation, neuroimaging findings, and laboratory metrics proves indispensable for a differential diagnosis. As such, this study aimed to establish, clearly and objectively, the similarities and differences between MS and the main demyelinating leukodystrophies. The study analyzed the parameters of the McDonald criteria, including clinical, laboratory, and magnetic resonance imaging aspects, as found in patients with leukodystrophies through scoping literature review. The data were compared with the determinations of the revised 2017 McDonald criteria to facilitate the differential diagnosis of these diseases in clinical practice.
Assuntos
Doenças Desmielinizantes , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico por imagem , Diagnóstico Diferencial , Doenças Desmielinizantes/diagnóstico , Sistema Nervoso Central , Imageamento por Ressonância Magnética/métodosRESUMO
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, <1 to 55 yars), and mean disease duration was 17 ± 12.7 years (range, 1-62 years). Compared with baseline, we did not find significant differences between groups in primary and secondary outcomes, except for reduction in adductor tone (P = 0.01). The adverse events were transient and tolerable, and their incidence did not significantly differ between treatments (P = 0.17). CONCLUSIONS: BoNT-A was safe in patients with hereditary spastic paraplegias and reduced the adductor tone, but it was not able to produce functional improvement considering the doses, injection protocol, measures, and instruments used. © 2021 International Parkinson and Movement Disorder Society.
Assuntos
Toxinas Botulínicas Tipo A , Fármacos Neuromusculares , Paraplegia Espástica Hereditária , Adolescente , Adulto , Criança , Pré-Escolar , Método Duplo-Cego , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/tratamento farmacológico , Fármacos Neuromusculares/uso terapêutico , Paraplegia Espástica Hereditária/tratamento farmacológico , Resultado do Tratamento , Adulto JovemAssuntos
Betacoronavirus/patogenicidade , Encéfalo/patologia , Infecções por Coronavirus/tratamento farmacológico , Transtornos Parkinsonianos/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Adulto , COVID-19 , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Encefalite/complicações , Encefalite/tratamento farmacológico , Feminino , Humanos , Pandemias , Transtornos Parkinsonianos/complicações , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , SARS-CoV-2RESUMO
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.
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Neuropatias Amiloides Familiares/genética , Neuropatias Amiloides Familiares/terapia , Terapia Genética , Interferência de RNA , RNA Interferente Pequeno/uso terapêutico , Animais , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Vias de Administração de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Inativação Gênica , Humanos , Oligonucleotídeos/administração & dosagem , Pré-Albumina/genética , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/efeitos adversos , RNA Interferente Pequeno/farmacocinética , Resultado do TratamentoRESUMO
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.
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Ataxia/diagnóstico , Adulto , Idoso , Ataxia/fisiopatologia , Avaliação da Deficiência , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Psicometria , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Avaliação de SintomasRESUMO
INTRODUCTION: 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). METHODS: 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). RESULTS: Mean age of patients was 50.9⯱â¯10.3 years and there were 18 men. npSN patients had higher SCOPA-Aut scores than controls (26.63⯱â¯12.72 vs. 12.66⯱â¯9.11, pâ¯<â¯.001). QSART was abnormal in 92% of the patients - sweat volumes in all examined sites were smaller among patients (pâ¯<â¯.001). Cardiovascular autonomic neuropathy was more frequent in these patients as well (pâ¯<â¯.001). CONCLUSION: 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.
Assuntos
Doenças do Sistema Nervoso Autônomo/fisiopatologia , Sistema Nervoso Autônomo/fisiopatologia , Frequência Cardíaca/fisiologia , Doenças do Sistema Nervoso Periférico/fisiopatologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reflexo/fisiologia , Manobra de ValsalvaRESUMO
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.
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Imageamento por Ressonância Magnética/métodos , Espasticidade Muscular/diagnóstico por imagem , Espasticidade Muscular/genética , Neurônios Retinianos/patologia , Análise de Sequência de DNA/métodos , Ataxias Espinocerebelares/congênito , Tomografia de Coerência Óptica/métodos , Adolescente , Adulto , Brasil/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Espasticidade Muscular/epidemiologia , Neuroimagem/métodos , Ataxias Espinocerebelares/diagnóstico por imagem , Ataxias Espinocerebelares/epidemiologia , Ataxias Espinocerebelares/genéticaRESUMO
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.
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Antiparkinsonianos/uso terapêutico , Levodopa/uso terapêutico , Mutação/genética , Transtornos Parkinsonianos , Proteínas/genética , Adulto , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Estudos de Coortes , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Feminino , Humanos , Masculino , Transtornos Mentais/etiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Compostos de Organotecnécio/farmacocinética , Transtornos Parkinsonianos/complicações , Transtornos Parkinsonianos/diagnóstico por imagem , Transtornos Parkinsonianos/tratamento farmacológico , Transtornos Parkinsonianos/genética , Método Simples-Cego , Estatísticas não Paramétricas , Tomógrafos Computadorizados , Tomografia Computadorizada de Emissão de Fóton Único , Tropanos/farmacocinética , Adulto JovemRESUMO
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 3â¯T MRI scan. Mean age and disease duration were 29 and 13.2â¯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.
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Gânglios da Base/diagnóstico por imagem , Mutação , Proteínas/genética , Paraplegia Espástica Hereditária/genética , Substância Branca/diagnóstico por imagem , Adolescente , Adulto , Imagem de Tensor de Difusão , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuroimagem , Testes Neuropsicológicos , Paraplegia Espástica Hereditária/diagnóstico por imagem , Adulto JovemRESUMO
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.