Myasthenia Gravis

Dr.G.Ashok M.D., Asst professor General Medicine CHRI

Introduction Acquired autoimmune disorder Clinically characterized by: Weakness of skeletal muscles Fatigability on exertion.

Initiation Of Autoimmunity ??? Thymus plays an important role Thymus is abnormal in 75% of patients with MG 65% the thymus is "hyperplastic," 10% of patients have thymic tumors (thymomas).

Pathophysiology 1.Accelerated turnover of AChRs by a mechanism involving crosslinking and rapid endocytosis of the receptors 2.Damage to the postsynaptic muscle membrane by the antibody in collaboration with complement 3. Blockade of the active site of the AChR - the site that normally binds ACh.

The pathogenic antibodies are IgG, and are T cell-dependent.

(A) Normal (B) Myasthenic neuromuscular junctions. The MG junction demonstrates a normal nerve terminal; A reduced number of AChRs (stippling); flattened, simplified postsynaptic folds; and a widened synaptic space.

Pathophysiology
Anti-AChR antibody is found in 80-90% of patients with Myasthenia gravis Myasthenia may be considered as 1. B cell-mediated disease Antibodies
2. T cell mediated disease because of thymic hyperplasia and thymoma

Epidemiology Risk factors for high mortality

Age > 40 Short history of disease Thymoma

Sex
Female : Male (6:4) - synonoymous with any autoimmune disorder Mean age of onset (M-42, F-28) Incidence peaks- M- 6-7th decade F- 3rd decade

Clinical Presentation
The Hallmark Of Myasthenia Is Weakness And Fatiguabilty
Weakness increases during the day and improves with rest

Extraocular muscle weakness

Ptosis is present initially in 50% of patients and during the course of disease in 90% of patients

Head extension and flexion weakness

Weakness may be worse in proximal muscles

Clinical presentation
Progression of disease Mild to more severe over weeks to months Usually spreads from ocular to facial to bulbar to truncal and limb muscles Often, symptoms may remain limited to EOM and eyelid muscles for years The disease remains ocular in 16% of patients Remissions Spontaneous remissions rare Most remissions with treatment occur within the first three years

Basic physical exam findings Higher mental functions are normal EOM weakness ptosis Muscle strength is reduced and increased fatiguability present DTR Preserved Single Breath Count to test for respiratory failure

Muscle strength Facial muscle weakness Bulbar muscle weakness Limb muscle weakness Respiratory weakness Ocular muscle weakness

Bulbar muscle weakness Palatal muscles 1.Nasal voice, nasal regurgitation 2.Chewing may become difficult 3.Swallowing may be difficult and aspiration may occur with fluidscoughing and choking while drinking Neck muscles Neck flexors affected more than extensors

Myasthenia Gravis Foundation of America Clinical Classification Class I: Only EOM weakness, possible ptosis Class II: EOM weakness of any severity, mild weakness of other muscles Class IIa: Predominantly limb or axial muscles Class IIb: Predominantly bulbar and/or respiratory muscles Class III: Eye muscle weakness of any severity, moderate weakness of other muscles Class IIIa: Predominantly limb or axial muscles Class IIIb: Predominantly bulbar and/or respiratory muscles Class IV: Eye muscle weakness of any severity, severe weakness of other muscles Class IVa: Predominantly limb or axial muscles Class IVb: Predominantly bulbar and/or respiratory muscles (Can also include feeding tube without intubation) Class V: Intubation needed to maintain airway

Co-existing autoimmune diseases

Hyperthyroidism Occurs in 10-15% MG patients Exopthalamos and tachycardia point to hyperthyroidism Weakness may not improve with treatment of MG alone in patients with co-existing hyperthyroidism

Rheumatoid arthritis Scleroderma Lupus

Drugs Exacebrating Myasthenia gravis

1.Pencillamine 2.Aminoglycosides, Quinolones, Macrolides 3.Lithium 4.Magnesium 5.Chloroquine 6.Verapamil

Differential diagnosis 1.Lambert Eaton Syndrome 2.Multiple sclerosis 3.Oculo pharyngeal myopathy 4.Botulism 5.Dermatomyositis

History Diplopia, ptosis, weakness Fluctuation and fatigue: worse with repeated activity, improved by rest Physical examination Motor power survey: quantitative testing of muscle strength Forward arm abduction time (5 min)
Vital capacity Absence of other neurologic signs Laboratory testing Anti-AChR radioimmunoassay: 85% positive in generalized MG; 50% in ocular MG; Definite diagnosis if positive Negative result does not exclude MG.

40% of AChR antibodynegative patients with generalized MG have anti-MuSK antibodies.

Repetitive nerve stimulation: decrement of >15% at 3 Hz: highly probable Single-fiber electromyography Edrophonium chloride (Tensilon) 2 mg + 8 mg IV highly probable diagnosis if unequivocally positive For ocular or cranial MG: exclude intracranial lesions by CT or MRI

Edrophonium test( Tensilon ) Improvement in ptosis, nasal speech or dysphagia

Shorter duration of action

Anti-acetylcholine receptor antibody( AChR Ab) MuSK antibodies Repeated Nerve Stimulation Test Decremental Response Imaging studies Chest x-ray Chest CT scan is mandatory to identify thymoma MRI brain - if purely ocular myasthenia Thyroid function Testing

Treatment AChE inhibitors Immunomodulators Plasmapheresis Thymectomy Important in treatment, especially if thymoma is present

Treatment AChE inhibitor Pyridostigmine bromide (Mestinon) Starts working in 30-60 minutes and lasts 3-6 hours Individualize dose Adult dose: 60-960mg/d PO 2mg IV/IM q2-3h Caution Check for cholinergic crisis Neostigmine Bromide Every 4 th hourly or 6 th hourly

Treatment 1.Steroids Prednisolone at 1 mg/kg and tapered according to the improvement 2.Azathioprine Used as ateroid sparing agent

3.Mycophenolate mofetil
4.Cyclosporine 5.Cyclophosphamide 6.Tacrolimus

Patients with severe weakness or impending respiratory failure 1.Plasmapheresis 2.IV immunoglobulins Resistant to steroids Thymectomy is tried

Eaton Lambert Syndrome 1.Paraneoplastic syndrome 2.Improvement with activity 3.Ocular muscle involvement is rare 4.Antibodies are negative 5.RNS Incremental response 6.Small cell carcinoma lung is the most important associated malignancy

Complications of MG Respiratory failure Dysphagia Complications secondary to drug treatment Long term steroid use Osteoporosis, cataracts, hyperglycemia, HTN Gastritis, peptic ulcer disease

Prognosis Untreated Myasthenia carries a mortality rate of 25-30% Treated Myasthenia has a 4% mortality rate

Rehabilatation Strategies emphasize Patient education Timing activity Providing adaptive equipment Providing assistive devices Exercise is not useful

Prominent Indian Personalities With MG