RESUMO
OBJECTIVE: Antibodies against glutamic acid decarboxylase (GAD), originally associated with stiff person syndrome (SPS), define the GAD antibody-spectrum disorders that also include cerebellar ataxia, autoimmune epilepsy, limbic encephalitis, progressive encephalomyelitis with rigidity and myoclonus (PERM), and eye movement disorders, all of which are characterized by autoimmune neuronal excitability. This article elaborates on the diagnostic criteria for SPS and SPS spectrum disorders, highlights disease mimics and misdiagnoses, describes the electrophysiologic mechanisms and underlying autoimmunity of stiffness and spasms, and provides a step-by-step therapeutic scheme. LATEST DEVELOPMENTS: Very-high serum GAD antibody titers are diagnostic for GAD antibody-spectrum disorders and also predict the presence of GAD antibodies in the CSF, increased intrathecal synthesis, and reduced CSF γ-aminobutyric acid (GABA) levels. Low serum GAD antibody titers or the absence of antibodies generates diagnostic challenges that require careful distinction in patients with a variety of painful spasms and stiffness, including functional neurologic disorders. Antibodies against glycine receptors, first found in patients with PERM, are seen in 13% to 15% of patients with SPS, whereas amphiphysin and gephyrin antibodies, seen in 5% of patients with SPS spectrum disorders, predict a paraneoplastic association. GAD-IgG from different SPS spectrum disorders recognizes the same dominant GAD intracellular epitope and, although the pathogenicity is unclear, is an excellent diagnostic marker. The biological basis of muscle stiffness and spasms is related to autoimmune neuronal hyperexcitability caused by impaired reciprocal γ-aminobutyric acid-mediated (GABA-ergic) inhibition, which explains the therapeutic response to GABA-enhancing agents and immunotherapies. ESSENTIAL POINTS: It is essential to distinguish SPS spectrum disorders from disease mimics to avoid both overdiagnoses and misdiagnoses, considering that SPS is treatable if managed correctly from the outset to prevent disease progression. A step-by-step, combination therapy of GABA-enhancing medications along with immunotherapies ensures prolonged clinical benefits.
Assuntos
Autoanticorpos , Glutamato Descarboxilase , Rigidez Muscular Espasmódica , Humanos , Rigidez Muscular Espasmódica/diagnóstico , Rigidez Muscular Espasmódica/imunologia , Rigidez Muscular Espasmódica/fisiopatologia , Rigidez Muscular Espasmódica/sangue , Glutamato Descarboxilase/imunologia , Autoanticorpos/sangue , Masculino , Feminino , Rigidez Muscular/diagnóstico , Rigidez Muscular/imunologia , Rigidez Muscular/tratamento farmacológico , Encefalomielite/diagnóstico , Encefalomielite/imunologia , Encefalomielite/sangue , Pessoa de Meia-Idade , Adulto , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/imunologia , Ataxia Cerebelar/sangue , Ataxia Cerebelar/fisiopatologia , Encefalite Límbica/diagnóstico , Encefalite Límbica/imunologia , Encefalite Límbica/terapia , Encefalite Límbica/sangue , Encefalite Límbica/fisiopatologiaRESUMO
OBJECTIVES: Seizure-related 6 homolog like 2 (SEZ6L2) antibody-associated ataxia is an extremely rare disease. Six patients have been reported and none of them improved significantly with immunotherapy. Herein, we present the case of a patient with cerebellar ataxia and SEZ6L2 antibodies who benefited from immunotherapy, which dramatically altered the course of her disease. METHODS: We present a case report of a 73-year-old woman with progressive balance problems. Her condition had rapidly deteriorated in the 2 weeks before the admission to our hospital leading to repeated falls and eventually left her bed-ridden. RESULTS: She presented with severe trunk ataxia, bidirectional nystagmus, dysarthric speech, and persistent nausea. With the exception of cerebellar atrophy, extensive imaging studies revealed no pathology. SEZ6L2 antibodies were found in both CSF and serum. Over a period of 9 months, our patient received immunotherapy consisting of steroid pulse therapy, IV immunoglobulin infusions, rituximab, and cyclophosphamide. Consequently, her condition improved markedly, and she was discharged home from the neurologic rehabilitation unit. DISCUSSION: Our case report shows that intense sequential immunotherapy may considerably improve level of functioning in some patients with SEZ6L2 antibody-associated cerebellar ataxia. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is a single observational study without controls.
