Myasthenia Gravis

Introduction

Understanding the normal physiologic condition of the neuromuscular junction is a key in diagnosing and treating certain diseases such as Myasthenia Gravis and Lambert-Eaton Myasthenic Syndrome­¹. In this seminar report, we will be presenting the pathologic condition of neuromuscular junction in the form of Myasthenia Gravis. Emphasis will be given to the underlying cause of the disease, its clinical manifestations and various treatments that can be used to cure or at least, lessen the severity of the disease in some cases.

Myasthenia Gravis and the Parameters in the Prediction of              its Occurrence

Fauci, Braunwald and Kasper (2008) define Myasthenia Gravis as a neuromuscular disorder caused by immune-mediated loss of acetylcholine receptors characterized by weakness and fatigability of skeletal muscles. Milani and Kaminski (2006) suggest that this can be caused by circulating antibodies that block acetylcholine receptors at the post-synaptic neuromuscular junction, inhibiting the stimulative effect of the neurotransmitter acetylcholine.

Myasthenia gravis occurs in all ethnic groups and both genders. This is supported by Poulas (2000) in his study of the incidence of the disease, stating that this may occur from 3 out of 100,000 persons. It commonly affects women under 40 years of age and people from 50 to 70 years old of either sex, but it has been known to occur at any age. Kumar, Abbas and Fausto (2005) also indicated that Myasthenia Gravis is reflected with patients suffering in thymic hyperplasia and thymoma. Common risk factors are the female gender with ages 20 – 40, familial myasthenia gravis, D-penicillamine ingestion (drug induced myasthenia), and having other autoimmune diseases.

The disease may also occur in children. According to Baets (1993), 12% of the pregnancies may cause neonatal myasthenia gravis by passing the antibodies from the mother to the infant through the placenta. It can also develop at birth, known as congenital myasthenic syndrome which is not caused by an autoimmune response, but due to synaptic malformation, which in turn is caused by genetic mutations. Another form of myasthenia gravis is the Juvenile Myasthenia Gravis which occurs in childhood but after the peripartum period.

Pathophysiologic Events of the Disease

Upon discussing the normal physiologic function of the neuromuscular junction, let us now compare this to the pathophysiologic events which happen with Myasthenia Gravis.

As shown in the diagram below (refer to Diagram 1), normal neuromuscular transmission begins with action potential traveling down the motor neuron. This is initialized in the neuromuscular junction wherein acetylcholine is synthesized in the motor end terminal and stored in vesicles. When an action potential travels down a motor nerve and reaches the nerve terminal, this leads to the activation of calcium-gated channels. In turn, this will lead to an increase of the calcium levels causing the release of ACh (acetylcholine) from 150–200 synaptic vesicles into the synaptic cleft.

Afterwards, acetylcholine combines with acetylcholine receptors (AChRs) that are densely packed at the peaks of postsynaptic folds. The structure of the AChR has been fully elucidated; it consists of five subunits (2a, 1b, 1d, and 1c) arranged around a central pore (see Figure 4-A). When ACh combines with the binding sites on the subunits of the AChR, the channel in the AChR opens, permitting the rapid entry of cations, chiefly sodium, which produces depolarization at the end-plate region of the muscle fiber.  If the depolarization is sufficiently large, it initiates an action potential that is propagated along the muscle fiber, triggering muscle contraction. This process is rapidly terminated by hydrolysis of ACh by acetylcholinesterase (AChE), which is present within the synaptic folds, and by diffusion of ACh away from the receptor.

Thus, Myasthenia Gravis may be associated but are not limited to risk factors such as autoimmune disease (diabetes mellitus or thyroid disease)⁵, thymus abnormalities (tumor, hyperplasia) and genetic link. Considering this initiating event, T-cells process produces ACh receptor antibodies. The antibodies are normally produced by plasma cells, derived from B cells. These B-cells convert into plasma cells by T-helper cell stimulation. In order to carry out this activation, T-helpers must first be activated themselves, which is done by binding of the T-cell receptor (TCR) to the acetylcholine receptor antigenic peptide fragment (epitope) resting within the major histocompatibility complex of an antigen presenting cells.⁶

The production of acetylcholine receptor antibodies results in decreased efficiency of neuromuscular transmission by three distinct mechanisms. First, it directly alters function of receptor by blocking the active site of the acetylcholine receptor which is the site that normally binds acetylcholine. Second, there is an accelerated turnover of AChRs by a mechanism involving cross-linking and rapid endocytosis of the receptors. This consequently accelerates the degradation of acetylcholine receptors. Third, it causes damage to the postsynaptic muscle membrane by the antibody in collaboration with complement system.³ This also leads to a decreased in the number of AChR.

