Duisean Coitcheann Dèanadais Nàdur

Neuromuscular Junction Disorder

• An abnormality of the neuromuscular junction (NMJ) typically presents with painless weakness.
• This is regardless of the cause.

Objective

• Understand the basics of neuromuscular junction pathophysiology.
• Familiarise yourself with disorders connected to the NMJ.
• Learn the pathology of Myasthenia Gravis.
• Learn the pathology of Lambert-Eaton myasthenic syndrome.

Neuromuscular Junction Anatomy

• Axon: Component of a nerve.
• Nerve Terminal: End of a nerve.
• Mitochondrion: Organelle in nerve terminal.
• Synaptic Vesicle: Stores neurotransmitters.
• Acetylcholine Receptors (ACh receptors): Located on the muscle fiber.
• Muscle Fiber: The muscle cell.

Neurotransmitter Process

• Synaptic Vesicle: Contains neurotransmitters.
• Voltage-gated Ca²⁺ channel: Opens due to nerve impulse. Allows calcium entry.
• Post-synaptic density: Region near the receptor.
• Neurotransmitters: Released into the synaptic cleft.
• Neurotransmitter Receptors: Bind neurotransmitters.
• Neurotransmitter re-uptake pump: Recycles unused neurotransmitters.

Antibody-Mediated Diseases of the Neuromuscular Junction

• Myasthenia Gravis

• Lambert-Eaton myasthenic syndrome

Myasthenia Gravis

• An autoimmune disorder commonly linked to autoantibodies targeting acetylcholine receptors.
• This causes damage to postsynaptic membranes and a reduction in acetylcholine receptors.
• This limits muscle response to acetylcholine.

Myasthenia Gravis Pathophysiology

• Autoantibodies: Target acetylcholine receptors.
• Acetylcholine Receptors: Located on the postsynaptic membrane.
• Synaptic Cleft: Area between neuron and muscle.
• Postsynaptic Membrane: Damage prevents muscle activation.

Pathogenesis of Myasthenia Gravis

• About 85% of patients have autoantibodies against postsynaptic acetylcholine receptors.
• The remaining patients have antibodies against sarcolemmal protein muscle-specific receptor tyrosine kinase.

Anti-acetylcholine Receptor Antibodies

• Thought to cause aggregation and degradation of receptors within postsynaptic membranes.
• These Antibodies cause damage through complement fixation leading to a reduced number of acetylcholine receptors.

Autoantibodies against muscle-specific receptor tyrosine kinase

• These antibodies interfere with the trafficking and clustering of acetylcholine receptors within the sarcolemmal membrane.
• A consequent effect is a reduction in acetylcholine receptor function.

Thymic Abnormalities in Myasthenia Gravis

• A strong association exists between pathogenic antiacetylcholine receptor autoantibodies and thymic abnormalities.
• About 10% of myasthenia gravis patients display thymoma, a cancerous thymic epithelial cell tumor.

Clinical Picture of Myasthenia Gravis

• Head position: May maintain a flexed posture and be unable to fully extend.
• Mental status: Normal cognition.
• Speech: Dysarthric.
• Eyes: Partial ptosis (drooping).
• Pupils: bilaterally equal and responsive to light.
• Cranial nerves: Normal eye movement.
• CN 9 and 10 (soft palate): May not move.
• Limbs: Normal examination and reflexes.
• Sensation: No deficits.
• Cerebellar function: Normal.
• Fatigue: Occurs with repetitive motions, e.g., closing the eyes.
• No abnormalities: Observed in a general examination.

Treatment of Myasthenia Gravis

• Acetylcholinesterase inhibitors: Used to enhance acetylcholine levels at the neuromuscular junction.
• Plasmapheresis and immunosuppressive drugs (glucocorticoids, cyclosporine, rituximab): Can decrease autoantibody titers and control symptoms.
• Thymectomy: Effective in patients with thymoma.

Lambert-Eaton Myasthenic Syndrome

• An autoimmune disorder where antibodies block acetylcholine release by inhibiting presynaptic calcium channels.
• In contrast to myasthenia gravis, repeated stimulation improves muscle activity after some time.

Symptoms of Lambert-Eaton Myasthenic Syndrome

• Patients typically present with weakness of their extremities.
• In half of cases, there is an underlying neuroendocrine carcinoma of the lung.
• Symptoms may precede cancer diagnosis by years.

Quiz Question (1)

• Myasthenia Gravis dysfunction occurs in neuromuscular junctions.

Quiz Question (2)

• Resting tremor is not commonly associated with Myasthenia Gravis.

Anns a' chùrsa seo, tuigidh tu bun-bheachdan pathology na duisean coitcheann dèanadais nàdur. Bidh e na chothrom dhut fìrinn a dh'fhoillsicheas na duisean a tha ceangailte ris an NMJ a thuigsinn, a' toirt a-steach Myasthenia Gravis agus syndrom Lambert-Eaton.