RESUMO
OBJECTIVES: To approximate the rate of familial myasthenia gravis and the coexistence of other autoimmune disorders in the patients and their families. DESIGN: Retrospective cohort study. SETTING: Clinics across North America. PARTICIPANTS: The study included 1032 patients diagnosed with acetylcholine receptor antibody (AChR)-positive myasthenia gravis. METHODS: Phenotype information of 1032 patients diagnosed with AChR-positive myasthenia gravis was obtained from clinics at 14 centres across North America between January 2010 and January 2011. A critical review of the epidemiological literature on the familial rate of myasthenia gravis was also performed. RESULTS: Among 1032 patients, 58 (5.6%) reported a family history of myasthenia gravis. A history of autoimmune diseases was present in 26.6% of patients and in 28.4% of their family members. DISCUSSION: The familial rate of myasthenia gravis was higher than would be expected for a sporadic disease. Furthermore, a high proportion of patients had a personal or family history of autoimmune disease. Taken together, these findings suggest a genetic contribution to the pathogenesis of myasthenia gravis.
Assuntos
Miastenia Gravis , Autoanticorpos , Humanos , Miastenia Gravis/epidemiologia , Miastenia Gravis/genética , América do Norte/epidemiologia , Receptores Colinérgicos , Estudos RetrospectivosRESUMO
Complementary and alternative treatment modalities are commonly utilized by patients for neuropathy and neuropathic pain due to perceived lack of benefit from conventional medical treatment. As the association between metabolic syndrome and neuropathy is increasingly recognized, diet and lifestyle interventions are becoming important components in the management of neuropathy. Progress in the understanding of the gut-immune interaction highlights the role the gut microbiome and inflammation plays in the modulation of neuropathy and neuropathic pain. Evidence for nutritional interventions, exercise, supplements, acupuncture, and mindfulness-based practices in the treatment of neuropathic pain is encouraging. This article reviews the available evidence to support the safe use of complementary and alternative treatments for commonly encountered conditions associated with neuropathy and neuropathic pain. Muscle Nerve 60: 124-136, 2019.
Assuntos
Dietoterapia , Suplementos Nutricionais , Terapia por Exercício , Estilo de Vida , Neuralgia/terapia , Doenças do Sistema Nervoso Periférico/terapia , Complexo Vitamínico B/uso terapêutico , Acetilcarnitina/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Curcumina/uso terapêutico , Dieta , Disbiose/metabolismo , Exercício Físico , Ácidos Graxos Ômega-3/uso terapêutico , Ácido Fólico/análogos & derivados , Ácido Fólico/uso terapêutico , Microbioma Gastrointestinal , Humanos , Medicina Integrativa , Síndrome Metabólica/metabolismo , Neuralgia/metabolismo , Doenças do Sistema Nervoso Periférico/metabolismo , Fosfato de Piridoxal/uso terapêutico , Ácido Tióctico/uso terapêutico , Vitamina B 12/análogos & derivados , Vitamina B 12/uso terapêutico , Complexo Vitamínico B/metabolismo , Deficiência de Vitaminas do Complexo B , Vitamina D/uso terapêuticoRESUMO
IMPORTANCE: Myasthenia gravis is a chronic, autoimmune, neuromuscular disease characterized by fluctuating weakness of voluntary muscle groups. Although genetic factors are known to play a role in this neuroimmunological condition, the genetic etiology underlying myasthenia gravis is not well understood. OBJECTIVE: To identify genetic variants that alter susceptibility to myasthenia gravis, we performed a genome-wide association study. DESIGN, SETTING, AND PARTICIPANTS: DNA was obtained from 1032 white individuals from North America diagnosed as having acetylcholine receptor antibody-positive myasthenia gravis and 1998 race/ethnicity-matched control individuals from January 2010 to January 2011. These samples were genotyped on Illumina OmniExpress single-nucleotide polymorphism arrays. An independent cohort