Assuntos
Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/imunologia , Fatores Imunológicos/farmacologia , Proteínas de Membrana/imunologia , Idoso , Ataxia Cerebelar/sangue , Ataxia Cerebelar/líquido cefalorraquidiano , Feminino , Humanos , ImunoterapiaRESUMO
Mutations in ITPR1 cause ataxia and aniridia in individuals with Gillespie syndrome (GLSP). However, the pathogenic mechanisms underlying aniridia remain unclear. We identified a de novo GLSP mutation hotspot in the 3'-region of ITPR1 in five individuals with GLSP. Furthermore, RNA-sequencing and immunoblotting revealed an eye-specific transcript of Itpr1, encoding a 218amino acid isoform. This isoform is localized not only in the endoplasmic reticulum, but also in the nuclear and cytoplasmic membranes. Ocular-specific transcription was repressed by SOX9 and induced by MAF in the anterior eye segment (AES) tissues. Mice lacking seven base pairs of the last Itpr1 exon exhibited ataxia and aniridia, in which the iris lymphatic vessels, sphincter and dilator muscles, corneal endothelium and stroma were disrupted, but the neural crest cells persisted after completion of AES formation. Our analyses revealed that the 218-amino acid isoform regulated the directionality of actin fibers and the intensity of focal adhesion. The isoform might control the nuclear entry of transcriptional regulators, such as YAP. It is also possible that ITPR1 regulates both AES differentiation and muscle contraction in the iris.
Assuntos
Aniridia/sangue , Aniridia/genética , Segmento Anterior do Olho/crescimento & desenvolvimento , Ataxia Cerebelar/sangue , Ataxia Cerebelar/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Deficiência Intelectual/sangue , Deficiência Intelectual/genética , Mutação , Crista Neural/crescimento & desenvolvimento , Adolescente , Animais , Segmento Anterior do Olho/metabolismo , Criança , Pré-Escolar , Modelos Animais de Doenças , Éxons , Feminino , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Células NIH 3T3 , Crista Neural/metabolismo , Isoformas de Proteínas/metabolismo , Transfecção , Adulto JovemRESUMO
In the current study we report a novel autoantibody against Purkinje cells in a patient with primary autoimmune cerebellar ataxia (PACA) associated with Sjogren's syndrome (SS). Tissue-based indirect immunofluorescence assay (TBA) of the patient's serum and cerebrospinal fluid (CSF) revealed IgG antibody to Purkinje cells and the granular layer of the rat cerebellum. Rab6A was identified as autoantigen by mass spectrometry (MS) and Western blotting, and the interactions between Rab6A or its homologous Rab6B and autoantibody in patient serum were verified by recombinant cell-based assay (CBA) and neutralization experiments. This autoantibody may represent a novel biomarker in the diagnosis of PACA.
Assuntos
Autoanticorpos/sangue , Ataxia Cerebelar/sangue , Síndrome de Sjogren/sangue , Proteínas rab de Ligação ao GTP/sangue , Adulto , Animais , Ataxia Cerebelar/complicações , Ataxia Cerebelar/diagnóstico por imagem , Feminino , Células HEK293 , Humanos , Ratos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/diagnóstico por imagemRESUMO
Acquired cerebellar ataxia is a rare, in many cases immune-modulated and paraneoplastic illness. Acute and slowly progredient processes are possible. An early treatment is important for a good clinical outcome. Here we present the case of female patient in her 60s with an antirecoverin associated cerebellitis without retinopathia and neoplasia. After an immunosuppressive therapy with steroids and rituximab the symptoms improved, and the progression could be stopped.
