Myasthenia gravis


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Myasthenia gravis

  3. 3. Ach RECEPTORS<br />MUSCARNIC --- M1,M2,M3,M4 ,M5<br />NICOTINIC—NM,NN<br />M1,M3,M5 are excitatory<br />M4,M5 are inhibitory<br />Ganglia of PNS,Heart,muscle,smooth muscle.<br />M1-gastric parietal cells,M2 cardiac<br />M3 – BLADDER<br />At high doses act on nicotinic receptors<br />Influx of na on activation of N receptors.<br />Ganglionic- hexamethonium<br />NMJ -tubocurarine<br />
  4. 4. Introduction<br />It is a neuromuscular disorder.<br />Weakness and fatiguability of skeletal muscles.<br />Antibody mediated autoimmune attack.<br />Decreased number of available AchRs at NMJ.<br />
  5. 5. Normal AcH Receptor <br />
  6. 6. NMJ <br />
  8. 8. What happens in MG?<br /> number of available AchRs at the post synaptic muscle membrane.<br />Postsynaptic folds are simplified or flattened.<br /> neuromuscular transmission.<br />Ach is released normally.<br />Only small endplate potentials – no muscle contraction.<br />Failure of NMT at many NMJ – weakness of muscle contractions<br />
  9. 9. What is Presynaptic rundown?<br />Amount of Ach released per impulse normally declines on repeated activity.<br />
  10. 10. Autoimmune response<br />Mediated by specific anti AchRab<br />How do they act ?<br />
  11. 11.
  12. 12. Ach R clustering interference --- anti MuSKab<br />(normally MuSK is involved in Ach R clustering ,5 subunits)<br />Antibodies are IgG,T cell dependent.<br />So,treatment is against T cells… <br />
  13. 13. What is the basis of autoimmune response?<br />Unknown<br />Hypothesis –THYMUS plays a role..<br />ABNORMAL in 75% pts with MG.<br />Of them 65% -HYPERPLASTIC (presence of active germinal centers histologically)<br />10% -thymomas.<br />Which cells are the initiators?<br />MUSCLE LIKE CELLS (myoid cells) IN THYMUS.<br />Have AchR on surface –autoantigen – autoimmune reaction <br />
  14. 14. Epidemiology<br />Prevalence 1-7 in 10,000<br />All age groups<br />Women in 20-30’s <br />Men in 40-60’s <br />W:M--- 3:2<br />
  15. 15. Clinical features<br />Weakness - 85% generalised weakness<br />Fatiguability of muscles<br />Weakness on repeated use…worsening at the end of the day…<br />Decreased on rest and sleep.<br />What is the course of disease?<br />Variable.<br />
  16. 16. ptosis<br />
  17. 17. Clinical pattern<br />Characteristic pattern<br />
  18. 18.
  19. 19. assessment<br />Forward arm abduction time 5 min<br />Upward gaze test<br />Repetitively say words<br />
  20. 20.
  21. 21. Bulbar weakness – MuSKab positive MG<br />Ocular MG –EOM only for 3 yrs unlikely to become generalised.<br />How to differentiate from other muscle weakness?<br />On activity only.<br />Limb muscles –proximal,asymmetric<br />DTRs are present.<br />How do you diagnose MG?<br />Based on history,preservedreflexes,normal sensation and cofirmatory test –tensilon test.<br />
  22. 22. Lab testing<br />Antibodies to Ach R - 85% pts<br />Only 50% of ocular weakness<br />Presence is diagnostic of MG <br />Negative test does not exclude MG<br />Measured levels does not correlate with severity of MG<br />Fall in Ab on treatment –clinical improvement .<br />Antibodies to MuSK<br />40% of Ach R Ab negative patients with generalised MG<br />Rarely in AchRAb positive patients,ocular weakness. <br />Electrodiagnostic testing<br />Repititive nerve stimulation<br />Anti Ach E medication to be stopped before 6-24 hrs.<br />Weak and proximal muscles to be tested.<br />Deliver shocks at 2-3 sec<br />Normally amplitude does not change<br />In MG 10-15% DECREASE<br />Single dose of EDROPHONIUM to be given. <br />
  24. 24. Ach E test***<br />Edrophonium –MC drug used.<br />Other is neostigmine –for long assesssment.<br />Edrophonium–rapid onset,short duration<br />To be used only in clinical features suggestive of MG ,but negative Ab<br />Initially IV dose of 2 mg of EDROPHONIUM –if definite improvement occurs it is positive,no change additional 8 mg.<br />WHY TWO DOSES?<br />Nausea,diarrhea,salivation,fasciculation,syncope,bradycardia.<br />Have 0.6 mg ATROPINE <br />False positive ---AML<br />False negative results also do occur.<br />***2marks<br />
  25. 25. DIFFERENTIAL DIAGNOSIS<br />Lambert Eaton Myasthenic Syndrome***:<br />Presynaptic disorder .<br />Proximal muscles of lower limbs mostly affected.<br />Ptosis -70% cases<br /> or absent reflexes.<br />Autonomic features present <br />Incremental response on repetitive nerve stimulation.<br />P/Q type Ca channels at motor nerve terminals -85% cases.<br />Usually assosciated with Small Cell Ca Lung.<br />Rx – Plasmapheresis,immunosuppression<br />3,4 diaminopyridine –blocks K channels- inc Ach release<br />Pyridostigmine –prolongs Ach actions<br />****2marks<br />
  26. 26.