of 423 Italian cases and 467 Italian control individuals were used for replication. MAIN OUTCOMES AND MEASURES: We calculated P values for association between 8,114,394 genotyped and imputed variants across the genome and risk for developing myasthenia gravis using logistic regression modeling. A threshold P value of 5.0×10(-8) was set for genome-wide significance after Bonferroni correction for multiple testing. RESULTS: In the overall case-control cohort, we identified association signals at CTLA4 (rs231770; P=3.98×10(-8); odds ratio, 1.37; 95% CI, 1.25-1.49), HLA-DQA1 (rs9271871; P=1.08×10(-8); odds ratio, 2.31; 95% CI, 2.02-2.60), and TNFRSF11A (rs4263037; P=1.60×10(-9); odds ratio, 1.41; 95% CI, 1.29-1.53). These findings replicated for CTLA4 and HLA-DQA1 in an independent cohort of Italian cases and control individuals. Further analysis revealed distinct, but overlapping, disease-associated loci for early- and late-onset forms of myasthenia gravis. In the late-onset cases, we identified 2 association peaks: one was located in TNFRSF11A (rs4263037; P=1.32×10(-12); odds ratio, 1.56; 95% CI, 1.44-1.68) and the other was detected in the major histocompatibility complex on chromosome 6p21 (HLA-DQA1; rs9271871; P=7.02×10(-18); odds ratio, 4.27; 95% CI, 3.92-4.62). Association within the major histocompatibility complex region was also observed in early-onset cases (HLA-DQA1; rs601006; P=2.52×10(-11); odds ratio, 4.0; 95% CI, 3.57-4.43), although the set of single-nucleotide polymorphisms was different from that implicated among late-onset cases. CONCLUSIONS AND RELEVANCE: Our genetic data provide insights into aberrant cellular mechanisms responsible for this prototypical autoimmune disorder. They also suggest that clinical trials of immunomodulatory drugs related to CTLA4 and that are already Food and Drug Administration approved as therapies for other autoimmune diseases could be considered for patients with refractory disease.
Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Cadeias alfa de HLA-DQ/genética , Miastenia Gravis/genética , Adulto , Idade de Início , Antígeno CTLA-4/genética , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Estados UnidosRESUMO
OBJECTIVE: To identify patients with GFPT1-related limb-girdle myasthenia and analyze phenotypic consequences of the mutations. METHODS: We performed genetic analysis, histochemical, immunoblot, and ultrastructural studies and in vitro electrophysiologic analysis of neuromuscular transmission. RESULTS: We identified 16 recessive mutations in GFPT1 in 11 patients, of which 12 are novel. Ten patients had slowly progressive limb-girdle weakness responsive to cholinergic agonists with onset between infancy and age 19 years. One patient (no. 6) harbored a nonsense mutation and a second mutation that disrupts the muscle-specific GFPT1 exon. This patient never moved in utero, was apneic and arthrogrypotic at birth, and was bedfast, tube-fed, and barely responded to therapy at age 6 years. Histochemical studies in 9 of 11 patients showed tubular aggregates in 6 and rimmed vacuoles in 3. Microelectrode studies of intercostal muscle endplates in 5 patients indicated reduced synaptic response to acetylcholine in 3 and severely reduced quantal release in patient 6. Endplate acetylcholine receptor content was moderately reduced in only one patient. The synaptic contacts were small and single or grape-like, and quantitative electron microscopy revealed hypoplastic endplate regions. Numerous muscle fibers of patient 6 contained myriad dilated and degenerate vesicular profiles, autophagic vacuoles, and bizarre apoptotic nuclei. Glycoprotein expression in muscle was absent in patient 6 and reduced in 5 others. CONCLUSIONS: GFPT1-myasthenia is more heterogeneous than previously reported. Different parameters of neuromuscular transmission are variably affected. When disruption of muscle-specific isoform determines the phenotype, this has devastating clinical, pathologic, and biochemical consequences.