Assuntos
Autoanticorpos/sangue , Ataxia Cerebelar/diagnóstico , Marcha Atáxica/diagnóstico , Imunossupressores/uso terapêutico , Recoverina/imunologia , Idade de Início , Autoanticorpos/imunologia , Ataxia Cerebelar/sangue , Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/imunologia , Cerebelo/diagnóstico por imagem , Cerebelo/imunologia , Tecnologia de Rastreamento Ocular , Feminino , Marcha Atáxica/sangue , Marcha Atáxica/tratamento farmacológico , Marcha Atáxica/imunologia , Glucocorticoides/uso terapêutico , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imageamento por Ressonância Magnética , Pessoa de Meia-Idade , Rituximab/uso terapêuticoRESUMO
Combined checkpoint inhibition therapy targeting the programmed cell death 1 (PD-L1) and cytotoxic T-lymphocyte associated protein 4 pathways has been a successful approach in the treatment of metastatic melanoma, leading to its investigation in the treatment of head and neck squamous cell carcinoma (HNSCC) with PD-L1 expression. Despite the potential for excellent responses, an increased rate of autoimmune neurological toxicity and paraneoplastic conditions has been observed when using these treatment modalities. We present the case of a patient with metastatic HNSCC treated with combination ipilimumab/nivolumab who experienced severe cerebellar ataxia with a positive screen for the anti-Zic4 antibody. This is the first case, to our knowledge, of anti-Zic4 antibody-mediated cerebellar toxicity reported in association with HNSCC. Although the patient experienced an impressive partial response with dual checkpoint inhibition, he suffered grade 4 neurotoxicity. Despite exciting advances in cancer immunotherapy, clinicians must be aware of the rare, debilitating and possibly previously undescribed paraneoplastic and autoimmune toxicities that may occur.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Ataxia Cerebelar/imunologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Pulmonares/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Adulto , Autoanticorpos/sangue , Autoanticorpos/imunologia , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Broncoscopia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Ataxia Cerebelar/sangue , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/tratamento farmacológico , Cerebelo/diagnóstico por imagem , Cerebelo/imunologia , Quimiorradioterapia/efeitos adversos , Quimiorradioterapia/métodos , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Glucocorticoides/administração & dosagem , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Ipilimumab/efeitos adversos , Pulmão/diagnóstico por imagem , Pulmão/patologia , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/secundário , Imageamento por Ressonância Magnética , Masculino , Proteínas do Tecido Nervoso/imunologia , Nivolumabe/efeitos adversos , Uso Off-Label , Rituximab/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Fatores de Transcrição/imunologia , Resultado do TratamentoRESUMO
A 30-year-old woman presented with recurrent hiccups, vomiting and painful diminution of vision and gait instability for 1 day. She had one-and-a-half syndrome, bilateral seventh cranial nerve paresis with bilateral symptomatic optic neuritis and left-sided ataxic haemiparesis. We described her disorder as the 'twenty syndrome' (11/2+7+7+2+2+½=20). MRI of her brain revealed demyelination predominantly in right posterolateral aspect of pons, medulla and bilateral optic nerves. Serum antiaquaporin-4 antibody came out positive. Thus, she was diagnosed as neuromyelitis optica spectrum disorder (NMOSD). She responded brilliantly to immunosuppressive therapy. This is the first ever reported case of the 'twenty syndrome' secondary to cerebral NMOSD.
