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
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.
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.
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.
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….