Assuntos
Potenciais de Ação/fisiologia , Glutamina-Frutose-6-Fosfato Transaminase (Isomerizante)/genética , Músculo Esquelético/patologia , Miastenia Gravis/genética , Miastenia Gravis/patologia , Miastenia Gravis/fisiopatologia , Acetilcolina/farmacologia , Acetilcolinesterase/metabolismo , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Técnicas In Vitro , Lactente , Masculino , Microscopia Eletrônica de Transmissão , Músculo Esquelético/metabolismo , Músculo Esquelético/ultraestrutura , Mutação/genética , Miastenia Gravis/tratamento farmacológico , Junção Neuromuscular/efeitos dos fármacos , Junção Neuromuscular/genética , Junção Neuromuscular/ultraestrutura , Brometo de Piridostigmina/farmacologia , Brometo de Piridostigmina/uso terapêutico , Receptores Colinérgicos/metabolismo , Receptores Colinérgicos/ultraestrutura , Retículo Sarcoplasmático/patologia , Adulto JovemRESUMO
Forkhead box P3 (FOXP3) is a transcription factor necessary for the function of regulatory T cells (T(reg) cells). T(reg) cells maintain immune homeostasis and self-tolerance and play an important role in the prevention of autoimmune disease. Here, we discuss the role of T(reg) cells in the pathogenesis of myasthenia gravis (MG) and review evidence indicating that a significant defect in T(reg) cell in vitro suppressive function exists in MG patients, without an alteration in circulating frequency. This functional defect is associated with a reduced expression of key functional molecules, such as FOXP3 on isolated T(reg) cells, and appears to be more pronounced in immunosuppression-naive MG patients. In vitro administration of granulocyte macrophage-colony-stimulating factor (GM-CSF) enhanced the suppressive function of T(reg) cells and upregulated FOXP3 expression. These findings indicate a clinically relevant T(reg) cell-intrinsic defect in immune regulation in MG that may reveal a novel therapeutic target.
Assuntos
Miastenia Gravis/metabolismo , Linfócitos T Reguladores/metabolismo , Antígenos CD4/imunologia , Antígenos CD4/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Humanos , Tolerância Imunológica , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Miastenia Gravis/imunologia , Tolerância a Antígenos Próprios , Linfócitos T Reguladores/imunologiaRESUMO
Previous studies have reported alterations in numbers or function of regulatory T (Treg) cells in myasthenia gravis (MG) patients, but published results have been inconsistent, likely due to the isolation of heterogenous "Treg" populations. In this study, we used surface CD4, CD25(high), and CD127(low/-) expression to isolate a relatively pure population of Tregs, and established that there was no alteration in the relative numbers of Tregs within the peripheral T cell pool in MG patients. In vitro proliferation assays, however, demonstrated that Treg-mediated suppression of responder T (Tresp) cells was impaired in MG patients and was associated with a reduced expression of FOXP3 in isolated Tregs. Suppression of both polyclonal and AChR-activated Tresp cells from MG patients could be restored using Tregs isolated from healthy controls, indicating that the defect in immune regulation in MG is primarily localized to isolated Treg cells, and revealing a potential novel therapeutic target.
Assuntos
Miastenia Gravis/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Células Apresentadoras de Antígenos/imunologia , Antígenos CD4/metabolismo , Estudos de Casos e Controles , Separação Celular , Citocinas/biossíntese , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Técnicas In Vitro , Interleucina-10/biossíntese , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Subunidade alfa de Receptor de Interleucina-7/metabolismo , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Miastenia Gravis/genética , Miastenia Gravis/metabolismo , Receptores Colinérgicos/imunologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo , Adulto JovemRESUMO
INTRODUCTION: In this study we describe a patient with a prolonged myasthenic crisis refractory to conventional immunomodulatory therapy who was treated with GM-CSF (granulocyte macrophage colony-stimulating factor, sargramostim). METHODS: T-regulatory cell (Treg) suppressive function and Foxp3 expression were evaluated before and after treatment with GM-CSF. RESULTS: Treatment with GM-CSF was associated with clinical improvement, expansion in the circulating numbers of Foxp3(+) cells, increase in Foxp3 expression levels in Tregs, early improvement in Treg suppressive capacity for AChR-α-induced T-cell proliferation, and subsequent enhancement in Treg suppression of polyclonal T-cell proliferation. CONCLUSION: Although definitive conclusions cannot be drawn from a single case, the correlation with similar findings in GM-CSF-treated animals with experimental autoimmune myasthenia gravis suggests further exploration of the effects of GM-CSF in myasthenia gravis should be studied in a clinical trial setting.
Assuntos
Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Linfócitos T Reguladores/efeitos dos fármacos , Idoso , Proliferação de Células/efeitos dos fármacos , Fatores de Transcrição Forkhead/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Masculino , Miastenia Gravis/imunologia , Miastenia Gravis/metabolismo , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Resultado do TratamentoRESUMO
Broken heart syndrome or stress-induced non-ischemic cardiomyopathy (SICM) has rarely been reported in the setting of myasthenic crisis. We describe a case of reversible SICM that occurred simultaneously with myasthenic crisis in a 77-year-old man without prior cardiac history, and we discuss the previous findings that support an association of other cardiac disorders with myasthenia gravis.