Assuntos
Ataxia Cerebelar/imunologia , Paralisia Facial/imunologia , Imunossupressores/uso terapêutico , Neuromielite Óptica/diagnóstico , Transtornos da Motilidade Ocular/imunologia , Neurite Óptica/imunologia , Adulto , Aquaporina 4/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Ataxia Cerebelar/sangue , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/tratamento farmacológico , Paralisia Facial/sangue , Paralisia Facial/diagnóstico , Paralisia Facial/tratamento farmacológico , Feminino , Humanos , Imageamento por Ressonância Magnética , Neuromielite Óptica/sangue , Neuromielite Óptica/complicações , Neuromielite Óptica/imunologia , Transtornos da Motilidade Ocular/sangue , Transtornos da Motilidade Ocular/diagnóstico , Transtornos da Motilidade Ocular/tratamento farmacológico , Nervo Óptico/diagnóstico por imagem , Nervo Óptico/imunologia , Neurite Óptica/sangue , Neurite Óptica/diagnóstico , Neurite Óptica/tratamento farmacológico , Tegmento Pontino/diagnóstico por imagem , Tegmento Pontino/imunologia , Síndrome , Resultado do TratamentoRESUMO
OBJECTIVE: Antibodies against glutamic acid decarboxylase 65 (anti-GAD65) are associated with a number of neurologic syndromes. However, their pathogenic role is controversial. Our objective was to describe clinical and paraclinical characteristics of anti-GAD65 patients and analyze their response to immunotherapy. METHODS: Retrospectively, we studied patients (n = 56) with positive anti-GAD65 and any neurologic symptom. We tested serum and CSF with ELISA, immunohistochemistry, and cell-based assay. Accordingly, we set a cutoff value of 10,000 IU/mL in serum by ELISA to group patients into high-concentration (n = 36) and low-concentration (n = 20) groups. We compared clinical and immunologic features and analyzed response to immunotherapy. RESULTS: Classical anti-GAD65-associated syndromes were seen in 34/36 patients with high concentration (94%): stiff-person syndrome (7), cerebellar ataxia (3), chronic epilepsy (9), limbic encephalitis (9), or an overlap of 2 or more of the former (6). Patients with low concentrations had a broad, heterogeneous symptom spectrum. Immunotherapy was effective in 19/27 treated patients (70%), although none of them completely recovered. Antibody concentration reduction occurred in 15/17 patients with available pre- and post-treatment samples (median reduction 69%; range 27%-99%), of which 14 improved clinically. The 2 patients with unchanged concentrations showed no clinical improvement. No differences in treatment responses were observed between specific syndromes. CONCLUSION: Most patients with high anti-GAD65 concentrations (>10,000 IU/mL) showed some improvement after immunotherapy, unfortunately without complete recovery. Serum antibody concentrations' course might be useful to monitor response. In patients with low anti-GAD65 concentrations, especially in those without typical clinical phenotypes, diagnostic alternatives are more likely.
Assuntos
Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso , Ataxia Cerebelar , Epilepsia , Glutamato Descarboxilase/imunologia , Encefalite Límbica , Avaliação de Resultados em Cuidados de Saúde , Rigidez Muscular Espasmódica , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/sangue , Doenças Autoimunes do Sistema Nervoso/tratamento farmacológico , Doenças Autoimunes do Sistema Nervoso/fisiopatologia , Ataxia Cerebelar/sangue , Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/fisiopatologia , Criança , Pré-Escolar , Epilepsia/sangue , Epilepsia/tratamento farmacológico , Epilepsia/fisiopatologia , Feminino , Humanos , Imunoterapia , Encefalite Límbica/sangue , Encefalite Límbica/tratamento farmacológico , Encefalite Límbica/fisiopatologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Rigidez Muscular Espasmódica/sangue , Rigidez Muscular Espasmódica/tratamento farmacológico , Rigidez Muscular Espasmódica/fisiopatologia , Adulto JovemRESUMO