An immune response to muscle-specific kinase (MuSK) can also result in myasthenia gravis, possibly by interfering with AChR clustering. MuSK antibodies inhibit the signaling of MuSK by its nerve-derived ligand, agrin. The result is a decrease in patency of the neuromuscular junction leading to decreased efficiency of the neuromuscular transmission. Therefore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger muscle action potentials. Failure of transmission at many neuromuscular junctions results in weakness of muscle contraction.

During normal neurotransmission, the amount of ACh released with each impulse is reduced or declined upon repeated activity. This is termed as presynaptic rundown. In the myasthenic patient, the decreased efficiency of neuromuscular transmission combined with the normal rundown results in the activation of fewer and fewer muscle fibers by successive nerve impulses and hence increasing weakness, or myasthenic fatigue. This mechanism also accounts for the decremental response to repetitive nerve stimulation seen on electrodiagnostic testing.³ The sequence of pathophysiologic events in Myasthenia Gravis is shown in Diagram 2, which also presents the clinical manifestations of patients affected with the disease.

Clinical Manifestation of Myasthenia Gravis

            The cardinal features of Myasthenia Gravis are weakness and fatigability of muscles. The weakness increases during repeated use (fatigue) and may improve following rest or sleep.³ Muscles become progressively weaker during periods of activity and improve after periods of rest. Muscles that control eye and eyelid movement, facial expression, chewing, talking, and swallowing are especially susceptible. The muscles that control breathing and neck and limb movements can also be affected. Often the physical examination is within normal limits.⁷

            The onset of the disorder can be sudden. Often symptoms are intermittent. The diagnosis of myasthenia gravis may be delayed if the symptoms are subtle or variable. The distribution of muscle weakness often has a characteristic pattern. It may vary among patients, ranging from a localized form, limited to eye muscles (ocular myasthenia), to a severe or generalized form in which many muscles - sometimes including those that control breathing - are affected.

Symptoms result from weakness of the voluntary muscles innervated by the ten cranial nerves originating in the brainstem. The cranial muscles, particularly the lids and extraocular muscles, are often involved early in the course of Myasthenia Gravis, and diplopia (double vision) and ptosis (drooping of one or both eyelids) are common initial complaints.

Other symptoms are related to a change in facial expression. Facial weakness produces a "snarling" expression when the patient attempts to smile. Weakness in chewing is most noticeable after prolonged effort, as in chewing meat. Speech may have a nasal timbre caused by weakness of the palate or a dysarthric "mushy" quality due to tongue weakness. Difficulty in swallowing (dysphagia) may occur as a result of weakness of the palate, tongue, or pharynx, giving rise to nasal regurgitation or aspiration of liquids or food (Fauci, 2008).

Bulbar weakness is especially prominent in MuSK antibody–positive MG. In ~85% of patients, the weakness becomes generalized, affecting the limb muscles as well. They vary from person to person, but can include severe fatigue, an unstable or waddling gait, weakness in the arms resulting in an inability to raise the arms over the head, and proximal limb weakness e.g. affecting the hands and fingers. If weakness remains restricted to the extraocular muscles for 3 years, it is likely that it will not become generalized, and these patients are said to have ocular Myasthenia Gravis. The limb weakness in Myasthenia Gravis is often proximal and may be asymmetric. Despite the muscle weakness, deep tendon reflexes are preserved (Fauci, 2008).

Muscle weakness may develop over a few days or weeks, or remain at the same level for long periods. Repeated use resulting to fatigue may be partially alleviated by rest or sleep, while it tends to worsen with exercise and at the end of the day. Symptoms in female patients are often more severe during menses and pregnancy. Exacerbations and remissions may occur, particularly during the first few years after the onset of the disease. Remissions are rarely complete or permanent. Unrelated infections or systemic disorders often lead to increased myasthenic weakness and may precipitate "crisis".

