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Myasthenia Gravis & Lambert-Eaton Myasthenic Syndrome

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Pathophysiology

Summary

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.

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FAQs

How does acetylcholine function within the neuromuscular junction?

The neuromuscular junction serves as the communication bridge between the motor neuron and muscle fiber. When an action potential arrives at the motor neuron, it prompts the opening of presynaptic voltage-gated calcium channels, facilitating calcium ions to enter the nerve terminal. This calcium influx cues vesicles laden with acetylcholine (ACh) to merge with the membrane, discharging ACh into the synaptic cleft. Upon reaching the postsynaptic motor endplate, ACh attaches to nicotinic ACh receptors, which are ligand-gated ion channels. This interaction permits sodium and calcium to infiltrate the myocyte and potassium to exit, instigating depolarization, an action potential, and ultimately muscle contraction. Acetylcholinesterase in the synaptic cleft degrades any residual ACh.

How do myasthenia gravis and Lambert-Eaton myasthenic syndrome differ in their etiologies and clinical presentations?

Myasthenia gravis (MG) and Lambert-Eaton myasthenic syndrome (LEMS) are autoimmune disorders causing muscle weakness, but they target distinct elements of the neuromuscular junction. MG arises from IgG autoantibodies attacking the nicotinic ACh receptors on the motor end plate, diminishing neurotransmission and inducing muscle weakness. MG symptoms manifest as fluctuating muscle weakness, intensifying with repetition and as the day progresses. Conversely, LEMS originates from IgG autoantibodies against presynaptic P/Q-type voltage-gated calcium channels, curtailing ACh release and causing muscle weakness. LEMS typically exhibits symmetric muscle weakness in the proximal lower extremities and, in some instances, is linked to small cell lung cancer.

How is the thymus gland related to the development of myasthenia gravis?

The thymus gland holds a pivotal role in myasthenia gravis (MG). A significant number of MG patients exhibit thymic hyperplasia, with some even developing thymomas. The thymus is implicated in producing the detrimental autoantibodies observed in MG. Consequently, thymectomy, the surgical excision of the thymus, can ameliorate MG symptoms by curtailing the production of these autoantibodies.

4. Which diagnostic tests are employed for myasthenia gravis, and how do they function?

The edrophonium (Tensilon) test is a primary diagnostic tool for myasthenia gravis (MG). Edrophonium, a brief-acting acetylcholinesterase inhibitor, yields a swift augmentation in muscle strength in MG patients when administered due to the increased presence of ACh in the synapse. Another diagnostic modality is the ice pack test. Applying cold ice over the eyelid amplifies the sensitivity of the postsynaptic ACh receptors and diminishes ACh degradation by acetylcholinesterase. This leads to a bolstered eyelid muscle strength, indicative of MG.

What therapeutic options are available for myasthenia gravis and Lambert-Eaton myasthenic syndrome?

Myasthenia gravis (MG) can be managed with pyridostigmine, an acetylcholinesterase inhibitor. Inhibition of acetylcholinesterase mitigates the breakdown of ACh, increases the amount of ACh in the synapse and enhanced muscle strength. Additionally, thymectomy can offer symptomatic relief for MG patients. In contrast, Lambert-Eaton myasthenic syndrome (LEMS) necessitates distinct therapeutic strategies, often tailored to the root cause, such as addressing an associated small cell lung cancer when present.