Myasthenia Gravis

05 November 2004

An autoimmune disorder characterised by abnormal muscle fatiguability due to nicotinic acetylcholine receptor antibodies  in motor end plates of striated muscle.

Epidemiology

Prevalence 6/100,000

Bimodal:            20 – 30 in women

                        50 – 60 in men (tend to be associated with thymomas)

Inducible by certain drugs especially penicillamine

Clinical Features

I:          15-20%     ocular myasthenia

IIA:      30%                 mild generalised myasthenia with slow progression, no crises, drug responsive

IIB:      25%                 moderately severe generalised myasthenia, severe skeletal & bulbar involvement but no crises; less than satisfactory drug response

III:        15%                 acute fulminating myasthenia, rapid progression of severe symptoms with respiratory crises & poor drug response; high incidence thymoma; high mortality

IV:       10%                 late severe myasthenia, same as III but progression over 2 yrs from class I to II

Compston Classification

1.      myasthenia gravis with thymoma, no sex nor HLA association, high antibody titre

2.      onset < 40 yo, no thymoma, female predominant,  HLA A1, B8, DRW3 associations.

3.      Onset > 40 yo, no thymoma, male predominant, low antibody titre, HLA A3, B7, DRW2 associations.

50 % initial manifestation is ocular symptoms (ptosis, palsy, pseudoINO)

90% will eventually develop ocular symptoms at some stage

80% will eventually develop some form of faciobulbar palsy

neck flexion (parallels bulbar & respiratory function)

sustained upward eye gaze, trident tongue, ice eye test, Cogan’s lid twitch sign.

Associated Disorders

10% thymomas

65% lymphofollicular hyperplasia in thymus

6% diabetes

5% thyrotoxicosis

SLE

Rheumatoid arthritis

Sjogren syndrome

Mixed connective tissue disease

Antiphospholipid syndrome

Aplastic anemia

Pernicious anemia

30% FHx of autoimmune disorder

Diagnosis

1.      Tensilon/Neostigmine test

2.      Ach Receptor antibody: 80% with generalised myasthenia, 60% ocular myasthenia. Associated with blocking of Ach binding, degradation of Ach receptors, destruction of postsynaptic folds.

3.      Repetitive nerve stimulation +/- Tensilon (75-80% sensitive): decrementing CMAP >10% at 3 Hertz in distal ulnar/median, accessory, facial; exercise for 1 min followed by RNS at 0 sec, 30 sec, 1, 2 & 3 min.

4.      Single fibre EMG: 92 % sensitive

5.      CT chest

6.      Antistriated muscle antibody (thymoma association): titin, myosin, actin, alpha actinin.

7.      Ryanodine receptor antibody (thymoma association)

8.      Antibody negative maybe due to failure of assay, antibody strongly bound to antigen, antibody binding to voltage gated sodium channels, other end plate antigens.

9.     Ice pack test: apply ice pack to eye with ptosis for 2 minutes to see whether ptosis resolves or improves. (This is essentially a reverse Uhthoff's phenomenon in the peripheral nervous system).

Investigations of flare-ups

1.      Septic workup and check medications

2.      Tensilon test exclude cholinergic crisis

3.      Repeat repetitive nerve stimulation / EMG: steroid myopathy vs myasthenia

4.      CT chest for residual thymus tissue

5.      TFT

6.      CK

7.      ANA, ENA

Treatment

1.      Anticholinesterases

2.      Thymectomy recommended virtually for all patients from puberty to 60 yo especially so for thymoma and myasthenics with poor drug response. In case of thymoma, radiation for residual tissue & platinum based chemo for invasion/spread. Achieves 35 % remission rate & 50% will improve. Best response after 3 yrs.

3.      Prednisolone 1 – 1.5 mg/kg/day initially. 75% patients will improve. Eventually reduce to alternate day regimen. May initially exacerbate myasthenia.

4.      Azathioprine (Myasthenia Gravis Clinical Study Group): steroid sparing agent or who fail to respond to steroids. Slow onset of action from 3 –12 mths. Combination of pred & aza better than either drug alone in severe disease, achieves longer remission.  Main SE is mutagenicity, monitor LFT & wcc.

5.      Cyclophosphamide rarely used due to toxic profile.

6.      Cyclosporine with improvement in 1 –2 mths.

7.      Intragam 0.4 mg/kg/d for 5 days (NB based on studies for ITP & Kawasaki’s disease). Occasionally used long term as monthly infusions.

8.      Plasma exchange for myasthenic crisis as fastest acting at 250 ml/kg for at least 5 exchanges. Occasionally used long term.

9.      Immunoadsorption

10.  Total body irradiation

11.   Mycophenolate

Myasthenic Crisis

20% patients have one episode of myasthenic crisis usually within first 2 yrs.

40% mortality untreated

Neck flexion & oropharyngeal weakness marker impending crisis.

Perform flare-up investigations.

See triage chart

Pregnancy

No set pattern except 30% will have postpartum exacerbation.

Avoid cytotoxics.

Plasmapharesis is safe

Avoid MgSO4

Beware of myasthenia in babies.