BACKGROUND: Dilated cardiomyopathy with ataxia syndrome (DCMA) is an understudied autosomal recessive disease caused by loss-of-function mutations in the poorly characterized gene DNAJC19. Clinically, DCMA is commonly associated with heart failure and early death in affected children through an unknown mechanism. DCMA has been linked to Barth syndrome, a rare but well-studied disorder caused by deficient maturation of cardiolipin (CL), a key mitochondrial membrane phospholipid. METHODS: Peripheral blood mononuclear cells from 2 children with DCMA and severe cardiac dysfunction were reprogrammed into induced pluripotent stem cells (iPSCs). Patient and control iPSCs were differentiated into beating cardiomyocytes (iPSC-CMs) using a metabolic selection strategy. Mitochondrial structure and CL content before and after incubation with the mitochondrially targeted peptide SS-31 were quantified. RESULTS: Patient iPSCs carry the causative DNAJC19 mutation (rs137854888) found in the Hutterite population, and the iPSC-CMs demonstrated highly fragmented and abnormally shaped mitochondria associated with an imbalanced isoform ratio of the mitochondrial protein OPA1, an important regulator of mitochondrial fusion. These abnormalities were reversible by incubation with SS-31 for 24 hours. Differentiation of iPSCs into iPSC-CMs increased the number of CL species observed, but consistent, significant differences in CL content were not seen between patients and control. CONCLUSIONS: We describe a unique and novel cellular model that provides insight into the mitochondrial abnormalities present in DCMA and identifies SS-31 as a potential therapeutic for this devastating disease.
Assuntos
Cardiomiopatia Dilatada/sangue , Ataxia Cerebelar/sangue , Células-Tronco Pluripotentes Induzidas , Leucócitos Mononucleares/citologia , Erros Inatos do Metabolismo/sangue , Mitocôndrias Cardíacas/fisiologia , Miopatias Mitocondriais/sangue , Miócitos Cardíacos , Diferenciação Celular , Células Cultivadas , HumanosRESUMO
Background: Ataxias represent a challenging group of disorders due to significant clinical overlap. Here, we present a patient with early-onset progressive ataxia, polyneuropathy and discuss how elevation of alpha fetoprotein (AFP) narrows the differential diagnosis. Case report: Ataxia, polyneuropathy, and mild elevation of AFP are features compatible with ataxia with oculomotor apraxia type 2 (AOA2) but also with ataxia with oculomotor apraxia type 4 (AOA4). A genetic analysis demonstrated biallelic mutations in senataxin (SETX), confirming the diagnosis of AOA2. Discussion: Mild elevation of AFP is found in patients with AOA2 and AOA4, and higher levels are commonly seen in ataxia-telangiectasia. AFP is a useful diagnostic tool but not a biomarker for disease progression in AOA2.
Assuntos
Ataxia Cerebelar/sangue , Ataxia Cerebelar/diagnóstico por imagem , Progressão da Doença , alfa-Fetoproteínas/metabolismo , Adulto , Biomarcadores/sangue , Ataxia Cerebelar/genética , Feminino , Humanos , alfa-Fetoproteínas/genéticaRESUMO
Background: Antibodies against glutamic acid decarboxylase (GAD) are associated with Stiff Person Syndrome (SPS). Case report: A 50-year-old woman presented with symptoms progressed over 9 years, resulting in a cerebellar ataxia and right upper limb tremor. Investigations revealed elevated serum and CSF anti-GAD antibody titres (98.6 and 53.4 µ/ml, respectively). Treatment included intravenous immunoglobulin and immunomodulation (infliximab and rituximab), improving her stiffness, but with no impact on the ataxia-related symptoms. Subsequent high-dose steroids led to diabetic ketoacidosis and unmasking of an insulin-dependent diabetes mellitus. Discussion: This case illustrates several key features: (1) the combined clinical picture of SPS and cerebellar ataxia is a rare phenotype associated with anti-GAD antibodies; (2) the cerebellar ataxia described was progressive and poorly responsive to immunomodulatory therapy; and (3) the potential for development of further autoimmune sequelae in response to immunosuppression, namely, the development of insulin-dependent diabetes in response to treatment with high-dose oral steroids.
