Myasthenia Gravis & Lambert-Eaton Myasthenic Syndrome

Myasthenia gravis (MG) is an autoimmune disorder affecting the neuromuscular junction, leading to characteristic muscle weakness. The underlying pathophysiology centers around the skeletal muscle's motor endplate, specifically on the postsynaptic surface of the muscle fiber. Communication between the presynaptic neuron and the muscle fiber occurs across a gap known as the synaptic cleft. Normally, an action potential in the motor neuron induces the opening of presynaptic voltage-gated calcium channels (P/Q type), resulting in calcium ions entering the nerve terminal. Accumulation of calcium in the axon terminal signals vesicles filled with acetylcholine (ACh) to migrate and fuse with the plasma membrane, releasing ACh into the synaptic cleft. At the postsynaptic motor endplate, ACh binds to nicotinic ACh receptors, which function as ligand-gated ion channels. The binding of ACh facilitates the inflow of sodium and calcium ions into the myocyte, while potassium flows out, leading to myocyte depolarization. This depolarization event culminates in an action potential, initiating muscle contraction. Acetylcholinesterase then hydrolyzes any remaining ACh in the synaptic cleft to terminate this process.

In myasthenia gravis, nicotinic ACh receptors of the motor end plate become the target of IgG autoantibodies, resulting in inhibition of neurotransmission in two primary ways: activation of the complement cascade, which leads to the destruction and depletion of receptors thereby decreasing neurotransmission and resulting in muscle weakness, and increased receptor turnover, which further limits neurotransmission.

MG has a bimodal onset, with an initial peak around age 20 (more common in women), and a subsequent peak around age 60, (more common in men). Furthermore, MG is associated with the HLA-B8 serotype, a marker that's also linked with Graves' disease. Clinically, MG is typified by fluctuating skeletal muscle weakness that intensifies with repetition due to the progressive depletion of ACh in presynaptic vesicles, rendering them incapable of releasing adequate ACh to depolarize the postsynaptic membrane.

Common clinical features of MG include an exacerbation of symptoms later in the day, ptosis, diplopia, and ‘bulbar symptoms’, which include dysarthria, dysphagia, and difficulty chewing due to the affected muscles innervated by cranial nerves IX, X, XI, and XII. In advanced MG, patients might find it challenging to raise their arms or legs due weakness of the proximal extremity muscles. Myasthenic crisis is an acute exacerbation of MG that can present with respiratory failure necessitating intubation, as well as bulbar weakness, which increases the risk of aspiration. Many patients with MG display signs of thymic hyperplasia and, in certain cases, thymoma. Thymectomy can improve symptoms as the thymus plays a role in antibody production in MG.

Diagnosis employs the edrophonium (Tensilon) test. Edrophonium, a short-acting acetylcholinesterase inhibitor, increases the concentration of ACh in the synaptic cleft, inducing an immediate enhancement in muscle strength in patients with MG. Another diagnostic tool, the ice pack test, involves placing cold ice over the eyelid, which augments the sensitivity of postsynaptic ACh receptors and slows ACh degradation, thereby increasing eyelid muscle strength. Treatment involves pyridostigmine an acetylcholinesterase inhibitor.

Lambert-Eaton myasthenic syndrome (LEMS) arises when IgG autoantibodies specifically attack the presynaptic P/Q-type voltage-gated calcium channels, resulting in a disruption in the transport of acetylcholine (ACh) vesicles to the membrane. This disruption causes a significant decrease in ACh within the synapse, culminating in muscle weakness.

Unlike myasthenia Gravis (MG), where repeated stimulation of the motor neuron leads to diminished muscle response, LEMS displays the opposite effect. With each stimulation of the motor neuron, a small amounts of calcium escapes into the nerve channel despite the presence of antibodies, which accumulates over time and can reach levels sufficient to induce the fusion of ACh vesicles, releasing ACh into the synaptic cleft. Consequently, repeated stimulation in LEMS leads to progressively larger muscle contractions.

Clinically, LEMS manifests as symmetric muscle weakness in the proximal lower extremities, resulting in difficulty standing up or climbing stairs. LEMS also affects the ANS, leading to symptoms such as xerostomia and erectile dysfunction. Some cases of LEMS can be induced by cancer cells, resulting in paraneoplastic LEMS—typically associated with small cell lung cancer.