What is the pathophysiology of Myasthenia Gravis (MG)?

From the Guidelines

Myasthenia gravis is an autoimmune disorder characterized by antibody-mediated attack on acetylcholine receptors at the neuromuscular junction, leading to muscle weakness and fatigue that worsen with repeated use and improve with rest. The pathophysiology of myasthenia gravis involves the binding of antibodies to acetylcholine receptors, triggering their degradation and activating complement-mediated damage to the postsynaptic membrane 1. This results in fewer available receptors and a simplified, flattened postsynaptic membrane with reduced efficiency in neuromuscular transmission. The thymus gland plays a crucial role in this pathology, with about 70% of patients showing thymic abnormalities such as hyperplasia or thymoma 1.

Key Features of Myasthenia Gravis

• The disease typically affects ocular muscles first, causing ptosis and diplopia, but can progress to involve bulbar and limb muscles, and in severe cases, respiratory muscles, potentially leading to myasthenic crisis requiring ventilatory support 1
• Patients are at risk for having or developing a thymoma, and thymectomy is indicated in some cases, always in the presence of thymoma, and may substantially reduce symptoms for certain subpopulations with myasthenia gravis 1
• The patient population includes adults with myasthenia gravis without geographic or racial predilection, although this disorder occurs in children as well in the form of transient neonatal myasthenia, congenital myasthenia, and juvenile autoimmune myasthenia 1

Diagnosis and Management

• Diagnosis and management of myasthenia gravis requires the training and clinical judgment of an experienced ophthalmologist typically working in concert with a treating neurologist 1
• Counselling and referral to a neurologist or neuro-ophthalmologist, and sometimes a general surgeon, is often indicated in the management of myasthenia 1
• Pyridostigmine bromide administered orally two to four times a day is the first-line treatment for myasthenia gravis, but about half of patients with strabismus-associated myasthenia show minimal response 1

From the Research

Pathophysiology of Myasthenia Gravis

• Myasthenia gravis is a rare disease that causes impairment of the neuromuscular junction, characterized by muscle weakness and abnormal fatigability 2, 3.
• The disease is caused by the presence of antibodies against components of the muscle membrane localized at the neuromuscular junction, with the acetylcholine receptor (AChR) being the most common target 2, 3, 4.
• Other targets of autoantibodies in myasthenia gravis include the MuSK protein (muscle-specific kinase) and the LRP4 (lipoprotein related protein 4) 3, 4.
• The presence of a high number of long-lived plasma cells in myasthenia gravis patients contributes to the perpetuation of the autoimmune response, and treatments targeting these cells, such as proteasome inhibitors, have shown promise in experimental models 2.

Clinical Features and Classification

• Myasthenia gravis can be classified according to the profile of autoantibodies, the location of affected muscles, the age of onset of symptoms, and thymic abnormalities 3, 4.
• The disease typically begins with ocular symptoms, such as ptosis and diplopia, and may extend to other muscles in 80% of cases 3.
• Other clinical features of myasthenia gravis include variability, effort-induced worsening, and successive periods of exacerbation, with severity dependent on respiratory and swallowing impairment 3, 4.

Diagnosis and Treatment

• Diagnosis of myasthenia gravis is based on clinical features, the benefit of cholinesterase inhibitors, detection of specific autoantibodies, and significant decrement evidenced by electrophysiological tests 3, 4.
• Treatment options for myasthenia gravis include symptomatic treatment, immunosuppressive treatment, and thymectomy, with advances in understanding the pathophysiology leading to new treatment options targeting B or T cells, the complement cascade, and cytokines 5, 4.
• Despite available treatments, a large proportion of patients remain chronically dependent on corticosteroids, highlighting the need for more personalized and effective treatment approaches 4.