MYASTHENIA GRAVISMYASTHENIA 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

PATHOPHYSIOLOGYIn NMJ Ach is stored in vesicles---released on Action potential.

Combines with AchRs at peak of POST SYNAPTIC FOLDS.---binds with subunit of Ach R ---Rapid influx of cations Na.

Depolarization at the end plate region of muscle fiber---if sufficiently large – MUSCLE CONTRACTION.

Ach is rapidly hydrolized by AchE present in synaptic folds,diffuse away from receptors

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.

Myasthenia gravis

Decreased efficiency of NMT

Myasthenia fatigue

Normal presynpatic rundown

Autoimmune response Mediated by specific anti AchR ab How do they act ?

AntiAch Receptor Ab

CROSS LINKING,ENDOCYTOSIS

RAPID TURNOVER OF AchRs

BLOCKADE OF ACTIVE SITE OF AchRsDecreased effiicacy

COMBINED WITH COMPLEMENTDAMAGE TO POST SYNAPTIC MEMBRANE

Ach R clustering interference --- anti MuSK ab (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.

• Not complete or permanent

remissions

ptosis

Clinical pattern Characteristic pattern

Early in course

lids,EOMs

Facial weakness

Bulbar weakness

Respiratory muscles

Ptosis ,diplopia

Snarling expression

.Difficulty

in chewing meat

Nasal timbre voiceNasal

regurgitation aspiration of

liquids and food

Difficulty in respiration..

Decreased breath holding time

assessment Forward arm abduction time 5 min Upward gaze test Repetitively say words

Bulbar weakness – MuSK ab 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,preserved reflexes,normal sensation and

cofirmatory test –tensilon test.

Lab testingAntibodies 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 AchR Ab 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 ---AMLFalse 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 antitoxin3.Sphenoid ridge meningioma4.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 improvementPYRIDOSTIGMINE :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 MusK Ab POSITIVE pts does not respond to thymectomy To be done only in specialised centres

immunosuppression Immediate improvement –IV Ig, plasmapheresis Intermediate – glucocorticoids,cyclosporine,tacrolimus Late – mycophenolate mofetil,tacrolimus Refractory cases -High dose cyclophosphamide reboots

the immune system –eliminates mature lymphocytes,but stem cells are spared for the presence of aldehyde dehydrogenase .

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

Mycophenolate mofetil 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

Myasthenic Weakness

exaggerated

ErythromycinAzithromycin

Local anaestheticxylocaine

Streptomycin

CiprofloxacinLevofloxacin

OfloxacinGatifloxacin

Non depolarizing muscle relaxants –DTC,pancuroniumPropanol

atenololQuininineMagnesium

penicilliamine

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 MuSK ab 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 MuSK ab 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,incremental

response,associated with scc of lung. Botulism –autonomic feauteres,depressed DTRs,ascending

paralysis,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….

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