Late-Onset Myasthenia Gravis

Introduction:

Myasthenia gravis (MG) is an autoimmune disease that causes muscle weakness at the neuromuscular junction. In most cases, patients have antibodies against the skeletal muscle nicotinic acetylcholine receptor (AchR), while others may have autoantibodies against muscle-specific tyrosine kinase receptor (MuSK) or low-density lipoprotein 4 (Lrp4). The prevalence of MG is estimated to be 15 to 179 cases per one million people, and late-onset MG (LOMG) is becoming more common. About 15 % of MG patients may experience life-threatening respiratory weakness, known as myasthenic crisis. MG treatment options include short-term symptom relief, long-term immunosuppression, and therapies like plasmapheresis or intravenous immunoglobulin (IVIg) in severe cases or during a crisis.

What Is Meant by Late-Onset Myasthenia Gravis?

Late-onset MG is defined as the onset of the disease after age 50 in individuals who do not exhibit clinical or paraclinical evidence of a thymoma. However, these patients may present immunological findings that resemble those found in individuals with thymoma.

Myasthenia gravis (MG) is the most common neuromuscular junction disorder, resulting from harmful autoantibodies affecting the muscle endplate. It is characterized by muscle weakness and fatigue that comes and goes. The prevalence of MG is approximately seven to 20 cases per 100,000 people, with an incidence of 0.5 cases per 100,000.

Late-onset MG occurs after age 75, and diagnosing MG in older individuals can be challenging due to the lack of information, difficulty recognizing symptoms in the context of age-related changes, and numerous potential differential diagnoses. Underdiagnosis is more common in patients over 80 years of age.

What Are the Symptoms of Late-Onset Myasthenia Gravis?

Myasthenia gravis (MG) is primarily characterized by fluctuating muscle weakness that gets worse with physical activity and improves with rest. Various factors can trigger or worsen these symptoms, including infections, surgery, immunization, heat, stress, pregnancy, certain drugs (like aminoglycosides, fluoroquinolones, and beta blockers), and exacerbations of chronic medical conditions. When interviewing patients, it is essential to ask about the timing of their symptoms, the time of day when symptoms are most noticeable, and whether they experience relief with rest. Subtle signs such as coughing after swallowing, difficulty in finishing meals, hoarseness, muscle fatigue while climbing stairs, and frequent errors in writing or typing may also be present, often more pronounced at the end of the day or a work shift.

The most common symptoms include:

1. Extraocular Muscle Weakness: Present in around 85 percent of patients, with complaints of diplopia (double vision), ptosis (drooping eyelids), or both. These symptoms can progress to involve other muscle groups.

2. Bulbar Muscle Weakness: Occurs in 15 percent of patients and leads to difficulties with chewing, choking, dysphagia (swallowing problems), hoarseness, and dysarthria (difficulty speaking clearly). Facial muscle involvement can result in a lack of facial expression, while neck muscles may cause a dropped-head syndrome.

3. Limb Weakness: Typically affects proximal muscles more than distal ones, with the upper limbs more commonly affected than the lower limbs.

4. Myasthenic Crisis: A medical emergency caused by the involvement of intercostal muscles and the diaphragm.

MG does not typically involve autonomic symptoms such as palpitation bowel, or bladder disturbances, as it primarily affects the nicotinic cholinergic receptors.

During a physical examination, muscle power may appear normal due to the fluctuating nature of the disease. Weakness can be demonstrated through repeated or sustained muscle contractions, and improvement is often seen after rest or the application of ice to the affected muscle group. Pupils, deep tendon reflexes, and sensory examinations are usually normal.

MuSK MG, a specific subtype, differs from n-AChR MG in clinical features, with a higher prevalence in females. It tends to spare extraocular muscles and more commonly involves bulbar, facial, and neck muscles, with myasthenic crises being frequent.

How Does Myasthenia Gravis Occur?