Assuntos
Autoanticorpos , Ataxia Cerebelar/diagnóstico , Ataxia Cerebelar/tratamento farmacológico , Glutamato Descarboxilase , Rigidez Muscular Espasmódica/diagnóstico , Rigidez Muscular Espasmódica/tratamento farmacológico , Autoanticorpos/sangue , Ataxia Cerebelar/sangue , Feminino , Glutamato Descarboxilase/sangue , Humanos , Imunoglobulinas Intravenosas/administração & dosagem , Pessoa de Meia-Idade , Rigidez Muscular Espasmódica/sangueRESUMO
To report three cases of autoimmune ataxia patients with positive neurochondrin (NCDN) antibodies. Patients with unknown cerebellar ataxia were screened for autoimmune cerebellar ataxia (ACA)-related antibodies, including glutamic acid decarboxylase 65 (GAD65), delta/notch-like epidermal growth factor-related receptor (Tr/DNER), zinc finger protein 4 (ZIC4), inositol 1,4,5-triphosphate receptor 1 (ITPR1), Homer protein homologue 3 (Homer-3), neurochondrin (NCDN), Purkinje cell antibody 2 (PCA-2) and carbonic anhydrase-related protein VII (CARPVII). The antibodies were assessed by indirect immunofluorescence using transfected cells (cell-based assay, CBA) and monkey cerebellum (tissue-based assay, TBA) with the multi-antigen co-plate biochip mosaic technique. Patients with positive antibodies received immunotherapy and were followed up in the clinic. Clinical characteristics, laboratory data, and outcomes of antibody-positive patients were described, analysed and compared with previously reported cases. The NCDN antibody was positive in three male patients in whom the onset ages were four years and 11 months, two years and seven months and 67 years old. Serum antibody titres were 1:32, 1:100 and 1:320. Cerebral ataxia was the most prominent presentation. Cerebellar atrophy was found in one of the patients. Immunotherapy was effective in all three patients. The NCDN antibody is associated with autoimmune ataxia, and it has been suggested that the NCDN antibody should be tested in patients with cerebellar ataxia who are negative for routine ACA antibodies. Early immunotherapy may have a beneficial impact on prognosis.
Assuntos
Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/diagnóstico por imagem , Ataxia Cerebelar/sangue , Ataxia Cerebelar/diagnóstico por imagem , Proteínas do Tecido Nervoso/sangue , Idoso , Biomarcadores/sangue , Pré-Escolar , Humanos , MasculinoRESUMO
Anti-Homer-3 antibody associated cerebellar ataxia is a rare autoimmune cerebellar ataxia, which had been previously reported in 2 cases only. Here we present the third case where a middle-aged female experienced progressive cerebellar ataxia. A novel cerebellar ataxia antibody panel indicated sera of the patient was positive for anti-Homer-3 antibodies and established the diagnosis. Given steroids and long-term mycophenolate mofetil, the patient experienced partial improvement and remained stable in the follow-ups. Our report indicated immune-mediated causes should be considered in the context of 'idiopathic' cerebellar ataxia and immunotherapy could have therapeutic effects.