In myasthenic crisis a paralysis of the respiratory muscles occurs, necessitating assisted ventilation to sustain life. It usually consists of respiratory failure caused by diaphragmatic and intercostal muscle weakness.³ In patients whose respiratory muscles are already weak, crises may be triggered by infection, fever, an adverse reaction to medication, or emotional stress.⁸ Since the heart muscle is stimulated differently, it is never affected by Myasthenia Gravis.

Classification of Myasthenia Gravis

Based on Jaretzki (2000), the most widely accepted classification of myasthenia gravis is the Myasthenia Gravis Foundation of America Clinical Classification:

• Class I: Any eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere
• Class II: Eye muscle weakness of any severity, mild weakness of other muscles
• Class IIa: Predominantly limb or axial muscles
• Class IIb: Predominantly bulbar and/or respiratory muscles
• Class III: Eye muscle weakness of any severity Moderate weakness of other muscles
• Class IIIa: Predominantly limb or axial muscles
• Class IIIb: Predominantly bulbar and/or respiratory muscles
• Class IV: Eye muscle weakness of any severity, severe weakness of other muscles
• Class IVa: Predominantly limb or axial muscles
• Class IVb: Predominantly bulbar and/or respiratory muscles (Can also include feeding tube without intubation)
• Class V: Intubation needed to maintain airway

 Clinical Treatment for Myasthenia Gravis

The prognosis has improved strikingly as a result of advances in treatment; virtually all myasthenic patients can be returned to full productive lives with proper therapy. The most useful treatments for MG include anticholinesterase medications, immunosuppressive agents, thymectomy, and plasmapheresis or intravenous immunoglobulin.

The treatment for Myasthenia Gravis discussed in this seminar report is taken from Harrison’s Principles of Internal Medicine by A. Fauci and D. Longo (2008), which is briefly summarized. The following treatments taken from the book are medications such as anticholinesterase and immunosuppressive drugs, surgery (thymectomy), plasmapheresis and management of myasthenic crisis.

A.    Medications

Acetylcholinesterase inhibitors produce at least partial improvement in most myasthenic patients, although improvement is complete in only a few. Pyridostigmine is the most widely used anticholinesterase drug. As a rule, the beneficial action of oral pyridostigmine begins within 15–30 min and lasts for 3–4 h, but individual responses vary. Treatment is begun with a moderate dose, e.g., 30–60 mg three to four times daily. The frequency and amount of the dose should be tailored to the patient's individual requirements throughout the day. Neostigmine can also improve muscle function by slowing the natural enzyme cholinesterase that degrades acetylcholine in the motor end plate. In some patients, muscarinic side effects of the anticholinesterase medication (diarrhea, abdominal cramps, salivation, nausea) may limit the dose tolerated.

Immunosuppression using glucocorticoids, azathioprine, and other drugs is effective in nearly all patients with MG. Glucocorticoids, when used properly, produce improvement in myasthenic weakness in the great majority of patients. To minimize adverse side effects, prednisone should be given in a single dose rather than in divided doses throughout the day. The initial dose should be relatively low (15–25 mg/d) to avoid the early weakening that occurs in about one-third of patients treated initially with a high-dose regimen. For the intermediate term, glucocorticoids and cyclosporine or tacrolimus generally produce clinical improvement within a period of 1–3 months. The beneficial effects of azathioprine and mycophenolate mofetil usually begin after many months (up to a year), but these drugs have advantages for the long-term treatment of patients with MG.

B.     Surgery

Two separate issues should be distinguished: (1) surgical removal of thymoma, and (2) thymectomy as a treatment for MG. Surgical removal of a thymoma is necessary because of the possibility of local tumor spread, although most thymomas are histologically benign. In the absence of a tumor, the available evidence suggests that up to 85% of patients experience improvement after thymectomy; of these, ~35% achieve drug-free remission. However, the improvement is typically delayed for months to years. The advantage of thymectomy is that it offers the possibility of long-term benefit, in some cases diminishing or eliminating the need for continuing medical treatment.

C.    Plasmapheresis

Plasmapheresis has been used therapeutically in MG. Plasma, which contains the pathogenic antibodies, is mechanically separated from the blood cells, which are returned to the patient. A course of five exchanges (3–4 L per exchange) is generally administered over a 10- to 14-day period. Plasmapheresis produces a short-term reduction in anti-AChR antibodies, with clinical improvement in many patients.