Assuntos
Miastenia Gravis/complicações , Miastenia Gravis/diagnóstico , Cardiomiopatia de Takotsubo/complicações , Cardiomiopatia de Takotsubo/diagnóstico , Idoso , Humanos , MasculinoRESUMO
We report a patient with intravascular large B-cell lymphoma who initially presented with acute ascending weakness and sensory changes. Electrodiagnostic testing and cerebral spinal fluid (CSF) studies were initially suggestive of a demyelinating polyneuropathy. Further clinical evaluation and testing were consistent with mononeuropathy multiplex. Autopsy revealed disseminated intravascular large-cell lymphoma. Intravascular large-cell lymphoma should be considered in the differential diagnosis of a rapidly evolving neuropathy associated with other organ involvement.
Assuntos
Síndrome de Guillain-Barré/patologia , Linfoma Imunoblástico de Células Grandes/patologia , Anti-Inflamatórios/uso terapêutico , Autopsia , Axônios/patologia , Diagnóstico Diferencial , Eletrodiagnóstico , Evolução Fatal , Síndrome de Guillain-Barré/líquido cefalorraquidiano , Síndrome de Guillain-Barré/diagnóstico , Humanos , Linfoma Imunoblástico de Células Grandes/líquido cefalorraquidiano , Linfoma Imunoblástico de Células Grandes/induzido quimicamente , Masculino , Pessoa de Meia-Idade , Força Muscular/fisiologia , Debilidade Muscular/etiologia , Músculo Esquelético/patologia , Condução Nervosa/fisiologia , Nervos Periféricos/fisiopatologia , Doenças do Sistema Nervoso Periférico/etiologia , Doenças do Sistema Nervoso Periférico/patologia , Pupila/fisiologia , Insuficiência Respiratória/etiologia , Esteroides/uso terapêuticoRESUMO
Etanercept is a tumor necrosis factor (TNF) blocking agent that has been shown to suppress ongoing experimental autoimmune myasthenia gravis (EAMG). This subcutaneously administered TNF blocking agent has also been shown to be safe and effective in several rheumatological diseases including rheumatoid arthritis, psoriasis, and ankylosing spondylitis. A prospective clinical pilot trial of etanercept in corticosteroid-dependent autoimmune myasthenia gravis (MG) patients supports further study into etanercept as a treatment for MG.
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Imunoglobulina G/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Animais , Avaliação Pré-Clínica de Medicamentos , Etanercepte , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Projetos PilotoRESUMO
We present three cases of dropped head syndrome that occurred as a complication of mantle field (i.e., lymph nodes of the neck, axillae, and mediastinum) or whole-body radiation therapy for Hodgkin's disease. These cases are characterized by a late onset (2-27 years after radiation treatment), fibrosis, and contraction of the anterior cervical muscles, and atrophy of the posterior neck and shoulder girdle. This report adds to the increasing literature about the late neurological complications of radiation therapy and describes a previously unrecognized cause of dropped head syndrome.
Assuntos
Movimentos da Cabeça/efeitos da radiação , Doença de Hodgkin/radioterapia , Debilidade Muscular/etiologia , Atrofia Muscular/etiologia , Músculos do Pescoço/efeitos da radiação , Radioterapia/efeitos adversos , Plexo Braquial/fisiopatologia , Plexo Braquial/efeitos da radiação , Neuropatias do Plexo Braquial/etiologia , Neuropatias do Plexo Braquial/patologia , Neuropatias do Plexo Braquial/fisiopatologia , Tecido Conjuntivo/patologia , Tecido Conjuntivo/fisiopatologia , Tecido Conjuntivo/efeitos da radiação , Feminino , Movimentos da Cabeça/fisiologia , Humanos , Linfonodos/patologia , Linfonodos/efeitos da radiação , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/patologia , Debilidade Muscular/fisiopatologia , Atrofia Muscular/patologia , Atrofia Muscular/fisiopatologia , Músculos do Pescoço/patologia , Músculos do Pescoço/fisiopatologia , Doses de Radiação , Raízes Nervosas Espinhais/fisiopatologia , Raízes Nervosas Espinhais/efeitos da radiação , TempoRESUMO
Components of the complement cascade and circulating immune complexes play important roles in both experimental autoimmune myasthenia gravis and myasthenia gravis in humans. Thus far, no serological factor has been identified to predict the clinical severity of either myasthenia gravis. Upon immunization with acetylcholine receptor, levels of complement factors C1q, C3 and CIC increase with time in sera from C57BL/6 (B6) mice. Both these and plasma samples from myasthenia gravis patients also contain anti-C1q antibodies. The serum levels of anti-C1q antibodies but not C1q, C3 and CIC are significantly correlated with the clinical severity in the experimental myasthenia mice. However, this correlation is not observed in myasthenia gravis patients.