Autoimmune MG occurs due to an immunological attack, which is antibody-mediated and T-cell dependent, on the postsynaptic membrane at the neuromuscular junction. This attack leads to abnormal neuromuscular transmission and the characteristic muscle weakness seen in MG. Antibodies target various epitopes on the skeletal endplate region. In most cases, these antibodies bind to the primary immunogenic region of the alpha-subunit of the acetylcholine receptor (AChR). However, MG patients with antibodies to muscle-specific tyrosine kinase receptor (MuSK) exhibit clinical weakness and electrophysiological findings similar to those with AChR antibodies. The precise function of MuSK in mature skeletal muscle and the pathophysiology of MuSK antibody-related MG still need to be fully understood.

An autoimmune disorder like MG occurs due to a breakdown of self-antigen tolerance. T-lymphocyte tolerance to self-antigens is typically established in the thymus, and thymic abnormalities are frequently observed in MG. Patients with thymoma tend to have more severe and generalized weakness, higher AChR antibody levels, and more significant electrophysiological abnormalities. Therefore, individuals with seronegative (SN) and ocular MG are less likely to have thymomas. Most thymic tumors are benign, well-differentiated, and encapsulated. Patients with MG are suggested to undergo a chest CT (computed tomography) scan to rule out thymoma presence. Thymoma resection is necessary to prevent compression of mediastinal structures.

What Is the Treatment and Management of Myasthenia Gravis?

The management of MG involves individualized treatment based on factors such as the extent, duration, and severity of muscle weakness, as well as the patient’s age, gender, and medical conditions. The main goal is to restore or approximate normal neuromuscular function while minimizing side effects. Several therapeutic approaches are available. These include:

1. Acetylcholinesterase Inhibitors: These drugs slow down the breakdown of acetylcholine at the neuromuscular junction, temporarily relieving muscle weakness. They are often used for ocular or mild generalized MG and as an adjunctive therapy in combination with immunosuppressive treatments. Adjusting the dosing to match the patient’s symptom pattern is important.

2. Corticosteroids: These are widely used to modulate the immune system in MG; although their exact mechanism of action remains unclear, they can rapidly improve MG symptoms but are associated with significant side effects. Dosing usually starts with higher amounts and is gradually tapered based on clinical improvement.

3. Azathioprine: An immunosuppressive medication often used to spare patients from the side effects of corticosteroids. It may take several months for patients to experience improvement, and potential side effects include myelosuppression, hepatotoxicity, and allergic reactions.

4. Cyclosporine: This suppresses the immune system by blocking T lymphocyte proliferation. It can be an effective steroid-sparing agent in MG, but its use is limited due to nephrotoxicity and drug interactions.

5. Mycophenolate Mofetil (MMF): MMF is a newer immune modulator with fewer side effects. It can be used as a steroid-sparing agent or as initial immunotherapy. Patients typically experience improvement within a couple of months.

6. Plasma Exchange (PEX): PEX is used for rapid but temporary improvement in MG, especially during exacerbations or crises or as a preparation for surgery. It involves removing plasma containing MG-related antibodies and replacing it with albumin or plasma. Potential complications are associated with vascular access and fluid volume shifts.

7. Intravenous Immunoglobulin (IVIg): IVIg is used for short-term improvement in MG symptoms, particularly in exacerbations and crises, and as a surgical preparation. Its side effects include volume overload, renal failure, and idiosyncratic reactions.

8. Thymectomy: Thymectomy is considered for non-thymomatous MG and is associated with an increased chance of medication-free remission. The best outcomes tend to occur when thymectomy is performed early during the disease.

Conclusion:

Late-onset MG represents a significant and evolving aspect of autoimmune disorder. Research indicates that late-onset MG, occurring after age 50, is becoming more prevalent and is expected to continue. Understanding the characteristics and treatment of late-onset MG is essential as it presents unique challenges. Effective management is considered depending on individual needs and clinical profile.