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Myasthenia gravis
 

Myasthenia gravis

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date:19/09/2011

date:19/09/2011

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    Myasthenia gravis Myasthenia gravis Presentation Transcript

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