Assuntos
Autoanticorpos/sangue , Ataxia Cerebelar/sangue , Ataxia Cerebelar/diagnóstico por imagem , Proteínas de Arcabouço Homer/sangue , Feminino , Humanos , Pessoa de Meia-IdadeAssuntos
Ataxia Cerebelar/induzido quimicamente , Ayurveda/efeitos adversos , Intoxicação por Mercúrio/complicações , Mercúrio/sangue , Adulto , Ataxia Cerebelar/sangue , Ataxia Cerebelar/tratamento farmacológico , Quelantes/uso terapêutico , Dimercaprol/uso terapêutico , Humanos , Masculino , Intoxicação por Mercúrio/sangue , Intoxicação por Mercúrio/tratamento farmacológico , Resultado do TratamentoRESUMO
Oxygen is the most mandatory component of living organism and it may at times produce highly reactive species, the free radicals, which are destructive to normal living tissues. Degenerative diseases of central nervous system (CNS) are quite common, contributing significantly to morbidity as well as mortality %. In neurodegenerative diseases such as motor neuron disease (MND), Cerebellar Ataxia (CA) and Parkinson's disease (PD), there is no direct evidence for involvement of metals and free radicals in the etiology but circumstantial evidence provides a hypothesis that alteration in metals and free radicals contribute to the pathogenesis of neurodegeneration in these disorders. The aim of the present study was to estimate free radicals cascade i.e. damage caused in terms of malondialdehyde (MDA) and defense system Superoxide dismutase (SOD) and catalase in blood and cerebro-spinal fluid (CSF) of neurodegenerative diseases (MND, CA and PD), to analyze correlation with level of free radical and the clinical variables like age, severity of diseases and duration of illness and any possibility from this clinical parameters to identify a biomarker for diagnosis of neurodegenerative diseases. The level of MDA in CSF was 0.46⯱â¯0.17 in case of MND, 0.49⯱â¯0.13 in case of CA and 0.47⯱â¯0.16 in case of PD as compared control group (0.22⯱â¯0.06) whereas in blood MDA level was 0.10⯱â¯0.04 in case of MND, 0.33⯱â¯0.41 in case of CA and 0.47⯱â¯0.46 in case of PD as compared control group (0.04⯱â¯0.03). It was found to be highly significant (pâ¯<â¯.001). In CSF and blood both catalase activity was statistically significantly higher as compared to control group of all cases (MND, CA and PD) and SOD activity was statistically significantly lower as compared to control group of all cases. Free radical parameters in human CSF might be a novel biomarker for the early clinical identification of neurodegenerative diseases.
Assuntos
Ataxia Cerebelar/sangue , Doença dos Neurônios Motores/sangue , Doença de Parkinson/sangue , Adolescente , Adulto , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Gluten sensitivity refers to prominent immunological responses to gluten, usually in conjunction with elevated levels of serum antigliadin antibody (AGA). The association between AGA and cerebellar ataxias has been inconsistently reported. METHODS: We performed a systematic literature search and a meta-analysis to study the weighted pooled OR of idiopathic cerebellar ataxia (IDCA) cases to controls or to hereditary ataxia (HA) for AGA seropositivity using fixed effect model. RESULTS: Eleven studies were included, with a total of 847 IDCA cases, 1654 controls and 445 HA cases. IDCA cases had fourfold higher odds than controls (OR 4.28, 95% CI 3.10 to 5.90) and twofold higher odds than HA cases (OR 2.23, 95% CI 1.45 to 3.44) of having AGA seropositivity. Sensitivity analysis excluding the most weighted study, which accounted for 69% of the total weight, still showed similar associations (IDCA vs controls, OR 3.18, 95% CI 1.79 to 5.67 and IDCA vs HA, OR 1.72, 95% CI 1.03 to 2.86, respectively). The subgroup analysis showed that, when compared with controls, IDCA cases of both East Asian and Western countries had approximately threefold to fourfold higher odds to have AGA seropositivity (OR 3.41, 95% CI 1.67 to 6.97 and OR 4.53, 95% CI 3.16 to 6.49, respectively), suggesting the lack of ethnic heterogeneity. The odds of AGA seropositivity for HA cases was not significantly higher than controls (OR 1.41, 95% CI 0.82 to 2.44). CONCLUSION: Our study indicates the association between AGA and IDCA, across different geographic regions.
