42. Myasthenia gravis and Lambert-Eaton syndrome - etiology, pathogenesis, clinical manifestations.

Myasthenia gravis and Lambert-Eaton syndrome- etiology, pathogenesis, and clinical manifestations.

Myasthenia gravis is a chronic autoimmune disease affecting the neuromuscular junction, causing fluctuating weakness and fatigue of skeletal muscles.

Etiology

• Autoimmune disease caused by IgG autoantibodies against nicotinic acetylcholine receptors ( AChR) on the postsynaptic muscle membrane.
• Strong association with thymic abnormalities (thymic hyperplasia or thymoma).
• Can be triggered or worsened by infections, stress, surgery, or certain drugs (e.g., aminoglycosides).

Pathogenesis

• The immune system mistakenly produces antibodies targeting AChR.
• Main mechanisms:

1. Antibodies block acetylcholine from binding to its receptor.
2. Antibodies cross-link receptors, leading to internalization and degradation of receptors → fewer functional receptors on muscle membrane.
3. Activation of complement system, causing structural damage to the postsynaptic membrane.

• Result: Reduced number and function of ACh receptors → reduced end-plate potentials → decreased muscle fiber depolarization → weakness.
• The disease involves a type II hypersensitivity reaction (antibody- mediated).

Clinical manifestations

• Fluctuating skeletal muscle weakness, typically worsens with activity and improves with rest.
• Ocular muscles:
• Ptosis (drooping of eyelids).
• Diplopia (double vision).
• Facial and bulbar muscles:
• Difficulty chewing, swallowing (dysphagia), and speaking (dysarthria).
• Mask- like facial expression ("myasthenic snarl").
• Limb muscles:
• Proximal muscles usually affected more (difficulty lifting arms, climbing stairs).
• Respiratory muscles:
• Severe involvement may cause respiratory failure → "myasthenic crisis".
• Reflexes and sensory functions are usually normal.

Other important points

• Thymectomy can improve symptoms in some patients.
• Edrophonium ( Tensilon) test used diagnostically — transient improvement of weakness after administration.
• Associated autoantibodies can also target muscle-specific kinase ( MuSK) in some cases.

Lambert- Eaton Myasthenic Syndrome (LEMS)

Lambert-Eaton syndrome is an autoimmune disorder of the neuromuscular junction, characterized by proximal muscle weakness and autonomic dysfunction, due to impaired acetylcholine release.

Etiology

• Autoantibodies against presynaptic P/Q-type voltage-gated calcium channels (VGCC).
• Often a paraneoplastic syndrome, commonly associated with small cell lung carcinoma.
• May also occur without cancer (idiopathic autoimmune form).

Pathogenesis

• Antibodies target presynaptic VGCC → reduced calcium influx into the nerve terminal during depolarization.
• Reduced calcium entry → less acetylcholine released into the synaptic cleft.
• Initially, small amounts of acetylcholine → weak muscle contraction.
• With repeated activity, calcium builds up in nerve terminal → increased acetylcholine release → transient improvement of strength (facilitation phenomenon).

Clinical manifestations

• Proximal muscle weakness:
• Especially lower limbs → difficulty standing up, climbing stairs.
• Improves temporarily with repeated activity (unlike MG).
• Autonomic symptoms (present in about 70% of patients):
• Dry mouth.
• Constipation.
• Erectile dysfunction.
• Reduced sweating.
• Ocular and bulbar muscles:
• Less commonly involved compared to MG.
• Reflexes: