..... Myasthenia Gravis is a neuro-muscular disorder charecterized by weakness and fatigability of
skeletal muscles.
Defect: Decrease in the number of available Acetyl-Choline receptors(AChRs) at the neuro-muscular(NM) junctions due to an antibody-mediated autoimmune attack.
Normal Phyz at NM Junction:
.... At NM Junction Acetyl Choline(ACh) is synthesized in motor nerve terminals and stored in vesicles(quanta).
.... When action potential travels down a motor nerve and reaches the nerve terminal, ACh
from 150 to 200 such vesicles is released and combines with Acetyl-Choline Receptors on post-synaptic folds.
.... When ACh combines with AChR, the channels in AChR opens, permitting rapid entry of cations, chiefly sodiumm which produce depolarization at the end-plate region of the muscle fibre(End Plate Potential - EPP).
.... If the depolarization is sufficiently large, it initiates an action potential that is propagated along the muscle fibre and triggers muscle contraction.
.... This process is rapidly terminated by two mechanisms.
1) Hydrolysis of Acetyl Choline by Acetyl-Choline Esterase(AChE), which is present within synaptic folds.
2) Diffusion of ACh away from the receptors.
Patho-Physiology:
.... In MG, the fundamental defect is decrease in the number of available AChRs at the postsynaptic muscle membrane.
.... Hence, ACh is released normally but it produce a small end plate potential(EPP) that may fail to trigger muscle action potential and hence contraction and hence muscle weakness occurs.
.....
Presynaptic Rundown: Normally, the amount of ACh released per impulse declines on repeated activity. This is known as Presynaptic Rundown.
.... In MG patients, there is decreased efficiency of neuromuscular transmission, along with which is combined normal presynaptic rundown, so successively there is increased weakness and muscle fatigability.
.... The cause of this pathology in MG is antibody mediated autoimmune response towards Acetyl-Choline Receptors. This Anti-AChR antibodies reduce the number of available AChRs at the neuromuscular junctions by three distinct mechanisms:
1) By accelerated turnover of AChR
2) By blockade of active site of AChR that normally binds ACh
3) Damage to the post-synaptic muscle membrane in collaboration with complements.
Clinical Features:.... The cardinal features are weakness and fatigability of muscles. Weakness increases on repeated use(Presynaptic rundown + decreased efficiency of transmission).
Distribution of muscle weakness:1)
Cranial Muscle particularly lids and extraocular muscle are involved early in the course. So, Diplopia and Ptosis are common complains.
2)
Facial Weakness produces snarling expression when the patient attempts to smile. Weakness in chewing seen after prolonged effort.
3)
Speech has nasal timbre cause of weakness of palate.
4)
Difficulty in swallowing cause of weakness of palate, tongue and pharynx.
5)
Limb Weakness is often proximal but
deep tendon reflexes are preserved.
6)
Difficulty in Respiration: If it becomes so severe that patient require respiratory assistance then patient is said to be in
Myasthenic crisis.
Diagnosis: Suspected diagnosis on basis of clinical symtoms. Always confirm by various tests.
1) Edrophonium test: Edrophonium is a drug that inhibit anticholine esterase and thereby increase the life of ACh. So when Edrophonium is given, it produces rapid improvement in symptoms in MG patients.
2) Electro-diagnostic Testing: Repetitive nerve stimulation often provides diagnostic evidence of MG. On repetitive stimulation in MG patient decrease in response is very brisk as compared to normal. This is because of combined effects of Presynaptic rundown and decreased efficiency of transmission.
3) Anti-Acetylcholine receptor antibody: Virtually diagnostic and very specific. If found, its definately MG.
Treatment:
1) Anticholineesterase medications: Drugs that inhibit acetylcholine esterase(e.g. Pyridostigmine) decrease its breakdown and increase ACh and hence the response.
2) Thymectomy
3) Immunosuppression: Using glucocorticoids. IV Ig is also given.
4) Plasmapheresis: Reduces circulating anti-AChR antibodies.