Assuntos
Anticorpos/sangue , Ataxia Cerebelar/imunologia , Gliadina/imunologia , Ataxia Cerebelar/sangue , HumanosAssuntos
Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/imunologia , Ataxia Cerebelar/imunologia , Proteínas de Membrana/imunologia , Receptores de AMPA/imunologia , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/sangue , Proteínas de Ligação a Calmodulina/imunologia , Ataxia Cerebelar/sangue , Células HeLa , Humanos , Immunoblotting , Imunoprecipitação , Ligação ProteicaRESUMO
Background: Anti-GAD-related cerebellar ataxia has rarely been described as an acute cause of autoimmune ataxia. Phenomenology Shown: A young female who acutely developed anti-GAD-associated ataxia with magnetic resonance imaging (MRI) showing cerebellar edema and follow-up MRI 6 months later showing cerebellar atrophy. Educational Value: Recognizing that anti-GAD-associated cerebellar ataxia can present in a young adult as an acute and severe cause of ataxia, with cerebellar changes evident on MRI.
Assuntos
Autoanticorpos/sangue , Ataxia Cerebelar/sangue , Ataxia Cerebelar/diagnóstico por imagem , Glutamato Descarboxilase/sangue , Biomarcadores/sangue , Feminino , Humanos , Adulto JovemRESUMO
BACKGROUND: Myelin-associated glycoprotein (MAG) is a glycoprotein specific to Schwann cells. Schwann cells produce myelin for nerve cells in the peripheral nervous system. MAG also plays a role in the central nervous system (CNS) by maintaining myelin integrity and inhibiting axonal regeneration from cerebellar neurons. There is a well-established link between distal demyelinating neuropathy and anti-MAG antibodies in patients with monoclonal gammopathy of unknown significance. We describe a series of five patients with anti-MAG antibodies with evidence of cerebellar rather than just sensory ataxia and our experience of treatment with rituximab. METHODS: Cerebellar ataxia was clinically suspected and confirmed using magnetic resonance spectroscopy (MRS) of the cerebellum. All patients underwent detailed nerve conduction studies. RESULTS: Four patients were males. The ages ranged from 64 to 82 years. All patients were anti-MAG positive and also had IgM monoclonal gammopathy. Four patients had neuropathy, whilst one had no evidence of neuropathy. All patients were treated with rituximab and showed improvement in the MRS parameters of the cerebellum. CONCLUSION: Anti-MAG antibodies might be involved in the pathogenesis of idiopathic sporadic ataxias, even in the absence of peripheral neuropathy. Rituximab seems to be a promising therapeutic intervention for those cases.
Assuntos
Autoanticorpos/sangue , Ataxia Cerebelar/sangue , Fatores Imunológicos/uso terapêutico , Glicoproteína Associada a Mielina/imunologia , Rituximab/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Ataxia Cerebelar/diagnóstico por imagem , Creatina/metabolismo , Humanos , Imageamento por Ressonância Magnética , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Condução Nervosa/efeitos dos fármacos , Condução Nervosa/fisiologiaRESUMO
In 2010, a novel anti-neuronal autoantibody, termed anti-Ca, was described in a patient with subacute cerebellar ataxia, and Rho GTPase-activating protein 26 (ARHGAP26) was identified as the target antigen. Recently, three additional cases of anti-Ca-positive cerebellar ataxia have been published. In addition to ataxia, cognitive decline and depression have been observed in some patients. Here, we report two new cases of anti-Ca-associated autoimmune cerebellar ataxia. Patient 1 presented with dizziness and acute yet mild limb and gait ataxia. Symptoms stabilized with long-term oral corticosteroid therapy but transiently worsened when steroids were tapered. Interestingly, both initial occurrence and worsening of the patient's neurological symptoms after steroid withdrawal were accompanied by spontaneous cutaneous hematomas. Patient 2 initially presented with an increased startle response and myoclonic jerks, and subsequently developed severe limb and gait ataxia, dysarthria, oculomotor disturbances, head and voice tremor, dysphagia, cognitive symptoms and depression. Steroid treatment was started five years after disease onset. The symptoms then responded only poorly to corticosteroids. At most recent follow-up, 19 years after disease onset, the patient was wheelchair-bound. These cases extend the clinical spectrum associated with anti-ARHGAP26 autoimmunity and suggest that early treatment may be important in patients with this rare syndrome.