Myasthenia Gravis Flashcards
What is the defining feature of MG?
painless muscle weakness that gets worse with use
What are the causes of myasthenia gravis?
idiopathic; drugs e.g penicillamine; congenital myasthenias
What is the difference in gender balance with MG in young vs old age groups?
in young: women are affected twice as much as men but in older its equal
What are the 3 main types of MG?
ocular; bulbar; generalised
How does ocular MG present?
ptosis and double vision
What defines ocular MG?
affects eyes only for >2 year s
What is a major differential for ocular MG?
chronic progressive external opthalmoplegia- mitochondrial disorder
How does bulbar MG present?
dysphagia/dysarthria; weight loss; chest infections
what age group is affected more often with bulbar MG?
older patinets
What is hte major differential for bulbar MG?
MND
When do generalised MG patients typically present?
post op or intensive care
What is the tensilon test?
edrophonium blocks the breakdown of ACh, if muscle strenght gets better in the muscle group
What is the main issue with ocular MG if the patietns are generally well?
can get worse if get other illness and drugs etc
What is seen at hte NMJ of MG patients?
have fewer ACh receptors
Who mainly uses the ice pack test?
opthalmologists
How does the icec pack test work?
ice pack over ptotic eyelid for 2 minutes, if there is an improvement in ptosis of 2mm-diagnostic
How does EMG in the diagnosis of MG work?
repetitively stimulate the muscle to deplet it of ACh and stimulated muscle contraction gets weaker by at least 20%
What is the function of single fibre EMG?
gold standard - tests for failure of faulty NMJ function
What type of ACh receptor is blocked by autoantibodies in MG?
nicotinic not muscarinic
what is the problem with anti-ACh-esterases?
they block both nicotinic and muscarinic receptors which causes problems in the gut
What is given to ameliorate the gut problems seen with anti-ACh esterases?
propanthelline
How many patients with MG have a positive antibody?
70%
Which form of MG is antibody more common in?
generalised MG
How many thymoma patients develop MG?
1/3rd
What other type of antibody is common in thymoma cases?
antistriational
What is the main stay of acute severe treatment for MG>
plasma exchange
What is the remission rate for thymectomy in MG?
40-60% at 7-10 years
What are the symptoms of lambert eaton syndrome?
proximal muscle weakness; fatiguability; dry mouth and impotence
What is LEMS associated iwth?
small cell lung cancer
What are the antibodies to in LEMS?
presynaptic calcium channels
Why does LEMS improve with use?
with enough stimulation, calcium gets through allowing ACH release
What suggested taht there was a problem with antibodies in seronegative MG?
still responded to plasma exchange adn immunosuppression
What antibodies were found in seronegative MG?
muscle specific kinase antibodies
What is the first line symptomatic treatment for MG?
pyrostigmine
How does pyrostigmine work?
blocks breakdown of ACh by blocking ACh esterase
Why are steroids often given initially in hospital to MG patietns?
can make MG deteriorate if given at high doses too quickly
What immunotherapy is give nfor MG?
azathioprine
How long does azathioprine take to work?
6-12 months
What are the SE of azathioprine?
nausea; stomach problems; bone marrow suppression- regular bloods
What is the function of immunoglobulins in the acute treatment of MG?
blocks the effects of antibodies
When are immunoglobulins used in MG?
acute severe relapses in pregnancy/ post op
What is thought to be the cause of such high association of thymomas and thymic hyperplasia in MG?
loss of negative regulation- cortex is maintained in thymoma but medulla lost; very low expression of AIRE in thymomas
What factors are thought to play roles in patients with anti-AChr antibodies?
thymic abnormalities; defects in immune regulation; sex hormones
What is the structure of the ACHr?
five protein chains that are arranged in a long tube
What is the target of hte anti-ACHr antibodies?
alpha chains have binding sites for acetylcholine on the external side and contain the primary immunogenic region
What is the primary mechanism of hte reduced ACHRs at hthe NMJ of MG patients?