Assuntos
Anticorpos Anti-Idiotípicos/sangue , Complemento C1q/imunologia , Miastenia Gravis Autoimune Experimental/imunologia , Miastenia Gravis/imunologia , Adulto , Animais , Complemento C1/análise , Complemento C1/imunologia , Complemento C1q/análise , Complemento C3/análise , Complemento C3/imunologia , Complexo de Ataque à Membrana do Sistema Complemento/análise , Complexo de Ataque à Membrana do Sistema Complemento/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Debilidade Muscular/fisiopatologia , Miastenia Gravis/sangue , Miastenia Gravis/etiologia , Miastenia Gravis/fisiopatologia , Miastenia Gravis Autoimune Experimental/sangue , Miastenia Gravis Autoimune Experimental/etiologia , Miastenia Gravis Autoimune Experimental/fisiopatologia , Junção Neuromuscular/química , Junção Neuromuscular/patologia , Valor Preditivo dos Testes , Índice de Gravidade de DoençaRESUMO
Steroid-dependent myasthenia gravis patients improved following treatment with etanercept (recombinant human TNF receptor:Fc) in a prospective pilot trial. While the plasma anti-acetylcholine receptor antibody levels remained unaffected, etanercept treatment increased plasma levels of C3, circulating immune complexes, IL-10 and IFN-gamma. There was a direct correlation between plasma IL-6, TNF-alpha and IFN-gamma levels and the post-treatment clinical scores of patients. Moreover, patients with lower pre-treatment plasma IL-6 and IFN-gamma levels attained better clinical improvement following etanercept treatment.
Assuntos
Anti-Inflamatórios não Esteroides/administração & dosagem , Imunoglobulina G/administração & dosagem , Interferon gama/sangue , Interleucina-6/sangue , Miastenia Gravis/tratamento farmacológico , Receptores do Fator de Necrose Tumoral/administração & dosagem , Biomarcadores , Citocinas/sangue , Citocinas/imunologia , Etanercepte , Feminino , Humanos , Injeções Subcutâneas , Masculino , Miastenia Gravis/sangue , Projetos Piloto , Prognóstico , Estudos ProspectivosRESUMO
Mycophenolate mofetil (MM) is an immunosuppressive agent developed and originally used to prevent acute rejection of solid-organ transplantation. There have been preliminary reports of its successful use in the treatment of autoimmune myasthenia gravis (MG). We conducted a double-blind, placebo-controlled pilot trial of MM in the treatment of suboptimally controlled, stable MG. Results of this pilot study are promising and suggestive of greater improvement in the patients who received MM compared to placebo.
Assuntos
Imunossupressores/uso terapêutico , Miastenia Gravis/tratamento farmacológico , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/uso terapêutico , Adulto , Idoso , Anticorpos/análise , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Projetos Piloto , Receptores Colinérgicos/imunologia , Resultado do TratamentoRESUMO
In a placebo-controlled, therapeutic, pilot trial of mycophenolate mofetil (MM) in autoimmune myasthenia gravis (MG), the authors compared pretreatment and posttreatment single fiber electromyography (SFEMG) jitter measurements performed on the same muscle in a total of 11 patients. The mean jitter value decreased (improved) by an average of 15.4 micros in patients receiving MM (n = 6), compared to an increase (worsening) in mean jitter of 4.0 micros in patients receiving placebo (n = 5). This difference was statistically significant (P = 0.030). In most patients, the change in SFEMG measurements correlated with the change in clinical state as measured by quantitative testing of muscle function. The authors conclude that immunomodulation by MM improves neuromuscular junction function in MG and that SFEMG may be a useful marker of early response in future therapeutic trials in autoimmune MG.