  27. 27.
  28. 28. D.D.<br />2.BOTULISM :<br />Bacterial toxin by cl.botulinum<br />Blocks release of Ach from presynaptic junction.<br />Food borne is Most common.<br />Dilated pupils<br />Bulbar weankess.<br />DTR preserved in early course,later depressed<br />Autonomoic features present.<br />Prognosis good for type B<br />Diagnosis by toxin in serum,CMAPs<br />Rx – equine antitoxin<br />3.Sphenoid ridge meningioma<br />4.Neurasthenia<br />
  29. 29. Cholinergic crises<br />Muscular weakness resulting from depolarization due to overdosage of anticholinesterase agents used for MG<br />Excess dose of anti Ach ase inhibitors<br />Symptoms of OP poisoning<br />Worsened by edrophonium test<br /> treatment -atropine<br />
  30. 30. Associated conditions<br />Thymic abnormality 75% patients<br />Thymoma > 40 yrs<br />Hyperthyroidism 3-8%<br />Rheumatoid factor<br />ANA<br />Do TFT for every patient with symptoms of MG.<br />
  31. 31. Treatment<br />Anticholinesterase medications<br />Immunosuppressive agents<br />Thymectomy<br />Plasmapheresis<br />IVIg<br />
  32. 32. Anticholinesterase medications<br />At least partial improvement<br />PYRIDOSTIGMINE :most widely used drug<br />MOA within 15-30 min<br />Lasts for 3-4 hrs<br />30-60 mg tid<br />Long acitng at night time<br />Max dose 120 mg 3-6 hrs daytime<br />Muscarnic side effects –diarrhea,abdominal cramps .salivation –atropine,lopermaide . <br />
  33. 33. Thymectomy<br />Surgical removal ,or as treatment option<br />85 % IMPROVE after thymectomy<br />35% ACHIEVE drug free remission<br />Improvement delayed for months-years<br />Adv –long term benefit<br />Ind – generalised MG ,puberty -55 yrs.<br />Why not others? --children,<15 yrs,localised MG<br />MusKAb POSITIVE pts does not respond to thymectomy<br />To be done only in specialisedcentres<br />
  34. 34. immunosuppression<br />Immediate improvement –IV Ig, plasmapheresis<br />Intermediate – glucocorticoids,cyclosporine,tacrolimus<br />Late – mycophenolatemofetil,tacrolimus<br />Refractory cases -High dose cyclophosphamide reboots the immune system –eliminates mature lymphocytes,but stem cells are spared for the presence of aldehydedehydrogenase .<br />
  35. 35. Glucocorticoids<br />Single dose only<br />15-25mg/d<br />High doses –weakening<br />Increase by 5 mg/d at 2-3 day interval<br />50-60 mg/d for 1-3 months<br />Alt day 1-3 months<br />Zero dose when off symptoms<br />
  36. 36. Mycophenolatemofetil<br />1-1.5 g bid<br />Inhibition of purine synthesis by denovo pathway<br />Inhibits proliferation of lymphocytes<br />Lack of adverse side effects<br />Skin rashes,leucopenia. <br />
  37. 37. Azathioprine<br />50mg/d should be used<br />2-3 mg/kg in children<br />10 % develop idiosyncratic reactions<br />Not to give allopurinol.<br />Cyclosporine ,tacrolimus as adjunctives<br />
  38. 38. Plasmapheresis<br />IMMEDIATE RESPONSE<br />3- 4l/ exchange<br />5 exchanges over 10-14 days period<br />Before surgery<br />In crisis cases<br />
  39. 39. IVIg<br />In crisis<br />Before surgery<br />MOA not known<br />2g/kg over 5 days <br />400mg/kg /day<br />70% pts improve.<br />
  40. 40.
  41. 41. Myasthenic crisis***<br />Respiratory failure to diaphragmatic weakness.<br />ICU treatment<br />Rule out cholinergic crisis<br />Rx like a immunocompromised patient<br />AB <br />Plasmapheresis<br />IVIg<br />Ppted by intercurrent infections <br />2 marks<br />
  42. 42. Drugs to be avoided in MG <br />Not all patients have adverse effects <br />
  43. 43. Summary<br />It is a neuromuscular disorder<br />It is an autoimmune disorder at NMJ<br />Post synaptic junctions are affected<br />Anti ACHR ab are most common<br />Those negative have anti MuSKab<br />Thymus is involved in pathogenesis<br />Anti AchE test is classical one for diagnosis<br />Most common presentation is ptosis,ocular muscle weakness<br />Bulbar weakness in anti MuSKab<br />Weak proximal muscles to checked by electrography<br />
  44. 44. Symptoms worsen at the end of day.<br />Normal preserved DTRs,sensory function<br />Decremental response on reptitive stimuli<br />To be differentiated fromLEMS –PRESYNAPTIC,incrementalresponse,associated with scc of lung.<br />Botulism –autonomic feauteres,depressedDTRs,ascendingparalysis,dilated pupils<br />Immunosuppression for immdiate effect<br />Thymectomy is treatment option<br />IVIG,plasmapheresis –before surgery<br />Avoid aminoglycosides,quinolone,vecuronium,quinine in MG pts<br />Do TFTS for all patients….<br />
  45. 45.
  46. 46. Thank you <br />Thank you <br />Thank you<br />