destruction of the postsynaptic membrane by complement pathway activation leading to generation of MAC
What is the difference between early onset and late onset MG?
early onset present with high level of ACHr ab and thymic follicular hyperplasia caharacterised by ectopic germinal centres- 80% women; late onset is associated with thymoma and anti-striated mucscle antibodies –more severe and generalised
What is hte function of muscle specific kinase?
plays a major role in the development of the NMJ and is essential for clustering of ACHr- no aggregates of ACHrs are seen in its absence
What is a newly identified antibody target in MG?
anti-LRP4 antibodies
What is the function of the LRP4 protein?
receptor for the neural agrin that activates MuSK and AChR clustering
What are the thymomas caused by?
abnormal development of epithelial cells- medullary vs cortical
How are thymomas thought to relate to MG onset?
thymic medulla is site of neg selection- in thymoma, effective deletion of autoreactive T cells doesn’t occur; also- lack of AIRE, FOXP3 and MHC-II antigens
What demonstrates that in thymic follicular hyperplasia the MG thyus contains B cells producting anti-AChR antibodies?
thymic tissue or thymic cells frmo the AChR-MG patients can induce the production of antibodies against AChR in immunodeficient mice and the loss of AChR at the muscle endplates
What other autoimmune dieases have ectopic GCs been described in?
salivary glands in Sjogrens; joints in RA; meninges in secondary progressive MS–thymuc is the inflamed tissue in AChR-MG patients
What was the inflammatory state of hte MG thymus demonstrated by?
overexpression of numberus IFNy induced genes
What indicates that both Th1 and Th2 cells are involved in MG?
have larger numbers of cells that express IFNy or IL-4
What does the activation of the immune system in MG patients suggest?
presence of a number of inflammatory signs suggests taht the efficiency of immune regulation mechanisms is compromised
What is seen with the Tregs in MG?
severe defects in their suppressive function when cultured with CD4 cells and other PBMCs
What suggests that Th1 and Th17 cells are involved in the pathology of MG?
higher levels of IL-17 in serum; many genes in the IL-17 family are increased in MG Tregs - tregs themselves are frive to secrete pro-inflammatory IL-17
Give an overview of a model of the pathogenic mechnisms in MG leading to thymic hyperplasia?
triggering event e.g viral infection in genetically favourable environment–thymic epithlium overprduce IL-1; IL-6 and IFNb and lymphocytes produce TNFa and IFNy- increase MHC-II; AChR and chemokines which attract B cells. estrogens proote B cell proliferation- inflammatory mileu modulates the T cell phenotype- Tregs produce Th17; all T cells produce IFNy; TNfa; IL-21;IL17 favouring Tfh development and generation of GCs. Tregs become inefficient in inflam environment and T cells resistant to suppression
What is thought to be the reason for reduced severity and remission with thymectomy?
eliminates the main site of anti-AChR autoantibody production and leads to decreased AChR
What is the MZ concordance of MG?
35%
What are the HLA associations?
HLA-B8; HLA-DR3
What is the PTPN22 gene?
member of the tyrosine phosphatase subfamily and intereferes with signalling in T cells leading to inhibition of T cell activation
What are microRNAs?
small non-coding RNAs that mediate post-transcriptional silencing of target genes
What is the significance of miRNAs in autoimmune disease generally?
dysregulation has been described in a variety of AI diseases
Is there a role for miRNAs in MG?
there was a decrease in miR-320a levels- correlated with increases in levels of pro-inflammatory cytokines–miR-320a regulates ERK pathway
What is the function of estrogen in autoimmune disease?
favour processes involving CD4 Th2 cells nad B cells-B cell mediated AI disease- allows autoreactive B cells to escape? however other studies suggest that they promote Th1 responses—complex roles based on dose, timing, microenvionment
What needs further addressing in MG?
role of miRNAs in the modulation of immune function; there has been recent research on the importance of physical exercise in MG, where there are no guidelines- previously been restricted , suggests that symptoms can be improved
